US 20170172915A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172915 A1 Ni (43) Pub. Date: Jun. 22, 2017 (54) COMPOSITIONS AND METHODS FOR A6IR 9/08 (2006.01) TREATING PTERYGUM A6DF 9/00 (2006.01) (71) Applicant: Cloudbreak Therapeutics, LLC, A63L/404 (2006.01) Irvine, CA (US) (52) U.S. Cl. (72) Inventor: Jinsong Ni, Irvine, CA (US) CPC .......... A61K 9/0048 (2013.01); A61F 9/0017 (2013.01); A61 K3I/496 (2013.01); A61 K (21) Appl. No.: 15/375,820 31/404 (2013.01); A61K 31/407 (2013.01); (22) Filed: Dec. 12, 2016 A61K 9/08 (2013.01); A61K 9/107 (2013.01); A61K 9/0051 (2013.01); A61 F 2210/0004 Related U.S. Application Data (2013.01) (63) Continuation of application No. PCT/US2016/ 035726, filed on Jun. 3, 2016. (57) ABSTRACT (60) Provisional application No. 62/172,063, filed on Jun. 6, 2015, provisional application No. 62/186,660, filed on Jun. 30, 2015. Compositions and methods for inducing pterygium regres sion from visual axis/central cornea, stabilizing pterygium, Publication Classification treating hyperemia and symptoms in pterygium patients, and (51) Int. Cl. treating pterygium recurrence following pterygiectomy are 3. e96 3:08: disclosed. The methods include administration of a multi A 6LX 9/07 (2006.01) kinase inhibitor, an antimetabolite or a combination thereof A6 IK 3/407 (2006.01) to patients in need thereof. Patent Application Publication Jun. 22, 2017 Sheet 1 of 5 US 2017/0172915 A1 tay is average area with Six is ws wei: *88,33;** {{.{33; ***xt.txs 3.338& 8. 3.x:S. 838. ::::::::::::::::: ::::::8:8::::: :::::::::::::::: :::::: 8: :::: Day iá average area with SD ITEST vs veh: K.CS; **z),33; ***kc.gos 3.3% is: 8.2% O.S: 3S4. Wes: si:it:::it: 8 sited&isit is existii aisedatia intets; it 88: ": 3: 3. 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In certain aspect, the disclosed methods reduce TREATING PTERYGUM hyperemia, abnormal neovascularization and other symp toms in pterygium patients. In another aspect, the disclosed CLAIM OF PRIORITY methods prevent pterygium recurrence following pterygium 0001. This application is a continuation of International Surgery. In certain aspect, the disclosed methods are per Application No. PCT/US2016/035726, filed on Jun. 3, 2016, formed before Surgical removal of pterygium, in conjunction which claims the benefit of U.S. Provisional Patent Appli with Surgery for pterygium removal or after Surgical removal cation Ser. No. 62/172,063, filed on Jun. 6, 2015 and U.S. of pterygium, to reduce or prevent pterygium recurrence. In Provisional Patent Application Ser. No. 62/186,660, filed on certain aspect, the disclosed multikinase inhibitor targets Jun. 30, 2015, the entire contents of each are hereby incor minimum kinase receptors of VEGFR (1, 2, 3), PDGFR (C. porated by reference. B), FGFR (1, 2, 3, 4) and optimal kinase receptors of FLT3, Lck, Lyn and Src as additional. In certain aspect, the TECHNICAL FIELD disclosed multikinase inhibitor is nintedanib. In certain aspect, the disclosed methods use a topical ocular formula 0002 The present disclosure relates to ocular composi tion. In certain aspect, the formulation is an aqueous solu tions and methods for treating primary and recurrent ptery tion, a Suspension or an emulsion. In certain aspect, the gium, and more particularly to compositions and methods concentration of nintedanib in the formulation is from for inducing pterygium regression from visual axis/central 0.001% to 10%. In certain aspect, the formulation is an cornea, stabilize pterygium, reducing ocular hyperemia and implant or semi-solid Sustained release formulation injected pterygium recurrence prior to, in conjunction with or fol into the affected eye. In certain aspect, the amount of lowing pterygium Surgery. nintedanib in the implant is from 1 Jug to 100 mg. 0005. In one aspect, the disclosure provides for a method BACKGROUND for inducing pterygium regression from visual axis/central 0003 Pterygium is an ocular surface disease, where an cornea, including administering to an affected eye of a abnormal epithelial and fibroblast growth extends from the subject in need of such treatment a therapeutically effective nasal or temporal conjunctiva across the limbus onto the amount of (1) a multikinase inhibitor; (2) an antimetabolite cornea. Pterygium patients often experience symptoms of that blocks epithelial and fibroblast cell proliferation; or (3) ocular discomfort, hyperemia, and are at risk of visual a combination thereof In some embodiments of all aspects, impairment if the lesion encroaches on the visual axis. the administration of the multikinase inhibitor, the antime tabolite, or combination thereof results in a decrease of the SUMMARY pterygium size in the affected eye. In some instances, the 0004. In certain aspects, the disclosure provides a method administration of the multikinase inhibitor, the antimetabo for treating primary and recurrent pterygium by administer lite, or combination thereof results in a negative pterygium ing (1) a multikinase inhibitor, (2) an antimetabolite or (3) growth rate in the affected eye. a combination of a multikinase inhibitor and an antimetabo 0006. In another aspect, the disclosure provides for a lite to the eye of a subject in need of such treatment. In method for stabilizing pterygium, including administering to certain aspect, the disclosed methods stabilize pterygium an affected eye of a Subject in need of Such treatment a and prevent further growth of the diseased tissue. In another therapeutically effective amount of (1) a multikinase inhibi aspect, the disclosed methods induce pterygium regression tor; (2) an antimetabolite that blocks epithelial and fibroblast from visual axis/central cornea. In certain aspect, the dis cell proliferation; or (3) a combination thereof. In some closed multikinase inhibitor targets kinase receptors of cases, the administration of the multikinase inhibitor, the VEGFR (1, 2, 3) and PDGFR (C., B). In certain aspect, the antimetabolite, or combination thereof results in stabiliza multikinase inhibitor is in a topical ocular formulation tion of the pterygium size in the affected eye. In some administered topically to the affected eye. In certain aspect, instances, the administration of the multikinase inhibitor, the the topical ocular formulation is a solution, a suspension or antimetabolite, or combination thereof results in an about an emulsion. In another aspect, the multikinase inhibitor is Zero pterygium growth rate in the affected eye. in an implant or semi-solid Sustained release formulation 0007. In some embodiments of all aspects, the multiki injected into the affected eye. In certain aspect, the antime nase inhibitor reduces the activity of one or more intracel tabolites are Mitomycin C, 5-Fluorouracil and Thiotepa. In lular and/or cell surface protein kinases selected from certain aspect, the antimetabolite is in a topical ocular EGFR, ErbB2, ErbB3, FGFR1, FGFR2, FGFR3, FGFR4, formulation administered topically to the affected eye. In TrkA, NGFR, VEGFR (1, 2, 3), PDGFR (ol, B), TGF-BR (I, certain aspect, the topical ocular formulation is a solution, a II, III), FLT3, Lck, Lyn, Src, c-Kit, c-Fms, Raf-1, B-Raf, Suspension or an emulsion. In another aspect, the antime RET, CSF-1R) in pterygium. In some cases the multikinase tabolite is in an implant or semi-solid Sustained release inhibitor has an IC50 against VEGFR (1, 2, 3) of <200 nM, formulation injected into the affected eye. In certain aspect, an IC50 against PDGFR (C., B) of <200 nM, and/or an IC50 the disclosed methods are performed by the combination of against FGFR (1, 2, 3) of <1000 nM. a multikinase inhibitor and an antimetabolite. In certain 0008. In some embodiments of all aspects, the multiki aspect, the combination of a multikinase inhibitor and an nase inhibitor is selected from the group consisting of antimetabolite is in a topical ocular formulation adminis Afatinib, Amuvatinib, Axitinib, Cabozantinib, Canertinib, tered topically to the affected eye. In certain aspect, the Cediranib, Ceritinib, Crenolanib, Crizotinib, Dabrafenib, topical ocular formulation is a solution, a Suspension or an Dacomitinib, Dasatinib, Erlotinib, Foretinib, Gefitinib, Gol emulsion. In another aspect, the combination of a multiki vatinib, Ibrutinib, Icotinib, Idelalisib, Imatinib, Lapatinib, nase inhibitor and an antimetabolite is in an implant or Lenvatinib, Neratinib, Nilotinib, Nintedanib, Palbociclib, semi-solid Sustained release formulation injected into the Pazopanib, Ponatinib, Quizartinib, Regorafenib, Ruxoli US 2017/0172915 A1 Jun. 22, 2017 tinib, Sorafenib, Sunitinib, Tandutinib, Tivantinib, Tivoza free base, a hydrate, Solvate or pharmaceutically acceptable nib, Trametinib, Vandetanib, Vatalanib, and Vemurafenib.