Topical ophthalmic compositions and methods for treating abnormal neovascularization.

Abstract

The present invention provides a topical ophthalmic composition for delivering multi-kinase inhibitors with very low solubility in water or aqueous vehicles to a target site. [Solution] A topical ophthalmic composition comprising a multikinase inhibitor as an active pharmaceutical ingredient and perfluorohexyl octane (F6H8) as a liquid vehicle, wherein the multikinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR), or inhibits both VEGFR and fibroblast growth factor receptor (FGFR), and the multikinase inhibitor is selected from the group consisting of afatinib, amvatinib, axitinib, cabozantinib, cediranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, etc.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 032,920, filed June 1, 2020, which is hereby incorporated by reference in its entirety for all purposes as if fully set forth herein.

[0002] The present invention relates to topical ophthalmic compositions and methods for treating abnormal angiogenesis and fibrosis, and more particularly to topical ophthalmic compositions comprising a multi-kinase inhibitor as an active pharmaceutical ingredient and perfluorohexyl octane (F6H8 or CF3(CF2)5(CH2)7CH3) as a liquid vehicle, and methods for treating ophthalmic disorders associated with abnormal angiogenesis.

Background Art

[0003] Multi-kinase inhibitor(s) are molecules that inhibit multiple kinases. These inhibitors are often used in cancer treatment. Many of these inhibitors target tyrosine kinase receptors such as vascular endothelial growth factor receptor (VEGFR). Inhibitors that target VEGFR can inhibit the formation of new blood vessels or abnormal blood vessels under disease conditions. These inhibitors also inhibit platelet-derived growth factor receptor (PDGFR), which is involved in blood vessel maintenance, with varying potencies. Another family of kinases they target is fibroblast growth factor receptor (FGFR), which can be involved in fibroblast proliferation and fibrosis. Inhibitors with such target profiles may be useful for treating diseases associated with abnormal angiogenesis or blood vessel distribution, including many eye diseases. They may also be useful for treating diseases associated with abnormal fibrosis.

Summary of the Invention

Problems to be Solved by the Invention

[0004] Multi-kinase inhibitors are well known to be highly hydrophobic small molecules with very low solubility in water or aqueous vehicles. Therefore, there is a need to develop formulations that can deliver multi-kinase inhibitors at concentrations sufficient to achieve the desired pharmacological effect to the target site. [Means for solving the problem]

[0005] (Summary of the invention) In one embodiment, a topical ophthalmic composition comprises a multikinase inhibitor as an active pharmaceutical ingredient and perfluorohexyl octane (F6H8) as a liquid vehicle. The multikinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR).

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

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

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

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

[0010] In another embodiment, the liquid vehicle does not contain water.

[0011] In another embodiment, the topical ophthalmic composition further comprises an organic cosolvent selected from the group consisting of ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol.

[0012] In another embodiment, the topical ophthalmic composition comprises a multikinase inhibitor as the active pharmaceutical ingredient and perfluorohexyl octane (F6H8) as the liquid vehicle. The multikinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR).

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

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

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

[0016] In another embodiment, a method for treating an ophthalmic disorder comprises providing a topical ophthalmic composition comprising a multikinase inhibitor at a concentration of about 1-10% (w / v); and treating a patient with the topical ophthalmic composition to treat the ophthalmic disorder. The multikinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR).

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

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

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

[0020] In another embodiment, the topical ophthalmic composition is a non-aqueous formulation in the form of a suspension, solution, or emulsion, comprising perfluorohexyl octane (F6H8) as a liquid vehicle. Preferably, F6H8 is the sole liquid vehicle, and the liquid vehicle does not contain water.

[0021] In another embodiment, the ophthalmic disorder is selected from the group consisting of failure of glaucoma surgery, failure of minimally invasive glaucoma surgery, neovascular glaucoma, meibomian gland dysfunction, dry eye disease, Sjögren's syndrome, alkaline burns, ulcers, graft-versus-host disease, atopic conjunctivitis, ocular rosacea, scarring pemphigoid, stem cell deficiency, Lyell's syndrome, Stevens-Johnson syndrome, viral diseases, bacterial diseases, fungal diseases, pterygium, pinguecula, corneal transplant infections, corneal parasitic infections, and neovascularization due to contact lenses.

[0022] In another embodiment, the failure of the glaucoma surgery is due to conventional trabeculectomy, Trabectome surgery, gonioscopy-assisted transluminal trabeculotomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation, and the failure of the minimally invasive glaucoma surgery is due to the implantation of an ocular filtration device.

[0023] In another embodiment, the ocular filtration device used in the minimally invasive glaucoma surgery is selected from the group consisting of a subconjunctival stent, a Schlemm's canal stent, and a suprachoroidal stent.

[0024] It will be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0025] The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention and illustrate embodiments of the invention together with the description to explain the principles of the invention. [Invention 1001] As an active pharmaceutical ingredient, a multi-kinase inhibitor, and As a liquid vehicle, perfluorohexyl octane (F6H8), are included, where the multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR), a topical ophthalmic composition. [Invention 1002] The topical ophthalmic composition of Invention 1001, wherein the multi-kinase inhibitor inhibits VEGFR and fibroblast growth factor receptor (FGFR). [Invention 1003] The topical ophthalmic composition of Invention 1001 or 1002, wherein the multi-kinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof. [Invention 1004] A topical ophthalmic composition according to any one of the present invention 1001 to 1003, wherein the multikinase inhibitor has a concentration of approximately 0.01-0.1% (w / v), approximately 0.1-1% (w / v), approximately 1-10% (w / v), approximately 1.5-5% (w / v), approximately 1.5% (w / v), approximately 2% (w / v), approximately 2.5% (w / v), approximately 3% (w / v), approximately 3.5% (w / v), approximately 4% (w / v), approximately 4.5% (w / v), approximately 5% (w / v), approximately 6% (w / v), approximately 7% (w / v), approximately 8% (w / v), approximately 9% (w / v), or approximately 9% (w / v). [Invention 1005] A topical ophthalmic composition according to any one of the present invention 1001 to 1004, wherein the topical ophthalmic composition is a non-aqueous formulation in the form of a suspension, solution, or emulsion. [Invention 1006] A topical ophthalmic composition according to any one of the present invention 1001 to 1005, wherein the perfluorohexyl octane (F6H8) is the liquid vehicle of the topical ophthalmic composition. [Invention 1007] A topical ophthalmic composition according to any one of the present invention 1001 to 1006, wherein the topical ophthalmic composition further comprises an organic cosolvent selected from the group consisting of ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol. [Invention 1008] The active pharmaceutical ingredients include multi-kinase inhibitors, and It is composed of perfluorohexyloctane (F6H8) as the liquid vehicle. Herein, the multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR), in a topical ophthalmic composition. [Invention 1009] The topical ophthalmic composition of the present invention 1008, wherein the multi-kinase inhibitor inhibits VEGFR and fibroblast growth factor receptor (FGFR). [Invention 1010] The topical ophthalmic composition of the present invention 1008 or 1009, wherein the multikinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof. [Invention 1011] A topical ophthalmic composition according to any of the present invention 1008 to 1010, wherein the multikinase inhibitor has a concentration of approximately 0.01-0.1% (w / v), approximately 0.1-1% (w / v), approximately 1-10% (w / v), approximately 1.5-5% (w / v), approximately 1.5% (w / v), approximately 2% (w / v), approximately 2.5% (w / v), approximately 3% (w / v), approximately 3.5% (w / v), approximately 4% (w / v), approximately 4.5% (w / v), approximately 5% (w / v), approximately 6% (w / v), approximately 7% (w / v), approximately 8% (w / v), approximately 9% (w / v), or approximately 9% (w / v). [Invention 1012] A method for treating ophthalmic disorders, To provide a topical ophthalmic composition containing a multi-kinase inhibitor at a concentration of approximately 0.01-10% (w / v), and This includes treating a patient with the topical ophthalmic composition to treat the aforementioned ophthalmic disorder, Herein, the multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR). [Invention 1013] The method of the present invention 1012, wherein the multi-kinase inhibitor inhibits VEGFR and fibroblast growth factor receptor (FGFR). [Invention 1014] The method of the present invention 1012 or 1013, wherein the multikinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof. [Invention 1015] The method according to any one of the present invention 1012 to 1014, wherein the multikinase inhibitor has a concentration of approximately 0.01-0.1% (w / v), approximately 0.1-1% (w / v), approximately 1-10% (w / v), approximately 1.5-5% (w / v), approximately 1.5% (w / v), approximately 2% (w / v), approximately 2.5% (w / v), approximately 3% (w / v), approximately 3.5% (w / v), approximately 4% (w / v), approximately 4.5% (w / v), approximately 5% (w / v), approximately 6% (w / v), approximately 7% (w / v), approximately 8% (w / v), approximately 9% (w / v), or approximately 9% (w / v). [Invention 1016] The method according to any of items 1012 to 1015 of the present invention, wherein the topical ophthalmic composition is a non-aqueous formulation in the form of a suspension, solution, or emulsion, and comprises perfluorohexyl octane (F6H8) as a liquid vehicle, and the liquid vehicle is water-free. [Invention 1017] The method according to any of items 1012 to 1016 of the present invention, wherein the ophthalmic disorder is selected from the group consisting of failure of glaucoma surgery, failure of minimally invasive glaucoma surgery, neovascular glaucoma, meibomian gland dysfunction, dry eye disease, Sjögren's syndrome, alkaline burns, ulcers, graft-versus-host disease, atopic conjunctivitis, ocular rosacea, scarring pemphigoid, stem cell deficiency, Lyell's syndrome, Stevens-Johnson syndrome, viral diseases, bacterial diseases, fungal diseases, pterygium, pinguecula, corneal transplant infection, corneal parasitic infection, and neovascularization due to contact lenses. [Invention 1018] The method of the present invention 1017, wherein the failure of the aforementioned glaucoma surgery is due to conventional trabeculectomy, trabectome surgery, gonioscopy-assisted transcanal trabeculotomy, excimer laser trabeculotomy, and endoscopic ciliary body photocoagulation, and the failure of the aforementioned minimally invasive glaucoma surgery is due to the implantation of an ocular filtration device. [Invention 1019] The method of the present invention 1018, wherein the ocular filtration device is selected from the group consisting of a subconjunctival stent, a Schlemm's canal stent, and a suprachoroidal stent. [Brief explanation of the drawing]

[0026] [Figure 1] The fibroblast density scores for groups 1 through 4 are shown. Group 1: vehicle control, Group 2: MMC-positive control, Group 3: treated with 0.3% nintedanib from day 7 to day 30, Group 4: treated with 0.3% nintedanib from day 1 to day 30. [Modes for carrying out the invention]

[0027] Detailed description of the illustrated embodiment Embodiments of the present invention will be described in detail below, with examples shown in the accompanying drawings.

[0028] A multi-kinase inhibitor (MKI) is a drug compound (e.g., a small molecule) that inhibits the activity of two or more kinases, including, for example, intracellular and / or cell surface tyrosine protein kinases. “Small molecule” is understood to mean a chemical compound having a molecular weight of less than 2,000 daltons. This small molecule is preferably an organic molecule. In certain embodiments, the “small molecule” does not include peptides or nucleic acid molecules.

[0029] The exemplary multi-kinase inhibitors for use in the methods described herein exhibit specific kinase inhibition profiles, such as in vitro IC50 for VEGFR(1, 2, 3). 50 (I C 50 <100 nM), in vitro IC2 for PDGFRα 50 (I C 50 In vitro IC50 for <1000nM and FGFR1 50 (I C 50The multikinase inhibitor has a kinase inhibition profile exhibiting <500 nM. Examples of multikinase inhibitors for use in the method described herein include, for example, afatinib, amvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, clenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golbatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, and palbociclib. Pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib, batalanib, and vemurafenib; preferably axitinib, nintedanib, pazopanib, cejiranib, regorafenib, ponatinib, and lenvatinib; and more preferably axitinib, nintedanib, pazopanib, and regorafenib. The structures and in vitro potencies of the preferred kinase inhibitors are shown below and in Table 1. [ka]

[0030] [Table 1]

[0031] MKIs are commonly used in the treatment of cancer. Their mechanism involves inhibiting angiogenesis / angiogenesis at the cancer site, leading to a nutrient deficiency in the cancerous tissue and thereby regressing its growth. This mechanism is also applicable to other diseases involving abnormal vascular distribution. Some MKIs, such as those listed herein, can also inhibit FGFR and have the potential to treat diseases involving abnormal fibrosis. The compositions and methods described herein are useful for treating patients with anterior ocular diseases involving abnormal angiogenesis / vascular distribution, fibrosis, or both.

[0032] For example, this disclosure provides compositions and methods of treatment using one of the described examples of MKIs, such as regorafenib, to improve the success rate of glaucoma surgery (e.g., glaucoma filtration surgery) by administration to the eye of a subject in need of treatment. One embodiment features a method for adjunct treatment related to glaucoma surgery in a subject, comprising administering a composition comprising an effective amount of regorafenib or a pharmaceutically acceptable salt thereof to a subject in need of treatment. This method improves the success rate of glaucoma surgery. Glaucoma surgery includes, for example, conventional trabeculectomy, or methods selected from the group consisting of trabectome surgery, gonioscopy-assisted transcanal trabeculotomy, excimer laser trabeculotomy, and endoscopic ciliary photocoagulation. The glaucoma surgery performed may also aim at the implantation of an ocular filtration device, which is an ocular stent. For example, the eye filtration device may be selected from the group consisting of iStent, Xen Gel Stent, Hydrus, and CyPass microstent.

[0033] In another embodiment, the disclosed method reduces scarring in glaucoma surgery by mitigating abnormal vascular distribution and fibrosis at the surgical site. In certain embodiments, the disclosed method is performed preoperatively, concurrently with surgery, or postoperatively to reduce failure in glaucoma surgery. In some embodiments, the amount of regorafenib administered is effective in extending the period of reduced intraocular pressure (IOP) for at least 10 days, at least 365 days, or at least 3650 days postoperatively. In some embodiments, the amount of regorafenib administered is effective in extending the duration of filtration bleb retention.

[0034] The substances, methods, and examples described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0035] In summary, excessive vascular distribution and fibrosis are major risk factors for excessive scarring and failure in glaucoma surgery. This disclosure provides compositions and methods that utilize anti-angiogenic and anti-fibrotic mechanisms to improve the success rate of glaucoma surgery.

[0036] MKIs are well known to be highly hydrophobic small molecules with very low solubility in water or aqueous vehicles. For example, the solubility of axitinib in water is only 0.2 mg / ml at neutral pH. Therefore, it is difficult to formulate it into a stable eye drop composition for ophthalmic use. This disclosure provides a composition and therapeutic method using an MKI in a stable formulation comprising perfluorohexyl octane (F6H8) as a liquid vehicle for the treatment of ophthalmic diseases with abnormal vascular distribution and / or fibrosis. Perfluorohexyl octane (F6H8) is an amphiphilic liquid in which two immiscible parts (a hydrocarbon segment and a perfluorinated segment) are covalently bonded. Other related analogs used in the compositions of the present invention include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10); preferably perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6), and perfluorohexyloctane (F6H8); more preferably perfluorohexyloctane (F6H8).

[0037] The structure of F6H8 is shown below. [ka]

[0038] In some embodiments, the disclosure is based on studies described in the examples, which demonstrate that the use of regorafenib in combination with F6H8 is a preferred choice for treating the ocular indications enumerated in the disclosure. More specifically, the combination is selected to reduce the failure rate of glaucoma surgery.

[0039] Example 1 describes an effort to develop an aqueous formulation of nintedanib. Nintedanib has a reported solubility of less than 0.01 mg / mL, or 0.001%, and is very poorly soluble in water. Various aqueous formulation carriers and combinations were tested to formulate nintedanib at a moderately high concentration. As a result, it was found that an aqueous emulsion formulation could hold 0.3% nintedanib with good long-term stability. Example 2 describes the testing of 0.3% nintedanib in the emulsion formulation in a rabbit glaucoma filtration surgery model. However, in this example, it was found that this formulation could not deliver enough drug to the surgical site to exert the intended effect of preventing filtration bleb loss. At the same time, efficacy signals indicating a decrease in fibroblast density were detected by this formulation. Since fibrosis is a major step in surgical failure, this example suggests that the intended effect may be achieved if more nintedanib can be delivered to the surgical site with a more effective vehicle.

[0040] Because higher concentrations of nintedanib may cause undesirable side effects such as yellow conjunctival discoloration observed clinically due to the yellow color of the nintedanib molecule, regorafenib, a colorless compound with a similar pharmacological profile to nintedanib, was selected for further formulation development and in vivo animal model studies. Furthermore, experiments were conducted to evaluate various solvents to determine which solvent is optimal for regorafenib in order to form a high-concentration formulation for topical ophthalmic use. In Example 3, among all the solvents tested, F6H8 was a preferred non-aqueous vehicle for formulating regorafenib at high concentrations, for example, about 0.01-0.1% (w / v) or about 0.1-1% (w / v); preferably about 1-10% (w / v), about 1.5-5% (w / v), or about 1.5% (w / v); more preferably about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), 8% (w / v), or about 9% (w / v). The thought experiment in Example 4 demonstrates that a 2% regorafenib formulation in F6H8 can improve the success rate of glaucoma surgery in a canine model. This disclosure of MKI formulations in F6H8 represents a novel use for delivering sufficient concentrations of multikinase inhibitors to target sites to achieve desired pharmacological effects. [Examples]

[0041] Example 1: Emulsion formulation of a multi-kinase inhibitor

[0042] The formulations of nintedanib were investigated using the following procedure: 1. Perform a tare measurement on a 1.5 mL Eppendorf tube. 2. Add nintedanib and record the weight. 3. Add the solubilizer and record the weight. 4. Add water with a pH of 5 (except for F3 and F4) and record the weight. 5. Mix with a Beadbeater for 120 seconds. 6. Place the mixture on the rotary mixer overnight at ambient temperature. 7. Filter using a 0.2 μm SPIN-X centrifugal filter. 8. Measure the pH of the filtrate. 9. Assay the filtrate using the CBT-001 standard solution.

[0043] Despite many of the solubilizers investigated having similar structural properties, significantly different results were obtained for each solubilizer (see, for example, Tables 2 and 3). Solubilizers such as castor oil and polysorbate 80 were found to have high solubilizing performance for nintedanib.

[0044] [Table 2]

[0045] [Table 3]

[0046] Based on the results of the solubilization agents, various aqueous emulsion systems were identified for investigation. As a result, it was found that an aqueous emulsion system combining castor oil, polysorbate 80, and polyoxyl-35 castor oil could suitably solubilize nintedanib. As shown in Table 4, one of the emulsion systems could dissolve nintedanib to approximately 3-5 mg / ml, i.e., 0.3-0.5% of the ophthalmic emulsion concentration.

[0047] [Table 4]

[0048] Example 2: Rabbit glaucoma filtration surgery model study of nintedanib

[0049] In this example, nintedanib 0.3% emulsion was tested in a rabbit glaucoma filtration surgery model. Nintedanib is one of four MKIs that can inhibit angiogenesis and fibrosis. This study showed a positive efficacy signal to fibroblast density, but did not demonstrate filtration bleb retention, suggesting that higher concentrations of the drug may be necessary for potential usefulness in actual glaucoma surgery.

[0050] method

[0051] Model settings: The glaucoma filtration surgery model was set up as described above (Cordeiro et al., 1997; Zhong et al., 2011).

[0052] Negative control: Vehicle BID (twice daily) administered from day 7 to day 30 (Group 1).

[0053] Positive control: Mitomycin C (MMC) administered for 5 minutes during surgery (Group 2).

[0054] Test substance: 0.3% CBT-001 (nintedanib). BID was administered from day 7 to day 30 (group 3) and from day 1 to day 30 (group 4).

[0055] Measurements: IOP, filtration bleb score, histological examination for fibroblast density, fibrosis staining, and inflammation level.

[0056] Time points: Day 2, 4, 7, 10, 14, 21, and 30 postoperatively.

[0057] Animals: 24 New Zealand white rabbits (female) (6 per group).

[0058] The test design is shown in Table 5 below.

[0059] [Table 5]

[0060] Results and Conclusions

[0061] Of all the measured values, only fibroblast density showed a signal of efficacy. The results are shown in Figure 3. The inventors observed a significant decrease in fibroblast density in group 4 (treated with nintedanib for 30 days). A statistically insignificant downward trend was also observed in group 3 (treated with nintedanib from day minus 7 to day 30). No difference was observed in the two treatment groups compared to the vehicle control group for the primary effect endpoint, bleb retention rate.

[0062] From these results, the inventors concluded that nintedanib 0.3% emulsion does not have an effect on improving the filtration bleb retention rate. However, a signal of efficacy was detected in fibroblast density. Furthermore, although the current 0.3% formulation did not deliver sufficient drug to the surgical site, the inventors concluded that the mechanism by which multi-kinase inhibitors reduce glaucoma surgery failure is effective. These results indicate that MKIs with a targeted pharmacological profile like nintedanib are effective if they can be delivered to the surgical site in sufficient quantities.

[0063] Example 3: Regorafenib was formulated into a 2% non-aqueous eye drop solution.

[0064] In this example, experiments were conducted to formulate regorafenib into a high concentration (e.g., 2%) for topical ocular use. F6H8 was identified as the most suitable non-aqueous vehicle for this purpose.

[0065] 400 mg of finely powdered regorafenib monohydrate was suspended in 20 ml of perfluorohexyl octane (F6H8). The suspension was homogenized by stirring at room temperature for 15 minutes. The measured regorafenib concentrations ranged from 95.4% to 99.1% of the theoretical concentration. The observed variations were most likely due to heterogeneity of the sample after manual shaking of the suspension. No unspecified degradation products were observed in the chromatogram obtained by HPLC, as described below.

[0066] The HPLC method for measuring regorafenib concentration was as follows: Samples were prepared by diluting collected formulation aliquots with water:acetonitrile (25 / 75) to a final regorafenib concentration of 100 μg / ml. 100 ml of each sample was injected into an Agilent 1100 HPLC system (Agilent, Waldbronn, Germany), and the samples were subjected to a Symmetry C18 column (150 × 4.6 mm - 3.5 μm particle size, Waters, Eschborn, Germany) heated (40°C) at a flow rate of 1 ml / min. The mobile phase consisted of a mixture of potassium phosphate buffer pH 2.4 (A) and acetonitrile / ethanol (6 / 4) (B). The following gradients were applied: 0 min: A, 60% / B, 40%, 12 min: A, 20% / B, 80%, 16 min: A, 20% / B, 80%, 16.5 min: A, 60% / B, 40%, 20 min: A, 60% / B, 40%. Regorafenib was quantified using a DAD detector at a wavelength of 265 nm. The peak of regorafenib appeared at 12.5 min.

[0067] Example 4: Regorafenib study in a canine glaucoma filtration surgery model.

[0068] In this thought experiment, a 2% regorafenib formulation prepared in a perfluorohexyloctan (F6H8) vehicle is tested in a canine model of glaucoma filtration surgery. Regorafenib is another MKI in this disclosure that can inhibit angiogenesis and fibrosis. Its in vitro potency against VEGFR and FGFR is approximately twice that of nintedanib. This test demonstrates that the formulation can improve the success rate of glaucoma surgery in the canine model and suggests its potential usefulness in reducing the failure rate of glaucoma surgery in humans.

[0069] method

[0070] Model setup: The glaucoma filtration surgery model was set up as described above (Kojima et al., 2015). After surgery, ofloxacin ointment was applied to the eye.

[0071] Test substance: 2% regorafenib in perfluorohexyl octane, BID 4 weeks post-surgery.

[0072] Control: Perfluorohexyl octane, BID 4 weeks post-surgery.

[0073] Measurements: IOP, filtration bleb score, collagen level.

[0074] Time points: 14th and 28th day post-surgery.

[0075] The test design is shown in Table 6 below.

[0076] [Table 6]

[0077] Results and Conclusions

[0078] As shown in Table 7, the regorafenib treatment group showed significant differences compared to the vehicle group. While there were no significant changes in the vehicle group, lower IOPs were observed on days 14 and 28. Filtration bleb scores were higher in the regorafenib group than in the vehicle group, and collagen levels were lower in the regorafenib group.

[0079] [Table 7]

[0080] These results indicate that a formulation of regorafenib at 2% in perfluorohexyloctan (F6H8) can improve the success of glaucoma filtration surgery in a canine model. This formulation of regorafenib, or a similar formulation, has the potential to reduce long-term failure rates for use in human glaucoma surgery and may also be used to treat other ocular diseases in the anterior part of the eye with abnormal vascular distribution and / or fibrosis.

[0081] It will be apparent to those skilled in the art that various modifications and variations are possible in the present invention without departing from the spirit or scope of the invention. Accordingly, the present invention is intended to cover modifications and variations of the invention, provided that they fall within the scope of the appended claims and their equivalents.

Claims

1. The active pharmaceutical ingredient is a multi-kinase inhibitor, and The liquid vehicle contains perfluorohexyloctane (F6H8), Herein, the multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR), or the multi-kinase inhibitor inhibits both VEGFR and fibroblast growth factor receptor (FGFR), in a topical ophthalmic composition.

2. The topical ophthalmic composition according to claim 1, wherein the multikinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof.

3. The topical ophthalmic composition according to claim 1 or 2, wherein the multikinase inhibitor has a concentration of about 0.01-0.1% (w / v), about 0.1-1% (w / v), about 1-10% (w / v), about 1.5-5% (w / v), about 1.5% (w / v), about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 9% (w / v).

4. The topical ophthalmic composition according to any one of claims 1 to 3, wherein the topical ophthalmic composition is a non-aqueous formulation in the form of a suspension, solution, or emulsion.

5. A topical ophthalmic composition according to any one of claims 1 to 4, further comprising an organic cosolvent selected from the group consisting of ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol.

6. The active pharmaceutical ingredients include multi-kinase inhibitors, and A topical ophthalmic composition according to any one of claims 1 to 5, comprising perfluorohexyl octane (F6H8) as a liquid vehicle.

7. A topical ophthalmic composition according to any one of claims 1 to 6 for use in the treatment of ophthalmic disorders.

8. The topical ophthalmic composition according to claim 7, wherein the topical ophthalmic composition is a non-aqueous formulation in the form of a suspension, solution, or emulsion, and comprises perfluorohexyl octane (F6H8) as a liquid vehicle, and the liquid vehicle does not contain water.

9. The topical ophthalmic composition according to claim 7 or 8, wherein the ophthalmic disorder is selected from the group consisting of failure of glaucoma surgery, failure of minimally invasive glaucoma surgery, neovascular glaucoma, meibomian gland dysfunction, dry eye disease, Sjögren's syndrome, alkaline burns, ulcers, graft-versus-host disease, atopic conjunctivitis, ocular rosacea, scarring pemphigoid, stem cell deficiency, Lyell's syndrome, Stevens-Johnson syndrome, viral diseases, bacterial diseases, fungal diseases, pterygium, pinguecula, corneal transplant infection, corneal parasitic infection, and neovascularization due to contact lenses.

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