WO2025090761A1 - Traitement de la dégénérescence rétinienne avec de la minocycline et des analogues de la minocycline - Google Patents

Traitement de la dégénérescence rétinienne avec de la minocycline et des analogues de la minocycline Download PDF

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WO2025090761A1
WO2025090761A1 PCT/US2024/052809 US2024052809W WO2025090761A1 WO 2025090761 A1 WO2025090761 A1 WO 2025090761A1 US 2024052809 W US2024052809 W US 2024052809W WO 2025090761 A1 WO2025090761 A1 WO 2025090761A1
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acetyl
butyl
hydrogen
methyl
molecule
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Susan BERGESON
Ted W. Reid
Mayank SHASHTRI
Kelly Mitchell
Joshua O. WILMS
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Texas Tech University TTU
Texas Tech University System
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Texas Tech University System
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Definitions

  • the present disclosure relates in general to the field of treatments for retinal degeneration, and more particularly, to novel molecules, compositions and methods of treating retinal degeneration.
  • CNV pathologic choroidal neovascularization
  • AMD age-related macular degeneration
  • VEGF vascular endothelial growth factor
  • RPE retinal pigment epithelium
  • MMPs matrix metalloproteinases
  • intravitreal anti-VEGF injections e.g., ranibizumab, aflibercept
  • photodynamic therapy e.g., photodynamic therapy.14-17
  • intravitreal anti-VEGF injections are effective to treat CNV-related disorders, they may increase risk for systemic vascular events (e.g., cerebrovascular accidents, nonocular hemorrhage) and require frequent, expensive, uncomfortable injections into the eye.15, 18
  • the treatment involves intraocular injections, which have a low but nonzero risk of serious adverse effects (e.g., endophthalmitis).
  • these injections are only administered by ophthalmologists specially trained to do so safely.
  • Intravitreal shot administration can consume a large portion of an ophthalmologist’s clinical time each day. Even when the injection goes well, patients describe the experience as generally unpleasant with the eye usually mildly irritated for 12 to 24 hours after each injection.
  • a cohort study conducted in 2018 found that more than 20% of patients treated with intraocular anti-VEGF injections do not return for follow-up treatments.19 Anti-VEGF medications range in cost from several hundred to several thousand dollars per injection and contribute a substantial burden to the US health care system: ranibizumab and aflibercept alone consume 12% of the annual Medicare Plan B budget.20 Antioxidant/zinc supplementation is only effective for prevention or delay of age-related macular degeneration, not for treatment.15
  • an aspect of the present disclosure relates to a method of treating an ocular disease or disorder, comprising: administering to a subject a composition, wherein the composition comprises a molecule or a pharmaceutically acceptable salt thereof, and having reduced or no antimicrobial activity, wherein the molecule is selected from at least one of Structure A, B, C, or D:
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N, 2 ,2-trimethyl propan -1 -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acetyl
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, hl, N-dimethyi glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acet
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l-amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, R4 is hydrogen or dimethyl amino. . or Structure D
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, and R4 is hydrogen or dimethyl amino
  • R 1 Is methyl ethyl prooyl butyl acetyl, alkyl, R?it OH or acetyl R’is 0, OH, acetyl R 4 Is Her acetyl and R5 is H or acetyl and epimeric and tautameric forms thereof.
  • the ocular disease or disorder is selected from the group consisting of abnormal angiogenesis, choroidal neovascularization (CNV), age-related macular degeneration (AMD), neovascular (exudative) age-related macular degeneration (nAMD), diabetic retinopathy, retinal vascular permeability, retinal edema, pterygia, pinguecula, diabetic macular edema (DME), CNV associated with nAMD, sequela associated with retinal ischemia, central retinal vein occlusion, and posterior segment neovascularization.
  • CNV choroidal neovascularization
  • AMD age-related macular degeneration
  • nAMD neovascular (exudative) age-related macular degeneration
  • diabetic retinopathy retinal vascular permeability
  • retinal edema pterygia
  • pinguecula diabetic macular edema
  • DME diabetic macular edem
  • the molecule is:
  • the molecule is:
  • the molecule is:
  • the molecule is:
  • the molecule is provided at a dose of 0.01, 0.05, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, or 1,000 mg.
  • the administration is topical (aqueous, gelatinous or hyaluronic add solution), an insert, or a local ocular administration, subconjunctival injection, slow release insert or orally.
  • the administration is local ocular administration selected from subconjunctival (sub-tenons), intravitreal, retrobulbar, posterior juxtascleral or intracameral administration.
  • the molecule is in a composition further comprises a pharmaceutically acceptable excipient, carrier, vehicle, or polymer.
  • the excipient, carrier or vehicle pharmaceutically acceptable is suitable for oral, topical, intravenous, enteral or parenteral administration.
  • the polymer is selected from the group consisting of chitosan, gelatin, sodium alginate, albumin, poly-L-lactide (PLLA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic co-glycolic acid) (PLGA), polycaprolactone, polyOactide co-caprolactone), poly(methyl methacrylates), poloxamer, poly(ethylene glycol) (PEG), PEG-PLLA, PEG-PLGA, poly(methyl vinyl ether/maleic anhydride), cellulose acetate phthalate, and combinations thereof.
  • PLLA poly(lactic acid)
  • PGA poly(glycolic acid)
  • PLGA poly(lactic co-glycolic acid)
  • polycaprolactone polyOactide co-caprolactone
  • poly(methyl methacrylates) poloxamer
  • PEG poly(ethylene glycol)
  • PEG-PLLA poly(methyl vinyl ether/maleic anhydride)
  • an aspect of the present disclosure relates to a molecule selected from at least one of Structure A, B, C, or D:
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2 ⁇ 2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acetyl
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l-amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acetyl, R
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethy1propan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, R4 is hydrogen or dimethyl amino . or Structure D
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, and R4 is hydrogen or dimethyl amino.
  • the molecule is selected from at least one molecule of claim 3. In another aspect, the molecule is:
  • the molecule is: [0020] In another aspect, wherein the molecule is:
  • the molecule is provided at a dose of 0.01 , 0.05, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, ’ 900, or 1,000 mg.
  • the molecule is formulated for administration that is topical, an insert, or a local ocular administration.
  • the molecule is formulated for administration selected from subconjunctival (sub-tenons), intravitreal, retrobulbar, posterior juxtascleral or intracameral administration.
  • the excipient, carrier or vehicle pharmaceutically acceptable is suitable for oral, topical, intravenous, enteral or parenteral administration.
  • the polymer is selected from the group consisting of chitosan, gelatin, sodium alginate, albumin, poly-L-lactide (PLLA), polyflactic add) (PLA), poly(glycolic add) (PGA), poly(lactic co-glycolic add) (PLGA), polycaprolactone, poly(lactide co-caprolactone), polyfmethyl methacrylates), poloxamer, polyethylene glycol) (PEG), PEG-PLLA, PEG-PLGA, poly(methyl vinyl ether/maleic anhydride), cellulose acetate phthalate, and combinations thereof.
  • an aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a molecule having reduced or no antimicrobial activity and a pharmaceutically acceptable excipient, carrier, vehicle, or polymer, wherein the molecule is selected from at least one of Structure A, B, C, or D:
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimetiiyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acet
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acetyl,
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, R4 is hydrogen or dimethyl amino . or
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l-amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, and R4 is hydrogen or dimethyl amino.
  • R 1 is methyl, ethyl, propyl butyl, acetyl alkyl
  • R 2 is OH or acetyl
  • R 4 is H or acetyl
  • the molecule is provided at a dose of 0.01 , 0.05, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, or 1,000 mg.
  • the molecule is selected from at least one molecule described hereinabove.
  • the molecule is formulated for administration that is topical, an insert, or a local ocular administration.
  • the molecule is formulated for administration selected from subconjunctival (sub-tenons), intravitreal, retrobulbar, posterior juxtascleral or intracameral administration.
  • the excipient, carrier or vehicle is suitable for oral, topical, intravenous, enteral or parenteral administration.
  • the polymer is a water-soluble cellulose selected from hydroxyethylcellulose, hydroxy-n- propylcellulose, hydroxy-n-butylcellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, and ethylhydroxyethylcellulose; starch; dextran; polyvinylpyrrolidone, a polyester selected from compounds under the tradename Eudagrit; or a polyalkylene glycol.
  • the polymer is selected from the group consisting of chitosan, gelatin, sodium alginate, albumin, poly-L-lactide (PLLA), poly(lactic acid) (PLA), poly(glycolic add) (PGA), polyflactic co-glycolic acid) (PLGA), polycaprolactone, poly(lactide co-caprolactone), poly(methyl methacrylates), poloxamer, polyethylene glycol) (PEG), PEG-PLLA, PEG-PLGA, polymethyl vinyl ether/maldc anhydride), cellulose acetate phthalate, and combinations thereof.
  • the molecule is: [0025]
  • the molecule is:
  • an aspect of the present disclosure relates to a molecule having the formula:
  • R 1 is methyl, ethyl propyl, butyl, acetyl alkyl
  • R 2 is OH or acetyl
  • R 3 Is 0, OH, acetyl R*ls H cr acetyl
  • R5 Is H or acetyl.
  • FIG. 1 A shows the experimental timeline and methods.
  • FIG. 1 A Timeline of ocular laser surgeries, drug treatments, dissections, immunohistochemistry, and confocal microscopy. Laser disruption of Bruch’s membrane to induce CNV formation. Topical eye drop administration technique. Enucleation and dissection of eyes: eyes were hemisected to separate anterior and posterior halves, retina was separated from underlying choroid, and radial cuts were made to facilitate flattening of samples for staining, flat mounting, and microscopy.
  • FIGS. 2A to 2B show that minocycline and diacetyl minocycline (DAM) eye drops reduce CNV volume in female and male mice.
  • FIG. 2B Plot of CNV lesion volumes in saline, minocycline, and DAM treatment groups. Each point corresponds to the average volume of CNV lesions in both left and right eyes of a single mouse.
  • a one-way ANOVA with Bonferroni's multiple comparisons test was used to analyze differences between control, minocycline, and DAM treatment groups with data from male and female mice combined. *P ⁇ 0.0005, **P ⁇ 0.001. Error bars represent standard error of the mean.
  • FIGS. 5A to 5C show the antimicrobial activity of minocycline and DAM.
  • FIG. 5A CFU assays to determine antibacterial activity of minocycline and DAM. DAM exhibited no antibacterial activity against E. coll at concentrations up to 10 pg/mL.
  • FIG. 5B Zone of inhibition assays to determine antibacterial activity of minocycline and DAM. DAM exhibited no antibacterial activity against E. colt at concentrations up to 10 pg/mL.
  • FIG. 5C CFU assays to determine antifungal activity of minocycline and DAM. DAM exhibited no antifungal activity against C. albicans at concentrations up to 100 pg/mL. All experiments were repeated in triplicate. Error bars represent standard error of the mean.
  • FIGS.6A and 6B show BEM and Mino exhibit significant MMP-9 inhibition at 60 and 80 ⁇ M (FIG. 6A).
  • the inhibitory potential of BEM against MMP-9 was evaluated in terms of percentage inhibition at various concentrations (20, 40, 60, 80 pM) in comparison to the prototypic inhibitor A'-Isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH) through a colorimetric assay in a 96-well microplate format using a chromogenic substrate (Ac-PLG-[2- mercapto-4-methyi-pentanoyl]-LG-OC2Hs).
  • the inhibitory potential of BEM against MMP-8 was evaluated in terms of percentage inhibition at various concentrations (30, 60, 90, 120 pM) in comparison to the prototypic inhibitor Mlsobutyl- V-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH) through a colorimetric assay in a 96-well microplate format using a chromogenic substrate (Ac-PLG-[2-mercapto-4-methyl- pentanoylJ-LG-OCaHs).
  • FIGS. 8A and 8B Ibal was significantly reduced in N9-microglial cells that were grown in vitro and treated with LPS (25 ng/mL) for 12 hours, and subsequently treated with BEM and Mino at 25 pM concentration for another 12 hours.
  • the western blot was treated with Anti-Ibal rabbit recombinant monoclonal antibody at 1:100 ratio, overnight.
  • Goat anti-rabbit HRP conjugated secondary antibody was added at 1 : 100 and, the blot was visualized with ECL reagent at 1:10.
  • FIG. 10 BEM showed anti-oxidant activity against L-ghitamine induced ROS-oxidative stress.
  • the percentage inhibition of BEM and Mino against L-Glu induced ROS was evaluated in terms of percentage positive control at various concentrations (30, 60, 90, 120 pM). Both BEM and Mino showed a dose-response inhibition of ROS, with highest inhibition at 120 pM.
  • the present inventors found that minocycline and minocycline analog(s) given as eye drops prevent new vasculature in an ocular neovascularization mouse model.
  • the eye drops might be any minocycline analog modified to remove its antimicrobial action, but retain the antiangiogenic properties.
  • the drugs block angiogenesis, in diseases such as age-related macular degeneration and diabetic retinopathy.
  • Treatment currently uses injections into the eye and patients often have poor compliance, which in many cases leads to blindness.
  • the current standard of care is a biologic, which is cost prohibitive.
  • the novel molecules and medications can be easily given as eye drops where compliance should show striking improvement, The treatment is by eyedrop and is painless, with a drug that should be magnitudes less expensive.
  • Minocycline is a tetracycline antibiotic with known immunomodulatory and antiangiogenic properties.
  • the antimicrobial action of minocycline can cause problematic side effects, contribute to antimicrobial resistance, and devastate microbiota, particularly with long-term use and systemic administration.
  • the present inventors tested two alternatives to reduce the potential side effects of minocycline: (1) targeted administration of minocycline via topical eye drops to treat CNV, and (2) modification of minocycline to remove the antimicrobial action, thereby generating a novel modified minocycline analogue, diacetyl minocycline (DAM; also delivered via eye drops), to treat CNV. Both treatment strategies woe tested in a model of CNV in female and male mice.
  • DAM diacetyl minocycline
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l-amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acetyl, R
  • R1 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-trimethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium
  • R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is hydrogen or acetyl, R4 is a hydrogen or acetyl and R5 is a hydrogen or acetyl,
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2,2-triinethylpropan-l -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, R4 is hydrogen or dimethyl amino.
  • Rl is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3- methyl butyl, isopentyl, acetyl, N,2.2 -tri meth ylpropan-1 -amine, azido, amino, nitro, acyl amino, N,N-dimethyl glycylamino, ethoxythiocarbonylthio, diazonium, R2 is hydrogen, methyl, ethyl, propyl, acetyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl butyl, isopentyl, acetyl, R3 is H or acetyl, and R4 is hydrogen or dimethyl amino. including those that follow.
  • the molecules of the present invention can be combined with any pharmaceutically acceptable excipients, carriers, solvents, diluents, salts, buffers, and/or polymers.
  • Various salt forms can be used to alter the physicochemical properties to increase solubility, stability, bioavailability and enable the use of easier formulation strategies at lower doses.
  • Some examples not limited to but including, salts of hydrochloride, hydrobromide, sulfate, tosylate, mesylate, napsylate, besylate oxalate, malate, phosphate, pamoate, tartarate, fumarate, citrate, hippurate, benzoate, succinate, acetate, or carbonate.
  • Non-limiting examples of pharmaceutically acceptable carriers for delivery to the eye include, but are not limited to, suspension-type eye drops, eye wash, an eye gel, an eye cream, ointment, gel, liposomal dispersion, self-emulsifying drag delivery systems, colloidal microparticle suspension, and the like, and other preparations known to those of skill in the art to be suitable for ocular administration.
  • the pharmaceutical compositions of the present invention containing human comeal epithelial stem cells, the human comeal epithelial stem cell supernatant, or both may be administered using commonly known devices configured for the delivery of the pharmaceutical compositions in the form of to the region surrounding the eye.
  • An ocular insert may also include a biodegradable controlled release polymeric matrix, that can be implanted in the conjunctiva, sclera, pars plana, anterior segment, or posterior segment of the eye.
  • the pharmaceutically acceptable carrier of the pharmaceutical composition of the invention may comprise a wide variety of non-active ingredients which are useful for formulation purposes and which do not materially affect the novel and useful properties of human comeal epithelial stem cells, the human comeal epithelial stem cell supernatant, or both.
  • the present invention may also include suitable thickeners known to those of ordinary skill in the art of ophthalmic formulation, e.g., cellulosic polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyhnethylcellulose (HPMC), and sodium carboxymethylcellulose (NaCMC), and other swellable hydrophilic polymers such as polyvinyl alcohol (PVA), hyaluronic acid or a salt thereof (e.g., sodium hyaluronate), and crosslinked acrylic acid polymers commonly referred to as "carbomers" that may or may not be biodegradable.
  • cellulosic polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyhnethylcellulose (HPMC), and sodium carboxymethylcellulose (NaCMC)
  • PVA polyvinyl alcohol
  • the preferred amount of any thickener is such that a viscosity in the range of about 15 cps to 25 cps is provided, as a solution having a viscosity in the aforementioned range is generally considered optimal for both comfort and retention of the formulation in the eye.
  • the present invention may also include suitable isotonic agents and buffering agents commonly used in ophthalmic formulations, providing that the osmotic pressure of the solution does not deviate from that of lacrymal fluid by more than 2-3% and that the pH of the formulation is maintained in the range of about 6.5 to about 8.0, preferably in the range of about 6.8 to about 7.8, and optimally at a pH of about 7.4.
  • buffering agents include carbonates such as phosphate, sodium and potassium bicarbonate.
  • the present invention may also be used in a hydrogel, dispersion, or colloidal suspension.
  • Hydrogels are typically made by incorporating a gel-forming polymer such as those set forth above as suitable thickening agents, except that a formulation referred to in the art as a "hydrogel” typically has a higher viscosity than a formulation referred to as a "thickened” solution or suspension.
  • a pharmaceutical composition may also be prepared that forms a hydrogel in situ following application to the eye.
  • Such gels are liquid at room temperature but gel at higher temperatures (and thus are termed "thermoreversible” hydrogels), such as when placed in contact with body fluids.
  • Biocompatible polymers that impart this property include acrylic acid polymers and copolymers, N-isopropylacrylamide derivatives, and block copolymers of ethylene oxide and propylene oxide.
  • the present invention may also prepared in the form of a dispersion or colloidal suspension.
  • the present invention may also be used in colloidal suspensions formed from microparticles, e.g., microspheres, nanospheres, microcapsules, or nanocapsules, where the microspheres and nanospheres are generally monolithic particles of a polymer matrix in which the pharmaceutical composition is trapped, adsorbed, or otherwise contained, while with microcapsules and nanocapsules, the formulation is actually encapsulated.
  • compositions for use with the present invention may be of a wide range of types known to those of skill in the art.
  • the present invention can be provided as an ophthalmic solution or suspension, in which case the carrier is at least partially aqueous and can support living cells.
  • the pharmaceutical compositions may also be ointments, in which case the pharmaceutically acceptable carrier comprises an ointment base, e.g., having a melting or softening point close to body temperature, and any ointment bases commonly used in ophthalmic preparations may be advantageously employed.
  • Common ointment bases include petrolatum and mixtures of petrolatum and mineral oil.
  • controlled release refers to an agent-containing formulation or fraction thereof in which release of the active agent is not immediate, i.e., with a "controlled release” formulation, administration does not result in immediate release of the agent into an absorption pool.
  • the term is used interchangeably with "non- immediate release” as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995).
  • controlled release refers to "sustained release” rather than to "delayed release” formulations.
  • sustained release (synonymous with "extended release”) is used in its conventional sense to refer to a formulation that provides for gradual release of an active agent over an extended period of time.
  • the human comeal epithelial stem cells, the human comeal epithelial stem cell supernatant, or both, and other agents may be released over a period of at least 2, 4, 6, 8, 10, 12 hours, at least 18 hours, at least 24 hours, at least 48 hours, at least 3 days, at least 7 days, or longer.
  • the supernatant may be isolated after incubating the cells for at least 18 hours, at least 24 hours, at least 48 hours, at least 3 days, at least 7 days, or longer.
  • Hie human comeal epithelial stem cells, the human comeal epithelial stem cell supernatant, or both or pharmaceutical composition can be administered, as described herein, according to any of a number of standard methods including, but not limited to injection, drops, serum, spray, time-release implant, transdermal patch, eye drops, gels, ointments, orally, intraocular injection, subconjunctival injection, peri-/retrobulbar injection, transdermally, or topically to the ocular region by an eye drop dispenser, or the like, including topical intranasal administration or administration by inhalant, and the like, spray, emulsion, suspension, via any drug carriers as sponges, contact lenses, polymers, microspheres, and implants.
  • standard methods including, but not limited to injection, drops, serum, spray, time-release implant, transdermal patch, eye drops, gels, ointments, orally, intraocular injection, subconjunctival injection, peri-/retrobulbar injection, transderma
  • Topical ophthalmic products may be packaged in multidose form, and may also include preservatives to prevent microbial contamination during use.
  • Suitable preservatives include: biguanides, hydrogen peroxide, hydrogen peroxide producers, benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquatemium-1, or other agents known to those skilled in the art.
  • Such preservatives are typically employed at a level of from 0.001 to 1% (w/w).
  • Unit dose formulations of the present invention will be sterile, but typically unpresaved. Such formulations, therefore, generally will not contain preservatives.
  • the pharmaceutical composition may further include corticosteroids.
  • corticosteroids include cortisone, prednisolone, triamcinolone, flurometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone triamcinolone, betamethasone, prednisone, methylprednisolone, triamcinolone acetonide, triamcinolone hexacetonide, paramethasone acetate, diflorasone, fluocinolone and fluocinonide, derivatives thereof, and mixtures thereof.
  • the pharmaceutical composition may further comprise immunosuppressive agents.
  • immunosuppressive agents include cyclosporine, azathioprine, tacrolimus, TNFalpha-inhibitors, infliximab, (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), and etanercept (Enbrel) and derivatives thereof.
  • the pharmaceutical composition may further comprise antiviral agents.
  • antiviral agents include and are not limited to, interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, valciclovir, dideoxycytidine, and derivatives thereof.
  • the pharmaceutical composition may further comprise antihistamines.
  • antihistamines include, and are not limited to, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazme doxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, and derivatives thereof.
  • CNV was induced via laser injury in female and male C57BL/6J mice.
  • Minocycline, DAM, or saline was administered via topical eye drops twice a day for 2 weeks starting the day after laser injury.
  • CNV volume was measured using immunohistochemistry labeling and confocal microscopy.
  • Minocycline reduced lesion volume by 79% (P ⁇ 0.0004) in female and male mice.
  • DAM reduced lesion volume by 73% (P ⁇ 0.001) in female and male mice. There was no significant difference in lesion volume between minocycline and DAM treatment groups or between female and male mice.
  • CNV Laser-Induced Choroidal Neovascularization.
  • CNV was induced in male and female C57BL/6J mice (7 9 weeks old) via laser disruption of Bruch's membrane as previously described.39-41 Briefly, pupils were dilated with topical 1% tropicamide and 2.5% phenylephrine (Alcon, Fort Worth, TX, USA), and mice were anesthetized with isoflurane (1.5-2% at 0.5 L/min) during ocular surgeries. The retina was visualized with an indirect ophthalmoscope using a 30- diopter lens.
  • Bruch's membrane was disrupted via laser ablation by an individual masked to treatment groups using a Nd:YAG 532-nm laser (Alcon) adjusted to 80 to 90 mW with an exposure time of 0.100 seconds and a spot size of 50 pm. Breakage of Bruch's membrane was verified with observation of bubble formation. Three to four laser shots were placed in both left and right eyes at approximately two disc diameters away from the edge of the optic nerve. One mouse was used as a nonlasered control for visualization of normal choroid-RPE structure.
  • Minocycline HC1 Sigma-Aldrich, St. Louis, MO, USA, catalog no. 13614-98-7) and DAM HCI (>98% purity, structure confirmed by Liquid Chromatography-Mass Spectrometry (LCMS) and Nuclear Magnetic Resonance (NMR), created by MS, and purchased from AttachChem, Lubbock, TX, USA) were dissolved and suspended, respectively, in sterile saline (0.9% NaCl in water) to a concentration of 10 mg/mL. Sterile saline (0.9% NaCl in water) was used for controls.
  • LCMS Liquid Chromatography-Mass Spectrometry
  • NMR Nuclear Magnetic Resonance
  • Eyes were transferred to lx PBS for further dissection. Eyes were hemisected using microsurgery scissors and fine tweezers to separate the anterior and posterior halves of the eyes. The crystalline lens and vitreous humor were removed. Retinas were separated from the underlying choroid/sclera eye cups. Radial cuts were made in the choroidal sections to allow them to flatten when mounted.
  • Fluorescent signals for DAPI (405 nm, blue), phalloidin (488 run, green), and isolectin IB4 (568 nm, red) were used to visualize nuclei, RPE, and blood vessels, respectively.
  • Choroid/sclera eye cups were washed with cold Immunocytochemistry (ICC) buffer (0.5% bovine serum albumin, 0.2% Tween 20, 0.05% sodium azide) in lx PBS (9 g/L NaCl, 0.232 g/L KH2PO4, 0.703 g/L Na 2 HPO 4 [pH 7.3]), then incubated with the fluorescent dyes at 4°C with gentle rotation for 4 hours in a humidified chamber.
  • ICC Immunocytochemistry
  • CNV Evaluation and Quantification CNV complexes were visualized using a Nikon Ti-E inverted microscope with Al confocal module (Nikon, Melville, NY, USA). Horizontal optical sections were collected from the surface of the RPE/choroid/sclera complexes to a depth at which choroidal vascular networks could no longer be observed. All images were taken at 20* magnification at 1024 x 1024-pixel resolution and at a depth of 8 bits per channel. All lesions were imaged and evaluated for each mouse.
  • CNV bum lesions were excluded from analysis if an error occurred during laser surgeries (one lesion), if lesions were damaged during eye removal or dissection (six lesions), if two lesions merged as a result of being placed too close together (four lesions), or if a major non-CNV vessel crossed the lesion (one lesion).
  • CNV volumes were quantified in cubic micrometers as previously described, 39, 40 with the exceptions that NIS-Elements Imaging Software (Nikon) was used for analysis and non-CNV blood vessels on the periphery of microscopy frames were excluded from analysis. Images of individual cross sections were saved as confocal ND2 files and used to generate three-dimensional reconstructions of each CNV complex. All settings were kept constant across all images. The red channel (TRJTC, isolectin IB4) was used to identify CNV complexes.
  • All three channels (blue, DAPI, nuclei; green, FITC, RPE; and red, TRJTC, blood vessels) were used to draw a Bezier region of interest fbr each lesion to exclude any blood vessels outside the diameter of the lesions.
  • a conservative intensity threshold for the red channel was used to exclude any background signal.
  • the summation of fluorescent area within the Bezier regions of interest within each horizontal section was used as an index for CNV volume. All imaging and analyses were carried out by an individual blinded to treatment groups.
  • results of the volume measurements were analyzed with Prism version 7.00 (GraphPad Software, San Diego, CA, USA). CNV volumes were averaged across all bums for each mouse. CNV volumes were expressed as mean ⁇ SEM. Two-way analyses of variance (ANOVAs) with Tukey's multiple comparisons test were used to determine any differences in CNV volume between treatment groups and between female and male mice. A one-way ANOVA with Bonferroni's multiple comparisons test was used to analyze differences between control, minocycline, and DAM treatment groups with data from male and female mice combined. [0070] Antimicrobial Activity of Minocycline and DAM.
  • ZOI zone of inhibition
  • CPU colony-forming unit
  • MH Mueller Hinton
  • MH broth #70192; Sigma-Aldrich
  • ODsoo 0.1 (which is equivalent to the 0.5 McFarland standard; ⁇ 1 x 10 7 bacterial cell/mL) in MH broth according to the standard guidelines of the National Committee for Clinical Laboratory Standards.44,45
  • a sterile cotton swab was dipped into the adjusted bacterial culture, and a lawn of bacteria was spread on an LB Agar plate.
  • test discs were prepared by adding 20 pL DAM, minocycline, or sterile water solutions onto 6 mm diameter blank BD BBL Sensi-Disc Antimicrobial Susceptibility Test Discs (#831039; Fisher Scientific, Waltham, MA, USA). Triplicate discs were distributed evenly onto the LB Agar surface. The plates were then incubated at 37°C for 24 hours before the results were read and recorded. The diameters of the zones of complete and clear inhibition, including the diameter of the disc, were measured to the nearest millimeter with a caliper.
  • C. albicans (ATCC 3147, Pamela Parr) was grown in Yeast Peptone Dextrose (YPD) broth at 35°C for 48 hours. Aliquots of the 48 hour cultures were inoculated into fresh YPD broth to an ODeoo ⁇ 1.00. DAM was diluted in YPD broth at concentrations of 10, 25, 50, or 100 pg/mL and 1 mL aliquots of each were pipetted in triplicate into the wells of a 24 microtiter well plate.
  • the wells were inoculated using 10 pL aliquots of the adjusted cultures for an initial inoculum of 10 s CFU/mL and the microtiter well plates were incubated at 35°C. After 24 hours of incubation, the cultures were serially diluted 10-fold, plated on YPD agar, and incubated at 35°C for 24 hours to quantify the CFU/mL present.
  • MMP-9 inhibition was tested using a dose response of 0, 25, 50, and 75 pM minocycline and DAM using the Abeam assay (AB284517; Abeam, Waltham, MA, USA).
  • Minocycline and DAM Inhibit Experimental Choroidal Neovascularization.
  • DAM had no antibacterial activity against E. coli at doses 400 times higher than the antibacterial dose of minocycline (Fig. 5). DAM had no antifungal activity against C. albicans at doses twice the antifungal dose of minocycline (Fig. 5).
  • the present inventors show that minocycline and/or DAM eye drops increase effectiveness and patient satisfaction while lowering the overall treatment burden of current anti- VEGF injections used in treating vision-threatening CNV.
  • the novel molecules, compositions and methods lower the cost of treatment for CNV-related disorders compared to intravitreal injections because they require fewer serial, or even, no injections. Not having to inject the active agent directly into or about the eye decreases the overall treatment burden as patients’ ophthalmology visits are decreased.
  • another benefit of the present invention is the lack of need for a specialist to administer shots, which also increases treatment accessibility. Topical administration (as opposed to intravitreal injection) significantly reduces the risk for adverse events, such as endophthalmitis, infection, and eye irritation.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps.
  • “comprising” may be replaced with “consisting essentially of” or “consisting of*.
  • the phrase “consisting essentially of’ requires the specified integers) or steps as well as those that do not materially affect the character or function of the claimed invention.
  • the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/'process step or a limitation) or group of integers (e.g., foature(s), elements), characteristics), properties), method/process steps or limitation(s)) only.
  • words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
  • the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
  • a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
  • each dependent claim can depend both from the independent claim and from each of the prior dependent claims for each and every claim so long as the prior claim provides a proper antecedent basis for a claim term or element.
  • Campochiaro PA the First ARVO/Pfizer Institute Working Group. Ocular versus extraocular neovascularization: mirror images or vague resemblances. Invest Ophthalmol Vis Sci. 2006; 47(2): 462-474.
  • VEGF is major stimulator in model of choroidal neovascularization.
  • Aqueous interleukin-6 (IL-6) level is a marker for treatment resistance to bevacizumab in age-related macular degeneration — aqueous cytokines after bevacizumab. Open J Ophthalmol. 2014; 2014: 24-30. [PMC free article]

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Abstract

L'invention concerne des molécules, des compositions et des méthodes de traitement d'une maladie ou d'un trouble oculaire, comprenant : l'administration à un sujet d'une composition pharmaceutique aqueuse, la composition comprenant une molécule, ou un sel pharmaceutiquement acceptable de celle-ci, et ayant une activité antimicrobienne réduite ou nulle, la molécule étant choisie parmi au moins l'une de la structure A, B, C ou D dont les groupes-R sont listés pour chacune. La maladie ou le trouble oculaire est sélectionné dans le groupe constitué par une angiogenèse anormale, une néovascularisation choroïdienne (NVC), une dégénérescence maculaire liée à l'âge (DMLA), une dégénérescence maculaire liée à l'âge néovasculaire (exsudative) (DMLAn), une rétinopathie diabétique, une perméabilité vasculaire rétinienne, un œdème rétinien, une rétinopathie diabétique, un œdème maculaire diabétique (OMD), une NVC associée à une DMLAn, une séquelle, associée à une ischémie rétinienne, une occlusion veineuse rétinienne centrale, et une néovascularisation de segment postérieur.
PCT/US2024/052809 2023-10-24 2024-10-24 Traitement de la dégénérescence rétinienne avec de la minocycline et des analogues de la minocycline Pending WO2025090761A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100173991A1 (en) * 2007-07-20 2010-07-08 Peter Lorenz Method for the synthesis of a-ring aromatized acetyl minocyclines
US20210403416A1 (en) * 2018-06-13 2021-12-30 Texas Tech University System Novel Modified Tetracyclines for Treatment of Alcohol Use Disorder, Pain and Other Disorders Involving Potential Inflammatory Processes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100173991A1 (en) * 2007-07-20 2010-07-08 Peter Lorenz Method for the synthesis of a-ring aromatized acetyl minocyclines
US20210403416A1 (en) * 2018-06-13 2021-12-30 Texas Tech University System Novel Modified Tetracyclines for Treatment of Alcohol Use Disorder, Pain and Other Disorders Involving Potential Inflammatory Processes

Non-Patent Citations (3)

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Title
DATABASE PUBCHEM COMPOUND 26 December 2011 (2011-12-26), XP093311832, Database accession no. 54685925 *
LI XIAOLI, ZHANG WENHUA, YE ZHIQIANG, PEI SHUAILI, ZHENG DONGLIANG, ZHU LIN: "Safety evaluation and pharmacodynamics of minocycline hydrochloride eye drops", MOLECULAR VISION, MOLECULAR VISION, US, vol. 28, 21 December 2022 (2022-12-21), US , pages 460 - 479, XP093312625, ISSN: 1090-0535 *
WILLMS JOSHUA O., MITCHELL KELLY, SHASHTRI MAYANK, SUNDIN OLOF, LIU XIAOBO, PANTHAGANI PRANEETHA, TRAN PHAT, NAVARRO STEPHANY, SNI: "Minocycline and Diacetyl Minocycline Eye Drops Reduce Ocular Neovascularization in Mice", TRANSLATIONAL VISION SCIENCE & TECHNOLOGY, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, US, vol. 12, no. 12, 8 December 2023 (2023-12-08), US , pages 10, XP093312628, ISSN: 2164-2591, DOI: 10.1167/tvst.12.12.10 *

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