Search

CN-122028922-A - Method for treating diabetic macular edema

CN122028922ACN 122028922 ACN122028922 ACN 122028922ACN-122028922-A

Abstract

The present disclosure relates to a method of treating diabetic macular edema in a human subject in need thereof, the method comprising (i) topically administering an eye drop formulation comprising 1.5% (w/v) dexamethasone to the subject's diseased eye at a dose of 5-7 drops per day for 3 weeks, 4 weeks, 5 weeks, 6 weeks, followed by (ii) a maintenance period, topically administering the eye drop formulation comprising 1.5% (w/v) dexamethasone to the subject's diseased eye at a daily dose less frequent than the induction period (e.g., 1-3 drops).

Inventors

  • R Sheriff
  • S. Marcabi
  • P. Dugger

Assignees

  • 奥库里斯经营管理有限责任公司

Dates

Publication Date
20260512
Application Date
20241016
Priority Date
20231016

Claims (20)

  1. 1.A method of treating diabetic macular edema in a human subject in need thereof, the method comprising (I) An induction period, an eye drop formulation comprising 1.5% (w/v) dexamethasone was topically administered to the subject's diseased eye at a dose of 5, 6, 7 drops per day, followed by, (Ii) A maintenance period, wherein the eye drop formulation comprising 1.5% (w/v) dexamethasone is topically administered to the subject's diseased eye at a daily dose of 1, 2, 3 drops per day.
  2. 2. The method of claim 1, wherein the eye drop formulation is a microsuspension comprising a solid complex of dexamethasone, gamma-cyclodextrin, and poloxamer.
  3. 3. The method of claim 1 or 2, wherein the eye drop formulation is a microsuspension comprising microparticles having a diameter D 50 of about 1 μιη to 20 μιη.
  4. 4. The method of any one of claims 1-3, wherein the induction period comprises topical administration of an eye drop formulation at a dose of 5, 6, 7, or 8 drops per day for a period of 5 days to up to 3 weeks, 4 weeks, 5 weeks, or 6 weeks.
  5. 5. The method of any one of claims 1-4, wherein the induction period comprises topically administering the eye drop formulation at a dose of 6 drops per day for a period of up to 3 weeks, 4 weeks, 5 weeks, or 6 weeks.
  6. 6. The method of any one of claims 1-5, wherein the induction period comprises topically administering the eye drop formulation at a dose of 6 drops per day for a period of up to 6 weeks.
  7. 7. The method of any one of claims 1-6, wherein the maintenance period comprises topically administering the eye drop formulation at a dose of 1,2, or 3 drops per day for at least 3 weeks, at least 6 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 46 weeks, provided that the patient requires a period of time or indefinitely.
  8. 8. The method of any one of claims 1-6, wherein the maintenance period comprises topically administering the eye drop formulation at a dose of 1, 2, or 3 drops per day for a period of at least 46 weeks.
  9. 9. The method of any one of claims 1-6, wherein the maintenance period comprises topically administering an eye drop formulation at a dose of 3 drops per day for at least 3 weeks, at least 6 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 46 weeks, provided the patient requires a period of time or indefinitely.
  10. 10. The method of any one of claims 1-6, wherein the maintenance period comprises topical administration of an eye drop formulation at a dose of 3 drops per day for a period of at least 46 weeks.
  11. 11. The method of any one of claims 1-6, wherein the maintenance period comprises topically administering an eye drop formulation comprising 1.5% (w/v) dexamethasone to the subject's diseased eye at a dose of 1, 2, or 3 drops per day.
  12. 12. The method of any one of claims 1-6, wherein the maintenance period comprises topically administering an eye drop formulation comprising 1.5% (w/v) dexamethasone to the subject's diseased eye at a dose of 3 drops per day.
  13. 13. The method of any one of claims 1-3, wherein the dosage regimen comprises (I) An induction period, wherein an eye drop formulation comprising 1.5% (w/v) dexamethasone is topically administered to the subject's diseased eye at a dose of 6 drops per day, followed by (Ii) A maintenance period, wherein the eye drop formulation is topically administered at a dose of 1,2 or 3 drops per day for at least 6 weeks.
  14. 14. The method according to claim 13, wherein the maintenance period comprises administration of the eye drop formulation at a dose of 3 drops per day for at least 6 weeks.
  15. 15. The method of any one of claims 1-3, wherein the dosage regimen comprises (I) An induction period, in which an eye drop formulation comprising 1.5% (w/v) dexamethasone was topically administered to the diseased eye of the subject at a dose of 6 drops per day for 6 weeks, followed by (Ii) The eye drop formulation was topically applied at a dose of 3 drops per day during the maintenance period.
  16. 16. The method of any one of claims 1-15, wherein the eye drop formulation comprises an amount of gamma cyclodextrin of 10-25% by weight of cyclodextrin based on the volume of the composition.
  17. 17. The method of any one of claims 1-16, wherein the eye drop formulation comprises or consists essentially of: -1.5% dexamethasone; -12-16% gamma-cyclodextrin; -2-2.7% poloxamer; -0-0.1% of a chelating agent, e.g. 0.1% disodium edentate; -0-1% electrolyte, for example 0.57% sodium chloride; -0% -0.6% of an additive to prevent oxidation of dexamethasone, and -Water; And wherein the pH is from 4.7 to 6.0, Wherein% is weight% based on the volume of the composition.
  18. 18. The method of any one of claims 1-17, wherein the subject is unresponsive or under-responsive to VEGF inhibitor treatment and/or does not support invasive treatment of diabetic macular edema.
  19. 19. The method of any one of claims 1-18, wherein the subject is selected from VEGFi natural patients having retinal thickening in the diseased eye due to diabetic macular edema.
  20. 20. The method of any one of claims 1-19, wherein the subject is an adult subject.

Description

Method for treating diabetic macular edema Technical Field The present disclosure describes improved methods of treating diabetic macular edema with topical drops in a human subject in need thereof in a manner that provides a similar or better therapeutic effect than the prior art using ocular implants. Background Diabetic Macular Edema (DME) is a major cause of vision loss and legal blindness in diabetics. Currently, it is estimated that about 37,000,000 people worldwide are affected, and as diabetes increases, it is expected that the 2040 year prevalence will increase to 53,000,000 that （Yau et al. Diabetes Care 2012 Mar; 35(3): 556-564; International Diabetes Federation – diabetesatlas.org Estimated diabetes prevalence worldwide in 2021: 537m, reaching 783m in 2045）.DME is an irreversible and progressive complication of diabetic retinopathy and is associated with constantly high blood glucose levels that damage nerves and blood vessels in the macula (the area of the retina responsible for acute vision). DME can occur when blood vessels in the retina swell and then leak, resulting in fluid accumulation (edema) into the retina. There remains a great need for safer, more effective, more durable and less burdened treatments for DME patients. Most ocular disorders can be treated and/or managed to reduce negative effects, including total blindness. However, current treatments for ocular conditions are limited by the difficulty in delivering an effective dose of the drug to the target tissue in the eye. In current treatments, topical eye drops are the preferred means of administering the drug to the eye because eye drops are convenient and safe compared to other ocular drug administration routes such as intravitreal injection and implantation (Le Souriais, c., et al, 1998, progress IN RETINAL AND EYE RESEARCH, 33-58). The drug is transported from the ocular surface into the eye and surrounding tissues primarily by passive diffusion, wherein the drug is transported into the eye by a gradient of dissolved drug molecules according to Fick's law. Diffusion of passive drugs into the eye is hindered by three major obstacles （Gan, L., et al, 2013. Drug Discov. Today 18, 290-297; Loftsson, T., et al., 2008. Pharmazie 63, 171-179; Urtti, A, 2006. Adv. Drug Del. Rev. 58, 1131-1135）. However, achieving therapeutic concentrations of drug in the posterior segment of the eye following topical administration using eye drops is highly challenging. Currently, more invasive methods of application such as intravitreal injection, vitreous implant, periocular injection or systemic administration are the only available options. This invasive approach has a number of individual disadvantages. For example, dexamethasone was registered as an intravitreal implant for DME, macular edema in retinal vein occlusion, and posterior uveitis (OZURDEX. Mu.g intravitreal implant in applicator, complete US prescription information, available at https:// www.ozurdex.com /). In OZURDEX of 2 separate DME clinical studies, all patients (pooled) had an average change baseline of 6 in the letters of Best Corrected Vision (BCVA) at 3 months. At 39 months, the average change from baseline for all patients in the BCVA alphabet (pooled) was 2.2. The percentage of all study subjects (pooled) experiencing ≡15 letter improvement at 3 months was 13% relative to baseline and 20% at 39 months. However, the use of OZURDEX cubes is associated with significant ocular adverse events. As shown in the U.S. prescription information, intravitreal implants are associated with endophthalmitis, ocular inflammation, increased intraocular pressure, and retinal detachment. Separately, as indicated in the U.S. prescription information, the use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections caused by bacteria, fungi, or viruses. OZURDEX U.S. prescription information reports that 68% of study patients who received OZURDEX volts developed cataracts, including cataracts, cataract nuclei, subcapsular cataracts, and clouding of the lens, and 61% of study patients who developed cataracts underwent surgery. In addition, 28% of study subjects who received OZURDEX% had an increase in IOP of ≡10mmHg relative to baseline at any visit, with 15% of study subjects having IOP of ≡30mmHg at any visit and 6% of study subjects having IOP of ≡35mmHg at any visit. Although current eye drop formulations are the preferred route for the treatment of anterior ocular segment disorders, drug permeation, particularly of insoluble molecular entities, is often limited （Johannsdottir S, Jansook P, Stefansson E., Topical drug delivery to the posterior segment of the eye: Dexamethasone concentrations in various eye tissues after topical administration for up to 15 days to rabbits. J Drug Deliv Sci Tech. 2018; 45: 449-54）. by pre-corneal losses due to tear and nasolacrimal drainage, dexame