WO2017210132A1 - Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization - Google Patents

Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization Download PDF

Info

Publication number
WO2017210132A1
WO2017210132A1 PCT/US2017/034795 US2017034795W WO2017210132A1 WO 2017210132 A1 WO2017210132 A1 WO 2017210132A1 US 2017034795 W US2017034795 W US 2017034795W WO 2017210132 A1 WO2017210132 A1 WO 2017210132A1
Authority
WO
WIPO (PCT)
Prior art keywords
abnormal neovascularization
involving abnormal
neovascularization
indication involving
nintedanib
Prior art date
Application number
PCT/US2017/034795
Other languages
French (fr)
Inventor
Jinsong Ni
Rong Yang
Original Assignee
Cloudbreak Therapeutics, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=60477780&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017210132(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to MX2018014869A priority Critical patent/MX2018014869A/en
Priority to EP17807296.3A priority patent/EP3463315B1/en
Priority to CA3026118A priority patent/CA3026118A1/en
Priority to KR1020227019229A priority patent/KR20220080222A/en
Priority to JP2019515767A priority patent/JP7082115B2/en
Priority to AU2017274197A priority patent/AU2017274197B2/en
Priority to EP23177028.0A priority patent/EP4248971A3/en
Application filed by Cloudbreak Therapeutics, Llc filed Critical Cloudbreak Therapeutics, Llc
Priority to CN201780033761.9A priority patent/CN109475506A/en
Priority to KR1020187037408A priority patent/KR102408596B1/en
Priority to US16/306,152 priority patent/US11246864B2/en
Priority to BR112018074454-9A priority patent/BR112018074454A2/en
Priority to KR1020247011013A priority patent/KR20240049636A/en
Publication of WO2017210132A1 publication Critical patent/WO2017210132A1/en
Priority to US17/570,928 priority patent/US11911379B2/en
Priority to AU2022202629A priority patent/AU2022202629B2/en
Priority to JP2022085867A priority patent/JP7475395B2/en
Priority to US18/416,302 priority patent/US20240238279A1/en
Priority to JP2024065832A priority patent/JP2024083587A/en
Priority to AU2024219639A priority patent/AU2024219639A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure relates to ocular compositions and methods of using nintedanib for the treatment and prevention of graft rej ection in high-risk corneal transplant patients, and for the treatment of eye diseases involving abnormal neovascularization in the front part of the eye.
  • Abnormal neovascularization is involved in many diseases in the front part of the eye. Abnormal neovascularization is involved with graft rejection in high-risk corneal transplant patients. Current treatments for many of these indications need improvements. The methods disclosed herein address the problems in current treatments and provide improved treatments for these diseases.
  • the disclosure provides a method for treating eye diseases involving abnormal neovascularization in the front part of the eye, the method comprising an effective amount of administering nintedanib or a pharmaceutically acceptable salt thereof to the eye of a subject in need of such treatment.
  • the disclosed methods treat, prevent, or delay onset of graft rejection in corneal transplant patients.
  • the disclosed methods treat, prevent, or delay onset of graft rejection in corneal transplant patients with high risk of graft rej ection.
  • the disclosed methods are performed before operation, in conjunction with operation or after operation, to prevent graft rejection in high-risk corneal transplant.
  • nintedanib is administered in the form of a topical ocular formulation administered topically to the affected eye.
  • concentration of nintedanib in the formulation is from 0.001 % to 10% by weight or by volume the total amount of composition.
  • an aqueous composition comprises 0.001 %, 0.01 %, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib.
  • the topical ocular formulation is a solution, a suspension, gel, or an emulsion.
  • nintedanib is administered in the form of an implant or semi-solid sustained release formulation injected into the affected eye.
  • the amount of nintedanib in the implant is from 1 ⁇ g to 100 mg.
  • subject refers to an animal or human, or to one or more cells derived from an animal or human.
  • the subject is a human.
  • Subjects can also include non-human primates.
  • a human subject can be known as a patient.
  • Figure 1 is a schematic diagram demonstrating an exemplary mechanism to prevent graft rejection in high-risk corneal transplant patients according to the present disclosure.
  • Figure 2A and 2B are graphs demonstrating the reduced cornea
  • FIG. 2A provides results on day 12 and Figure 2B provides results on day 14.
  • T-test significance levels comparing each group vs vehicle are shown by asterisk symbols.
  • Corneal transplant is a common surgical procedure. Although the overall success of corneal transplant is good, graft failure is still a problem in some high-risk patients. These patients have high inflammation and neovascularization in the host bed that confers increased immune responses and rejection of allograft (Yu et al. World J Transplant. 2016;6(1): 10-27). Oral immunosuppressive drugs are sometimes used to reduce the risk of graft failure but they have systemic side effects.
  • the disclosed methods will inhibit vascular endothelial growth factor (“VEGF”) and platelet-derived growth factor (“PDGFR”) mediated excess neovascularization and attenuate VEGF and fibroblast growth factor (“FGF”) related immune responses to prevent graft rejection in high-risk patients.
  • VEGF vascular endothelial growth factor
  • PDGFR platelet-derived growth factor
  • FGF fibroblast growth factor
  • the disclosed methods can be used to treat any ocular indications involving abnormal neovascularization in the front part of the eye.
  • These indications include graft versus host disease, atopic conjunctivitis, ocular rosacea, ocular pemphigoid, Lyell's syndrome, neovascularization induced by viral, bacterial, fungal, or parasitic infection, contact lens induced neovascularization, ulceration, alkali burns, stem cell deficiency, Pinguecula, neovascular glaucoma, dry eye diseases, Sjogren's syndrome, Meibomian gland dysfunction, Steven Johnson syndrome, tumor in the eye.
  • treatment used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect can be prophylactic in terms of completely or partially preventing a disease or symptom(s) thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
  • treatment encompasses any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease and/or symptom(s) from occurring in a subject who may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease and/or symptom(s), i.e., arresting their development; or (c) relieving the disease symptom(s), i.e., causing regression of the disease and/or symptom(s).
  • Those in need of treatment include those already inflicted (e.g., those with increased corneal neovascularizatoin, etc.) as well as those in which prevention is desired.
  • Nintedanib ⁇ Methyl (3Z)-3- ⁇ [(4- ⁇ methyl[(4-methylpiperazin-l-yl) acetyl] amino ⁇ phenyl)amino] (phenyl)methylidene ⁇ -2-oxo-2,3-dihydro-lH-indole-6- carboxylate ⁇ is a kinase inhibitor as described herein.
  • Nintedanib inhibits primarily receptor tyrosine kinases including, for example vascular endothelial growth factor receptor (VEGFR 1-3), platelet-derived growth factor receptor (PDGFR a and ⁇ ), fibroblast growth factor receptor (FGFR 1-4).
  • VEGFR 1-3 vascular endothelial growth factor receptor
  • PDGFR a and ⁇ platelet-derived growth factor receptor
  • FGFR 1-4 fibroblast growth factor receptor
  • compositions which include compounds identified by a method described herein as active ingredients. Also included are the pharmaceutical compositions themselves.
  • compositions typically include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • phrases "pharmaceutically acceptable salt” as used herein means those salts of a compound of interest that are safe and effective for administration to a mammal and that possess the desired biological activity.
  • Pharmaceutically acceptable acid salts include, but are not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, I 0 isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartarte, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, thanesulfonate, benzenesulfonate, p-toluenesulfonate
  • solutions, suspensions, creams, ointments, Gels, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or emulsions used for ophthalmic application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents; antioxidants; chelating agents; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the pharmaceutical composition disclosed herein may include a
  • therapeutically effective amount of an agent described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter or amelioration of at least one symptom of the disorder. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.
  • Effective doses of the compositions of the present disclosure, for the treatment of conditions vary depending upon many different factors, including means of administration, target site, physiological state of the subject, whether the subject is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Treatment dosages can be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
  • compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid.
  • Such formulations can be prepared using standard techniques, or obtained commercially.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • compositions and formulations of nintedanib can be administered topically or as an injection of semi-solid formulation or solid implant, or by any other suitable methods known in the art. While it is possible to use the agent disclosed herein for therapy as is, it may be preferable to administer the agent as a pharmaceutical formulation, e.g., in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical formulations include at least one active compound, in association with a pharmaceutically acceptable excipient, diluent, and/or carrier.
  • Administration of a composition or formulation can be once a day, twice a day, three times a day, four times a day or more often. Frequency may be decreased during a treatment maintenance phase of the treatment, e.g., once every second or third day instead of every day or twice a day.
  • the dose and the administration frequency can be adjusted based on the judgment of the treating physician, for example, taking into account the clinical signs, pathological signs and clinical and subclinical symptoms of a disease of the conditions treated with the present methods, as well as the patient's clinical history.
  • compositions will typically contain an effective amount of nintedanib. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration can be performed according to art-accepted practices.
  • Length of treatment i.e., number of days
  • the number of days of treatment may range from about 1 day to about 365 days.
  • the efficacy of treatment can be monitored during the course of treatment to determine whether the treatment has been successful, or whether additional (or modified) treatment is necessary.
  • Dosage, toxicity and therapeutic efficacy of the therapeutic compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • Dosage forms for nintedanib can be readily determined by the ordinarily skilled artisan, and can e.g., be obtained in animal models and in clinical studies reported in the literatures, for determining dosage, safety and efficacy according to standard methods known in the art. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
  • compositions for use in the present methods may include nintedanib at a concentration of 0.001 % to 10% by weight or by volume the total amount of composition.
  • nintedanib at a concentration of 0.001 % to 10% by weight or by volume the total amount of composition.
  • an aqueous composition comprises 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib.
  • administration to the eye of an aqueous solution may be in the form of "drop" or number of drops (e.g. of nintedanib solution) from a dropper or pipette or other dedicated sterile devices.
  • drops e.g. of nintedanib solution
  • Such drops will typically be up to 50 microliters in volume, but maybe smaller e.g. less than 10 microliters.
  • the rabbit cornea suture model of neovascularization demonstrates the method's ability to reduce abnormal corneal neovascularization.
  • Topical compositions comprising 0.2% or 0.05% nintedanib in 10% 2- hydroxypropyl beta cyclodextrin in phosphate buffer solution, pH 7.4 were prepared. Animals and treatment procedure
  • TID Twice per day (approximately 10 to 12 hours apart).
  • TID Three times per day (approximately 6 to
  • the dose volume was approximately 40 uL/eye.
  • NIH ImageJ ® software was used to analyze the ocular images. Each image was opened in ImageJ ® , the scale was calibrated using the ruler in the photograph and the neovascularized area on the cornea near the suture was selected by the selection tool. The area in mm 2 was calculated by measurement tool in the software, recorded in excel and the image was captured and saved. Two-tailed t-TEST was used to determine whether pairs of groups are significantly different. The results were plotted as histograms of average with standard deviation for easy comparison.
  • nintedanib had a marked inhibitory effect on suture-induced neovascularization in the rabbit cornea 12 and 14 days after the suture induction.
  • Higher dose of 0.2% nintedanib showed better efficacy than 0.05% nintedanib, while more frequent dosing regimen of TID dosing showed higher efficacy compared with BID dosing.
  • nintedanib strongly inhibited corneal neovascularization induced by suture.
  • the strong activity is likely due to the special target profile of nintedanib that has potent activities against VEGFRl-3 and FGFRl-2.
  • Example 2 Mouse corneal graft rejection model
  • cornea of C57BL/6 mice would be transplanted onto BALB/c mice cornea as described (Sonoda et al. Invest Ophthalmol Vis Sci. 1995
  • mice would be divided into two groups. Group 1 would be treated with the nintedanib 0.2% solution and group 2 with the vehicle solution. Treatment would start immediately after transplant, TID for 8 weeks. The corneal opacity and graft rejection will be assessed weekly for 8 weeks as described.
  • the nintedanib treated group would show a significantly increased survival of the graft (lower rejection rate) over the 8 weeks of experiment. The result would indicate that the nintedanib 0.2% solution can prevent corneal graft rejection.
  • the drug product is an isotonic ophthalmic solution prepared in 2-hydroxypropyl beta cyclodextrin or other similar cyclodextrins, and buffer solution, pH range from 5.5 to 8.0. Other viscosity, lubricant, preservative agents might be added to enhance functionality of the formulation.
  • the compositions of the ophthalmic solution are disclosed in Table 2.
  • the drug product is an isotonic ophthalmic suspension prepared in carboxymethylcellulose sodium and buffer solution, pH range from 5.5 to 8.0.
  • the drug particle sizes are reduced to below 40 micron.
  • Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the formulation suspension.
  • the compositions are disclosed in Table 3.
  • the drug product is an isotonic ophthalmic emulsion.
  • the drug is dissolved in the mixture oil phase and emulsifier excipients which is then emulsified and mixed with an aqueous phase with pH range from 5.5 to 8.0.
  • Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the emulsion formulation.
  • Table 4 The compositions are disclosed in Table 4.
  • Citric acid monohydrate Buffer/preservative 0-0.13
  • the drug product is an isotonic sustained release semi-solid formulation.
  • the drug is dissolved and/or suspended in a semi-solid medium with pH range from 5.5 to 8.0.
  • Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the sustained release semi-solid formulation.
  • compositions are disclosed in Table 5.
  • the drug product is a solid implant.
  • the drug is mixed and blended with one or more polymers.
  • the mixture of drug and polymers is melted at a predetermined temperature and extruded into a filament with a predetermined diameter size.
  • the formulation filament is cut into a predetermined size of segment which can be implanted into ocular tissues.
  • Table 6 The compositions are disclosed in Table 6.
  • an example composition for use in the methods according to the invention, may be modified from existing ophthalmically acceptable compositions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compositions and methods of using nintedanib for treating indications with abnormal neovascularization in the front part of the eye are disclosed.

Description

COMPOSITIONS AND METHODS OF USING NINTEDANIB FOR TREATING OCULAR DISEASES WITH ABNORMAL NEOVASCULARIZATION
CLAIM OF PRIORITY
This application claims the benefit of U. S. Provisional Patent Application Serial No. 62/344,878, filed on June 02, 2016 and U. S. Provisional Patent Application Serial No. 62/344,870, filed on June 02, 2016, the entire contents of each are hereby
incorporated by reference.
TECHNICAL FIELD
The present disclosure relates to ocular compositions and methods of using nintedanib for the treatment and prevention of graft rej ection in high-risk corneal transplant patients, and for the treatment of eye diseases involving abnormal neovascularization in the front part of the eye.
BACKGROUND
Abnormal neovascularization is involved in many diseases in the front part of the eye. Abnormal neovascularization is involved with graft rejection in high-risk corneal transplant patients. Current treatments for many of these indications need improvements. The methods disclosed herein address the problems in current treatments and provide improved treatments for these diseases.
SUMMARY
In certain aspects, the disclosure provides a method for treating eye diseases involving abnormal neovascularization in the front part of the eye, the method comprising an effective amount of administering nintedanib or a pharmaceutically acceptable salt thereof to the eye of a subject in need of such treatment. In certain aspect, the disclosed methods treat, prevent, or delay onset of graft rejection in corneal transplant patients. For example, the disclosed methods treat, prevent, or delay onset of graft rejection in corneal transplant patients with high risk of graft rej ection. In certain aspect, the disclosed methods are performed before operation, in conjunction with operation or after operation, to prevent graft rejection in high-risk corneal transplant.
In certain aspect, nintedanib is administered in the form of a topical ocular formulation administered topically to the affected eye. In certain aspect, the concentration of nintedanib in the formulation is from 0.001 % to 10% by weight or by volume the total amount of composition. For example, an aqueous composition comprises 0.001 %, 0.01 %, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib. In certain aspect, the topical ocular formulation is a solution, a suspension, gel, or an emulsion. In another aspect, nintedanib is administered in the form of an implant or semi-solid sustained release formulation injected into the affected eye. In certain aspect, the amount of nintedanib in the implant is from 1 μg to 100 mg.
The term "subject" refers to an animal or human, or to one or more cells derived from an animal or human. Preferably, the subject is a human. Subjects can also include non-human primates. A human subject can be known as a patient.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.
DESCRIPTION OF DRAWINGS
Figure 1 is a schematic diagram demonstrating an exemplary mechanism to prevent graft rejection in high-risk corneal transplant patients according to the present disclosure.
Figure 2A and 2B are graphs demonstrating the reduced cornea
neovascularization in the presence of nintedanib in a rabbit cornea suture model. Figure 2A provides results on day 12 and Figure 2B provides results on day 14. The area of cornea neovascularization are shown for each treatment groups (CBT-1 = nintedanibe ocular formlation: 0.2% CBT-1 BID, 0.2% CBT-1 TID; 0.05% CBT-1 BID, 0.0.5% CBT-1 TID; vehicle control TID. T-test significance levels comparing each group vs vehicle are shown by asterisk symbols.
DETAILED DESCRIPTION
Corneal transplant is a common surgical procedure. Although the overall success of corneal transplant is good, graft failure is still a problem in some high-risk patients. These patients have high inflammation and neovascularization in the host bed that confers increased immune responses and rejection of allograft (Yu et al. World J Transplant. 2016;6(1): 10-27). Oral immunosuppressive drugs are sometimes used to reduce the risk of graft failure but they have systemic side effects. The disclosed methods will inhibit vascular endothelial growth factor ("VEGF") and platelet-derived growth factor ("PDGFR") mediated excess neovascularization and attenuate VEGF and fibroblast growth factor ("FGF") related immune responses to prevent graft rejection in high-risk patients. The mechanism is illustrated in Figure 1.
In addition to corneal graft rejection, the disclosed methods can be used to treat any ocular indications involving abnormal neovascularization in the front part of the eye. These indications include graft versus host disease, atopic conjunctivitis, ocular rosacea, ocular pemphigoid, Lyell's syndrome, neovascularization induced by viral, bacterial, fungal, or parasitic infection, contact lens induced neovascularization, ulceration, alkali burns, stem cell deficiency, Pinguecula, neovascular glaucoma, dry eye diseases, Sjogren's syndrome, Meibomian gland dysfunction, Steven Johnson syndrome, tumor in the eye.
The terms "treatment", "treating", "treat" and the like are used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom(s) thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. The term "treatment" encompasses any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease and/or symptom(s) from occurring in a subject who may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease and/or symptom(s), i.e., arresting their development; or (c) relieving the disease symptom(s), i.e., causing regression of the disease and/or symptom(s). Those in need of treatment include those already inflicted (e.g., those with increased corneal neovascularizatoin, etc.) as well as those in which prevention is desired.
Nintedanib {Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-l-yl) acetyl] amino} phenyl)amino] (phenyl)methylidene}-2-oxo-2,3-dihydro-lH-indole-6- carboxylate}is a kinase inhibitor as described herein. Nintedanib inhibits primarily receptor tyrosine kinases including, for example vascular endothelial growth factor receptor (VEGFR 1-3), platelet-derived growth factor receptor (PDGFR a and β), fibroblast growth factor receptor (FGFR 1-4).
Formulations and Dosing Regimen
The methods described herein include the manufacture and use of
pharmaceutical compositions, which include compounds identified by a method described herein as active ingredients. Also included are the pharmaceutical compositions themselves.
Pharmaceutical compositions typically include pharmaceutically acceptable excipients. As used herein the language "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
The phrase "pharmaceutically acceptable salt" as used herein means those salts of a compound of interest that are safe and effective for administration to a mammal and that possess the desired biological activity. Pharmaceutically acceptable acid salts include, but are not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, I 0 isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartarte, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, thanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., I, I'rnethylene-bis-(2-hydroxy-3-naphthoate )) salts. Suitable base salts include, but are not limited to, 15 aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.
Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions, suspensions, creams, ointments, Gels, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or emulsions used for ophthalmic application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents; antioxidants; chelating agents; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
The pharmaceutical composition disclosed herein may include a
"therapeutically effective amount" of an agent described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter or amelioration of at least one symptom of the disorder. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.
Effective doses of the compositions of the present disclosure, for the treatment of conditions vary depending upon many different factors, including means of administration, target site, physiological state of the subject, whether the subject is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Treatment dosages can be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially.
The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
Compositions and formulations of nintedanib, can be administered topically or as an injection of semi-solid formulation or solid implant, or by any other suitable methods known in the art. While it is possible to use the agent disclosed herein for therapy as is, it may be preferable to administer the agent as a pharmaceutical formulation, e.g., in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical formulations include at least one active compound, in association with a pharmaceutically acceptable excipient, diluent, and/or carrier.
Administration of a composition or formulation can be once a day, twice a day, three times a day, four times a day or more often. Frequency may be decreased during a treatment maintenance phase of the treatment, e.g., once every second or third day instead of every day or twice a day. The dose and the administration frequency can be adjusted based on the judgment of the treating physician, for example, taking into account the clinical signs, pathological signs and clinical and subclinical symptoms of a disease of the conditions treated with the present methods, as well as the patient's clinical history.
It will be appreciated that the amount of an agent disclosed herein required for use in treatment will vary with the route of administration, the nature of the condition for which treatment is required, and the age, body weight and condition of the patient, and will be ultimately at the discretion of the attendant physician. Compositions will typically contain an effective amount of nintedanib. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration can be performed according to art-accepted practices.
Length of treatment, i.e., number of days, will be readily determined by a physician treating the subject; however, the number of days of treatment may range from about 1 day to about 365 days. As provided by the present methods, the efficacy of treatment can be monitored during the course of treatment to determine whether the treatment has been successful, or whether additional (or modified) treatment is necessary.
Dosage, toxicity and therapeutic efficacy of the therapeutic compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). Dosage forms for nintedanib can be readily determined by the ordinarily skilled artisan, and can e.g., be obtained in animal models and in clinical studies reported in the literatures, for determining dosage, safety and efficacy according to standard methods known in the art. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
Compositions for use in the present methods may include nintedanib at a concentration of 0.001 % to 10% by weight or by volume the total amount of composition. For example, an aqueous composition comprises 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib.
As will be familiar to those skilled in the art, administration to the eye of an aqueous solution may be in the form of "drop" or number of drops (e.g. of nintedanib solution) from a dropper or pipette or other dedicated sterile devices. Such drops will typically be up to 50 microliters in volume, but maybe smaller e.g. less than 10 microliters.
EXAMPLES
The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.
Example 1: Rabbit Cornea Suture Model
The rabbit cornea suture model of neovascularization demonstrates the method's ability to reduce abnormal corneal neovascularization.
Topical ocular formulations
Topical compositions comprising 0.2% or 0.05% nintedanib in 10% 2- hydroxypropyl beta cyclodextrin in phosphate buffer solution, pH 7.4 were prepared. Animals and treatment procedure
Thirty female Zealand White rabbits were used to perform the study. Briefly, five sutures were placed in the upper cornea of the right eye of each animal on Day 1 to induce neovascularization. The animals were treated in both eyes with either drug, vehicle or saline as described in Table 1.
Table 1
Figure imgf000010_0001
BID: Twice per day (approximately 10 to 12 hours apart). TID: Three times per day (approximately 6 to
8 hours apart). OD= right eye. OS= left eye.
Both eyes were dosed, the dose volume was approximately 40 uL/eye.
Note: The first dose of saline on Day 1 was done 4 hr post suture placement.
During the study, the animals were closely observed for various ocular indications as well as general physical conditions including body weight. Ocular images were taken on days 7, 10, 12, 14, 21, 28 for analysis of hyperemia.
Data analysis
NIH ImageJ® software was used to analyze the ocular images. Each image was opened in ImageJ®, the scale was calibrated using the ruler in the photograph and the neovascularized area on the cornea near the suture was selected by the selection tool. The area in mm2 was calculated by measurement tool in the software, recorded in excel and the image was captured and saved. Two-tailed t-TEST was used to determine whether pairs of groups are significantly different. The results were plotted as histograms of average with standard deviation for easy comparison.
Results and discussions
As shown in Figure 2A and 2B, nintedanib had a marked inhibitory effect on suture-induced neovascularization in the rabbit cornea 12 and 14 days after the suture induction. Higher dose of 0.2% nintedanib showed better efficacy than 0.05% nintedanib, while more frequent dosing regimen of TID dosing showed higher efficacy compared with BID dosing.
In summary, nintedanib strongly inhibited corneal neovascularization induced by suture. The strong activity is likely due to the special target profile of nintedanib that has potent activities against VEGFRl-3 and FGFRl-2. These results support the methods disclosed here.
Example 2: Mouse corneal graft rejection model
In this example, cornea of C57BL/6 mice would be transplanted onto BALB/c mice cornea as described (Sonoda et al. Invest Ophthalmol Vis Sci. 1995
Feb;36(2):427-34; Invest Ophthalmol Vis Sci. 2000 Mar;41(3):790-8.; Yamagami et al. Invest Ophthalmol Vis Sci. 2001 May;42(6): 1293-8). The suture would be removed on day 7 after transplant. The mice would be divided into two groups. Group 1 would be treated with the nintedanib 0.2% solution and group 2 with the vehicle solution. Treatment would start immediately after transplant, TID for 8 weeks. The corneal opacity and graft rejection will be assessed weekly for 8 weeks as described.
The nintedanib treated group would show a significantly increased survival of the graft (lower rejection rate) over the 8 weeks of experiment. The result would indicate that the nintedanib 0.2% solution can prevent corneal graft rejection.
Example 3: Formulations
Nintedanib Ophthalmic Solution
The drug product is an isotonic ophthalmic solution prepared in 2-hydroxypropyl beta cyclodextrin or other similar cyclodextrins, and buffer solution, pH range from 5.5 to 8.0. Other viscosity, lubricant, preservative agents might be added to enhance functionality of the formulation. The compositions of the ophthalmic solution are disclosed in Table 2.
Table 2 Nintedanib Ophthalmic Solution
Figure imgf000011_0001
Functions Concentration Range
Ingredients
(%w/v)
Polyvinyl alcohol Viscosity /Lubrication Agent 0-1.5
Hypromellose Lubricant/dry eye relief 0- 1
Carbomers Lubricant/dry eye relief 0-0.5
Carmellose sodium Lubricant/dry eye relief 0-1
Sodium hyaluronate Lubricant/dry eye relief 0-1.5
Polyethylene glycol 400 Lubricant/dry eye relief 0-0.4
Propylene glycol Lubricant/dry eye relief 0-0.6
2-hydroxypropyl beta Solubilizer 0- 10 cyclodextrin
Sulfobutyl-beta- Solubilizer 0- 10 cyclodextrin
Randomly methylated beta- Solubilizer 0-5 cyclodextrin
a-cyclodextrin Solubilizer 0-4 β-cyclodextrin Solubilizer 0- 1 γ-cyclodextrin Solubilizer 0- 1
Poloxamer 188, or 237, or Solubilizer/lubricant 0-5 407
Polysorbate 80 Solubilizer/lubricant/surfactant 0-1
Edetate disodium Chelating Agent/Preservative 0-0.01
Benzalkonium chloride Preservative 0 - 0.02
Sodium phosphate Buffer Agent 0-0.43 monobasic monohydrate
Sodium phosphate dibasic Buffer Agent 0-0.8 heptahydrate
Boric acid Buffer Agent 0-0.6
Sodium borate, Buffer Agent 0-0.045 decahydrate
Citric acid, monohydrate Buffer Agent/preservative 0-0.13
Sodium citrate, dihydrate Buffer Agent/preservative 0-0.45
Glycerin Tonicity Agent 0-2.2
Sodium chloride Tonicity Agent 0-0.83
IN Sodium hydroxide pH Adjustment
IN Hydrochloric acid pH 5.5 -8.0
Water for injection Vehicle Q.S. to 100
Nintedanib Ophthalmic Suspension The drug product is an isotonic ophthalmic suspension prepared in carboxymethylcellulose sodium and buffer solution, pH range from 5.5 to 8.0. The drug particle sizes are reduced to below 40 micron. Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the formulation suspension. The compositions are disclosed in Table 3.
Nintedanib Ophthalmic Suspension
Figure imgf000013_0001
Functions Concentration Range
Ingredients
(%w/v)
Sodium phosphate Buffer Agent 0 - 0.43 monobasic monohydrate
Sodium phosphate dibasic Buffer Agent 0 - 0.8 heptahydrate
Boric acid Buffer Agent 0 - 0.6
Sodium borate, Buffer Agent 0 - 0.045 decahydrate
Citric acid, monohydrate Buffer Agent/preservative 0 - 0.13
Sodium citrate, dihydrate Buffer Agent/preservative 0 - 0.45
Glycerin Tonicity Agent 0 - 2.2
Sodium chloride Tonicity Agent 0 - 0.83
IN Sodium hydroxide pH Adjustment
IN Hydrochloric acid pH 5.5 - 8.0
Water for injection Vehicle Q.S. to 100
Nintedanib Ophthalmic Emulsion
The drug product is an isotonic ophthalmic emulsion. The drug is dissolved in the mixture oil phase and emulsifier excipients which is then emulsified and mixed with an aqueous phase with pH range from 5.5 to 8.0. Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the emulsion formulation. The compositions are disclosed in Table 4.
Nintedanib Ophthalmic Emulsion
Functions Concentration
Ingredients
(% w/w)
CBT-001 (Nintedanib free Active Pharmaceutical Ingredient 0.001 - 10 base)
Castor oil Oil solvent 0-1.25
Polyoxyl-40-Stearate Emulsifier 0 - 0.25
Polysorbate 80 Solubilizer/Emulsifier/Surfactant 0-1
Sulfobutyl--cyclodextrin Solubilizer 0-5
2-Hydroxypropyl-beta- Solubilizer 0-5 cyclodextrin
Randomly methylated beta- Solubilizer 0-5 cyclodextrin
a-cyclodextrin Solubilizer 0-4 β-cyclodextrin Solubilizer 0- 1 γ-cyclodextrin Solubilizer 0- 1
Glycerin Tonicity Agent 0-2.2
Sodium Chloride Tonicity Agent 0-0.83
Pemulen TR2 Viscosity Agent 0-0.1
Sodium Viscosity Agent 0-0.5 carboxymethylcellulose
Polyvinyl alcohol Viscosity /Lubrication Agent 0-1.5
Hypromellose Lubricant/dry eye relief 0-1
Carbomers Lubricant/dry eye relief 0-0.5
Carmellose sodium Lubricant/dry eye relief 0-1
Sodium hyaluronate Lubricant/dry eye relief 0-1.5
Polyethylene glycol 400 Lubricant/dry eye relief 0-0.4
Propylene glycol Lubricant/dry eye relief 0-0.6
Poloxamer 188, or 237, or Solubilizer/lubricant 0-5 407
Boric acid Buffer 0-0.6
Sodium borate, Buffer 0-0.045 decahydrate
Citric acid, monohydrate Buffer/preservative 0-0.13
Sodium citrate, dihydrate Buffer/preservative 0 - 0.45
Sodium phosphate, Buffer 0-0.43 monobasic monohydrate
Sodium phosphate dibasic Buffer 0-0.8 heptahydrate Functions Concentration
Ingredients
(% w/w)
IN & 5N Sodium pH Adjustment pH 5.5 - 8.0 hydroxide
IN Hydrochloric acid
Water for injection Aqueous Vehicle Q.S. 100
Nintedanib Sustained Release Semi-Solid Formulation
The drug product is an isotonic sustained release semi-solid formulation. The drug is dissolved and/or suspended in a semi-solid medium with pH range from 5.5 to 8.0. Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the sustained release semi-solid formulation. The
compositions are disclosed in Table 5.
Table 5 Sustained Release Semi-Solid Formulation
Figure imgf000017_0001
Nintedanib Sustained Release Implants
The drug product is a solid implant. The drug is mixed and blended with one or more polymers. The mixture of drug and polymers is melted at a predetermined temperature and extruded into a filament with a predetermined diameter size. The formulation filament is cut into a predetermined size of segment which can be implanted into ocular tissues. The compositions are disclosed in Table 6.
Table 6 Sustained Release Implants
Figure imgf000018_0001
Without limitation, an example composition, for use in the methods according to the invention, may be modified from existing ophthalmically acceptable compositions.
OTHER EMBODIMENTS
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:
1. A method for treating ocular indications involving abnormal neovascularization, comprising administering to an eye of a subject an effective amount of nintedanib or a pharmaceutically acceptable salt thereof in a form of topical eye drop or implant.
2. The method of claim 1, wherein the indication involving abnormal neovascularization is corneal graft rejection after a high-risk patient received corneal transplant.
3. For the method of claim 1, wherein nintedanib is administered in an amount effective to prevent graft rejection by inhibiting abnormal neovascularization and inflammation in the eye of the subject.
4. The method of claim 1, wherein the indication involving abnormal neovascularization is graft versus host disease.
5. The method of claim 1, wherein the indication involving abnormal neovascularization is atopic conjunctivitis.
6. The method of claim 1, wherein the indication involving abnormal neovascularization is ocular rosacea.
7. The method of claim 1, wherein the indication involving abnormal neovascularization is ocular pemphigoid.
8. The method of claim 1, wherein the indication involving abnormal neovascularization is Lyell's syndrome.
9. The method of claim 1, wherein the indication involving abnormal neovascularization is neovascularization induced by viral, bacterial, fungal, or parasitic infection.
10. The method of claim 1 , wherein the indication involving abnormal neovascularization is contact lens induced neovascularization.
11. The method of claim 1 , wherein the indication involving abnormal neovascularization is ulceration.
12. The method of claim 1, wherein the indication involving abnormal neovascularization is alkali burns.
13. The method of claim 1, wherein the indication involving abnormal neovascularization is stem cell deficiency.
14. The method of claim 1, wherein the indication involving abnormal neovascularization is Pinguecula.
15. The method of claim 1, wherein the indication involving abnormal neovascularization is neovascular glaucoma.
16. The method of claim 1 , wherein the indication involving abnormal neovascularization is dry eye diseases.
17. The method of claim 1, wherein the indication involving abnormal neovascularization is Sjogren's syndrome.
18. The method of claim 1, wherein the indication involving abnormal neovascularization is Meibomian gland dysfunction.
19. The method of claim 1 , wherein the indication involving abnormal neovascularization is Steven Johnson syndrome.
20. The method of claim 1 , wherein the indication involving abnormal neovascularization is tumor in the eye.
21. The method of claim 1, wherein nintedanib is administered in the form of topical ocular formulation or ocular implant
22. The method of claim 21, wherein the ocular implant is in the form of a semi-solid or solid sustained-release implant.
23. The method of claim 22, wherein the implant is injected into the eye eye of the subject.
24. The method of claim 21, wherein the topical ocular formulation is a topical eye drop.
25. The method of claim 21, wherein the topical ocular formulation is a solution, suspension, cream, ointment, gel, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or emulsion.
PCT/US2017/034795 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization WO2017210132A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
CN201780033761.9A CN109475506A (en) 2016-06-02 2017-05-26 The composition and method of the eye disease formed with aberrant nascent vessels are treated using Nintedanib
KR1020247011013A KR20240049636A (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
CA3026118A CA3026118A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
KR1020227019229A KR20220080222A (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
JP2019515767A JP7082115B2 (en) 2016-06-02 2017-05-26 Compositions and Methods Using Nintedanib to Treat Eye Diseases Associated with Abnormal Neovascularization
AU2017274197A AU2017274197B2 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
EP23177028.0A EP4248971A3 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US16/306,152 US11246864B2 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
KR1020187037408A KR102408596B1 (en) 2016-06-02 2017-05-26 Compositions and methods using nintedanib for the treatment of ocular diseases with abnormal neovascularization
MX2018014869A MX2018014869A (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization.
EP17807296.3A EP3463315B1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
BR112018074454-9A BR112018074454A2 (en) 2016-06-02 2017-05-26 compositions and methods of using nintedanib to treat eye disease with abnormal neovascularization
US17/570,928 US11911379B2 (en) 2016-06-02 2022-01-07 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
AU2022202629A AU2022202629B2 (en) 2016-06-02 2022-04-20 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
JP2022085867A JP7475395B2 (en) 2016-06-02 2022-05-26 Compositions and methods of using nintedanib to treat ocular diseases involving abnormal neovascularization
US18/416,302 US20240238279A1 (en) 2016-06-02 2024-01-18 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
JP2024065832A JP2024083587A (en) 2016-06-02 2024-04-16 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
AU2024219639A AU2024219639A1 (en) 2016-06-02 2024-09-12 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662344878P 2016-06-02 2016-06-02
US201662344870P 2016-06-02 2016-06-02
US62/344,870 2016-06-02
US62/344,878 2016-06-02

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/306,152 A-371-Of-International US11246864B2 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US17/570,928 Continuation US11911379B2 (en) 2016-06-02 2022-01-07 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization

Publications (1)

Publication Number Publication Date
WO2017210132A1 true WO2017210132A1 (en) 2017-12-07

Family

ID=60477780

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2017/034795 WO2017210132A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
PCT/US2017/034792 WO2017210130A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2017/034792 WO2017210130A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success

Country Status (10)

Country Link
US (5) US11246864B2 (en)
EP (3) EP4248971A3 (en)
JP (4) JP7082115B2 (en)
KR (6) KR102496234B1 (en)
CN (2) CN109475506A (en)
AU (5) AU2017274195B2 (en)
BR (2) BR112018074450A2 (en)
CA (2) CA3025325A1 (en)
MX (4) MX2018014869A (en)
WO (2) WO2017210132A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019524880A (en) * 2017-05-01 2019-09-05 アイビバ バイオファーマ インコーポレイテッド Multikinase inhibitor
WO2020047146A1 (en) 2018-08-28 2020-03-05 Cloudbreak Therapeutics, Llc Emulsion formulations of multikinase inhibitors
JP2021525710A (en) * 2018-05-25 2021-09-27 クラウドブレイク セラピューティクス リミテッド ライアビリティ カンパニー Compositions for treating red eye and methods for treating red eye with it
CN114340618A (en) * 2019-09-10 2022-04-12 克劳德布雷克医疗有限责任公司 Method for mitigating pterygium-related eye appearance concerns
EP3836927A4 (en) * 2018-08-15 2022-05-11 AiViva Biopharma, Inc. Multi-kinase inhibitors of vegf and tgf beta and uses thereof
EP3463315B1 (en) 2016-06-02 2023-06-14 ADS Therapeutics LLC Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US12138252B2 (en) 2020-12-29 2024-11-12 Aiviva Biopharma, Inc. Multikinase inhibitors of VEGF and TGF beta and uses thereof

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102643821B1 (en) 2015-06-06 2024-03-07 클라우드브레이크 테라퓨틱스, 엘엘씨 Compositions and methods for treating pterygium
GB201714392D0 (en) 2017-09-07 2017-10-25 Marsteller Laurence Methods and devices for treating glaucoma
WO2021142298A1 (en) * 2020-01-08 2021-07-15 Radiance Therapeutics, Inc. Methods, systems, and compositions for maintaining functioning drainage blebs
JP2022502160A (en) 2018-09-28 2022-01-11 ラディアンス セラピューティクス、インコーポレイテッド Methods, systems, and compositions for maintaining functioning drainage vesicles associated with minimally invasive microscleral incision.
JP7368472B2 (en) 2018-11-29 2023-10-24 ラディアンス セラピューティクス、インコーポレイテッド Ophthalmic brachytherapy systems and devices for the application of beta radiation
CN110787127A (en) * 2019-12-11 2020-02-14 龚雁 Eye temperature-sensitive gel and preparation method thereof
DK3884929T3 (en) 2020-03-25 2023-09-25 Ocular Therapeutix Inc EYE IMPLANT CONTAINING A TYROSINE KINASE INHIBITOR
CN116251186A (en) * 2021-12-09 2023-06-13 成都瑞沐生物医药科技有限公司 Tyrosine kinase inhibitor ophthalmic preparation and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130324481A1 (en) 2004-10-01 2013-12-05 Ramscor, Inc. Sustained release eye drop formulations
US20140128395A1 (en) 2011-07-04 2014-05-08 Giulio Ferrari Novel Method
WO2014074823A1 (en) 2012-11-08 2014-05-15 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
WO2016209555A1 (en) 2015-06-22 2016-12-29 Allgenesis Biotherapeutics Inc. Ophthalmic formulations of tyrosine kinase inhibitors, methods of use thereof, and preparation methods thereof

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69814612T2 (en) 1997-02-14 2004-03-11 Kissei Pharmaceutical Co., Ltd., Matsumoto SUBSTANCES FOR INHIBITING PTERYGIUM EDUCATION AND ITS POSTOPERATIVE RECURRENCE
UA75054C2 (en) 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Substituted in position 6 indolinones, producing and use thereof as medicament
US7442372B2 (en) * 2003-08-29 2008-10-28 Biomarin Pharmaceutical Inc. Delivery of therapeutic compounds to the brain and other tissues
WO2006004795A2 (en) 2004-06-25 2006-01-12 The Johns Hopkins University Angiogenesis inhibitors
US20060052286A1 (en) 2004-08-13 2006-03-09 Yale University Factor VII conjugates for selectively treating neovascularization disorders
WO2007038453A2 (en) 2005-09-26 2007-04-05 Advanced Ocular Systems Limited Use of an anti-vascular endothelial growth factor (vegf) agent to ameliorate inflammation
US20080003219A1 (en) 2005-09-26 2008-01-03 Minu, L.L.C. Delivery of an ocular agent
US8558002B2 (en) 2006-11-16 2013-10-15 Allergan, Inc. Sulfoximines as kinase inhibitors
US11078262B2 (en) 2007-04-30 2021-08-03 Allergan, Inc. High viscosity macromolecular compositions for treating ocular conditions
RU2351298C1 (en) 2007-11-27 2009-04-10 Государственное учреждение "УФИМСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ГЛАЗНЫХ БОЛЕЗНЕЙ" Академии наук Республики Башкортостан (УфНИИ ГБ АН РБ) Method of prevention of pterygium relapse
TW201201808A (en) 2010-01-06 2012-01-16 Glaxo Wellcome Mfg Pte Ltd Treatment method
CN102018686B (en) 2010-12-16 2012-12-05 浙江大学医学院附属邵逸夫医院 Mitomycin-containing film agent and preparation method thereof
KR20140010031A (en) * 2011-01-13 2014-01-23 노파르티스 아게 Bace-2 inhibitors for the treatment of metabolic disorders
HUE056808T2 (en) 2011-06-03 2022-04-28 Xoma Technology Ltd Antibodies specific for tgf-beta
AU2012277905A1 (en) 2011-06-28 2014-01-16 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing regorafenib
CA2840491A1 (en) 2011-06-28 2013-01-03 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing sorafenib
CN107115294B (en) 2012-01-19 2019-10-18 北京康弘生物医药有限公司 A kind of eye drops containing VEGF antagonist
JP2015508104A (en) 2012-02-22 2015-03-16 トラスティーズ オブ タフツ カレッジ Compositions and methods for the delivery of therapeutic agents to the eye
JP6720443B2 (en) 2012-05-03 2020-07-08 カラ ファーマシューティカルズ インコーポレイテッド Pharmaceutical nanoparticles showing improved mucosal transport
US20150164790A1 (en) 2012-06-12 2015-06-18 Bayer Healthcare Llc Topical Ophthalmological Pharmaceutical Composition containing Axitinib
WO2013188268A1 (en) 2012-06-12 2013-12-19 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing pazopanib
EP2858628A1 (en) 2012-06-25 2015-04-15 Bayer HealthCare LLC Topical ophthalmological pharmaceutical composition containing sunitinib
JP2015520231A (en) 2012-06-25 2015-07-16 バイエル・ヘルスケア・エルエルシーＢａｙｅｒ ＨｅａｌｔｈＣａｒｅＬＬＣ Ophthalmic topical pharmaceutical composition containing cediranib
EP2906145A4 (en) 2012-10-11 2016-07-06 Univ Colorado Regents Ocular filtration devices, systems and methods
CN104955471A (en) * 2012-11-15 2015-09-30 塔夫斯大学 Methods, compositions and kits for treating, modulating, or preventing ocular angiogenesis or fibrosis in a subject using a galectin protein inhibitor
US8747852B1 (en) 2012-12-28 2014-06-10 Randal Tanh Hoang Pham Methods of treating pterygium
US20160038760A1 (en) 2013-03-14 2016-02-11 Massachusetts Eye And Ear Infirmary Conjunctival diseases
EP3417896B1 (en) 2013-05-03 2024-01-24 Clearside Biomedical, Inc. Apparatus and methods for ocular injection
EA201790434A1 (en) * 2014-08-22 2017-07-31 Окленд Юнисервисиз Лимитед CHANNEL MODULATORS
CN104448300B (en) 2014-12-09 2017-01-11 西安医学院 Low-molecular-weight L-polyglutamine-mitomycin C as well as synthesis method and applications thereof
CA2974702C (en) 2015-01-26 2023-10-10 University Of Washington Compositions and methods for treating toxoplasmosis, cryptosporidiosis and other apicomplexan protozoan related diseases
KR102643821B1 (en) 2015-06-06 2024-03-07 클라우드브레이크 테라퓨틱스, 엘엘씨 Compositions and methods for treating pterygium
PE20180252A1 (en) 2015-06-09 2018-02-02 Bayer Pharma AG ALOSTERIC POSITIVE MODULATORS OF THE MUSCARINIC RECEIVER M2
EP3324902A1 (en) 2015-07-22 2018-05-30 Incept, LLC Coated punctal plug
CN108295072A (en) * 2015-12-09 2018-07-20 瑞阳(苏州)生物科技有限公司 Nintedanib prevents the purposes of eye disease
CN106902117A (en) * 2015-12-23 2017-06-30 瑞阳(苏州)生物科技有限公司 A kind of medicine for preventing or treating CNV to be formed
MX2018008078A (en) 2016-02-04 2018-11-29 Ni Jinsong Antibody-drug synergism technology for treating diseases.
CA3025325A1 (en) 2016-06-02 2017-12-07 Cloudbreak Therapeutics, Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
US11278546B2 (en) 2016-07-22 2022-03-22 Aiviva Biopharma, Inc. Multikinase inhibitors and uses in ocular fibrosis
US11510931B2 (en) 2016-09-28 2022-11-29 Medicon Pharmaceuticals, Inc. Compositions and methods for treating ophthalmic conditions
BR112021026662A2 (en) 2019-09-10 2022-04-12 Cloudbreak Therapeutics Llc Methods to alleviate pterygium-associated concern about the appearance of the eye

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130324481A1 (en) 2004-10-01 2013-12-05 Ramscor, Inc. Sustained release eye drop formulations
US20140128395A1 (en) 2011-07-04 2014-05-08 Giulio Ferrari Novel Method
WO2014074823A1 (en) 2012-11-08 2014-05-15 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
WO2016209555A1 (en) 2015-06-22 2016-12-29 Allgenesis Biotherapeutics Inc. Ophthalmic formulations of tyrosine kinase inhibitors, methods of use thereof, and preparation methods thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005
HUU ET AL., JOURNAL OF CONTROLLED RELEASE, vol. 200, 28 February 2015 (2015-02-28), pages 71 - 77
HUU, VAN ET AL.: "Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye", JOURNAL OF CONTROLLED RELEASE, vol. 200, 28 February 2015 (2015-02-28), pages 71 - 77, XP029222017 *
INVEST OPHTHALMOL VIS SCI, vol. 41, no. 3, March 2000 (2000-03-01), pages 790 - 8
SONODA ET AL., INVEST OPHTHALMOL VIS SCI, vol. 36, no. 2, February 1995 (1995-02-01), pages 427 - 34
YAMAGAMI ET AL., INVEST OPHTHALMOL VIS SCI, vol. 42, no. 6, May 2001 (2001-05-01), pages 1293 - 8
YU ET AL., WORLD J TRANSPLANT, vol. 6, no. 1, 2016, pages 10 - 27

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3463315B1 (en) 2016-06-02 2023-06-14 ADS Therapeutics LLC Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US11278546B2 (en) 2016-07-22 2022-03-22 Aiviva Biopharma, Inc. Multikinase inhibitors and uses in ocular fibrosis
JP2019524880A (en) * 2017-05-01 2019-09-05 アイビバ バイオファーマ インコーポレイテッド Multikinase inhibitor
EP3813793A4 (en) * 2018-05-25 2022-03-09 ADS Therapeutics LLC A composition for treating ocular hyperemia and a method for treating ocular hyperemia with the same
JP2021525710A (en) * 2018-05-25 2021-09-27 クラウドブレイク セラピューティクス リミテッド ライアビリティ カンパニー Compositions for treating red eye and methods for treating red eye with it
JP7365056B2 (en) 2018-05-25 2023-10-19 エーディーエス・セラピューティクス・エルエルシー Compositions for treating ocular redness and methods for treating ocular redness using the same
JP7365056B6 (en) 2018-05-25 2023-12-15 エーディーエス・セラピューティクス・エルエルシー Compositions for treating ocular redness and methods for treating ocular redness using the same
EP3836927A4 (en) * 2018-08-15 2022-05-11 AiViva Biopharma, Inc. Multi-kinase inhibitors of vegf and tgf beta and uses thereof
EP3843704A4 (en) * 2018-08-28 2022-05-18 Cloudbreak Therapeutics, LLC Emulsion formulations of multikinase inhibitors
US11666533B2 (en) * 2018-08-28 2023-06-06 Cloudbreak Therapeutics, Llc Emulsion formulations of multikinase inhibitors
WO2020047146A1 (en) 2018-08-28 2020-03-05 Cloudbreak Therapeutics, Llc Emulsion formulations of multikinase inhibitors
EP4349327A3 (en) * 2018-08-28 2024-07-24 Cloudbreak Therapeutics, LLC Emulsion formulations of multikinase inhibitors
CN114340618A (en) * 2019-09-10 2022-04-12 克劳德布雷克医疗有限责任公司 Method for mitigating pterygium-related eye appearance concerns
EP4027997A4 (en) * 2019-09-10 2023-10-11 Cloudbreak Therapeutics, LLC Methods for alleviating pterygium-associated worry about eye appearance
US12138252B2 (en) 2020-12-29 2024-11-12 Aiviva Biopharma, Inc. Multikinase inhibitors of VEGF and TGF beta and uses thereof

Also Published As

Publication number Publication date
US11911379B2 (en) 2024-02-27
KR102657707B1 (en) 2024-04-15
CN109561985B (en) 2022-03-04
KR20230023812A (en) 2023-02-17
US20190015409A1 (en) 2019-01-17
EP3463315C0 (en) 2023-06-14
JP7475395B2 (en) 2024-04-26
EP4248971A2 (en) 2023-09-27
JP2022116191A (en) 2022-08-09
KR20240049636A (en) 2024-04-16
JP7079243B2 (en) 2022-06-01
JP2019517578A (en) 2019-06-24
AU2024219639A1 (en) 2024-10-03
CA3026118A1 (en) 2017-12-07
EP3463315A1 (en) 2019-04-10
KR102496234B1 (en) 2023-02-06
JP2024083587A (en) 2024-06-21
WO2017210130A1 (en) 2017-12-07
MX2018014869A (en) 2019-09-13
AU2017274197A1 (en) 2018-12-06
AU2017274195B2 (en) 2022-04-07
AU2022202629A1 (en) 2022-05-19
KR20220080222A (en) 2022-06-14
AU2022202629B2 (en) 2024-06-13
US20220125783A1 (en) 2022-04-28
EP4248971A3 (en) 2024-02-14
EP3463315A4 (en) 2020-01-15
US11246864B2 (en) 2022-02-15
BR112018074454A2 (en) 2019-03-19
CN109561985A (en) 2019-04-02
AU2022204216A1 (en) 2022-07-14
AU2017274197B2 (en) 2022-02-10
US20240238279A1 (en) 2024-07-18
AU2022204216B2 (en) 2024-10-17
EP3463225A4 (en) 2020-03-11
KR20240052865A (en) 2024-04-23
CN109475506A (en) 2019-03-15
KR20190032300A (en) 2019-03-27
JP2019518790A (en) 2019-07-04
US20200323844A1 (en) 2020-10-15
MX2022000754A (en) 2022-02-14
AU2017274195A1 (en) 2018-12-13
KR20190040935A (en) 2019-04-19
CA3025325A1 (en) 2017-12-07
MX2018014868A (en) 2019-09-13
EP3463225A1 (en) 2019-04-10
EP3463315B1 (en) 2023-06-14
JP7082115B2 (en) 2022-06-07
MX2024007658A (en) 2024-07-04
US10335408B2 (en) 2019-07-02
BR112018074450A2 (en) 2019-03-19
US10688092B2 (en) 2020-06-23
US20190290643A1 (en) 2019-09-26
KR102408596B1 (en) 2022-06-13

Similar Documents

Publication Publication Date Title
AU2022202629B2 (en) Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
AU2021218212B2 (en) Compositions and methods for treating pterygium
BR122024009541A2 (en) COMPOSITION COMPRISING NINTEDANIB FOR TREATING EYE DISEASES WITH ABNORMAL NEOVASCULARIZATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17807296

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3026118

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2019515767

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112018074454

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2017274197

Country of ref document: AU

Date of ref document: 20170526

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20187037408

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017807296

Country of ref document: EP

Effective date: 20190102

ENP Entry into the national phase

Ref document number: 112018074454

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20181127