Ophthalmic preparation of methotrexate

Abstract

The present disclosure provides methotrexate formulations for ocular administration, including intravitreal administration, and uses of the formulations to treat proliferative vitreoretinopathy (PVR), intraocular lymphoma (e.g., PVRL), and intraocular inflammation. The present disclosure provides a composition comprising methotrexate (MTX) and a density enhancer. The composition may be characterized by a transit time of less than 10 minutes through a 1 cm depth of silicone oil (SiO). The SiO may be SiO used to treat retinal detachment. The SiO may be SiO having a viscosity of at least 1000 centistokes, for example, polydimethylsiloxane having a viscosity of 1000 centistokes.

Description

Technical Field

[0001] 1. Cross - Reference to Related Applications This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62 / 900,060, filed on September 13, 2019, and U.S. Provisional Application No. 63 / 044,288, filed on June 25, 2020, the entire disclosures of each of which are incorporated herein by reference.

Background Art

[0002] 2. Background Proliferative vitreoretinopathy (PVR) is a clinical syndrome that occurs after rhegmatogenous retinal detachment, such as caused by retinal breaks (e.g., retinal tears or retinal holes) and their surgical repair. The etiology of PVR involves the release of cells into the vitreous cavity (epiretinal cells) where cells replicate to form epiretinal fibrocellular membranes on the inner and / or outer surfaces of the retina, creating retinal shortening and retinal traction. PVR is characterized by intraretinal fibrosis and elastosis, leading to increased retinal traction and subsequent new retinal breaks and recurrent retinal detachment. PVR can occur in untreated eyes with retinal detachment or after retinal procedures such as retinal cryopexy, laser retinal reattachment, pneumatic retinal reattachment, scleral buckling, and / or pars plana vitrectomy. The prevalence of PVR varies widely but is estimated to be in the range of about 5 - 12% of all cases of rhegmatogenous retinal detachment (Kwon et al., Dev Ophthalmol., 2016;55:154 - 62). PVR and its associated retinal traction are one of the main reasons for the failure of initially successful retinal detachment repair (i.e., recurrent retinal detachment) and are present in approximately 75% of failed retinal detachment repairs (Sadaka et al., Clinical Ophthalmology, 2016;10:1811 - 1817).

[0003] Retinal detachment surgery may 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. The tamponade agent provides surface tension across the retinal break and prevents further fluid flow into the subretinal space until a retinal reattachment procedure (photocoagulation or cryopexy) provides a permanent seal. For complex detachments associated with PVR, silicone oil is often used. Commonly used viscosities of silicone oil include 1,000 and 5,000 centistokes. Silicone oil has a lower specific gravity (0.97 g / mL) than vitreous (1.005 - 1.008 g / mL), and as a result, these float in the vitreous cavity. Similarly, gases also float in the vitreous cavity due to their very low specific gravity (about 0.001 g / mL) and have a much higher buoyancy than silicone oil. Lighter silicone oils and gases can be less effective tamponades against retinal breaks in these positions, so heavy silicone oil (HSO) and liquid perfluorocarbons have been used for inferior retinal breaks. Considering the morbidity of retinal detachment and PVR after retinal detachment surgery, anti-inflammatory and immunosuppressive drugs have been administered to control PVR and reduce the failure rate of PPV. The use of anti-inflammatory or immunosuppressive drugs can be beneficial for subjects at high risk of PVR. Methotrexate (MTX) is an antineoplastic antimetabolite with immunosuppressive properties that inhibits enzymes that require folate as a cofactor, including enzymes involved in nucleotide biosynthesis necessary for DNA replication. MTX is used to treat chronic inflammatory and fibrotic conditions. In ophthalmology, MTX is used to treat uveitis, pemphigoid, scleritis and episcleritis, as well as primary intraocular lymphoma. Studies of intravitreal MTX administration after retinal reattachment surgery have shown promise in reducing the incidence of postoperative retinal detachment (Benner et al., BMJ Open Ophth., 2019;4:e000293; Sadaka et al., Clinical Ophthalmology, 2016;10:1811-1817). There is a need for formulations of MTX for treating proliferative vitreoretinopathy (PVR) after retinal detachment, particularly when used as tamponade agents where silicone oil is preferred, and for treating other eye disorders that can be treated with MTX, such as intraocular lymphoma and intraocular inflammatory conditions.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0005] 3. Summary The present disclosure provides a composition comprising methotrexate (MTX) and a density enhancer. In some embodiments, the composition is characterized by a passage time of less than 10 minutes through silicone oil (SiO) having a depth of 1 cm. In some embodiments, the SiO is the SiO used in the treatment of retinal detachment. In some embodiments, the SiO is an SiO having a viscosity of at least 1000 centistokes, for example, polydimethylsiloxane having a viscosity of 1000 centistokes. In some embodiments, the SiO is an SiO having a viscosity of about 5000 centistokes. In some embodiments, the SiO is polydimethylsiloxane having a viscosity of about 5000 centistokes.

[0006] In some embodiments, the density enhancer is selected from sucrose, trehalose, glucose, carbopol, polyvinyl acetate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol (PEG), glycerol, poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolide (PGA), polyhydroxybutyric acid, polycaprolactone, polyvalerolactone, polyphosphazene, polyorthoester, cyclodextrin, and mixtures thereof. In some embodiments, the density enhancer is used in an appropriate amount to provide the desired density. In some embodiments, 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 ~ about 1.08 g / cm 3 is.

[0007] In some embodiments, the composition further comprises a surfactant. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant can enhance the dispersion of MTX in the aqueous phase. In some embodiments, 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 monooleate (Tween® 80), polyoxyethylene (20) sorbitan tristearate (Tween® 65), polyoxyethylene (20) sorbitan trioleate (Tween® 85), sorbitan trioleate (Span® 85), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), and sorbitan tristearate (Span® 65). In some embodiments, the surfactant is Tween® 20 (polysorbate 20) or Tween® 80 (polysorbate 80). In some embodiments, the surfactant is present at about 0.001 w / v to about 0.05% w / v.

[0008] In some embodiments, the composition comprises a buffering agent. In some embodiments, the buffering agent is a pharmaceutically acceptable buffering agent, particularly for intravitreal administration. In some embodiments, the buffering agent is borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, diphosphate, tromethamine, hydroxyethylmorpholine, or THAM (trishydroxymethylamino-methane).

[0009] In some embodiments, 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 suitable for intravitreal administration.

[0010] In some embodiments, the composition has MTX or a pharmaceutically acceptable salt thereof at a concentration of about 2 mg / mL to about 20 mg / mL. In some embodiments, MTX or a pharmaceutically acceptable salt thereof is at a concentration of about 5 mg / mL to about 15 mg / mL.

[0011] In another aspect, the MTX composition is used to prevent, reduce the risk of, or treat proliferative vitreoretinopathy (PVR). In some embodiments, a method of preventing, reducing the risk of, or treating PVR comprises administering a therapeutically effective amount of the composition described herein to the eye of a subject in need thereof. In some embodiments, the composition is administered intravitreally.

[0012] In some embodiments, the subject for treatment has suffered an injury to the eye. In some embodiments, the subject has a retinal detachment. In some embodiments, the eye of the subject for treatment has been treated with a pars plana vitrectomy for retinal detachment. In some embodiments, the retinal detachment is a primary or secondary retinal detachment. In some embodiments, the retinal detachment is a rhegmatogenous retinal detachment.

[0013] In some embodiments, the eye of the subject for treatment has been treated or is being treated by administration of silicone oil (SiO) to the posterior segment, such as a tamponade for retinal detachment. In some embodiments, the MTX composition is administered by intravitreal injection into the SiO in the vitreous cavity. In some embodiments, the MTX composition is co-administered with SiO administered to treat retinal detachment. In some embodiments, the SiO has a viscosity of at least 1000 centistokes. In some embodiments, the SiO has a viscosity of about 1000 centistokes or about 5000 centistokes.

[0014] In some embodiments, the dosage of MTX administered is a therapeutically effective amount in terms of frequency and duration for preventing PVR, or reducing the risk thereof, or treating the same. In some embodiments, the dosage of MTX administered is from about 50 μg to about 600 μg. In some embodiments, the dosage of MTX administered is about 400 μg. In some embodiments, the composition is administered once a day, twice a week, or once a week.

[0015] In some embodiments, 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 six months, at least nine months, or one year. In some embodiments where the subject is treated with gas or SiO as tamponade, the subject is treated with the composition until the duration of treatment with intravitreal gas or removal of SiO.

[0016] In some embodiments, the subject for treatment with the composition has one or more risk factors for developing PVR. In some embodiments, the subject for treatment has a history of one or more of the following conditions: chronic uveitis, 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. In some embodiments, the subject for treatment has had vitreous or subretinal hemorrhage, excessive cryotherapy, pigment release during endodrainage, or combinations thereof.

[0017] In some embodiments, the compositions herein are also useful for treating other diseases, disorders, or conditions that would benefit from intravitreal administration of methotrexate.

[0018] In some embodiments, the compositions herein are used to treat intraocular lymphoma. In some embodiments, a method of treating intraocular lymphoma comprises intravitreally administering a therapeutically effective amount of the compositions herein, including the exemplary formulations disclosed herein, to the eye of a subject having intraocular lymphoma.

[0019] In some embodiments, the intraocular lymphoma being treated is primary vitreoretinal lymphoma (PVRL). In some embodiments, the intraocular lymphoma (e.g., PVRL) is associated with primary central nervous system lymphoma (PCNSL). In some embodiments, the intraocular lymphoma is diffuse large B-cell lymphoma.

[0020] In some embodiments, the compositions herein are used to treat intraocular inflammation. In some embodiments, a method of treating intraocular inflammation comprises intravitreally administering a therapeutically effective amount of the compositions herein to a subject having intraocular inflammation. In some embodiments, the inflammatory diseases, disorders or symptoms for treatment with the MTX compositions herein include, inter alia, uveitis, such as panuveitis, intermediate uveitis and posterior uveitis, particularly non-infectious posterior uveitis; cystoid macular edema (CME); macular edema associated with uveitis or diabetic macular edema, for example; choroidal neovascularization; and prosthetic membranopathy.

[0021] In some embodiments, the dosage of MTX administered is a therapeutically effective amount at a frequency and duration for preventing intraocular lymphoma, or reducing the risk thereof, or treating the same, or for preventing intraocular inflammation, or reducing the risk thereof, or treating the same.

[0022] In some embodiments for treating intraocular lymphoma or intraocular inflammation, the MTX composition is administered once every 4 weeks (months), once every 2 weeks, once a week, twice a week, three times a week, or four times a week to treat intraocular lymphoma or intraocular inflammation.

[0023] In some embodiments for treating intraocular lymphoma or intraocular inflammation, the treatment regimen includes an induction phase and, optionally, a consolidation phase and / or a maintenance phase.

[0024] In some embodiments, the induction phase is administration of the MTX composition two times per week, three times per week, up to four times per week.

[0025] In some embodiments, the consolidation phase, if present, includes administration once per week or twice per week.

[0026] In some embodiments, the maintenance phase, if present, includes administration once every two weeks, once every three weeks, or once per month.

[0027] In another aspect, the present disclosure provides a kit comprising the MTX composition described herein. In some embodiments of the kit, the MTX composition can be provided as a multi - dose vial or a single - dose vial. In some embodiments, the MTX composition can be in a dried form that is reconstituted with a suitable solvent for preparing the composition for administration. 4. Brief Description of the Drawings

Brief Description of the Drawings

[0028]

Figure 1

Modes for Carrying Out the Invention

[0029] 5. Detailed Description 5.1. Methotrexate Composition The present disclosure provides a composition of methotrexate (MTX) or a pharmaceutically acceptable salt thereof for preventing, reducing the risk of, or treating proliferative vitreoretinopathy (PVR), intraocular lymphoma, or intraocular inflammation.

[0030] In some embodiments, the composition of MTX is used as a prophylaxis against PVR, such as after retinal detachment surgery. In some embodiments, the composition is used in silicone oil (SiO) used in retinal detachment surgery to provide a sufficient rate of passage through the silicone oil to deliver MTX in a therapeutically effective amount to prevent, reduce the risk of, or treat PVR.

[0031] In some embodiments, the composition of MTX is used to treat intraocular lymphoma, such as primary vitreoretinal lymphoma (PVRL).

[0032] In some embodiments, the composition of MTX is used to treat intraocular inflammation, such as uveitis; cystoid macular edema (CME) or diabetic macular edema; choroidal neovascularization; or chorioretinopathy.

[0033] Referring to the present disclosure and the following detailed description, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" refers to two or more compounds.

[0034] Also, the use of "or" means "and / or" unless specifically stated otherwise. Similarly, "comprise", "comprises", "comprising", "include", "includes", and "including" are interchangeable and not intended to be limiting.

[0035] When the description of various embodiments uses the term "comprising", those skilled in the art should further understand that in some specific examples, the embodiments can alternatively be described using the language "consisting essentially of" or "consisting of".

[0036] As used herein, the terms "treating" or "treatment" of a disease, disorder, or syndrome, when used herein, (i) prevent the occurrence of the disease, disorder, or syndrome in a subject, i.e., in an animal that may be exposed to, or have a predisposition for, the disease, disorder, or syndrome but has not yet experienced or manifested the symptoms of the disease, disorder, or syndrome, prevent the clinical symptoms of the disease, disorder, or syndrome from occurring; (ii) inhibit the disease, disorder or syndrome, i.e., stop its onset; and (iii) alleviate the disease, disorder or syndrome, i.e., cause regression of the disease, disorder or syndrome. As is known in the art, adjustments may be necessary for systemic versus local delivery, age, weight, general health, sex, diet, time of administration, drug interactions and severity of symptoms and can be ascertained by those skilled in the art.

[0037] As used herein, the term "prophylactic treatment" refers to a treatment administered to a subject that shows no signs or symptoms of a disease, condition, or medical disorder, or only shows the initial signs or symptoms of the disease, condition, or disorder, for the purpose of reducing, preventing, or lowering the risk of onset of the disease, condition, or medical disorder. Prophylactic treatment functions as a prophylactic treatment against a disease or disorder.

[0038] As used herein, the term "therapeutically effective amount" means any amount that, compared to a corresponding subject not receiving such amount, results in an improved treatment, cure, prevention or amelioration of a disease or disorder, or a decrease in the rate of progression of a disease or disorder, and includes an amount effective to enhance normal physiological function.

[0039] As used herein, the term "pharmaceutically acceptable" refers to compounds, biological agents, materials, compositions and / or dosage forms that are suitable for administration to a subject, such as a mammal or a human, without undue toxicity, irritation, allergic reaction and other problems complications, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0040] In one aspect, the present disclosure provides a composition comprising MTX or a pharmaceutically acceptable salt thereof and a density enhancer. In some embodiments, the density enhancer is present in an amount effective to provide a transit rate of less than 10 minutes in 1 ml of silicone oil (SiO). As used herein, "transit rate" refers to the time for the MTX composition to reach the interface between the SiO layer and the aqueous layer when the MTX composition is applied to the SiO layer separated from the immiscible aqueous layer, preferably phosphate buffered saline (PBS). In some embodiments, when the composition has a density higher than that of SiO, the transit rate can be referred to as the "descent rate". In some embodiments, the transit rate or descent rate of the composition is less than 10 minutes, less than 8 minutes, less than 7 minutes, less than 6 minutes, or less than 5 minutes in 1 ml of SiO having a depth of 1 cm. In some embodiments, the transit rate or descent rate of the composition is measured with SiO used as a tamponade for treating retinal detachment.

[0041] In some embodiments, SiO has a lower density than water. In these SiO, the SiO layer floats on top of the aqueous layer and the MTX composition sinks in the SiO to the interface between the SiO layer and the aqueous layer.

[0042] In some embodiments, the passing rate or the dropping rate is in SiO having a viscosity of at least 1000 centistokes. In some embodiments, the SiO has a viscosity of about 1000 centistokes. In some embodiments, the SiO having a viscosity of 1000 centistokes is polydimethylsiloxane 1000 centistokes oil.

[0043] In some embodiments, the passing rate or the dropping rate is in SiO having a viscosity of about 5000 centistokes. In some embodiments, the SiO having a viscosity of 5000 centistokes is polydimethylsiloxane 5000 centistokes oil.

[0044] In some embodiments, the density of the MTX composition is higher than the density of the SiO in order to provide an appropriate passing rate or dropping rate. In some embodiments, 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 , or at least about 1.25 g / cm 3 or more.

[0045] In some embodiments, the density of the MTX composition is from about 1.01 to about 1.2 g / cm at 20°C 3 , about 1.02 g / cm 3 ~ about 1.2 g / cm 3 , about 1.03 g / cm 3 ~ about 1.2 g / cm 3 , about 1.04 g / cm 3 ~ about 1.2 g / cm 3 , about 1.05 g / cm 3 ~ about 1.2 g / cm 3 , about 1.06 g / cm 3 ~ about 1.2 g / cm 3 , about 1.07 g / cm 3 ~ about 1.2 g / cm 3 , about 1.08 g / cm 3 ~ about 1.2 g / cm 3 , about 1.09 g / cm 3 ~ about 1.2 g / cm 3 , about 1.10 g / cm 3 ~ about 1.2 g / cm 3 , about 1.11 g / cm 3 ~ about 1.2 g / cm 3 , about 1.12 g / cm 3 ~ about 1.2 g / cm 3 , about 1.13 g / cm 3 ~ about 1.2 g / cm 3 , about 1.14 g / cm 3 ~ about 1.2 g / cm 3 , about 1.15 g / cm 3 ~ about 1.2 g / cm 3 , about 1.16 g / cm 3 ~ about 1.2 g / cm 3 , about 1.17 g / cm 3 ~ about 1.2 g / cm 3 , about 1.18 g / cm 3 ~ about 1.2 g / cm 3 , or about 1.19 g / cm 3 ~ about 1.2 g / cm 3 . In some embodiments, the composition has a density of from about 1.01 g / cm 3 ~ about 1.08 g / cm 3 at 20°C.

[0046] In some embodiments, the density of the composition is from about 1.01 to about 1.25 g / cm at 20 °C 3 In some embodiments, the density of the composition is from about 1.02 to about 1.2 g / cm at 20 °C 3 In some embodiments, the density of the composition is from about 1.03 to about 1.15 g / cm at 20 °C 3 In some embodiments, the density of the composition is from about 1.04 to about 1.1 g / cm at 20 °C 3 is.

[0047] In some embodiments, the density of the composition is about 1.01 g / mL, about 1.02 g / cm at 20 °C 3 , about 1.03 g / cm 3 , about 1.04 g / cm 3 , about 1.05 g / cm 3 , about 1.06 g / cm 3 , about 1.07 g / cm 3 , about 1.08 g / cm 3 , about 1.09 g / cm 3 , about 1.10 g / cm 3 , about 1.11 g / cm 3 , about 1.12 g / cm 3 , about 1.13 g / cm 3 , about 1.14 g / cm 3 , about 1.15 g / cm 3 , about 1.16 g / cm 3 , about 1.17 g / cm 3 , about 1.18 g / cm 3 , about 1.19 g / mL, about 1.2 g / cm 3 , about 1.21 g / cm 3 , about 1.22 g / cm 3 , about 1.23 g / cm 3 , about 1.24 g / cm 3 , or about 1.25 g / cm 3 is.

[0048] In some embodiments, the SiO is heavy silicone oil (HSO), which refers to SiO having a density higher than that of water. In such embodiments, the aqueous layer floats on top of the HSO layer. In some embodiments, the MTX composition is formulated to have a density lower than that of the HSO, thus enabling the MTX composition to float from the SiO to the interface of the SiO and the aqueous layer. In some embodiments, the passage rate of the MTX composition is less than 10 minutes in 1 ml of HSO at a depth of 1 cm. In some embodiments, the passage rate of the MTX composition is less than 8 minutes, less than 7 minutes, less than 6 minutes, or less than 5 minutes in 1 ml of HSO having a depth of 1 cm. In some embodiments, 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 evaluate the passage rate.

[0049] In some embodiments, the HSO is Oxane HD (a mixture of 5700 centistokes SiO and RMN-3, a partially fluorinated olefin; density 1.02 g / cm at 25 °C 3 and viscosity 3,300 - 3,500 mPas), Densiron 68 (a mixture of perfluorohexyl octane (F6H8) and 5,000 centistokes silicone oil; density 1.06 g / cm at 25 °C 3 ; viscosity 1400 mPas), or HSV-45 3000. In some embodiments, the HSO is a liquid perfluorocarbon (PFCL) or a semi-fluorinated alkane such as perfluorohexyl octane (F6H8; density 1.331 g / cm 3 ). PFCLs include perfluoro-n-octane (C8F18; density 1.759 g / cm 3 ) and perfluorodecalin (C10F18). The specific gravity of these SiO can range from 1.7 g / mL to over 2.0 g / mL.

[0050] In some embodiments where HSO is used, the density of the MTX composition is lower than that of the HSO. In some embodiments, 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 / cm3 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 1.11 g / cm 3 less than about 1.10 g / cm 3 less than about 1.09 g / cm 3 less than about 1.08 g / cm 3 less than about 1.07 g / cm 3 less than about 1.06 g / cm 3 less than about 1.05 g / cm 3 less than about 1.04 g / cm 3 less than about 1.03 g / cm 3 less than or about 1.02 g / cm 3 is less than.

[0051] In some embodiments, the density of the composition is about 2.0 g / cm 3 ~ about 1.01 g / cm 3 about 1.8 g / cm 3 ~ about 1.01 g / cm 3 about 1.6 g / cm 3 ~ about 1.01 g / cm 3 about 1.5 g / cm 3 ~ about 1.01 g / cm 3 about 1.4 g / cm 3 ~ about 1.01 g / cm 3 about 1.3 g / cm 3 ~ about 1.01 g / cm 3 about 1.2 g / cm 3 ~ about 1.01 g / cm 3 about 1.19 g / cm 3 ~ about 1.01 g / cm 3 about 1.18 g / cm3 ~ about 1.01 g / cm 3 、 about 1.17 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.16 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.15 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.14 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.13 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.12 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.11 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.10 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.09 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.08 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.07 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.06 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.05 g / cm 3 ~ about 1.01 g / cm 3 、 about 1.04 g / cm 3 ~ about 1.01 g / cm 3 、 or about 1.03 g / cm 3 ~ about 1.01 g / cm 3 is.

[0052] In some embodiments, when a combination of an oil having a density lower than water and an oil having a density higher than water is used as a tamponade, the MTX composition has a density higher than that of the oil having a density lower than water and lower than that of the oil having a density higher than water. An MTX composition having an appropriate density can be selected based on the guidance provided herein. In some embodiments, a composition having an appropriate density within the above applicable range can be used.

[0053] In certain embodiments, the composition includes a density enhancer to provide an appropriate density for imparting a desired passage or descent rate. In some embodiments, the density enhancer is sucrose, trehalose, glucose, carbopol, polyvinyl acetate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol (PEG), glycerol, poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolide (PGA), polyhydroxybutyrate, polycaprolactone, polyvalerolactone, polyphosphazene, polyorthoester, cyclodextrin, or a mixture thereof. In some embodiments, the preferred density enhancer is sucrose or PEG 4000.

[0054] In some embodiments, the density enhancer includes sucrose. In some embodiments, the composition includes 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 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 about 20%, or about 16% w / v to about 20%.

[0055] In some embodiments, the composition comprises sucrose at a concentration of from about 0.5% w / v to about 18% w / v, from about 1% w / v to about 17% w / v, from 2% w / v to about 16% w / v, from about 3% w / v to about 15% w / v, from about 4% w / v to about 14% w / v, from about 5% w / v to about 1% w / v, from about 6% w / v to about 13% w / v, from about 7% w / v to about 12% w / v, or from about 8% to about 11% w / v. In some embodiments, the composition comprises sucrose at a concentration of from about 7% w / v to about 9% w / v, preferably at a concentration of about 7.7% w / v.

[0056] In some embodiments, 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. In some embodiments, the composition has sucrose at a concentration of about 7.5% w / v, 8.5% w / v, or about 9.5% w / v.

[0057] In some embodiments, the density enhancer comprises polyethylene glycol (PEG). In some embodiments, the PEG is PEG 400 to PEG 20000. In some embodiments, 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 a mixture thereof. In some embodiments, 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 a mixture thereof. In a preferred embodiment, the PEG is PEG 4000.

[0058] In some embodiments, the composition comprises PEG at a concentration sufficient to provide a density such that the composition has the passage rate or descent rate described herein. Densities of PEG solutions of various molecular weights are available in the art (see, e.g., Gonzalez-Tello et al., J Chem Eng Data, 1994;39:611-614; Regupahti et al., J.Chem.Eng.Data, 2009;54(3):1100-1106; publications incorporated herein by reference). For example, 50% w / v PEG 4000 in water has a density of about 1.13 g / cm 3 at 20 °C.

[0059] In some embodiments, 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% w / v, about 35% w / v to about 60% w / v, about 40% w / v to about 60% w / v, about 45% w / v to about 60%, about 50% w / v to about 60% w / v, or about 55% w / v to about 60% w / v.

[0060] In some embodiments, 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. In some embodiments, 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.

[0061] In some embodiments, 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.

[0062] In the description of the MTX composition herein, sucrose or PEG 4000 is used as an exemplary density enhancer, but it should be understood that other density enhancers at appropriate concentrations to achieve the desired passage or descent rate and / or the desired density can be used considering the knowledge in the art of the density of the various density enhancers described herein.

[0063] In some embodiments, the MTX composition further comprises one or more surfactants. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant is suitable for intravitreal administration. In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monolaurate (Tween® 20), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan tristearate (Tween® 65), polyoxyethylene (20) sorbitan trioleate (Tween® 85), sorbitan trioleate (Span® 85), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), sorbitan tristearate (Span® 65), or a combination thereof. In some embodiments, the surfactant is Tween® 20 (polysorbate 20) or Tween® 80 (polysorbate 80).

[0064] In some embodiments, the composition comprises a surfactant in an amount of from about 0.001% w / v to about 0.5% w / v, from about 0.002% w / v to about 0.5% w / v, from about 0.004% w / v to about 0.5% w / v, from about 0.006% w / v to about 0.5% w / v, from about 0.008% w / v to about 0.5% w / v, from about 0.010% w / v to about 0.5% w / v, from about 0.012% w / v to about 0.5% w / v, from about 0.014% w / v to about 0.5% w / v, from about 0.016% w / v to about 0.5% w / v, from about 0.018% w / v to about 0.5% w / v, from about 0.02% w / v to about 0.5% w / v, from about 0.03% w / v to about 0.5% w / v, from about 0.04% w / v to about 0.5% w / v, from about 0.05% w / v to about 0.5% w / v, from about 0.06% w / v to about 0.5% w / v, from about 0.07% w / v to about 0.5% w / v, from about 0.08% w / v to about 0.5% w / v, from about 0.1% w / v to about 0.5% w / v, from about 0.12% w / v to about 0.5% w / v, from about 0.14% w / v to about 0.5% w / v, from about 0.16% w / v to about 0.5% w / v, from about 0.18% w / v to about 0.5% w / v, from about 0.2% w / v to about 0.5% w / v, from about 0.3% w / v to about 0.5% w / v, or from about 0.4% w / v to about 0.5% w / v. In some embodiments, the surfactant is present at from 0.0015% w / v to about 0.05% w / v. In some embodiments, the surfactant is present at from 0.01% w / v to 0.05% w / v. In some embodiments, the surfactant is present at from 0.015% w / v to about 0.03% w / v.

[0065] In some embodiments, the composition has a 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 0.28% w / v, about 0.3% w / v, about 0.32% w / v, about 0.34% w / v, about 0.36% w / v, about 0.38% w / v, about 0.4% w / v, about 0.42% w / v, about 0.44% w / v, about 0.46% w / v, about 0.48% w / v, or about 0.5% w / v.

[0066] In some embodiments, the composition includes a preservative, particularly a pharmaceutically acceptable preservative for intravitreal injection. In some embodiments, the preservative is benzyl alcohol. In some embodiments, the composition is preservative-free.

[0067] In some embodiments, the composition further includes a buffer. In some embodiments, the buffer is a pharmaceutically acceptable buffer, particularly a buffer suitable for intravitreal administration. In some embodiments, the buffer is borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, diphosphate, tromethamine, hydroxyethylmorpholine, or THAM (trishydroxymethylaminomethane). In some embodiments, the buffer is phosphate.

[0068] In some embodiments, a buffering agent is present in an amount sufficient to provide buffering capacity to the composition. In some embodiments, 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.

[0069] In some embodiments, the buffering agent is present, as needed, 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 greater.

[0070] In some embodiments, 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. Preferably, the pH of the composition is approximately the pH of the vitreous humor in the eye.

[0071] In some embodiments, MTX is present in the composition at a concentration sufficient to prevent, or reduce the risk of, or treat the diseases, disorders, or symptoms disclosed herein when administered. In some embodiments, MTX is present in the composition at a concentration sufficient to prevent, or reduce the risk of, or treat PVR. In some embodiments, MTX is present in the composition at a concentration sufficient to prevent, or reduce the risk of, or treat intraocular lymphoma. In some embodiments, 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 name N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid and 4-amino-10-methylfolic acid. In some embodiments, MTX in the composition is present in an amount such that intravitreal administration provides a therapeutically effective dose that includes a prophylactically effective dose.

[0072] In some embodiments, MTX or a pharmaceutically acceptable salt thereof is present at about 2 mg / mL to about 20 mg / mL. In some embodiments, 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 / mL, or about 18 mg / mL to about 20 mg / mL.

[0073] In some embodiments, MTX or a pharmaceutically acceptable salt thereof 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. In some embodiments, 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.

[0074] In some embodiments, MTX or a pharmaceutically acceptable salt thereof 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. Preferably, MTX is present at about 8 mg / mL.

[0075] In some embodiments, MTX is present in the composition as a pharmaceutically acceptable salt of MTX or as an ester. Pharmaceutically acceptable salts can be selected from, but are not limited to, alkali metal salts such as sodium or potassium, alkaline earth salts or ammonium salts (all of which are referred to herein as pharmaceutically acceptable salts). In some embodiments, methotrexate refers to methotrexate disodium. Methotrexate also includes compounds produced by acetylated forms, benzhydryl-sulfinylacetic acid forms, sulfone forms, hydroxylated forms, polymorphic forms, analogs, derivatives, cogeners, prodrugs, metabolic acids, and mixtures thereof. In some embodiments, methotrexate also includes individual enantiomers or racemic mixtures of methotrexate.

[0076] In some embodiments, the composition has an osmolality in a volume that is compatible with its use in the treatment of the diseases, disorders, or conditions disclosed herein. In some embodiments, the osmolality of the composition is compatible with intravitreal use. In some embodiments, the composition has an osmolality of about 200 to about 1000 mOsm / L or about 200 to about 500 mOsm / L, or any specific value within said range, 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 mOsm / L, 350 mOsm / L, 360 mOsm / L, 370 mOsm / L, 380 mOsm / L, 390 mOsm / L, or 400 mOsm / L. In certain embodiments, the ophthalmic formulation is adjusted to an osmolality in the range of about 250 to about 450 mOsm / L, or about 300 to about 400 mOsm / L, by an isotonicity agent. Preferably, the osmolality of the composition is about 350 ± 50 mOsm / L.

[0077] In some embodiments, the composition can have one or more isotonicity agents that can be used to adjust the tonicity of the composition, for example, to a tonicity suitable for intravitreal use. Suitable isotonicity agents include, by way of example and not limitation, dextran (e.g., dextran 40 or 70), dextrose, glycerin, potassium chloride, propylene glycol, and sodium chloride. Cations such as potassium, ammonium, etc.; and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate; and equivalent amounts of one or more salts composed of sodium bisulfate and ammonium sulfate salts can also be used. The amount of the isotonicity agent can vary depending on the specific agent added.

[0078] In some embodiments, the MTX composition is as follows: Methotrexate: 2 mg / mL to about 20 mg / mL; and Sucrose: 0.5% w / v to about 20% w / v and contain.

[0079] In some embodiments, the MTX composition is as follows: Methotrexate: 5 mg / mL to about 15 mg / mL; and Sucrose: 4% w / v to about 15% w / v and contain.

[0080] In some embodiments, the MTX composition is as follows: Methotrexate: 2 mg / mL to about 20 mg / mL; and PEG 4000: 1% w / v to about 60% w / v and contain.

[0081] In some embodiments, the MTX composition is as follows: Methotrexate: 5 mg / mL to about 15 mg / mL; and PEG 4000: 4% w / v to about 15% w / v and contain.

[0082] In some embodiments, each of the above compositions further comprises a surfactant. In some embodiments, any of the surfactants disclosed herein can be used. In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monolaurate (Tween® 20), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan tristearate (Tween® 65), polyoxyethylene (20) sorbitan trioleate (Tween® 85), and sorbitan trioleate (Span® 85), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), or sorbitan tristearate (Span® 65). In some embodiments, the surfactant is Tween® 20 or Tween® 80.

[0083] In some embodiments, the MTX composition is as follows: Methotrexate: 2 mg / mL to about 20 mg / mL; and Sucrose: 0.5% w / v to about 20% w / v; and Surfactant: 0.001% to about 0.5% w / v and comprises.

[0084] In some embodiments, the MTX composition is as follows: Methotrexate: 5 mg / mL to about 15 mg / mL; and Sucrose: 4% w / v to about 15% w / v; and Surfactant: 0.01% to about 0.05% w / v and comprises.

[0085] In some embodiments, the MTX composition is as follows: 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 and comprise.

[0086] In some embodiments, the MTX composition is as follows: Methotrexate: 5 mg / mL to about 15 mg / mL; and PEG 4000: 4% w / v to about 15% w / v; and Surfactant: 0.01% to about 0.05% w / v and comprise.

[0087] In some embodiments, the surfactant in the above embodiments is Tween (registered trademark) 20, also known as polysorbate 20. In some embodiments, the surfactant in the above embodiments is Tween (registered trademark) 80, also known as polysorbate 80.

[0088] In some embodiments, the MTX composition has the following formulation (F1):

Table 2

[0089] In some embodiments, the MTX composition has the following formulation (F2):

Table 3

[0090] In some embodiments, the MTX composition has the following formulation (F3):

Table 4

[0091] In some embodiments, the MTX composition has the following formulation (F4):

Table 5

[0092] In some embodiments, the MTX composition has the following formulation (F5):

Table 6

[0093] In some embodiments, the MTX composition has the following formulation (F6):

Table 7

[0094] In some embodiments, the MTX composition has the following formulation (F7):

Table 8

[0095] In some embodiments, the MTX composition has the following formulation (F8):

Table 9

[0096] It should be understood that variations of the above specific embodiments can be prepared according to the guidance provided herein. 5.2. Use and Methods

[0097] In another aspect, the disclosure provides for the use of an MTX composition for preventing, or reducing the risk of, or treating PVR, intraocular lymphoma, or intraocular inflammation.

[0098] In some embodiments, the present disclosure provides the use of an MTX composition for preventing PVR, or reducing the risk thereof, or treating PVR. In some embodiments, a method of preventing PVR, or reducing the risk thereof, or treating the same comprises administering a therapeutically effective amount of the MTX composition described herein to a subject in need thereof. In some embodiments, the MTX composition is administered intravitreally.

[0099] In some embodiments, the present disclosure provides the use of MTX in the preparation of a medicament for treating PVR, intraocular lymphoma, or intraocular inflammation, wherein the medicament comprises any of the above compositions. In some embodiments, the medicament comprises the MTX described herein and a density enhancer. In some embodiments, the medicament comprises the MTX described herein, a density enhancer, and a surfactant.

[0100] In some embodiments, the subject for treatment with the MTX composition has retinal damage such as a retinal tear or hole but has not resulted in retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone laser surgery (e.g., photocoagulation) for treating a retinal tear or hole. In some embodiments, the subject for treatment with the MTX composition has undergone cryocoagulation for treating a retinal tear or hole. In some embodiments, 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, further discussed below. In some embodiments, the method comprises administering a therapeutically effective amount of the MTX composition of the present disclosure to the eye of a subject who has undergone laser surgery (e.g., laser retinal reattachment) or cryocoagulation for treating a retinal tear or hole.

[0101] In some embodiments, the subject for treatment with the MTX composition has retinal damage that is retinal detachment. In some embodiments, the subject for treatment with the composition has primary retinal detachment. In some embodiments, the subject for treatment has primary retinal detachment that is rhegmatogenous retinal detachment. In some embodiments, the subject for treatment with the MTX composition has secondary retinal detachment. In some embodiments, the subject for treatment with the MTX composition has rhegmatogenous retinal detachment, tractional retinal detachment, or combined tractional-rhegmatogenous retinal detachment.

[0102] In some embodiments, the retinal detachment is localized retinal detachment, and in some embodiments, the retinal detachment is total retinal detachment. In some embodiments, the method comprises administering a therapeutically effective amount of the MTX composition of the present disclosure to the eye of a subject affected with retinal detachment.

[0103] In some embodiments, the subject for treatment with the MTX composition is undergoing treatment for retinal detachment. In some embodiments, the method comprises administering a therapeutically effective amount of the MTX composition of the present disclosure to the eye of a subject treated for retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone laser surgery (e.g., photocoagulation, laser retinopexy, etc.) for treating a retinal tear or hole associated with retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone cryopexy for treating a retinal tear or hole associated with retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone gas retinopexy for treating retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone scleral buckling for treating retinal detachment. In some embodiments, the subject for treatment with the MTX composition has undergone vitrectomy for treating retinal detachment, e.g., pars plana vitrectomy (PPV) using an intravitreal tamponade such as gas or silicone oil.

[0104] In some embodiments, a subject for treatment with an MTX composition has had, or is having, SiO administered intravitreally in the affected eye, such as a tamponade for treating retinal detachment. In some embodiments, the SiO administered is SiO having a viscosity of at least 1000 centistokes. In some embodiments, the SiO administered has a viscosity of about 1000 to about 5000 centistokes. In some embodiments, the SiO administered is 1000 centistokes oil, particularly polydimethylsiloxane 1000 centistokes oil. In some embodiments, the SiO administered is 5000 centistokes oil, particularly polydimethylsiloxane 5000 centistokes oil.

[0105] In some embodiments, a subject for treatment with an MTX composition has had, or is having, heavy silicone oil (HSO) administered intravitreally in the affected eye, such as a tamponade for treating inferior retinal detachment. In some embodiments, the HSO is Oxane HD, Densiron 68, or HSV-45 3000. In some embodiments, the subject's eye for treatment has had, or is having, a liquid perfluorocarbon (PFCL) or semi-fluorinated alkane, such as perfluorohexyl octane (F6H8), administered intravitreally. PFCLs include perfluoro-n-octane (C8F18) and perfluorodecalin (C10F18).

[0106] In some embodiments, the MTX composition is administered by intravitreal injection into the SiO of a subject who has been treated with intravitreal SiO. In some embodiments, the MTX composition is co-administered with the SiO administered to an eye treated with SiO and the MTX composition. In some embodiments, the composition is present in the SiO when the SiO is administered posteriorly.

[0107] In some embodiments, a subject for treatment with an MTX composition has one or more risk factors for rhegmatogenous retinal detachment. In some embodiments, a subject for treatment with an MTX composition has one or more of the following: chronic uveitis, 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 one or more previous histories of these combinations.

[0108] In some embodiments, a subject for treatment with an MTX composition is characterized by vitreous or subretinal hemorrhage, excessive cryotherapy, pigment release during endodrainage, or combinations thereof.

[0109] In some embodiments, the compositions described herein can be used to treat other eye diseases, disorders, or conditions that benefit from treatment with methotrexate.

[0110] In some embodiments, the compositions of the present specification are used to treat intraocular lymphoma. In some embodiments, a method of treating intraocular lymphoma comprises intravitreal administration of a therapeutically effective amount of the compositions disclosed herein, including the exemplary formulations disclosed herein, to the eye of a subject having intraocular lymphoma.

[0111] In some embodiments, the intraocular lymphoma being treated is primary vitreoretinal lymphoma (PVRL). Thus, the subject has or has been diagnosed with PVRL. In some embodiments, intraocular lymphoma (e.g., PVRL) is associated with primary central nervous system lymphoma (PCNSL). In some embodiments, the intraocular lymphoma is diffuse large B-cell lymphoma.

[0112] The administration and dosage for treating intraocular lymphoma are provided in more detail herein.

[0113] In addition to disorders or PVR and intraocular lymphoma, the MTX compositions disclosed herein can also be used to treat inflammatory diseases, disorders, or conditions of the eye, particularly intraocular inflammation. In some embodiments, a method of treating intraocular inflammation comprises intravitreally administering to the eye of a subject having intraocular inflammation a therapeutically effective amount of a composition disclosed herein, including an exemplary formulation disclosed herein.

[0114] In some embodiments, the inflammatory diseases, disorders or conditions for treatment with the MTX compositions herein include, inter alia, uveitis, such as panuveitis, intermediate uveitis and posterior uveitis, particularly non-infectious posterior uveitis; cystoid macular edema (CME); for example, macular edema associated with uveitis or diabetic macular edema; choroidal neovascularization; and prosthetic membranopathy.

[0115] Administration and dosage for treating intraocular inflammation are provided in more detail herein. 5.3. Administration and Dosage

[0116] In some embodiments, the methods or uses described herein include the use of an MTX composition described herein in a "therapeutically effective amount". "Therapeutically effective amount" refers to an amount sufficient to produce a beneficial or desired result.

[0117] In some embodiments, an eye of a subject in need of administration is administered a therapeutically effective amount of an MTX composition of the present disclosure that includes a prophylactically effective amount to prevent PVR or reduce the risk of developing it. In some embodiments, an eye of a subject in need of administration is administered a therapeutically effective amount of an MTX composition of the present disclosure for treating PVR.

[0118] In some embodiments, an MTX composition of the present disclosure for treating an intraocular lymphoma in an amount effective for treatment is administered to the eye of a subject in need thereof. In some embodiments, an MTX composition of the present disclosure for treating PVRL in an amount effective for treatment is administered to the eye of a subject in need thereof.

[0119] In some embodiments, an MTX composition of the present disclosure for preventing, reducing the risk of, or treating an intraocular inflammation in an amount effective for treatment is administered to the eye of a subject in need thereof. In some embodiments, an MTX composition of the present disclosure for treating an intraocular inflammation in an amount effective for treatment is administered to the eye of a subject in need thereof.

[0120] The amount of MTX administered can take into account, among other things, the type of disease, disorder or condition being treated (e.g., the nature or location of the damage to the eye; the extent of intraocular lymphoma; or the type of intraocular inflammation), the age and gender of the subject, the presence of risk factors, and the type of treatment administered to the subject to treat the eye.

[0121] An amount effective for treatment can be administered in one or more administrations, applications, or dosages. In some embodiments, an MTX composition described herein sufficient to deliver a dosage of MTX of from about 25 μg to about 600 μg is administered to the eye of a subject. In some embodiments, a dosage of MTX of from about 30 μg to about 580 μg, from about 35 μg to about 560 μg, from about 40 μg to about 540 μg, from about 45 μg to about 520 μg, from about 50 μg to about 500 μg, from about 60 μg to about 480 μg, from about 70 μg to about 460 μg, from about 80 μg to about 440 μg, from about 90 μg to about 430 μg, from about 100 μg to about 420 μg, from about 120 μg to about 400 μg, from about 140 μg to about 380 μg, from about 160 μg to about 360 μg, from about 180 μg to about 340 μg, or from about 200 μg to about 320 μg is administered to the eye of a subject. In some embodiments, the dosage of MTX is from about 200 μg to about 600 μg, or from about 300 μg to about 500 μg.

[0122] In some embodiments, MTX is administered to the eye of interest at a dose of about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg, about 95 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, about 300 μg, about 320 μg, about 340 μg, about 360 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 550 μg, or about 600 μg. Preferably, the dose of MTX is about 200 μg, 300 μg, 400 μg, or about 500 μg.

[0123] In some embodiments for intravitreal administration, the volume of the composition administered is suitable for intravitreal administration. By way of example, but not limitation, if the administration is intravitreal administration to an eye filled with gas or SiO, the volume can be adjusted. In some embodiments, the volume of the composition administered is about 20 μl to about 300 μl, about 25 μl to about 200 μl, about 30 μl to about 190 μl, about 35 μl to about 180 μl, about 40 μl to about 170 μl, about 45 μl to about 150 μl, about 50 μl to about 140 μl, about 55 μl to about 130 μl, about 60 μl to about 120 μl, about 70 μl to about 110 μl, or about 80 μl to about 100 μl.

[0124] In some embodiments for intravitreal administration, the volume of the composition administered is about 25 μl, about 30 μl, about 35 μl, about 40 μl, about 45 μl, about 50 μl, about 60 μl, about 70 μl, about 80 μl, about 90 μl, about 100 μl, about 120 μl, about 140 μl, about 160 μl, about 180 μl, about 200 μl, about 220 μl, about 240 μl, about 260 μl, about 280 μl, or about 300 μl. An exemplary volume for intravitreal administration is 100 μl.

[0125] In some embodiments, 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 an affected eye.

[0126] In some embodiments, the MTX composition is administered at a frequency and duration to provide a prophylactic effect or to treat PVR.

[0127] In some embodiments for treating PVR, the dosage, frequency, and duration can be adjusted, inter alia, considering factors such as the degree of retinal damage, the location of the retinal damage, the type of surgery used to treat the eye injury, the age and gender of the subject, the duration of tamponade required with gas or SiO, and the presence of one or more risk factors for PVR. In some embodiments, 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 six days, or once every seven days. In some embodiments, the MTX composition is administered once a week, once every two weeks, once every three weeks, or once a month.

[0128] In some embodiments, the following are used to treat PVR. In some embodiments, the MTX composition is administered more than once a day, for example, twice a day or three times a day. In some embodiments, to the subject, after surgery, for example, on the day the surgery is completed and / or one, two, three, or four days after the surgical procedure, the MTX composition is administered twice or three times a day.

[0129] In some embodiments, the MTX composition can be administered at least once a day, starting 3, 4, 5, 6, or 7 days after the initial retinal damage and / or postoperative surgery, followed by a lower dosing frequency. In some embodiments, the MTX composition is administered at least once a day for at least two weeks, followed by a lower dosing frequency.

[0130] In some embodiments, the duration of treatment extends over at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 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., 1 year). In some embodiments, when the treatment involves a gas or SiO, for example as a tamponade, the duration of treatment is until the treatment with the gas or the removal of SiO is completed, respectively. In some embodiments, the treatment with the MTX composition is continued after the completion of the treatment with the gas or the removal of SiO, for example when the subject has 1 or more risk factors for PVR.

[0131] In some embodiments, the intravitreal administration of the MTX composition for treating the diseases, disorders, or symptoms described herein is carried out according to standard methods used in the art. In some embodiments, the intravitreal administration is carried out aseptically after topical administration of anesthetic and disinfectant, such as 5% povidone iodine, into the conjunctival sac. In some embodiments, an intravitreal injection of the MTX composition is administered to the subject's eye, for example with a 30-gauge needle.

[0132] In some embodiments for treating PVR, when the MTX composition is intravitreally administered to intraocular SiO, the subject is in a position suitable for the MTX composition to pass through the SiO (e.g., lying supine) after the administration of SiO, and in some embodiments, is maintained for a time sufficient for the passage of the MTX composition through the SiO and its dispersion into the aqueous phase for adsorption to the retinal tissue, particularly on the posterior pole. In some embodiments, the patient can be positioned in another position (e.g., lying on the side) for directing methotrexate to a particular region. In some embodiments, the subject is appropriately positioned for at least 30 minutes, at least 25 minutes, at least 20 minutes, at least 15 minutes, at least 10 minutes, or at least 5 minutes after administering the MTX composition to the SiO.

[0133] In some embodiments, the MTX composition is administered at a frequency and duration effective to treat intraocular lymphoma, such as PVRL.

[0134] In some embodiments for treating intraocular lymphoma, the dosage, frequency, and duration can be adjusted, inter alia, considering factors such as the severity or stage of the intraocular lymphoma and other symptoms, such as the presence or absence of concomitant PCNSL. In some embodiments, the MTX composition is administered once every 4 weeks (months), once every 2 weeks, once a week, twice a week, three times a week, or four times a week to treat intraocular lymphoma.

[0135] In some embodiments for treating intraocular lymphoma, the treatment regimen includes an induction phase and, optionally, a consolidation phase and / or a maintenance phase.

[0136] In some embodiments, the induction phase is administration of the MTX composition twice a week, up to four times a week.

[0137] In some embodiments, the consolidation phase, if present, includes administration once a week or twice a week.

[0138] In some embodiments, the maintenance phase, if present, includes administration once every 2 weeks or once a month.

[0139] In some embodiments for treating intraocular lymphoma, the dosage administered is sufficient to provide a therapeutic effect. In some embodiments, any of the dosages disclosed above can be used in an effective amount to treat intraocular lymphoma. In some embodiments, the dosage of MTX administered is about 100 - 800 μg, about 200 - 600 μg, or about 300 - 500 μg.

[0140] In some embodiments, the dose of MTX administered to treat intraocular lymphoma is about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, or about 800 μg. In preferred embodiments, the dose of MTX administered is about 200 μg, about 300 μg, about 400 μg, or about 500 μg. In some embodiments, the dose of MTX administered is about 400 μg.

[0141] 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 - 800 μg / 0.1 mL, about 200 - 600 μg / 0.1 mL, or about 300 - 500 μg / 0.1 mL.

[0142] In some embodiments, the dose of MTX administered to treat intraocular lymphoma is about 100 μg / 0.1 mL, about 200 μg / 0.1 mL, about 300 μg / 0.1 mL, about 400 μg / 0.1 mL, about 500 μg / 0.1 mL, about 600 μg / 0.1 mL, about 700 μg / 0.1 mL, or about 800 μg / 0.1 mL. In preferred embodiments, the dose of MTX administered is about 200 μg / 0.1 mL, about 300 μg / 0.1 mL, about 400 μg / 0.1 mL, or about 500 μg / 0.1 mL. In some embodiments, the dose of MTX administered is about 400 μg / 0.1 mL.

[0143] In some embodiments for treating intraocular lymphoma, the treatment with MTX is combined with a secondary therapeutic agent effective for treating lymphoma. In some embodiments, the secondary therapeutic agent administered in combination with MTX is an anti - CD20 antibody. In some embodiments, the anti - CD20 antibody is selected from rituximab, ofatumumab, obinutuzumab, ocrelizumab, and belimumab.

[0144] In some embodiments, the MTX composition is administered at a frequency and duration effective to treat intraocular inflammation. In some embodiments, the intraocular inflammation for treatment is uveitis, such as panuveitis, intermediate uveitis or posterior uveitis, particularly non-infectious posterior uveitis; cystoid macular edema (CME); such as macular edema associated with uveitis or diabetic macular edema; choroidal neovascularization; and choroidopathy.

[0145] In some embodiments for treating intraocular inflammation, the dosage, frequency, and duration can be adjusted, inter alia, taking into account factors such as the type of intraocular inflammation and the severity or stage of the intraocular inflammation. In some embodiments, the MTX composition is administered once every 4 weeks (months), once every 2 weeks, once a week, twice a week, three times a week, or four times a week to treat intraocular inflammation.

[0146] In some embodiments for treating intraocular inflammation, the treatment regimen includes an induction phase, and, optionally, a consolidation phase and / or a maintenance phase.

[0147] In some embodiments, the induction phase is administration of the MTX composition twice a week, up to four times a week.

[0148] In some embodiments, the consolidation phase, if present, includes administration once a week or twice a week.

[0149] In some embodiments, the maintenance phase, if present, includes administration once every 2 weeks or once a month.

[0150] In some embodiments for treating intraocular inflammation, the dosage administered is sufficient to provide a therapeutic effect. In some embodiments, any of the dosages disclosed above can be used in an effective amount to treat intraocular inflammation. In some embodiments, the dosage of MTX administered is about 100 - 800 μg, about 200 - 600 μg, or about 300 - 500 μg.

[0151] In some embodiments, the dose of MTX administered to treat intraocular inflammation is about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, or about 800 μg. In preferred embodiments, the dose of MTX administered is about 200 μg, about 300 μg, about 400 μg, or about 500 μg. In some embodiments, the dose of MTX administered is 400 μg.

[0152] In some embodiments for treating intraocular inflammation, the dose administered is sufficient to provide a therapeutic effect. In some embodiments, the dose of MTX administered is about 100 - 800 μg / 0.1 mL, about 200 - 600 μg / 0.1 mL, or about 300 - 500 μg / 0.1 mL.

[0153] In some embodiments, the dose of MTX administered to treat intraocular inflammation is about 100 μg / 0.1 mL, about 200 μg / 0.1 mL, about 300 μg / 0.1 mL, about 400 μg / 0.1 mL, about 500 μg / 0.1 mL, about 600 μg / 0.1 mL, about 700 μg / 0.1 mL, or about 800 μg / 0.1 mL. In preferred embodiments, the dose of MTX administered is about 200 μg / 0.1 mL, about 300 μg / 0.1 mL, about 400 μg / 0.1 mL, or about 500 μg / 0.1 mL. In some embodiments, the dose of MTX administered is about 400 μg / 0.1 mL. 5.4. Kit

[0154] In another aspect, the MTX composition is provided in the form of a kit. In some embodiments, the MTX composition in the kit is provided in multiple-dose vials. In some embodiments, the MTX composition in the kit is provided as a single-use vial. In some embodiments, the kit includes one or more single-use vials of the MTX composition. In some embodiments, the MTX composition is provided in the form of a dry composition for reconstitution with a suitable solvent such as pyrogen-free sterile water or buffer. In some embodiments, when the kit is provided as a dry composition, it includes a vial of solvent for reconstitution of the injectable MTX solution.

[0155] In some embodiments, the kit further includes a syringe for injecting the MTX composition. In some embodiments, the kit includes one or more syringes for injecting the MTX composition. In some embodiments, the MTX composition is provided in a pre-filled syringe for administration to the eye of a subject.

[0156] In certain embodiments, the kit also includes prescription information for proper use of the composition. The information may be in the form of a printed matter or a computer-readable medium.

[0157] The following examples are provided to further illustrate embodiments of the present disclosure. The examples described are merely illustrative and are not intended to limit the scope of the invention in any way.

Example

[0158] 6. Example Example 1: Preparation of the Composition and Evaluation of Passage through Silicone Oil Put water into a suitable container and add each component, such as a surfactant suitable for the formulation, a buffer, a density enhancer, methotrexate, etc., one at a time and dissolve in the solution. Adjust the pH to 7.4 ± 0.2 by adding 1M sodium hydroxide or HCl. Add water to make the desired final volume.

[0159] The effect of the formulation composition on the migration time of methotrexate through silicone layers of various viscosities and amounts was investigated using two grades of silicone oil: polydimethylsiloxane 1,000 cps (Sigma Aldrich, UK) and 5,000 cps (Mistral industrial chemicals, UK). 1. Two heights of silicone oil were tested: To determine the best height to use, 0.5 cm or 1 cm of oil was placed on top of 2 mL of PBS buffer. 2. One drop of formulation (approx. 50 mg) was placed on top of the silicone layer. The time taken for the API (formulation droplet, yellow) to move (cm / min) was monitored, and visual observations were also made regarding the distribution of the formulation phase into the aqueous phase after moving through the silicone phase, e.g., spontaneous, slow, etc.

[0160] The transit times of several different formulations investigated are shown in Figure 1.

[0161] Some of the formulations were also evaluated for the number of times the formulation passed through the oil interface within 2 hours. Each formulation was measured for a maximum of 2 hours, and the results represent the number of times the formulation passed through the silicone oil - PBS buffer interface during the evaluated period. The total number and % at both heights and both viscosities (out of 9 tests) are shown in the table below.

[0162]

Table 1

[0163] All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was specifically indicated to be incorporated by reference for all purposes.

[0164] Although various specific embodiments have been illustrated and described, it will be understood that various changes can be made without departing from the spirit and scope of the present invention. The present invention provides, for example, the following items. (Item 1) A composition for intravitreal administration, comprising methotrexate and a density enhancer, having a viscosity of at least 1000 centistokes and a passage rate of less than 10 minutes in 1 mL of silicone oil (SiO) having a depth of 1 cm. (Item 2) The composition according to Item 1, wherein the passage rate is less than 8 minutes. (Item 3) The composition according to Item 1 or 2, wherein the SiO is polydimethylsiloxane 5000 centistokes oil or polydimethylsiloxane 1000 centistokes oil. (Item 4) The composition according to any one of Items 1 to 3, wherein methotrexate is at a concentration of about 2 mg / mL to about 20 mg / mL. (Item 5) The composition according to Item 4, wherein the methotrexate is at a concentration of about 8 mg / mL. (Item 6) Having a density of about 1.0 to about 1.20 g / cm at 20 °C The composition according to any one of Items 1 to 5. 3 (Item 7) Having a density of at least about 1.03 g / cm at 20 °C The composition according to Item 6. 3 (Item 8) The composition according to any one of Items 1 to 7, wherein the density enhancer comprises sucrose, trehalose, glucose, carbopol, polyvinyl acetate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol (PEG), glycerol, poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolide (PGA), polyhydroxybutyric acid, polycaprolactone, polyvalerolactone, polyphosphazene, polyorthoester, cyclodextrin, or a mixture thereof. (Item 9) The composition according to Item 8, wherein the density enhancer comprises sucrose. (Item 10) The composition according to Item 9, wherein the sucrose is at a concentration of about 0.5% w / v to about 20% w / v. (Item 11) The composition according to Item 10, wherein the sucrose is at a concentration of about 7.5% w / v. (Item 12) The composition according to Item 8, wherein the density enhancer is PEG. (Item 13) The composition according to Item 12, wherein the PEG is PEG 4000. (Item 14) The composition according to Item 13, wherein the PEG 4000 is at a concentration of about 5% to 10% w / v. (Item 15) ​ The composition according to item 14, wherein the PEG 4000 is about 7.5% w / v. (Item 16) The composition according to any one of items 1 to 15, further comprising a surfactant. (Item 17) The composition according to item 16, wherein the surfactant comprises a nonionic surfactant. (Item 18) The composition according to item 16, wherein 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 monooleate (Tween® 80), polyoxyethylene (20) sorbitan tristearate (Tween® 65), polyoxyethylene (20) sorbitan trioleate (Tween® 85), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), sorbitan tristearate (Span® 65), and sorbitan trioleate (Span® 85). (Item 19) The composition according to item 18, wherein the surfactant is polyoxyethylene (20) sorbitan monolaurate (Tween® 20) or polyoxyethylene (20) sorbitan monooleate (Tween® 80). (Item 20) The composition according to any one of items 17 to 19, wherein the surfactant is present at a concentration of 0.0015% w / v to about 0.05% w / v. (Item 21) The composition according to any one of items 1 to 20, further comprising a buffer. (Item 22) The composition according to item 21, wherein the buffer is selected from borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, diphosphate, tromethamine, hydroxyethylmorpholine, and THAM (trishydroxymethylamino-methane). (Item 23) The composition according to any one of items 1 to 22, having a pH of about 5.5 to about 8.5. (Item 24) The composition according to item 23, wherein the pH is about 6.5 to about 7.5. (Item 25) 8 mg / mL methotrexate, and 7.5% w / v sucrose and the composition according to item 1, comprising (Item 26) the composition according to item 25, further comprising a surfactant (Item 27) the composition according to item 26, wherein the surfactant is a non-ionic surfactant (Item 28) the composition according to item 26, wherein 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 monooleate (Tween® 80), polyoxyethylene (20) sorbitan tristearate (Tween® 65), polyoxyethylene (20) sorbitan trioleate (Tween® 85), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), sorbitan tristearate (Span® 65), and sorbitan trioleate (Span® 85) (Item 29) the composition according to item 28, wherein the surfactant is Tween® 20 or Tween® 80 (Item 30) the composition according to any one of items 26 to 29, wherein the surfactant is present at a concentration of 0.0015% w / v to about 0.05% w / v (Item 31) the composition according to any one of items 25 to 30, further comprising a buffer (Item 32) the composition according to item 31, wherein the buffer is selected from borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, diphosphate, tromethamine, hydroxyethylmorpholine, and THAM (trishydroxymethylamino-methane) (Item 33) the composition according to item 32, wherein the buffer is phosphate (Item 34) the composition according to any one of items 25 to 33, having a pH of about 5.5 to about 8.5 (Item 35) the composition according to item 34, wherein the pH is about 6.5 to about 7.5 (Item 36) 8 mg / mL methotrexate, 7.5% w / v sucrose, 0.142 w / v - disodium phosphate dihydrate and The composition according to item 1, which contains and has a pH of about 6 to 8. (Item 37) 8 mg / mL methotrexate, and 7.5% PEG4000, and 0.142 w / v-sodium phosphate dibasic dihydrate and The composition according to item 1, which contains and has a pH of about 6 to 8. (Item 38) A method for preventing or reducing the risk of or treating proliferative vitreoretinopathy (PVR), the method comprising intravitreally administering to the eye of a subject in need thereof a therapeutically effective amount of the composition according to any one of items 1 to 37. (Item 39) The method according to item 38, wherein the subject has suffered trauma to the eye. (Item 40) The method according to item 38, wherein the eye of the subject has suffered retinal detachment. (Item 41) The method according to any one of items 38 to 40, wherein the eye of the subject has undergone retinal vitreous surgery for the retinal detachment. (Item 42) The method according to any one of items 38 to 41, wherein the retinal detachment is a primary retinal detachment. (Item 43) The method according to item 42, wherein the primary retinal detachment is rhegmatogenous retinal detachment. (Item 44) The method according to any one of items 38 to 41, wherein the retinal detachment is a secondary retinal detachment. (Item 45) The method according to item 44, wherein the secondary retinal detachment is rhegmatogenous retinal detachment, tractional retinal detachment, or combined tractional-rhegmatogenous retinal detachment. (Item 46) The method according to any one of items 38 to 45, wherein the eye has been treated or is being treated by administration of silicone oil (SiO) to the posterior segment of the eye. (Item 47) The method according to item 46, wherein the SiO is administered as a postoperative tamponade. (Item 48) The method according to item 46 or 47, wherein the composition is administered by intravitreal injection into the SiO. (Item 49) The method according to item 46 or 47, wherein the composition is co-administered with the SiO. (Item 50) The method according to any one of items 46 to 49, wherein the SiO is SiO having a viscosity of at least 1000 centistokes. (Item 51) The method according to item 50, wherein the SiO is polydimethylsiloxane having a viscosity of about 1000 centistokes. (Item 52) The method according to any one of items 46 to 49, wherein the SiO is SiO having a viscosity of about 5000 centistokes. (Item 53) The method according to item 52, wherein the SiO is polydimethylsiloxane having a viscosity of about 5000 centistokes. (Item 54) The method according to any one of items 38 to 53, wherein the dose of methotrexate administered is about 50 μg to about 600 μg for each administration. (Item 55) The method according to item 54, wherein the dose of methotrexate administered is about 400 μg for each administration. (Item 56) The method according to any one of items 38 to 55, wherein the composition is administered to the eye at least once a day for at least 5 days after retinal damage. (Item 57) The method according to any one of items 38 to 55, wherein the composition is administered to the eye at least once a day for at least 5 days after treatment for retinal damage. (Item 58) The method according to any one of items 38 to 55, wherein the composition is administered to the eye once a week or every other week. (Item 59) The method according to any one of items 38 to 58, wherein the treatment lasts for at least one week. (Item 60) The method according to item 59, wherein the treatment lasts for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 1 year. (Item 61) The method according to any one of items 38 to 60, wherein the subject has one or more risk factors for developing PVR. (Item 62) The method according to item 61, wherein the subject has a history of one or more of chronic uveitis, 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. (Item 63) The method according to item 61, wherein the subject had vitreous or subretinal hemorrhage, excessive cryotherapy, pigment release during endodrainage, or a combination thereof. (Item 64) A method of treating intraocular lymphoma or intraocular inflammation, comprising intravitreally administering a therapeutically effective amount of the composition according to any one of items 1 to 37 to the eye of a subject in need thereof. (Item 65) The method according to item 64, wherein the subject is being treated for intraocular lymphoma. (Item 66) The method according to item 65, wherein the intraocular lymphoma is primary vitreoretinal lymphoma (PVRL). (Item 67) The method according to any one of items 65 to 66, wherein the subject also has primary central nervous system lymphoma (PCNSL). (Item 68) The method according to item 65, wherein the lymphoma is diffuse large B-cell lymphoma. (Item 69) The method according to item 64, wherein the subject is treated for intraocular inflammation. (Item 70) The method according to item 69, wherein the intraocular inflammation is selected from uveitis; cystoid macular edema (CME); macular edema or diabetic macular edema; choroidal neovascularization; and choroidopathy. (Item 71) The method according to any one of items 64 to 70, wherein the dose of methotrexate administered is 100 μg to 800 μg, or 100 μg / 0.1 mL to 800 μg / 0.1 mL. (Item 72) The method according to item 71, wherein the dose of methotrexate administered is 400 μg or 400 μg / 0.1 mL. (Item 73) The method according to any one of items 64 to 72, wherein the composition is administered once every 4 weeks (months), once every 2 weeks, once a week, twice a week, three times a week, or four times a week. (Item 74) The method according to any one of items 64 to 73, wherein the treatment includes an induction phase, and a consolidation phase and / or a maintenance phase as required. (Item 75) The method according to item 74, wherein the induction phase is administration of the composition twice a week or up to four times a week. (Item 76) The method according to any one of items 74 to 75, wherein the consolidation phase, if present, includes administration once a week or once every two weeks. (Item 77) The method according to any one of items 74 to 76, wherein the maintenance phase, if present, includes administration once every two weeks or once a month.

Claims

1. A composition suitable for intravitreal administration, comprising methotrexate, a phosphate buffer, and a density enhancer, having a passing rate of less than 10 minutes in 1 mL of silicone oil (SiO) having a viscosity of at least 1000 centistokes and a depth of 1 cm, wherein the methotrexate has a concentration of 7 mg / mL to 9 mg / mL, the density enhancer is sucrose or PEG 4000, the density enhancer has a concentration of 7% w / v to 9% w / v, and the composition has a pH of 6 to 8.

2. The composition according to claim 1, wherein the passing rate is less than 8 minutes.

3. The composition according to claim 1, wherein the SiO is polydimethylsiloxane 5000 centistokes oil or polydimethylsiloxane 1000 centistokes oil.

4. The composition according to claim 1, wherein the methotrexate has a concentration of 8 mg / mL.

5.

6. The composition according to claim 1, having a density of 1.0 to 1.20 g / cm at 20 °C ３ .

7. The composition according to claim 5, having a density of at least 1.03 g / cm at 20 °C ３ . The composition according to claim 1, wherein the density enhancer has a concentration of 7.0% w / v to 8% w / v.

8. The composition according to claim 7, wherein the density enhancer is sucrose having a concentration of 7.5% w / v.

9. The composition according to claim 1, further comprising a surfactant, wherein the surfactant is a nonionic surfactant selected from polyoxyethylene (20) sorbitan monolaurate (Tween (registered trademark) 20), polyoxyethylene (20) sorbitan monopalmitate (Tween (registered trademark) 40), polyoxyethylene (20) sorbitan monostearate (Tween (registered trademark) 60), polyoxyethylene (20) sorbitan monooleate (Tween (registered trademark) 80), polyoxyethylene (20) sorbitan tristearate (Tween (registered trademark) 65), polyoxyethylene (20) sorbitan trioleate (Tween (registered trademark) 85), sorbitan monopalmitate (Span (registered trademark) 40), sorbitan monostearate (Span (registered trademark) 60), sorbitan monooleate (Span (registered trademark) 80), sorbitan tristearate (Span (registered trademark) 65), and sorbitan trioleate (Span (registered trademark) 85).

10. ​ The composition according to claim 9, wherein the surfactant is present at a concentration of 0.0015% w / v to 0.05% w / v.

11. The composition according to claim 1, further comprising a buffer selected from borate, bicarbonate, carbonate, citrate, tetraborate, diphosphate, tromethamine, hydroxyethylmorpholine, and THAM (trishydroxymethylamino-methane).

12. The composition according to claim 1, having a pH of 6.5 to 7.

5.

13. The composition according to claim 1, wherein the composition has an osmolality of 250 mOsm / L to 350 mOsm / L.

14. The composition according to claim 1, wherein the phosphate buffer is disodium phosphate dihydrate present at a concentration of 0.113 mg / mL to 0.142 mg / mL.

15. The composition according to claim 14, wherein the hydrate of the disodium phosphate has a concentration of 0.113 mg / mL.

16. The composition according to claim 14, wherein the hydrate of the disodium phosphate has a concentration of 0.142 mg / mL.

17. 8 mg / mL methotrexate, 7.5% w / v sucrose as a density enhancer, 0.142 w / v-disodium phosphate dihydrate and having a pH of 6 to 8, the composition according to claim 1.

18. 8 mg / mL methotrexate, 7.5% PEG4000 as a density enhancer, 0.142 w / v-disodium phosphate dihydrate and having a pH of 6 to 8, the composition according to claim 1.

19. The composition according to any one of claims 1, 17, and 18, wherein the composition is in a filled syringe and has a dosing volume of 40 μL, 45 μL, 50 μL, or 60 μL.

20. A composition for treating proliferative vitreoretinopathy (PVR) in a subject in need thereof, comprising methotrexate at a concentration of 7 mg / mL to 9 mg / mL, sucrose at a concentration of 7% w / v to 9% w / v, and a phosphate buffer, wherein the composition has a viscosity of at least 1000 centistokes and a passage rate of less than 10 minutes in 1 mL of silicone oil (SiO) having a depth of 1 cm.

21. The composition according to claim 20, wherein the phosphate buffer is disodium phosphate dihydrate.

22. The composition according to claim 21, wherein the disodium phosphate dihydrate is at a concentration of 0.113 mg / mL to 0.142 mg / mL, and the composition has a pH of 7.4 ± 0.

2.

23. The composition according to claim 20, wherein the subject has a previous medical history of one or more of chronic uveitis, infectious retinitis, multiple retinal detachments, large retinal breaks or giant retinal tears, multiple retinal breaks, ocular trauma, retinal detachment associated with vitreous hemorrhage, and choroidal detachment, and combinations thereof.

24. A composition for treating intraocular lymphoma, comprising methotrexate at a concentration of 7 mg / mL to 9 mg / mL, sucrose at a concentration of 7% w / v to 9% w / v, and a phosphate buffer, wherein the composition is intravitreally administered to the eye of a subject in need of treatment for intraocular lymphoma, the composition has a passing rate of less than 10 minutes in 1 mL of silicone oil (SiO) having a viscosity of at least 1000 centistokes and a depth of 1 cm, the volume of the administered composition is 20 μL to 300 μL, and the composition has a pH of 6 to 8.

25. The composition according to claim 24, wherein the intraocular lymphoma is primary vitreoretinal lymphoma (PVRL), intraocular lymphoma associated with primary central nervous system lymphoma (PCNSL), or diffuse large B-cell lymphoma.

26. The composition according to claim 25, wherein the intraocular lymphoma is primary vitreoretinal lymphoma (PVRL).

27. The composition according to claim 24, wherein the volume of the administered composition is 40 μL to 170 μL.

28. The composition according to claim 24, wherein the volume of the administered composition is 50 μL and the dose of methotrexate administered is 400 μg.

29. A composition for treating primary vitreoretinal lymphoma (PVRL), comprising methotrexate at a concentration of 8 mg / mL, sucrose at a concentration of 7.5% w / v, and a phosphate buffer having a pH of 6 to 8, in the eye of a subject in need of treatment for primary vitreoretinal lymphoma (PVRL), wherein the composition is intravitreally administered to the eye of a subject in need of treatment for primary vitreoretinal lymphoma (PVRL), and the volume of the administered composition is 20 μL to 300 μL.

30. The composition according to claim 29, wherein the buffer solution contains disodium phosphate dihydrate at a concentration of 0.113 mg / mL to 0.142 mg / mL, and the pH of the composition is 7.4 ± 0.

2.

31. The composition according to claim 29, wherein the composition has an osmolality of 250 mOsm / L to 350 mOsm / L.

32. The composition according to claim 29, wherein the volume of the composition to be administered is 40 μL, 45 μL, 50 μL or 60 μL.

33. The composition according to claim 29, wherein the volume of the composition to be administered is 50 μL, and the dose of methotrexate to be administered is 400 μg.

34. The composition according to any one of claims 20, 24 and 29, wherein the composition is administered once every 4 weeks (months), once every 2 weeks, once a week, twice a week, three times a week, or four times a week during the treatment.

35. The composition according to any one of claims 20, 24 and 29, wherein the treatment includes an induction period, and if necessary, a consolidation period and / or a maintenance period if necessary.

36. The composition according to claim 35, wherein the induction period is administration of the composition twice a week or up to four times a week.

37. The composition according to claim 35, wherein the consolidation period, if present, includes administration once a week or once every two weeks.

38. The composition according to claim 35, wherein the maintenance period, if present, includes administration once every two weeks or once a month.

39. The composition according to claim 35, wherein the treatment includes the consolidation period immediately after the start period, the consolidation period includes administration once a week or once every two weeks, the treatment further includes the maintenance period immediately after the consolidation period, and the maintenance period includes administration once every two weeks or once a month.

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