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US-12616699-B2 - Ophthalmic formulations of methotrexate

US12616699B2US 12616699 B2US12616699 B2US 12616699B2US-12616699-B2

Abstract

The present disclosure provides formulations of methotrexate for ocular administration, including intravitreal administration, and use of the formulations for treating proliferative vitreoretinopathy (PVR), intraocular lymphoma (e.g., PVRL), and intraocular inflammation.

Inventors

  • Dean Eliott
  • Stephen Gitu Machatha
  • Pramod Sarpotdar
  • Tomasz STRYJEWSKI

Assignees

  • ALDEYRA THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20200911

Claims (18)

  1. 1 . A composition suitable for intravitreal administration, comprising: methotrexate at a concentration of about 7 mg/mL to about 9 mg/mL, and a density enhancing agent selected from sucrose, trehalose, glucose, polyvinyl acetate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethylcellulose, hydroxypropyl methylcellulose, 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 mixtures thereof, wherein the composition has a density of about 1.0 to about 1.20 g/cm 3 at 20° C.
  2. 2 . The composition of claim 1 , wherein the composition has a transit rate of less than 10 min in 1 mL of silicone oil (SiO) having a viscosity of at least 1000 centistoke and depth of 1 cm.
  3. 3 . The composition of claim 2 , wherein the SiO is polydimethyl siloxane 5000 centistoke oil or polydimethyl siloxane 1000 centistoke oil.
  4. 4 . The composition of claim 1 , wherein the composition has a density of at least about 1.03 g/cm 3 at 20° C.
  5. 5 . The composition of claim 1 , wherein the density enhancing agent is PEG.
  6. 6 . The composition of claim 5 , wherein the PEG is PEG 4000.
  7. 7 . The composition of claim 6 , wherein the PEG 4000 is at a concentration of about 5% to 10% w/v of the composition.
  8. 8 . The composition of claim 7 , wherein the PEG 4000 is at about 7.5% w/v of the composition.
  9. 9 . The composition of claim 1 , further comprising a surfactant.
  10. 10 . The composition of claim 9 , wherein the surfactant comprises a non-ionic surfactant.
  11. 11 . The composition of claim 9 , wherein the surfactant is selected from polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan tri-oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan mono-oleate, sorbitan tristearate, and sorbitan trioleate.
  12. 12 . The composition of claim 11 , wherein the surfactant is polyoxyethylene (20) sorbitan monolaurate or polyoxyethylene (20) sorbitan mono-oleate.
  13. 13 . The composition of claim 10 , wherein the surfactant is present at a concentration of 0.0015% w/v to about 0.05% w/v.
  14. 14 . The composition of claim 1 , further comprising a buffering agent.
  15. 15 . The composition of claim 14 , wherein the buffering agent is selected from borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, biphosphate, tromethamine, hydroxyethyl morpholine, and THAM (trishydroxymethylamino-methane).
  16. 16 . The composition of claim 1 , wherein the composition is at a pH of about 5.5 to about 8.5.
  17. 17 . The composition of claim 16 , wherein the pH is about 6.5 to about 7.5.
  18. 18 . The composition of claim 1 , wherein the density enhancing agent is sucrose present at a concentration of about 7.5% w/v of the composition.

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS This application is a National Stage of International Application No. PCT/US2020/050565, filed Sep. 11, 2020, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/044,288, filed Jun. 25, 2020, and U.S. Provisional Application No. 62/900,060, filed Sep. 13, 2019; the contents of each of which are incorporated herein by reference in their entirety. 2. BACKGROUND Proliferative vitreoretinopathy (PVR) is a clinical syndrome that occurs after rhegmatogenous retinal detachment, such as caused by a break in the retina (e.g., retinal tear or retinal hole) and its surgical repair. The pathogenesis of PVR involves the release of cells into the vitreous cavity (extraretinal cells) where they replicate and form periretinal fibrocellular membranes on the inner and/or outer surfaces of the retina, creating shortening of the retina and retinal traction. PVR is characterized by intraretinal fibrosis and reduced elasticity, which leads to tractional elevation of the retina and subsequently new retina breaks and recurrent retinal detachment. PVR can occur in untreated eyes with retinal detachment or after retinal procedures such as retinal cryopexy, laser retinopexy, pneumatic retinopexy, scleral buckle and/or pars plana vitrectomy. The prevalence of PVR varies widely but is estimated to range about 5 to 12% of all rhegmatogenous retinal detachment cases (Kwon et al., Dev Ophthalmol., 2016; 55:154-62). PVR and its associated retinal traction is one of the main reasons for failure (i.e., recurrent retinal detachment) of initially successful repairs of retinal detachment and is present in approximately 75% of failed retinal detachment repairs (Sadaka et al., Clinical Ophthalmology, 2016; 10 1811-1817). Retinal detachment surgery can include scleral buckling, pneumatic retinopexy, and pars plana vitrectomy (PPV). Pneumatic retinopexy involves injecting gas into the vitreous cavity while PPV for retinal detachment involves removal of the vitreous and its replacement with a tamponade agent, such as silicone oil or gas. Tamponade agents provide surface tension across retinal breaks, preventing further fluid flow into the subretinal space until the retinopexy (photocoagulation or cryopexy) provides a permanent seal. For complex detachments involving PVR, silicone oil is often used. Commonly used viscosities of silicone oils include 1,000 and 5,000 centistokes. Silicone oils have a lower specific gravity (0.97 g/mL) than vitreous (1.005-1.008 g/mL), and as a result, they float in the vitreous cavity. Similarly, gases also float in the vitreous cavity due to their very low specific gravities (˜0.001 g/mL) and they have a much greater buoyancy than silicone oils. Heavier silicone oils (HSOs) and perfluorocarbon liquids have been used for inferior retinal breaks because the lighter silicone oils and gases may be less effective tamponade for retinal breaks at these locations. Given the prevalence of PVR following retinal detachment and retinal detachment surgery, anti-inflammatory and immunosuppressive agents have been administered to control PVR and reduce the failure rates of PPV. Use of anti-inflammatory or immunosuppressive agents may be beneficial for subjects at higher risk of PVR. Methotrexate (MTX) is an antineoplastic antimetabolite with immunosuppressant properties and inhibits enzymes requiring folate as a cofactor, including enzymes involved in nucleotide biosynthesis necessary for DNA replication. MTX has been used to treat chronic inflammatory and fibrotic conditions. In ophthalmology, MTX has been used to treat uveitis, pemphigoids, scleritis and episcleritis, and primary intraocular lymphoma. Studies of intravitreal MTX administration following retinal reattachment surgery show promise in reducing the incidence of retinal detachment following surgery (Benner et al., BMJ Open Ophth., 2019; 4:e000293; Sadaka et al., Clinical Ophthalmology, 2016; 10:1811-1817). Desirable are formulations of MTX for treating PVR following retinal detachment, particularly for cases when silicone oil is used as the preferred tamponade agent, as well as for treating other ocular disorders amenable to treatment with MTX, such as intraocular lymphoma and intraocular inflammatory conditions. 3. SUMMARY The present disclosure provides a composition comprising methotrexate (MTX), and a density enhancing agent. In some embodiments, the composition is characterized by a transit time of less than 10 min through a silicone oil (SiO) of 1 cm depth. In some embodiments, the SiO is SiO used in treatment of retinal detachment. In some embodiments, the SiO is SiO having a viscosity of at least 1000 centistoke, e.g., polydimethyl siloxane having viscosity of 1000 centistoke. In some embodiments, the SiO is SiO having a viscosity of about 5000 centistoke. In some embodiments, the SiO is polydimethyl siloxane having a viscosity of about 5000 centistoke. In some embodiments, the densi