Emulsion formulation of multi-kinase inhibitors

Abstract

To provide compositions for the delivery of multikinase inhibitors, and to provide compositions and methods for treating one or more ocular conditions.SOLUTION: Compositions comprising a therapeutically effective amount of a multikinase inhibitor, such as nintedanib or axitinib or pazopanib, are provided, in which the composition is an emulsion, such as a nanoemulsion, with lipophilic carrier, a polyoxyl oil, optionally with a surfactant, optionally with a cyclic oligosaccharide, such as a cyclodextrin as a solubilizer. Methods for treating ocular conditions with the compositions are also provided.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 723,998, filed on August 28, 2018, the entire disclosure of which is incorporated herein by reference.

[0002] Field of the Invention The present specification provides a formulation for delivering a multi - kinase inhibitor.

Background Art

[0003] Background A multi - kinase inhibitor is an inhibitor that targets two or more protein kinases. A protein kinase is an enzyme that can add a phosphate group to a protein to regulate its function. Since phosphorylation controls many biological processes, multi - kinase inhibitors can be used in the treatment of various diseases or in the regulation of cell functions. The therapeutic potential of such compounds depends, at least in part, on how suitably the compound can be formulated and delivered for a particular treatment.

Summary of the Invention

[0004] Summary The present specification provides a composition for delivering a multi - kinase inhibitor. In some embodiments, compositions and methods for treating one or more eye conditions are provided.

[0005] This disclosure provides compositions for treating ocular conditions, including diseases affecting the anterior segment of the eye. The compositions may comprise a therapeutically effective amount of a multikinase inhibitor such as nintedanib, axitinib, or pazopanib, and the compositions are emulsions such as nanoemulsions (e.g., containing castor oil, polyoxyl-35 castor oil, and optionally polysorbate 80), comprising a cyclic oligosaccharide such as cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin) as a solubilizer, and are suitable for topical administration to the eye. This disclosure further provides methods for treating ocular conditions using the disclosed compositions.

[0006] In some embodiments, compositions suitable for topical administration to the eye are provided, comprising a therapeutically effective amount of a multikinase inhibitor such as nintedanib, axitinib, or pazopanib, comprising an emulsion such as a nanoemulsion containing a cyclodextrin such as 2-hydroxypropyl-β-cyclodextrin as a solubilizer. In some embodiments, methods are provided for treating ocular conditions associated with angiogenesis, such as hyperemia, neovascularization, pterygium, pinguecula, glaucoma filtration surgery and minimally invasive glaucoma surgery (MIGS), corneal transplantation with graft rejection, graft-versus-host disease, dry eye diseases, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, Stevens-Johnson syndrome, viral infections (e.g., HSV-1), bacterial infections, fungal infections, parasitic infections, neovascularization due to contact lenses, ulcers, alkaline burns, and stem cell deficiency.

[0007] In one aspect, an emulsion is provided comprising a therapeutically effective amount of a multikinase inhibitor; a solubilizer; a lipophilic carrier; and one or more surfactants. In another aspect, an emulsion is provided comprising a therapeutically effective amount of a multikinase inhibitor; a polyoxyl oil; a solubilizer; a lipophilic carrier; and one or more surfactants.

[0008] This and other embodiments may optionally further include one or more of the following features: In some embodiments, the emulsion may be a nanoemulsion. In some embodiments, the multikinase inhibitor may be afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cedilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, or idelalisib The following may be selected: imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof.

[0009] In some embodiments, the solubilizer may be a cyclic polysaccharide. In some embodiments, the cyclic polysaccharide may be selected from cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof.

[0010] In some embodiments, the lipophilic carrier may be selected from castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. In some embodiments, the surfactant may be selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, polyoxyl-35 castor oil, polyoxyl-40 castor oil, tocopherol, and other polymer emulsifiers, and combinations thereof.

[0011] In some embodiments, the multikinase inhibitor is nintedanib, the solubilizer is 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier is castor oil, and the surfactant is polysorbate 80, polyoxyl-35 castor oil, or a combination thereof.

[0012] In some embodiments, the multikinase inhibitor may be present in an amount of approximately 0.001% w / w to approximately 10.0% w / w. In some embodiments, the multikinase inhibitor is nintedanib, and nintedanib may be present in an amount of approximately 0.01% w / w to approximately 10.0% w / w. In some embodiments, the multikinase inhibitor is axitinib, and axitinib may be present in an amount of approximately 0.001% w / w to approximately 1.0% w / w in the emulsion. In some embodiments, the multikinase inhibitor is axitinib, and axitinib may be present in an amount of approximately 0.001% w / w to approximately 10.0% w / w in the emulsion. In some embodiments, the multikinase inhibitor is pazopanib, and pazopanib may be present in an amount of approximately 0.01% w / w to approximately 10.0% w / w. In some embodiments, the lipophilic carrier may be present in an amount of approximately 0.01% w / w to approximately 5.0% w / w.

[0013] In some embodiments, the surfactant may be present in an amount of about 0.01% w / w to about 10% w / w. In some embodiments, the solubilizer may be present in the emulsion in an amount of about 1% w / w to about 20% w / w.

[0014] In some embodiments, the emulsion may further contain additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, preservatives, and combinations thereof. In some embodiments, the thickener may be selected from the group consisting of carbomers, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, xanthan gum, and combinations thereof. In some embodiments, the thickener may be hydroxypropyl methylcellulose or sodium carboxymethylcellulose, and the thickener is present in an amount of about 0.01% w / w to about 1.0% w / w. In some embodiments, the buffer may be selected from the group consisting of phosphates, citrates, acetates, borates, and combinations thereof. In some embodiments, the buffer may be selected from the group consisting of sodium phosphate monobasic monohydrate, sodium phosphate monohydrate, sodium phosphate dibasic heptahydrate, and boric acid, and the buffer is present in the emulsion in an amount sufficient to maintain the pH in the range of 4.0 to 8.0. In some embodiments, the antioxidant may be selected from the group consisting of disodium edetate, dibutylhydroxytoluene, citric acid, sodium metabisulfite, tocopherol acetate, and combinations thereof. In some embodiments, the antioxidant may be disodium edetate, and the antioxidant is present in an amount of about 0.01% w / w to about 1.0% w / w. In some embodiments, the isotonic agent may be selected from the group consisting of sodium chloride, glycerin, mannitol, potassium chloride, erythritol, and combinations thereof. In some embodiments, the isotonic agent may be glycerin, and the isotonic agent is present in an amount of about 0.1% w / w to about 10% w / w. In some embodiments, the isotonic agent may be present in an amount sufficient to maintain the molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg.

[0015] In some embodiments, the emulsion may be preservative-free. In some embodiments, the emulsion may further contain preservatives selected from the group consisting of BAK, PHMB, Purite®, sorbic acid, and combinations thereof.

[0016] In some embodiments, the emulsion may have an average droplet size of about 10 nm to 100,000 nm. In some embodiments, the emulsion may have an average droplet size of 200 nm or less. In some embodiments, the emulsion may have an average droplet size of about 100 nm or less. In some embodiments, the emulsion may have an average droplet size of about 75 nm or less. In some embodiments, the emulsion may have an average droplet size of about 25 to about 200 nm (e.g., about 25 to about 150 nm, about 25 to about 100 nm, about 25 to about 75 nm, about 50 to about 200 nm, about 50 to about 150 nm, or about 50 to about 100 nm). While not bound by any particular theory, it is thought that for at least some emulsions (e.g., those described herein), a smaller droplet size may result in a longer time to phase separation of the emulsion and / or a longer stabilization time of the emulsion. Similarly, although not bound by any particular theory, it is thought that for at least some emulsions (for example, those described herein), smaller droplet sizes can increase the transparency of the emulsion. For example, emulsions with small droplet sizes (e.g., about 50 nm) may be nearly transparent, while larger droplet sizes, or separated emulsions, may appear cloudy.

[0017] In some embodiments, the emulsion can remain stable at 25°C for at least 6 months. In some embodiments, the emulsion can remain stable at 25°C for at least 12 months. In some embodiments, the emulsion can remain stable at 25°C for at least 24 months. In some embodiments, the emulsion can remain stable at 40°C for at least 1 month. In some embodiments, the emulsion can remain stable at 40°C for at least 2 months.

[0018] In some embodiments, the emulsion may be formulated as eye drops, creams, gels, and ointments, films, or sustained-release implants. In another embodiment, a method is provided for prolonging the residence time of a multi-kinase inhibitor on the surface of the eye, the method comprising the step of administering any one or more emulsions described herein to the eye of a subject. In some embodiments, the administration step may include applying the emulsion to the eye at least once daily. In some embodiments, the administration step may include applying the emulsion to the eye at least twice daily. In some embodiments, the administration step may include applying the emulsion to the eye at least three times daily.

[0019] In another aspect, a method is provided for treating an eye condition, which includes the step of administering any one or more emulsions described herein to the eye of the subject. In some embodiments, the eye condition may be associated with neovascularization. In some embodiments, the eye condition may be selected from conjunctivitis, neovascularization, pterygium, pinguecula, glaucoma filtration surgery and minimally invasive glaucoma surgery (MIGS), corneal transplant surgery with graft rejection, graft-versus-host disease, dry eye disease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, Stevens-Johnson syndrome, viral infections (e.g., HSV-1), bacterial infections, fungal infections, parasitic infections, neovascularization due to contact lenses, ulcers, alkaline burns, and stem cell deficiency.

[0020] In another aspect, this specification provides an emulsion comprising a therapeutically effective amount of a multikinase inhibitor, a polyoxyl oil, a lipophilic carrier, and water.

[0021] The implementation may include one or more of the following features: The emulsion may be a nanoemulsion. The multikinase inhibitors are afatinib, amvatinib, axitinib, cabozantinib, canertinib, cedilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib The following may be selected: lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. The multikinase inhibitor may be selected from axitinib, nintedanib, and pazopanib. The multikinase inhibitor may be axitinib. The multikinase inhibitor may be nintedanib. The multikinase inhibitor may be pazopanib. The emulsion may further contain a solubilizer. The solubilizer may be a cyclic polysaccharide. The cyclic polysaccharide may be selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. The polyoxyl oil may be polyoxyl castor oil. The polyoxyl castor oil may be polyoxyl-40 castor oil, polyoxyl-35 castor oil, or combinations thereof. The lipophilic carrier may be selected from the group consisting of castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof.The emulsion may further contain a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof. The multikinase inhibitor may be nintedanib, the solubilizer may be 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier may be castor oil, and the polyoxyl oil may be polyoxyl-35 castor oil, or a combination thereof. The multikinase inhibitor may be present in amounts of about 0.001% w / w to about 10.0% w / w. The multikinase inhibitor may be present in amounts of about 0.01% to about 1% w / w. The multikinase inhibitor may be present in amounts of about 0.1% to about 0.5% w / w. The multikinase inhibitor may be nintedanib, and nintedanib may be present in amounts of about 0.01% w / w to about 10.0% w / w. Nintedanib may be present in amounts of approximately 0.01% to approximately 1% w / w. Nintedanib may be present in amounts of approximately 0.1% to approximately 0.5% w / w. The multikinase inhibitor may be axitinib, which may be present in amounts of approximately 0.001% to approximately 10.0% w / w in the emulsion. Axitinib may be present in amounts of approximately 0.01% to approximately 1% w / w. Axitinib may be present in amounts of approximately 0.1% to approximately 0.5% w / w. Axitinib may be present in amounts of approximately 0.05% to approximately 0.5% w / w. The multikinase inhibitor may be pazopanib, which may be present in amounts of approximately 0.01% to approximately 10.0% w / w. Pazopanib may be present in amounts of approximately 0.01% to approximately 1% w / w. Pazopanib may be present in amounts of approximately 0.1% to approximately 0.5% w / w. Lipophilic carriers may be present in amounts of approximately 0.01% to approximately 5.0% w / w. Lipophilic carriers may be present in amounts of approximately 0.05% to approximately 1% w / w. Lipophilic carriers may be present in amounts of approximately 0.1% to approximately 0.5% w / w. Polyoxyl oil may be present in amounts of approximately 0.01% to approximately 10% w / w. Polyoxyl oil may be present in amounts of approximately 0.05% to approximately 1% w / w. Polyoxyl oil may be present in amounts of approximately 0.1% to approximately 0.5% w / w. The emulsion may further contain a solubilizer, which may be present in the emulsion in an amount of approximately 1% w / w to approximately 20% w / w.Solubilizers may be present in amounts of approximately 5% to approximately 15% w / w. Solubilizers may be present in amounts of approximately 8% to approximately 12% w / w. The emulsion may further contain additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, and combinations thereof. Thickeners may be selected from the group consisting of carbomers, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, xanthan gum, and combinations thereof. Thickeners may be hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or combinations thereof. Thickeners may be present in amounts of approximately 0.01% w / w to approximately 1.0% w / w. Thickeners may be present in amounts of approximately 0.05% w / w to approximately 0.5% w / w. Buffers may be selected from the group consisting of phosphates, citrates, acetates, borates, and combinations thereof. The buffering agent may be selected from the group consisting of sodium citrate dihydrate, sodium citrate, monobasic sodium phosphate monohydrate, monosodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, boric acid, and combinations thereof. The buffering agent may be selected from the group consisting of sodium citrate dihydrate, sodium citrate, or combinations thereof. The buffering agent may be present in the emulsion in an amount sufficient to maintain the pH in the range of 4.0 to 8.0. The buffering agent may be present in the emulsion in an amount sufficient to maintain the pH in the range of about 5.5 to about 6.5. The buffering agent may be present in an amount of about 0.01% w / w to about 1.0% w / w. The buffering agent may be present in an amount of about 0.03% w / w to about 0.06% w / w. The antioxidant may be selected from the group consisting of disodium edetate, dibutylhydroxytoluene, citric acid, sodium metabisulfite, tocopherol acetate, and combinations thereof. The antioxidant may be selected from the group consisting of disodium edetate, citric acid, and combinations thereof. The antioxidant may be present in an amount of approximately 0.01% to approximately 1.0% w / w. The antioxidant may be present in an amount of approximately 0.05% to approximately 0.5% w / w. The antioxidant may include disodium edetate, which may be present in an amount of approximately 0.01% w / w to approximately 1.0% w / w.The antioxidant may include disodium edetate, which may be present in amounts of approximately 0.05% w / w to approximately 0.5% w / w. The antioxidant may include citric acid, which may be present in amounts of approximately 0.001% to approximately 0.1% w / w. The antioxidant may include citric acid, which may be present in amounts of approximately 0.005% to approximately 0.05% w / w. The isotonic agent may be selected from the group consisting of sodium chloride, glycerin, mannitol, potassium chloride, erythritol, and combinations thereof. The isotonic agent may be glycerin. The isotonic agent may be present in amounts of approximately 0.1% w / w to approximately 10% w / w. The isotonic agent may be present in amounts of approximately 0.01% w / w to approximately 1% w / w. The isotonic agent may be present in amounts of approximately 0.05% w / w to approximately 0.5% w / w. An isotonic agent may be present in an amount sufficient to maintain the molar osmotic pressure concentration in the range of 250–400 mOsm / kg. The emulsion may further contain a preservative. The preservative may be selected from the group consisting of benzalkonium chloride (BAK), polyhexamethylene biguanide biguanzide (PHMB), stable oxychloro complex, sorbic acid, and combinations thereof. The emulsion may be preservative-free. The emulsion has an average droplet size of approximately 10 nm to 100,000 nm. The emulsion has an average droplet size of 200 nm or less. The emulsion can remain stable at 25°C for at least 6 months. The emulsion can remain stable at 25°C for at least 12 months. The emulsion can remain stable at 25°C for at least 24 months. The emulsion can remain stable at 40°C for at least 6 months. The emulsion can remain stable at 40°C for at least 12 months. The emulsion can remain stable at 40°C for at least 24 months. The emulsion can remain stable at 50°C for at least 6 months. The emulsion can remain stable at 50°C for at least 12 months. The emulsion can remain stable at 50°C for at least 24 months. The emulsion can remain stable at 60°C for at least 6 months. The emulsion can remain stable at 60°C for at least 12 months. The emulsion can remain stable at 60°C for at least 24 months.The emulsion can be formulated as an eye drop, cream, gel, and ointment, film.

[0022] In another aspect, provided herein is an emulsion comprising from about 0.05% to about 1% w / w of a multi-kinase inhibitor, from about 0.1% to about 1% w / w of a polyoxyl oil, from about 0.05% to about 1% w / w of a lipophilic carrier, from about 5% to about 15% w / w of a solubilizer, and water.

[0023] In another aspect, provided herein is an emulsion comprising from about 0.005% to about 2% w / w of a multi-kinase inhibitor, from about 0.1% to about 1% w / w of a polyoxyl oil, from about 0.05% to about 1% w / w of a lipophilic carrier, from about 5% to about 15% w / w of a solubilizer, and water.

[0024] The implementation may include one or more of the following features. The multi-kinase inhibitor may be present in an amount of about 0.1% to about 0.5% w / w. The polyoxyl oil may be present in an amount of about 0.3% to about 0.7% w / w. The lipophilic carrier may be present in an amount of about 0.1% to about 0.5% w / w. The solubilizer may be present in an amount of about 8% to about 12% w / w.

[0025] In another aspect, provided herein is an emulsion comprising from about 0.1% to about 0.5% w / w of a multi-kinase inhibitor, from about 0.3% to about 0.7% w / w of a polyoxyl oil, from about 0.1% to about 0.5% w / w of a lipophilic carrier, from about 8% to about 12% w / w of a solubilizer, and water.

[0026] The implementation of the emulsion provided herein may include one or more of the following features. The multi-kinase inhibitor may be present in an amount of about 0.2% w / w. The polyoxyl oil may be present in an amount of about 0.5% w / w. The lipophilic carrier may be present in an amount of about 0.25% w / w. The solubilizer may be present in an amount of about 10% w / w.

[0027] ​In another aspect, this specification provides an emulsion comprising approximately 0.2% w / w of a multikinase inhibitor, approximately 0.5% w / w of polyoxyl oil, approximately 0.25% w / w of a lipophilic carrier, approximately 10% w / w of a solubilizer, and water.

[0028] The implementation of the emulsions provided herein may include one or more of the following features: The multikinase inhibitors are afatinib, amvatinib, axitinib, cabozantinib, canertinib, cedilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, The multikinase inhibitor may be selected from the group consisting of lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. The multikinase inhibitor may be selected from axitinib, nintedanib, and pazopanib. The multikinase inhibitor may be axitinib. The multikinase inhibitor may be nintedanib. The multikinase inhibitor may be pazopanib. The solubilizer may be a cyclic polysaccharide. The cyclic polysaccharide may be selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. The solubilizer may include (or may contain) 2-hydroxypropyl-β-cyclodextrin. The polyoxyl oil may be polyoxyl castor oil. The polyoxyl castor oil may be polyoxyl-40 castor oil, polyoxyl-35 castor oil, or combinations thereof. The lipophilic carrier may be selected from the group consisting of castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. The lipophilic carrier may contain (or may contain) castor oil.The emulsion may further contain a surfactant. In some embodiments, the surfactant may be selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof. The surfactant may be present in an amount of about 0.05% to about 5% w / w. The surfactant may be present in an amount of about 0.1% to about 1% w / w. The surfactant may be present in an amount of about 0.5% w / w. The emulsion may further contain additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, and combinations thereof. The thickener may include hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or combinations thereof. The thickener may be present in an amount of about 0.01% w / w to about 1.0% w / w. The thickener may be present in an amount of about 0.05% w / w to about 0.5% w / w. Thickeners may be present in an amount of approximately 0.1% w / w. Buffers may contain (or may contain) sodium citrate. Buffers may be present in an amount sufficient to maintain the pH in the emulsion between approximately 5.5 and 6.5. Buffers may be present in an amount of approximately 0.01% w / w to approximately 1.0% w / w. Buffers may be present in an amount of approximately 0.03% w / w to approximately 0.06% w / w. Buffers may be present in an amount of approximately 0.045% w / w. Antioxidants may contain disodium EDTA, citric acid, or a combination thereof. Antioxidants may contain disodium EDTA, which may be present in an amount of approximately 0.01% w / w to approximately 1.0% w / w. Antioxidants may contain disodium EDTA, which may be present in an amount of approximately 0.05% w / w to approximately 0.5% w / w. The antioxidant may include disodium edetate, which may be present in an amount of approximately 0.1% w / w. The antioxidant may include citric acid, which may be present in an amount of approximately 0.001% to approximately 0.1% w / w. The antioxidant may include citric acid, which may be present in an amount of approximately 0.005% to approximately 0.05% w / w. The antioxidant may include citric acid, which may be present in an amount of approximately 0.015%. The isotonic agent may include (or may contain) glycerin.The isotonic agent may be present in an amount of about 0.01% w / w to about 1% w / w. The isotonic agent may be present in an amount of about 0.05% w / w to about 0.5% w / w. The isotonic agent may be present in an amount of about 0.1% w / w.

[0029] In another aspect, provided herein is an emulsion comprising about 0.2% w / w of a multi-kinase inhibitor selected from the group consisting of nintedanib, axitinib, and pazopanib, about 0.5% w / w of polyoxyl castor oil, about 0.25% w / w of castor oil, about 10% w / w of 2-hydroxypropyl-β-cyclodextrin, and water.

[0030] The implementation may include one or more of the following features. The multi-kinase inhibitor may be axitinib. The multi-kinase inhibitor may be nintedanib. The multi-kinase inhibitor may be pazopanib. The polyoxyl castor oil may be polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. The emulsion may further comprise about 0.5% w / w of polysorbate 80. The emulsion may further comprise about 0.1% w / w of hydroxypropyl methylcellulose. The emulsion may further comprise about 0.045% w / w of sodium citrate. The emulsion may further comprise about 0.1% w / w of disodium edetate. The emulsion may further comprise about 0.015% of citric acid. The emulsion may further comprise about 0.1% w / w of glycerin.

[0031] In another aspect, provided herein is a method for prolonging the residence time of a multi-kinase inhibitor on the ocular surface, the method comprising administering any one or more of the emulsions provided herein.

[0032] The implementation may include one or more of the following features: The administration step may include applying the emulsion to the eye at least once a day. The administration step may include applying the emulsion to the eye at least twice a day. The administration step may include applying the emulsion to the eye at least three times a day. The administration step may include applying the emulsion to the eye once a day. The administration step may include applying the emulsion to the eye twice a day. The administration step may include applying the emulsion to the eye three times a day.

[0033] In another context, this specification provides a method for treating an eye condition, the method comprising the step of administering any one or more emulsions provided herein to the eye in question. The eye condition may be associated with angiogenesis.

[0034] Implementation may include one or more of the following features: The ocular condition may be selected from the group consisting of conjunctivitis, neovascularization, pterygium, pinguecula, glaucoma filtration surgery and minimally invasive glaucoma surgery (MIGS), corneal transplantation with graft rejection, graft-versus-host disease, dry eye disease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, Stevens-Johnson syndrome, viral infections (e.g., HSV-1), bacterial infections, fungal infections, parasitic infections, neovascularization due to contact lenses, ulcers, alkaline burns, and stem cell deficiency. The emulsion can remain stable at 40°C for at least one month. The emulsion can remain stable at 40°C for at least six months. The emulsion can remain stable at 40°C for at least twelve months. The emulsion can remain stable at 40°C for at least twenty-four months. The administration stage may include applying the emulsion to the eye at least once daily. The administration steps may include applying the emulsion to the eyes at least twice a day. The administration steps may include applying the emulsion to the eyes at least three times a day. The administration steps may include applying the emulsion to the eyes once a day. The administration steps may include applying the emulsion to the eyes twice a day. The administration steps may include applying the emulsion to the eyes three times a day.

[0035] In another aspect, this specification provides a method for preparing any of the emulsions described herein, the method comprising the steps of: forming a first emulsion; reducing the droplet size of the first emulsion to form a nanoemulsion; dissolving a multikinase inhibitor in a solution; combining the nanoemulsion and the solution to form a nanoemulsion containing the multikinase inhibitor; and optionally filtering the nanoemulsion containing the multikinase inhibitor.

[0036] In another aspect, this specification provides a method for preparing an emulsion, the method comprising the steps of: forming a first emulsion; reducing the droplet size of the first emulsion to form a nanoemulsion; dissolving a multikinase inhibitor in a solution; combining the nanoemulsion and the solution to form a nanoemulsion containing the multikinase inhibitor; and optionally filtering the nanoemulsion containing the multikinase inhibitor.

[0037] The method may include one or more of the following features: The step of forming the first emulsion may include high-shear mixing. The step of reducing droplet size may include using a microfluidizer. The filtration step may include using a 0.2-micron filter. The method may further include filling the filtered nanoemulsion into sterile eye drop bottles. The sterile eye drop bottles are preservative-free multi-dose (MDPF) containers or low-density polyethylene (LDPE) unit-dose containers. The first emulsion may include polyoxyl oil, a lipophilic carrier, and water. Multikinase inhibitors include afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, and lapatinib. The following can be selected: lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. The multikinase inhibitor can be selected from axitinib, nintedanib, and pazopanib. The multikinase inhibitor may be axitinib. The multikinase inhibitor may be nintedanib. The multikinase inhibitor may be pazopanib. The solution may further contain a solubilizer. The solubilizer may be a cyclic polysaccharide. The cyclic polysaccharide may be selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. The polyoxyl oil may be polyoxyl castor oil. The polyoxyl castor oil may be polyoxyl-40 castor oil, polyoxyl-35 castor oil, or combinations thereof.The lipophilic carrier may be selected from the group consisting of castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. The first emulsion may further contain a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-steart, tocopherol, and combinations thereof. The multikinase inhibitor may be nintedanib, the solubilizer may be 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier may be castor oil, the polyoxyl oil may be polyoxyl-35 castor oil, or a combination thereof. Multikinase inhibitors may be present in the first emulsion at an amount of approximately 0.001% w / w to approximately 10.0% w / w. Multikinase inhibitors may be present in the first emulsion at an amount of approximately 0.01% to approximately 1% w / w. Multikinase inhibitors may be present in the first emulsion at an amount of approximately 0.1% to approximately 0.5% w / w. Lipophilic carriers may be present in the first emulsion at an amount of approximately 0.01% w / w to approximately 5.0% w / w. Lipophilic carriers may be present in the first emulsion at an amount of approximately 0.05% to approximately 1% w / w. Lipophilic carriers may be present in the first emulsion at an amount of approximately 0.1% to approximately 0.5% w / w. Polyoxyl oil may be present in the first emulsion at an amount of approximately 0.01% w / w to approximately 10% w / w. Polyoxyl oil may be present in the first emulsion at an amount of approximately 0.05% to approximately 1% w / w. Polyoxyl oil may be present in the first emulsion at an amount of approximately 0.1% to approximately 0.5% w / w. The first emulsion may further contain a solubilizer, which may be present in the first emulsion at an amount of approximately 1% w / w to approximately 20% w / w. The solubilizer may be present in the first emulsion at an amount of approximately 5% to approximately 15% w / w. The solubilizer may be present in the first emulsion at an amount of approximately 8% to approximately 12% w / w.The first emulsion may further contain additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, and combinations thereof. The emulsion may be any emulsion described herein.

[0038] [Invention 1001] Therapeutic doses of multikinase inhibitors; Polyoxyl oil; Lipophilic carriers; and water An emulsion containing [something]. [Invention 1002] The aforementioned multikinase inhibitors include afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cedilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, and lapatinib. An emulsion of the present invention 1001, selected from lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. [Invention 1003] The emulsion of the present invention 1002, wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. [Invention 1004] An emulsion according to any of invention 1001 to 1003, further comprising a solubilizing agent. [Invention 1005] An emulsion according to any of the present invention 1001 to 1004, wherein the solubilizing agent is a cyclic polysaccharide. [Invention 1006] An emulsion according to any one of the present invention 1001 to 1005, wherein the polyoxyl oil is polyoxyl castor oil. [Invention 1007] The emulsion of the present invention 1006, wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. [Invention 1008] An emulsion according to any of invention 1001 to 1007, further comprising a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof. [Invention 1009] The emulsion of the present invention 1001, wherein the multikinase inhibitor is nintedanib, the solubilizer is 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier is castor oil, and the polyoxyl oil is polyoxyl-35 castor oil, or a combination thereof. [Invention 1010] An emulsion according to any of the present invention 1001 to 1009, wherein the multikinase inhibitor is present in an amount of approximately 0.001% w / w to approximately 10.0% w / w. [Invention 1011] Approximately 0.005% to 2% w / w multi-kinase inhibitors; Approximately 0.1% to 1% w / w polyoxyl oil; Approximately 0.05% to 1% w / w lipophilic carrier; Approximately 5% to approximately 15% w / w solubilizer; and water An emulsion containing [something]. [Invention 1012] The emulsion of the present invention 1011, wherein the multi-kinase inhibitor is present in an amount of approximately 0.1% to approximately 0.5% w / w. [Invention 1013] An emulsion of the present invention 1011 or 1012, wherein the polyoxyl oil is present in an amount of approximately 0.3% to approximately 0.7% w / w. [Invention 1014] An emulsion according to any of invention 1011 to 1013, wherein the lipophilic carrier is present in an amount of about 0.1% to about 0.5% w / w. [Invention 1015] An emulsion according to any of the present invention 1011 to 1014, wherein the solubilizer is present in an amount of approximately 8% to approximately 12% w / w. [Invention 1016] An emulsion according to any of invention 1011 to 1015, wherein the multi-kinase inhibitor is present in an amount of approximately 0.2% w / w. [Invention 1017] An emulsion according to any of invention 1011 to 1016, wherein the polyoxyl oil is present in an amount of approximately 0.5% w / w. [Invention 1018] An emulsion according to any of the present invention 1011 to 1017, wherein the lipophilic carrier is present in an amount of approximately 0.25% w / w. [Invention 1019] The aforementioned solubilizer is present in an emulsion of any of the present inventions 1011 to 1018 in an amount of approximately 10% w / w. [Invention 1020] The multikinase inhibitors include afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejiranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, and neratinib. An emulsion of any of the present invention 1011 to 1019, selected from the group consisting of bu, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. [Invention 1021] An emulsion according to any of the present invention 1011 to 1020, wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. [Invention 1022] An emulsion according to any of the present invention 1011 to 1021, wherein the solubilizing agent is a cyclic polysaccharide. [Invention 1023] The emulsion of the present invention 1022, wherein the cyclic polysaccharide is selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. [Invention 1024] An emulsion according to any of invention 1011 to 1023, wherein the solubilizing agent comprises 2-hydroxypropyl-β-cyclodextrin. [Invention 1025] A multi-kinase inhibitor selected from the group consisting of nintedanib, axitinib, and pazopanib, at a concentration of approximately 0.2% w / w; Approximately 0.5% w / w polyoxyl castor oil; Approximately 0.25% w / w castor oil: Approximately 10% w / w 2-hydroxypropyl-β-cyclodextrin; and water An emulsion containing [something]. [Invention 1026] A method for treating an eye condition, comprising the step of administering an emulsion according to any of invention 1001 to 1025 to the eye of a subject. Details of one or more embodiments of the present invention are shown in the accompanying drawings and the following detailed description. Other features, purposes, and advantages of the present invention will become apparent from the detailed description and drawings, as well as from the claims. [Brief explanation of the drawing]

[0039] [Figure 1] This is an illustrative diagram illustrating the concept of exemplary disynamic emulsions and solubilizer systems used in some embodiments of the compositions described herein. [Figure 2] This plot shows the reduction in CNV in rabbits with 0.2% nintedanib emulsion or solution of Example 6. [Modes for carrying out the invention]

[0040] Detailed description of the invention The detailed descriptions herein are intended to provide details for understanding various aspects of the invention, and the disclosures provided are not intended to limit the claims to any particular aspect, but rather to illustrate the subject matter of the claims. Accordingly, certain aspects disclosed herein may be combined with other specific aspects disclosed herein, such as certain aspects under various headings provided for convenience and structural purposes, but this should not be interpreted as limiting the claims in any way.

[0041] All public documents cited herein are incorporated herein by reference in their entirety.

[0042] As used herein, the singular forms “a,” “an,” and “the” include the plural form unless otherwise evident from the context.

[0043] As used herein, unless otherwise specified, the term “about” is provided to indicate that, when used in relation to a number or range of values, that value or range of values ​​may deviate to an extent that would be reasonable to a person skilled in the art (e.g., a particular temperature or temperature range). For example, when used in this context, the term “about” may, in some embodiments, indicate that a number or range of values ​​may differ from the described value or range of values ​​by only 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, the number or range of values ​​may differ by only 5%.

[0044] Nintedanib, axitinib, and pazopanib are three potent multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and / or fibroblast growth factor receptor (FGFR). When formulated as oral capsules or tablets, nintedanib, axitinib, and pazopanib constitute an effective drug therapy for treating various types of cancer. However, nintedanib, axitinib, and pazopanib are insoluble in water, with a solubility of less than 0.001 mg / mL at room temperature. These physical and chemical properties can limit their application and prevent effective delivery of therapeutically effective concentrations to target ocular tissue via topical intraocular administration. Surprisingly, the synergistic effect of emulsion systems, optionally combined with solubilizers such as cyclic oligosaccharides (e.g., 2-hydroxypropyl-β-cyclodextrin), was found to enable the successful formulation of therapeutically effective concentrations of multi-kinase inhibitors such as nintedanib, axitinib, or pazopanib with sufficient stability to achieve a desirable shelf life. For example, unexpectedly, the emulsion, and optionally the solubilizer, was found to have an effect on the solubility of multi-kinase inhibitors such as nintedanib, axitinib, or pazopanib that outweighed the additive effect. As shown in Figure 1, multi-kinase inhibitors such as nintedanib, axitinib, or pazopanib could be dissolved in this cyclic oligosaccharide system by effectively trapping them in the central cavity of the cyclic oligosaccharide. While cyclic oligosaccharides such as 2-hydroxypropyl-β-cyclodextrin alone can dissolve multi-kinase inhibitors such as nintedanib, axitinib, or pazopanib to desired concentrations, the cyclic oligosaccharide-multi-kinase inhibitor complex can still dissociate and precipitate the multi-kinase inhibitor during long-term storage. Furthermore, surprisingly, the emulsion systems described herein have been shown to demonstrate similar or superior efficacy and / or pharmacokinetic properties (e.g., in various tissues) compared to solution formulations (e.g., administered three or more times a day), even with less frequent administration (e.g., twice a day).

[0045] To further improve stability, in some embodiments, multikinase inhibitors such as nintedanib, axitinib, or pazopanib can form a complex with a lipophilic carrier system such as a castor oil lipophilic carrier, and one or more surfactants such as polysorbate 80 and polyoxyl-35 castor oil, so that the multikinase inhibitor dissolves effectively at the interface of the oil droplets of the lipophilic carrier system to form a stable formulation. In some embodiments, the solubility and stability of the multikinase inhibitor formulation can be further significantly improved when the oil droplet size is about 200 nm or less. However, the concentration of surfactants in lipophilic carrier systems such as castor oil alone, including surfactants such as polysorbate 80 and / or polyoxyl-35 castor oil, which is necessary to dissolve nintedanib, axitinib, or pazopanib to the desired concentration for topical intraocular administration, may irritate the human eye. By using low concentrations of castor oil, polysorbate 80, or polyoxyl-35 castor oil emulsions or nanoemulsions, optionally combined with cyclic oligosaccharides, a synergistic effect can be achieved to improve the overall solubility of nintedanib, axitinib, or pazopanib, thereby achieving the desired solubility, formulation stability, and sufficient shelf life.

[0046] In some embodiments, the compositions described herein can remain stable at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, the compositions described herein can remain stable at increased temperatures (e.g., 40°C to 60°C) for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer. In some embodiments, the compositions described herein can remain stable at 40°C for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer. In some embodiments, the compositions described herein can remain stable at 60°C for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer.

[0047] Stability can be determined by methods known in the art, such as observing the appearance of the formulation, observing precipitation, observing pH changes, observing molar osmotic pressure, observing emulsion phase stability, observing emulsion droplet size, etc. In some embodiments, the composition maintains a pH range of about 4 pH to about 8 pH at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, the composition maintains a pH range of about 4 pH to about 8 pH with increased temperature (e.g., 40°C to 60°C) for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer. In some embodiments, the composition maintains a pH range of about 5 pH to about 6 pH at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, the composition maintains a pH range of approximately 5 pH to approximately 6 pH for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more when heated (e.g., 40°C to 60°C). In some embodiments, the multi-kinase inhibitor does not precipitate from the composition at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, the multi-kinase inhibitor does not precipitate from the composition at at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more when heated (e.g., 40°C to 60°C).

[0048] In some embodiments, the composition maintains a molar osmotic concentration of approximately 250 mOsm / kg to approximately 400 mOsm / kg at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, the composition maintains a molar osmotic concentration of approximately 250 mOsm / kg to approximately 400 mOsm / kg at increased temperature (e.g., 40°C to 60°C) for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer.

[0049] In some embodiments, at least 99% of the multi-kinase inhibitor remains dissolved in the composition at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, at least 99% of the multi-kinase inhibitor remains dissolved in the composition at a higher temperature (e.g., 40°C to 60°C) for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer. In some embodiments, at least 99.5% of the multi-kinase inhibitor remains dissolved in the composition at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, at least 99.5% of the multi-kinase inhibitor remains dissolved in the composition at a higher temperature (e.g., 40°C to 60°C) for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer.

[0050] In some embodiments, 100% of the multikinase inhibitor remains dissolved in the composition at room temperature (25°C) for at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. In some embodiments, 100% of the multikinase inhibitor remains dissolved in the composition at a higher temperature (e.g., 40°C to 60°C) for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or longer.

[0051] This unique formulation system is well-tolerated in both humans and animals and can be an effective treatment option for various ocular conditions, including diseases affecting the anterior segment of the eye. Furthermore, emulsions such as nanoemulsions with added thickeners like sodium carboxymethylcellulose or hydroxypropylmethylcellulose, when administered topically, can increase the drug half-life on the affected ocular surface, thus increasing the drug residence time on the ocular surface and reducing the number of administrations while maintaining pharmaceutically effective treatment.

[0052] In some embodiments, the Disclosure provides an ophthalmic composition comprising a therapeutically effective amount of a multikinase inhibitor (e.g., nintedanib, axitinib, or pazopanib), wherein the above combination of an emulsion, such as a nanoemulsion, and a cyclic oligosaccharide, such as 2-hydroxypropyl-β-cyclodextrin, as a solubilizer is suitable for topical administration to the eye. In some embodiments, methods are provided for treating ocular conditions associated with angiogenesis, such as hyperemia, neovascularization, pterygium, pinguecula, glaucoma filtration surgery and minimally invasive glaucoma surgery (MIGS), corneal transplantation with graft rejection, graft-versus-host disease, dry eye diseases, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, Stevens-Johnson syndrome, viral infections (e.g., HSV-1), bacterial infections, fungal infections, parasitic infections, neovascularization due to contact lenses, ulcers, alkaline burns, and stem cell exhaustion, which are also disclosed herein, and the symptoms of at least one ocular condition are alleviated, regressed, or stopped. Where used herein, unless otherwise specified, the terms “nintedanib or axitinib or pazopanib” include their free bases, salts, analogs, esters, and combinations thereof.

[0053] Furthermore, the compositions disclosed herein include afatinib, amvatinib, cabozantinib, canertinib, cejiranib, ceritinib, clenoranib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, and ne This may include compounds with multikinase inhibitors having similar pharmacological profiles as well as physical and chemical properties, such as latinib, nilotinib, palbociclib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, and vemurafenib.

[0054] In some embodiments, the compositions described herein may be useful for treating one or more ocular conditions of an affected eye of a subject. Methods comprising the step of administering the compositions described herein to the affected eye of a subject are provided herein. In some embodiments, the ocular conditions may be any ocular condition arising from neovascularization in the anterior or posterior segment of the eye. The subject to be treated may be of any age or gender. In some embodiments, the subject may be human. In some embodiments, the subject may be a non-human mammal.

[0055] In some embodiments, the pharmaceutical compositions disclosed herein may contain a “therapeutic dose” of the agents described herein. Such a dose may be determined based on the effect of the agent administered, or, if two or more agents are used, based on the combined effect. The therapeutic dose of an agent 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 elicit a desired response in the individual, such as remission of at least one disorder parameter or remission of at least one symptom of the disorder. The therapeutic dose is also the amount in which the therapeutically beneficial effect of the composition outweighs any toxic or adverse effects. As used herein, a dose is considered effective if it relieves, prevents, reduces, or resolves the symptoms associated with the eye condition to be treated.

[0056] In some embodiments, multikinase inhibitors such as nintedanib, axitinib, or pazopanib may be present in the ophthalmic compositions described herein in amounts of about 0.001% to about 10.0% (w / w). In some embodiments, the multikinase inhibitor may be present in amounts of about 0.005% to about 2% (w / w), about 0.001% to about 1% (w / w), about 0.001% to about 0.005% (w / w), about 0.005% to about 0.01% (w / w), about 0.01% to about 0.05% (w / w), about 0.05% to about 0.1% (w / w), about 0.01% to about 1% (w / w), and about 0 The multikinase inhibitor is present in amounts of approximately 0.05% to 0.5%, approximately 0.01% to 0.8% (w / w), approximately 0.3% to 0.7% (w / w), approximately 0.4% to 0.6% (w / w), approximately 0.1% to 10% (w / w), approximately 0.1% to 0.5% (w / w), approximately 0.2% to 8% (w / w), approximately 0.4% to 5% (w / w), or approximately 0.4% to 2% (w / w). In some embodiments, the multikinase inhibitor is present at a concentration of approximately 0.5% (w / w). In some embodiments, the multikinase inhibitor is present at a concentration of approximately 0.2% (w / w). In some embodiments, at least 99% of the multikinase inhibitor is dissolved in the composition. In some embodiments, at least 99.5% of the multikinase inhibitor is dissolved in the composition. In some embodiments, 100% of the multi-kinase inhibitor is dissolved in the composition.

[0057] In some embodiments, the disclosed composition may be an emulsion, solution, suspension, gel, ointment, occlusive film, or sustained-release formulation, which may be a preserved or non-preserved formulation. In some embodiments, the disclosed composition may be an emulsion. In some embodiments, the disclosed composition may be a nanoemulsion. The emulsion may have any suitable droplet size (e.g., about 10 nm to about 10,000 nm, about 100 nm to about 500 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, or less than about 100 nm). The composition may be formulated as eye drops, creams, ointments, films, gels, and implants (e.g., sustained-release implants) applicable to the eye. The formulation may be administered to the eye of a target requiring it.

[0058] Table 1 lists possible formulation components and their non-limiting exemplary concentrations.

[0059] (Table 1) TIFF0007880912000001.tif226166

[0060] In some embodiments, the composition may contain lipophilic carriers such as castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. In some embodiments, the lipophilic carrier may contain castor oil. In some embodiments, the lipophilic vehicle may be present in an amount of about 0% to about 10% by weight of the composition (e.g., about 0.001% to about 10% (w / w), about 0.01% to about 5.0% (w / w), about 0.05% to about 1.0% (w / w), or about 0.1% to about 0.5% (w / w)). In some embodiments, the lipophilic carrier may be present in an amount of about 0.25% (w / w).

[0061] In some embodiments, the composition may comprise one or more surfactants, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, polyoxyl-35 castor oil, polyoxyl-40 castor oil, tocopherol, other polymer emulsifiers, and combinations thereof. In some embodiments, the composition may comprise a surfactant that is a polyoxyl oil, such as polyoxyl castor oil (e.g., polyoxyl-35 castor oil, polyoxyl-40 castor oil, or a combination thereof) (e.g., CREMOPHOR® or KOLLIPHOR®). In some such embodiments, the composition may further comprise one or more additional surfactants that are not polyoxyl oils (e.g., polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or combinations thereof). In some embodiments, the surfactant may be present in an amount of about 0% to about 10% by weight of the composition (e.g., about 0.001% to about 10% (w / w), about 0.05% to about 5% (w / w), about 0.01% to about 1.0% (w / w), or about 0.1% to about 0.5% (w / w)). In some embodiments, the surfactant may be present in an amount of about 0.5% (w / w). In some embodiments, the polyoxyl oil may be present in an amount of about 0% to about 10% by weight of the composition (e.g., about 0.001% to about 10% (w / w), about 0.05% to about 5% (w / w), about 0.01% to about 1.0% (w / w), or about 0.1% to about 0.5% (w / w)). In some embodiments, the polyoxyl oil may be present in an amount of about 0.5% (w / w). In some such embodiments, the second surfactant may be present in an amount of about 0% to about 10% by weight of the composition (e.g., about 0.001% to about 10% (w / w), about 0.05% to about 5% (w / w), about 0.01% to about 1.0% (w / w), or about 0.1% to about 0.5% (w / w)). In some embodiments, the second surfactant may be present in an amount of about 0.5% (w / w).

[0062] In some embodiments, the composition may contain an isotonic agent such as sodium chloride, glycerin, mannitol, potassium chloride, erythritol, and combinations thereof, in an amount sufficient to maintain the molar osmotic pressure concentration in the range of 250–400 mOsm / kg (e.g., about 250–about 300 mOsm / kg or about 300–about 400 mOsm / kg). In some embodiments, the isotonic agent may include glycerin. In some embodiments, the isotonic agent may be present in an amount of about 0–about 10% by weight of the composition (e.g., about 0%–about 3%, about 0.1%–about 10% (w / w), about 0.01%–about 1% (w / w), or about 0.05%–about 0.5% (w / w)). In some embodiments, the isotonic agent may be present in an amount of about 0.1% (w / w).

[0063] In some embodiments, the composition may contain antioxidants such as disodium edetate, dibutylhydroxytoluene, citric acid, sodium metabisulfite, tocopherol acetate, and combinations thereof. In some embodiments, the antioxidant may be selected from the group consisting of disodium edetate, citric acid, and combinations thereof. In some embodiments, the antioxidant may be present in an amount of about 0 to about 1% by weight of the composition (e.g., about 0.01% to about 1.0% (w / w) or about 0.05% to about 0.5% (w / w)). In some embodiments, the antioxidant may be present in an amount of about 0.115% (w / w). In some embodiments, the antioxidant may include disodium EDTA, which may be present in an amount of about 0.01% to about 1.0% (w / w), about 0.05% to about 0.5% (w / w), or about 0.1% (w / w). In some embodiments, the antioxidant may include citric acid, which may be present in an amount of about 0.001% to about 0.1% (w / w), 0.005% to about 0.05% (w / w), or about 0.015% (w / w).

[0064] In some embodiments, the composition may contain one or more buffers. Preferred buffers include, but are not limited to, phosphates, citrates, acetates, borates, and combinations thereof. In some embodiments, the buffer may be selected from the group consisting of sodium citrate dihydrate, sodium citrate, sodium phosphate monobasic monohydrate, sodium phosphate monohydrate, sodium phosphate dibasic heptahydrate, boric acid, and combinations thereof. In some embodiments, the buffer may be selected from the group consisting of sodium citrate dihydrate, sodium citrate, and combinations thereof. In some embodiments, the buffer may be selected from the group consisting of sodium citrate dihydrate, sodium citrate, or combinations thereof. The amount of buffer components used is sufficient to maintain the pH of the composition in the range of about 4 to about 8 (e.g., about 5.0 to about 7.0, or about 5.5 to about 6.5) throughout the shelf life of the product. In certain embodiments, the buffer is present in an amount of about 0 to about 2.0% by weight of the composition (e.g., about 0.01% to about 1.0% (w / w) or about 0.03% to about 0.06% (w / w)). In some embodiments, the buffer is present in an amount of about 0.045% (w / w).

[0065] In some embodiments, the composition may contain a thickening agent or viscosity modifier. In some embodiments, the viscosity modifier may be selected from carbomer, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose (e.g., HPMC with an average methoxyl group content of about 29% and an average hydroxypropyl group content of about 10%), polyvinyl alcohol, xanthan gum, and combinations thereof. In some embodiments, the thickening agent may be hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or a combination thereof. In some embodiments, the viscosity modifier may be present in an amount of about 0% to about 3% by weight of the composition (e.g., about 0.01% to about 1.0% (w / w) or about 0.05% to about 0.5% (w / w)). In some embodiments, the thickening agent may be present in an amount of about 0.1% (w / w).

[0066] In some embodiments, the composition may contain a solubilizer or solubility enhancer. In some embodiments, the solubilizer may be a cyclic oligosaccharide. In some embodiments, the solubilizer or solubility enhancer may be selected from cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (sometimes called HPBCD or HP-β-CD), 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. In some embodiments, the solubilizer may contain 2-hydroxypropyl-β-cyclodextrin. In some embodiments, the solubilizer or solubility enhancer may be present in an amount of about 0% to about 20% by weight of the composition (e.g., about 1% to about 20% (w / w), about 5% to about 15% (w / w), or about 8% to about 12% (w / w)). In some embodiments, the solubilizer or solubility enhancer may be present in an amount of about 10% (w / w).

[0067] In some embodiments, the composition may be administered topically in the form of eye drops, creams, ointments, films, suspensions, gels, etc. In some embodiments, the composition may be administered to one or both eyes of the subject.

[0068] The compositions of or used herein may contain one or more other components in amounts effective to provide one or more useful properties and / or benefits. For example, the compositions may not contain substantially any added preservative components, but in other embodiments, the compositions may contain effective amounts of preservative components. Examples of such preservative components include, but are not limited to, stable oxychloro complexes (e.g., PURITE®), quaternary ammonium preservatives such as benzalkonium chloride ("BAC" or "BAK"), sorbic acid, and polyoxomers; biguanide biganide preservatives such as polyhexamethylene biguanide biguanzide (PHMB); methylparaben and ethylparaben; hexetidine; chlorite components such as stable chlorine dioxide and metal chlorites; and other intraocularly acceptable preservatives and mixtures thereof. Where preservative components are present in the compositions, their concentration is effective in preserving the composition and is often and commonly used in the range of about 0% to about 2.0% of the volume of the composition.

[0069] Typically, the remainder of the compositions described herein is water.

[0070] In some embodiments, this specification provides compositions with various combinations of components. Exemplary compositions are shown in Table A.

[0071] (Table A) TIFF0007880912000002.tif104166

[0072] The compositions provided herein may have additional components. Exemplary additional components are shown in Table B. Each combination of Table A and Table B is explicitly assumed (e.g., A1B1, A2B1, A3B1, A1B2, A2B2, A3B2, A1B3, A2B3, and A3B3).

[0073] (Table B) TIFF0007880912000003.tif104166

[0074] This specification also provides methods for preparing compositions (e.g., emulsions). In some embodiments, the composition may be any of the compositions described herein.

[0075] In some embodiments, the method may include the steps of dissolving the multikinase inhibitor in a first emulsion, reducing the droplet size of the first emulsion to form a nanoemulsion, and filtering the nanoemulsion. In some embodiments, the step of dissolving the multikinase inhibitor may include high shear mixing. In some embodiments, the method may include the steps of forming a first emulsion, reducing the droplet size of the first emulsion to form a nanoemulsion, dissolving the multikinase inhibitor in a solution, combining the nanoemulsion with the solution to form a nanoemulsion containing the multikinase inhibitor, and optionally filtering the nanoemulsion containing the multikinase inhibitor. In some embodiments, dissolving the multikinase inhibitor in a solution may include dissolving the multikinase inhibitor in a solution containing a solubilizer (e.g., any solubilizer described herein). In some embodiments, the solution may further include a buffer (e.g., sodium citrate), an antioxidant (e.g., citrate and / or trisodium EDTA), a thickener (e.g., HPMC), or a combination thereof.

[0076] In some embodiments, the step of reducing droplet size may include using a microfluidizer. The step of filtering the nanoemulsion may be performed using any suitable filter (e.g., a 0.2 micron filter). In some embodiments, the method may include filling the filtered nanoemulsion into sterile eye drop bottles. Non-limiting examples of sterile eye drop bottles include preservative-free multi-dose (MDPF) containers or low-density polyethylene (LDPE) unit-dose containers. In some embodiments, the first emulsion may comprise polyoxyl oil, a lipophilic carrier, and water. In some embodiments, the first emulsion may further comprise a surfactant. In some embodiments, the first emulsion may further comprise a solubilizer. In some embodiments, the first emulsion may comprise one or more thickeners, buffers, isotonic agents, antioxidants, and combinations thereof.

[0077] The frequency, duration, and amount of administration are determined by the prescribing physician. Dosage may vary depending on the formulation. The frequency of administration may be once or multiple times daily (e.g., once, twice, three times, or four or more times daily), every other week (e.g., every two weeks, or twice a week), and / or monthly. The duration of administration may continue until the eye condition to be treated is resolved, i.e., until one or more symptoms of the eye condition are in remission, reduced, or resolved. In some embodiments, the compositions described herein may be administered for hours, days, weeks, months, or years.

[0078] Symptoms are considered alleviated or in remission when they are prevented, reduced, or eliminated. In patients who typically experience specific symptoms of an eye condition, the symptoms are prevented, and the patient does not experience the onset of those symptoms after administration of the disclosed composition. Symptom reduction is considered achieved when the severity or duration of one or more symptoms associated with the patient's eye condition is reduced by 5%, 10%, 20%, 50%, 75%, 90%, or more. Elimination of one or more symptoms associated with an eye condition is achieved when they are absent or substantially absent in the patient. In some embodiments, elimination of one or more symptoms associated with an eye condition is achieved when one or more symptoms are absent by 90% or more.

[0079] Unless otherwise specified, all numbers used in this specification and the claims to represent quantities of components, molecular weights, and other properties, reaction conditions, etc., should be understood to be modified in all cases with the term "approximately." Therefore, unless specifically denied, the numerical parameters described herein and in the appended claims are approximations and may vary depending on the desired attributes sought by the present invention. At a minimum, but without attempting to limit the principle of equivalence with the claims of this application, each numerical parameter should be interpreted in light of the reported significant figures and the number to which ordinary rounding techniques are applied. While the numerical ranges and parameters describing the broad scope of the present invention are approximations, the numerical values ​​reported in specific examples are as accurate as possible. Nevertheless, every numerical value inherently contains some error, which is inherent in the standard deviation found in each test measurement. Descriptions of numerical ranges with two ends include all numbers within that range (for example, 1-5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0080] In the context describing this invention, “a,” “an,” “the,” and similar expressions should be interpreted as covering both singular and plural forms unless otherwise specified herein or unless the context clearly contradicts the usage. Descriptions of value ranges herein are merely abbreviations referring individually to each value within that range.

[0081] Unless otherwise specified herein, individual values ​​are incorporated herein as if they were described herein individually. All methods described herein may be performed in any preferred order unless otherwise specified herein or unless it is clearly inconsistent with the context. All examples or illustrative expressions provided herein (e.g., “e.g., “etc.”) are for illustrative purposes only and do not limit the scope of the claimed invention. No expression herein should be construed as referring to an unclaimed element essential to the practice of the invention. The group of alternative elements or embodiments of the invention disclosed herein should not be construed as limiting. Members of each group may be referred to and claimed individually or in any combination with other members of the group or other elements herein. It is conceivable that one or more members of a group may be included in or excluded from a group for convenience and / or patentable reasons.

[0082] Specific aspects of the present invention are described herein. Naturally, variations of these described aspects will be apparent to those skilled in the art upon reading the above specification. The inventors expect that those skilled in the art will use such variations as appropriate, and that the present invention will be practiced beyond the specific descriptions herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter described in the appended claims, as permitted by applicable law. Furthermore, unless otherwise specifically stated herein, or unless it is clearly inconsistent with the context, any combination of any possible variations of the elements described above is incorporated into the present invention.

[0083] The present invention is not limited to the precision shown in the illustrations and description. Specific embodiments disclosed herein may be further limited in the claims using the expressions "consisting of" or "essentially consisting of." Where used in a claim, whether at the time of filing or added by amendment, the transitional phrase "consisting of" excludes elements, processes, or components not described in the claim. The transitional phrase "essentially consisting of" limits the scope of the claim to the described material or process, and to such an extent that it does not materially affect the basic and novel features. Such claimed embodiments of the invention are essentially or expressly described and enabled herein.

[0084] The embodiments of the present invention disclosed herein should be understood as illustrative of the principles of the invention. Other modifications that may be used are also within the scope of the invention. Therefore, alternative configurations of the invention can be used in accordance with the disclosure herein, not as examples but as examples.

[0085] Exemplary examples Embodiment 1 is, Therapeutic doses of multikinase inhibitors; Polyoxyl oil; Lipophilic carrier; and water It is an emulsion containing [the specified ingredient]. Embodiment 2 is the emulsion of Embodiment 1, wherein the emulsion is a nanoemulsion. Embodiment 3 is an emulsion of any one of Embodiments 1 to 2, wherein the multikinase inhibitor is afatinib, amvatinib, axitinib, cabozantinib, canertinib, cedilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, ide The following are selected from larisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. Embodiment 4 is the emulsion of Embodiment 3, wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. Embodiment 5 is the emulsion of Embodiment 3, wherein the multi-kinase inhibitor is axitinib. Embodiment 6 is the emulsion of Embodiment 3, wherein the multi-kinase inhibitor is nintedanib. Embodiment 7 is the emulsion of Embodiment 3, wherein the multi-kinase inhibitor is pazopanib. Embodiment 8 is an emulsion according to any one of Embodiments 1 to 7, further comprising a solubilizing agent. Embodiment 9 is an emulsion according to any one of Embodiments 1 to 8, wherein the solubilizer is a cyclic polysaccharide. Embodiment 10 is an emulsion of Embodiment 4, wherein the cyclic polysaccharide is selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. Embodiment 11 is an emulsion according to any one of Embodiments 1 to 10, wherein the polyoxyl oil is polyoxyl castor oil. Embodiment 12 is the emulsion of Embodiment 11, wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. Embodiment 13 is an emulsion according to any one of Embodiments 1 to 12, wherein the lipophilic carrier is selected from the group consisting of castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. Embodiment 14 is an emulsion according to any one of Embodiments 1 to 13, further comprising a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof. Embodiment 15 is the emulsion of Embodiment 1, wherein the multikinase inhibitor is nintedanib, the solubilizer is 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier is castor oil, and the polyoxyl oil is polyoxyl-35 castor oil, or a combination thereof. Embodiment 16 is an emulsion according to any one of Embodiments 1 to 15, wherein the multikinase inhibitor is present in an amount of approximately 0.001% w / w to approximately 10.0% w / w. Embodiment 17 is the emulsion of Embodiment 16, wherein the multi-kinase inhibitor is present in an amount of approximately 0.01% to approximately 1% w / w. Embodiment 18 is an emulsion of Embodiment 16, wherein the multi-kinase inhibitor is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 19 is an emulsion according to any one of Embodiments 1 to 14, wherein the multikinase inhibitor is nintedanib, and nintedanib is present in an amount of approximately 0.01% w / w to approximately 10.0% w / w. Embodiment 20 is an emulsion of Embodiment 19, in which nintedanib is present in an amount of approximately 0.01% to approximately 1% w / w. Embodiment 21 is an emulsion of Embodiment 19, in which nintedanib is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 22 is an emulsion according to any one of Embodiments 1 to 14, wherein the multikinase inhibitor is axitinib, and axitinib is present in the emulsion in an amount of approximately 0.001% w / w to approximately 10.0% w / w. Embodiment 23 is the emulsion of Embodiment 22, in which axitinib is present in an amount of approximately 0.01% to approximately 1% w / w. Embodiment 24 is the emulsion of Embodiment 22, in which axitinib is present in an amount of approximately 0.05% to approximately 0.5% w / w. Embodiment 25 is an emulsion according to any one of Embodiments 1 to 14, wherein the multikinase inhibitor is pazopanib, and pazopanib is present in an amount of approximately 0.01% w / w to approximately 10.0% w / w. Embodiment 26 is an emulsion of Embodiment 25, in which pazopanib is present in an amount of approximately 0.01% to approximately 1% w / w. Embodiment 27 is the emulsion of Embodiment 25, in which pazopanib is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 28 is an emulsion according to any one of Embodiments 1 to 27, wherein the lipophilic carrier is present in an amount of approximately 0.01% w / w to approximately 5.0% w / w. Embodiment 29 is the emulsion of Embodiment 28, wherein the lipophilic carrier is present in an amount of approximately 0.05% to approximately 1% w / w. Embodiment 30 is the emulsion of Embodiment 28, wherein the lipophilic carrier is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 31 is an emulsion according to any one of Embodiments 1 to 30, wherein polyoxyl oil is present in an amount of approximately 0.01% w / w to approximately 10% w / w. Embodiment 32 is an emulsion of Embodiment 31, wherein polyoxyl oil is present in an amount of approximately 0.05% to approximately 1% w / w. Embodiment 33 is the emulsion of Embodiment 31, wherein polyoxyl oil is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 34 is an emulsion according to any one of Embodiments 1 to 33, further comprising a solubilizer, the solubilizer present in the emulsion in an amount of about 1% w / w to about 20% w / w. Embodiment 35 is the emulsion of Embodiment 34, wherein the solubilizer is present in an amount of approximately 5% to approximately 15% w / w. Embodiment 36 is the emulsion of Embodiment 34, wherein the solubilizer is present in an amount of approximately 8% to approximately 12% w / w. Embodiment 37 is an emulsion according to any one of Embodiments 1 to 36, further comprising additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, and combinations thereof. Embodiment 38 is the emulsion of Embodiment 37, wherein the thickener is selected from the group consisting of carbomer, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, xanthan gum, and combinations thereof. Embodiment 39 is the emulsion of Embodiment 38, wherein the thickener is hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or a combination thereof. Embodiment 40 is an emulsion according to any one of Embodiments 37 to 39, wherein the thickening agent is present in an amount of about 0.01% w / w to about 1.0% w / w. Embodiment 41 is an emulsion according to any one of Embodiments 37 to 39, wherein the thickening agent is present in an amount of about 0.05% w / w to about 0.5% w / w. Embodiment 42 is an emulsion according to any one of Embodiments 37 to 41, wherein the buffer is selected from the group consisting of phosphates, citrates, acetates, borates, and combinations thereof. Embodiment 43 is an emulsion according to any one of Embodiments 37 to 42, wherein the buffer is selected from the group consisting of sodium citrate dihydrate, sodium citrate, sodium phosphate monobasic monohydrate, monosodium phosphate monohydrate, sodium phosphate dibasic heptahydrate, boric acid, and combinations thereof. Embodiment 44 is an emulsion according to any one of Embodiments 37 to 43, wherein the buffer is selected from the group consisting of sodium citrate dihydrate, sodium citrate, or a combination thereof. Embodiment 45 is an emulsion according to any one of Embodiments 37 to 44, wherein the buffer is present in the emulsion in an amount sufficient to maintain the pH in the range of 4.0 to 8.0. Embodiment 46 is an emulsion according to any one of Embodiments 37 to 44, wherein the buffer is present in the emulsion in an amount sufficient to maintain the pH in the range of about 5.5 to about 6.5. Embodiment 47 is an emulsion according to any one of Embodiments 37 to 46, wherein the buffer is present in an amount of approximately 0.01% w / w to approximately 1.0% w / w. Embodiment 48 is an emulsion according to any one of Embodiments 37 to 46, wherein the buffer is present in an amount of approximately 0.03% w / w to approximately 0.06% w / w. Embodiment 49 is an emulsion according to any one of Embodiments 37 to 48, wherein the antioxidant is selected from the group consisting of disodium edetate, dibutylhydroxytoluene, citric acid, sodium metabisulfite, tocopherol acetate, and combinations thereof. Embodiment 50 is an emulsion according to any one of Embodiments 37 to 48, wherein the antioxidant is selected from the group consisting of disodium edetate, citric acid, and combinations thereof. Embodiment 51 is an emulsion according to any one of Embodiments 37 to 50, wherein the antioxidant is present in an amount of approximately 0.01% to approximately 1.0% w / w. Embodiment 52 is an emulsion according to any one of Embodiments 37 to 50, wherein the antioxidant is present in an amount of approximately 0.05% to approximately 0.5% w / w. Embodiment 53 is an emulsion according to any one of Embodiments 37 to 52, wherein the antioxidant contains disodium edetate, and the disodium edetate is present in an amount of approximately 0.01% w / w to approximately 1.0% w / w. Embodiment 54 is an emulsion according to any one of Embodiments 37 to 52, wherein the antioxidant contains disodium edetate, and the disodium edetate is present in an amount of approximately 0.05% w / w to approximately 0.5% w / w. Embodiment 55 is an emulsion according to any one of Embodiments 37 to 54, wherein the antioxidant g contains citric acid, and the citric acid is present in an amount of approximately 0.001% to approximately 0.1% w / w. Embodiment 56 is an emulsion according to any one of Embodiments 37 to 54, wherein the antioxidant is citric acid, and the citric acid is present in an amount of approximately 0.005% to approximately 0.05% w / w. Embodiment 57 is an emulsion according to any one of embodiments 37 to 56, wherein the isotonic agent is selected from the group consisting of sodium chloride, glycerin, mannitol, potassium chloride, erythritol, and combinations thereof. Embodiment 58 is an emulsion according to any one of embodiments 37 to 56, wherein the isotonic agent is glycerin. Embodiment 59 is an emulsion according to any one of Embodiments 37 to 58, wherein the isotonic agent is present in an amount of about 0.1% w / w to about 10% w / w. Embodiment 60 is an emulsion according to any one of Embodiments 37 to 58, wherein the isotonic agent is present in an amount of about 0.01% w / w to about 1% w / w. Embodiment 61 is an emulsion according to any one of Embodiments 37 to 58, wherein the isotonic agent is present in an amount of about 0.05% w / w to about 0.5% w / w. Embodiment 62 is an emulsion according to any one of Embodiments 37 to 61, wherein the isotonic agent is present in an amount sufficient to maintain the molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg. Embodiment 63 is an emulsion according to any one of Embodiments 1 to 62, wherein the emulsion further contains a preservative. Embodiment 64 is the emulsion of Embodiment 63, wherein the preservative is selected from the group consisting of benzalkonium chloride (BAK), polyhexamethylene biguanide biguanzide (PHMB), stable oxychloro complex, sorbic acid, and combinations thereof. Embodiment 65 is an emulsion according to any one of Embodiments 1 to 64, wherein the emulsion does not contain a preservative. Embodiment 66 is an emulsion according to any one of Embodiments 1 to 65, wherein the emulsion has an average droplet size of about 10 nm to 100,000 nm. Embodiment 67 is an emulsion according to any one of Embodiments 1 to 66, wherein the emulsion has an average droplet size of 200 nm or less. Embodiment 68 is an emulsion according to any one of Embodiments 1 to 67, wherein the emulsion remains stable at 25°C for at least 6 months. Embodiment 69 is an emulsion according to any one of Embodiments 1 to 68, wherein the emulsion remains stable at 25°C for at least 12 months. Embodiment 70 is an emulsion according to any one of Embodiments 1 to 69, wherein the emulsion remains stable at 25°C for at least 24 months. Embodiment 71 is an emulsion according to any one of Embodiments 1 to 70, wherein the emulsion is formulated as eye drops, creams, gels, ointments, and films. Embodiment 72 is, Approximately 0.005% to 2% w / w multi-kinase inhibitors; Approximately 0.1% to 1% w / w polyoxyl oil; Approximately 0.05% to 1% w / w lipophilic carrier; Approximately 5% to approximately 15% w / w solubilizer; and water It is an emulsion containing [the specified ingredient]. Embodiment 73 is an emulsion of Embodiment 72, wherein the multi-kinase inhibitor is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 74 is an emulsion of any one of Embodiments 72 to 73, wherein polyoxyl oil is present in an amount of approximately 0.3% to approximately 0.7% w / w. Embodiment 75 is an emulsion according to any one of Embodiments 72 to 74, wherein the lipophilic carrier is present in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 76 is an emulsion according to any one of Embodiments 72 to 75, wherein the solubilizer is present in an amount of about 8% to about 12% w / w. Embodiment 77 is, Approximately 0.1% to 0.5% w / w multi-kinase inhibitors; Approximately 0.3% to 0.7% w / w polyoxyl oil; Approximately 0.1% to 0.5% w / w lipophilic carrier; Approximately 8% to approximately 12% w / w solubilizer; and water It is an emulsion containing [the specified ingredient]. Embodiment 78 is an emulsion according to any one of embodiments 72 to 77, wherein the multikinase inhibitor is present in an amount of approximately 0.2% w / w. Embodiment 79 is an emulsion according to any one of Embodiments 72 to 78, wherein polyoxyl oil is present in an amount of approximately 0.5% w / w. Embodiment 80 is an emulsion according to any one of Embodiments 72 to 79, wherein the lipophilic carrier is present in an amount of approximately 0.25% w / w. Embodiment 81 is an emulsion according to any one of Embodiments 72 to 80, wherein the solubilizer is present in an amount of about 10% w / w. Embodiment 82 is, Approximately 0.2% w / w multi-kinase inhibitor; Approximately 0.5% w / w polyoxyl oil; Approximately 0.25% w / w lipophilic carrier; Approximately 10% w / w solubilizer; and water It is an emulsion containing [the specified ingredient]. Embodiment 83 is an emulsion of any one of embodiments 72 to 83, wherein the multikinase inhibitor is afatinib, amvatinib, axitinib, cabozantinib, canertinib, cejilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idela The following are selected from the group consisting of lisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or combinations thereof. Embodiment 84 is an emulsion according to any one of embodiments 72 to 83, wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. Embodiment 85 is an emulsion according to any one of embodiments 72 to 83, wherein the multi-kinase inhibitor is axitinib. Embodiment 86 is an emulsion according to any one of embodiments 72 to 83, wherein the multi-kinase inhibitor is nintedanib. Embodiment 87 is an emulsion according to any one of embodiments 72 to 83, wherein the multikinase inhibitor is pazopanib. Embodiment 88 is an emulsion according to any one of Embodiments 72 to 87, wherein the solubilizer is a cyclic polysaccharide. Embodiment 89 is an emulsion of Embodiment 88, wherein the cyclic polysaccharide is selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. Embodiment 90 is an emulsion according to any one of Embodiments 72 to 89, wherein the solubilizer comprises 2-hydroxypropyl-β-cyclodextrin. Embodiment 91 is an emulsion according to any one of Embodiments 72 to 90, wherein the polyoxyl oil is polyoxyl castor oil. Embodiment 92 is the emulsion of Embodiment 91, wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. Embodiment 93 is an emulsion according to any one of Embodiments 72 to 92, wherein the lipophilic carrier is selected from the group consisting of castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. Embodiment 94 is an emulsion according to any one of Embodiments 72 to 93, wherein the lipophilic carrier contains castor oil. Embodiment 95 is an emulsion according to any one of embodiments 72 to 94, further comprising a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof. Embodiment 96 is an emulsion of Embodiment 95, wherein the surfactant is present in an amount of approximately 0.05% to approximately 5% w / w. Embodiment 97 is an emulsion of Embodiment 95, wherein the surfactant is present in an amount of approximately 0.1% to approximately 1% w / w. Embodiment 98 is an emulsion of Embodiment 95, wherein the surfactant is present in an amount of approximately 0.5% w / w. Embodiment 99 is an emulsion according to any one of Embodiments 72 to 98, further comprising additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, and combinations thereof. Embodiment 100 is the emulsion of Embodiment 99, wherein the thickener comprises hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or a combination thereof. Embodiment 101 is an emulsion according to any one of Embodiments 99 to 100, wherein the thickening agent is present in an amount of about 0.01% w / w to about 1.0% w / w. Embodiment 102 is an emulsion according to any one of Embodiments 99 to 100, wherein the thickening agent is present in an amount of about 0.05% w / w to about 0.5% w / w. Embodiment 103 is an emulsion according to any one of Embodiments 99 to 100, wherein the thickening agent is present in an amount of approximately 0.1% w / w. Embodiment 104 is an emulsion according to any one of Embodiments 99 to 103, wherein the buffer contains sodium citrate. Embodiment 105 is an emulsion according to any one of Embodiments 99 to 104, wherein the buffer is present in the emulsion in an amount sufficient to maintain the pH in the range of about 5.5 to about 6.5. Embodiment 106 is an emulsion according to any one of Embodiments 99 to 105, wherein the buffer is present in an amount of approximately 0.01% w / w to approximately 1.0% w / w. Embodiment 107 is an emulsion according to any one of Embodiments 99 to 105, wherein the buffer is present in an amount of approximately 0.03% w / w to approximately 0.06% w / w. Embodiment 108 is an emulsion according to any one of Embodiments 99 to 105, wherein the buffer is present in an amount of approximately 0.045% w / w. Embodiment 109 is an emulsion according to any one of embodiments 99 to 108, wherein the antioxidant comprises disodium edetate, citric acid, or a combination thereof. Embodiment 110 is an emulsion according to any one of Embodiments 99 to 109, wherein the antioxidant comprises disodium edetate, and the disodium edetate is present in an amount of approximately 0.01% w / w to approximately 1.0% w / w. Embodiment 111 is an emulsion according to any one of Embodiments 99 to 109, wherein the antioxidant comprises disodium edetate, and the disodium edetate is present in an amount of approximately 0.05% w / w to approximately 0.5% w / w. Embodiment 112 is an emulsion according to any one of Embodiments 99 to 109, wherein the antioxidant comprises disodium edetate, and the disodium edetate is present in an amount of approximately 0.1% w / w. Embodiment 113 is an emulsion according to any one of Embodiments 99 to 112, wherein the antioxidant is citric acid, and the citric acid is present in an amount of approximately 0.001% to approximately 0.1% w / w. Embodiment 114 is an emulsion according to any one of Embodiments 99 to 112, wherein the antioxidant is citric acid, and the citric acid is present in an amount of approximately 0.005% to approximately 0.05% w / w. Embodiment 115 is an emulsion according to any one of Embodiments 99 to 112, wherein the antioxidant is citric acid, and the citric acid is present in an amount of approximately 0.015%. Embodiment 116 is an emulsion according to any one of embodiments 99 to 115, wherein the isotonic agent is glycerin. Embodiment 117 is an emulsion according to any one of Embodiments 99 to 116, wherein the isotonic agent is present in an amount of about 0.01% w / w to about 1% w / w. Embodiment 118 is an emulsion according to any one of Embodiments 99 to 116, wherein the isotonic agent is present in an amount of about 0.05% w / w to about 0.5% w / w. Embodiment 119 is an emulsion according to any one of embodiments 99 to 116, wherein the isotonic agent is present in an amount of approximately 0.1% w / w. Embodiment 120 is, A multi-kinase inhibitor selected from the group consisting of nintedanib, axitinib, and pazopanib, at a concentration of approximately 0.2% w / w; Approximately 0.5% w / w polyoxyl castor oil; Approximately 0.25% w / w castor oil; Approximately 10% w / w 2-hydroxypropyl-β-cyclodextrin; and water It is an emulsion containing [the specified ingredient]. Embodiment 121 is an emulsion of Embodiment 120, wherein the multi-kinase inhibitor is axitinib. Embodiment 122 is an emulsion of Embodiment 120, wherein the multi-kinase inhibitor is nintedanib. Embodiment 123 is an emulsion of Embodiment 120, wherein the multi-kinase inhibitor is pazopanib. Embodiment 124 is an emulsion of any one of embodiments 120 to 123, wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. Embodiment 125 is an emulsion according to any one of Embodiments 116 to 124, further comprising polysorbate 80 in an amount of about 0.5% w / w. Embodiment 126 is an emulsion according to any one of Embodiments 120 to 125, further comprising hydroxypropyl methylcellulose in an amount of about 0.1% w / w. Embodiment 127 is an emulsion according to any one of Embodiments 120 to 126, further comprising sodium citrate in an amount of about 0.045% w / w. Embodiment 128 is an emulsion according to any one of Embodiments 120 to 127, further comprising disodium edetate in an amount of about 0.1% w / w. Embodiment 129 is an emulsion according to any one of Embodiments 120 to 128, further comprising citric acid in an amount of about 0.015%. Embodiment 130 is an emulsion according to any one of Embodiments 120 to 129, further comprising glycerin in an amount of about 0.1% w / w. Embodiment 131 is a method for prolonging the residence time of a multi-kinase inhibitor on the surface of the eyeball, comprising the step of administering one emulsion of any one of Embodiments 1 to 130 to the target eye. Embodiment 132 is the method of Embodiment 131, wherein the administration step includes applying the emulsion to the eye at least once a day. Embodiment 133 is the method of Embodiment 131, wherein the administration step includes applying the emulsion to the eyes at least twice a day. Embodiment 134 is the method of Embodiment 131, wherein the administration step includes applying the emulsion to the eyes at least three times a day. Embodiment 135 is a method for treating an eye condition, comprising the step of administering one of the emulsions of Embodiments 1 to 130 to the eye of the subject. Embodiment 136 is the method of Embodiment 135, wherein the condition of the eye is related to angiogenesis. Embodiment 137 is the method of Embodiment 135, wherein the eye condition is selected from the group consisting of conjunctivitis, neovascularization, pterygium, pinguecula, glaucoma filtration surgery and minimally invasive glaucoma surgery (MIGS), corneal transplant surgery with graft rejection, graft-versus-host disease, dry eye disease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, Stevens-Johnson syndrome, viral infection (e.g., HSV-1), bacterial infection, fungal infection, parasitic infection, neovascularization due to contact lenses, ulcers, alkaline burns, and stem cell deficiency. Embodiment 138 is one of the methods of Embodiments 131 to 137, wherein the emulsion remains stable at 40°C for at least one month. Embodiment 139 is one of the methods of Embodiments 131 to 137, wherein the emulsion remains stable at 40°C for at least 6 months. Embodiment 140 is a method for preparing any one emulsion of Embodiments 1 to 130, The first step in forming the emulsion; A step in which the droplet size of the first emulsion is reduced to form a nanoemulsion; The step of dissolving the multi-kinase inhibitor in a solution; The steps of combining a nanoemulsion with the solution to form a nanoemulsion containing a multi-kinase inhibitor; and Optionally, a step of filtering the nanoemulsion containing the multi-kinase inhibitor. Includes. Embodiment 141 is a method for preparing an emulsion, The first step in forming the emulsion; A step in which the droplet size of the first emulsion is reduced to form a nanoemulsion; The step of dissolving the multi-kinase inhibitor in a solution; The steps of combining a nanoemulsion with the solution to form a nanoemulsion containing a multi-kinase inhibitor; and Optionally, a step of filtering the nanoemulsion containing the multi-kinase inhibitor. Includes. Embodiment 142 is the method of Embodiment 140 or 141, wherein the step of forming the first emulsion includes high shear mixing. Embodiment 143 is one of the methods of Embodiments 140 to 142, wherein the step of reducing the droplet size includes using a microfluidizer. Embodiment 144 is one of the methods described in Embodiments 140 to 143, wherein the filtration step includes using a 0.2 micron filter. Embodiment 145 is any one of embodiments 140 to 144, the method further comprising filling a filtered nanoemulsion into a sterile eye drop bottle. Embodiment 146 is the method of Embodiment 145, wherein the sterile eye drop bottle is a preservative-free multi-dose (MDPF) container or a low-density polyethylene (LDPE) unit dose container. Embodiment 147 is one of the methods of Embodiments 140 to 146, wherein the first emulsion is Polyoxyl oil: Lipophilic carriers; and water Includes. Embodiment 148 is one of the methods of Embodiments 140 to 147, wherein the multikinase inhibitor is afatinib, amvatinib, axitinib, cabozantinib, canertinib, cedilanib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, i The following are selected from delarisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tanzutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, vemurafenib, or a combination thereof. Embodiment 149 is the method of Embodiment 148, wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. Embodiment 150 is the method of Embodiment 148, wherein the multi-kinase inhibitor is axitinib. Embodiment 151 is the method of Embodiment 148, wherein the multi-kinase inhibitor is nintedanib. Embodiment 152 is the method of Embodiment 148, wherein the multi-kinase inhibitor is pazopanib. Embodiment 153 is one of the methods of Embodiments 140 to 152, wherein the solution further comprises a solubilizer. Embodiment 154 is the method of Embodiment 153, wherein the solubilizer is a cyclic polysaccharide. Embodiment 155 is the method of Embodiment 154, wherein the cyclic polysaccharide is selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof. Embodiment 156 is one of the methods of Embodiments 147 to 155, wherein the polyoxyl oil is polyoxyl castor oil. Embodiment 157 is the emulsion of Embodiment 156, wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. Embodiment 158 ​​is one of the methods of Embodiments 147 to 157, wherein the lipophilic carrier is selected from the group consisting of castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic / capric triglycerides, medium-chain triglycerides, and combinations thereof. Embodiment 159 is one of the methods of Embodiments 147 to 158, wherein the first emulsion further comprises a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof. Embodiment 160 is one of the methods of Embodiments 147 to 159, wherein the multikinase inhibitor is nintedanib, the solubilizer is 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier is castor oil, and the polyoxyl oil is polyoxyl-35 castor oil, or a combination thereof. Embodiment 161 is one of the methods of Embodiments 140 to 160, wherein the multikinase inhibitor is present in the first emulsion in an amount of approximately 0.001% w / w to approximately 10.0% w / w. Embodiment 162 is the method of Embodiment 161, wherein the multi-kinase inhibitor is present in the first emulsion in an amount of approximately 0.01% to approximately 1% w / w. Embodiment 163 is the method of Embodiment 161, wherein the multikinase inhibitor is present in the first emulsion in an amount of approximately 0.1% to approximately 0.5% w / w. Embodiment 164 is one of the methods described in Embodiments 147 to 163, wherein the lipophilic carrier is present in the first emulsion in an amount of about 0.01% w / w to about 5.0% w / w. Embodiment 165 is the method of Embodiment 164, wherein the lipophilic carrier is present in the first emulsion in an amount of about 0.05% to about 1% w / w. Embodiment 166 is the method of Embodiment 164, wherein the lipophilic carrier is present in the first emulsion in an amount of about 0.1% to about 0.5% w / w. Embodiment 167 is one of the methods described in Embodiments 147 to 166, wherein the polyoxyl oil is present in the first emulsion in an amount of about 0.01% w / w to about 10% w / w. Embodiment 168 is the method of Embodiment 167, wherein the polyoxyl oil is present in the first emulsion in an amount of about 0.05% to about 1% w / w. Embodiment 169 is the method of Embodiment 167, wherein the polyoxyl oil is present in the first emulsion in an amount of about 0.1% to about 0.5% w / w. Embodiment 170 is one of the methods of Embodiments 140 to 169, wherein the first emulsion further contains a solubilizer, and the solubilizer is present in the first emulsion in an amount of about 1% w / w to about 20% w / w. Embodiment 171 is the method of Embodiment 170, wherein the solubilizer is present in the first emulsion in an amount of about 5% to about 15% w / w. Embodiment 172 is the method of Embodiment 170, wherein the solubilizer is present in the first emulsion in an amount of about 8% to about 12% w / w. Embodiment 173 is one of the methods of Embodiments 147 to 172, wherein the first emulsion further comprises additional components selected from the group consisting of thickeners, buffers, isotonic agents, antioxidants, and combinations thereof. Embodiment 174 is one of the methods of Embodiments 141 to 173, wherein the filtered emulsion is one of the emulsions of Embodiments 1 to 130. [Examples]

[0086] Example 1: Stability of Emulsion Formulation Solution A and emulsion B were prepared and their stability assessed. Solution A: 0.2% nintedanib in a solution system containing 10% 2-hydroxypropyl-β-cyclodextrin. Emulsion B: 0.5% nintedanib in an emulsion system containing 5% 2-hydroxypropyl-β-cyclodextrin, castor oil, polysorbate 80, and polyoxyl-35 castor oil. Stability data under heated conditions (40°C, 50°C, and 60°C) can be used to estimate and predict long-term storage at room temperature. As shown in Table 2, the multi-kinase inhibitor remained stable when stored in emulsion B at 40°C, 50°C, and 60°C, indicating that this formulation system can maintain a shelf life of 2 years or more at room temperature. A typical desirable shelf life at room temperature for topical ophthalmic solutions is 2 years.

[0087] (Table 2) TIFF0007880912000004.tif67166

[0088] Example 2 Synergistic effect on the solubility of nintedanib in an emulsion system of castor oil, polysorbate 80, polyoxyl-35 castor oil, and 2-hydroxypropyl-β-cyclodextrin.

[0089] (Table 3) Maximum solubility of CBT-001 (nintedanib free base) in solvent TIFF0007880912000005.tif134166

[0090] According to the FDA's Industry Drug Stability Guidelines, storing a drug under heated (high-temperature) conditions can predict its long-term storage stability. Stability data under heated conditions can be used to estimate and predict the long-term storage stability of drug products when stored under recommended storage conditions (ideally room temperature).

[0091] The maximum solubility of nintedanib in 10% 2-hydroxypropyl-β-cyclodextrin was approximately 0.2%. This 0.2% nintedanib in 10% 2-hydroxypropyl-β-cyclodextrin was demonstrated to be stable at room temperature for approximately 5 months, after which it did not meet the acceptable stability specification (90% recovery). Under heated storage conditions (40°C), it was unstable on day 4. The recovery rate of nintedanib fell to less than 90% on day 4 and less than 70% on day 7. This indicates that 0.2% nintedanib in this 10% 2-hydroxypropyl-β-cyclodextrin solution may have stability issues when stored for 1-2 years.

[0092] The concentration and stability of nintedanib in the formulation system were improved using a 5% 2-hydroxypropyl-β-cyclodextrin and nanoemulsion system. 0.5% nintedanib in the 5% 2-hydroxypropyl-β-cyclodextrin and nanoemulsion system was demonstrated to be stable when stored at 40°C, 50°C, and 60°C. This indicates that the 5% 2-hydroxypropyl-β-cyclodextrin and nanoemulsion system had a synergistic effect on the stability of nintedanib in the nanoemulsion formulation system.

[0093] Table 3 lists the maximum solubility of nintedanib in each solvent. The theoretically maximum possible solubility of nintedanib in a mixture can be estimated by assuming that nintedanib is dissolved in each solvent and then combining the components to create a mixture of all components. The theoretically maximum possible solubility of nintedanib in the mixture calculated in this way is 2.91 mg / g. Surprisingly, an improved nintedanib solubility of 7.9 mg / g was obtained in a formulation system of 10% 2-hydroxypropyl-β-cyclodextrin, castor oil, 1% polysorbate 80, and 2% polyoxyl-35 castor oil nanoemulsion. This indicates that 10% 2-hydroxypropyl-β-cyclodextrin and the nanoemulsion of castor oil, 1% polysorbate 80, and 2% polyoxyl-35 castor oil had a synergistic effect on the solubility of nintedanib.

[0094] Example 3 The solubilizers for nintedanib were investigated according to the following procedure: 1. 1. Tare measurement of 1.5 mL Eppendorf tubes 2. Add nintedanib and record the weight. 3. Add a solubilizer and record the weight. 4. Add water with pH 5 (except for F3 and F4) and record the weight. 5. Mix with Beadbeater for 120 seconds. 6. Place in a rotary mixer overnight at ambient temperature. 7.0.2 μm filtration with SPIN-X centrifugal filter 8. pH measurement of the filtrate 9. Assay the filtrate using CBT-001 standard solution.

[0095] Despite many of the solubilizers investigated having similar structural properties (see, for example, Tables 4 and 5), the significantly different results obtained for each solubilizer were a surprising finding. The discovery that solubilizers such as castor oil and polysorbate 80 (see, for example, Table 3) exhibited high solubilization performance for nintedanib was particularly remarkable.

[0096] (Table 4) Selected compositions (% wt) TIFF0007880912000006.tif82166

[0097] (Table 5) Solubilities of nintedanib in various solubilizers TIFF0007880912000007.tif69166

[0098] Based on the results of the solubilizing agents, various emulsion systems were identified for investigation. Surprisingly, an emulsion system combining castor oil, polysorbate 80, and polyoxyl-35 castor oil was found to suitably solubilize nintedanib. As shown in Table 6, one emulsion system was surprisingly able to dissolve nintedanib up to approximately 3–5 mg / ml, which is far above the previously calculated theoretical upper limit of solubility of nintedanib in this combination (see Table 3).

[0099] (Table 6) Solubleness of nintedanib in typical emulsion systems TIFF0007880912000008.tif36166

[0100] Example 4 We identified emulsion systems for developing formulations of nintedanib and other multi-kinase inhibitors with similar physicochemical properties.

[0101] Phase separation occurs when oil and water are mixed and left for a period of time; this is a common phenomenon. Formulations that have undergone phase separation are unsuitable for use as certain ophthalmic formulations, such as eye drops. Regarding the potential use of nintedanib and other multi-kinase inhibitors with similar physicochemical properties in the development of ophthalmic formulations, the physical stability and homogeneity of various emulsion systems were investigated. As shown in Table 7, some emulsion systems exhibited phase stability, while others, despite having components with similar properties, were unstable after 3 days, a surprising finding. The reason why some systems are stable while others are unstable remains unclear.

[0102] The physical stability of the emulsion system was investigated using the following procedure: 1. Adjust the pH of 100 mL of water to 5. Tare weight measurement of 2.15 mL tubes 3. Add the ingredients and record the weight. 4. QS with water 5. Mix by vortexing for 1 minute. 6. Mix with high shear until a uniform emulsion is formed. 7. Record the appearance and pH. 8. Dispense each preparation into three 1.5 mL tubes. 9. Store at -20°C, 2-8°C, and 40°C for 3 days. 10. Remove from storage and allow to equilibrate at room temperature. 11. Record the exterior 12. Take only the vehicle, which is a homogeneous single-phase emulsion, and transfer it to a centrifuge. Centrifuge at 13.13K RPM for 10 minutes. 14. Record the exterior 15. pH measurement of a homogeneous single-phase emulsion vehicle

[0103] (Table 7) Results of the stability of various excipient combinations TIFF0007880912000009.tif58166

[0104] Furthermore, we selected emulsion-based F20 as a base system for further formulation development.

[0105] Example 5 In this example, it was determined that a cyclodextrin-based solubilizer system, when mixed with a selected castor oil, polysorbate 80, and polyoxyl-35 castor oil-based emulsion system, is compatible and does not cause crash-out or phase separation. Furthermore, emulsion formulations containing HP-β-CD, castor oil, polysorbate 80, and polyoxyl-35 castor oil were found to achieve superior stability compared to solution formulations. While not bound by any particular theory, it is thought that the interaction between the drug in the complex and all of its components resulted in this superiority over single-component formulations. This remarkable finding was determined by extensive, comprehensive, and sophisticated experiments in which many components were sequentially investigated to select the final combination. Superior compositions were determined after several tests. For example, emulsion C showed very good stability for several months at high temperatures (>40°C), indicating that this formulation would have good stability during long-term storage at room temperature. These results were surprising because the solution formulation had been found to be unstable under the same conditions, and the emulsion formulation, which was investigated earlier, had also been found to be not very stable. As shown in Table 8, after one month at 40°C, only slightly more than half of the nintedanib remained in the solution formulation, while almost all of the nintedanib in emulsion C remained even after six months under the same conditions. Table 8 also surprisingly showed that emulsion C kept nintedanib stable for at least three months even at higher temperatures of 50°C and 60°C. These results were surprising because the solution formulation had been found to be unstable under the same conditions, and after four weeks at 40°C, only slightly more than half of the nintedanib remained in the solution formulation, while all of the nintedanib in emulsion C remained even after six months under the same conditions (Table 8). Similar emulsion systems also demonstrated the potential for long-term stability under room temperature storage conditions, keeping axitinib, another MKI class compound, stable at 40°C, 50°C, and 60°C for at least three months (Table 9).

[0106] Method for developing emulsion formulations The initial development involved designing, preparing, and testing multiple emulsion compositions to evaluate drug solubilization, droplet size, and the physical stability of heated emulsions (size change or aggregation). Each test composition contained basic components such as APIs (e.g., nintedanib), oils, surfactants, solubilizers, emulsifiers, lubricants, isotonic agents, and water. Two to three compositions were selected from the initial work, modified as needed, and evaluated for viscosity, osmotic pressure, and the physical stability of the emulsion. One exemplary composition was selected and further evaluated after meeting predefined requirements.

[0107] A pilot-scale manufacturing process was developed to produce prototype formulations in batch sizes of 0.1–1 L. The manufacturing process included (1) dissolving the API in a primary emulsion using a high-shear mixer, (2) reducing the droplet size to the desired size using a microfluidizer, (3) passing the nanoemulsion through a 0.2 micron filter, and (4) filling the nanoemulsion into sterile eye drop bottles (multi-dose containers without preservatives or MDPF and LDPE unit-dose containers) in a biosafety hood. Batches of the prototype formulation (approximately 250 mL) were prepared at four different strengths (0, 0.05%, 0.2%, and 0.5%). Using aseptic methods, the prototype formulation batches were loaded into 5.5 mL Aptar dropper bottles (3 mL / bottle) or LDPE unit-dose containers (0.3 mL / unit).

[0108] The formulations were tested for pH, appearance (visual and microscopic), osmotic pressure, viscosity, droplet size, API concentration, and impurities for each batch strength. These test results were used as the initial value (T=0) for the stability test. Prototype formulations were placed in stability chambers set at various temperatures for various durations at each batch strength. Stability tests for appearance (visual and microscopic), particulate matter (number), droplet size, drug concentration, impurities / degraded product, molar osmotic pressure concentration, and pH were performed at selected points in time.

[0109] Formulations of emulsion C, F134, and F135 were prepared as follows: Part 1: Oil / Surfactant Emulsions Tare measurement of a 1.50 mL Falcon tube. 2.1. Add 25 g of castor oil. 3. Add 250 g of tween 80. 4.0.250 g of polyoxyl-35 castor oil is added. 5. Heat the mixture in a sonicator to 50°C, then vortex until uniform and clear. Add 6.13.25 g of deionized water. 7. Homogenize the mixture at high speed until the oil droplet size is less than 100 nm. Mixing speed: 4000 RPM Mixing time: 30 minutes Emulsion C Z-Avg: 35 nm F-134 Z-Avg: 37 nm F-135 Z-Avg: 33 nm Part 2: Nintedanib, Axitinib, and Pazopanib in HP-β-CD Solution Tare measurement of a 1.50 mL Falcon tube. Add 2.25 g of DI water to the container. 3. Add 5.0 g of HP-β-CD while stirring, and stir until completely dissolved. Add 4.0.008 g of citric acid and stir until completely dissolved. 5. Add 0.100 g of API to the mixture. 6. Sonicate the mixture for 15 minutes, then vortex until completely dissolved. 7. Add 0.023 g of sodium citrate to the mixture and mix until completely dissolved. 8. Add 0.050 g of trisodium EDTA to the mixture and mix until completely dissolved. 9. While stirring the mixture, slowly add 0.050 g of HPMC and mix until completely dissolved. Part 3. Formulations of Emulsion C, F134, and F135 1. Tare weight measurement of 100 mL glass bottles 2. Add the aqueous solution (Part 2). 3. Add the oil emulsion (Part 1). Add 4.5 g of deionized water. 5. Add 0.05 g of glycerin to the mixture and mix well. Adjust the pH to 6.0 using 6.1N NaOH or 1N HCl. Emulsion C: Initial pH: 6.66, Final pH: 5.87 F-134 initial pH: 2.51 final pH: 6.12 F-135 initial pH: 1.24 final pH: 6.03 QS in 7.50 g of deionized water and mix. Part 4. Filtration and Filling 1. Aseptically filter the preparation into a sterile container using a sterile 0.2 μm syringe filter. 2.5 mL of the formulation is aseptically filled into 5 x 10 mL Type 1 glass vials. 3. Seal the vial with a rubber septum and press to seal. 4. Store two vials of each formulation at 2-8°C, 25°C, 40°C, 50°C, and 60°C. 5. Observe the PPT for one week.

[0110] The final concentrations of CBT-001 (nintedanib) and excipients in the formulations were determined for each of the following formulations: Solution A: 0.2% nintedanib in a solution system containing 10% 2-hydroxypropyl-β-cyclodextrin. Emulsion C: 0.2% nintedanib in an emulsion system containing 10% 2-hydroxypropyl-β-cyclodextrin, castor oil, polysorbate 80, and polyoxyl-35 castor oil.

[0111] (Table 8) In-lab stability of emulsion C under heating compared to solution A. Percentage of residual nintedanib at each time point is shown. TIFF0007880912000010.tif68166*5 months;^6 months

[0112] In addition to nintedanib, another multikinase inhibitor, axitinib, was investigated and showed remarkably good safety for 3 months at high temperatures in a similar emulsion (Table 9). This experiment demonstrated that multikinase inhibitors with similar physical and chemical properties, such as nintedanib and axitinib, can be formulated as specific, similar emulsion formulations for long-term storage.

[0113] (Table 9) In-laboratory stability of axitinib in a representative emulsion (F134) under heating conditions. Percentage of remaining axitinib at each time point is shown. TIFF0007880912000011.tif44159

[0114] Example 6 In a rabbit model of corneal neovascularization (CNV), emulsion formulations were superior to solution formulations used at the same intensity in terms of efficacy and ophthalmic pharmacokinetic profile, although the safety profiles of the emulsion and solution formulations were similar. The solution formulation used in this study has been shown to be safe and effective in human clinical trials.

[0115] Research Overview This study evaluated the efficacy of emulsion and solution formulations in inhibiting hyperemia and neovascularization in a rabbit model of corneal sutures, starting 7 days after topical intraocular BID (twice daily) administration of 0.2% nintedanib emulsion, 0.05% axitinib emulsion, and 0.1% pazopanib emulsion, or TID (three times daily) administration of 0.2% nintedanib solution and vehicle emulsion. The solutions were those described in Example 5. The emulsions were very similar to emulsion C in Example 5. Furthermore, systemic and intraocular pharmacokinetics and intraocular tolerance were evaluated in these animals.

[0116] All tested formulations were well-tolerated both orally and systemically. While the frequency of administration to rabbits was lower for the 0.2% nintedanib emulsion twice daily (BID) compared to the 0.2% nintedanib solution three times daily (TID), the 0.2% nintedanib emulsion BID surprisingly showed efficacy equal to or better than the 0.2% nintedanib solution TID, as shown in Figure 2. On day 10, the efficacy of the emulsion and solution was similar. On day 12, the emulsion was statistically significantly more effective than the solution (p=0.0025).

[0117] The intraocular pharmacokinetic profile shows that the emulsion has a higher C max The AUC and other metrics indicated that more drug could be delivered to the target tissues of the conjunctiva and cornea (Table 10). Further analysis of the concentration / IC50 ratio over time showed that the emulsion may have more effective inhibition of the target VEGFR2, as a ratio >10 would result in near-complete inhibition of the target (Table 11). This demonstrated that the 0.2% nintedanib emulsion was superior to the 0.2% nintedanib solution in delivering more drug to the ocular surface, resulting in higher efficacy and a longer duration of action.

[0118] (Table 10) Comparison of PK between nintedanib emulsion and solution TIFF0007880912000012.tif38141

[0119] (Table 11) Concentrations of the two nintedanib formulations / VEGFR2 IC2 50 ratio TIFF0007880912000013.tif42159

[0120] Example 7 The effectiveness of the surfactants PEG40 stearate and polyoxyl-35 castor oil in emulsion systems was investigated. The compositions investigated are shown in Table 12.

[0121] (Table 12) Composition of Formulations F70 and F72 TIFF0007880912000014.tif42128

[0122] Formulations F70 and F72 (Table 12) were prepared and investigated as follows. Adjust the pH of 1100 mL of water to pH 2.0 using 1N HCl. Labeled 2.15 mL conical tubes. 3. Tare weight measurement of conical tubes 4. Add water and record the weight. 5. Vortex to make a clear solution. 6. Add Tween 80 and polyoxyl-35 castor oil or PEG40 stealth, and record the weight. 7. Add castor oil and record the weight. 8.1 min vortex 9. Achieve a clear or homogeneous solution by high shear mixing. 10. Add API 11. Place the cone tube in an ice bath. 12.30 minutes high shear mixing 13. After 30 minutes, centrifuge to settle the insoluble API at the bottom of the tube. 14. Take 50 μL from the top of the emulsion and test the droplet size using LLS. If the wavelength is greater than 15,200 nm, continue with high shear mixing and repeat the test. 16. Record the final droplet size. 17. pH measurement 18. If the pH is less than 6, adjust the pH to 6 using 1N NaOH. If the pH is between 6 and 8, no adjustment is necessary. 19.0. Filtration using a 0.2 μm syringe filter 20. Measure the pH and particle size of the filtrate. 21. Assay using CBT-001 (nintedanib) standard solution

[0123] The results of this experiment are shown in Table 13. Since the concentration of nintedanib was higher in formulation F70 than in formulation F72, the combination of polyoxyl-35 castor oil and polysorbate 80 is considered to be a superior surfactant system for emulsifying castor oil and dissolving nintedanib compared to the combination of PEG40 stearate and polysorbate 80.

[0124] (Table 13) Results TIFF0007880912000015.tif16128

Claims

1. Therapeutic doses of multi-kinase inhibitors; Polyoxyl oil; Lipophilic carrier; Solubilizers; and water Includes, The multi-kinase inhibitor is selected from axitinib, nintedanib, and pazopanib, or their salts. The polyoxyl oil is polyoxyl castor oil, The solubilizing agent is a cyclic polysaccharide. Emulsion.

2. The emulsion according to claim 1, wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof.

3. The emulsion according to claim 1 or 2, further comprising a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stealth, tocopherol, and combinations thereof.

4. The emulsion according to any one of claims 1 to 3, wherein the multikinase inhibitor is nintedanib or a salt thereof, the cyclic polysaccharide is 2-hydroxypropyl-β-cyclodextrin, the lipophilic carrier is castor oil, and the polyoxyl oil is polyoxyl-35 castor oil, or a combination thereof.

5. A multi-kinase inhibitor in a concentration of 0.005% to 2% w / w; 0.1% to 1% w / w polyoxyl oil; 0.05% to 1% w / w lipophilic carrier; 5% to 15% w / w solubilizer; and water Includes, The multi-kinase inhibitor is selected from axitinib, nintedanib, and pazopanib, or their salts. The polyoxyl oil is polyoxyl castor oil, The solubilizing agent is a cyclic polysaccharide. Emulsion.

6. The multi-kinase inhibitor is present in an amount of 0.1% to 0.5% w / w, and / or The polyoxyl oil is present in an amount of 0.3% to 0.7% w / w, and / or The lipophilic carrier is present in an amount of 0.1% to 0.5% w / w, and / or The emulsion according to claim 5, wherein the solubilizer is present in an amount of 8% to 12% w / w.

7. The emulsion according to claim 5 or 6, wherein the multikinase inhibitor is present in an amount of 0.1% or 0.2% w / w.

8. The emulsion according to any one of claims 5 to 7, wherein the polyoxyl oil is present in an amount of 0.5% w / w.

9. The emulsion according to any one of claims 5 to 8, wherein the cyclic polysaccharide is selected from the group consisting of cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and combinations thereof.

10. The emulsion according to any one of claims 5 to 9, wherein the solubilizing agent comprises 2-hydroxypropyl-β-cyclodextrin.

11. A 0.1% w / w or 0.2% w / w multikinase inhibitor selected from the group consisting of nintedanib, axitinib, and pazopanib, or salts thereof; 0.5% w / w polyoxyl castor oil; 0.25% w / w castor oil: 10% w / w 2-hydroxypropyl-β-cyclodextrin; and water An emulsion containing [something].

12. An emulsion according to any one of claims 1 to 11, for use in a method for treating an eye condition, wherein the method includes the step of administering the emulsion to the eye of a subject.

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