WO2019148291A1 - Ocular inserts comprising a covalently linked steroid dimer - Google Patents

Ocular inserts comprising a covalently linked steroid dimer Download PDF

Info

Publication number
WO2019148291A1
WO2019148291A1 PCT/CA2019/050133 CA2019050133W WO2019148291A1 WO 2019148291 A1 WO2019148291 A1 WO 2019148291A1 CA 2019050133 W CA2019050133 W CA 2019050133W WO 2019148291 A1 WO2019148291 A1 WO 2019148291A1
Authority
WO
WIPO (PCT)
Prior art keywords
article
compound
melt
glassy state
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2019/050133
Other languages
English (en)
French (fr)
Inventor
Ian Charles PARRAG
Matthew Alexander John STATHAM
Kyle Battiston
Dimitra LOUKA
Wendy Alison NAIMARK
Hans Christian FISCHER
Leonard Pinchuk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Interface Biologics Inc
Original Assignee
Interface Biologics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Interface Biologics Inc filed Critical Interface Biologics Inc
Priority to US16/966,453 priority Critical patent/US11612567B2/en
Publication of WO2019148291A1 publication Critical patent/WO2019148291A1/en
Anticipated expiration legal-status Critical
Priority to US18/738,907 priority patent/US20250049719A1/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6953—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a fibre, a textile, a slab or a sheet
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts or implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
    • C07J7/0055—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • Steroids are useful drugs in ophthalmology, for example corticosteroids are used in the treatment of ocular inflammation associated with inflammatory diseases or following ocular surgery.
  • the disclosure features ocular inserts that enable sustained release of ocular therapeutics, e.g., steroids.
  • the disclosure features a method of treating an ocular condition in an eye of a subject in need thereof, said method including contacting the eye with an article formed from a compound of formula (A- 1):
  • each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an anti-angiogenic steroid, an intraocular pressure (IOP) lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2.
  • the article is free of controlled release excipient, free of a crystallization inhibiting excipient, free of a mechanical integrity enhancing excipient, and/or free of a binding excipient; or the article optionally has a glassy state.
  • L is covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.
  • L is covalently linked to D1 and to D2 via one or more carbonate linkages.
  • L includes the radical -(C(0)-(R A )-C(0)- or -0-(R A )-0-;
  • R A is a radical of a polyol and includes at least one free hydroxyl group or R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2- 20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, -(CFhCI-hOjqCI-hCI-h-,
  • D1 and D2 are formed from the same steroid and the compound is further described by one of formulas (ll-a)-(ll-r). In other embodiments, D1 and D2 are formed from different steroids and each of D1 and D2 are, independently, further described by one of formulas (l-a)-(l- r).
  • At least 70% (w/w) of the article is a compound of formula (A-l), e.g., at least 75% (w/w), at least 80% (w/w), at least 85% (w/w), at least 90% (w/w), at least 95% (w/w), or at least 99% (w/w).
  • at least 90% (w/w) of the article is a compound of formula (A-l).
  • the compound, D1 , or D2 are released from the article through surface erosion.
  • the compound is released from the article through surface erosion. In certain embodiments, the surface erosion releases less than 20%
  • the surface erosion releases less than 2.0% (e.g., less than 1.8%, 1.5%,
  • D1 or D2 (as a percentage of the total drug, D1 or D2, present in the article in prodrug form) at 37 °C in PBS over 5 days, 7 days, 10 days, or 14 days (e.g., less than 2% of D1 or D2 at 37 °C in PBS over 5 days).
  • the surface erosion releases greater than 20% (e.g., greater than 22%, 24%, 26%, 28%, or 30%) of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the article in prodrug form) at 37 °C in 100% bovine serum over not fewer than 6 days, 8 days, 10 days, or 12 days (e.g., greater than 24% of D1 or D2 at 37 °C in 100% bovine serum over 10 days).
  • the surface erosion releases greater than 5.0% (e.g., greater than 6.0%, 8.0%, 10%, 12%, or 15%) of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the article in prodrug form) at 37 °C in PBS over not fewer than 6 days, 8 days, 10 days, or 12 days (e.g., greater than 5% of D1 or D2 at 37 °C in PBS over 10 days).
  • the compound (D1 and/or D2) can be released from the article at a rate such that tio is greater than or equal to 1/10 of tso
  • the article further includes from 0.1 % to 10% (e.g., from 0.1 to 5%, from 0.1 to 2%, from 0.5 to 2%, from 1 to 10%) (w/w) of one or more additives, in which the one or more additives are plasticizers (e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated
  • plasticizers e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol
  • antioxidants e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated
  • the article further includes from 0.1 % to 10% (w/w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, dyes, and mixtures thereof.
  • the article is a fiber, fiber mesh, woven fabric, non-woven fabric, pellet, cylinder, microparticle (e.g., a microbead), nanoparticle (e.g., a nanobead), or shaped article.
  • microparticle e.g., a microbead
  • nanoparticle e.g., a nanobead
  • the article is in the form of glassy state fibers having a mean diameter of from about 0.01 to 1 mm, e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm.
  • 0.05 to 0.3 mm e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7
  • a mean length of the fiber can range from about 20 mm to 20 meters, e.g., 20 to 100 mm, 75 to 300 mm, 100 mm to 1 meter, 0.5 meters to 6 meters, or 1 .0 meters to 20 meters.
  • the article is in the form of glassy state pellets having a mean diameter of from about 0.2 to 5 mm, e.g., from about 0.2 to 1 mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5 mm, from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, from about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.
  • the article is in the form of glassy state cylinders of from about 0.01 to 1 mm in diameter (e.g., about 0.01 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9 mm) and 0.5 to 20 mm in length (e.g., about to 0.5 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm).
  • the length of the cylinder is about 0.5 to 10 mm, or about 1 to 10 mm.
  • the article is in the form of glassy state microparticles, e.g., microbeads having a mean diameter of from about 1 to 1000 pm, e.g., about 10 to 1000 pm, about 100 to 1000 pm, about 200 to 1000 pm, about 500 to 1000 pm, about 700 to 1000 pm, or about 900 to 1000 pm.
  • the article is in the form of a punctal plug, a stent, or a tube.
  • the article is a fiber, a cylinder, a stent, or a tube.
  • the article is administered by intravitreal, subretinal, or suprachoroidal injection into the eye of a subject.
  • the article is a cylinder and the method further includes intravitreal, subretinal, or suprachoroidal injection of the article into the eye.
  • the ocular condition to be treated can be an inflammatory condition or a condition associated with a risk of developing inflammation.
  • the methods of the disclosure can be useful for the treatment of macular edema from retinal vein occlusion, diabetic macular edema, uveitis, diabetic retinopathy, or age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the compound of formula (A-1) can be selected such that, upon hydrolysis, D1 and D2 form a corticosteroid or a glucocorticoid steroid.
  • the compound can be a compound further described by the formula (III):
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or O-(R A )-0 is selected from: -C CF CI- C nCI- CI- O-,
  • n, m, and p are integers from 1 to 10.
  • the ocular condition can be a bacterial infection or a condition associated with a risk of developing a bacterial infection.
  • the methods of the disclosure can be useful for the treatment of conjunctivitis, keratitis, trachoma, or endophthalmitis.
  • the compound of formula (A-1) can be selected such that, upon hydrolysis, at least one of D1 and D2 form fusidic acid.
  • D1 and D2 upon hydrolysis D1 and D2 form an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid.
  • IOP intraocular pressure
  • D1 and D2 upon hydrolysis D1 and D2 form anecortave acetate, anecortave, 11-epicortisol, 17a-hydroxyprogesterone, tetrahydrocortexolone, or
  • the compound of formula (A-l) can be administered intravitreally to the eye of the subject, or can be administered to the suprachoroidal space of an eye of the subject.
  • the subject has age related macular degeneration, and upon hydrolysis D1 and D2 form an anti-angiogenic steroid, a corticosteroid, or a glucocorticosteroid.
  • the subject has glaucoma, and upon hydrolysis D1 and D2 form an intraocular pressure (IOP) lowering steroid.
  • IOP intraocular pressure
  • 0-(R A )-0 is a radical of a polyol formed from a cyclitol (e.g., bornesitol, conduritol, inositol, ononitol, pinitol, pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, or viscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol, maltitol, lactitol, erythritol, isomalt), or glycerin.
  • a cyclitol e.g., bornesitol, conduritol, inositol, ononitol, pinitol, pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, or viscumitol
  • a sugar alcohol e.g., sorbitol
  • the article is formed by a process including the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and (b) evaporating the solvent to form the article.
  • Articles of the disclosure can be formed by the steps of (a) heating a compound of formula (A-l) above its melting point (e.g., depending upon the compound, heating to 1 10-145 °C, 130-185 °C, 150-215 °C, or 180-240 °C) to form a melt, and (b) cooling the melt to form an article.
  • the article can be shaped during step (a), prior to cooling, by pressing the melt into a mold, by extruding the melt from an orifice (e.g., to form a cylinder, stent, tube, or another shape), or by forming droplets of the melt and allowing the droplets to cool into glassy state droplets.
  • Fibers can be formed by spinning (e.g. melt spinning), or pulling the melt (e.g., with tweezers) at different rates to yield glassy state fibers of different diameters.
  • Nanoparticles can be prepared by electrospraying a solution containing the compound at a concentration of about 3% to 15% w/v or 5% to 18% w/v of the solution.
  • a shaped article can be formed by placing the solution in a mold and evaporating the volatile organic solvent to form a shaped article.
  • the methods of the disclosure can include forming the article by a process including the steps of:
  • Step (b) evaporating the solvent to form a glassy state composition; and (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a shaped article.
  • Step (c) can include extruding, molding, blow molding, heat spinning, electrospinning, or electrospraying the glassy state composition to form the shaped article.
  • the methods of the disclosure can further include forming the article by a process including the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution; (b) electrospraying or electrospinning the solution to form a glassy state composition; and (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a coating.
  • the compound is processed as described herein (e.g., melt processed or solvent processed) to form a glassy state solid.
  • the glassy state solid is subsequently heated above its glass transition temperature, Tg, and molded or extruded to form a shaped article (e.g., a fiber, cylinder, stent, tube, microparticle (e.g., a microbead), or nanoparticle (e.g., a nanobead), or another shaped article).
  • a shaped article e.g., a fiber, cylinder, stent, tube, microparticle (e.g., a microbead), or nanoparticle (e.g., a nanobead), or another shaped article.
  • the article is free of controlled release excipient.
  • the article is free of a crystallization inhibiting excipient
  • the article is free of a mechanical integrity enhancing excipient.
  • the article is free of a binding excipient.
  • the article optionally has a glassy state.
  • R15 represents H or OH;
  • L is -C(0)0-(R A )-0C(0)- or -C(0)-0C(0)-(R A )-C(0)0-C(0)-, and
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the compound is formed from anecortave acetate, anecortave, 1 1 -epicortisol, 17a-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.
  • R15 represents H or OH
  • L is -C(0)0-(R A )-0C(0)- or -C(0)-0C(0)-(R A )-C(0)0-C(0)-
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2- 20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2
  • the compound is formed from anecortave acetate, anecortave, 1 1 -epicortisol, 17a-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.
  • R15 represents H or OH
  • L is -C(0)0-(R A )-0C(0)- 0r -C(O)-OC(O)-(R A )-C(O)O-C(O)-
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • O- (R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, -0(CH 2 CH 2 CH 2 CH 2 0)mCH
  • the compound is formed from anecortave, 1 1-epicortisol, tetrahydrocortexolone, or tetrahydrocortisol.
  • R A is selected from C 1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C 2-20 alkenylene, a linear or branched C 2 - 20 alkynylene, a C5- 10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, - 0(CH 2 CH 2 CH 2 CH 2 0)mCH 2 CH 2 CH 2 CH 2 0-, or -0(CH 2 CH(CH3)0)pCH 2 CH(CH3)0-; and n, m,
  • the disclosure features a method of treating the eye of a subject in need thereof, the method including:
  • each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an IOP lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2, wherein the article is a fiber, a cylinder, a stent, or a tube; and
  • the article is free of controlled release polymer, free of a crystallization inhibiting excipient, free of a binding excipient, and/or free of a mechanical integrity enhancing excipient; or wherein the article optionally has a glassy state.
  • the article does not block the fluid passage in the canal.
  • D1-L-D2 (A-l), or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an IOP lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2, wherein the article is sized to provide a fluid passageway between the suprachoroidal space and the anterior chamber thereby reducing intraocular pressure in the eye; and
  • the article inserting the article into a suprachoroidal space of the eye, wherein the article is positioned to extend from the suprachoroidal space to the anterior chamber of the eye to provide the fluid passageway, wherein the article is free of controlled release polymer (i.e., non-drug carrier), free of a crystallization inhibiting excipient, free of a mechanical integrity enhancing excipient, and/or free of a binding excipient; or wherein the article optionally has a glassy state.
  • the article does not itself physically compromise flow in the canal with its presence.
  • L is covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.
  • L is covalently linked to D1 and to D2 via one or more carbonate linkages.
  • L includes the radical -(C(0)-(R A )-C(0)- or -0-(R A )-0-;
  • R A is a radical of a polyol and includes at least one free hydroxyl group or R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2- 20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, -(ChfcCI-fcOJqCI-fcCI-fc-,
  • D1 and D2 are formed from the same steroid and the compound is further described by one of formulas (ll-a)-(ll-m). In other embodiments, D1 and D2 are formed from different steroids and each of D1 and D2 are, independently, further described by one of formulas (l-a)-(l- k).
  • At least 70% (w/w) of the article is a compound of formula (A-l), e.g., at least 75% (w/w), at least 80% (w/w), at least 85% (w/w), at least 90% (w/w), at least 95% (w/w), at least 98% (w/w), or at least 99% (w/w).
  • at least 90% (w/w) of the article is a compound of formula (A-l).
  • the compound, D1 , or D2 are released from the article through surface erosion.
  • the compound is released from the article through surface erosion. In certain embodiments, the surface erosion releases less than 20%
  • the surface erosion releases less than 2.0% (e.g., less than 1.8%, 1.5%,
  • D1 or D2 (as a percentage of the total drug, D1 or D2, present in the article in prodrug form) at 37 °C in PBS over 5 days, 7 days, 10 days, or 14 days (e.g., less than 2% of D1 or D2 at 37 °C in PBS over 5 days).
  • the surface erosion releases greater than 20% (e.g., greater than 22%, 24%, 26%, 28%, or 30%) of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the article in prodrug form) at 37 °C in 100% bovine serum over not fewer than 6 days, 8 days, 10 days, or 12 days (e.g., greater than 24% of D1 or D2 at 37 °C in 100% bovine serum over 10 days).
  • the surface erosion releases greater than 5.0% (e.g., greater than 6.0%, 8.0%, 10%, 12%, or 15%) of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the article in prodrug form) at 37 °C in PBS over not fewer than 6 days, 8 days, 10 days, or 12 days (e.g., greater than 5% of D1 or D2 at 37 °C in PBS over 10 days).
  • the compound (D1 and/or D2) can be released from the article at a rate such that tio is greater than or equal to 1/10 of tso
  • the article further includes from 0.1 % to 10% (e.g., from 0.1 to 5%, from 0.1 to 2%, from 0.5 to 2%, from 1 to 10%) (w/w) of one or more additives, in which the one or more additives are plasticizers (e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated
  • plasticizers e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol
  • antioxidants e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated
  • the article further includes from 0.1 % to 10% (w/w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, dyes, and mixtures thereof.
  • the article is a fiber, a cylinder, a stent, or a tube.
  • the article is in the form of glassy state fibers having a mean diameter of from about 0.01 to 1 mm, e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm.
  • 0.05 to 0.3 mm e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7
  • the article is positioned and sized to support the Schlemm’s canal and keep the Schlemm’s canal open.
  • the ocular condition is an inflammatory condition.
  • the methods of the disclosure can be performed to reduce inflammation associated with cataract surgery or inflammation associated with glaucoma surgery.
  • the compound of formula (A-1) can be selected such that, upon hydrolysis, D1 and D2 form a corticosteroid or a glucocorticoid steroid.
  • the compound can be a compound further described by the formula (III):
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or O-(R A )-0 is selected from: -C CF CI- OjnCI- CI- O-,
  • n, m, and p are integers from 1 to 10.
  • the ocular condition can be a bacterial infection or a condition associated with a risk of developing a bacterial infection.
  • the methods of the disclosure can be useful for the treatment of conjunctivitis, keratitis, trachoma, or endophthalmitis.
  • 0-(R A )-0 is a radical of a polyol formed from a cyclitol (e.g., bornesitol, conduritol, inositol, ononitol, pinitol, pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, or viscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol, maltitol, lactitol, erythritol, isomalt), or glycerin.
  • a cyclitol e.g., bornesitol, conduritol, inositol, ononitol, pinitol, pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, or viscumitol
  • a sugar alcohol e.g., sorbitol
  • the linker L is formed from a polyol and includes 1 , 2, 3, or 4 hydroxyl groups.
  • 0-(R A )-0 is a radical formed from an alkane diol (e.g., a C1-10 diol), diethylene glycol, triethylene glycol, tetraethylene glycol, or pentaethylene glycol.
  • the article is formed by a process including the steps of: (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and (b) heat molding the melt to form the article.
  • the article is formed by a process including the steps of: (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and (b) blow molding the melt to form the article.
  • the article is formed by a process including the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and (b) evaporating the solvent to form the article.
  • the article is formed by a process including the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and (b) electrospinning, dry spinning, wet spinning, gel spinning, or electrospraying the solution to form the article.
  • the article is formed by a process including the steps of: (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and (b) electrospinning or electrospraying the melt to form the article.
  • the article is formed by a process including the steps of: (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; (b) extruding the melt to form the article.
  • Articles of the disclosure can be formed by the steps of (a) heating a compound of formula (A-l) above its melting point (e.g., depending upon the compound, heating to 1 10-145 °C, 130-185 °C, 150-215 °C, or 180-240 °C) to form a melt, and (b) cooling the melt to form an article.
  • the article can be shaped during step (a), prior to cooling, by pressing the melt into a mold, by extruding the melt from an orifice (e.g., to form a cylinder, stent, tube, or another shape), or by forming droplets of the melt and allowing the droplets to cool into glassy state droplets.
  • Fibers can be formed by spinning (e.g. melt spinning, or electrospinning), or pulling the melt (e.g., with tweezers) at different rates to yield glassy state fibers of different diameters.
  • articles of the disclosure can be formed by the steps of (a) dissolving a compound of formula (A-l) in a volatile organic solvent (e.g., acetone, methanol, dichloromethane, tetrahydrofuran, chloroform, or mixtures thereof) to form a solution, and (b) removing the organic solvent to form an article.
  • a volatile organic solvent e.g., acetone, methanol, dichloromethane, tetrahydrofuran, chloroform, or mixtures thereof
  • the article can be shaped during step (b), prior to completely removing the organic solvent, by electrospraying, electrospinning, or fiber spinning the solution.
  • a 50:50 v/v mixture of dichloromethane/tetrahydrofuran at 100% wt/v solution of the compound can be loaded at a rate of 0.5 ml_/h and electrospun onto a cylindrical mandrel rotating at 1 150 rpm, forming aligned glassy state fibers.
  • Fibers can be also formed by wet, dry, or gel spinning, or pulling the solution (e.g., with tweezers) at different rates, to form glassy state fibers of different diameters.
  • Microparticles can be prepared by electrospraying a solution containing the compound at a concentration of about 20% to 40% w/v or 25% to 50% w/v of the solution.
  • Nanoparticles can be prepared by electrospraying a solution containing the compound at a concentration of about 3% to 15% w/v or 5% to 18% w/v of the solution.
  • a shaped article can be formed by placing the solution in a mold and evaporating the volatile organic solvent to form a shaped article.
  • Step (b) evaporating the solvent to form a glassy state composition; and (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a shaped article.
  • Step (c) can include extruding, molding, blow molding, heat spinning, electrospinning, or electrospraying the glassy state composition to form the shaped article.
  • the compound is processed as described herein (e.g., melt processed or solvent processed) to form a glassy state solid.
  • the glassy state solid is subsequently heated above its glass transition temperature, Tg, and molded or extruded to form a shaped article (e.g., a fiber, cylinder, stent, or tube).
  • the article comprises less than 5% (e.g., less than 4%, less than 3%, less than 2%, or less than 1 %) (w/w) of polymeric material of greater than 5 kDa.
  • the article is free of a binding excipient.
  • the article is a glassy state composition.
  • drug release from the article exhibits a tio that is equal to or greater than 1/10 of tso when the drug release from the article is measured at 37 °C in phosphate buffered saline or in bovine serum.
  • free of controlled release polymer refers to the absence of an amount of a polymeric material of greater than 10 KDa in the articles of the disclosure that is sufficient to delay or slow the release of the steroid dimer from the article in comparison to the release profile observed for an otherwise identical article containing none of the polymeric material, where the release profile is measured at 37 °C in 100% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • the term“free of a crystallization inhibiting excipient,” as used herein, refers to the absence of an amount of an excipient in the articles of the disclosure that is sufficient to reduce the amount of crystalline steroid dimer in the article in comparison to the amount of crystalline steroid dimer observed in an otherwise identical article containing none of the excipient.
  • the level of crystallinity can be measured using DSC or XRD.
  • the articles of the disclosure are free of a crystallization inhibiting excipient that is a polymeric material of greater than 10 KDa.
  • the mechanical integrity can be tested using a 3-point mechanical bend test (ASTM D790-17) or 4-point mechanical bend test (ASTM D6272) on the formulation with or without excipient either in the dry state (prior to drug release) or after 15-30% drug release.
  • a reduction in mechanical integrity causes the articles to break apart sooner, increasing the total surface area of the quantity of articles, and resulting in a more rapid release profile , where the release profile is measured at 37 °C in 100% FBS.
  • the articles of the disclosure are free of a mechanical integrity enhancing excipient that is a polymeric material of greater than 10 KDa.
  • the term“free of a binding excipient,” as used herein, refers to the absence of an amount of an excipient in the articles of the disclosure that is sufficient to delay or slow the release of the steroid dimer from the article in comparison to the release profile observed for an otherwise identical article containing none of the binding excipient, where the release profile is measured at 37 °C in 100% FBS.
  • anti-angiogenic steroid refers to a steroid that is capable of inhibiting the growth of new blood vessels (i.e., angiogenesis).
  • anti-angiogenic steroids include anecortave acetate, anecortave, 11-epicortisol, 17a-hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol.
  • glassy state refers to an amorphous solid including greater than 70%, 80%, 90%, 95%, 98%, or 99% (w/w) of one or more drug dimers of the disclosure and exhibiting a glass transition temperature in the range of from 38 to 150 °C.
  • the level of crystallinity is low, ranging from 0-15%, e.g., 0-1 %, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%.
  • Glass formulations of the disclosure can be formed using heat processing or solvent processing one or more drug dimers.
  • a mean length of the cylinder can range from about 0.05 to 20 mm, e.g., about 0.05 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm.
  • the mean diameter of the cylinder is in the range of about 0.01 to 1 mm and the mean length of the cylinder is about 0.1 mm to 4.0 mm.
  • the mean length of the cylinder is about 0.5 to 10 mm, or about 1 to 10 mm.
  • fiber refers to the shape of the pharmaceutical compositions of the disclosure that is elongated or threadlike.
  • a mean diameter of the fiber can range from about 0.01 to 1 mm, e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm.
  • a mean length of the fiber can range from about 20 mm to 20 meters, e.g., about 20 to 1000 mm, about 20 to 2,000 mm, about 100 to 2,000 mm, about 100 to 5,000 mm, about 1 ,000 to 8,000 mm, about 2,000 to 8,000 mm, about 2,000 to 10,000 mm, about 2,000 to 12,000 mm, about 2,000 to 15,000 mm, or about 5,000 to 18,000 mm.
  • intraocular pressure (IOP) lowering steroid refers to a steroid that is capable of lowering intraocular pressure following administration to the eye of a subject.
  • IOP intraocular pressure
  • Examples of intraocular pressure (IOP) lowering steroids include anecortave acetate, anecortave, 11-epicortisol, 17a- hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol.
  • microparticle refers to the shape of the pharmaceutical compositions of the disclosure, which can be regularly or irregularly shaped.
  • a mean diameter of the microparticle can range from about 1 to 1000 pm, e.g., about 10 to 1000 pm, about 100 to 1000 pm, about 200 to 1000 pm, about 500 to 1000 pm, about 700 to 1000 pm, or about 900 to 1000 pm.
  • a“microbead” refers to a microparticle that is spherical.
  • nanoparticle refers to the shape of the pharmaceutical compositions of the disclosure, which can be regularly or irregularly shaped.
  • a mean diameter of the nanoparticle can range from about 0.01 to 1 pm, e.g., about 0.05 to 1 pm, about 0.1 to 1 pm, about 0.2 to 1 pm, about 0.3 to 1 pm, about 0.4 to 1 pm, about 0.5 to 1 pm, about 0.6 to 1 pm, about 0.7 to 1 pm, about 0.8 to 1 pm, or about 0.9 to 1 pm.
  • a“nanobead” refers to a nanoparticle that is spherical.
  • non-woven fabric refers to a web structure bonded together by entangling fibers.
  • An“ocular disease or condition” as used herein is a disease or condition that affects or involves the eye or one or more parts of the eye.
  • the parts of the eye are known to those of skill in the art and, broadly speaking, include the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles and the portion of the optic nerve which is within or adjacent to the eyeball.
  • pellet refers to the shape of the pharmaceutical compositions of the disclosure that is rounded, spherical, or cylindrical, or a combination thereof.
  • a mean diameter of the pellet can range from about 0.2 to 5 mm, e.g., from about 0.2 to 1 mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1 .5 to 5 mm, from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, from about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • stent refers to a tubular support in which the walls of the tube are optionally porous and wherein the stent has a mean diameter in its shortest dimension ranging from about 120 to 350 pm, e.g., 120 to 140 pm, 120 to 160 pm, 120 to 180 pm, 120 to 200 pm, 120 to 220 pm, 120 to 240 pm, 120 to 260 pm, 120 to 280 pm, 120 to 300 pm, 120 to 320 pm, or 120 to 340 pm.
  • the mean length of the stent is in the range of about 0.05 to 10 mm, e.g., 0.5 to 10 mm, 1 .0 to 8.0 mm, 0.5 to 6.0 mm, or 2.5 to 8.0 mm.
  • the mean diameter of the stent is in the range of about 0.01 to 1 mm and the mean length of the stent is about 0.5 to 10 mm.
  • surface erosion refers to a process of a gradual disintegration of the pharmaceutical compositions of the disclosure and release of a free drug from the drug dimer.
  • Surface erosion can be tailored to achieve desired drug release rates.
  • Surface erosion can depend on the drug composition of the drug dimer, and can be modulated by the cleavage of drug-linker bond through hydrolysis and/or enzymatic degradation.
  • the rate of surface erosion and release of a given drug from a drug dimer can also depend on the quantity of the loaded drug dimer as a percent of the final drug dimer formulation, article size, solubility of drug dimer (e.g., through selection of appropriate drug and/or linker), and/or surface area of the article.
  • surface erosion mechanism of drug release allows drug delivery articles to be tailored with specific physical features (dimensions, diameters, surface areas, total mass, etc.) to achieve desired drug release rates, and drug release can be designed to be initiated within minutes or hours, and may continue to occur over days, weeks, months, or years.
  • tso is the time at which 50% of the releasable drug has been released from an article of the disclosure.
  • Time tio is, correspondingly, the time at which 10% of the releasable drug has been released from an article of the disclosure.
  • tio 1/5 of tso.
  • tio is much less than 1/5 of tso.
  • tio can be equal to or greater than 1/10 of tso.
  • Drug release from an article or compound of the disclosure can be measured at 37 °C in 100% bovine serum, or at 37 °C in PBS, as described in Example 1 .
  • the term“tube” refers to a hollow, cylindrical body with a mean diameter ranging from about 120 to 350 pm, e.g., 120 to 140 pm, 120 to 160 pm, 120 to 180 pm, 120 to 200 pm, 120 to 220 pm, 120 to 240 pm, 120 to 260 pm, 120 to 280 pm, 120 to 300 pm, 120 to 320 pm, or 120 to 340 pm.
  • the mean length of the tube is in the range of about 0.05 to 10 mm, e.g., 0.5 to 10 mm, 1 .0 to 8.0 mm, 0.5 to 6.0 mm, or 2.5 to 8.0 mm.
  • the mean diameter of the tube is in the range of about 0.01 to 1 mm and the mean length of the tube is about 0.5 to 10 mm.
  • woven fabric refers to pharmaceutical compositions that resemble materials that are formed by weaving of fibers.
  • treating refers to administering a compound or composition as described herein, for prophylactic, adjunctive, and/or therapeutic purposes.
  • A“prophylactic” use refers to reducing the likelihood or severity of a condition or disease in a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease by administering treatment to the subject.
  • To“treat disease” refers to administering treatment to a subject already suffering from a disease to improve or stabilize the subject's condition.
  • treating is the administration to a subject either for therapeutic or prophylactic purposes.
  • acyl is meant a chemical moiety with the formula -C(0)R’, where R’ is selected from the group consisting of C-MO alkyl, C2-20 alkene, heteroalkyl, C2-20 alkyne, C5-10 aryl, and cyclic system.
  • acyl groups include, without limitation, acetyl, propanoyl, butanoyl, pentanoyl, and tetrahydrofuran-2-oyl.
  • aliphatic is meant a non-aromatic chemical moiety of hydrocarbons. Aliphatics may be cyclic, straight, or branched chains, and may be saturated or unsaturated, and may have single, double, or triple bonds.
  • alkoxy is meant a chemical substituent of the formula -OR, wherein R is an alkyl group.
  • aryloxy is meant a chemical substituent of the formula -OR, wherein R is a C5-10 aryl group.
  • the terms“alkylene,”“alkenylene,”“alkynylene,” and the prefix“alk” refer to divalent groups having a specified size, typically C 1-10 or C 1-20 for the saturated groups (e.g., alkylene or alk) and C 2-20 or C 2-2 o for the unsaturated groups (e.g., alkenylene or alkynylene). They include straight- chain, branched-chain, and cyclic forms as well as combinations of these, containing only C and H when unsubstituted. Because they are divalent, they can link together two parts of a molecule.
  • alkylthio is meant a chemical substituent of the formula -SR, wherein R is an alkyl group.
  • arylthio is meant a chemical substituent of the formula -SR, wherein R is a C5-10 aryl group.
  • C 1-20 alkyl is meant a branched or unbranched saturated hydrocarbon group, having 1 to 20 carbon atoms, inclusive.
  • An alkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members.
  • the alkyl group may be substituted or unsubstituted.
  • Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2-20 alkene is meant a branched or unbranched hydrocarbon group containing one or more double bonds, desirably having from 2 to 10 carbon atoms.
  • a C 2-20 alkene may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the C 2-20 alkene group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2 - 20 alkyne is meant a branched or unbranched hydrocarbon group containing one or more triple bonds, desirably having from 2 to 10 carbon atoms.
  • a C 2-20 alkyne may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the C 2-20 alkyne group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • carbonate ester is meant a linkage group having the formula -C(0)0-C(0)-0-.
  • cyclic system refers to a compound that contains one or more covalently closed ring structures, in which the atoms forming the backbone of the ring are composed of any combination of the following: carbon, oxygen, nitrogen, sulfur, and phosphorous.
  • the cyclic system may be substituted or unsubstituted.
  • substituents include, without limitation, alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl,
  • fluoroalkyl is meant an alkyl group that is substituted with a fluorine.
  • heteroalkyl is meant a branched or unbranched alkyl group in which one or more methylenes (-CH2-) are replaced by nitrogen, oxygen, sulfur, carbonyl, thiocarbonyl, phosphoryl, or sulfonyl moieties. Some examples include tertiary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, phosphoramidates, sulfonamides, and disulfides.
  • a heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members.
  • the heteroalkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • hydroxyalkyl is meant a chemical moiety with the formula -(R)-OH, wherein R is an alkyl group.
  • FIG. 1 A to FIG. 1 F are a series of images and a graph showing Compound 1 (Dexamethasone- Triethylene Glycol-Dexamethasone, Dex-TEG-Dex) formed into pellets in the glassy state and drug release through surface erosion from an intact pellet.
  • Compound 1 Compound 1 (Dexamethasone- Triethylene Glycol-Dexamethasone, Dex-TEG-Dex) formed into pellets in the glassy state and drug release through surface erosion from an intact pellet.
  • FIG. 2A to FIG. 2G are a series of images showing Compound 1 (Dex-TEG-Dex) processed into different glassy state forms by multiple processing methods from the melt state.
  • FIG. 3A to FIG. 3F are a series of images and graphs showing Compound 1 formed into heat extruded cylinders (Figs. 3A-3D), purity of extrudate over time (Fig. 3E), and coating formed from Compound 1 (Fig. 3F).
  • FIG. 5 is a series of images showing surface erosion of an intravitreal implant of Compound 1 (Dex-TEG-Dex) over time.
  • FIG. 6A to FIG. 6I are a series of images and graphs showing intravitreal implants of Compound 1 (Dex-TEG-Dex) formed into cylinders that inhibit inflammation in the eye.
  • FIG. 7A to FIG. 7D are a series of images and graphs showing intravitreal implants of Compound 1 (Dex-TEG-Dex) and drug release over time.
  • FIG. 8A to FIG. 8D are a series of images showing that intravitreal implants of Compound 1 (Dex- TEG-Dex) inhibit VEGF-induced retinal vascular leakage in the eye.
  • FIG. 9A to FIG. 9E are a series of images and a graph showing Compound 2 (Hydrocortisone- Triethylene Glycol-Hydrocortisone, HC-TEG-HC) formed into heat-molded pellets, fibers, and extruded cylinders, as well as drug release over time.
  • Compound 2 Hydrocortisone- Triethylene Glycol-Hydrocortisone, HC-TEG-HC
  • FIG. 10A to FIG. 10E are a series of images and a graph showing Compound 3 (T riamcinolone Acetonide-Triethylene Glycol-Triamcinolone Acetonide, TA-TEG-TA) formed into heat-molded pellets, fibers, and extruded cylinders, as well as drug release over time.
  • Compound 3 T riamcinolone Acetonide-Triethylene Glycol-Triamcinolone Acetonide, TA-TEG-TA
  • FIG. 11A to FIG. 11 C are an image and a graph showing Compound 4 (Dexamethasone- Triethylene Glycol-Hydrocortisone, Dex-TEG-HC) formed into heat-molded pellets and drug release over time.
  • Compound 4 Examethasone- Triethylene Glycol-Hydrocortisone, Dex-TEG-HC
  • FIG. 12A to FIG. 12E are a series of images and a graph showing Compound 5
  • FIG. 13A to FIG. 13E are a series of images and a graph showing Compound 6 (Hydrocortisone- Succinate-Hydrocortisone, HC-SUCC-HC) formed into heat-molded pellets and fibers, as well as drug release over time.
  • Compound 6 Hydrocortisone- Succinate-Hydrocortisone, HC-SUCC-HC
  • FIG. 15A to FIG. 15C are an image and a graph showing Compound 8 (Dexamethasone- Pentaethylene Glycol-Dexamethasone, Dex-EG5-Dex) formed into heat-molded pellets and drug release over time.
  • Compound 8 Dexamethasone- Pentaethylene Glycol-Dexamethasone, Dex-EG5-Dex
  • FIG. 16A to FIG. 16E are a series of images and a graph showing Compound 9 (Fusidic Acid- Triethylene Glycol-Fusidic Acid (carbonate ester), FA-TEG-FA (CE)) formed into heat-molded pellets and fibers, as well as drug release over time.
  • Compound 9 Fudic Acid- Triethylene Glycol-Fusidic Acid (carbonate ester), FA-TEG-FA (CE)
  • FIG. 17A to FIG. 17D are a series of images and a graph showing Compound 10
  • FIG. 18A and FIG. 18B are a series of images showing Compound 11 (Dexamethasone- Heptaethylene Glycol-Dexamethasone, Dex-EG7-Dex) formed into heat-molded pellets.
  • FIG. 19A and FIG. 19B are a series of images showing Compound 12 (Dexamethasone- Nonaethylene Glycol-Dexamethasone, Dex-EG9-Dex) formed into heat-molded pellets.
  • FIG. 21 A and FIG. 21 B are a series of images showing Compound 14 (Cholesterol-Triethylene Glycol-Cholesterol, CHS-TEG-CHS) formed into heat-molded pellets.
  • FIG. 22A and FIG. 22B are a series of images showing Compound 15 (Fusidic Acid-Triethylene Glycol-Fusidic Acid (ester), FA-TEG-FA (E)) formed into heat-molded pellets.
  • Compound 15 Fusidic Acid-Triethylene Glycol-Fusidic Acid (ester), FA-TEG-FA (E)
  • FIG. 23A and FIG. 23B are a series of images showing Compound 16 (Ethinylestradiol- Triethylene Glycol-Ethinylestradiol, Ethin-TEG-Ethin) formed into heat-molded pellets.
  • FIG. 24A and FIG. 24B are a series of an image and a graph showing a mixture of Compound 1 (Dex-TEG-Dex) and Compound 2 (HC-TEG-HC) formed into heat-molded pellets and drug release.
  • FIG. 25A and FIG. 25B are a series of an image and a graph showing a mixture of Compound 1 (Dex-TEG-Dex) and Compound 3 (TA-TEG-TA) formed into heat-molded pellets and drug release.
  • FIG. 26A and FIG. 26B are a series of an image and a graph showing a mixture of Compound 2 (HC-TEG-HC) and Compound 3 (TA-TEG-TA) formed into heat-molded pellets and drug release.
  • FIG. 27A to FIG. 27C are a series of images showing Compound 17 (Prednisolone-Triethylene Glycol-Prednisolone, Pred-TEG-Pred) formed into heat-molded pellets and fibers.
  • Compound 17 Prednisolone-Triethylene Glycol-Prednisolone, Pred-TEG-Pred
  • ocular barriers include tear dilution, blood flow, lymphatic clearance and blood-ocular barriers that impede drug transport and lower the efficacy of many drugs [see e.g., Gower et al. Drug discovery in ophthalmology: past success, present challenges, and future opportunities, BMC Ophthalmology , 16:1 1 , (January 16, 2016).].
  • static barriers different layers of cornea, sclera, and retina including blood aqueous and blood-retinal barriers
  • dynamic barriers choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution
  • efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the back of the eye, e.g., the posterior segment [AAPS J. 2010 Sep; 12(3); 348-360]
  • compositions and methods for the treatment of the eye and amelioration of ophthalmic diseases and conditions therewith are also featured in this disclosure.
  • treatments of the eye including a Schlemm’s canal insert or a suprachoroidal insert.
  • the treatment includes insertion of an article formed from therapeutic steroid prodrug dimers that are formed by conjugation of two steroids with a short chain linker.
  • the prodrug dimers disclosed have properties that differ from that of the corresponding stand-alone drugs allowing them to be processed in various forms (e.g. fibers, cylinders, microparticles, etc.) in the glassy state and leading to sustained release of drug in the eye.
  • This disclosure also features ocular inserts made of steroid drug dimers (e.g., anti-inflammatory steroid drug dimers or antibiotic steroid drug dimers).
  • the ocular inserts can be in a form of fibers or cylinders, e.g., stents or tubes.
  • the ocular inserts can provide a controlled rate of drug release over days, weeks, months, or even years.
  • the ocular inserts can be in the form of cylinders or fibrous meshes (woven or non-woven) implanted intravitreally, subretinally, or suprachoroidally.
  • the ocular insert of the disclosure can minimize inflammation associated with cataract or glaucoma surgery.
  • the Schlemm’s canal and suprachoroidal inserts can provide a controlled rate of drug release over days, weeks, months, or even years.
  • the Schlemm’s canal inserts are inserted into the Schlemm’s canal during cataract or glaucoma surgery to facilitate keeping the canal open, and functioning as a scaffold.
  • the article does not include non- therapeutic materials that could contribute to obstructing the passage of fluids.
  • the Schlemm’s canal insert of the disclosure can minimize inflammation of the canal and the surgical insertion point associated with cataract or glaucoma surgery.
  • a suprachoroidal insert is used to reduce intraocular pressure.
  • each of D1 and D2 is, independently, a radical formed from a steroid; and L is a linker covalently linking D1 to D2.
  • Each of D1 and D2 can be, independently, selected from a steroid (e.g., a glucocorticoid steroid, a corticosteroid, an IOP lowering steroid, or fusidic acid).
  • L can be covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.
  • the articles of the disclosure can be machined, molded, emulsion-processed, electrospun, electrosprayed, blow molded, dry spun, heat spun, melt spun, gel spun, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, pellet, cylinder, microparticle (e.g., a microbead), nanoparticle (e.g., a nanobead), tube, stent, or another shaped article sized and shaped for insertion adjacent to, or within, an eye.
  • microparticle e.g., a microbead
  • nanoparticle e.g., a nanobead
  • tube stent, or another shaped article sized and shaped for insertion adjacent to, or within, an eye.
  • each of D1 -0 and D2-0 is, independently, a radical formed from a steroid (e.g., a glucocorticoid steroid, a corticosteroid, an IOP lowering steroid, or fusidic acid).
  • a steroid e.g., a glucocorticoid steroid, a corticosteroid, an IOP lowering steroid, or fusidic acid.
  • R1 represents H or a halogen atom
  • Rs represents H, C1-6 alkyl, or a halogen atom
  • R6 represents H or a halogen atom
  • R1 1 represents H, OH, C1-6 alkyl, optionally substituted -C(0)Ci-6
  • alkyl -0C(0)Ph, -OC(0)heterocyclyl, -CH 2 C(0)CH 2 0H, -C(0)C(0)0H, -C(0)C(0)0Ci- 6
  • R10 and Rn taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl;
  • R12 represents
  • R10 and R12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl;
  • R16 represents H or a halogen atom;
  • R1 represents H or a halogen atom
  • Rs represents H, C1-6 alkyl, or a halogen atom
  • R6 represents H or a halogen atom
  • R12 represents H, OH, optionally substituted -C(O)0i-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, optionally substituted -OC(O)0i-6 alkyl, or -0C(0)Ph
  • R10 and Rn taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl
  • Ri6 represents H or a halogen atom
  • R1 represents H or a halogen atom
  • Rs represents H, a halogen atom, or CH3
  • R6 represents H, a halogen atom
  • R12 represents optionally substituted -C(0)Ci-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, or -C(0)SCH 2 F
  • R16 represents H or a halogen atom
  • R1 represents H or a halogen atom
  • Rs represents H, C1-6 alkyl, or a halogen atom
  • R6 represents H or a halogen atom
  • Ri 1 represents H, OH, C1-6 alkyl, optionally substituted -C(O)0i-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, optionally substituted -0C(0)Ci-6 alkyl, -0C(0)Ph, -OC(0)heterocyclyl, -CH 2 C(0)CH 2 0H, -C(0)C(0)0H, -C(0)C(0)0Ci-e
  • R10 and Rn taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl;
  • R12 represents H, OH, C1-6 alkyl, optionally substituted -C(0)Ci-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, optionally
  • R10 and R12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; and R16 represents H or a halogen atom;
  • R15 represents a halogen atom or OH
  • R16 represents H or a halogen atom
  • R16 represents H or a halogen atom
  • Rs represents H, CH3, or a halogen atom
  • R12 represents H or a halogen atom
  • R15 0 or OH
  • R12 and R10 each, independently, represent -H, C1-10 alkyl, -OH, -O-acyl, or R12 and R10 combine to form a cyclic acetal of formula (XVIII-a) where:
  • R 20 , R 21 , and R 22 each, independently, represent H or C 1-10 alkyl; and W 1 represents H or CH3;
  • R15 represents H or OH.
  • Drug dimers useful in the methods and compositions of the disclosure include homodimers (e.g., where D1 and D2 are the same) and heterodimers (e.g., where D1 and D2 differ).
  • Glucocorticoids, anti- angiogenic steroids, intraocular pressure (IOP) lowering steroids, and corticosteroids that can be used in the methods and articles of the disclosure include, for example, medrysone, alclometasone,
  • the disclosure features homodimers of the formula (A-l), or a pharmaceutically acceptable salt thereof, wherein D1 and D2 are radicals formed from the same steroid.
  • L can be covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.
  • Ester, carbonate, carbonate ester, or anhydride linkages formed from a functional group on D1 and D2 can be selected from, e.g., hydroxyl or carboxy.
  • L can include the radical -C(0)-(R A )-C(0)-, -C(0)-0C(0)- (R A )-C(0)0-C(0)-, or -0-(R A )-0-, where R A is a radical of a polyol and includes at least one free hydroxyl group or R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, -(Ch Cl- C qCI- Cl- -, -(CH2CH2CH2CH20)rCH2CH2CH 2 CH2-, or
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II):
  • R1 represents H or a halogen atom
  • Rs represents H, C1-6 alkyl, or a halogen atom
  • R6 represents H or a halogen atom
  • R1 1 represents H, OH, C1-6 alkyl, optionally substituted -C(0)Ci-6
  • R12 represents H, OH, C1-6 alkyl, optionally
  • R10 and R12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl;
  • R16 represents H or a halogen atom;
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heterocyclyl
  • fluorocortisone fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
  • meprednisone 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate
  • methylprednisolone aceponate mometasone, mometasone furoate, mometasone furcate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ulobetasol.
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-b):
  • R1 represents H or a halogen atom
  • Rs represents H, C1-6 alkyl, or a halogen atom
  • R6 represents H or a halogen atom
  • R12 represents H, OH, optionally substituted -C(O)0i-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, optionally substituted -OC(O)0i-6 alkyl, or -0C(0)Ph
  • RI 6 represents H or a halogen atom
  • L is -C(0)0-(R A )
  • the drug dimer of formula (ll-b) can be formed from a glucocorticoid steroid selected from the group consisting of alclometasone, beclometasone, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, cortisol, cortisone, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflucortolone, difluorocortolone, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocortolone, fluorocortisone,
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-c):
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the drug dimer of formula (ll-c) can be formed from the glucocorticoid steroid fluclorolone acetonide.
  • R1 represents H or a halogen atom
  • Rs represents H, a halogen atom, or CH3
  • R6 represents H, a halogen atom
  • R12 represents optionally substituted -C(0)Ci-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, or -C(0)SCH 2 F
  • R16 represents H or a halogen atom
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )- C(0)0-C(0)-
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a
  • the drug dimer of formula (ll-d) can be formed from a glucocorticoid steroid selected from the group consisting of alclometasone, beclometasone, betamethasone, clobetasol, clobetasone, cortisol, cortisone, dexamethasone, diflorasone, fluclorolone, flumetasone, flumethasone, flumethasone pivalate, fluocinolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, meprednisone, 6a- methylprednisolone, methylprednisolone, methylprednisolone acetate, mometasone
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-e):
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the drug dimer of formula (ll-e) can be formed from the glucocorticoid steroid cortivazol.
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-f):
  • R1 represents H or a halogen atom
  • Rs represents H, C1-6 alkyl, or a halogen atom
  • R6 represents H or a halogen atom
  • Rn represents H, OH, C1-6 alkyl, optionally substituted -C(0)Ci-6 alkyl, -C(0)CH 2 0C(0)CI-6 alkyl, optionally substituted -0C(0)Ci-6 alkyl, -0C(0)Ph, -OC(0)heterocyclyl, -CH 2 C(0)CH 2 0H, -C(0)C(0)0H, -C(0)C(0)0Ci-e alkyl, -C(0)SCH2F, or -0C(0)0Ci-6 alkyl; or Rio and Rn taken together with carbons to
  • the drug dimer of formula (ll-f) can be formed from a glucocorticoid steroid selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, flud
  • meprednisone 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate
  • methylprednisolone aceponate mometasone, mometasone furoate, mometasone furcate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ulobetasol.
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-g):
  • the drug dimer of formula (ll-g) can be formed from the glucocorticoid steroid cortivazol.
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-h):
  • R15 represents a halogen atom or OH
  • R16 represents H or a halogen atom
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the drug dimer of formula (ll-h) can be formed from a glucocorticoid steroid selected from the group consisting of fluclorolone, fluocinolone, and triamcinolone.
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-i):
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the drug dimer of formula (ll-i) can be formed from fluperolone.
  • the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (ll-j):
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the drug dimer of formula (ll-j) can be formed from formocortal.
  • the steroid is a corticosteroid and the drug dimer is further described by the formula (ll-k):
  • R5 represents H, CH3, or a halogen atom
  • R12 represents H or a halogen atom
  • R15 0 or OH
  • R12 and R10 each, independently, represent -H, C1-10 alkyl, -OH, -O-acyl, or R12 and R10 combine to form a cyclic acetal of formula (ll-ka) wherein: N-ka),
  • the drug dimer of formula (ll-k) can be formed from a corticosteroid selected from the group consisting of alclometasone, beclomethasone, betamethasone, betamethasone valerate, budesonide, chloroprednisone, cloprednol, corticosterone, cortisone, desonide, desoximerasone, dexamethasone, diflorasone, diflucortolone, enoxolone, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocortolone, fluprednisolone, flurandrenolide, halometasone, hydrocortisone, hydrocortisone butyrate, meprednisone,
  • methylprednicolone paramethasone, prednisolone, prednisone, prednival, prednylidene, triamcinolone, and triamcinolone acetonide.
  • 0-(R A )-0 can be a radical of a polyol formed from a cyclitol, and sugar alcohol, or glycerin; or 0-(R A )-0 can be a radical formed from an alkane diol (e.g., a C1-10 alkane diol), diethylene glycol, triethylene glycol, tetraethylene glycol, or pentaethylene glycol.
  • the steroid is an antibiotic steroid and the drug dimer is further described by the formula (ll-m):
  • the drug dimer of formula (ll-m) can be formed from fusidic acid.
  • the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid
  • IOP intraocular pressure
  • R15 represents H or OH; and
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C 2 -20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, -
  • the drug dimer of formula (ll-n) can be formed from anecortave acetate, anecortave, 11-epicortisol, 17a-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.
  • the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by the formula (ll-o):
  • R15 represents H or OH
  • L is - C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2- 20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2
  • the drug dimer of formula (ll-o) can be formed from anecortave acetate, anecortave, 11-epicortisol, 17a-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.
  • the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid
  • IOP intraocular pressure
  • the drug dimer is further described by the formula (ll-p):
  • R15 represents H or OH
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected
  • the drug dimer of formula (ll-p) can be formed from anecortave, 11 -epicortisol, tetrahydrocortexolone, or tetrahydrocortisol.
  • the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by the formula (ll-r):
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2- 20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, - 0(CH 2 CH 2 CH 2 CH 2 0)mCH 2 CH 2 CH 2 CH 2 0-, or -0(CH 2 CH(CH3)0)pCH 2 CH(CH3)0-; and n, m, and p are integers from 1 to 10.
  • the drug dim is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or
  • the pharmaceutical compositions of the disclosure can include an article in the form of fibers, fiber meshes, woven fabrics, non-woven fabrics, pellets, cylinders, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads), or other shaped articles, such as stents/tubes suitable for ophthalmology including contact lenses, sutures, microshunt devices, optical rings, punctal plugs, and ocular inserts. Additionally, the pharmaceutical compositions of the disclosure can include an article in the form of fibers, cylinders, or other shaped articles, such as stents/tubes sized for insertion into the Schlemm’s canal of an eye. Alternatively, the pharmaceutical compositions of the disclosure can include an article in the form of pellets or cylinders sized for insertion into the suprachoroidal space of an eye. The articles can achieve desired drug loading and long term release profile relative to the corresponding stand-alone
  • the articles of the disclosure may be injected intraocularly (e.g., for the treatment of inflammation occurring at the back of the eye).
  • Articles of the disclosure can be formed using any number of the methods, for example, heat processing or solvent processing of the drug dimer of formula (I).
  • Heat processing can include heat molding, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, and/or blow molding.
  • Solvent processing may include coating, micro printing, emulsion processing, dot printing, micropatterning, fiber spinning, solvent blow molding, electrospraying, and electrospinning. Electrospraying method
  • the pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., acetone) at concentrations ranging from, e.g., 10-30% w/v, and are electrosprayed to form micro- and nanobeads.
  • a solvent e.g., acetone
  • the solutions can be loaded into a syringe and can be injected at a particular rate, e.g., 0.5 mL/h, onto a stationary collection plate. Between the needle and collecting surface, a potential difference of, e.g., 18 kV, can be maintained. Exemplary concentration of 10% w/v is used to obtain nanoparticles. In other embodiments, a concentration of 30% w/v is used to obtain microbeads.
  • a solvent e.g., acetone
  • the pharmaceutical compositions of the disclosure e.g., fibers or fibrous meshes with aligned and unaligned morphologies are prepared by electrospinning.
  • the pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., THF, or 1 :1 ratio of DCM/THF).
  • the solutions may be injected from a syringe at a particular rate, e.g., 0.5 mL/h, onto a cylindrical mandrel rotating at a particular rotational speed, e.g., 1150 rpm, to obtain aligned fibers, or onto a stationary collector surface to obtain unaligned fibers.
  • a potential difference e.g., 18 kV or 17 kV
  • fibers are prepared either from the melt at elevated temperatures, the glassy state intermediate, or from solution by dissolving the pharmaceutical compositions of the disclosure in a solvent (e.g., DCM, THF, or chloroform).
  • a solvent e.g., DCM, THF, or chloroform.
  • microparticles or nanoparticles made from the pharmaceutical composition can be formed using an emulsion process.
  • the pharmaceutical composition may be dissolved in an organic solvent (e.g., DCM, THF, etc.) and a surfactant (e.g., SDS, PVA, etc.) may be added to the solution/mixture at a low percentage (e.g., 1 %).
  • a surfactant e.g., SDS, PVA, etc.
  • the resulting mixture may be stirred for the appropriate time at room temperature to form an emulsion.
  • the emulsion may be subsequently added to Milli-Q water under stirring for an appropriate time (e.g., 1 h) to remove residual solvent.
  • the resulting micro- or nanoparticles may be collected by centrifugation and dried to obtain the desired form.
  • injectable cylinders made from the pharmaceutical composition may be formed by heat extrusion.
  • the pharmaceutical composition may be loaded into a hot melt extruder, heated to a temperature above the melting point (for crystalline compositions) or glass transition temperature (for pre-melted or amorphous compositions), and extruded using a light compressive force to push the material through the nozzle and a light tensile force to pull the material out of the extruder.
  • the extrudate may be cut to the desired length for appropriate drug dosing for the indication of interest.
  • a milling process may be used to reduce the size of an article of the disclosure to form sized particles, e.g., beads, in the micrometer (microbeads) to nanometer size range (nanobeads).
  • the milling process may be performed using a mill or other suitable apparatus. Dry and wet milling processes such as jet milling, cryo-milling, ball milling, media milling, sonication, and homogenization are known and can be used in methods described herein.
  • a suspension of the material to be used as the core is agitated with or without excipients to reduce particle size.
  • Dry milling is a process wherein the material to be used as the article core is mixed with milling media with or without excipients to reduce particle size.
  • a suspension of the material to be used as the core is mixed with milling media with or without excipients under cooled temperatures.
  • subsequent heating of the milled microparticle above the Tg is needed to achieve a spherical shape, or particles with non-spherical shapes can be used as milled.
  • the prodrug dimer has a limited window (e.g., short timeframe of seconds to minutes) of thermal stability, whereby the purity of the dimer is minimally affected at elevated temperatures.
  • it is beneficial to make an intermediate glassy state form e.g., film, pellet, micro-particles, or other shaped article. This can be accomplished by heat or solvent processing to remove or reduce the crystallinity of the material to form a glassy state composition.
  • the glassy state composition is subsequently heat processed at a lower temperature (e.g., processing just above the glass transition temperature (Tg), and below the melt temperature (Tm)).
  • the process can include shaping the article by extrusion, or any other process described herein.
  • the formulations of the disclosure provide optimal delivery of a drug as they release the drug from an article of the disclosure in a controlled manner, for example, by surface erosion.
  • the surface erosion mechanism of drug release may allow the shaped article to maintain its physical form (shape), while gradually decreasing in size as the surface erodes (e.g., like a bar of soap), rather than bulk erosion that is characteristic of some polymer-based drug release vehicles (e.g., polylactic/glycolic acid). This can inhibit burst release and reduce the formation of inflammatory particulates (e.g., no crystalline particulates are formed when drug is released in the manner described herein).
  • the drug can be controlled to be delivered over a desired period of time to a desired site of the eye.
  • a slower and steadier rate of delivery e.g., release of less than 10% of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the fiber in prodrug form) at 37 °C in 100% bovine serum over 5 days
  • D1 or D2 a percentage of the total drug, D1 or D2, present in the fiber in prodrug form
  • Drug release can also be tailored to avoid side effects of slower and longer release of the drug by engineering the article to provide steady release over a comparatively shorter period of time.
  • the drug release can be tailored for dose and duration appropriate to the indication of interest.
  • the rate of release of a drug can depend on many factors, for example, the drug composition of the drug dimer. Drug release rate from the drug dimer can be modulated by the cleavage of drug-linker bond through hydrolysis or enzymatic degradation. Therefore, the selection of linking moiety can affect drug release rate. Further, the drug release rate can be controlled by the selection of the functional group on the drug to conjugate through to the linker, for example, a primary vs. a secondary steroid hydroxyl group. The rate of release of a given drug from a drug dimer can also depend on the quantity of the loaded drug dimer as a percent of the final drug dimer formulation, e.g., by using an appropriate pharmaceutical excipient (e.g., bulking agent/excipient).
  • an appropriate pharmaceutical excipient e.g., bulking agent/excipient
  • drug release is tailored based on the solubility of drug dimer (e.g., through selection of appropriate drug and/or linker) that will influence the rate of surface erosion (e.g., dissolution/degradation) from the article.
  • drug release is affected by changes in surface area of the formulation, e.g., by changing the diameter of the articles.
  • dissolution, degradation, diffusion, and controlled release may be varied over wide ranges. For example, release can be designed to be initiated over minutes to hours, and may extend over the course of days, weeks, months, or years.
  • the drug dimers of the disclosure are used as a drug delivery device (or, e.g., a drug depot) with a minimal need for additives. This can achieve a local, sustained release and a local biological effect, while minimizing a systemic response.
  • the additives when present, are in small amounts and do not affect the physical or bulk properties. In some embodiments, when present, the additives do not alter the drug release properties from the pharmaceutical composition but rather act to improve processing of the prodrug dimer into the shaped article.
  • the pharmaceutical compositions contain additives such as a plasticizer (e.g., to reduce thermal transition temperatures), an antioxidant (e.g., to increase stability during heat processing), a binder (e.g., to add flexibility to the fibers), a bulking agent (e.g., to reduce total drug content), a lubricant, dyes, or mixtures thereof.
  • the additives may be present at 30% (w/w), e.g., 20% (w/w), 10% (w/w), 7% (w/w), 5% (w/w),
  • plasticizers are polyols, e.g., glycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, propylene glycol, triacetin, sorbitol, mannitol, xylitol, fatty acids, monosaccharides (e.g., glucose, mannose, fructose, sucrose), ethanolamine, urea, triethanolamine, vegetable oils, lecithin, or waxes.
  • Exemplary antioxidants are glutathione, ascorbic acid, cysteine, or tocopherol.
  • the binders and bulking agents can be, e.g., polywinylpyrrolidone (PVP), starch paste, pregelatinized starch, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), or polyethylene glycol (PEG) 6000.
  • PVP polywinylpyrrolidone
  • HPMC hydroxypropyl methyl cellulose
  • CMC carboxymethyl cellulose
  • PEG polyethylene glycol
  • a formulation is sterile before or upon administration to a subject.
  • a sterile formulation is essentially free of pathogenic microorganisms, such as bacteria, microbes, fungi, viruses, spores, yeasts, molds, and others generally associated with infections.
  • articles of the disclosure may be subject to an aseptic process and/or other sterilization process.
  • An aseptic process typically involves sterilizing the components of a formulation, final formulation, and/or container closure of a drug product through a process such as heat, gamma irradiation, ethylene oxide, or filtration and then combining in a sterile environment. In some cases, an aseptic process is preferred. In other embodiments, terminal sterilization is preferred.
  • a method of treating a subject for an ocular disease or condition including administering to the subject a compound, article, or ocular insert described herein.
  • Diseases and conditions that can be treated using compounds, compositions and dosage forms as described herein include, but are not limited to, disorders of the eyelid, lacrimal system and orbit; inflammatory disorders of the conjunctiva; disorders of the sclera, iris and ciliary body; disorders of the lens; disorders of the choroid and retina, including disorders and conditions associated with chorioretinal inflammation or infection; disorders of the vitreous body and globe; disorders of the optic nerve and visual pathways; and disorders of the ocular muscles.
  • An anterior ocular inflammatory disease or condition, or an infection primarily affects or involves an anterior ocular region or site (i.e. front of the eye), such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles.
  • a posterior ocular disease or condition primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site.
  • compositions and dosage forms as described herein may be used to treat a posterior ocular disease or condition by placement of an article of the disclosure adjacent to or within a structure of the eye.
  • the articles of the disclosure may be used to treat, prevent, or manage inflammation or infection in the eye of a subject.
  • the ocular condition to be treated may be at the front of the eye.
  • a front of the eye ocular condition includes a disease, ailment or condition, such as for example, post- surgical inflammation; uveitis; infections; aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; corneal neovascularization; refractive disorders and strabismus.
  • articles of the disclosure may be used to treat, prevent, or manage an ocular condition at the back of the eye of a subject.
  • a posterior ocular condition can include a disease, ailment, or condition, such as intraocular melanoma; acute macular neuroretinopathy; Behcet’s disease; choroidal neovascularization; diabetic uveitis;
  • macular degeneration such as acute macular degeneration, non-exudative age related macular degeneration and exudative age related macular degeneration
  • edema such as macular edema (e.g., cystoid macular edema (CME), diabetic macular edema (DME), and macular edema from retinal vein occlusion); multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease; sympathetic opthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion;
  • VKH Vogt Koyanagi-Harada
  • the articles of the disclosure may be used to treat, prevent, or manage inflammation in the eye of a subject (e.g., where the drug dimer is formed from one or more
  • the pharmaceutical agent that is delivered into the eye by the articles of the disclosure and/or methods described herein may be a corticosteroid.
  • the pharmaceutical agent includes one or more of hydrocortisone, cortisone, tixocortol, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone, halcinonide,
  • betamethasone dexamethasone, fluocortolone, hydrocortisone, aclometasone, prednicarbate, clobetasone, clobetasol, fluprednidene, glucocorticoid, mineralocorticoid, aldosterone,
  • deoxycorticosterone deoxycorticosterone, fludrocortisone, halobetasol, diflorasone, desoximetasone, fluticasone,
  • the articles of the disclosure may be used to treat, prevent, or manage infection in the eye of a subject (e.g., where the drug dimer is formed from an antibiotic steroid).
  • the pharmaceutical agent that is delivered into the eye by the articles of the disclosure and/or methods described herein may be fusidic acid.
  • the ocular inserts are shaped as fibers, rods, tubes, or stents.
  • the fibers have diameters in the range of 0.01 -0.15 mm, e.g., 0.01-0.10 mm, 0.04-0.09 mm, 0.05-0.08 mm, or 0.05-0.15 mm.
  • the fibers have lengths sized for placement within the ocular space.
  • the ocular inserts are smaller than the canal diameter which ranges between 120 and 350 pm.
  • the ocular inserts may have a blunt tip with a rounded shape.
  • the blunt tip may have a hemispherical shape.
  • Schlemm’s canal is located approximately in the apex of the angle of the junction of the cornea and the sclera and runs parallel to the margin of the cornea.
  • the canal is lined with a single layer of vascular-derived endothelial cells and transports 2 to 3 pL per minute of aqueous humor from the anterior chamber to the venous plexus.
  • the canal diameter ranges between 170 and 350 pm.
  • Schlemm’s canal inserts may be placed into Schlemm’s canal of an eye to facilitate the flow of aqueous humor out of the anterior chamber of the eye by, e.g., supporting tissue in the trabecular meshwork and in Schlemm’s canal.
  • the flow facilitated by the presence of the Schlemm’s canal insert may include axial flow along Schlemm’s canal, flow into Schlemm’s canal from the anterior chamber of the eye, and flow leaving Schlemm’s canal via the outlets that communicate with the canal.
  • aqueous humor After exiting Schlemm’s canal via the outlets, aqueous humor enters the venous blood stream and is carried along with the venous blood leaving the eye.
  • the pressure of the venous system tends to be around 5-10 mmHg above atmospheric pressure. Accordingly, the venous system provides a pressure backstop which assures that the pressure in the anterior chamber of the eye remains above atmospheric pressure.
  • the Schlemm’s canal inserts act as reinforcing structures that hold the walls of Schlemm’s canal in a patent state so that the walls of the canal provide a flow channel or fistula.
  • the Schlemm’s canal inserts may be sized and shaped to reinforce Schlemm’s canal while occupying a relatively small portion of the total lateral cross sectional area of Schlemm’s canal.
  • the Schlemm’s canal insert provides minimal obstruction to aqueous humor flowing along the length of Schlemm’s canal. Reinforcing Schlemm’s canal with the Schlemm’s canal insert of the disclosure may also encourage a safe healing response over time.
  • Schlemm’s canal inserts of the disclosure may be sized and shaped to facilitate the lateral flow of aqueous humor across and/or through the body of the Schlemm’s canal insert.
  • the lateral flow of aqueous humor may include the flow of aqueous humor through the trabecular mesh and into Schlemm’s canal.
  • the lateral flow of aqueous humor may also include the flow of aqueous humor through outlets that communicate with Schlemm’s canal.
  • Schlemm’s canal may have become compartmentalized. When this is the case, Schlemm’s canal becomes a series of small compartments separated by discontinuities or partitions.
  • the distal tip of the Schlemm’s canal insert penetrates the discontinuities/partitions. This penetrating action re-establishes fluid communication between adjacent compartments.
  • the body of the Schlemm’s canal insert facilitates flow across the partitions by remaining in Schlemm’s canal after fluid communication has been re-established.
  • Schlemm’s canal and/or the upstream tissue can become closed in a way that the outflow of the aqueous humor is less than the inflow and thus the pressure inside the eye increases so that the optic nerve is correspondingly pinched.
  • This visual disturbance which is known as glaucoma, often leads to blindness of the affected eye or of both eyes.
  • the Schlemm’s canal inserts are used in the treatment of glaucoma arising from local inflammation of the Schlemm’s canal and/or the upstream tissue.
  • the Schlemm’s canal inserts can be shaped as fibers, rods, tubes, or stents and are capable of reducing local inflammation.
  • the fibers have diameters in the range of 0.01 -0.15 mm, e.g., 0.01 -0.10 mm, 0.04-0.09 mm, 0.05-0.08 mm, or 0.05-0.15 mm.
  • the fibers have lengths sized for placement within the Schlemm’s canal. In other embodiments, the
  • Schlemm’s canal inserts are stiff and do not occupy the whole space of the Schlemm’s canal. In some embodiments, the Schlemm’s canal inserts are smaller than the canal diameter which ranges between 120 and 350 pm.
  • the Schlemm’s canal inserts may have a blunt tip with a rounded shape.
  • the blunt tip may have a hemispherical shape.
  • the rounded shape of the blunt tip may increase the likelihood that the body of the Schlemm’s canal implant will track Schlemm’s canal as the Schlemm’s canal insert is advanced into the canal during insertion of the article of the disclosure.
  • Some Schlemm’s canal inserts may include an inlet portion that is shaped and sized to extend through the trabecular meshwork of the eye. This inlet portion may provide a flow path between the anterior chamber and Schlemm’s canal.
  • the Schlemm’s canal insert is a hollow tube and can facilitate the flow of aqueous humor through its structure.
  • the Schlemm’s canal insert can be introduced into the Schlemm’s canal using a syringe or a surgical instrument specifically configured for the injection of the insert into the trabecular formations.
  • This instrument may be a surgical probe that is introduced into Schlemm’s canal during the procedure, and subsequently removed completely from the canal after the treatment.
  • the curved probe is connected to an injection introduced into Schlemm’s canal.
  • the Schlemm’s canal insert is placed into the Schlemm’s canal using a Y- shaped tube that has a dual-bonded end and is small enough to fit inside Schlemm’s canal.
  • the procedure similar to a nonpenetrating sclerostomy, begins with the creation of a deep scleral flap and the unroofing of a portion of Schlemm’s canal.
  • Schlemm’s canal is defined, the two legs of the tube are inserted in opposite directions down the canal, and the main stem is inserted through a small incision into the anterior chamber.
  • the Schlemm’s canal insert is delivered to the canal and bypasses the juxtacanalicular portion of the trabecular meshwork.
  • the Schlemm’s canal insert is a stent used in a bypass procedure that reestablishes normal outflow by stenting open the trabecular meshwork and Schlemm’s canal.
  • the stent may be inserted into Schlemm’s canal internally through a clear corneal incision. This may allow aqueous to flow directly into the canal toward the episcleral drainage system, thus avoiding the trabecular meshwork.
  • the suprachoroidal inserts can be introduced into the suprachoroidal space using a syringe or a surgical instrument specifically configured for the implantation of the insert to relieve intraocular pressure.
  • the inserts of the disclosure can create a permanent conduit from the anterior chamber to the suprachoroidal space, draining the aqueous internally rather than accessing Schlemm’s canal or the conventional aqueous outflow pathway. Implanted into the supraciliary space through a clear corneal incision, the insert may prevent the formation of a filtering bleb and spare the conjunctiva.
  • the insert of the disclosure can be used for treatment of primary open-angle glaucoma. In an eye with glaucoma, the trabecular outflow pathway may be compromised.
  • the insert of the disclosure can enhance fluid outflow from the anterior chamber of the eye.
  • Articles of the disclosure may be administered to the eye by intravitreal, subretinal, or suprachoroidal injection.
  • the article e.g., a small cylinder sized for injection into the eye
  • the vitreous cavity which is filled with the vitreous humor gel.
  • Intravitreal injections may be used to administer medications to treat a variety of conditions, including, without limitation, macular edema from retinal vein occlusion, diabetic macular edema, age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and uveitis.
  • the articles can be implanted subretinally or suprachoroidally.
  • Compounds 1 -17 can be used in the methods, compositions, and articles of the disclosure.
  • Example 1 Compound 1 (dexamethasone-triethylene glycol-dexamethasone) can be synthesized, processed into pellets in the glassy state by heat molding, and release drug through surface erosion from an intact pellet
  • Dexamethasone (1 mol equivalent) was suspended in dichloromethane on an ice bath and triethylamine (2 mol equivalent) and triethylene glycol bis(chloroformate) (0.6 mol equivalent) were added to the mixture. The ice bath was allowed to warm to room temperature and the reaction was stirred overnight. The solvent was removed and the solid residue was purified by column chromatography. Product was recrystallized twice from acetonitrile to give Compound 1 (Fig. 1 A) as an off-white crystalline solid.
  • Compound 1 was formed into pellets in the glassy state by heat molding (Fig. 1 B). Crystalline powder was melted at 185 °C and pellets were formed from 1 mm x 1 mm cylindrical molds. The starting powder and heat-processed pellets were tested by differential scanning calorimetry (DSC; Fig. 1 C) and powder x-ray diffraction (PXRD; Fig. 1 D) to confirm heat-processing converted compound 1 from the crystalline state to the glassy state.
  • DSC differential scanning calorimetry
  • PXRD powder x-ray diffraction
  • Heat-molded pellets from Compound 1 were placed in 20 ml_ glass vials and 2 mL of release buffer (either 100% phosphate buffered saline (PBS), 1 % fetal bovine serum (FBS) in PBS, or 100% FBS) was added. Samples were incubated at 37 °C on a shaker rotating at 115 rpm. After 1 day, 3 days, 7 days, and subsequently in alternating 3 and 4 day intervals (i.e., 1 , 3, 7, 10, 14 days etc.), release buffer was sampled directly (PBS) or syringe filtered, proteins were precipitated with acetonitrile, and drug release products were extracted.
  • release buffer either 100% phosphate buffered saline (PBS), 1 % fetal bovine serum (FBS) in PBS, or 100% FBS
  • Samples were incubated at 37 °C on a shaker rotating at 115 rpm. After 1 day, 3 days, 7 days, and subsequently in
  • Example 2 Compound 1 (Dex-TEG-Dex) can be processed into different forms in the glassy state by multiple processing methods from the melt and solution states
  • Compound 1 was processed into different forms in the glassy state from the melt and solution states.
  • Compound 1 was coated onto different surfaces from the solution state by dissolving in an organic solvent and applying on a surface using common coating techniques (e.g., dip-coating, spray coating, drop-coating, electrospraying, etc.).
  • Figs. 2A and 2B show Compound 1 coated on titanium and poly(styrene-block-isobutylene-block-styrene) (SIBS) surfaces, respectively, from acetone.
  • Extruded cylinders were prepared by adding Compound 1 as a crystalline powder into a micro-extruder with different nozzles to form extruded material of different diameters.
  • Fig. 2C shows an extruded cylinder with a 23G diameter nozzle.
  • Fibers of Compound 1 (Fig. 2D) were prepared by heat extrusion at 185 °C using a small diameter nozzle (e.g., 30-32G) combined with a tensile force to pull the extrudate out of the nozzle. Fibers were also prepared by melting Compound 1 from a powder at 185 °C and pulling the melted material at different rates to yield fibers of different diameters.
  • Compound 1 was processed into fibrous meshes by electrospinning from the solution state in tetrahydrofuran (Fig. 2E).
  • Micro- and nano-particles were prepared by electrospraying (Fig. 2F) and emulsion (Fig. 2G) from the solution state.
  • Different preparation conditions solvents, concentrations, surfactants, surfactant concentrations, mixing conditions, etc.
  • Example 3 Processing Compound 1 (Dex-TEG-Dex) into an intermediate glassy state to manufacture the final article
  • Compound 1 (Dex-TEG-Dex) was formed into heat extruded cylinders directly from the crystalline powder by heating above the melting point (185 °C), as shown in Figs. 3A and 3B, using the methods described above in Example 14.
  • Compound 1 was also formed into heat extruded cylinders by forming an intermediate glassy state form from the melt followed by heat extrusion above the glass transition temperature (150 °C) as shown in Figs. 3C and 3D. Purity of the extrudate over time is shown in Fig. 3E and demonstrates longer extrusion run times using the intermediate glassy state before Compound 1 drops in purity when compared to extrusion from the melt state.
  • Example 4 Drug release from Compound 1 (Dex-TEG-Dex) coated on different surfaces
  • Compound 1 was coated onto titanium and SIBS as described in Example 3 above. Drug release from the coated material was carried out in PBS as described in Example 1 above. Cumulative drug release was calculated and plotted as a percentage of the total drug in each coated surface released over time (Fig. 4).
  • Example 5 Intravitreal implants of Compound 1 (Dex-TEG-Dex) undergo surface erosion in the eye
  • Compound 1 was formed into cylinders by heat molding as described in Example 1 .
  • the cylinders were injected intravitreally into rat eyes.
  • Fundus microscopy was used to image the implants non-invasively over time to demonstrate surface erosion of the implant (Fig. 5).
  • Example 6 Intravitreal implants of Compound 1 (Dex-TEG-Dex) release dexamethasone that inhibits endotoxin-induced inflammation in the eye
  • Compound 1 was formed into cylinders by heat molding ( ⁇ 0.34 mm x 0.8 mm; Fig. 6A) and heat extrusion from the intermediate glassy state ( ⁇ 0.12 mm x 1 mm; Fig. 6B) as described in Examples 1 and 3 above.
  • the implants were loaded into 23G and 30G needles respectively and were sterilized by ethylene oxide (ETO) gas.
  • ETO ethylene oxide
  • An acute study evaluating only the 23G heat molded implants was performed and a sub-chronic study evaluating both implants followed.
  • the implants for each study were injected intravitreally into rat eyes and were imaged by fundus microscopy as seen in Figs. 6C and 6D for the 23G and 30G implants, respectively.
  • Inflammation in the eye was induced using an intravitreal injection of the endotoxin lipopolysaccharide (LPS) 1 -day post-implantation for the acute study and 60 days postimplantation for the sub-chronic study. Both studies had a negative control arm with eyes receiving a sham 23G injection and a positive control arm with eyes receiving a sham 23G injection and
  • Optical coherence tomography was used to image the eyes (Fig. 6E) and inflammation was assessed by quantifying the number of cells in the vitreous humour and the thickness of the retinal tissue measured from the OCT images. Vitreal cell count and retinal thickness data are shown in Figs. 6F and 6G, respectively, for the acute study and in Figs. 6H and 6I, respectively, for the sub-chronic study and demonstrate dexamethasone released from intravitreal implants of Compound 1 inhibit endotoxin-induced inflammation in the eye.
  • Example 7 Intravitreal implants of Compound 1 (Dex-TEG-Dex) release a consistent dose of dexamethasone in the eye
  • Compound 1 was formed into cylinders by heat extrusion from the intermediate glassy state as described in Example 3.
  • the cylinders were extruded with 23G and 30G nozzles.
  • the cylinders were cut to length to form 30G x 1 mm cylinders, 30G x 6 mm cylinders, and 23G x 6 mm cylinders as shown in Fig. 7A.
  • In vitro drug release in PBS was carried out as described in Example 1 with the dose and duration roughly following surface erosion theory as shown in Figs. 7B and 7C.
  • the cylinders were injected intravitreally into New Zealand white rabbits and dexamethasone was quantified in the vitreous humour at different time points.
  • Fig. 7D plots the drug concentration over time for the different cylinders and shows a consistent dose of dexamethasone is released from the cylinders of Compound 1 in the eye.
  • Example 8 Intravitreal implants of Compound 1 (Dex-TEG-Dex) inhibit vascular endothelial growth factor (VEGF)-induced retinal vascular leakage in the eye
  • VEGF vascular endothelial growth factor
  • Compound 1 was formed into cylinders by heat extrusion from the intermediate glassy state as described in Example 3.
  • the cylinders were extruded with 27G and 30G nozzles to get diameters ⁇ 0.2 mm and ⁇ 0.12 mm respectively.
  • the cylinders were cut to different lengths, ETO gas sterilized, and injected intravitreally into the eyes of Dutch belted rabbits.
  • VEGF was injected intravitreally at 1 week and 10 weeks post-implantation to induce retinal vascular leakage. Sham injection was used as a negative control.
  • Intravitreal implants of Compound 1 provided sustained release of dexamethasone that inhibited VEGF-induced retinal vascular leakage as demonstrated by fundus microscopy (Fig. 8A) and fluorescein angiography (Fig. 8B) compared to negative control (Figs. 8C and 8D).
  • Example 9 Intravitreal implants of Compound 1 (Dex-TEG-Dex) are used to treat inflammatory or neovascularization conditions or to prevent or reduce inflammation in the eye
  • Cylinders of Compound 1 are formed using methods described above.
  • the cylinders are injected into the vitreous humour and release dexamethasone to the surrounding tissues including tissues in the anterior eye, the posterior eye, and surrounding tissues.
  • Dexamethasone released from the cylinder is released by surface erosion over the course of months to years.
  • the intravitreal implants release drug that may be used in subjects with diabetic macular edema, macular edema from retinal vein occlusion, uveitis, cystoid macular edema, post-surgical inflammation (e.g. cataract or glaucoma surgery), age- related macular degeneration, and other ocular conditions.
  • Example 10 Compound 1 (Dex-TEG-Dex) as a coating on minimally invasive glaucoma devices (MIGS)
  • Coating of Compound 1 is applied onto a MIGS device as described in the methods above.
  • the device is inserted into the eye of a subject to provide fluid flow and reduce intraocular pressure associated with glaucoma.
  • the coating releases dexamethasone into the surrounding tissue to inhibit a tissue response to the device and reduce fibrosis. Drug is released from the device coating into the eye over months to years.
  • Example 11 Schlemm’s canal fiber implant of Compound 1 (Dex-TEG-Dex) are used to prevent or reduce post-surgical inflammation in the eye
  • a fiber or tube of Compound 1 is formed using the methods described above.
  • the implant is inserted into the Schlemm’s canal of a subject having received surgery and releases dexamethasone by surface erosion over weeks to months. The drug released helps to prevent or reduce inflammation associated with the surgical procedure.
  • Example 12 Intracameral implants or wafers of Compound 1 (Dex-TEG-Dex) are used to prevent post-surgical inflammation in the eye
  • Fibers or cylinders are formed from Compound 1 according to the methods described above.
  • the fibers are woven into a mesh and are placed into the eye of a subject having received surgery.
  • Dexamethasone is released from the fiber mesh or cylinder by surface erosion at a steady rate over several months, e.g., three months. Inflammation in the eye is reduced as a result.
  • Example 13 Micro- or nanoparticles of Compound 1 (Dex-TEG-Dex) in the suprachoroidal space used to treat inflammatory or neovascularization-based conditions or prevent inflammation in the eye
  • Micro- or nanoparticles of Compound 1 are formed using the methods described above.
  • the particles are injected into the suprachoroidal space of a subject with an ocular condition associated with inflammation or neovascularization or as an adjunctive therapy to reduce inflammation associated with ocular surgery.
  • Dexamethasone is released from the particles over months to years and reduces inflammation or neovascularization associated with the condition or surgery.
  • Example 14 Suprachoroidal insert of Compound 1 (Dex-TEG-Dex) reduces intraocular pressure
  • a cylinder or tube of Compound 1 is formed using the methods described above.
  • the implant is inserted into the eye of a subject with glaucoma to create a conduit from the anterior chamber into the suprachoroidal space.
  • the conduit allows fluid to flow out of the eye to reduce intraocular pressure.
  • the cylinder or tube undergoes surface erosion to release dexamethasone to modulate the tissue response to the implant and reduce inflammation associated with its placement.
  • the conduit and drug release may last from months to years.
  • Example 15 Synthesis, processing, and drug release from heat -molded glassy state pellets of Compounds 2-10 and 17
  • Compounds 2-10 and 17 were synthesized using standard methods known in the art, similar to the synthesis of Compound 1 in Example 1 above. Details of synthesized Compounds 2 to 10 and 17 are shown in the tables below. Melting points (Tm) and glass transition temperatures (Tg) were determined to establish processing temperatures needed to heat-process the compounds into pellets, fibers, and cylinders for further testing.
  • Melting points (Tm) and glass transition temperatures (Tg) were determined to establish processing temperatures needed to heat-process the compounds into pellets, fibers, and cylinders for further testing.
  • Compounds 11-16 were processed into heat molded pellets as described in Example 1 above (see table below) using the appropriate temperature for each compound (i.e. above the Tm). All pellets were in the glassy state with the exception of Compound 14 which had residual crystallinity. Drug release from the pellets was carried out in PBS and/or 100% FBS. Pellets from Compounds 11-13 had physical form (shape) and drug release changes occur over time while no drug release was observed from pellets of Compounds 14-16.
  • Cylinders, pellets, or fibrous meshes of Compound 7 are formed using the methods described above.
  • the implants are inserted intracamerally into subjects with glaucoma.
  • the implants release anecortave through surface erosion over months to years and lower intraocular pressure in the eye.
  • Example 18 Suprachoroidal inserts of Compound 7 (Anec-TEG-Anec) are used to lower intraocular pressure in the eye
  • a cylinder or tube of Compound 7 is formed using the methods described above.
  • the implant is inserted into the eye of a subject with glaucoma to create a conduit from the anterior chamber into the suprachoroidal space.
  • the cylinder or tube undergoes surface erosion to release anecortave. Both the conduit and released drug act to reduce intraocular pressure and may last from months to years.
  • Example 19 Intracameral implants of Compound 9 (FA-TEG-FA (CE)) are used to prevent post- surgical infection in the eye
  • Cylinders, pellets, or fibrous meshes of Compound 9 are formed using the methods described above.
  • the implants are inserted intracamerally into subjects that are receiving an ocular surgical procedure.
  • the implants release fusidic acid over days to weeks to a few months to prevent infection.
  • Example 20 Heat-molded pellets in the glassy state can be formed from mixtures of two dimers and drugs are released from both compounds of the intact pellet
  • Pellets in the glassy state were formed by heat molding a mixture of compounds as shown in the table below.
  • the starting crystalline compounds were mixed together and were heat molded at a temperature above the higher melting point compound.
  • Drug release from the pellets ( ⁇ 1 mm x 1 mm and ⁇ 1 mg of total mixture) was carried out in PBS as described in Example 1. Cumulative drug release was calculated and plotted as a percentage of the total drug released over time. Linear drug release from intact pellets was observed for both compounds in the mixed pellets.
  • Example 21 Intracameral implants of Compound 1 (Dex-TEG-Dex) and Compound 9 (FA-TEG-FA (CE)) are used to inhibit post-surgical inflammation and infection
  • Cylinders, pellets, or fibrous meshes of Compound 1 and 9 are formed using the methods described above.
  • the implants are inserted intracamerally into subjects that are receiving an ocular surgical procedure.
  • the implants release dexamethasone and fusidic acid over days to weeks to a few months to reduce inflammation associated with the surgery and prevent infection.
  • the articles of the disclosure can be inserted into the Schlemm’s canal in a surgical procedure that generally includes the steps of creating an incision in the ocular wall that provides access to the anterior chamber of the eye; advancing a cannula of the system through the incision, across a portion of the anterior chamber, to the trabecular meshwork, and piercing the trabecular meshwork; accessing Schlemm’s canal with the cannula; and implanting the article (i.e., a Schlemm’s canal insert) within the canal.
  • a surgical procedure that generally includes the steps of creating an incision in the ocular wall that provides access to the anterior chamber of the eye; advancing a cannula of the system through the incision, across a portion of the anterior chamber, to the trabecular meshwork, and piercing the trabecular meshwork; accessing Schlemm’s canal with the cannula; and implanting the article (i.e., a Schlemm’s canal insert) within the canal.
  • the cannula typically includes a proximal end and a distal curved portion, the distal curved portion having a proximal end and a distal end and a radius of curvature defined between the ends; a body; a distal tip having a bevel, the bevel directly engaging the distal end of the curved portion of the cannula; and a lumen extending from the proximal end through the distal tip.
  • a positioning element slidable within the cannula lumen may be employed during the step of implanting the Schlemm’s canal insert within the canal.
  • the Schlemm’s canal insert may be implanted to reduce inflammation, reduce intraocular pressure, or to treat a medical condition such as glaucoma, pre-glaucoma, or ocular hypertension.
  • the method for treating conditions of the eye may include advancing a conduit into Schlemm’s canal, where the conduit has been loaded with the Schlemm’s canal insert, and delivering the Schlemm’s canal insert into Schlemm’s canal at a size sufficient to disrupt the trabeculocanalicular tissues to reduce intraocular pressure.
  • the method can be performed in conjunction with cataract surgery to insert the anti-inflammatory steroids for the purpose of reducing the risk of post-surgical complications.
  • L comprises the radical -(C(0)-(R A )-C(0)- or -0-(R A )-0-;
  • R A is a radical of a polyol and includes at least one free hydroxyl group or R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms,
  • the article further comprises from 0.1 % to 10% (w/w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, dyes, and mixtures thereof.
  • the inflammatory condition is macular edema from retinal vein occlusion, diabetic macular edema, uveitis, diabetic retinopathy, or age-related macular
  • ATD AFD degeneration
  • L is -C(0)0-(R A )-0C(0)-, -C(0)-0C(0)-(R A )-C(0)0-C(0)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from:
  • n, m, and p are integers from 1 to 10.
  • step (c) comprises extruding, molding, blow molding, heat spinning, electrospinning or electrospraying the glassy state composition to form the shaped article.
  • R 15 represents H or OH
  • L is -C(0)0-(R A )-0C(0)- or -C(0)-0C(0)-(R A )-C(0)0-C(0)-,
  • R A is selected from Ci -2 o alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C 2-2 o alkenylene, a linear or branched C 2-2 o alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, -0(CH 2 CH 2 CH 2 CH 2 0) m CH 2 CH 2 CH 2 CH 2 0-, or
  • n, m, and p are integers from 1 to 10.
  • the bond between C 3 and R 2 is a single or a double bond
  • R 15 represents H or OH
  • R A is selected from Ci -2 o alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C 2-2 o alkenylene, a linear or branched C 2-2 o alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, -0(CH 2 CH 2 CH 2 CH 2 0)mCH 2 CH 2 CH 2 CH 2 0-, or - 0(CH 2 CH(CH3)0)pCH 2 CH(CH3)0-; and
  • n, m, and p are integers from 1 to 10.
  • the bond between C3 and R2 is a single or a double bond
  • R 15 represents H or OH;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • 0-(R A )-0 is a radical of a polyol and includes at least one free hydroxyl group or 0-(R A )-0 is selected from: -0(CH 2 CH 2 0) n CH 2 CH 2 0-, -0(CH 2 CH 2 CH 2 CH 2 0)mCH 2 CH 2 CH 2 CH 2 0-, or
  • n, m, and p are integers from 1 to 10.
  • the bond between C3 and R2 is a single or a double bond
  • L is -C(0)0-(R A )-0C(0)- 0r-C(O)-OC(O)-(R A )-C(O)O-C(O)-;
  • R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms, or
  • n, m, and p are integers from 1 to 10.
  • each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an IOP lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2, wherein the article is a fiber, a cylinder, a stent, or a tube; and
  • the article is free of controlled release polymer, free of a crystallization inhibiting excipient, free of a binding excipient, and/or free of a mechanical integrity enhancing excipient; or wherein the article optionally has a glassy state.
  • each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an IOP lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2, wherein the article is sized to provide a fluid passageway between the suprachoroidal space and the anterior chamber thereby reducing intraocular pressure in the eye; and (ii) inserting the article into a suprachoroidal space of the eye, wherein the article is positioned to extend from the suprachoroidal space to the anterior chamber of the eye to provide the fluid passageway, wherein the article is free of controlled release polymer, free of a crystallization inhibiting excipient, free of a binding excipient, and/or free of a mechanical integrity enhancing excipient; or wherein the article optionally has a glassy state.
  • L comprises the radical -(C(0)-(R A )-C(0)- or -0-(R A )-0-;
  • R A is a radical of a polyol and includes at least one free hydroxyl group or R A is selected from C1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C2-20 alkenylene, a linear or branched C2-20 alkynylene, a C5-10 arylene, a cyclic system of 3 to 10 atoms,

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Botany (AREA)
  • Neurosurgery (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
PCT/CA2019/050133 2018-02-02 2019-02-01 Ocular inserts comprising a covalently linked steroid dimer Ceased WO2019148291A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/966,453 US11612567B2 (en) 2018-02-02 2019-02-01 Ocular inserts comprising a covalently linked steroid dimer
US18/738,907 US20250049719A1 (en) 2018-02-02 2024-06-10 Dexamethasone prodrug compositions and uses thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201862625460P 2018-02-02 2018-02-02
US62/625,460 2018-02-02
US201862627608P 2018-02-07 2018-02-07
US62/627,608 2018-02-07
US201862758234P 2018-11-09 2018-11-09
US62/758,234 2018-11-09

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/966,453 A-371-Of-International US11612567B2 (en) 2018-02-02 2019-02-01 Ocular inserts comprising a covalently linked steroid dimer
US18/170,403 Continuation-In-Part US20230225975A1 (en) 2018-02-02 2023-02-16 Dexamethasone prodrug compositions and uses thereof

Publications (1)

Publication Number Publication Date
WO2019148291A1 true WO2019148291A1 (en) 2019-08-08

Family

ID=67479137

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/CA2019/050133 Ceased WO2019148291A1 (en) 2018-02-02 2019-02-01 Ocular inserts comprising a covalently linked steroid dimer
PCT/CA2019/050135 Ceased WO2019148293A1 (en) 2018-02-02 2019-02-01 Glass formulations comprising steroid dimers and uses thereof
PCT/CA2019/050136 Ceased WO2019148294A1 (en) 2018-02-02 2019-02-01 Dimeric dexamethasone prodrug compositions and uses thereof

Family Applications After (2)

Application Number Title Priority Date Filing Date
PCT/CA2019/050135 Ceased WO2019148293A1 (en) 2018-02-02 2019-02-01 Glass formulations comprising steroid dimers and uses thereof
PCT/CA2019/050136 Ceased WO2019148294A1 (en) 2018-02-02 2019-02-01 Dimeric dexamethasone prodrug compositions and uses thereof

Country Status (9)

Country Link
US (9) US11612567B2 (https=)
EP (1) EP3740494A4 (https=)
JP (1) JP7502186B2 (https=)
KR (1) KR102952719B1 (https=)
CN (1) CN111971292B (https=)
AU (1) AU2019214347B2 (https=)
CA (1) CA3087898A1 (https=)
MX (1) MX2020008017A (https=)
WO (3) WO2019148291A1 (https=)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021005417A1 (en) * 2019-07-10 2021-01-14 Ripple Therapeutics Corporations Surface coatings and implantable devices comprising dimeric steroid prodrugs, and uses thereof
WO2021014217A1 (en) * 2019-07-25 2021-01-28 Ripple Therapeutics Corporation Articles comprising steroid dimers and their use in the delivery of therapeutic agents
US10945958B2 (en) 2018-02-02 2021-03-16 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US11279729B2 (en) 2020-05-01 2022-03-22 Ripple Therapeutics Corporation Heterodimer compositions and methods for the treatment of ocular disorders
EP4108231A1 (en) 2021-06-25 2022-12-28 Johann-Wolfgang-Goethe-Universität Frankfurt am Main In-situ dissolving electrospun polymer fibers for ocular drug delivery
WO2024013565A1 (en) * 2022-07-12 2024-01-18 Ripple Therapeutics Corporation Compositions and methods for improving vision
US12473326B2 (en) 2019-02-01 2025-11-18 Ripple Therapeutics Corporation Crystalline forms of dexamethasone dimers and uses thereof
US12509469B2 (en) 2019-08-07 2025-12-30 Ripple Therapeutics Corporation Compositions and methods for the treatment of pain and dependence disorders

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111485325A (zh) * 2020-04-16 2020-08-04 青岛科技大学 一种耐高温的抗菌纳米纤维无纺布及其制备方法和用途
WO2023079362A1 (en) * 2021-11-03 2023-05-11 Ripple Therapeutics Corporation Processable compositions and use for the same
AU2024238803A1 (en) * 2023-03-23 2025-10-09 Praesidia Biotherapeutics Inc. Prodrugs, prodrug compositions and related methods
TR2024002978A1 (tr) * 2024-03-12 2025-09-22 İstanbul Tekni̇k Üni̇versi̇tesi̇ Elektroeği̇rme yöntemi̇yle elde edi̇len ve i̇laç yüklü bi̇yopoli̇mer nanoli̇flerle kaplanan göz i̇mplanti üreti̇m yöntemi̇

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3663579A (en) * 1968-05-03 1972-05-16 Hoechst Ag Dimeric steroid-21-alkyl-carbonates and process for their manufacture
US5250524A (en) * 1990-12-06 1993-10-05 Hoechst Aktiengesellschaft Bile acid derivatives, process for their preparation and use of these compounds as pharmaceuticals
US5512558A (en) * 1993-05-08 1996-04-30 Hoechst Aktiengesellschaft Nor-bile acid derivatives, processes for their preparation and the use of these compounds as medicaments
US9056048B2 (en) * 2001-08-16 2015-06-16 The Trustees Of The University Of Pennsylvania Synthesis and use of cationic steroids for anti-inflammatory drug therapy

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1058886A (en) 1910-04-13 1913-04-15 Alfred Mueller Firing mechanism for firearms.
FR7604M (https=) 1968-04-22 1970-01-19
US4024871A (en) 1975-07-23 1977-05-24 Ethicon, Inc. Antimicrobial sutures
WO2001007657A1 (en) 1999-07-27 2001-02-01 Phylos, Inc. Peptide acceptor ligation methods
US4532316A (en) 1984-05-29 1985-07-30 W. L. Gore & Assoc., Inc. Phase separating polyurethane prepolymers and elastomers prepared by reacting a polyol having a molecular weight of 600-3500 and isocyanate and a low molecular weight chain extender in which the ratios of reactants have a limited range
PL257230A1 (en) 1985-12-31 1988-03-03 Zaklad Polimerow Pan Novel segmented polymer and method of obtaining them
IL88003A (en) 1987-10-16 1992-11-15 Dainippon Pharmaceutical Co Quinoline derivatives,their preparation and pharmaceutical compositions containing them
US4916193A (en) 1987-12-17 1990-04-10 Allied-Signal Inc. Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
US5321099A (en) 1992-01-02 1994-06-14 The Dow Chemical Company Blends of semi-crystalline polyamides and polyesteramides
US5217493A (en) 1992-03-11 1993-06-08 Board Of Regents, The University Of Texas System Antibacterial coated medical implants
IT1270836B (it) 1993-10-27 1997-05-13 Archimica Spa Procedimento per la preparazione di rufloxacina e suoi sali
PT740650E (pt) * 1994-01-28 2004-10-29 Univ Kentucky Res Found Co-farmacos como um metodo de administracao controlada de farmacos
US6051576A (en) 1994-01-28 2000-04-18 University Of Kentucky Research Foundation Means to achieve sustained release of synergistic drugs by conjugation
US5387598A (en) 1994-04-13 1995-02-07 Rossignol; Jean-Francois Composition and galenic formulation suitable for combatting affections of the lower abdomen
US5578621A (en) 1994-09-08 1996-11-26 Romark Lab Lc Benzamide derivatives
PT755386E (pt) 1994-04-13 2002-11-29 Romark Lab Lc Derivado de benzamida composicoes contendo o referido derivado e sua utilizacao
US5965590A (en) 1994-09-08 1999-10-12 Romark Lab Lc Method for treatment of opportunistic infections with pharmaceutical compositions of tizoxanide and nitazoxanide
US5968961A (en) 1997-05-07 1999-10-19 Romark Laboratories, L.C. Pharmaceutical compositions of tizoxanide and nitazoxanide
US5859038A (en) 1994-09-08 1999-01-12 Romark Laboratories, L.C. Method for treatment of helicobacter pylori infections
MX9604483A (es) 1994-09-08 1998-02-28 Jean-Francois Rossignol Derivados de benzamida, composiciones que contienen dicho derivado y uso de las mismas.
US5856348A (en) 1994-09-08 1999-01-05 Romark Laboratories, L.C. Method for treatment of trematodes with pharmaceutical compositions of tizoxanide and nitazoxanide
DE19521642C2 (de) 1995-06-14 2000-11-09 Aesculap Ag & Co Kg Implantat, seine Verwendung in der Chirurgie und Verfahren zu seiner Herstellung
NZ313583A (en) 1995-08-03 1999-01-28 Paul J Santerre Fluoroligomer surface modifiers for polymers
DE69708461T2 (de) 1996-02-15 2002-06-27 Marc W. Mittelman Bioresponsive pharmakologisch aktive polymere und daraus hergestellte gegenstände
KR0176334B1 (ko) 1996-08-19 1999-04-01 박원훈 내인체 감염성 삽입금속표면의 코팅방법 및 그 치료기술
US5728751A (en) 1996-11-25 1998-03-17 Meadox Medicals, Inc. Bonding bio-active materials to substrate surfaces
ES2232687T3 (es) 1997-05-07 2005-06-01 Romark Laboratories, L.C. Composiciones farmaceuticas de tizoxanida y/o nitazoxanida.
NZ502358A (en) 1997-07-18 2002-11-26 Infimed Therapeutics Inc Hydrogel composition comprising a biologically active substance combined with a macromer
HN1998000106A (es) 1997-08-01 1999-01-08 Pfizer Prod Inc Composiciones parenterales de alatroflaxacino
PT1032605E (pt) 1997-09-10 2007-12-12 Univ Rutgers Polianidridos com produtos de degradação terapeuticamente úteis
US6468519B1 (en) 1997-09-10 2002-10-22 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
WO1999055396A1 (en) 1998-04-27 1999-11-04 Surmodics, Inc. Bioactive agent release coating
CA2340652C (en) 1998-08-20 2013-09-24 Cook Incorporated Coated implantable medical device comprising paclitaxel
CA2771263A1 (en) 2000-07-27 2002-02-07 Rutgers, The State University Therapeutic polyesters and polyamides
US6602915B2 (en) 2000-07-27 2003-08-05 Rutgers, The State University Of New Jersey Therapeutic azo-compounds for drug delivery
WO2002087586A1 (en) 2001-04-26 2002-11-07 Control Delivery Systems, Inc. Sustained release drug delivery system containing codrugs
CA2349989A1 (en) 2001-06-07 2002-12-07 Paul J. Santerre Bioactive surface modifiers for polymers and articles made therefrom
US20030158598A1 (en) 2001-09-17 2003-08-21 Control Delivery Systems, Inc. System for sustained-release delivery of anti-inflammatory agents from a coated medical device
BR0212897A (pt) 2001-09-21 2004-08-24 Univ Tulane Conjugados de análogos de somatostatina ou bombesina diagnóstica ou terapêutica e usos dos mesmos
AUPR879601A0 (en) 2001-11-09 2001-12-06 Biota Scientific Management Pty Ltd Novel chemical compounds and their use
EP1448231A1 (en) * 2001-11-19 2004-08-25 Control Delivery Systems, Inc. Topical delivery of codrugs
US20050164994A1 (en) 2001-12-10 2005-07-28 Control Deliver Systems, Inc. Treatment of genitourinary tract disorders
CA2472188C (en) * 2002-01-18 2011-06-21 Control Delivery Systems, Inc. Polymeric gel system for the controlled delivery of codrugs
CA2493748A1 (en) 2002-08-14 2004-02-26 Medical College Of Georgia Research Institute, Inc. Methods and compositions for treatment of macular and retinal disease
TW200500067A (en) 2003-01-21 2005-01-01 Control Delivery Sys Inc Salts of codrugs and uses related thereto
WO2004112838A2 (en) 2003-05-21 2004-12-29 Control Delivery Systems, Inc. Codrugs of diclofenac
CA2553816A1 (en) 2004-01-15 2005-08-04 Warner Chilcott Company, Inc. Di-steroidal prodrugs of ethinyl estradiol
US20050220841A1 (en) 2004-04-06 2005-10-06 Dewitt David M Coating compositions for bioactive agents
US8147865B2 (en) 2004-04-30 2012-04-03 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
CA2571320C (en) 2004-05-14 2016-05-10 Paul J. Santerre Polymeric coupling agents and pharmaceutically-active polymers made therefrom
WO2005110485A1 (en) 2004-05-14 2005-11-24 Interface Biologics Inc. Polymeric coupling agents and pharmaceutically-active polymers made therefrom
CA2467321A1 (en) 2004-05-14 2005-11-14 Paul J. Santerre Polymeric coupling agents and pharmaceutically-active polymers made therefrom
US8357385B2 (en) 2008-04-07 2013-01-22 Interface Biologics Inc. Combination therapy for the treatment of bacterial infections
US8461171B2 (en) 2010-02-09 2013-06-11 QRxPharma Ltd. Hybrid opioid compounds and compositions
WO2011120044A1 (en) 2010-03-26 2011-09-29 Duke University Conjugated neuroactive steroid compositions and methods of use
US8968626B2 (en) 2011-01-31 2015-03-03 Arsenal Medical, Inc. Electrospinning process for manufacture of multi-layered structures
WO2013106528A1 (en) 2012-01-10 2013-07-18 Virginia Commonwealth University Bivalent ligands for the treatment of neurological disorders
WO2014138425A1 (en) 2013-03-08 2014-09-12 Allergan, Inc. Cyclosporine a-steroid conjugates
DK3357522T3 (da) 2013-03-15 2020-01-27 Ripple Therapeutics Corp Coatet medicinsk genstand til lægemiddelsfrigivelse
LT3137081T (lt) 2014-04-28 2018-02-26 Orphomed, Inc. Buprenorfino dimeras ir jo naudojimas gydant virškinamojo trakto sutrikimus
EP3374369B1 (en) * 2015-11-12 2020-03-18 Board of Regents of the University of Nebraska Polyethylene glycol-conjugated glucocorticoid prodrugs and compositions and methods thereof
CN111971292B (zh) 2018-02-02 2024-12-13 波纹疗法公司 包含类固醇二聚体的玻璃制剂及其用途
WO2020154815A1 (en) 2019-02-01 2020-08-06 Ripple Therapeutics Corporation Crystalline forms of dexamethasone dimers and uses thereof
CN114599406A (zh) 2019-07-10 2022-06-07 波纹疗法公司 包含二聚类固醇前药的表面涂层和可植入装置及其用途
JP2022541341A (ja) 2019-07-25 2022-09-22 リップル セラピューティクス コーポレーション ステロイド二量体を含む物品と治療剤の送達におけるそれらの使用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3663579A (en) * 1968-05-03 1972-05-16 Hoechst Ag Dimeric steroid-21-alkyl-carbonates and process for their manufacture
US5250524A (en) * 1990-12-06 1993-10-05 Hoechst Aktiengesellschaft Bile acid derivatives, process for their preparation and use of these compounds as pharmaceuticals
US5512558A (en) * 1993-05-08 1996-04-30 Hoechst Aktiengesellschaft Nor-bile acid derivatives, processes for their preparation and the use of these compounds as medicaments
US9056048B2 (en) * 2001-08-16 2015-06-16 The Trustees Of The University Of Pennsylvania Synthesis and use of cationic steroids for anti-inflammatory drug therapy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LI ET AL.: "Dimeric and Oligomeric Steroids", CHEMICAL REVIEWS, vol. 97, no. 1, 5 February 1997 (1997-02-05), pages 283 - 304, XP055628247, ISSN: 0009-2665, Retrieved from the Internet <URL:https://pubs.acs.ora/doi/pdf/10.1021/cr9600565> *
PARYZEK ET AL.: "A new approach to steroid dimers and macrocycles by the reaction of 3-chlorocarbonyl derivatives of bile acids with 0,0-, N,N-, and S,S-dinucleophiles", TETRAHEDRON LETTERS, vol. 53, no. 46, 7 September 2012 (2012-09-07), pages 6212 - 6215, XP028946604, ISSN: 0040-4039, Retrieved from the Internet <URL:https://doi.ore/10.1016/j.tetlet.2012.08.151> doi:10.1016/j.tetlet.2012.08.151 *
XUE ET AL.: "New dimeric cholesteryl-based A(LS)2 gelators with remarkable gelling abilities: Organogel formation at room temperature", JOURNAL OF COLLOID AND INTERFACE SCIENCE, vol. 361, no. 2, 15 September 2011 (2011-09-15), pages 556 - 564, XP028239220, ISSN: 0021-9797, Retrieved from the Internet <URL:https://doi.ors/10.1016/i.icis.2011.05.074> doi:10.1016/j.jcis.2011.05.074 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10945958B2 (en) 2018-02-02 2021-03-16 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US10959954B2 (en) 2018-02-02 2021-03-30 Ripple Therapeutics Corporation Dexamethasone prodrug compositions and uses thereof
US11612567B2 (en) 2018-02-02 2023-03-28 Ripple Therapeutics Corporation Ocular inserts comprising a covalently linked steroid dimer
US12473326B2 (en) 2019-02-01 2025-11-18 Ripple Therapeutics Corporation Crystalline forms of dexamethasone dimers and uses thereof
WO2021005417A1 (en) * 2019-07-10 2021-01-14 Ripple Therapeutics Corporations Surface coatings and implantable devices comprising dimeric steroid prodrugs, and uses thereof
WO2021014217A1 (en) * 2019-07-25 2021-01-28 Ripple Therapeutics Corporation Articles comprising steroid dimers and their use in the delivery of therapeutic agents
US12509469B2 (en) 2019-08-07 2025-12-30 Ripple Therapeutics Corporation Compositions and methods for the treatment of pain and dependence disorders
US11279729B2 (en) 2020-05-01 2022-03-22 Ripple Therapeutics Corporation Heterodimer compositions and methods for the treatment of ocular disorders
EP4108231A1 (en) 2021-06-25 2022-12-28 Johann-Wolfgang-Goethe-Universität Frankfurt am Main In-situ dissolving electrospun polymer fibers for ocular drug delivery
WO2022268938A1 (en) 2021-06-25 2022-12-29 Johann Wolfgang Goethe Universität Frankfurt In-situ dissolving electrospun polymer fibers for ocular drug delivery
WO2024013565A1 (en) * 2022-07-12 2024-01-18 Ripple Therapeutics Corporation Compositions and methods for improving vision

Also Published As

Publication number Publication date
US20210113457A1 (en) 2021-04-22
MX2020008017A (es) 2020-12-03
US11612567B2 (en) 2023-03-28
KR20200121816A (ko) 2020-10-26
US20190247311A1 (en) 2019-08-15
US20200113833A1 (en) 2020-04-16
EP3740494A1 (en) 2020-11-25
EP3740494A4 (en) 2021-11-03
AU2019214347A1 (en) 2020-08-20
US20230225975A1 (en) 2023-07-20
WO2019148293A1 (en) 2019-08-08
AU2019214347B2 (en) 2023-09-28
KR102952719B1 (ko) 2026-04-14
CA3087898A1 (en) 2019-08-08
CN111971292B (zh) 2024-12-13
US20210205222A1 (en) 2021-07-08
WO2019148294A1 (en) 2019-08-08
US20190275167A1 (en) 2019-09-12
US20250049719A1 (en) 2025-02-13
JP2021512852A (ja) 2021-05-20
US10959954B2 (en) 2021-03-30
JP7502186B2 (ja) 2024-06-18
US10588862B2 (en) 2020-03-17
US20200113834A1 (en) 2020-04-16
CN111971292A (zh) 2020-11-20
US20210030667A1 (en) 2021-02-04
US10945958B2 (en) 2021-03-16
US10632075B2 (en) 2020-04-28

Similar Documents

Publication Publication Date Title
US11612567B2 (en) Ocular inserts comprising a covalently linked steroid dimer
Won et al. 3D printing of drug-loaded multi-shell rods for local delivery of bevacizumab and dexamethasone: A synergetic therapy for retinal vascular diseases
RU2664686C2 (ru) Способ лечения повышенного внутриглазного давления с помощью внутриглазной системы доставки лекарственного средства с замедленным высвобождением
DE602005003957T2 (de) Mit doppelextrusionsverfahren hergestelltes augenimplantat
JP2008520547A (ja) 眼部送達のためのポリマー送達処方
JP2016537370A (ja) 眼科用デバイス
US12473326B2 (en) Crystalline forms of dexamethasone dimers and uses thereof
WO2009035565A1 (en) Prostaglandin analogues for implant devices and methods
EP3265103A1 (en) Compositions and methods for treating ocular diseases
KR20050102653A (ko) 병적 눈 혈관신생 치료용 글루코코르티코이드 제제
KR20240024815A (ko) 녹내장 치료 시스템 및 시술

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19747052

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19747052

Country of ref document: EP

Kind code of ref document: A1