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
  • A61K31/505—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
  • 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
  • A61K47/26—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
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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 or implants
• • 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
  • A61P35/00—Antineoplastic agents

Definitions

• Proliferative vitreoretinopathy is a clinical syndrome that occurs after rhegmatogenous retinal detachment, such as caused by a break in the retina (e.g., retinal tear or retinal hole) and its surgical repair.
• the pathogenesis of PVR involves the release of cells into the vitreous cavity (extraretinal cells) where they replicate and form periretinal fibrocellular membranes on the inner and/or outer surfaces of the retina, creating shortening of the retina and retinal traction.
• PVR is characterized by intraretinal fibrosis and reduced elasticity, which leads to tractional elevation of the retina and subsequently new retina breaks and recurrent retinal detachment.
• PVR can occur in untreated eyes with retinal detachment or after retinal procedures such as retinal cryopexy, laser retinopexy, pneumatic retinopexy, scleral buckle and/or pars plana vitrectomy.
• retinal cryopexy laser retinopexy
• pneumatic retinopexy pneumatic retinopexy
• scleral buckle and/or pars plana vitrectomy.
• the prevalence of PVR varies widely but is estimated to range about 5 to 12% of all rhegmatogenous retinal detachment cases (Kwon et al., Dev Ophthalmol., 2016; 55:154-62).
• PVR and its associated retinal traction is one of the main reasons for failure (i.e., recurrent retinal detachment) of initially successful repairs of retinal detachment and is present in approximately 75% of failed retinal detachment repairs (Sadaka et al., Clinical Ophthalmology, 2016; 10 1811-1817).
• Retinal detachment surgery can include scleral buckling, pneumatic retinopexy, and pars plana vitrectomy (PPV).
• Pneumatic retinopexy involves injecting gas into the vitreous cavity while PPV for retinal detachment involves removal of the vitreous and its replacement with a tamponade agent, such as silicone oil or gas.
• Tamponade agents provide surface tension across retinal breaks, preventing further fluid flow into the subretinal space until the retinopexy (photocoagulation or cryopexy) provides a permanent seal.
• silicone oil is often used for complex detachments involving PVR. Commonly used viscosities of silicone oils include 1,000 and 5,000 centistokes.
• Silicone oils have a lower specific gravity (0.97 g/mL) than vitreous (1.005-1.008 g/mL), and as a result, they float in the vitreous cavity. Similarly, gases also float in the vitreous cavity due to their very low specific gravities (-0.001 g/mL) and they have a much greater buoyancy than silicone oils. Heavier silicone oils (HSOs) and perfluorocarbon liquids have been used for inferior retinal breaks because the lighter silicone oils and gases may be less effective tamponade for retinal breaks at these locations.
• HSOs Heavier silicone oils
• perfluorocarbon liquids have been used for inferior retinal breaks because the lighter silicone oils and gases may be less effective tamponade for retinal breaks at these locations.
• anti-inflammatory and immunosuppressive agents have been administered to control PVR and reduce the failure rates of PPV.
• Use of anti-inflammatory or immunosuppressive agents may be beneficial for subjects at higher risk of PVR.
• Methotrexate is an antineoplastic antimetabolite with immunosuppressant properties and inhibits enzymes requiring folate as a cofactor, including enzymes involved in nucleotide biosynthesis necessary for DNA replication.
• MTX has been used to treat chronic inflammatory and fibrotic conditions.
• MTX has been used to treat uveitis, pemphigoids, scleritis and episcleritis, and primary intraocular lymphoma.
• Desirable are formulations of MTX fortreating PVR following retinal detachment, particularly for cases when silicone oil is used as the preferred tamponade agent, as well as for treating other ocular disorders amenable to treatment with MTX, such as intraocular lymphoma and intraocular inflammatory conditions.
• the present disclosure provides a composition comprising methotrexate (MTX), and a density enhancing agent.
• the composition is characterized by a transit time of less than 10 min through a silicone oil (SiO) of 1 cm depth.
• the SiO is SiO used in treatment of retinal detachment.
• the SiO is SiO having a viscosity of at least 1000 centistoke, e.g., polydimethyl siloxane having viscosity of 1000 centistoke.
• the SiO is SiO having a viscosity of about 5000 centistoke.
• the SiO is polydimethyl siloxane having a viscosity of about 5000 centistoke.
• the density enhancing agent is selected from sucrose, trehalose, glucose, carbopol, polyvinyl acetate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, polyethylene glycol (PEG), glycerol, poly(lactide) (PEA), poly(lactide-co-glycolide) (PLGA), polyglycolide (PGA), polyhydroxybutyric acid, polycaprolactone, polyvalerolactone, polyphosphazene, polyorthoester, cyclodextrin, and mixtures thereof.
• the density enhancing agent is used in an appropriate amount to provide the desired density.
• the density of the composition is 1.01 g/cm 3 or greater. In some embodiments, the density of the composition is about 1.01 g/cm 3 to about 1.08 g/cm 3 .
• the composition further comprises a surfactant.
• the surfactant is a non-ionic surfactant.
• the surfactant can enhance the dispersion of the MTX in the aqueous phase.
• the surfactant is selected from polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan mono-oleate (Tween 80), polyoxyethylene (20) sorbitan tristearate (Tween 65), polyoxyethylene (20) sorbitan tri-oleate (Tween 85), sorbitan trioleate (Span 85), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan mono-oleate (Span 80), and sorbitan tristearate (Span 65).
• the surfactant is Tween 20 (polysorbate 20) or Tween 80 (polysorbate 80).
• the surfactant is present at about 0.001 w/v to about 0.05% w/v.
• the composition includes a buffering agent.
• the buffering agent is a pharmaceutically acceptable buffering agent, in particular for intravitreal administration.
• the buffering agent is borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, biphosphate, tromethamine, hydroxyethyl morpholine, or THAM (trishydroxymethylamino-methane).
• the composition has a pH of about 6 to 8. In some embodiments, the composition has a pH of about 6.5 to about 7.5. In some embodiments, the composition has a pH appropriate for intravitreal administration.
• the composition has MTX, or a pharmaceutical salt thereof, at a concentration of about 2 mg/mL to about 20 mg/mL. In some embodiments, the MTX, or a pharmaceutical salt thereof, is at a concentration of about 5 mg/mL to about 15 mg/mL.
• the MTX composition is used to prevent or to reduce the risk of or to treat proliferative vitreoretinopathy (PVR).
• a method of preventing or reducing the risk of or treating PVR comprises administering to an eye of a subject in need thereof a therapeutically effective amount of a composition described herein.
• the composition is administered intravitreally.
• the subject for treatment with the composition has suffered trauma to the eye.
• the subject has suffered a retinal detachment.
• the eye of the subject for treatment has been treated with vitreoretinal surgery for retinal detachment.
• the retinal detachment is primary retinal detachment or secondary retinal detachment.
• the retinal detachment is rhegmatogenous retinal detachment.
• the eye of the subject for treatment is treated or has been treated by administration of silicone oil (SiO) into the posterior segment, such as a tamponade for retinal detachment.
• the MTX composition is administered by intravitreal injection into the SiO in the vitreous cavity.
• the MTX composition is co-administered with the SiO administered to treat the retinal detachment.
• the SiO has a viscosity of at least 1000 centistoke. In some embodiments, the SiO has a viscosity of about 1000 centistoke or about 5000 centistoke.
• the dose of MTX administered is a therapeutically effective amount at a frequency and duration to prevent or reduce the risk of or to treat PVR.
• the dose of MTX administered is about 50 pig to about 600 pig.
• the dose of MTX administered is about 400 pig.
• the composition is administered once per day, twice per week, or once a week.
• the subject is treated with the composition for at least one week, at least two weeks, at least three weeks, at least one month, at least 6 months, at least 9 months, or for 1 year.
• the subject is treated with the composition for the duration of treatment with the gas in the eye or until removal of the SiO.
• the subject for treatment with the composition has one or more risk factors for developing PVR.
• the subject for treatment has a prior history of one or more of the following conditions: chronic ocular inflammation, infectious retinitis, multiple retinal detachments, large retinal breaks or giant retinal tears, multiple retinal breaks, ocular trauma, retinal detachment associated with vitreous hemorrhage, choroidal detachment, and combinations thereof.
• the subject for treatment has had vitreous or subretinal hemorrhage, excessive cryotherapy, pigment release during endodrainage, or combinations thereof.
• the compositions herein are also useful for treating other diseases, disorders, or conditions that would benefit from intravitreal administration of methotrexate.
• compositions herein are used to treat intraocular lymphoma.
• a method of treating intraocular lymphoma comprises administering intravitreally to an eye of a subject with intraocular lymphoma a therapeutically effective amount of a composition disclosed herein, including the exemplary formulations disclosed herein.
• the intraocular lymphoma to be treated is primary vitreoretinal lymphoma (PVRL).
• the intraocular lymphoma e.g., PVRL
• PCNSL cerebral nervous system lymphoma
• the intraocular lymphoma is diffuse large B-cell lymphoma.
• compositions herein are used to treat intraocular inflammation.
• a method of treating intraocular inflammation comprises administering intravitreally to a subject with intraocular inflammation a therapeutically effective amount of a composition disclosed herein.
• the inflammatory diseases, disorders, or conditions for treatment with the MTX compositions herein include, among others, uveitis, for example pan uveitis, intermediate uveitis, and posterior uveitis, particularly non-infectious posterior uveitis; cystoid macular edema (CME); macular edema, for example accompanying uveitis or diabetic macular edema; choroidal neovascularization; and prosthetic membranopathy.
• uveitis for example pan uveitis, intermediate uveitis, and posterior uveitis, particularly non-infectious posterior uveitis
• cystoid macular edema (CME) cystoid macular edema
• macular edema for example accompanying uveitis or diabetic macular edema
• choroidal neovascularization choroidal neovascularization
• the dose of MTX administered is a therapeutically effective amount at a frequency and duration to prevent or reduce the risk of or to treat intraocular lymphoma or to prevent or reduce the risk of or to treat intraocular inflammation.
• the MTX composition is administered once every 4 weeks (month), once every two weeks, once a week, two times a week, three times a week, or four times a week to treat the intraocular lymphoma or intraocular inflammation.
• the treatment regimen includes an induction phase, and optionally a consolidation phase, and/or a maintenance phase.
• the induction phase is administration of the MTX composition two times a week, three times a week, up to four times a week.
• the consolidation phase when present, comprises administration once a week or two times a week.
• the maintenance phase when present, comprises administration once every two weeks, once every three weeks, or once every month.
• kits comprising the MTX compositions described herein.
• the MTX composition can be provided as multi dose vial or single dose vial.
• the MTX composition can be in dry form, which is reconstituted with an appropriate solvent for preparing the composition for administration.
• FIG. 1 illustrates the properties of formulations FI, F2, and F3 in transiting through polydimethyl siloxane 5000 centistoke oil to reach the bottom of the silicone oil layer, i.e., oil-buffer interface, of a non-miscible silicone oil/buffer mixture.
• PVR proliferative vitreoretinopathy
• the composition of MTX is used as prophylaxis against PVR, such as following retinal detachment surgery.
• the present compositions provide sufficient rate of transit through silicone oil (SiO) used in retinal detachment surgery to deliver MTX in a therapeutically effective amount to prevent, reduce the risk of, or treat PVR.
• the composition of MTX is used to treat intraocular lymphoma, such as primary vitreoretinal lymphoma (PVRL).
• intraocular lymphoma such as primary vitreoretinal lymphoma (PVRL).
• PVRL primary vitreoretinal lymphoma
• compositions of MTX are used to treat intraocular inflammation, such as uveitis; cystoid macular edema (CME) or diabetic macular edema; choroidal neovascularization; or prosthetic membranopathy.
• intraocular inflammation such as uveitis; cystoid macular edema (CME) or diabetic macular edema; choroidal neovascularization; or prosthetic membranopathy.
• the term “treating” or “treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a subject, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
• adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and is ascertainable by one of ordinary skill in the art.
• prophylactic treatment refers to a treatment administered to a subject who does not display signs or symptoms of a disease, pathology, or medical disorder, or displays only early signs or symptoms of a disease, pathology, or disorder, for the purpose of diminishing, preventing, or decreasing the risk of developing the disease, pathology, or medical disorder.
• a prophylactic treatment functions as a preventative treatment against a disease or disorder.
• the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease or disorder, or a decrease in the rate of advancement of a disease or disorder, and also includes amounts effective to enhance normal physiological function.
• the term “pharmaceutically acceptable” refers to those compounds, biologic agents, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for administration to a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
• the present disclosure provides a composition comprising MTX, or a pharmaceutically acceptable salt thereof, and a density enhancing agent.
• the density enhancing agent is present in an amount effective to provide a transit rate of less than 10 min in 1 ml of silicone oil (SiO).
• a “transit rate” refers to the time in which the MTX composition when applied to SiO layer separated from a non-miscible aqueous layer, preferably phosphate buffered saline (PBS), reaches the interface of the SiO and aqueous layer.
• the transit rate can be referred to as the “sink rate.”
• the transit or sink rate of the composition is less than 10 min, less than 8 min, less than 7 min, less than 6 min, or less than 5 min in 1 ml of SiO having a depth of 1 cm.
• the transit rate or sink rate of the composition is measured in SiO used as a tamponade for treating retinal detachment.
• the SiO has a lower density than water.
• the SiO layer floats on top of an aqueous layer, and the MTX composition sinks in the SiO to the interface of the SiO and aqueous layer.
• the transit rate or sink rate is in SiO having a viscosity of at least 1000 centistoke. In some embodiments, the SiO has a viscosity of about 1000 centistoke. In some embodiments, the SiO having a viscosity of 1000 centistoke is polydimethyl siloxane 1000 centistoke oil.
• the transit rate or sink rate is in SiO having a viscosity of about 5000 centistoke.
• the SiO having a viscosity of 5000 centistoke is polydimethyl siloxane 5000 centistoke oil.
• the density of the MTX composition is higher than the density of the SiO to provide an appropriate transit rate or sink rate.
• the density of the composition is at least about 1.01 g/cm 3 , at least about 1.02 g/cm 3 , at least about 1.03 g/cm 3 , at least about 1.04 g/cm 3 , at least about 1.05 g/cm 3 , at least about 1.06 g/cm 3 , at least about 1.07 g/cm 3 , at least about 1.08 g/cm 3 , at least about 1.09 g/cm 3 , at least about 1.10 g/cm 3 , at least about 1.11 g/cm 3 , at least about 1.12 g/cm 3 , at least about 1.13 g/cm 3 , at least about 1.14 g/cm 3 , at least about 1.15 g/cm 3 , at least about 1.20 g/cm 3 ,
• the density of the MTX composition is about 1.01 to about 1.2 g/cm 3 , about 1.02 g/cm to about 1.2 g/cm , about 1.03 g/cm to about 1.2 g/cm , about 1.04 g/cm to about
• 1.2 g/cm about 1.05 g/cm to about 1.2 g/cm , about 1.06 g/cm to about 1.2 g/cm , about 1.07 g/cm to about 1.2 g/cm , about 1.08 g/cm to about 1.2 g/cm , about 1.09 g/cm to about 1.2 g/cm , about 1.10 g/cm to about 1.2 g/cm , about 1.11 g/cm to about 1.2 g/cm , about 1.12 g/cm to about
• the composition has a density of about 1.01 g/cm 3 to about 1.08 g/cm 3 at 20°C.
• the density of the composition is about 1.01 to about 1.25 g/cm 3 at 20°C. In some embodiments, the density of the composition is about 1.02 to about 1.2 g/cm 3 at 20°C. In some embodiments, the density of the composition is about 1.03 to about 1.15 g/cm 3 at 20°C. In some embodiments, the density of the composition is about 1.04 to about 1.1 g/cm 3 at 20°C.
• the density of the composition is about 1.01 g/iuL, about 1.02 g/cm 3 , about 1.03 g/cm , about 1.04 g/cm , about 1.05 g/cm , about 1.06 g/cm , about 1.07 g/cm , about 1.08 g/cm , about 1.09 g/cm , about 1.10 g/cm , about 1.11 g/cm , about 1.12 g/cm , about 1.13 g/cm , about 1.14 g/cm , about 1.15 g/cm , about 1.16 g/cm , about 1.17 g/cm , about 1.18 g/cm , about 1.19 g/iuL, about 1.2 g/cm , about 1.21 g/cm , about 1.22 g/cm , about 1.23 g/cm , about 1.24 g/cm , about 1.19 g/i
• the SiO is heavy silicone oil (HSO), which refers to SiO that has a higher density than the density of water.
• HSO heavy silicone oil
• the aqueous layer floats on top of the HSO layer.
• the MTX composition is formulated to have a lower density than the density of HSO, thus allowing the MTX composition to float from the SiO to the interface of the SiO and aqueous layer.
• the transit rate of the MTX composition is less than 10 min in 1 ml of HSO at a depth of 1 cm.
• the transit rate of the MTX composition is less than 8 min, less than 7 min, less than 6 min, or less than 5 min in 1 ml of HSO having a depth of 1 cm.
• the MTX composition is applied to the bottom of the SiO layer 1 cm away from the interface of the HSO and the aqueous layer to assess the transit rate.
• the HSO is Oxane HD (mixture of 5700-centistoke SiO and RMN-3, a partially fluorinated olefin; density of 1.02 g/cm 3 and a viscosity of 3,300-3,500 mPas at 25°C), Densiron 68 (mixture of perfluorohexyloctane (F6H8) and 5,000-centistoke silicone oil; density 1.06 g/cm 3 ; viscosity 1400 mPas at 25°C), or HSV-45 3000.
• Oxane HD mixture of 5700-centistoke SiO and RMN-3, a partially fluorinated olefin; density of 1.02 g/cm 3 and a viscosity of 3,300-3,500 mPas at 25°C
• Densiron 68 mixture of perfluorohexyloctane (F6H8) and 5,000-centistoke silicone oil; density 1.06 g/
• the HSO is perfluorocarbon liquids (PFCLs) or semifluorinated alkanes, such as perfluorohexyloctane (F6H8; density of 1.331 g/cm 3 ).
• PFCLs include perfluoro-n-octane (C8F18; density of 1.759 g/cm 3 ) and perfluorodecalin (Cl OF 18).
• the specific gravity of these SiOs can range from 1.7 g/mL to more than 2.0 g/mL.
• the density of the MTX composition is lower than the density of the HSO.
• the density of the composition is less than about 2.0 g/cm 3 , less than about 1.8 g/cm 3 , less than about 1.6 g/cm 3 , less than about 1.5 g/cm 3 , less than about 1.4 g/cm 3 , less than about 1.3 g/cm 3 , less than about 1.2 g/cm 3 , less than about 1.19 g/cm 3 , less than about 1.18 g/cm 3 , less than about 1.17 g/cm 3 , less than about 1.16 g/cm 3 , less than about 1.15 g/cm 3 , less than about 1.14 g/cm 3 , less than about 1.13 g/cm 3 , less than about 1.12 g/cm 3 , less than about
• the density of the composition is about 2.0 g/cm 3 to about 1.01 g/cm 3 , about 1.8 g/cm 3 to about 1.01 g/cm 3 , about 1.6 g/cm 3 to about 1.01 g/cm 3 , about 1.5 g/cm 3 , to about 1.01 g/cm 3 , about 1.4 g/cm 3 to about 1.01 g/cm 3 , about 1.3 g/cm 3 to about 1.01 g/cm 3 , about 1.2 g/cm 3 to about 1.01 g/cm 3 , about 1.19 g/cm 3 to about 1.01 g/cm 3 , about 1.18 g/cm 3 to about 1.01 g/cm 3 , about 1.17 g/cm 3 to about 1.01 g/cm 3 , about 1.16 g/cm 3 to about 1.01 g/cm 3 , about 1.15 g/cm 3
• the MTX composition has a density greater than the oil having lower density than water and a density lower than the oil having a higher density than water.
• the MTX composition having the appropriate density can be selected based on the guidance provide herein. In some embodiments, compositions having the appropriate density in the applicable ranges describe above can be used.
• the composition comprises a density enhancing agent to provide an appropriate density to impart a desired transit rate or sink rate.
• the density enhancing agent is sucrose, trehalose, glucose, carbopol, polyvinyl acetate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, polyethylene glycol (PEG), glycerol, poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolide (PGA), polyhydroxybutyric acid, polycaprolactone, polyvalerolactone, polyphosphazene, polyorthoester, cyclodextrin, or mixtures thereof.
• a preferred density enhancing agent is sucrose or PEG 4000.
• the density enhancing agent comprises sucrose.
• the composition comprises sucrose at a concentration of about 0.5% w/v to about 20% w/v; about 1% w/v to about 20% w/v, 2% w/v to about 20% w/v, about 3% w/v to about 20% w/v, about 4% w/v to about 20% w/v, about 5% w/v to about 20% w/v, about 6% w/v to about 20% w/v, about 7% w/v to about 20% w/v, about 8% w/v to about 20% w/v, about 9% to w/v about 20% w/v, about 10% w/v to about 20% w/v, about 11% w/v to about 20% w/v, about 12% w/v to about 20% w/v, about 13% w/v to about 20%, about 14% w/v to about 20%, about 15% w/v to
• the composition comprises sucrose at a concentration of about 0.5% w/v to about 18% w/v, about 1% w/v to about 17%, w/v 2% w/v to about 16% w/v, about 3% w/v to about 15% w/v, about 4% w/v to about 14% w/v, about 5% w/v to about 1% w/v, about 6% w/v to about 13% w/v, about 7% to about 12% w/v, or about 8% to about 11% w/v.
• the composition comprises sucrose at a concentration of about 7% w/v to about 9% w/v, preferably about 7.7% w/v.
• the composition comprises sucrose at a concentration of about 0.5% w/v, about 0.6% w/v, about 0.7% w/v, about 0.8% w/v, about 0.9% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 11% w/v, about 12% w/v, about 13% w/v, about 14% w/v, about 15% w/v, about 16% w/v, about 17% w/v, about 18% w/v, about 19% w/v, or about 20% w/v.
• the composition has sucrose at a concentration of about 7.5% w/v, 8.5% w/v, or about 9.5% w/v.
• the density enhancing agent comprises polyethylene glycol (PEG).
• the PEG is PEG 400 to PEG 20000.
• the PEG is PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1450, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, or mixtures thereof.
• the PEG is PEG 9000, PEG 10000, PEG 11000, PEG 12000, PEG 13000, PEG 14000, PEG 15000, PEG 16000, PEG 17000, PEG 18000, PEG 19000, PEG 20000, or mixtures thereof.
• the PEG is PEG 4000.
• the composition comprises PEG at a concentration to provide sufficient density for the composition to have the transit rate or sink rate described herein.
• the densities of PEG solutions of different molecular weights are available in the art (see, e.g., Gonzalez- Tello et ah, J Chem Eng Data, 1994; 39:611-614; Regupahti et ah, J. Chem. Eng. Data, 2009;
• PEG 4000 at 50% w/v in water has a density of about 1.13 g/cm 3 at 20°C.
• the composition comprises PEG 4000 at a concentration of about 1% w/v to about 60% w/v, about 1% w/v to about 60% w/v, about 2 % w/v to about 60% w/v, about 3 % w/v to about 60% w/v, about 4 % w/v to about 60% w/v, about 5 % w/v to about 60% w/v, about 6 % w/v to about 60% w/v, about 7 % w/v to about 60% w/v, about 8 % w/v to about 60% w/v, about 9 % w/v to about 60% w/v, about 10 % w/v to about 60% w/v, about 15 % w/v to about 60% w/v, about 20 % w/v to about 60% w/v, about 25 % w/v to about 60% w/v, about 30 % w/v to about 60%
• the composition comprises PEG 4000 at a concentration of about 1% w/v to about 60% w/v, about 1% w/v to about 55% w/v, about 2% w/v to about 50% w/v, about 3% w/v to about 45% w/v, about 4% w/v to about 40% w/v, about 5% w/v to about 35% w/v, about 6% w/v to about 30% w/v, about 7% w/v to about 28% w/v, about 8 % w/v to about 26% w/v, about 9% w/v to about 24% w/v, about 10% w/v to about 22% w/v, or about 15% w/v to about 20% w/v.
• the composition comprises PEG 4000 at a concentration of about 1% w/v to about 15% w/v, 12% w/v to about 14% w/v, 3% w/v to about 13% w/v, 4% w/v to about 12% w/v, 5% w/v to about 11% w/v, 6% w/v to about 10% w/v, or 7% w/v to about 9% w/v.
• the composition comprises PEG 4000 at a concentration of about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 11% w/v, about 12% w/v, about 13% w/v, about 14% w/v, about 15% w/v, about 16% w/v, about 17% w/v, about 18% w/v, about 19% w/v, about 20% w/v, about 25% w/v, about 30% w/v, about 35% w/v, about 40% w/v, about 45% w/v, about 50% w/v, about 55% w/v, or about 60% w/v.
• the MTX composition further comprises one or more surfactants.
• the surfactant is a non-ionic surfactant.
• the surfactant is suitable for intravitreal administration.
• the surfactant is polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan mono-oleate (Tween 80), polyoxyethylene (20) sorbitan tristearate (Tween 65), polyoxyethylene (20) sorbitan tri oleate (Tween 85), sorbitan trioleate (Span 85), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan mono-oleate (Span 80), sorbitan tristearate (Span 65), or combinations thereof.
• the surfactant is polyoxyethylene (20) sorbitan monolaurate (Tween
• the composition comprises a surfactant at about 0.001% w/v to about 0.5% w/v, about 0.002% w/v to about 0.5% w/v, about 0.004% w/v to about 0.5% w/v, about 0.006% w/v to about 0.5% w/v, about 0.008% w/v to about 0.5% w/v, about 0.010% w/v to about 0.5% w/v, about 0.012% w/v to about 0.5% w/v, about 0.014% w/v to about 0.5% w/v, about 0.016% w/v to about 0.5% w/v, about 0.018% w/v to about 0.5% w/v, about 0.02% w/v to about 0.5% w/v, about 0.03% w/v to about 0.5% w/v, about 0.04% w/v to about 0.5% w/v, about 0.05% w/v to about 0.5% w/v/v, about 0.05%
• the surfactant is present at 0.0015% w/v to about 0.05% w/v. In some embodiments, the surfactant is present at 0.01% w/v to 0.05% w/v. In some embodiments, the surfactant is present at 0.015% w/v to about 0.03% w/v.
• the composition has surfactant at about 0.001% w/v, about 0.002% w/v, about 0.004% w/v, about 0.006% w/v, about 0.008% w/v, about 0.010% w/v, about 0.012% w/v, about 0.014% w/v, about 0.016% w/v, about 0.018% w/v, about 0.02% w/v, about 0.03% w/v, about 0.04% w/v, about 0.05% w/v, about 0.06% w/v, about 0.07% w/v, about 0.08% w/v, about 0.1% w/v, about 0.12% w/v, about 0.14% w/v, about 0.16% w/v, about 0.18% w/v, about 0.2% w/v, about 0.22% w/v, about 0.24% w/v, about 0.26% w/v, about 0.26% w/v, about 0.24% w/
• the composition includes a preservative, particularly a pharmaceutically acceptable preservative for intravitreal injection.
• the preservative is benzyl alcohol.
• the composition is free of preservatives.
• the composition further comprises a buffering agent.
• the buffering agent is a pharmaceutically acceptable buffering agent, in particular a buffering agent suitable for intravitreal administration.
• the buffering agent is borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, biphosphate, tromethamine, hydroxyethyl morpholine, or THAM (trishydroxymethylamino-methane).
• the buffering agent is phosphate.
• the buffering agent is present in a sufficient amount to provide buffering capacity to the composition.
• the buffering agent is present at a concentration of about 0.005 mM to about 5 mM, about 0.01 mM to about 4 mM, about 0.02 mM to about 3 mM, about 0.03 mM to about 2 mM, about 0.04 mM to about 1.5 mM, about 0.05 mM to about 1 mM, or about 0.1 mM to about 0.8 mM.
• the buffering agent is present at a concentration of about 0.005 mM, 0.01 mM, 0.02 mM, 0.03 mM, 0.04 mM, 0.05 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM or more as needed.
• the pH of the composition is about 5.5 to about 8.5. In some embodiments, the pH is about 6 to about 8, or about 6.5 to about 7.5. In some embodiments, the composition has a pH of about 5.5, about 6.0, about 6.5, about 7, about 7.5 or about 8.
• the pH of the composition is approximate pH of the vitreous in the eye.
• the MTX is present in the composition at a concentration that when administered is sufficient to prevent or reduce the risk of or treat a disease, disorder, or conditions disclosed herein. In some embodiments, the MTX is present in the composition at a concentration sufficient to prevent or reduce the risk of or treat PVR. In some embodiments, the MTX is present in the composition at a concentration sufficient to prevent or reduce the risk of or treat intraocular lymphoma. In some embodiments, the MTX is present in the composition at a concentration sufficient to prevent or reduce the risk of or treat intraocular inflammation.
• Methotrexate is also known by its chemical names N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L- glutamic acid and 4-amino- 10-methylfolic acid.
• the MTX in composition is present in an amount such that intravitreal administration provides a therapeutically effective dose, including a prophylactically effective dose.
• the MTX, or a pharmaceutically acceptable salt thereof is present at about 2 mg/mL to about 20 mg/mL. In some embodiments, the MTX, or a pharmaceutically acceptable salt thereof, is present at about 3 mg/mL to about 20 mg/mL, about 4 mg/mL to about 20 mg/mL, about 5 mg/mL to about 20 mg/mL, about 6 mg/mL to about 20 mg/mL, about 7 mg/mL to about 20 mg/mL, about 8 mg/mL to about 20 mg/mL, about 9 mg/mL to about 20 mg/mL, about 10 mg/mL to about 20 mg/mL, about 11 mg/mL to about 20 mg/mL, about 12 mg/mL to about 20 mg/mL, about 13 mg/mL to about 20 mg/mL, about 14 mg/mL to about 20 mg/mL, about 15 mg/mL to about 20 mg/mL, about 16 mg/mL to about 20 mg/
• the MTX is present at about 2 mg/mL to about 19 mg/mL, about 3 mg/mL to about 18 mg/mL, about 4 mg/mL to about 18 mg/mL, about 5 mg/mL to about 17 mg/mL, about 6 mg/mL to about 16 mg/mL, about 7 mg/mL to about 15 mg/mL, about 8 mg/mL to about 14 mg/mL, about 9 mg/mL to about 13 mg/mL, about 10 mg/mL to about 12 mg/mL.
• the MTX, or a pharmaceutically acceptable salt thereof is present at about 5 mg/ml to about 12 mg/mL, 6 mg/mL to about 11 mg/mL, or about 7 mg/mL to about 10 mg/mL.
• the MTX is present at about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 18 mg/mL, or about 20 mg/mL.
• the MTX is present at about 8 mg/mL.
• the MTX is present in the composition as a pharmaceutically acceptable salt or as esters of MTX.
• Pharmaceutically acceptable salts can be selected from, but are not limited to, alkali metal salts such as sodium or potassium, alkaline earth salts or an ammonium salt (all of which are herein referred to as a pharmaceutically acceptable salts).
• methotrexate refers to methotrexate disodium. Methotrexate also includes acetylated forms, benzhydryl-sulfmylacetic acid forms, sulfone forms, hydroxylated forms, polymorphic forms, analogs, derivatives, cogeners, prodrugs, metabolic acids and compounds made by mixtures thereof. In some embodiments, the methotrexate also includes individual enantiomers or racemic mixtures of methotrexate.
• the composition has an osmolarity that is compatible with its use in treating a disease, disorder, or condition disclosed herein. In some embodiments, the osmolarity of the composition is compatible with intravitreal use. In some embodiments, the composition has an osmolarity of about 200 to about 1000 mOsm/L or about 200 to about 500 mOsm/L, or any specific value within said ranges, for example, 200 mOsm/L, 210 mOsm/L, 220 mOsm/L, 230 mOsm/L, 240 mOsm/L, 250 mOsm/L, 260 mOsm/L, 270 mOsm/L, 280 mOsm/L, 290 mOsm/L, 300 mOsm/L, 310 mOsm/L, 320 mOsm/L, 330 mOsm/L, 340
• the ophthalmic formulations are adjusted with a tonicity agent to an osmolarity in the range of about 250 to about 450 mOsm/L, or about 300 to about 400 mOsm/L.
• the osmolarity of the composition is about 350 ⁇ 50 mOsm/L.
• the compositions can have one or more tonicity agents, which can be used to adjust the tonicity of the composition, for example, to the tonicity appropriate for intravitreal use.
• Suitable tonicity agents include, by way of example and not limitation, dextrans (e.g., dextran 40 or 70), dextrose, glycerin, potassium chloride, propylene glycol, and sodium chloride.
• Equivalent amounts of one or more salts made up of cations, such as potassium, ammonium; and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate; the salts sodium bisulfate and ammonium sulfate, can also be used.
• the amount of tonicity agent can vary, depending on the particular agent to be added.
• the MTX composition comprises the following:
• Methotrexate 2 mg/mL to about 20 mg/mL; and Sucrose: 0.5% w/v to about 20% w/v.
• the MTX composition comprises the following:
• Methotrexate 5 mg/mL to about 15 mg/mL; and Sucrose: 4% w/v to about 15% w/v.
• the MTX composition comprises the following:
• Methotrexate 2 mg/mL to about 20 mg/mL; and PEG 4000: 1% w/v to about 60% w/v.
• the MTX composition comprises the following:
• Methotrexate 5 mg/mL to about 15 mg/mL; and PEG 4000: 4% w/v to about 15% w/v.
• each of the above compositions further includes a surfactant.
• a surfactant any of the surfactants disclosed herein can be used.
• the surfactant is polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan mono-oleate (Tween 80), polyoxyethylene (20) sorbitan tristearate (Tween 65), polyoxyethylene (20) sorbitan tri-oleate (Tween 85), and sorbitan trioleate (Span 85).
• the surfactant is Tween 20 or Tween 80.
• the MTX composition comprises the following:
• Methotrexate 2 mg/mL to about 20 mg/mL;
• Sucrose 0.5% w/v to about 20% w/v; and Surfactant: 0.001 % to about 0.5% w/v.
• the MTX composition comprises the following: Methotrexate: 5 mg/mLto about 15 mg/mL;
• Surfactant 0.01% to about 0.05% w/v.
• the MTX composition comprises the following:
• Methotrexate 2 mg/mL to about 20 mg/mL; and PEG 4000: 1% w/v to about 60% w/v; and Surfactant: 0.001 % to about 0.5% w/v.
• the MTX composition comprises the following:
• Methotrexate 5 mg/mLto about 15 mg/mL;
• PEG 4000 4% w/v to about 15% w/v; and Surfactant: 0.01% to about 0.05% w/v.
• the surfactant in the above embodiments is Tween 20, also referred to as polysorbate 20.
• the surfactant in the above embodiments is Tween 80, also referred to as polysorbate 80.
• the MTX composition has the following formulation (FI):
• the MTX composition has the following formulation (F2): [0090] In some embodiments, the MTX composition has the following formulation (F3):
• the MTX composition has the following formulation (F4):
• the MTX composition has the following formulation (F5):
• the MTX composition has the following formulation (F6):
• the MTX composition has the following formulation (F7):
• the MTX composition has the following formulation (F8):
• the present disclosure provides use of the MTX compositions for preventing or reducing the risk of or treating PVR, intraocular lymphoma, or intraocular inflammation.
• the present disclosure provides use of the MTX compositions for preventing or reducing the risk of PVR or treating PVR.
• a method of preventing or reducing the risk of or treating PVR comprises administering to a subject in need thereof a therapeutically effective amount of an MTX composition described herein.
• the MTX composition is administered intravitreally.
• the present disclosure provides use of MTX in the preparation of a medicament for treating PVR, intraocular lymphoma, or intraocular inflammation, wherein the medicament comprises any of the compositions described above.
• the medicament comprises MTX and a density enhancing agent, as described herein.
• the medicament comprises MTX, a density enhancing agent, and a surfactant, as described herein.
• the subject for treatment with the MTX composition has a retinal injury, such as a tear or hole in the retina but which has not resulted in retinal detachment.
• the subject for treatment with the MTX composition has undergone laser surgery (e.g., photocoagulation) for treatment for the retinal tear or hole.
• the subject for treatment with the MTX composition has undergone cryopexy for treatment of the retinal tear or hole.
• the subject for treatment with the MTX composition has undergone treatment for a retinal tear or hole and has one or more risk factors for PVR, as discussed further below.
• the method comprises administering to an eye of a subject who has undergone laser surgery (e.g., laser retinopexy) or cryopexy for treatment of a retinal tear or hole a therapeutically effective amount of an MTX composition of the present disclosure.
• laser surgery e.g., laser retinopexy
• cryopexy for treatment of a retinal tear or hole a therapeutically effective amount of an MTX composition of the present disclosure.
• the subject for treatment with the MTX composition has suffered a retinal injury which is a retinal detachment. In some embodiments, the subject for treatment with the composition has suffered a primary retinal detachment. In some embodiments, the subject for treatment has a primary retinal detachment which is a rhegmatogenous retinal detachment. In some embodiments, subject for treatment with the MTX composition has suffered a secondary retinal detachment. In some embodiments, the subject for treatment with the MTX composition has suffered a rhegmatogenous retinal detachment, tractional retinal detachment, or a combined tractional- rhegmatogenous retinal detachment.
• the retinal detachment is a localized retinal detachment, and in some embodiments, the retinal detachment is a complete retinal detachment.
• the method comprises administering to an eye of a subject afflicted with retinal detachment a therapeutically effective amount of a MTX composition of the present disclosure.
• the subject for treatment with the MTX composition has undergone treatment for a retinal detachment.
• the method comprises administering to an eye of a subject treated for retinal detachment a therapeutically effective amount of a MTX composition of the present disclosure.
• the subject for treatment with the MTX composition has undergone laser surgery (e.g., photocoagulation, laser retinopexy, etc.) for treatment of the retinal tear or hole associated with retinal detachment.
• the subject for treatment with the MTX composition has undergone cryopexy for treatment of the retinal tear or hole associated with the retinal detachment.
• the subject for treatment with the MTX composition has undergone pneumatic retinopexy to treat retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone scleral buckling to treat retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone a vitrectomy to treat retinal detachment, e.g., pars plana vitrectomy (PPV) with an intraocular tamponade, such as gas or silicone oil.
• PSV pars plana vitrectomy
• the subject for treatment with the MTX composition is administered or has been administered intravitreally SiO in the affected eye, such as a tamponade for treating retinal detachment.
• the SiO administered is SiO having a viscosity of at least 1000 centistoke. In some embodiments, the SiO administered has a viscosity of about 1000 to about 5000 centistoke. In some embodiments, the SiO administered is 1000 centistoke oil, in particular polydimethyl siloxane 1000 centistoke oil. In some embodiments, the SiO administered is 5000 centistoke oil, in particular polydimethyl siloxane 5000 centistoke oil.
• the subject for treatment with the MTX composition is administered or has been administered intravitreally heavy silicone oil (HSO), such as a tamponade for treating inferior retinal detachment.
• HSO intravitreally heavy silicone oil
• the HSO is Oxane HD, Densiron 68, or HSV-45 3000.
• the eye of the subject for treatment is administered or has been administered intravitreally perfluorocarbon liquids (PFCLs) or semifluorinated alkanes, such as perfluorohexyloctane (F6H8).
• PFCLs include perfluoro-n-octane (C8F18) and perfluorodecalin (C10F18).
• the MTX composition is administered by intravitreal injection into the SiO of a subject who has been treated with intravitreal SiO.
• the MTX composition is co-administered with the SiO administered to the eye treated with the SiO and MTX composition.
• the composition is present in the SiO when the SiO is administered into the posterior segment.
• the subject for treatment with the MTX composition has one or more risk factors for rhegmatogenous retinal detachment.
• the subject for treatment with the MTX compositions has a prior history of one or more of the following: chronic ocular inflammation, infectious retinitis, multiple retinal detachments, large retinal breaks or giant retinal tears, multiple retinal breaks, ocular trauma, retinal detachment associated with vitreous hemorrhage, choroidal detachment, and combinations thereof.
• the subject for treatment with the MTX composition is characterized by vitreous or subretinal hemorrhage, excessive cryotherapy, pigment release during endodrainage, or combinations thereof.
• compositions described herein can be used to treat other ocular diseases, disorders, or conditions that would benefit from treatment with methotrexate.
• compositions herein are used to treat intraocular lymphoma.
• a method of treating intraocular lymphoma comprises administering intravitreally to an eye of a subject with intraocular lymphoma a therapeutically effective amount of a composition disclosed herein, including the exemplary formulations disclosed herein.
• the intraocular lymphoma treated is primary vitreoretinal lymphoma (PVRL).
• PVRL primary vitreoretinal lymphoma
• the subject is afflicted or diagnosed with PVRL.
• the intraocular lymphoma e.g., PVRL
• PCNSL cerebral nervous system lymphoma
• the intraocular lymphoma is diffuse large B-cell lymphoma.
• MTX compositions disclosed herein can also be used to treat inflammatory diseases, disorders, or conditions of the eye, particularly intraocular inflammation.
• a method of treating intraocular inflammation comprises administering intravitreally to an eye of a subject with intraocular inflammation a therapeutically effective amount of a composition disclosed herein, including the exemplary formulations disclosed herein.
• the inflammatory diseases, disorders, or conditions for treatment with the MTX compositions herein include, among others, uveitis, for example pan uveitis, intermediate uveitis, and posterior uveitis, particularly non-infectious posterior uveitis; cystoid macular edema (CME); macular edema, for example accompanying uveitis or diabetic macular edema; choroidal neovascularization; and prosthetic membranopathy.
• uveitis for example pan uveitis, intermediate uveitis, and posterior uveitis, particularly non-infectious posterior uveitis
• cystoid macular edema (CME) cystoid macular edema
• macular edema for example accompanying uveitis or diabetic macular edema
• choroidal neovascularization choroidal neovascularization
• the methods or use described herein include the use of a “therapeutically effective amount” of MTX composition described herein.
• a “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desired results.
• the eye of the subject in need thereof is administered a therapeutically effective amount, which includes a prophylactically effective amount of the MTX composition of the present disclosure that prevents or reduces the risk of developing PVR.
• the eye of the subject in need thereof is administered a therapeutically effective amount of the MTX composition of the present disclosure to treat PVR.
• the eye of the subject in need thereof is administered a therapeutically effective amount of the MTX composition of the present disclosure to treat intraocular lymphoma. In some embodiments, the eye of the subject in need thereof is administered a therapeutically effective amount of the MTX composition of the present disclosure to treat PVRL.
• the eye of the subject in need thereof is administered a therapeutically effective amount of the MTX composition of the present disclosure to prevent, reduce the risk of, or treat intraocular inflammation. In some embodiments, the eye of the subject in need thereof is administered a therapeutically effective amount of the MTX composition of the present disclosure to treat intraocular inflammation.
• the amount of MTX administered can take into consideration, among others, the type of disease, disorder, or condition being treated (e.g., the nature or location of damage to the eye; the extent of intraocular lymphoma; or types of intraocular inflammation), the age and sex of the subject, the presence of risk factors, and the type of treatment given to the subject to treat the eye.
• the type of disease, disorder, or condition being treated e.g., the nature or location of damage to the eye; the extent of intraocular lymphoma; or types of intraocular inflammation
• the age and sex of the subject e.g., the presence of risk factors, and the type of treatment given to the subject to treat the eye.
• a therapeutically effective amount can be administered in one or more administrations, applications, or dosages.
• the eye of the subject is administered the MTX composition described herein sufficient to deliver MTX at a dose of about 25 pig to about 600 pg.
• the eye of the subject is administered a dose of MTX of about 30 pg to about 580 pg, about 35 pg to about 560 pg, about 40 pg to about 540 pg, about 45 pg to about 520 pg, about 50 pg to about 500 pg, about 60 pg to about 480 pg, about 70 pg to about 460 pg, about 80 pg to about 440 pg, about 90 pg to about 430 pg, about 100 pg to about 420 pg, about 120 pg to about 400 pg, about 140 pg to about 380 pg, about 160 pg to about 360 pg, about 180 pg to about 340 pg, or about 200 pg to about 320 pg, In some embodiments, the dose of MTX is about 200 pg to about 600 pg, or about 300 pg to about 500 pg.
• the eye of the subject is administered a dose of MTX of about 25 pg, about 30 pg, about 35 pg, about 40 pg, about 45 pg, about 50 pg, about 60 pg, about 65 pg, about 70 pg, about 75 pg, about 80 pg, about 85 pg, about 90 pg about 95 pg, about 100 pg, about 110 pg, about 120 pg, about 130 pg, about 140 pg, about 150 pg, about 160 pg, about 170 pg, about 180 pg, about 190 pg, about 200 pg, about 210 pg, about 220 pg, 230 pg, 240 pg, 250 pg, 260 pg, 270 pg, 280 mg, 290 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 300 mg, about 350 mg, about 400 mg
• the volume of composition administered is suitable for intravitreal administration.
• the volume can be adjusted if the administration is intravitreally into gas or SiO filled eye.
• the volume of composition administered is about 20 m ⁇ to about 300 m ⁇ , about 25 m ⁇ to about 200 m ⁇ , about 30 m ⁇ to about 190 m ⁇ , about 35 m ⁇ to about 180 m ⁇ , about 40 m ⁇ to about 170 m ⁇ , about 45 m ⁇ to about 150 m ⁇ , about 50 m ⁇ to about 140 m ⁇ , about 55 m ⁇ to about 130 m ⁇ , about 60 m ⁇ to about 120 m ⁇ , about 70 m ⁇ to about 110 m ⁇ , or about 80 m ⁇ to about 100 m ⁇ .
• the volume of composition administered is about 25 m ⁇ , about 30 m ⁇ , about 35 m ⁇ , about 40 m ⁇ , about 45 m ⁇ , about 50 m ⁇ , about 60 m ⁇ , about 70 m ⁇ , about 80 m ⁇ , about 90 m ⁇ , about 100 m ⁇ , about 120 m ⁇ , about 140 m ⁇ , about 160 m ⁇ , about 180 m ⁇ , about 200 m ⁇ , about 220 m ⁇ , about 240 m ⁇ , about 260 m ⁇ , about 280 m ⁇ , or about 300 m ⁇ .
• An exemplary volume for intravitreal administration is 100 m ⁇ .
• the MTX composition is administered at a frequency and duration to provide a prophylactic effect or to treat a disease, disorder, or condition disclosed herein in the affected eye.
• the MTX composition is administered at a frequency and duration to provide a prophylactic effect or to treat PVR.
• the dose, frequency, and duration can be adjusted taking into consideration factors such as, among others, extent of retinal injury, location of the retinal injury, type of surgery used to treat the eye damage, the age and sex of the subject, duration of tamponade needed with gas or SiO, and presence of one or more risk factors for PVR.
• the MTX composition is administered once a day, once every two days, once every three days, once every four days, once every five days, once every 6 days, or once every seven days.
• the MTX composition is administered once every week, or once every 2 weeks, once every three weeks, or once a month. [00128] In some embodiments, the following is used to treat PVR.
• the MTX composition is administered more than once per day, for example two times per day or three times per day. In some embodiments, the subject is administered the MTX composition twice or three times per day postoperatively, for example, in the day surgery has been completed, and/or 1 day, 2 days, 3 days or 4 days following surgical treatment.
• the MTX composition can be administered at least once a day for 3, 4, 5, 6, or 7 days following initial retinal damage and/or post-operative surgery followed by a lower frequency of administration. In some embodiments, the MTX composition is administered at least once a day for at least for two weeks followed by a lower frequency of administration.
• the duration of treatment is for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least one week, at least two weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, or at least 12 months (i.e., one year).
• the treatment duration is until completion of treatment with the gas or removal of the SiO, respectively.
• the treatment with the MTX composition is continued following completion of treatment with the gas or removal of the SiO, for example where the subject has one or more risk factors for PVR.
• intravitreal administration of the MTX composition for treating a disease, disorder, or condition described herein is performed according to standard methods used in the art.
• intravitreal administration is performed aseptically after the topical application of anesthesia and an antiseptic agent, e.g., 5% povidone iodine, to the conjunctival sac.
• eye of the subject is administered an intravitreal injection of the MTX composition, for example with a 30-gauge needle.
• the subject is maintained in an appropriate position (e.g., lying face up) following administration of SiO, for the MTX composition to transit through the SiO, and in some embodiments, sufficient time for transit through the SiO and dispersion of the MTX composition in the aqueous phase for adsorption into the retinal tissues, especially over the posterior pole.
• the patient may be positioned in other positions (e.g., lying on one’s side) to direct the methotrexate to a specific area.
• the subject is positioned appropriately for at least 30 min, at least 25 min, at least 20 min, at least 15 min, at least 10 min, or at least 5 min following administration of the MTX composition into the SiO.
• the MTX composition is administered at a frequency and duration to effective to treat intraocular lymphoma, e.g., PVRL.
• the dose, frequency, and duration can be adjusted taking into consideration factors such as, among others, the severity or stage of the intraocular lymphoma and other conditions, such as the presence or absence of accompanying PCNSL.
• the MTX composition is administered once every 4 weeks (month), once every two weeks, once a week, two times a week, three times a week, or four times a week to treat intraocular lymphoma.
• the treatment regimen includes an induction phase, and optionally a consolidation phase, and/or a maintenance phase.
• the induction phase is administration of the MTX composition two times a week, up to four times a week.
• the consolidation phase when present, comprises administration once a week or two times a week.
• the maintenance phase when present, comprises administration once every two weeks or once every month.
• the dose administered is sufficient to provide a therapeutic effect.
• any of the doses disclosed above can be used in an effective amount for treating intraocular lymphoma.
• the dose of MTX administered is about 100 to 800 pig. about 200 to 600 pig. or about 300 to 500 pig.
• the dose of MTX administered for treating intraocular lymphoma is about 100 pig. about 200 pig. about 300 pig. about 400 pig. about 500 pig. about 600 pig. about 700 pig. or about 800 pig . In preferred embodiments, the dose of MTX administered is about 200 pig. about 300 pig. about 400 pig. or about 500 pig. In some embodiments, the dose of MTX administered is about 400 pg. [00141] In some embodiments for treating intraocular lymphoma, the dose administered is sufficient to provide a therapeutic effect. In some embodiments, the dose of MTX administered is about 100 to 800 pg/0.1 mL, about 200 to 600 pg/0.1 mL, or about 300 to 500 pg/0.1 mL.
• the dose of MTX administered for treating intraocular lymphoma is about 100 pg/0.1 mL, about 200 pg/0.1 mL, about 300 pg/0.1 mL, about 400 pg/0.1 mL, about 500 pg/0.1 mL, about 600 pg/0.1 mL, about 700 pg/0.1 mL, or about 800 pg/0.1 mL.
• the dose of MTX administered is about 200 pg/0.1 mL, about 300 pg/0.1 mL, about 400 pg/0.1 mL, or about 500 pg/0.1 mL.
• the dose of MTX administered is about 400 pg/0.1 mL.
• the treatment with MTX is in combination with a secondary therapeutic agent effective for treatment of the lymphoma.
• the secondary therapeutic administered in combination with the MTX is an anti-CD20 antibody.
• the anti-CD20 antibody is selected from rituximab, ocrelizumab, veltuzumab, obinutuzumab, and ofatumumab.
• the MTX composition is administered at a frequency and duration to effective to treat intraocular inflammation.
• the intraocular inflammation for treatment is uveitis, for example pan uveitis, intermediate uveitis, or posterior uveitis, particularly non-infectious posterior uveitis; cystoid macular edema (CME); macular edema, for example accompanying uveitis, or diabetic macular edema; choroidal neovascularization; and prosthetic membranopathy .
• the dose, frequency, and duration can be adjusted taking into consideration factors such as, among others, the type of intraocular inflammation, and the severity or stage of the intraocular inflammation.
• the MTX composition is administered once every 4 weeks (month), once every two weeks, once a week, two times a week, three times a week, or four times a week to treat intraocular inflammation.
• the treatment regimen includes an induction phase, and optionally a consolidation phase, and/or a maintenance phase.
• the induction phase is administration of the MTX composition two times a week, up to four times a week.
• the consolidation phase when present, comprises administration once a week or two times a week.
• the maintenance phase when present, comprises administration once every two weeks or once every month.
• the dose administered is sufficient to provide a therapeutic effect.
• any of the doses disclosed above can be used in an effective amount for treating intraocular inflammation.
• the dose of MTX administered is about 100 to 800 pg, about 200 to 600 pg, or about 300 to 500 pg.
• the dose of MTX administered for treating intraocular inflammation is about 100 pg, about 200 pg, about 300 pg, about 400 pg, about 500 pg, about 600 pg, about 700 pg, or about 800 pg.
• the dose of MTX administered is about 200 pg, about 300 pg, about 400 pg, or about 500 pg.
• the dose of MTX administered is 400 rig ⁇
• the dose administered is sufficient to provide a therapeutic effect.
• the dose of MTX administered is about 100 to 800 pg/0.1 mL, about 200 to 600 pg/0.1 mL, or about 300 to 500 pg/0.1 mL.
• the dose of MTX administered for treating intraocular inflammation is about 100 pg/0.1 mL, about 200 pg/0.1 mL, about 300 pg/0.1 mL, about 400 pg/0.1 mL, about 500 pg/0.1 mL, about 600 pg/0.1 mL, about 700 pg/0.1 mL, or about 800 pg/0.1 mL.
• the dose of MTX administered is about 200 pg/0.1 mL, about 300 pg/0.1 mL, about 400 pg/0.1 mL, or about 500 pg/0.1 mL.
• the dose of MTX administered is about 400 pg/0.1 mL.
• the MTX composition is provided in the form of a kit.
• the MTX composition in the kit is provided in a multi -dose vial.
• the MTX composition in the kit is provided as single use vials.
• the kit comprises one or more single use vials of the MTX composition.
• the MTX composition is provided in the form of a dry composition for reconstitution with an appropriate solvent, such as pyrogen free sterile water or buffer.
• the kit when provided as a dry composition includes a vial of solvent for reconstitution of MTX solution for injection.
• the kit further comprises a syringe for injection of the MTX composition.
• the kit includes one or more syringes for injection of the MTX composition.
• the MTX composition is provided in pre-fdled syringes for administration into an eye of a subject.
• the kit also includes prescribing information for proper use of the compositions.
• the information may be in the form of printed material or on a computer readable medium.
• Example 1 Preparation of Compositions and Assessment of Transit Through
• each ingredient e.g., surfactants, buffer, density building agent, methotrexate, etc.
• each ingredient e.g., surfactants, buffer, density building agent, methotrexate, etc.
• the pH is adjusted to 7.4 ⁇ 0.2 by addition of 1M sodium hydroxide or HC1. Water is added to make up to the desired final volume.

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• 2020
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