WO2016178900A1 - Implant oculaire pour l'administration de dérivé pyridine-carboxamide - Google Patents

Implant oculaire pour l'administration de dérivé pyridine-carboxamide Download PDF

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Publication number
WO2016178900A1
WO2016178900A1 PCT/US2016/029754 US2016029754W WO2016178900A1 WO 2016178900 A1 WO2016178900 A1 WO 2016178900A1 US 2016029754 W US2016029754 W US 2016029754W WO 2016178900 A1 WO2016178900 A1 WO 2016178900A1
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WIPO (PCT)
Prior art keywords
implant
formula
layer
ocular implant
ocular
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PCT/US2016/029754
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English (en)
Inventor
Karl CSAKY
Sreenivasu Mudumba
Sayo OBATA
Kazuhito Yamada
Original Assignee
Odin Biotech
Santen Pharmaceutical Co., Ltd
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Application filed by Odin Biotech, Santen Pharmaceutical Co., Ltd filed Critical Odin Biotech
Publication of WO2016178900A1 publication Critical patent/WO2016178900A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/00781—Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment

Definitions

  • the present invention generally relates to local therapies for the eye and, more particularly, to curved controlled-release ocular implant devices, including methods for making and using such devices, for delivery of 2-[[[2-[(hydroxyacetyl)amino]-4- pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof to the eye.
  • Ocular angiogenesis the formation of new blood vessels from the existing vascular tree, is an important cause for severe loss of vision. It can occur in a spectrum of ocular disorders such as age-related macular degeneration (AMD), diabetic retinopathy, retinal artery or vein occlusion, and retinopathy of prematurity (ROP).
  • AMD age-related macular degeneration
  • ROP retinopathy of prematurity
  • One of the underlying causes of vision loss in proliferative retinal diseases is the increased vascular permeability leading to retinal edema, vascular fragility resulting in hemorrhage, or fibrovascular proliferation with tractional and rhegmatogenous retinal detachment.
  • Abnormal retinal vascular permeability such as hyperpermeability causing edema in the area of the macula is the leading cause of vision loss in diseases such as diabetic retinopathy, exudative macular degeneration, retinal vascular occlusions, and inflammatory and neoplastic conditions.
  • Age-related macular degeneration is a common disease associated with aging that gradually impairs sharp, central vision.
  • AMD Age-related macular degeneration
  • AMD is a common disease associated with aging that gradually impairs sharp, central vision.
  • AMD has two common forms of AMD: dry AMD and wet AMD.
  • About ninety percent of the cases of AMD are the dry form, caused by degeneration and thinning of the tissues of the macula; a region in the center of the retina that allows people to see straight ahead and to discern fine details.
  • CNVM choroidal neovascular membranes
  • Formula I is described in US Patent 7,544,703, the entire contents of which are incorporated herein by reference in their entirety.
  • Formula I is shown to exhibit a cell proliferation inhibiting effect in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system and exhibit a choroidal neovascularization inhibiting effect in a test system using a rat choroidal neovascularization model.
  • Formula I is useful as a pharmaceutical, prophylactic or therapeutic agent for diseases such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema and the like.
  • Ocular drug levels following systemic administration of drugs is usually limited by various blood/ocular barriers (i.e., tight junctions between the endothelial cells of the capillaries). These barriers limit the amounts of drugs entering the eye via systemic circulation.
  • variable gastrointestinal drug absorption and/or liver metabolism of the medications can lead to dosage-dependent and inter-individual variations in vitreous drug levels.
  • adverse side effects have been associated with systemic administration of certain drugs to the eyes.
  • CsA immune response modifier cyclosporine A
  • CsA is a recognized effective active agent for treatment of a wide variety of eye diseases and indications, such as endogenous or anterior uveitis, corneal transplantation, Behcet's disease, vernal or capitaous keratoconjunctivitis, dry eye syndrome, and the like.
  • rejection of corneal allografts and stem cell grafts occurs in up to 90% of patients when associated with risk factors such as corneal neovascularization.
  • CsA has been identified as a possibly useful drug for reducing the failure rate of such surgical procedures for those patients.
  • other feasible delivery routes for such drugs that can avoid such drawbacks associated with systemic delivery are in demand.
  • Topical delivery Apart from implant therapies, other local administration routes for the eye have included topical delivery.
  • Such therapies include ophthalmic drops and topical ointments containing the medicament. Tight junctions between corneal epithelial cells limit the intraocular penetration of eye drops and ointments.
  • Topical delivery to the eye surface via solutions or ointments can in certain cases achieve limited, variable penetration of the anterior chamber of the eye.
  • therapeutic levels of the drug are not achieved and sustained in the middle or back portions of the eye. This is a major drawback, as the back (posterior) chamber of the eye is a frequent site of inflammation or otherwise the site of action where, ideally, ocular drug therapy should be targeted for many indications.
  • one local therapy route for the eye has involved direct intravitreal injection of a treatment drug through the sclera (i.e., the spherical, collagen-rich outer covering of the eye).
  • the intravitreal injection delivery route tends to result in a short half-life and rapid clearance without sustained release capability being attained. Consequently, weekly to monthly injections are frequently required to maintain therapeutic ocular drug levels. This is not practical for many patients.
  • the present invention provides a shaped ocular implant for delivery of 2-[[[2- [(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3- pyridinecarboxamide or a salt thereof (hereinafter also referred to as "Formula I") to the eye for treatment of diseases and disorders of the eye.
  • certain aspects of the present invention provide local treatment of a variety of eye diseases.
  • Other aspects of the present invention also provide a method for the delivery of Formula I to the eye to effectively treat eye disease, while reducing or eliminating any systemic side effects.
  • Certain aspects of the present invention also provide shaped sustained-release ocular implants for administration of Formula I to the eye for prolonged periods of time.
  • certain aspects of the present invention provide approaches to alter the areas of the eye that are affected by diffusion of Formula I from sustained-release ocular implants.
  • Certain aspects of the present invention also provide methods for making shaped ocular implants with reduced product variability.
  • a method for forming a molded single-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a silicone adhesive comprising Formula I dispersed therein on a mold body to form a silicone layer having a curved external surface in contact with the bottom of the curved depression and further comprising an exposed upper surface; b) generating a curvature in the exposed upper surface of the silicone layer, thereby forming a curved silicone layer interface surface; c) curing the silicone layer, thereby providing the molded single-layer ocular implant.
  • a method for forming a molded two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a polymer into a curved depression on a mold body to form a polymer layer having a curved external surface in contact with the bottom of the curved depression and further comprising an exposed upper surface; b) generating a curvature in the exposed upper surface of the polymer layer, thereby forming a curved polymer layer interface surface; c) curing the polymer layer, thereby providing a cured polymer curved polymer layer interface surface; d) dispensing a silicone adhesive comprising Formula I dispersed therein onto the hardened interface surface to provide a silicone layer with an exposed surface; e) generating a curvature in the exposed surface of the silicone layer thereby forming a curved eye-contacting surface; and f) curing the silicone layer such that the first layer and second
  • the invention is a single-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a layer comprising silicone and Formula I.
  • the invention is a two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a first layer comprising a polymer; and a second layer comprising silicone and Formula I.
  • Another aspect of the invention is a single- or two-layer implant formed by the methods described herein.
  • the implants of certain embodiments may be used for
  • the implant of other embodiments may be used for implantation into the sub-Tenon's space of a rodent.
  • the invention is a method of treating a disease or disorder in a subject in need thereof, comprising placing an implant comprising: a layer comprising silicone and therapeutically effective amount of Formula I; in an ocular region.
  • the invention is a method of treating a disease or disorder in a subject in need thereof, comprising placing an implant comprising: a first layer comprising a polymer; and a second layer comprising silicone and therapeutically effective amount of Formula I; in an ocular region.
  • the disease or disorder is age-related macular degeneration (AMD), wet age related macular degeneration, choroidal neovascularization, diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy, proliferative diabetic retinopathy, polypoidal chorioretinopathy, uveitis, retinopathy of prematurity in newborns, choroidal melanoma, chorodial metastasis, retinal capillary hemangioma, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, myopic choroidal neovascularization, eye tumor, radiation retinopathy, rubeosis iridis, rubeotic glaucoma, and proliferative vitreoretinopathy.
  • AMD age-related macular degeneration
  • DME diabetic macular edema
  • DME diabetic macular edema
  • FIG. 3 Another aspect of the invention is a molded two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a first hardened layer comprising a polymer, the first hardened layer comprising curvature at both the upper and lower surfaces (see FIG. 3); and a second hardened layer comprising a silicone adhesive and Formula I, the second hardened layer comprising curvature at both the upper and lower surfaces (see FIG. 3).
  • inventive implants offer a myriad of advantages, improvements, benefits, and therapeutic opportunities.
  • the inventive implants are highly versatile and can be tailored to enhance the delivery regimen.
  • the implants of this invention permit continuous release of Formula I into the eye over a specified period of time, which can be weeks, months, or even years as desired.
  • inventive implant systems of this invention require intervention only for initiation and termination of the therapy (i.e., removal of the implant). Patient compliance issues during a regimen are eliminated.
  • the time-dependent delivery of one or more drugs to the eye by this invention makes it possible to maximize the pharmacological and physiological effects of the eye treatment.
  • the inventive implants have human and veterinary applicability.
  • FIG. 1 is a perspective view of an implant according to one embodiment of the invention with curved lines 12 and 14 showing the curvature of the upper surface of the implant.
  • FIG. 1 is reproduced from US Patent publication US2016/0081920.
  • FIG. 2 is a top view of the implant of FIG. 1.
  • FIG. 2 is reproduced from US Patent publication US2016/0081920.
  • FIG. 3 is a cross sectional side view of the implant of FIG. 1 and FIG. 2 taken along line 3'-3' of FIG. 2 (along dotted line 14) showing the lower layer 16 and upper layer 18 of the implant with drug particles 20 dispersed in the lower layer 16.
  • FIG. 3 is reproduced from US Patent publication
  • FIG. 4 is a schematic side slice view showing selected anatomy of an eye E with the placement of a perspective view of the implant of FIG. 1-3 in the sub-Tenon's space E0. Other structures of the eye E are shown for context.
  • FIG. 4 is reproduced from US Patent publication US2016/0081920.
  • FIG. 5 is a magnified view of the rectangular inset 5' of FIG. 4 showing a perspective view of the implant embodiment of FIG. 1-4. Also shown are additional layers of structures and tissues within the eye and diffusion of a drug 20 to the sclera E3 and the choroid E4.
  • FIG. 5 is reproduced from US Patent publication US2016/0081920.
  • FIG. 6 is a plot showing the kinetics of release of the drug Formula I from a 2.5 mm implant containing 30% by weight of Formula I into phosphate buffered saline (PBS). The drug is released to its solubility limit within about 6 hours.
  • PBS phosphate buffered saline
  • FIG. 7 is a plot showing the rate of release of Formula I into PBS from the same 2.5 mm implant described for FIG. 6 over a period of 12 days.
  • FIG. 8 is a plot showing the retinal concentration of Formula I in albino and pigmented rats which were subjected to the implant described in Example 3 over a period of 4 weeks.
  • FIG. 9 is a plot showing the rate of release of Formula I in vitro from the implant described in Example 4 over a period of 6 weeks.
  • FIG. 10 is a plot showing the cumulative release of Formula I in vitro from the implant described in Example 4 over a period of 6 weeks.
  • FIG. 11 is a plot showing the percent of cumulative release of Formula I in vitro from the implant described in Example 4 over a period of 6 weeks.
  • FIG. 12 is a plot showing the rate of release of Formula I in vitro from the implant described in Example 5 over a period of 6 weeks.
  • FIG. 13 is a plot showing the cumulative release of Formula I in vitro from the implant described in Example 5 over a period of 6 weeks.
  • FIG. 14 is a plot showing the percent of cumulative release of Formula I in vitro from the implant described in Example 5 over a period of 6 weeks.
  • the present invention provides a molded composite ocular implant comprising Formula I for treatment or prevention of a disorder of the eye. Also provided are methods of making the silicone composite ocular implant and using the implant for treatment of various diseases or disorders of the eye, including tests of the implant with experimental animals such as rodents.
  • This implant provides sustained release of Formula I during the treatment or prevention of the disorder of the eye.
  • This implant configuration is particularly well-suited for placement in the sub-Tenon's space (also known as the bulbar sheath), but is not limited thereto and could be installed on or in other eye regions where convenient and useful.
  • depression refers to a region of a surface which is lower with respect to the majority of the surface. More specifically, the present specification describes a depression in a mold body which represents a region with a lower surface than the remainder of the contact surface of the mold body.
  • excipient includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
  • Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21 st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety).
  • any conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other
  • impression body refers to a body used to alter a surface of another body by pressure.
  • the impression body may have one or more features that produce an impression having a specific shape such as a curvature for example.
  • hardened layer As used herein, the terms “hardened layer”, “hardened polymer”, “cured layer” and “cured polymer” can be used interchangeably and mean a polymer fluid which has been cured to form a substantially solid polymer.
  • ophthalmic permeation agent also known as "transport facilitator” refers to a compound that increases the permeability of a therapeutic agent into the tissues of the eye.
  • Methylsulfonylmethane is a non-limiting example of an ophthalmic permeation agent.
  • permeation agent refers to a molecule that increases the permeability of a therapeutic agent.
  • An ophthalmic permeation agent increases the permeability of a therapeutic agent with respect to tissues of the eye.
  • pharmaceutically acceptable excipient refers to any ingredient other than active agents (e.g., as described herein) present in pharmaceutical compositions and having the properties of being substantially nontoxic and non-inflammatory in subj ects.
  • pharmaceutically acceptable excipients are vehicles capable of suspending and/or dissolving active agents.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.
  • Excipients include, but are not limited to: butylated hydroxy toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine,
  • BHT butylated hydroxy toluene
  • BHT butylated hydroxy toluene
  • calcium carbonate calcium phosphate (dibasic)
  • calcium stearate calcium stearate
  • croscarmellose crosslinked polyvinyl pyrrolidone
  • citric acid crospovidone
  • cysteine ethylcellulose
  • gelatin hydroxypropyl cellulose, hydroxypropyl methylcellulose
  • radius of curvature refers to the radius of a circle that best fits the curved surface at a given point.
  • the term "subject” or “patient” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g. , mammals such as mice, rats, rabbits, non-human primates, and humans).
  • animals e.g. , mammals such as mice, rats, rabbits, non-human primates, and humans.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • An individual who is "suffering from” a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and/or condition.
  • An individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition but harbors a propensity to develop a disease or its symptoms.
  • an individual who is susceptible to a disease, disorder, and/or condition may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition.
  • a genetic mutation associated with development of the disease, disorder, and/or condition for example, cancer
  • a genetic polymorphism associated with development of the disease, disorder, and/or condition
  • increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition (4) habits and/
  • an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • therapeutic agent refers to any agent that, when administered to a subject has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.
  • the term "therapeutically effective amount” means an amount of an agent to be delivered (e.g. , nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.
  • a therapeutically effective amount is provided in a single dose.
  • a therapeutically effective amount is administered in a dosage regimen comprising a plurality of doses.
  • a unit dosage form may be considered to comprise a therapeutically effective amount of a particular agent or entity if it comprises an amount that is effective when administered as part of such a dosage regimen.
  • treating refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and/or condition.
  • treating cancer may refer to inhibiting survival, growth, and/or spread of a tumor.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition as well as to a subject who is exhibiting signs of a disease, disorder and/or condition.
  • salts or pharmaceutically acceptable salt of 2-[[[2- [(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4 -(trifluoromethoxy)phenyl]-3- pyridinecarboxamide refers to any pharmaceutically acceptable salt, and examples thereof include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; salts with an organic acid such as acetic acid, fumalic acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzensulfonic acid or p- toluenesulfonic acid; salts with an alkali metal such as lithium, sodium or potassium; salts with an alkaline earth metal such as calcium or magnesium
  • the ocular implants of the present invention contain between about 5 to about 80%, between about 5 to about 70%, between about 5 to about 60%, between about 5 to about 50%, between about 10 to about 60%, between about 10 to about 50%, between about 20 to about 40%, between about 25 to about 45%, and about 30% by weight Formula I.
  • Another aspect of the present invention is a method for forming a molded single- layer ocular implant, the implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a silicone adhesive comprising Formula I dispersed therein into a curved depression on a first mold body to form silicone layer with a curved silicone layer interface surface in contact with the bottom of the curved depression and further comprising an exposed upper silicone surface; b) generating a curvature in the exposed silicone surface, thereby forming a curved eye-contacting surface; c) curing the silicone layer to produce a hardened silicone layer.
  • the implant is circular or oval-shaped.
  • step b) is performed using an impression body with a curved protrusion for generating the curvature in the exposed surface of the exposed surface of the silicone layer.
  • the silicone layer is about a thickness ranging from about 1 mm to about 3 mm, or from about 1 mm to about 2 mm.
  • the silicone layer further comprise an agent that blocks lymphatic absorption of Formula I.
  • agents the block lymoathic absorption include, but are not limited to, nystatin, amiloride, and N-ethymaleimide.
  • the silicone layer further comprises an ophthalmic permeation agent that increases ocular permeability of Formula I into the eye.
  • the ophthalmic permeation agent is, for example, methylsulfonylmethane, dimethyl sulfoxide, dimethylformamide, azone, N-methyl-2- pyrolidone glycols (diethylene glycol and tetraethylene glycol), fatty acids (lauric acid, myristic acid and capric acid), nonic surfactant (polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether), oxazolidinones such as 4-decyloxazolidin-2-one or urea.
  • the radius of curvature of the curved eye-contacting surface of the silicone layer ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm. In certain embodiments, the radius of curvature of the silicone layer of the implant of the present invention ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm.
  • the implant of the present invention is circular with a diameter ranging between about 1 mm and about 14 mm, about 1 mm and about 10 mm, or about 1 mm and about 6 mm.
  • the implant of the present invention is circular with a diameter ranging between about 8 mm and about 14 mm.
  • the implant of the present invention is circular with a diameter ranging between about 6 mm and about 10 mm.
  • the implant of the present invention is circular with a diameter ranging between about 1 mm and about 3 mm.
  • the silicone layer further comprises an excipient that improves the release of Formula I.
  • the excipient is selected from one or more of isopropyl myristate, levomenthol, propylene and tetraglycol.
  • the ocular implants of the present invention contain between about 5 to about 80%, between about 5 to about 70%, between about 5 to about 60%, between about 5 to about 50%, between about 10 to about 60%, between about 10 to about 50%, between about 20 to about 40%, between about 25 to about 45%, and about 30% by weight Formula I.
  • Another aspect of the present invention is a method for forming a molded two- layer ocular implant, the implant comprising Formula I for treatment or prevention of a disorder of the eye, the method comprising: a) dispensing a polymer into a curved depression on a first mold body to form a polymer layer having a curved external surface in contact with the bottom of the curved depression and further comprising an exposed upper polymer surface; b) generating a curvature in the exposed upper surface of the polymer layer, thereby forming a curved polymer layer interface surface; c) curing the polymer layer to produce a hardened polymer layer, d) dispensing a silicone adhesive comprising Formula I dispersed therein into second curved depression on a second mold body to provide a silicone layer with a curved silicone layer interface surface in contact with the bottom of the curved depression and further comprising an exposed upper silicone surface; e) generating a curvature in the exposed silicone surface, thereby forming a curved eye-contacting
  • the implant is circular or oval-shaped.
  • steps b) and e) are performed using an impression body with a curved protrusion for generating the curvature in the exposed surface of the polymer layer and the exposed surface of the silicone layer.
  • step b) is performed using a first impression body comprising a first curved protrusion for generating the curvature in the exposed surface of the polymer layer and step e) is performed using a second impression body comprising a second curved protrusion for generating the curvature in the exposed surface of the silicone layer, wherein the curvature dimensions of the first and second curved protrusions are different.
  • the polymer layer is resistant to diffusion of Formula I from the silicone layer.
  • the polymer layer is substantially impermeable to diffusion of Formula I from the silicone layer.
  • the polymer is polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate co-polymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride,
  • polyacrylonitrile cross-linked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(l,4'-isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer or vinylidene chloride-acrylonitride copolymer.
  • the polymer layer and the silicone layer are each about a thickness ranging from about 1 mm to about 3 mm, or from about 1 mm to about 2 mm.
  • the polymer layer and/or the silicone layer further comprise an agent that blocks lymphatic absorption of Formula I.
  • agents the block lymoathic absorption include, but are not limited to, nystatin, amiloride, and N-ethymaleimide.
  • the silicone layer further comprises an ophthalmic permeation agent that increases ocular permeability of Formula I into the eye.
  • the ophthalmic permeation agent is, for example, methylsulfonylmethane, dimethyl sulfoxide, dimethylformamide, azone, N-methyl-2- pyrolidone glycols (diethylene glycol and tetraethylene glycol), fatty acids (lauric acid, myristic acid and capric acid), nonic surfactant (polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether), oxazolidinones such as 4-decyloxazolidin-2-one or urea.
  • the radius of curvature of the curved eye-contacting surface of the silicone layer ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm. In certain embodiments, the radius of curvature of the silicone layer of the implant of the present invention ranges from between about 5 mm to about 15 mm, from about 7 to about 14 mm, or from about 9 mm to about 12 mm.
  • the implant of the present invention is circular with a diameter ranging between about 1 mm and about 14 mm, about 1 mm and about 10 mm, or about 1 mm and about 6 mm.
  • the implant of the present invention is circular with a diameter ranging between about 8 mm and about 14 mm.
  • the implant of the present invention is circular with a diameter ranging between about 6 mm and about 10 mm.
  • the implant of the present invention is circular with a diameter ranging between about 1 mm and about 3 mm.
  • the silicone layer further comprises an excipient that improves the release of Formula I.
  • the excipient is selected from one or more of isopropyl myristate, levomenthol, propylene and tetraglycol.
  • FIG. 1 to 5 An example embodiment of the ocular implant of the present invention will now be described with reference to FIG. 1 to 5. Skilled artisans will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the features shown in the figures may be enlarged relative to other elements to better illustrate and/or facilitate the discussion herein of the embodiments of the invention. Features in the various figures identified with the same reference numerals represent like features, unless indicated otherwise. Altemative features of alternative embodiments will also be discussed in context of the features of this example embodiment.
  • One embodiment of the present invention is a curved two-layer composite ocular implant comprising Formula I.
  • the curved shape of the implant 10 is indicated by dotted lines 12 and 14 in FIG. 1 and FIG. 2. This shape may be formed by using a molding process which will be described in WO2014/179568.
  • the ocular implant is formed of two curved layers, a lower layer 16 and an upper layer 18 as can be seen in the cross-sectional view of FIG. 3 which is taken along line 3'-3' of FIG. 2.
  • the lower layer 16 is formed of a silicone adhesive which contains a therapeutic agent 20.
  • the two layers are demarcated by line 26 (FIG. 3).
  • the lower layer 16 has a lower surface 24 which makes contact with the sclera E3 when the implant is in use.
  • the upper layer 18 is formed of a polymer which may be a silicone polymer or another polymer.
  • polymers suitable for forming the upper layer 18 include, but are not limited to, polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate co-polymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate,
  • polyvinylformal polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, cross-linked
  • polyvinylpyrrolidone polytrifluorochloroethylene, chlorinated polyethylene, poly(l,4'- isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer or vinylidene chloride-acrylonitride copolymer or any suitable equivalent of these polymers or combinations thereof.
  • the polymer is a silicone adhesive which may be the same as the silicone adhesive used to form the lower layer 16.
  • the lower layer 16 is formed of a medical grade silicone adhesive, generally is a polydimethylsiloxane (PDMS)-based compound.
  • the silicone adhesive is biologically (physiologically) inert and is well tolerated by body tissues.
  • Suitable silicones for use in the practice of this embodiment include MED-6810 silicone, MED 1-4213, MED2- 4213 silicone, which can be obtained from NuSil Technology LLC (Carpinteria, CA, USA).
  • Other biocompatible silicone adhesives may be used and can be adapted for use in preparation of implants according to certain alternative embodiments of the present invention.
  • the time and temperature needed to cure the silicone will depend on the silicone used and the drug release profile desired. These silicones, if left to cure at room temperature (e.g., 20-30 °C) will require about 24 hours or more to cure. The cure rate will increase with increasing cure temperatures. For instance, MED2-4213 silicone will cure in about 30 minutes at about 100 °C. As will be discussed in more detail below, the more quickly the silicone is cured, the less opportunity for therapeutic agent, Formula I, to leach out of the layer. In some cases, a catalyst such as platinum may be used to induce curing.
  • the implant 10 has a diameter of 7 mm and a thickness of 2 mm.
  • each of the two layers 16 and 18 is 1 mm thick.
  • the upper surface 22 of the upper layer 18 has a radius of curvature of 5 - 15 mm for generally conforming to the radius of curvature of the surface of Tenon's capsule El of an average human eye (as indicated in FIG. 5).
  • the lower layer 16 is also curved with a similar radius of curvature configured to generally conform to the radius of curvature of the sclera E3 of an average human eye.
  • these dimensions provide the implant 10 with characteristics appropriate for implantation with scleral contact in the sub-Tenon's space E0 of a human. It will be understood by the skilled person that these dimensions should be modified appropriately for an implant designed for use in an experimental animal such as a rat, mouse or rabbit for example. Armed with the knowledge of average dimensions of the eye and radii of curvature of Tenon's capsule and sclera of the chose experimental animal, the dimensions of an ocular implant according to may be selected by the skilled person and appropriate molding tools may be constructed without undue experimentation.
  • the ocular implant with an upper layer 18 which is generally resistant to diffusion of the therapeutic agent 20 which is dispersed in the lower layer 16.
  • the upper layer 18 is impermeable to the therapeutic agent 20.
  • the therapeutic agent 20 has a rate of diffusion within the upper layer 18 which is significantly less than the rate of diffusion of the therapeutic agent 20 out of the lower layer 16 and into the sclera.
  • the term "significantly less” means 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% less than the rate of diffusion of the therapeutic agent 20 out of the lower layer 16 and into the sclera E3.
  • the reduced diffusion characteristics of the therapeutic agent 20 in the upper layer 18 relative to the lower layer 16 provide the advantage of preventing loss of the therapeutic agent 20 to tissues where it is not needed.
  • the reduced rate of diffusion of the therapeutic agent 20 through the upper layer 18 thereby encourages unidirectional diffusion of the therapeutic agent 20 from the lower layer 16 into the sclera E3 and choroid E4 for transfer to the macula E6 where its desired mechanism of action will be effected.
  • a further advantage provided by the reduced diffusion characteristics of the therapeutic agent 20 in the upper layer 18 relative to the lower layer 16 is gained in preventing the therapeutic agent 20 from entering the lymphatic system via Tenon's capsule El and the conjunctiva E2 for transfer to other tissues where it may cause undesirable side-effects.
  • the upper layer 18 or lower layer 16 further includes an agent that blocks lymphatic absorption.
  • the thickness of the implant is 2 mm with the two layers 16 and 18 each being 1 mm in thick.
  • the skilled person will appreciate that the thickness of each layer may be modified according to various embodiments of the invention, which may include variations with respect to the composition of silicone adhesive of the lower layer, the polymer of the upper layer, or the properties of drugs and/or formulations thereof used in the implant.
  • the dimensional thickness may be modified appropriately by the skilled person without undue experimentation.
  • FIG. 4 and FIG. 5 Positioning of the implant 10 with respect to the anatomical structures of an eye E is indicated in FIG. 4 and FIG. 5.
  • the features of the implant 10 are omitted for clarity.
  • the anatomical structures shown in FIG. 4 and FIG. 5 include the sub-Tenon's space E0, Tenon's capsule El (also known as the bulbar sheath), the sclera E3, the choroid E4 (shown in FIG. 5 only), the optic nerve E5, the macula E6, the vitreous humor E7 and the upper and lower eyelids E8 and E9.
  • FIG. 5 which represents a magnification of the inset labeled 5' in FIG. 4) there is provided additional detail regarding the placement of the implant 10.
  • the implant 10 is located in the sub-Tenon's space E0 with its lower surface 24 resting upon the surface of the sclera E3. It is also seen that the upper surface 22 of the implant 10 has a curvature which generally conforms to the curvature of the surface of Tenon's capsule El. This feature provides the advantage of minimizing discomfort to the eye as a result of contact of Tenon's capsule El with upper edges of the implant 10.
  • the curved upper surface 22 is smooth and does not have sharp edges which would otherwise cause irritations and/or damage to the tissues of Tenon's capsule and possibly also the conjunctiva E2 in the event that a sharp edge of an alternative implant were to completely puncture Tenon's capsule El and penetrate the conjunctiva E2.
  • Drug particles 20 will be released downward to the sclera E3 as indicated by the arrows in FIG. 5, because they are concentrated in the lower layer 16 and because the upper layer 18 is generally resistant to diffusion of the therapeutic agent 20 as described above.
  • FIG. 5 it is shown that three drug particles 20B have diffused from the lower layer 16 through the sclera E3 to the choroid E4 and one drug particle 20A has diffused from the lower layer 16 to the sclera E3.
  • These drug particles 20A and 20B are expected to be transferred by either diffusion or an active physiological mechanism, or a combination thereof, to the macula E6 where the desired pharmaceutical effect will be obtained.
  • FIG. 5 does not include arrows indicating diffusion of the therapeutic agent 20 into the upper layer 18 and to upper tissues in Tenon's capsule El and the conjunctiva E2. This is due to resistance of the upper layer 18 to diffusion of the therapeutic agent 20.
  • the implant 10 is provided with a suture platform (not shown) which can be formed as part of the implant to facilitate attachment of the implant 10 to the sclera E3.
  • a suture platform (not shown) which can be formed as part of the implant to facilitate attachment of the implant 10 to the sclera E3.
  • An implant having a suture platform with a mesh contained therein to hold sutures in place is described in U.S. Patent 7,658,364, the contents of which are incorporated herein by reference in entirety.
  • the implant described herein can be modified without undue experimentation to include such a suture platform by modification of the molding processes which will be described in detail herein below.
  • the implant of the invention may also be fixed to a suture stub as described also in U.S. Patent 7,658,364, the entire contents of which is incorporated herein by reference.
  • the implants used herein may be made using a mold assembly and molding process for forming a two-layer ocular implant as described in WO 1024/179568.
  • Another aspect of the invention is a two-layer implant formed by the methods described herein.
  • the implants of certain embodiments may be used for implantation into the sub-Tenon's space of a human.
  • the implant of other embodiments may be used for implantation into the sub-Tenon's space of a rodent.
  • FIG. 3 Another aspect of the invention is a molded two-layer ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the implant comprising: a first hardened layer comprising a polymer, the first hardened layer comprising curvature at both the upper and lower surfaces (see FIG. 3); and a second hardened layer comprising a silicone adhesive and Formula I, the second hardened layer and comprising curvature at both the upper and lower surfaces (see FIG. 3).
  • the curvature of one surface of the first hardened layer and the curvature of one surface of the second layer are both formed using an impression body with a curved protrusion.
  • the first and second hardened layers are formed as follows: the curvature of a first surface of the first hardened layer is formed by dispensing the polymer into a mold body; the curvature of a second surface of the first hardened layer is formed by a first curved protrusion on a first impression body; the curvature of a first surface of the second hardened layer is formed by dispensing the silicone adhesive onto the curvature of the second surface of the first hardened layer; and the curvature of a second surface of the second hardened layer is formed by a second curved protrusion on a second impression body.
  • the first hardened layer is resistant to diffusion of Formula I from the second hardened layer.
  • the first hardened layer is substantially impermeable to diffusion of Formula I from the second hardened layer.
  • the implants used herein are formed in a mold assembly described in WO2014/179568 the entire contents of which are incorporated herein by reference.
  • kits for preparing a molded single-layer composite ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the kit comprising: a) a mold assembly for molding the implant; b) a silicone adhesive comprising Formula I for forming a first layer.
  • the mold assembly of the kit is the mold assembly described herein which includes a single impression body. In other embodiments, the mold assembly of the kit is the mold assembly which includes two impression bodies.
  • the kit further comprises instructions for making a molded single-layer silicon composite ocular implant.
  • the present invention also contemplates a kit for production of single-layer ocular implants.
  • the kit may include any or all of the components and features thereof which are described above.
  • the kit includes a) a mold body with a depression on its contact surface; and b) an impression body with a protrusion on its contact surface configured to form a silicone-drug (Formula I) layer with curved upper and lower surfaces.
  • This particular embodiment will yield a resilient cured layer that is resistant to damage by pressure of the upper mold body part.
  • kits further includes c) a second impression body with a protrusion on its contact surface which is configured to form the sclera-contacting surface of the silicone-drug (Formula I) layer.
  • kits further includes d) silicone materials for forming the layers of the single-layer ocular implant.
  • the mold assembly body parts are cylindrical and the kit further includes e) centrifuge tubes for conducting degassing procedures.
  • the kit further includes a means for trimming the excess silicone from the contact surface of the mold body.
  • this means for trimming is provided by a punching device dimensioned to consistently cut the perimeter of a two layer implant to specific dimensions.
  • the kit includes instructions for using the components of the kit in a molding process for molding a two-layer ocular implant.
  • kits for preparing a molded two-layer composite ocular implant comprising Formula I for treatment or prevention of a disorder of the eye, the kit comprising: a) a mold assembly for molding the implant; b) a silicone adhesive comprising Formula I for forming a first layer; and c) a polymer for forming a second layer.
  • the mold assembly of the kit is the mold assembly described herein which includes a single impression body. In other embodiments, the mold assembly of the kit is the mold assembly which includes two impression bodies.
  • the kit further comprises instructions for making a molded two-layer silicon composite ocular implant by sequential layering of the polymer and the silicone adhesive comprising Formula I.
  • the present invention also contemplates a kit for production of two-layer ocular implants.
  • the kit may include any or all of the components and features thereof which are described above.
  • the kit includes a) a mold body with a depression on its contact surface; and b) an impression body with a protrusion on its contact surface configured to form a polymer layer with curved upper and lower surfaces and to also form a silicone-drug (Formula I) layer with curved upper and lower surfaces.
  • This particular embodiment is used in conjunction with polymer and silicone adhesive materials provided separately which yield resilient cured layers that are resistant to damage by pressure of the upper mold body part against both layers.
  • kits further includes c) a second impression body with a protrusion on its contact surface which is configured to form the sclera-contacting surface of the silicone-drug (Formula I) layer.
  • kits further includes d) polymer and silicone materials for forming the layers of the two-layer ocular implant.
  • the mold assembly body parts are cylindrical and the kit further includes e) centrifuge tubes for conducting degassing procedures.
  • the kit further includes a means for trimming the excess polymer and silicone from the contact surface of the mold body.
  • this means for trimming is provided by a punching device dimensioned to consistently cut the perimeter of a two layer implant to specific dimensions.
  • the kit includes instructions for using the components of the kit in a molding process for molding a two-layer ocular implant.
  • the subconjunctival matrix implant preferably is placed behind the surface epithelium within the sub-Tenon's space. This is done by a surgical procedure that can be performed in an out-patient setting. A lid speculum is placed and a conjunctival radial incision is made through the conjunctiva over the area where the implant is to be placed. Wescott scissors are used to dissect posterior to Tenon's fascia and the implant is inserted. The conjunctiva is reapproximated using a running 10-0 vicryl suture. The eye has many barriers that do not permit easy penetration of drugs.
  • an applicator device is used to inject the implant into the sub-Tenon's space.
  • Such devices are known in the art and have been used for intraocular injections into the vitreous humor of the eye, particularly in intraocular lens implantation after cataract surgery.
  • the device is provided with a retractor that engages the conjunctiva and the surface of Tenon's capsule to produce an opening into the sub-Tenon's space.
  • the device is also provided with a means for pushing the implant into the sub-Tenon's space such that withdrawal of the device allows the surrounding tissues to collapse back into place while holding the implant at the desired location.
  • the implant when the implant is placed near the limbus (i.e., the area where the conjunctiva attaches anteriorly on the eye) to encourage the drug diffusion to enter the cornea, it may be preferable to fixate the matrix implant with one or two absorbable sutures (e.g., 10-0 absorbable vicryl sutures). This is done by making holes with a 30 gauge needle in the peripheral portion of the implant, approximately 250-500 ⁇ away from the peripheral edge of the implant. The holes are made 180 degrees from each other. This is done because subconjunctival matrix implants of this invention, when placed near the cornea, are at higher risk to extrude because of the action of the upper eye lid when blinking.
  • absorbable sutures e.g., 10-0 absorbable vicryl sutures
  • subconjunctival matrix implants of this invention are placed about 4 mm or more away from the limbus, the sutures are optional.
  • the implants can be placed anywhere in the eye where treatment in needed, such as, on the sclera, on the choroid, on the retina, on the conjunctiva, or in the vitreous body.
  • the implant can in certain embodiments be placed in the eye by intravitreal injection.
  • the terms "on the sclera”, “on the choroid”, “on the retina”, and “on the conjunctiva” include placement of the implant on the inner surface, on the outer surface and anywhere inside these tissues.
  • This matrix implant can deliver therapeutic levels of different pharmaceuticals agents to the eye to treat a variety of diseases. Using a rabbit model, drug released from the implant placed in the eye produces negligible levels of the drug in the blood. This significantly reduces the chances of systemic drug side-effects.
  • This implant design of this invention is prepared by unique methodologies and selections of materials leading to and imparting the unique pharmacological performance properties present in the finished devices.
  • the present invention is a method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is caused by
  • angiogenesis or vascular hyperpermeability.
  • the implants of this invention can be used to treat a number of eye diseases and indications including, for example, age-related macular degeneration (AMD), wet age-related macular degeneration, choroidal neovascularization, diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy, proliferative diabetic retinopathy, polypoidal chorioretinopathy, uveitis, retinopathy of prematurity in newborns, choroidal melanoma, chorodial metastasis, retinal capillary hemangioma, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, myopic choroidal
  • AMD age-related macular degeneration
  • DME diabetic macular edema
  • DME diabetic macular edema
  • retinal vein occlusion diabetic retinopathy
  • proliferative diabetic retinopathy polypoidal chori
  • neovascularization eye tumor, radiation retinopathy, rubeosis iridis, rubeotic glaucoma, and proliferative vitreoretinopathy.
  • Another aspect of the present invention is a method for determining the effectiveness of the implant as described herein for treatment or prevention of wet macular degeneration in a rodent, rabbit or non-human primate model, the method comprising: a) placing the implant as described herein in the sub-Tenon's space of the eye of the animal, wherein the animal is, for example, exposed to laser to induce choroidal neovascularization or exposed to exogenous excess vascular endothelial growth factor to produce vascular leakage and b) monitoring the release of the Formula I over time by examining the eye of the animal with histology, electroretinography, direct measurement of tissues levels of Formula I or changes in gene expression in various retinal tissues, thereby indicating the effectiveness of the implant against macular degeneration.
  • Another aspect of the present invention is a method for evaluating the effectiveness of the implant as described herein for treatment or prevention of macular degeneration in a human, the method comprising: a) placing the implant as described herein into the sub-Tenon's space of the eye of the human; and b) examining the eye of the human using a technique selected from the group consisting of: optical coherence tomography, fluorescein angiography, indocyanine green angiography, best corrected visual acuity, fundus photography or fundus autofluorescence.
  • the macular degeneration is age- related macular degeneration.
  • Example 1 Release Kinetics of the drug Formula I from a silicone ocular implant
  • Example 2 Measurement of concentration of Formula I in ocular tissues after implantation of Formula I silicone implant on rat episclera and comparison with direct episcleral injection of Formula I alone.
  • the data shown in Table 1 provide an indication that the maximal concentration of Formula I in retina is obtained after about three days after implantation and that the maximal concentration of Formula I in SCC is obtained after about 2 days after implantation.
  • the concentrations of Formula I in the ocular tissues are in a ratio of approximately 2.5: 1 (episclera:retina).
  • measurement of Formula I levels in similarly processed tissues of rats subj ected to direct episcleral injections of similar doses of Formula I after three days indicated that the concentration of Formula I in SCC tissues was 5.4 ⁇ 1.3 ng/mL and undetectable in the retinal tissue (the lower limit of detection is 0.4 ng/mL).
  • Example 3 Concentration of Formula I in retina after implantation of Formula I silicone implant on epiclera of albino and pigmented rat.
  • Example 4 In vitro release of Formula I from an episcleral Formula I silicone implant designed for rat.
  • Example 5 In vitro release of Formula I from an episcleral Formula I silicone implant designed for rabbit

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Abstract

La présente invention porte, d'une manière générale, sur des traitements locaux de l'œil et, plus particulièrement, des dispositifs d'implants oculaires formés à libération contrôlée, y compris des procédés de fabrication et d'utilisation de tels dispositifs, pour l'administration dans l'œil du 2-[[[2-[(hydroxyacétyl)amino]-4-pyridinyl]méthyl]thio]-N-[4-(trifluorométhoxy)phényl]-3-pyridine carboxamide (formule I) ou un sel de celui-ci. Cet implant est destiné à être placé dans l'espace sous-ténonien de l'œil et permet une libération prolongée du composé pour le traitement ou la prévention d'un trouble de l'œil.
PCT/US2016/029754 2015-05-01 2016-04-28 Implant oculaire pour l'administration de dérivé pyridine-carboxamide WO2016178900A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070149574A1 (en) * 2004-02-17 2007-06-28 Santen Pharmaceutical Co., Ltd. Novel cyclic compound having 4-pyridylalkylthio group having substituted or unsubstituted amino group introduced therein
US20070190111A1 (en) * 2001-03-15 2007-08-16 Govemment Of The U.S.A, Represented By The Secretary, Department. Of Health And Human Ocular therapeutic agent delivery devices and methods for making and using such devices
US20100239637A1 (en) * 2008-12-11 2010-09-23 Massachusetts Institute Of Technology Contact lens drug delivery device
US20120116088A1 (en) * 2009-07-17 2012-05-10 Santen Pharmaceutical Co., Ltd. 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof
WO2014179568A2 (fr) * 2013-05-02 2014-11-06 Odin Biotech Implant oculaire à deux couches

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070190111A1 (en) * 2001-03-15 2007-08-16 Govemment Of The U.S.A, Represented By The Secretary, Department. Of Health And Human Ocular therapeutic agent delivery devices and methods for making and using such devices
US20070149574A1 (en) * 2004-02-17 2007-06-28 Santen Pharmaceutical Co., Ltd. Novel cyclic compound having 4-pyridylalkylthio group having substituted or unsubstituted amino group introduced therein
US20100239637A1 (en) * 2008-12-11 2010-09-23 Massachusetts Institute Of Technology Contact lens drug delivery device
US20120116088A1 (en) * 2009-07-17 2012-05-10 Santen Pharmaceutical Co., Ltd. 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof
WO2014179568A2 (fr) * 2013-05-02 2014-11-06 Odin Biotech Implant oculaire à deux couches

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