Compositions and methods for treating pterygium

Abstract

To provide an ophthalmic composition and a method for treating primary and recurrent pterygium.SOLUTION: Compositions and methods for inducing pterygium regression from the visual axis / central cornea, for stabilizing pterygium, for treating hyperemia and symptoms in pterygium patients, and for treating pterygium recurrence after pterygiectomy are disclosed. The methods include administering a multikinase inhibitor, an antimetabolite, or a combination thereof to a patient in need of the method.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to ophthalmic compositions and methods for treating primary and recurrent pterygia, and more specifically, to compositions and methods for inducing pterygium regression from the visual axis / central cornea, stabilizing the pterygium, and suppressing ocular hyperemia and pterygium recurrence before, simultaneously with, or after pterygium surgery.

Background Art

[0002] A pterygium is an ocular surface disease in which abnormal epithelial cell and fibroblast proliferation progresses from the nasal or temporal conjunctiva across the corneal limbus to the cornea. Pterygium patients often experience discomfort and hyperemia in the eyes, and when the lesion invades the visual axis, there is a risk of causing visual impairment.

Summary of the Invention

Means for Solving the Problems

[0003] In certain aspects, the present disclosure provides a method for treating primary and recurrent pterygia by administering to the eyes of a subject in need of treatment (1) a multi-kinase inhibitor, (2) an antimetabolite, or (3) a combination of a multi-kinase inhibitor and an antimetabolite. In certain aspects, the methods disclosed herein stabilize the pterygium and prevent further growth of the affected tissue. In another aspect, the methods disclosed herein induce regression of the pterygium from the visual axis / central cornea. In certain aspects, the multi-kinase inhibitor disclosed herein targets the kinase receptors of VEGFR (1, 2, 3) and PDGFR (α, β). In certain aspects, the multi-kinase inhibitor is formulated in a topical ophthalmic formulation for topical administration to the affected eye. In certain aspects, the topical ophthalmic formulation is a solution, suspension, or emulsion. In another aspect, the multi-kinase inhibitor is formulated in an implant or semi-solid sustained-release formulation for insertion into the affected eye. In certain aspects, the antimetabolite is mitomycin C, 5-fluorouracil, and thiotepa. In certain aspects, the antimetabolite is formulated in a topical ophthalmic formulation for topical administration to the affected eye. In certain aspects, the topical ophthalmic formulation is a solution, suspension, or emulsion. In another aspect, the antimetabolite is formulated in an implant or semi-solid sustained-release formulation for insertion into the affected eye. In certain aspects, the methods disclosed herein are carried out by a combination of a multi-kinase inhibitor and an antimetabolite. In certain aspects, the combination of the multi-kinase inhibitor and the antimetabolite is formulated in a topical ophthalmic formulation for topical administration to the affected eye. In certain aspects, the topical ophthalmic formulation is a solution, suspension, or emulsion. In another aspect, the combination of the multi-kinase inhibitor and the antimetabolite is formulated in an implant or semi-solid sustained-release formulation for insertion into the affected eye. In certain aspects, the methods disclosed herein reduce hyperemia, abnormal neovascularization, and other symptoms in pterygium patients. In another aspect, the methods disclosed herein prevent pterygium recurrence after pterygium surgery. In certain aspects, the methods disclosed herein are carried out before, simultaneously with, or after surgical removal of the pterygium to suppress or prevent pterygium recurrence.In certain embodiments, the multi-kinase inhibitor disclosed in the present application targets the optimal kinase receptors of FLT3, Lck, Lyn, and Src in addition to the minimal kinase receptors of VEGFR (1, 2, 3), PDGFR (α, β), and FGFR (1, 2, 3, 4). In certain embodiments, the multi-kinase inhibitor disclosed in the present application is nintedanib. In certain embodiments, the method disclosed in the present application uses a topical ophthalmic formulation. In certain embodiments, the formulation is an aqueous solution, suspension, or emulsion. In certain embodiments, the concentration of nintedanib in the formulation is from 0.001% to 10%. In certain embodiments, the formulation is an implant or semi-solid sustained-release formulation inserted into the affected eye. In certain embodiments, the amount of nintedanib in the implant is from 1 μg to 100 mg.

[0004] In one aspect, the present disclosure provides a method for inducing pterygium regression from the visual axis / center of the cornea, comprising administering a therapeutically effective amount of (1) a multi-kinase inhibitor; (2) an antimetabolite that suppresses epithelial and fibroblast proliferation; or (3) a combination thereof to the affected eye of a subject in need of such treatment. In certain embodiments of all aspects, as a result of the administration of the multi-kinase inhibitor, the antimetabolite, or the combination thereof, the size of the pterygium in the affected eye is reduced. Optionally, as a result of the administration of the multi-kinase inhibitor, the antimetabolite, or the combination thereof, the pterygium growth rate in the affected eye becomes negative.

[0005] In another aspect, the present disclosure provides a method for stabilizing a pterygium, comprising administering a therapeutically effective amount of (1) a multi-kinase inhibitor; (2) an antimetabolite that suppresses epithelial and fibroblast proliferation; or (3) a combination thereof to the affected eye of a subject in need of such treatment. Optionally, as a result of the administration of the multi-kinase inhibitor, the antimetabolite, or the combination thereof, the size of the pterygium in the affected eye is stabilized. Optionally, as a result of the administration of the multi-kinase inhibitor, the antimetabolite, or the combination thereof, the pterygium growth rate in the affected eye becomes approximately zero.

[0006] In certain embodiments of all aspects, the multi-kinase inhibitor reduces the activity in the wings of one or more intracellular and / or cell surface protein kinases selected from EGFR, ErbB2, ErbB3, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, NGFR, VEGFR (1, 2, 3), PDGFR (α, β), TGF-βR (I, II, III), FLT3, Lck, Lyn, Src, c-Kit, c-Fms, Raf-1, B-Raf, RET, CSF-1R. Optionally, the multi-kinase inhibitor has an IC50 of <200 nM for VEGFR (1, 2, 3), an IC50 of <200 nM for PDGFR (α, β), and / or an IC50 of <1000 nM for FGFR (1, 2, 3).

[0007] In certain embodiments of all aspects, the multi-kinase inhibitor is selected from the group consisting of afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, luxolitinib, sorafenib, sunitinib, tandutinib, tibatinib, tivozanib, trametinib, vandetanib, batatinib, and bemrafenib. Optionally, the antimetabolite is selected from the group consisting of mitomycin C, 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, azathioprine, methotrexate, mycophenolate mofetil, and thiotepa.

[0008] In certain embodiments of all aspects, the multi-kinase inhibitor, the antimetabolite, or a combination thereof is administered to the affected eye in the form of a topical ophthalmic preparation, ointment, gel, sustained-release semi-solid preparation, sustained-release solid preparation, or intraocular implant. Optionally, the multi-kinase inhibitor, the antimetabolite, or a combination thereof is administered to the affected eye in the form of a topical ophthalmic preparation and topically administered to the affected eye.

[0009] Optionally, the topical ophthalmic preparation is a solution, suspension, or emulsion. Optionally, the topical ophthalmic preparation further contains one or more pharmaceutically acceptable additives selected from stabilizers, surfactants, polymer-based carriers, gelling agents, organic co-solvents, pH adjusting components, and osmotic pressure adjusting components, and may or may not contain a preservative. Optionally, the sustained-release semi-solid preparation, sustained-release solid preparation, or intraocular implant is inserted into the affected eye. In certain embodiments, the sustained-release semi-solid preparation, sustained-release solid preparation, or intraocular implant further contains pharmaceutically acceptable additives. Optionally, the sustained-release semi-solid preparation, sustained-release solid preparation, or intraocular implant contains a multi-kinase inhibitor, an antimetabolite, or a combination thereof; and a biodegradable polymer selected from polylactic acid (PLA), polyglycolic acid (PLGA), and copolymers of polylactic acid and polyglycolic acid.

[0010] In certain embodiments of all aspects, administration is performed on patients with pterygium.

[0011] In another aspect, the present disclosure provides a method for reducing hyperemia and its symptoms in the pterygium, pinguecula, and pseudopterygium of a patient in need of treatment, the method comprising administering a therapeutically effective amount of a multi-kinase inhibitor to the affected eye of the subject.

[0012] In another aspect, the present disclosure provides a method for reducing or preventing pterygium recurrence in a subject in need of treatment, the method comprising administering a therapeutically effective amount of a multi-kinase inhibitor to the affected eye of the subject. In certain embodiments of all aspects, administration is performed before surgical removal of the pterygium. Optionally, administration is performed during the surgical removal procedure of the pterygium. Optionally, administration is performed after surgical removal of the pterygium.

[0013] In certain embodiments of all aspects, the multi-kinase inhibitor has an IC50 against VEGFR (1, 2, 3) of <50 nM, an IC50 against PDGFR (α, β) of <100 nM, an IC50 against FGFR (1, 2, 3) of <150 nM, an IC50 against FGFR4 of <1000 nM, an IC50 against FLT3 of <50 nM, an IC50 against Lck of <50 nM, an IC50 against Lyn of <200 nM, and an IC50 against Src of <200 nM. Optionally, the multi-kinase inhibitor is selected from the group consisting of nintedanib {(3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl}, its free base, hydrate, solvate or pharmaceutically acceptable salt. Optionally, the multi-kinase inhibitor is nintedanib free base or nintedanib esylate (ethanesulfonate).

[0014] In certain embodiments of all aspects, the multi-kinase inhibitor is administered to the affected eye in the form of a topical ophthalmic preparation, a sustained-release semi-solid preparation, a sustained-release solid preparation or an intraocular implant. Optionally, nintedanib is administered to the affected eye in the form of a topical ophthalmic preparation for topical administration to the affected eye. Optionally, the topical ophthalmic preparation is a solution, suspension or emulsion. In certain embodiments of all aspects, the concentration of nintedanib in the topical ophthalmic preparation is 0.001% to 10% by weight of the total amount of the preparation.

[0015] In certain embodiments of all aspects, the topical ophthalmic formulation further contains one or more pharmaceutically acceptable additives selected from stabilizers, surfactants, polymer-based carriers, gelling agents, organic co-solvents, pH adjusting components, osmotic pressure adjusting components, and preservatives. Optionally, the sustained-release semi-solid formulation, sustained-release solid formulation, or intraocular implant is inserted into the affected eye. Optionally, the sustained-release semi-solid formulation, sustained-release solid formulation, or intraocular implant contains nintedanib and a pharmaceutically acceptable additive. Optionally, the amount of nintedanib in the sustained-release semi-solid formulation, sustained-release solid formulation, or intraocular implant is 1 μg to 100 mg. Optionally, the sustained-release semi-solid formulation, sustained-release solid formulation, or intraocular implant contains nintedanib and a biodegradable polymer selected from polylactic acid (PLA), polyglycolic acid (PLGA), and a copolymer of polylactic acid and polyglycolic acid.

[0016] As used herein, the term "one or more" includes that the item(s) designated as "one or more" is at least 1, more preferably 1, 2, 3, 4, 5, 10, 20, 50, 100, 500, etc.

[0017] The term "subject" means an animal or a human, or one or more cells derived from an animal or a human. The subject is preferably a human. The subject also includes non-human primates. A human subject may also be referred to as a patient.

[0018] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials used in the present invention are described herein, other suitable methods and materials known in the art can also be used. These materials, methods, and specific examples are illustrative only and not limiting. All publications, patent applications, patents, sequences, database entries, and other references cited herein are incorporated by reference in their entirety. In case of conflict, the specification of the present application, including definitions, will control.

[0019] Other features and advantages of the present invention will be readily understood from the following detailed description, drawings, and claims.

[0020] Attach at least one sheet of color drawings to this patent or application documents. A copy of this patent or patent application publication including the color drawings will be delivered from the Patent Office after the application and payment of the necessary fees.

Brief Description of the Drawings

[0021]

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Mode for Carrying Out the Invention

[0022] A pterygium is an ocular surface disease in which fibro-vascular proliferation progresses from the nasal or temporal conjunctiva across the limbus to the cornea. Pterygium patients often experience eye discomfort and congestion symptoms, and when the lesion invades the visual axis, there is a risk of causing visual impairment. The incidence of pterygium is clearly related to the lifetime sunlight exposure, as well as other risk factors such as aging, male gender, and rural residence, and it has been shown that wearing glasses or hats has a protective effect. In addition, pterygium has a high incidence rate in certain occupational groups such as welders, manual laborers, and outdoor workers, reflecting the important role of ultraviolet (UV) exposure in the etiology of this disease.

[0023] Pterygium has an invasive growth tendency and a recurrence tendency, but since it has no metastatic tendency, it is often regarded as a benign tumor. According to the current understanding of the etiology of pterygium, multiple processes are involved, which can be divided into genetic factors, environmental inducing factors (ultraviolet rays, virus infections), and factors that sustain its growth (cytokines, growth factors, and matrix proteases). Among these, chronic ultraviolet exposure is the single largest factor in the etiology of pterygium. The relationship between ultraviolet exposure and pterygium is well supported not only by epidemiological studies but also by its association with other ultraviolet-related pathologies such as photoaging of the skin, cataracts, climatic droplet keratopathy, squamous cell carcinoma, and basal cell carcinoma. Ultraviolet-activated molecular mechanisms such as oxidative stress and growth factor receptor (GFR) signaling lead to the synthesis and secretion of effector molecules that sustain the growth of pterygium, such as cytokines, growth factors, and matrix proteases. Ultraviolet is a well-known inducer of oxidative stress and is also a contributing factor to photoaging of the skin. Oxidative stress caused by ultraviolet mediates the activation of epidermal growth factor receptor (EGFR) and then mediates downstream signaling through the mitogen-activated protein kinase pathway.

[0024] At present, there is no approved drug therapy for the treatment of pterygium. The method of performing conjunctival autograft after pterygium excision remains the definitive treatment method selected for both primary and recurrent pterygium. Many of these lesions can be easily removed, and initially, both the surgeon and the patient are satisfied, but recurrence of pterygium may occur. To reduce the recurrence rate of pterygium, antimetabolites such as 5-FU and MMC are used either simultaneously with or after pterygium surgery (Almond et al., Pterygium: Techniques and Technologies for Surgical Success. Hovanesian JA. Ed. SLACK Incorporated. 2012; pp 55-63).

[0025] Pterygium is a multifactorial disease, and several growth factors such as VEGF and PDGF may be etiological factors. However, no pharmaceuticals that antagonize these growth factors for treating this disease have been developed. Bevacizumab and ranibizumab, which are anti-VEGF antibodies, are being clinically tested in pterygium patients worldwide, but the results are very diverse, and it is unclear whether such treatment using antibodies is effective. A small number of tests have reported that bevacizumab can block pterygium growth, but most tests have reported negative results. So far, there has been no report of clinical testing of small molecule anti-angiogenic drugs on pterygium. Although the number of published cases is only two, a human pterygium mouse model has recently been developed (Lee et al. Graefes Arch Clin Exp Ophthalmol. 2014;252(4):609-18; Cox et al. Ophthalmology. 2010;117(9):1782-91). However, no anti-angiogenic drugs have been tested in this model so far. As will be described later, the present inventors have first demonstrated that a multi-kinase inhibitor having anti-angiogenic activity effectively inhibits and / or stabilizes pterygium growth and reduces the size of pterygium tissue lesions in a mouse model. Furthermore, the present inventors demonstrate that similar results can be obtained with antimetabolites. This disclosure is based in part on these new findings. Accordingly, this disclosure provides a composition and method for administering a multi-kinase inhibitor, an antimetabolite, or a combination of a multi-kinase inhibitor and an antimetabolite to treat pterygium by stabilizing pterygium and inducing regression.

[0026] As used herein, the term "pterygium retraction" means a decrease or reduction in the size of the pterygium in the affected eye. For example, the term "pterygium retraction" means a decrease or reduction of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100% in the size of the pterygium in the affected eye.

[0027] As used herein, the term "ocular congestion" or "congestion" means an excess of blood in the sclera (white of the eye), causing the eye to become red. The term "reduce congestion" means a reduction in the red area and / or an enlargement of the white area in the affected eye. The reduction in the red area and / or the enlargement of the white area can be confirmed or measured by methods well known to those skilled in the art, including visual evaluation by an expert.

[0028] As used herein, the term "stabilize the pterygium" or "stabilize the size of the pterygium" means maintaining the size of the pterygium in the affected eye.

[0029] As used herein, the term "pterygium recurrence" means the reappearance of a pterygium in the eye after removal of a primary pterygium (e.g., surgical removal).

[0030] As used herein, the terms "therapeutically effective" and "effective amount" mean an amount of a drug effective to produce a desired pharmacological, therapeutic, or prophylactic result. A pharmacologically effective amount produces an improvement in one or more symptoms of a disorder, or prevents the progression of a disorder, or causes regression of a disorder, or prevents a disorder. For example, with respect to inducing regression of a pterygium, a therapeutically effective amount means an amount of a therapeutic agent that reduces the size of the pterygium by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0031] The therapeutically effective dosage in the methods described herein can be determined by the treating physician. For example, a physician can initiate treatment using the dosage recommended by the manufacturer for a multi-kinase inhibitor or antimetabolite and can increase or decrease it based on observation of the treatment effect by the physician. Detailed guidance is provided in the specification and examples herein. Further, clinical trials can be conducted for the purpose of determining an effective dosage to produce a statistically significant treatment effect when treating a patient population.

[0032] The terms "or a combination thereof" or "in combination with" mean administration in all forms in which a first agent is provided together with a second agent, such as a second inhibitory nucleic acid molecule or a chemotherapeutic agent, and the two agents are administered simultaneously or sequentially in any order. When two or more agents are administered in combination with each other, it is not necessary to administer these agents simultaneously or as a single formulation. Agents administered in combination with each other exhibit or possess biological activity simultaneously in the body of the subject to which these agents are delivered. Whether an agent is present in the body of a subject can be readily determined by empirical experimental monitoring or by calculation using the pharmacokinetic properties known for this agent.

[0033] Terms such as "treatment", "for treatment", "treating", etc. are usually used in this application to mean obtaining a desired pharmacological and / or physiological effect. The effect may be a preventive effect in the sense of completely or partially preventing a disease or its symptoms, and / or a therapeutic effect in the sense of partially or completely stabilizing or curing a disease and / or the adverse effects resulting from this disease. The term "treatment" encompasses all treatments of diseases in mammals, particularly humans, and includes (a) preventing a disease and / or its symptoms from occurring in a subject who is considered to have a predisposition to the disease or its symptoms but has not yet been diagnosed as having the disease; (b) preventing the disease and / or its symptoms, i.e., preventing its onset; or (c) alleviating the disease symptoms, i.e., causing the disease and / or its symptoms to regress. Persons in need of treatment include those who are already suffering from the disease (e.g., cancer patients, infected persons, etc.), and those for whom prevention is desired (e.g., those prone to cancer, those prone to infection, those suspected of having cancer, those suspected of having an infection, etc.).

[0034] The term "multi-kinase inhibitor" (MKI) as used in this application means a pharmaceutical compound (e.g., a small molecule) that reduces or inhibits the expression or activity of two or more kinases, including intracellular and / or cell surface protein kinases.

[0035] The "small molecule" as used in this application means a compound having a molecular weight of less than 2,000 daltons, more preferably 200 - 1,000 daltons, and even more preferably 300 - 700 daltons. These small molecules are preferably organic molecules. In certain embodiments, the "small molecule" does not include peptide or nucleic acid molecules.

[0036] The exemplary multi-kinase inhibitors used in the methods described in this application exhibit a specific kinase inhibition profile. For example, the multi-kinase inhibitors used in the methods described in this application have an IC 50 < of 200 nM against VEGFR (1, 2, 3), and an IC 50 < of 200 nM against PDGFR (α, β), and an IC 50It can have a kinase inhibition profile with an IC50 of <1 μM.

[0037] Exemplary multi-kinase inhibitors used in the methods described in this application include, for example, afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, luxolitinib, sorafenib, sunitinib, tandutinib, tibatinib, tivozanib, trametinib, vandetanib, batatinib, and bemrafenib.

[0038] Nintedanib {(3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl} is an example of a multi-kinase inhibitor as described in this application. Nintedanib mainly inhibits receptor tyrosine kinases such as vascular endothelial growth factor receptors (VEGFR1-3), platelet-derived growth factor receptors (PDGFRα and β), and fibroblast growth factor receptors (FGFR1-4) (see Table 1 below), and shows a unique kinase inhibition profile.

[0039] [Table 1]

[0040] As used herein, the term "antimetabolite" refers to a pharmaceutical compound that inhibits the utilization of metabolites and thus reduces, impedes, or inhibits the growth of rapidly dividing cells. For example, the antimetabolites of the present disclosure can inhibit DNA replication by various mechanisms that result in the reduction, impediment, or inhibition of cell division. Exemplary antimetabolites used in the methods described herein include, for example, purine and pyrimidine analogs (such as 5-fluorouracil (5-FU)), antibiotics (such as mitomycin C (MMC)), and antifolate compounds (such as methotrexate). Exemplary antimetabolites used in the methods described herein include, for example, mitomycin C, 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, azathioprine, methotrexate, mycophenolate mofetil, and thiotepa.

[0041] Mitomycin C (MMC) is an example of an antimetabolite as described herein. MMC is an antitumor antibiotic that is activated by reduction and becomes a potent alkylating agent. Under hypoxic conditions, it is most effective in actively dividing cells as it usually interferes with DNA replication by cross-linking DNA at the N2 position of guanine. Under aerobic conditions, it generates toxic oxygen radicals that can nonspecifically interfere with RNA and protein synthesis. MMC is used intravenously as an antitumor agent, particularly against tumors of the gastrointestinal tract, pancreas, lung, and breast. It is also used in the intravesical application for bladder cancer.

[0042] 5-FU is an example of an antimetabolite as described herein. 5-FU is a fluorinated pyrimidine, and its main antimetabolic action is the inhibition of thymidylate synthase, resulting in a deficiency of intracellular thymidine for DNA production. 5-FU also has other actions resulting from the inhibition of other enzymes or the incorporation of its metabolites into RNA.

[0043] Multikinase inhibitors and antimetabolites are well known to those skilled in the art and are widely used in the treatment of cancer.

[0044] In the early stage of a pterygium, pinguecula, or pseudopterygium, patients experience eye discomfort, congestion, irritation, blurred vision, foreign body sensation, and pain. However, the compositions and methods described in this application are useful for treating such patients, and the treatment goal is to reduce congestion and symptoms. For example, the present disclosure provides a composition and a treatment method that use nintedanib, a multi-kinase inhibitor, in a suitable ophthalmic dosage form to reduce congestion and other symptoms.

[0045] In the late stage of a pterygium where fibrovascular proliferation progresses from the conjunctiva beyond the limbus to the central cornea and invades the visual axis, the method of performing conjunctival autograft or amniotic membrane transplantation after pterygium excision by scleral exposure has generally been the treatment method of choice. However, the compositions and methods described in this application are also useful for treating such patients. With the progress of surgical techniques and adjuvant therapies, the risk of recurrence has been significantly reduced, but recurrence remains a major problem for both surgeons and patients. For the purpose of preventing pterygium recurrence, the present disclosure provides a composition and a treatment method that use nintedanib in a suitable ophthalmic dosage form to reduce pterygium recurrence.

[0046] As shown in the rabbit suture thread model test described in Example 1, the compositions and methods described in the present application are also useful for treating congestion and alleviating the accompanying symptoms. In the same example, nintedanib had an excellent effect of inhibiting the neovascularization induced by suture threads in the cornea. As shown in Table 2 below, in the eyes administered with nintedanib, the rate of change in neovascular area (percentage) was substantially reduced compared to the vehicle administration group. The effect of nintedanib depends on the dose concentration and administration frequency regimen. Interestingly, nintedanib showed a clearly superior tendency compared to sunitinib regarding the reduction of neovascular area. Although the targets of these two kinase inhibitors substantially overlap, different effects were observed in this rabbit model. Since nintedanib inhibits fewer targets than sunitinib, there is another advantage that the safety limit is good and a higher dose can be increased. In fact, as shown in Example 1, potential toxicity in the form of lens abnormalities with partial lens opacity was observed in one rabbit in the sunitinib administration group during the administration period, but not at all in the nintedanib administration group. Also, in an in vivo corneal suture thread rabbit model test in which sutures were placed in the cornea of rabbits and sunitinib was administered for 7 days, an anterior chamber cell reaction was observed on the first day (Perez-Santonja JJ et al, Am J Ophthalmol. 2010;150(4):519-528). A yellowish tint on the iris surface indicating sunitinib deposition on the iris surface was observed throughout the administration period. Sunitinib deposited in the inferior quadrant of the iris starting from the pupil margin, spreading to some extent between the pupil and the anterior chamber angle, and potentially causing toxic effects over a long period. Furthermore, significant toxicity of sunitinib was observed after 24-hour incubation with addition to human corneal epithelial cells at a concentration of >3.3 μg / mL (Bayyoud T et al., Current Eye Research, 39(2):149-154, 2014).

[0047]

Table 2

[0048] Both nintedanib and sunitinib inhibit the major VEGFR and PDGFR families, but several targets do not overlap (see Table 1). However, nintedanib appears to be more effective and safer than sunitinib due to a unique combination of kinase targets, and nintedanib is thought to be one of the most potent multi-kinase inhibitors for reducing corneal neovascularization. Specifically showing the unique inhibition profile represented by the maximum in vitro IC50 against the following intracellular and / or cell surface protein kinases, VEGFR (1, 2, 3) (IC50 < 50 nM), PDGFR (α, β) (IC50 < 100 nM), FGFR (1, 2, 3) (IC50 < 150 nM), FGFR4 (IC50 < 1000 nM), FLT3 (IC50 < 50 nM), Lck (IC50 < 50 nM), Lyn (IC50 < 200 nM), and Src (IC50 < 200 nM). Three targets, FGFR4, Lyn, and Src, are not inhibited by sunitinib or other common kinase inhibitors, and these targets can distinguish nintedanib from sunitinib and the like. Also, nintedanib is substantially more potent against FGFR1-3 than sunitinib, and this is also thought to be one of the reasons why nintedanib has better effects in the corneal suture rabbit model.

[0049] In the mid-stage of pterygium, fibrovascular proliferation progresses from the conjunctiva to the corneal limbus and the cornea, and the compositions and methods described in the present application are also useful for the treatment of such patients. In the mid-stage of pterygium, the goal is to stabilize pterygium progression, delay or avoid surgery for removing the pterygium, or induce regression of the pterygium from the visual axis / corneal center. To achieve this goal, the present disclosure provides compositions and treatment methods that use multi-kinase inhibitors, antimetabolites, or combinations of both in suitable ophthalmic dosage forms.

[0050] An example of a composition and method for treating an eye of an affected area using a multi-kinase inhibitor to stabilize a pterygium and induce regression of the pterygium is described in Example 2 below, and the effect of such a composition on the growth of human pterygium cells on the cornea of immunodeficient mice is shown. In this test, nintedanib and sunitinib inhibited the growth of human pterygium on the mouse cornea, and nintedanib significantly reduced the size of the pterygium. As shown in Table 3 below, pterygium cells proliferated throughout the treatment period up to day 17, but among the groups treated with nintedanib, sunitinib, MMC, or a combination of nintedanib and MMC, pterygium cells did not proliferate or regressed in the case of nintedanib. Therefore, as a result of the inventors' novel insights from the mouse model, it has been shown that multi-kinase inhibitors such as nintedanib or sunitinib can be used to prevent pterygium growth or even induce regression of pterygium tissue. As an example, the target kinase profile of the multi-kinase inhibitor used in the composition and method described in the present application can target the following kinases. VEGFR (1, 2, 3) (IC 50 can target at). VEGFR (1, 2, 3) (IC 50 <200 nM), PDGFR (α, β) (IC 50 <200 nM), FGFR (1, 2, 3) (IC 50 <1 μM).

[0051]

Table 3

[0052] The composition and method described in the present application are also useful for treating a patient using an antimetabolite, which is an inhibitor of epithelial cell and fibroblast proliferation, to stabilize a pterygium and induce regression of the pterygium (see Example 2). As shown in Table 3 above, mitomycin C (MMC) can prevent the growth of human pterygium cells and showed a tendency to reduce the size of the pterygium tissue on the cornea.

[0053] Considering the multifactorial nature of pterygia, combination therapy with multiple pharmaceuticals may be required to obtain optimal effects. As shown in Table 3, pterygial cells on the cornea that received combination therapy with nintedanib and MMC did not show significant growth, while those in the saline control grew significantly.

[0054] Formulations and Administration Regimens The methods described in the present application include the manufacture and use of pharmaceutical compositions containing compounds identified as active ingredients by the techniques described in the present application. Such pharmaceutical compositions themselves are also included in the present application.

[0055] Pharmaceutical compositions generally contain pharmaceutically acceptable additives. The terms "pharmaceutically acceptable additives" or "pharmaceutically acceptable carriers" as used in the present application include physiological saline, solvents, dispersion media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. that are compatible with pharmaceutical administration.

[0056] Suitable methods for formulating pharmaceutical compositions are known in the art. For example, refer to Remington: The Science and Practice of Pharmacy, 21st ed., 2005, and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions, suspensions or emulsions used for ophthalmic applications can contain the following components: sterile diluents such as water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents; antioxidants; chelating agents; buffers such as acetate, citrate or phosphate; and tonicity adjusting agents such as sodium chloride or glucose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide.

[0057] Suitable pharmaceutical compositions for injection may include sterile aqueous solutions (in the case of water-soluble substances) or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. The compositions must be stable under the conditions of manufacture and storage and need to be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using coating agents such as lecithin, maintaining the required particle size in the case of dispersions, or further by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, it is preferable to include isotonic agents (such as saccharides, polyalcohols such as mannitol and sorbitol, and sodium chloride) in the composition. By including substances that delay absorption (such as aluminum monostearate and gelatin) in the composition, long-term absorption of the injection composition can be achieved.

[0058] Sterile injection solutions can be prepared by formulating the required amount of the active compound in a suitable solvent together with one or a combination of the above components as required, followed by sterile filtration. Generally, dispersions are prepared by formulating the active compound in a sterile base containing a basic dispersion medium and the other necessary components selected from the above components. In the case of sterile powders for the preparation of sterile injection solutions, the preferred manufacturing methods are vacuum drying and freeze-drying, and powders of the active ingredient and other desired components can be obtained from its solution that has been previously sterile filtered.

[0059] In one embodiment, the therapeutic compound is manufactured using a carrier that protects the therapeutic compound from rapid excretion in vitro (e.g., controlled release formulations including implants and microcapsule delivery systems). Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be manufactured using standard techniques or obtained as commercial products.

[0060] The pharmaceutical composition can be contained in a container, pack, or dispenser with an attached dosing instruction.

[0061] Compositions and formulations containing a multi-kinase inhibitor, an antimetabolite, or a combination of a multi-kinase inhibitor and an antimetabolite as described in the present application can be administered topically, inserted as a semi-solid formulation or a solid implant, or administered by any other suitable method known in the art. It is possible to use the drugs disclosed in the present application alone for treatment, but it is preferably administered as a pharmaceutical formulation mixed with, for example, appropriate pharmaceutical additives, diluents, or carriers selected in view of the intended route of administration and standard medical practice. The pharmaceutical formulation contains at least one active compound together with pharmaceutically acceptable additives, diluents, and / or carriers.

[0062] Administration of the composition or formulation can be once a day, twice a day, three times a day, four times a day, or more. During the treatment maintenance period with the therapeutic agent, the frequency can be reduced, for example, from once a day or twice a day to once every two or three days. The dosage and administration frequency can be adjusted based on the judgment of the treating physician considering, for example, the clinical signs, pathological signs, and clinical and subclinical symptoms of the disease state being treated by the method of the present application, as well as the patient's clinical history.

[0063] Of course, the amount of the agent disclosed in the present application required for treatment will vary depending on the route of administration, the type of medical condition requiring treatment, and the age, weight, and health status of the patient, and will ultimately be left to the discretion of the attending physician. The composition generally contains an effective amount of the active ingredient as a single agent or in combination. A provisional dosage can be determined according to animal tests, and the dosage can be increased or decreased to suit human administration in accordance with practices generally recognized in the art.

[0064] The treatment period, i.e., the number of days, can be easily determined by the physician treating the subject, and the number of treatment days can be from about 1 day to about 365 days. The therapeutic effect provided by the method of the present application can be monitored during the treatment period to determine whether the treatment is successful or whether additional (or changed) treatment is required.

[0065] For example, the dosage, toxicity, and therapeutic effect of a therapeutic compound can be determined in cell culture or experimental animals by standard pharmaceutical techniques as a means of determining LD50 (the dosage at which 50% of the population dies) and ED50 (the dosage at which a therapeutic effect appears in 50% of the population). The dosage and dosage form of multi-kinase inhibitors and antimetabolites, as well as their individual dose strengths in combination therapies, can be easily determined by those of ordinary skill in the art, and can be obtained, for example, from animal models and clinical trials reported in the literature as means of determining dosage, safety, and efficacy according to standard methods known in the art. The exact formulation, route of administration, and dosage can be selected by the individual physician taking into account the health status of the patient.

[0066] Examples of the dosage strength of the multi-kinase inhibitor include, for example, about 0.001 to about 100.0 mg, about 0.01 to about 90 mg, about 0.1 mg to about 75 mg, about 0.25 to about 50 mg, about 0.5 to about 25 mg, about 0.75 to about 20 mg, about 1.0 to about 15 mg, about 1.25 to about 10 mg, about 1.5 to about 5.0 mg, about 1.75 to about 2.5 mg, such as 0.001 mg, 0.01 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 75.0 mg or 100.0 mg. For example, examples of the dosage strength of nintedanib include, for example, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 75.0 mg or 100.0 mg of nintedanib.

[0067] The composition used in the method of the present application can contain a multi-kinase inhibitor at a concentration of 0.001% to 10% of the total amount of the composition in terms of weight or volume conversion. For example, the aqueous composition contains up to 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or 10% of nintedanib.

[0068] Examples of the dosage strength of the antimetabolite include, for example, about 0.001 to about 100.0 mg, about 0.01 to about 90 mg, about 0.1 mg to about 75 mg, about 0.25 to about 50.0 mg, about 0.5 to about 25 mg, about 0.75 to about 20 mg, about 1.0 to about 15 mg, about 1.25 to about 10 mg, about 1.5 to about 5.0 mg, about 1.75 to about 2.5 mg, for example, 0.001 mg, 0.01 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 75.0 mg or 100.0 mg. For example, examples of the dosage strength of MMC include, for example, MMC 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 75.0 mg or 100.0 mg.

[0069] The composition used in the method of the present application can contain an antimetabolite at a concentration of 0.001% to 10% of the total amount of the composition in terms of weight or volume conversion. For example, the aqueous composition can contain MMC up to 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or 10%.

[0070] As will be apparent to those skilled in the art, for ocular administration of an aqueous solution, it can be administered as "droplets" or multiple droplets (e.g., of a multi-kinase inhibitor solution, an antimetabolite solution, or a combination thereof) from a dropper or pipette or other dedicated sterilized instrument. Such droplets generally have a volume up to 50 microliters, but can be even smaller amounts, for example, less than 10 microliters.

Examples

[0071] Hereinafter, the present invention will be described in more detail by way of examples. However, the following examples do not limit the scope of the present invention described in the claims.

[0072] [Example 1]: Rabbit corneal suture model of neovascularization and hyperemia A rabbit corneal suture model has been established to evaluate the effect of drugs on corneal neovascularization (Ko et al. Cornea. 2013;32(5):689 - 695; Perez - Santonja et al. Am J Ophthalmol. 2010;150(4):519 - 528). In this model, nintedanib was tested for its anti - neovascularization activity.

[0073] Topical ophthalmic preparation Topical compositions containing 0.2% or 0.05% nintedanib in phosphate - buffered saline (pH 7.4) with 10% 2 - hydroxypropyl - β - cyclodextrin added were prepared. Also, a composition containing 0.05% sunitinib in the same base was prepared and used as a positive control.

[0074] Animals and treatment procedures The test was conducted using 36 female New Zealand White rabbits. Briefly, on day 1, sutures were placed at 5 sites in the corneal epithelial layer of the right eye of each animal to induce neovascularization. Administration was performed in both eyes of the animals as described in Table 4.

[0075]

Table 4

[0076] During the test, the animals were closely observed for various signs of the eyes and general health status including body weight. Images of the eyes were taken for analysis on days 7, 10, 12, 14, 21, and 28.

[0077] Data analysis The images of the eyes were analyzed using NIH ImageJ(R) software. Each image was opened in ImageJ(R), a scale was set using a ruler on the photo, and the neovascularization area on the cornea near the suture was selected using the selection tool. The area (mm2 ) was calculated, recorded in Excel, the images were captured and saved. A two-sided t-test was used to determine whether there was a significant difference for each pair of groups. The results were plotted as histograms of the mean and standard deviation for easy comparison.

[0078] Results and Discussion The results of this study are summarized in Figures 1A and 1B and Table 5 below. These results demonstrated that nintedanib had a significant inhibitory effect on neovascularization induced by sutures in rabbit corneas. High-dose 0.2% nintedanib showed an improvement in efficacy compared to 0.05% nintedanib, and the high-frequency dosing regimen of TID administration showed an improvement in efficacy compared to BID administration. Surprisingly, nintedanib showed a clear tendency for superiority over the positive control sunitinib with respect to the reduction of neovascular area in this model.

[0079] In a rabbit suture model, it has been shown that nintedanib inhibits angiogenesis more effectively than bevacizumab, an anti-VEGF antibody (Ko et al. Cornea. 2013;32(5):689-695; Perez-Santonja et al. Am J Ophthalmol. 2010;150(4):519-528). These observations suggest that small molecule kinase inhibitors targeting multiple receptor tyrosine kinase pathways may have advantages over antibody pharmaceuticals targeting very selective pathways. As a result of this study, it was found that nintedanib also inhibits neovascularization very effectively in the suture model. Although completely unexpected, the inventors discovered that kinase inhibitors may have different efficacies even when their kinase targets substantially overlap. Both nintedanib and sunitinib inhibit the major VEGFR family, but several targets do not overlap. As shown in Table 1, the target profile of nintedanib is different from that of sunitinib and the target profiles of several other MKIs that are considered to be very similar in the research community. The special combination of nintedanib's kinase targets appears to provide at least two surprising advantages. 1) As demonstrated in the rabbit suture model, nintedanib becomes a very effective inhibitor of neovascularization and is more effective than sunitinib; 2) Since the number of kinases targeted is less than that of sunitinib, the safety margin is improved and the dose can be increased. Therefore, it is speculated that nintedanib shows improved efficacy and a better safety profile compared to sunitinib.

[0080]

Table 5

[0081] The theoretical basis of the inventors' claims is supported by the conventional research results in cancer research, which is a field where MKI is widely used. In cancer, several MKIs with substantially overlapping targets may still have very different efficacies in patients. For example, a number of small molecule MKIs with overlapping targets have been tested in non-small cell lung cancer (NSCLC) patients. Interestingly, only nintedanib has shown efficacy and has been approved for combination therapy with other drugs (Hall RD et al. Transl Lung Cancer Res. 2015;4(5),515-23). From such observations, it has been shown that the target profile of kinase inhibitors can be dramatically effective in specific indications.

[0082] The inventors' new insights are summarized as follows. First, generally, small molecule MKIs with a specific target profile are superior to antibody pharmaceuticals for the treatment of abnormal corneal neovascularization. This has been implied in previous studies, but was based on a comparison of only the pair of bevacizumab and sunitinib. Now, the inventors' tests on nintedanib have significantly increased the weight of this theory compared to before. Second, the inventors' new idea is that each MKI has a unique target profile, but not all MKIs are equally safe and effective in treating pterygium symptoms. Without being bound by theory, the inventors believe that nintedanib provides a unique profile that realizes one of the most effective and stable treatments for pterygium.

[0083] That is, nintedanib can be a more effective and safer therapeutic agent for pterygium due to its unique target profile. Nintedanib inhibits FGFR1-3 more effectively than sunitinib. It also inhibits FGFR4, Lyn, and Src, which are not targets of sunitinib (see Table 1 in the Background Art section). Furthermore, sunitinib is known to attack more kinases than compounds of the same class (Kumar et al. Br J Cancer. 2009;101(10):1717-23) and inhibits some other kinases not listed in Table 1, so nintedanib is expected to have a better safety profile than sunitinib. Some of these kinases, such as the CaMK family, are important for normal cell function, and inhibition of these may cause safety problems.

[0084] [Example 2]: Human Pterygium Mouse Model A human pterygium mouse model has been described to evaluate the growth of human pterygium on the cornea of immunodeficient mice (Lee et al., Graefes Arch Clin Exp Ophthalmol. 2014;252(4):609-18). In this study, the effects of several pharmaceuticals on pterygium growth were examined. These pharmaceuticals were nintedanib, sunitinib, and mitomycin C.

[0085] Topical Ophthalmic Formulation The test drug was prepared with phosphate buffer (pH 7.4) containing 10% 2-hydroxypropyl-β-cyclodextrin. Detailed information on the formulation will be disclosed in the following section.

[0086] Animals 7-week-old male athymic nude mice were acclimatized under specific pathogen-free conditions in a closed filter-top cage.

[0087] Human Pterygium Primary Cell Culture Human pterygium epithelial cells (hPEC) were isolated and cultured from specimens taken after surgical resection. After all participants received a comprehensive explanation of the study, they submitted written informed consent. Fresh pterygium specimens were cultured for 3 days in DMEM / F12 medium supplemented with 10% fetal bovine serum, 0.5% dimethyl sulfoxide, and 1% antibiotic / antifungal agent on a surface coated with collagen (rat tail type I collagen). During this period, the cells migrated from the explants. Subsequently, the explants were removed, and the medium was changed to serum-free keratinocyte medium supplemented with 5% BCS and 1% antibiotic / antifungal agent to further promote epithelial cell growth.

[0088] Induction of human pterygium For subconjunctival injection, mice were anesthetized by intraperitoneal injection of ketamine (30 mg / kg) and rompun (2.5 mg / kg). On day 0, 1×10 4 hPEC were injected into the nasal subconjunctival space of both eyes to induce pterygium in mice. Seven days later, the mice induced with hPEC were used for the study.

[0089] Treatment The animals were treated as follows. Group 1: Vehicle in the right eye and saline in the left eye; Group 2: 0.2% nintedanib in the right eye and saline in the left eye; Group 3: 0.002% mitomycin in the right eye and saline in the left eye; Group 4: 0.05% sunitinib in the right eye and saline in the left eye; Group 5: A mixture of 0.2% nintedanib and 0.002% mitomycin in the right eye and saline in the left eye.

[0090] On days 7, 10, and 14, subconjunctival injections were performed, and the animals were treated by topical eye drops four times a day on days 8, 9, 11, 12, 13, 15, and 16. Before each injection and on day 17, the eyes were observed using a stereomicroscope and photographed.

[0091] Clinical findings During the experimental period, the mice were observed daily for clinical signs of toxicity. The eyes were observed and photographed before injection and on day 17. All findings, including disease, diagnosis, and treatment, were recorded. The body weights of the mice were measured on days 0, 7, 11, 15, and 17.

[0092] Pterygium analysis of the cornea ImageJ(R) was used to perform image analysis of the photographs, and the sizes of the lesions on days 0, 7, 10, 14, and 17 were measured. These data were calculated as the ratio of the pterygium to the entire cornea.

[0093] Corneal neovascularization analysis The clinical characteristics of the eyes of all mice were evaluated. The degree of corneal neovascularization (NV) was scored from 0 to 3, where 0 = no NV, 1 = NV limited to the corneal periphery, 2 = NV extending to the pupil margin, and 3 = NV extending beyond the pupil margin to the central cornea.

[0094] Statistical analysis The data were analyzed using SPSS version 18.0 for Windows (SPSS, Chicago, IL) and presented as mean ± standard deviation.

[0095] Results and discussion The results are shown in Figures 2A - B, 3A - B, 4A - B and 5A - B, and are further summarized in Table 4 above. In the human pterygium mouse model, as a result of administering 0.2% nintedanib, the pterygium areas on days 14 and 17 were reduced compared to the baseline level on day 7 (Figures 2A and 2B). In contrast, the eyes of the control group administered with physiological saline showed an increase in pterygium area on days 14 and 17. Nintedanib also decreased the neovascularization score on the cornea during the administration period, and the level on day 17 showed a significant difference compared to the baseline on day 7 (Figures 2A and 2B), while the eyes of the control group showed a slightly increased neovascularization that was not statistically significant (Figures 2A and 2B). In this model, 0.002% mitomycin and 0.05% sunitinib also showed a tendency to reduce the pterygium area, but did not reach statistical significance at any time point (Figures 3A - 3B, 4A - 4B). In contrast, the eyes of the control group administered with physiological saline showed an increase in pterygium area at almost all time points, and the increase was almost linear over time. Mitomycin and sunitinib also decreased the neovascularization score, and mitomycin showed a significant decrease on day 17, while sunitinib showed significant decreases on days 14 and 17 (Figures 3A - 3B, 4A - 4B). Also in this case, the eyes of the control group did not show a significant change in neovascularization during the administration period. In the eyes administered with a combination of nintedanib and mitomycin, the pterygium area did not increase, but significantly increased in the physiological saline control group (Figures 5A - 5B). The neovascularization score did not show a significant change in this animal group.

[0096] [Example 3]: Formulation Nintedanib ophthalmic solution This pharmaceutical 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 - 8.0. Other viscosity modifiers, lubricants, and preservatives may be added to enhance the functionality of the formulation. The composition of this ophthalmic solution is disclosed in Table 6.

[0097]

Table 6

[0098] Nintedanib Ophthalmic Suspension This pharmaceutical preparation is an isotonic ophthalmic suspension prepared with sodium carboxymethylcellulose and a buffer solution in the pH range of 5.5 to 8.0. The particle size of the active ingredient is reduced to less than 40 microns. Other viscosity modifiers, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the suspension preparation. The composition is disclosed in Table 7.

[0099] [Table 7] TIFF2025094111000009.tif100165

[0100] Nintedanib Ophthalmic Emulsion This pharmaceutical preparation is an isotonic ophthalmic emulsion. After dissolving the active ingredient in a mixed oil phase and an emulsifier, it is emulsified and then mixed with an aqueous phase in the pH range of 5.5 to 8.0. Other viscosity modifiers, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the emulsion preparation. The composition is disclosed in Table 8.

[0101] [Table 8] TIFF2025094111000011.tif33166

[0102] Nintedanib Sustained Release Semi-Solid Preparation This pharmaceutical preparation is an isotonic sustained release semi-solid preparation. The active ingredient is dissolved and / or suspended in a semi-solid medium in the pH range of 5.5 to 8.0. Other viscosity modifiers, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the sustained release semi-solid preparation. The composition is disclosed in Table 9.

[0103] [Table 9]

[0104] Nintedanib Sustained Release Implant This pharmaceutical preparation is a solid implant. The active ingredient is mixed and blended with one or more polymers. The mixture of the active ingredient and the polymer is melted at a predetermined temperature and extruded into a filamentous form with a predetermined diameter dimension. The pharmaceutical filaments are cut into segmental forms with predetermined dimensions that can be implanted into eye tissues. The composition is disclosed in Table 10.

[0105]

Table 10

[0106] By way of non-limiting example, the exemplary compositions used in the methods of the present invention can be modified from existing ophthalmically acceptable compositions.

[0107] Other embodiments The present invention has been described above, including a detailed description of the present invention. Of course, the above description is for the purpose of specifically describing the present invention and is not intended to limit the scope of the present invention. The scope of the present invention is defined by the following claims. Other aspects, advantages, and modifications are also included in the following claims.

Claims

1. A method for inducing pterygium regression from the visual axis / central cornea, comprising administering to an affected eye of a subject in need of treatment a therapeutically effective amount of: (1) a multikinase inhibitor; (2) an antimetabolite that inhibits epithelial cell proliferation and fibroblast proliferation; or (3) a combination thereof.

2. 13. The method of claim 1, wherein administration of the multikinase inhibitor, the antimetabolite, or a combination thereof results in a reduction in the size of the pterygium in the affected eye.

3. 10. The method of claim 1, wherein administration of the multikinase inhibitor, the antimetabolite, or a combination thereof results in a negative pterygium growth rate in the affected eye.

4. 1. A method for stabilizing pterygium, comprising administering to an affected eye of a subject in need of such treatment a therapeutically effective amount of: (1) a multikinase inhibitor; (2) an antimetabolite that inhibits epithelial cell proliferation and fibroblast proliferation; or (3) a combination thereof.

5. 5. The method of claim 4, wherein administration of the multikinase inhibitor, the antimetabolite, or a combination thereof results in stabilization of pterygium size in the affected eye.

6. 5. The method of claim 4, wherein administration of the multikinase inhibitor, the kinase antagonist, or a combination thereof results in a pterygium growth rate in the affected eye being approximately zero.

7. 7. The method of any one of claims 1 to 6, wherein the multikinase inhibitor reduces activity in pterygium of one or more intracellular and / or cell surface protein kinases selected from EGFR, ErbB2, ErbB3, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, NGFR, VEGFR(1,2,3), PDGFR(α,β), TGF-βR(I,II,III), FLT3, Lck, Lyn, Src, c-Kit, c-Fms, Raf-1, B-Raf, RET, CSF-1R.

8. The multikinase inhibitor is IC50 against VEGFR (1, 2, 3) is <200 nM; and / or an IC50 against PDGFR (α, β) of <200 nM; and / or The method of claim 7, wherein the IC50 against FGFR(1, 2, 3) is <1000 nM.

9. The multikinase inhibitor is, for example, afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, or lenvatinib.

9. The method of any one of claims 1 to 8, wherein the medicament is selected from the group consisting of: nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, vatalanib, and vemurafenib.

10. 7. The method of any one of claims 1 to 6, wherein the antimetabolite is selected from the group consisting of mitomycin C, 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, azathioprine, methotrexate, mycophenolate mofetil, and thiotepa.

11. 11. The method of any one of claims 1 to 10, wherein the multikinase inhibitor, the antimetabolite, or a combination thereof is administered to the affected eye in the form of a topical ophthalmic formulation, an ointment, a gel, a sustained release semi-solid formulation, a sustained release solid formulation, or an intraocular implant.

12. 12. The method of claim 11, wherein the multikinase inhibitor, the antimetabolite, or a combination thereof is administered to the affected eye in the form of a topical ophthalmic formulation and administered topically to the affected eye.

13. 12. The method of claim 11, wherein the topical ophthalmic formulation is a solution, suspension or emulsion.

14. 14. The method of claim 13, wherein the topical ophthalmic formulation further comprises one or more pharma- ceutically acceptable additives selected from stabilizers, surfactants, polymer-based carriers, gelling agents, organic cosolvents, pH adjusting components, and osmolality adjusting components, and may or may not contain preservatives.

15. 12. The method of claim 11, wherein the sustained release semi-solid formulation, sustained release solid formulation or intraocular implant is inserted into the affected eye.

16. 16. The method of claim 15, wherein the sustained release semi-solid formulation, sustained release solid formulation, or intraocular implant further comprises a pharma- ceutically acceptable excipient.

17. The sustained release semi-solid formulation, sustained release solid formulation, or intraocular implant is A multikinase inhibitor, antimetabolite, or a combination thereof; and A biodegradable polymer selected from polylactic acid (PLA), polyglycolic acid (PLGA), and a copolymer of polylactic acid and polyglycolic acid.

17. The method of claim 16 comprising:

18. 18. The method according to any one of claims 1 to 17, wherein administration is carried out on a pterygium patient.

19. 1. A method for reducing hyperemia and symptoms in pterygium, pinguecula and pseudopterygium in a patient in need of treatment, comprising administering a therapeutically effective amount of a multikinase inhibitor to an affected eye of the subject.

20. 1. A method for reducing or preventing pterygium recurrence in a subject in need of treatment, comprising administering a therapeutically effective amount of a multikinase inhibitor to an affected eye of the subject.

21. 21. The method of claim 20, wherein administration is performed prior to surgical removal of the pterygium.

22. 21. The method of claim 20, wherein administration is performed during a procedure for surgical removal of a pterygium.

23. 21. The method of claim 20, wherein the administration is performed after surgical removal of the pterygium.

24. The multikinase inhibitor is IC50 against VEGFR (1, 2, 3) is <50 nM; IC50 against PDGFR (α, β) is <100 nM; IC50 for FGFR (1, 2, 3) is <150 nM IC50 against FGFR4 is <1000 nM; IC50 against FLT3 is <50 nM; IC50 against Lck is <50 nM; IC50 for Lyn is <200 nM; 24. The method of any one of claims 19 to 23, wherein the IC50 against Src is <200 nM.

25. 25. The method of claim 24, wherein the multikinase inhibitor is selected from the group consisting of nintedanib {(3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate}, a free base, hydrate, solvate, or a pharma- ceutically acceptable salt thereof.

26. 26. The method of claim 25, wherein the multikinase inhibitor is nintedanib free base or nintedanib esylate (ethanesulfonate salt).

27. 27. The method of any one of claims 19 to 26, wherein the multikinase inhibitor is administered to the affected eye in the form of a topical ophthalmic formulation, a sustained release semi-solid formulation, a sustained release solid formulation, or an intraocular implant.

28. 28. The method of claim 27, wherein nintedanib is administered to the affected eye in the form of a topical ophthalmic formulation and administered topically to the affected eye.

29. 29. The method of claim 28, wherein the topical ophthalmic formulation is a solution, suspension or emulsion.

30. 29. The method of claim 28, wherein the concentration of nintedanib in the topical ophthalmic formulation is 0.001% to 10% by weight of the total volume of the formulation.

31. 28. The method of claim 27, wherein the topical ophthalmic formulation further comprises one or more pharma- ceutically acceptable additives selected from stabilizers, surfactants, polymer-based carriers, gelling agents, organic cosolvents, pH adjusting components, osmolality adjusting components, and preservatives.

32. 28. The method of claim 27, wherein the sustained release semi-solid formulation, sustained release solid formulation or intraocular implant is inserted into the affected eye.

33. 33. The method of claim 32, wherein the sustained release semi-solid formulation, sustained release solid formulation, or intraocular implant contains nintedanib and a pharma- ceutically acceptable excipient.

34. 34. The method of claim 33, wherein the amount of nintedanib in the sustained release semi-solid formulation, sustained release solid formulation, or intraocular implant is from 1 μg to 100 mg.

35. 28. The method of claim 27, wherein the sustained release semi-solid formulation, sustained release solid formulation, or intraocular implant contains nintedanib; and a biodegradable polymer selected from polylactic acid (PLA), polyglycolic acid (PLGA), and copolymers of polylactic acid and polyglycolic acid.

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