WO2019071275A1 - Dispositifs d'administration de médicament oculaire non invasive - Google Patents

Dispositifs d'administration de médicament oculaire non invasive Download PDF

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Publication number
WO2019071275A1
WO2019071275A1 PCT/US2018/055080 US2018055080W WO2019071275A1 WO 2019071275 A1 WO2019071275 A1 WO 2019071275A1 US 2018055080 W US2018055080 W US 2018055080W WO 2019071275 A1 WO2019071275 A1 WO 2019071275A1
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WO
WIPO (PCT)
Prior art keywords
active agent
composition
examples
eye
matrix
Prior art date
Application number
PCT/US2018/055080
Other languages
English (en)
Inventor
John W. Higuchi
Kongnara PAPANGKORN
Original Assignee
Aciont 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
Priority claimed from US15/727,452 external-priority patent/US20190105194A1/en
Priority claimed from US15/727,529 external-priority patent/US20190105264A1/en
Application filed by Aciont Inc. filed Critical Aciont Inc.
Publication of WO2019071275A1 publication Critical patent/WO2019071275A1/fr

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Classifications

    • 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
    • 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
    • A61F9/0026—Ophthalmic product dispenser attachments to facilitate positioning near the eye
    • 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
    • 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
    • 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

Definitions

  • ophthalmic drops offer a first line of treatment for ocular disorders.
  • eye drops often need to be administered frequently to be effective, which can lead to poor patient compliance and reduced effectiveness of the treatment.
  • Further eye drops often are ineffective at delivering adequate amounts of therapeutic agents into the eye, especially the posterior segment of the eye.
  • Other methods of treating ocular disorders can include painful ocular injections and other invasive procedures, which can have safety risks such as infection, retinal detachment, vitreous hemorrhage, etc.
  • Fig. la illustrates a front cross-sectional view of a non-invasive ocular drug delivery device, in accordance with an example embodiment.
  • Fig. lb illustrates a bottom view of the non-invasive ocular drug delivery device of Fig. la.
  • Fig. 2a illustrates a front cross-sectional view of a non-invasive ocular drug delivery device, in accordance with an example embodiment.
  • Fig. 2b illustrates a bottom perspective view of the non-invasive ocular drug delivery device of Fig. 2a.
  • Fig. 2c illustrates a bottom view of the non-invasive ocular drug delivery device of Fig. 2c.
  • Fig. 3 a illustrates a perspective view of a non-invasive ocular drug delivery device, in accordance with an example embodiment.
  • Fig. 3b illustrates a side cross-sectional view of the non-invasive ocular drug delivery device of Fig. 3 a.
  • Fig. 3 c illustrates a top view of the non-invasive ocular drug delivery device of Fig. 3 a.
  • Fig. 3d illustrates a bottom view of the non-invasive ocular drug delivery device of Fig. 3a.
  • Fig. 4 illustrates a side cross-sectional view of the device of Fig. 3a attached to an eye, in accordance with an example embodiment.
  • Fig. 5a illustrates a top view of a loading base, in accordance with an example embodiment.
  • Fig. 5b illustrates a side cross-sectional view of a loading base with the noninvasive ocular drug delivery device of Fig. 3a coupled thereto, in accordance with an example embodiment.
  • Fig. 6 is a graph of the drug release profile of a non-invasive ocular drug delivery device, in accordance with an example embodiment.
  • Fig. 7 is a graph of intraocular pressure changes in response to various ocular steroid treatment regimens.
  • Fig. 8 is a graph of vitreous scores of various treatment groups tested in an experimental uveitis rabbit model.
  • Fig. 9a is a magnified image of a posterior section of an untreated eye depicting severe inflammation and damaged photoreceptor layer (arrow).
  • Fig. 9b is a magnified image of a posterior section of an eye treated with 15% DSP (15 minutes, 4 doses) depicting minimal inflammation and well-preserved tissue structure.
  • Fig. 1 la is a graph of mean plasma concentration of DSP (solid line) and DEX (dotted line) following single administration of DSP via a non-invasive ocular drug delivery device.
  • Fig. l ib is a graph of mean plasma concentration of DSP equivalent following single administration of DSP via a non-invasive ocular drug delivery device. The data were calculated from Fig. 1 la based on the sum of DSP and DEX in gram equivalent. No standard deviation is given. To reveal all pharmacokinetic data, graph was not plotted in a linear time sale on the x-axis. DESCRIPTION OF EMBODIMENTS
  • Consisting essentially of or "consists essentially of have the meaning generally ascribed to them by U.S. Patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the compositions nature or characteristics would be permissible if present under the “consisting essentially of language, even though not expressly recited in a list of items following such terminology.
  • an open ended term like “comprising” or “including,” in this written description it is understood that direct support should be afforded also to “consisting essentially of language as well as “consisting of language as if stated explicitly and vice versa.
  • an "active delivery” device is a device that delivers a therapeutic agent or payload with the assistance of an extemal force, current or the like.
  • electrophoresis electroporation, sonophoresis, iontophoresis, etc.
  • Coupled is defined as directly or indirectly connected in an electrical or nonelectrical manner.
  • Directly coupled structures or elements are in physical contact with one another.
  • Objects described herein as being “adjacent to” each other may be in physical contact with each other, in close proximity to each other, or in the same general region or area as each other, as appropriate for the context in which the phrase is used.
  • comparative terms such as “increased,” “decreased,” “better,”
  • “worse,” “higher,” “lower,” “enhanced,” “maximized,” “minimized,” “improved,” and the like refer to a property of a device, component, or activity that is measurably different from other comparable devices, components, or activities, or from different iterations or embodiments of the same device, properties lacking the same features or characteristics. For example, a reservoir with properties that provide "improved” drug release would achieve a result that is measurably different than a reservoir with different properties.
  • the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles.
  • a composition that is "substantially free of an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.
  • the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. Unless otherwise stated, use of the term “about” in accordance with a specific number or numerical range should also be understood to provide support for such numerical terms or range without the term “about”. For example, for the sake of convenience and brevity, a numerical range of "about 50 milligrams to about 80 milligrams” should also be understood to provide support for the range of "50 milligrams to 80 milligrams.” Furthermore, it is to be understood that in this written description support for actual numerical values is provided even when the term "about” is used therewith.
  • the eyes are subject to numerous adverse health conditions that can impair vision and eventually lead to blindness.
  • effective administration of an active agent to the eye can be important in treating these ocular conditions in a timely manner.
  • eye drops are often inefficient at delivering active agents to the eye, especially the posterior segment of the eye.
  • intraocular injections, intraocular implants, etc. are invasive administration procedures that can be more effective at delivering active agents to the posterior segment of the eye.
  • invasive procedures also pose a number of significant risks, such as infection, retinal detachment, vitreous hemorrhage, etc.
  • there is a need for non-invasive administration devices and methods that can provide an adequate dose of a therapeutic agent to the eye in a timely manner.
  • non-invasive ocular drug delivery devices are disclosed herein that can provide an adequate dose of an active agent to the eye in a timely manner.
  • the non-invasive ocular drug delivery device can be a passive ocular drug delivery device.
  • the non-invasive ocular drug delivery device can be an active delivery device.
  • the non-invasive ocular drug delivery devices can include a housing adapted to couple to an eye of a subject.
  • An active agent matrix can be coupled to the housing.
  • the active agent matrix can include or be formed of an electrospun material having a combination of a density, a thickness, and an ocular surface area configured to hold and retain an active agent composition prior to application of the device to the eye, and then deliver an effective dose of an active agent within 30 minutes of application of the device to the eye.
  • the housing of the non-invasive ocular drug delivery device is not particularly limited, other than it is adapted to couple to an eye of a subject.
  • the housing can couple directly to the eye, such as via negative pressure, surface tension, adhesives, the like, or combinations thereof.
  • the housing can be shaped to interface with the eye and can be merely held against the eye using positive pressure from eye lids, and/or straps, cords, scaffolding, adhesives, the like, or combinations thereof that are attached to a surface outside of the eye, but nonetheless hold the housing in place against the eye.
  • the housing can be formed from a plurality of interconnecting pieces to prepare an integral housing.
  • the housing can be formed as a monolithic unit.
  • the housing can be formed from a mold or other suitable manufacturing process as a single monolithic unit without any need for further assembly or integration of additional components.
  • the monolithic unit can be formed of a molded elastomeric material, such as ethylene propylene diene monomer (EPDM), fluoroelastomers (e.g. FKMs, FFKMs, FEPMs, etc.), acrylonitrile-butadiene rubbers, silicones, the like, or combinations thereof.
  • the housing can include a variety of suitable materials, such as one or more of the elastomeric materials listed above, polyamides, polyesters, polyethylenes, polypropylenes, polycarbonates, polyurethanes, polytetrafluoroethylenes, metals, the like, or combinations thereof.
  • the housing can include or be formed of an EPDM material.
  • the housing can include or be formed of a fluoroelastomer material.
  • the housing can include or be formed of an acrylonitrile-butadiene rubber.
  • the housing can include or be formed of a silicone material.
  • the housing can include or be formed of a translucent or transparent material.
  • a translucent or transparent material For example, many of the materials listed above can be prepared in a way so that they are translucent or transparent. Other translucent or transparent materials can also be used.
  • portions of the housing can be translucent or transparent while others are not.
  • portions of the housing can be translucent while other parts of the housing can be transparent.
  • At least a portion of the housing that covers the cornea can be translucent or transparent.
  • the geometry of the housing is not particularly limited, so long as the housing adequately interfaces with a surface of the eye to facilitate administration of an active agent.
  • the housing (or at least the portion of the housing that interfaces with the eye) can have an elliptical geometry. While the overall shape of the eye approaches a spherical geometry, the part of the eye that is visible generally has an elliptical shape.
  • the housing (or at least the portion of the housing that interfaces with the eye) can be prepared so as to have an elliptical, or approximately elliptical, shape.
  • an elliptical shape can facilitate application of the device to the eye and maximize the comfort of the subject, while maintaining adequate surface coverage or interface area of the device with the eye to provide an adequate dose of an active agent in a timely manner.
  • the device can typically have an aspect ratio (width to height) of from about 1.05 : 1 to about 1.4: 1.
  • the device can have an aspect ratio of from about 1.10: 1 to about 1.3: 1.
  • the device can have an aspect ratio of from about 1.15 : 1 to about 1.25 : 1.
  • the housing can include a corneal dome shaped to cover the cornea of the eye.
  • the corneal dome can generally be shaped to maintain a gap between a portion of the cornea and an inner surface of the corneal dome. This gap can also facilitate the comfort of the user while using the device.
  • the cornea can be a very sensitive portion of the eye. As such, in some cases, it can facilitate user comfort by minimizing contact of the device with the cornea.
  • the gap between the portion of the cornea and the inner surface of the corneal dome can be at least 50 ⁇ or at least 100 ⁇ . In yet other examples, the gap between the portion of the cornea and the inner surface of the corneal dome can be at least 200 ⁇ or at least 500 ⁇ .
  • the gap between the portion of the cornea and the inner surface of the corneal dome can be at least 1000 ⁇ .
  • the portion of the cornea where the gap is maintained can generally be at least 50% of the corneal surface area.
  • a gap of at least 100 ⁇ between an inner surface of the corneal dome and the cornea of the eye can be maintained over at least 50% of the corneal surface.
  • the portion of the cornea where the gap is maintained can be at least 60%, 70%, 80%, or 90% of the corneal surface area.
  • the gap can be maintained across the entire corneal surface area.
  • the housing can include a corneal seal that is positioned to circumscribe the cornea and form a fluidic seal against the eye to minimize fluid transport across the corneal seal to the cornea when in use. It is noted that where the device does not include a corneal dome, the cornea can be exposed to ambient conditions. However, the corneal seal can still minimize fluid transport (e.g. from the active agent matrix, for example) across the surface of the eye to the cornea. Where the housing includes a corneal dome, the corneal seal can be disposed about a periphery of the corneal dome to minimize fluid transport to the cornea when in use. It is noted that when the diameter of the corneal seal becomes too large, it can be challenging to comfortably maintain the housing within the framework of the eyelids.
  • the corneal seal can be shaped to maintain a seal about the cornea without excessively increasing the overall size of the housing.
  • the corneal seal can be shaped to maintain a distance from a perimeter of the cornea (i.e. the corneal seal is positioned exterior to the cornea so as to not contact the cornea) of from about 50 ⁇ to about 5000 ⁇ .
  • the corneal seal can be shaped to maintain a distance from a perimeter of the cornea of from about 500 ⁇ to about 3000 ⁇ .
  • the corneal seal can be shaped to maintain a distance from a perimeter of the cornea of from about 1000 ⁇ to about 2000 ⁇ .
  • the corneal seal can be shaped to maintain a distance from a perimeter of the cornea of from about 50 ⁇ to about 1000 ⁇ , about 100 ⁇ to about 1500 ⁇ , or about 300 ⁇ to about 1200 ⁇ .
  • the housing can include a scleral flange extending radially outward from the corneal seal.
  • the scleral flange can have a shape that provides the elliptical geometry.
  • the scleral flange can be the portion of the housing to which the active agent matrix is attached. Where this is the case, the scleral flange can be shaped to maintain contact between the active agent matrix and the sclera of the eye when in use.
  • the scleral flange can generally be shaped and positioned on the housing so as to cover a portion of the sclera of the eye without covering the cornea. Additionally, in some examples, the scleral flange, or other similar segment of the housing, can include a scleral lip or scleral seal about a perimeter of the portion of the device that interfaces with the eye. In some examples, the scleral lip or scleral seal can be shaped to facilitate retention of the active agent matrix to the housing, such as via friction fitting, nesting, clamping, or the like. In some examples, the scleral lip or scleral seal can additionally form a fluidic seal against the eye to minimize fluid transport across the scleral seal. In some examples, this can help concentrate delivery of the active agent to a specific region of the sclera and improve delivery of the active agent to the posterior segment of the eye.
  • a pressure regulator can be operatively connected to the housing and adapted to induce negative pressure between the housing and the eye to couple the housing to the eye when in use.
  • the pressure regulator can form part of the housing, such as an integrated component of the housing or as part of a monolithic housing.
  • the pressure regulator can be a bulb, a pump, the like, or other suitable pressure regulator that can be operatively connected to the housing.
  • the pressure regulator can generally be adapted to induce a negative pressure between the housing and the eye to couple the housing to the eye when in use.
  • the negative pressure induced between the housing and the eye can be any pressure suitable to maintain the housing on the eye without significantly damaging the eye.
  • the pressure regulator can be adapted to induce a negative pressure of from about 0.98 atmospheres (atm) to about 0.1 atm between the housing and the eye. In yet other examples, the pressure regulator can be adapted to induce a negative pressure of from about 0.90 atm to about 0.3 atm. In still other examples, the pressure regulator can be adapted to induce a negative pressure of from about 0.8 atm to about 0.5 atm. In some examples, the pressure regulator can be adapted to reduce a pressure between the housing and the eye by an amount from about 0.1 atm to about 3 atm relative to atmospheric pressure. In yet other examples, the pressure regulator can be adapted to reduce a pressure between the housing and the eye by an amount from about 0.5 atm to about 1 atm relative to atmospheric pressure.
  • the active agent matrix can be coupled to the housing using any suitable coupling feature, such as an adhesive, stitching, friction-fitting, clips, clamps, magnets, snaps, hook and loop fasteners, the like, or combinations thereof.
  • the active agent matrix can be coupled to the housing via an adhesive.
  • suitable adhesives can be used. Non-limiting examples can include a silicone adhesive, an acrylic adhesive, a polyurethane adhesive, the like, or combinations thereof.
  • the active agent matrix can generally be positioned to interface with the sclera of the eye, but not the cornea of the eye.
  • the active agent matrix can be formed of a plurality of segments that are positioned adjacent to one another to form an integral active agent matrix.
  • the active agent matrix can be formed from 2, 3, 4, or more individual segments positioned adjacent to one another. In some examples, the individual segments can be spaced apart from one another. In yet other examples, the individual segments can be positioned so that there is substantially no space between adjacent segments.
  • the active agent matrix can be formed of an electrospun material. Electrospinning is a robust process capable of producing polymer fibers from a variety of polymer/solvent systems with diameters typically from about 100 nm to about 500 nm. Electrospinning can also be used to produce highly porous membranes with good structural integrity. Thus, electrospinning can be used to prepare a variety of materials that can be used as active agent reservoirs or matrices that have good structural integrity and porosity.
  • an electrospun material can allow a solvent or an active agent composition to quickly absorb thereto.
  • an electrospun material can also allow an active agent composition to transfer quickly from the material once placed in contact with an ocular surface, without otherwise dripping or leaking prior to application.
  • the electrospun material can be highly solvent-swellable, or highly solvent absorbable.
  • the electrospun material or active agent matrix can absorb a solvent or an active agent composition so as to more than double the dry weight or pre-loaded weight of the electrospun material or active agent matrix.
  • the electrospun material or active agent matrix can absorb a solvent or an active agent composition so as to increase the weight of the electrospun material or active agent matrix to from about 2 times to about 40 times the dry weight or pre-loaded weight of the electrospun material or active agent matrix.
  • the electrospun material or active agent matrix can absorb a solvent or an active agent composition so as to increase the weight of the electrospun material or active agent matrix to from about 3 times to about 30 times, from about 4 times to about 25 times, from about 5 times to about 20, or from about 6 times to about 10 or 15 times the dry weight or pre-loaded weight of the electrospun material or active agent matrix.
  • the electrospun material or active agent matrix can absorb a solvent or an active agent composition so as to increase the weight of the electrospun material or active agent matrix to from about 2 times to about 9 times, or from about 3 times to about 7 times the dry weight or pre-loaded weight of the electrospun material or active agent matrix.
  • the electrospun material or active agent matrix can swell to accommodate absorbed solvent.
  • the solvent can be or include water.
  • the electrospun material can be a hydrophobic material.
  • the electrospun material can be a hydrophilic material.
  • the electrospun material can be a hydrogel material.
  • the degree of hydrophobicity/hydrophilicity of the material can dependent on the active agent to be delivered and the carrier used to deliver the active agent.
  • the electrospun material can be formed of a variety of materials.
  • Non-limiting examples can include poly amides, polyurethanes, polycarbonates, polyvinyl alcohols, polylactic acids, polyglycolic acids, polyethylene-co-vinyl acetate, polyethylene oxide, polystyrene, collagen, polyvinylpyrrolidone, polyethylene, polypropylene, the like, or combinations thereof.
  • the active agent matrix can include or be formed of a non-biodegradable/non-bioabsorbable material.
  • the active agent matrix can include or be formed of a biodegradable/bioabsorbable material.
  • the electrospun material can be or include polyamide.
  • the electrospun material can be or include polyurethane.
  • the polyurethane can be formulated as either a hydrophilic or hydrophobic variety of polyurethane depending on the ratios and types of isocyanate groups, polyols, chain extenders, etc. that are incorporated into the polyurethane polymer.
  • the polyurethane can be a hydrophilic polyurethane, whereas in other examples the polyurethane can be a hydrophobic polyurethane.
  • the polyurethane can be a thermoplastic polyurethane.
  • the polyurethane can be a polyether-based polyurethane.
  • the polyurethane can be a polyester-based polyurethane.
  • the electrospun material can be or include polyvinyl alcohol. In other examples, the electrospun material can be or include polyvinylpyrollidone. In other examples, the electrospun material can be or include polylactic acid. In other examples, the electrospun material can be or include polyglycolic acid. In other examples, the electrospun material can be or include polycarbonate. In other examples, the electrospun material can be or include polyethylene. In other examples, the electrospun material can be or include polypropylene. In other examples, the electrospun material can be or include polyethylene oxide. In other examples, the electrospun material can be or include polystyrene. In other examples, the electrospun material can be or include collagen.
  • the active agent matrix can have a combination of a density, a thickness, and an ocular surface area that is configured to hold and retain an active agent composition prior to application of the device to the eye, and deliver an effective dose of an active agent within 30 minutes of application of the device to the eye.
  • hold and retain it is meant that the active agent matrix is configured to hold and retain a predetermined volume or threshold volume of a desired active agent composition without leaking, dripping, or otherwise prematurely releasing the active agent from the active agent matrix prior to application of the device to an eye of a subject.
  • the active agent matrix can be configured to facilitate loading of the active agent composition to the active agent matrix, retaining the active agent composition without leaking, dripping, or otherwise prematurely releasing the active agent, and delivering the active agent within a predetermined delivery period of application of the device to the eye.
  • the active agent matrix can have a variety of suitable densities.
  • the active agent matrix can have a density of from about 0.15 grams/cubic centimeter (cc) to about 0.4 grams/cc prior to loading with the active agent composition.
  • the active agent matrix can have a density of from about 0.18 g/cc to about 0.35 g/cc prior to loading the active agent composition.
  • the active agent matrix can have a density of from about 0.2 g/cc to about 0.31 g/cc prior to loading the active agent composition.
  • the active agent matrix can also have a variety of thicknesses.
  • the active agent matrix can have a thickness of from about 250 ⁇ to about 600 ⁇ prior to loading with the active agent composition. In yet other examples, the active agent matrix can have a thickness of from about 300 ⁇ to about 500 ⁇ prior to loading with the active agent composition. In still other examples, the active agent matrix can have a thickness of from about 350 ⁇ to about 450 ⁇ prior to loading with the active agent composition.
  • the post-loading thickness of the active agent matrix can typically be greater than the pre-loading thickness of the active agent matrix. For example, in some cases, the post-loading thickness can be from about 2 times to about 6 times the pre-loading thickness. In yet other examples, the post-loading thickness can be from about 3 times to about 5 times the pre-loading thickness.
  • the active agent matrix can have a variety of ocular surface areas or ocular interface areas (i.e. the area of the active agent matrix that interfaces with or otherwise faces toward the eye when the device/matrix is in use).
  • the ocular surface area can be a scleral surface area or scleral interface area.
  • the ocular surface area of the active agent matrix can be from about 50 mm 2 to about 300 mm 2 . In some additional examples, the ocular surface area of the active agent matrix can be from about 75 mm 2 to about 250 mm 2 .
  • the ocular surface area of the active agent matrix can be from about 100 mm 2 to about 200 mm 2 .
  • the combination of the density, thickness, and ocular surface area of the active agent matrix can generally provide a loading capacity to hold and retain at least 50 ⁇ , at least 100 ⁇ , or at least 150 of active agent composition.
  • the active agent matrix can have a loading capacity to hold and retain from about 50 to about 5000 ⁇ of the active agent composition prior to application.
  • the active agent matrix can have a loading capacity to hold and retain from about 100 ⁇ to about 1000 ⁇ of the active agent composition prior to application.
  • the active agent matrix can have a loading capacity to hold and retain from about 150 ⁇ to about 500 ⁇ of the active agent composition prior to application. In some specific examples, the active agent matrix can have a loading capacity to hold and retain from about 120 ⁇ to about 300 ⁇ of active agent composition prior to application.
  • the active agent matrix can hold and retain at least 99%, at least 98%, at least 95%, or at least 90% of a target volume of the active agent composition loaded thereto for a period of at least 30 seconds. In some examples, the active agent matrix can hold and retain at least 99%, at least 98%, at least 95%, or at least 90% of a target volume of the active agent composition loaded thereto for a period of at least 60 seconds. In other examples, the active agent matrix can hold and retain at least 99%, at least 98%, at least 95%, or at least 90% of a target volume of the active agent composition loaded thereto for a period of at least 5 minutes.
  • the active agent matrix can hold and retain at least 99%, at least 98%, at least 95%, or at least 90% of a target volume of the active agent composition loaded thereto for a period of at least 10 minutes. In still other examples, the active agent matrix can hold and retain at least 99%, at least 98%, at least 95%, or at least 90% of a target volume of the active agent composition loaded thereto for a period of at least 30 minutes, at least 60 minutes, or at least 120 minutes. This assumes that the active agent matrix is not interfaced with a surface, material, or medium similar to the active agent matrix or otherwise configured to similarly or preferentially hold and retain the active agent composition as compared to the active agent matrix.
  • the active agent composition can be pre-loaded into the active agent matrix and sealed in a container to provide added retentiveness or shelf-life for the active agent composition in the matrix.
  • the pre-loaded active agent matrix can be covered by a release liner, interfaced with an impermeable or minimally permeable surface, or the like to help maximize the retention of the active agent composition within the active agent matrix.
  • the active agent matrix can hold and retain a target volume, or at least 95%, 90%, or 80% of the target volume, of the active agent composition for a period of at least 1 month at ambient temperature without leaking, dripping, or otherwise prematurely releasing the active agent composition.
  • the active agent matrix can hold and retain a target volume, or at least 95%, 90%, or 80% of the target volume, of the active agent composition for a period of at least 3 months at ambient temperature without leaking, dripping, or otherwise prematurely releasing the active agent composition.
  • the active agent matrix can hold and retain a target volume, or at least 95%, 90%, or 80% of the target volume, of the active agent composition for a period of at least 6 months at ambient temperature without leaking, dripping, or otherwise prematurely releasing the active agent composition.
  • One way to measure the pre-application retentiveness of the active agent matrix for the active agent composition is to load the active agent matrix with the target volume of the active agent composition and record the weight.
  • the active agent matrix can be weighed again to determine any changes in mass over time.
  • the target volume can be from about 50 to about 5000 of the active agent composition. In other examples, the target volume can be from about 100 to about 1000 of the active agent composition. In yet other examples, the target volume can be from about 150 ⁇ to about 500 ⁇ of the active agent composition. In still other examples, the target volume can be from about 120 ⁇ to about 300 ⁇ of active agent composition.
  • the composition of the active agent matrix in combination with the density, thickness, and ocular surface area of the active agent matrix can typically facilitate rapid loading of the active agent composition into the active agent matrix.
  • the composition of the active agent matrix and the formulation of the active agent composition can be sufficiently compatible to facilitate rapid loading (e.g. hydrophilic matrix and hydrophilic formulation, hydrophobic matrix and hydrophobic formulation, etc.)
  • the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 150 ⁇ of the active agent composition within 10 minutes.
  • the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 150 ⁇ of the active agent composition within 5 minutes.
  • the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 150 ⁇ of the active agent composition within 2 minutes.
  • the active agent matrix can be sufficiently stable to maintain rapid loading of the active agent composition after storage of the active agent matrix in a dry state at ambient conditions for a prolonged period, and optionally after sterilization of the active agent matrix.
  • the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 140 ⁇ of the active agent composition within 2 minutes after a storage period of at least 3 months in a dry state and at ambient conditions.
  • the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 140 ⁇ of the active agent composition within 2 minutes after a storage period of at least 6 months in a dry state and at ambient conditions.
  • the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 140 ⁇ of the active agent composition within 2 minutes after a storage period of at least 12 months in a dry state and at ambient conditions. In yet other examples, the active agent matrix can be configured to passively absorb at least 100 ⁇ , at least 120 ⁇ , or at least 140 of the active agent composition within 2 minutes after a storage period of at least 24 months in a dry state and at ambient conditions.
  • the composition of the active agent matrix in combination with the density, thickness, and ocular surface area of the active agent matrix can typically facilitate rapid delivery of an effective dose of the active agent to the eye.
  • the active agent matrix can be configured to deliver the effective dose within 30 minutes. In other examples, the active agent matrix can be configured to deliver the effective dose within 20 minutes. In yet other examples, the active agent matrix can be configured to deliver the effective dose within 10 minutes. In still other examples, the active agent matrix can be configured to deliver the effective dose within 5 minutes.
  • the effective dose is from about 5 wt% to about 50 wt% of the active agent loaded into the active agent matrix.
  • the effective dose can be from 0.5 mg to 5 mg of that active agent.
  • the effective dose is from about 1 wt% to about 20 wt% of the active agent loaded into the active agent matrix.
  • the effective dose is from about 8 wt% to about 40 wt% of the active agent loaded into the active agent matrix.
  • the effective dose is from about 10 wt% to about 30 wt% of the active agent loaded into the active agent matrix.
  • the effective dose can be an amount from about 0.01 mg to about 100 mg of the active agent. In other examples, the effective dose can be an amount from about 0.05 mg to about 0.1 mg. In yet other examples, the effective dose can be an amount from about 0.1 mg to about 1 mg. In additional examples, the effective dose can be an amount from about 1 mg to about 10 mg, from about 5 mg to about 15 mg, or from about 10 mg to about 20 mg. In still other examples, the effective dose can be an amount from about 20 mg to about 100 mg. In yet other examples, the effective dose can be from about 0.1 mg to about 0.5 mg. In still other examples, the effective dose can be an amount from about 0.2 mg to about 0.4 mg.
  • the effective dose can be from about 5 vol% to about 50 vol% of the active agent composition or target volume loaded into the active agent matrix.
  • the effective dose can be from 5 to 50 of that active agent composition.
  • the effective dose is from about 1 vol% to about 20 vol% of the active agent composition or target volume loaded into the active agent matrix.
  • the effective dose is from about 8 vol% to about 40 vol% of the active agent composition or target volume loaded into the active agent matrix.
  • the effective dose is from about 10 vol% to about 30 vol% of the active agent composition or target volume loaded into the active agent matrix.
  • the active agent matrix can be sufficiently stable to maintain rapid delivery of an active agent composition that is subsequently loaded to the active agent matrix after storage of the active agent matrix in a dry state at ambient conditions for a prolonged period, and optionally after sterilization of the active agent matrix.
  • the active agent matrix can be configured to passively deliver an effective dose of at least 10 wt%, at least 20 wt%, or at least 40 wt% of the loaded active agent composition within 10 minutes of application after a storage period of at least 3 months in a dry state and at ambient conditions.
  • the active agent matrix can be configured to passively deliver an effective dose of at least 10 wt%, at least 20 wt%, or at least 40 wt% of the loaded active agent composition within 10 minutes of application after a storage period of at least 6 months in a dry state and at ambient conditions. In other examples, the active agent matrix can be configured to passively deliver an effective dose of at least 10 wt%, at least 20 wt%, or at least 40 wt% of the loaded active agent composition within 10 minutes of application after a storage period of at least 12 months in a dry state and at ambient conditions.
  • the active agent matrix can be configured to passively deliver an effective dose of at least 10 wt%, at least 20 wt%, or at least 40 wt% of the loaded active agent composition within 10 minutes of application after a storage period of at least 24 months in a dry state and at ambient conditions.
  • the effective dose can depend on the active agent employed and the type/severity of the condition being treated.
  • the non-invasive ocular delivery device can be used to deliver a large range of active agents. Generally, any active agent that is suitable for topical administration to the eye can be used in the non-invasive ocular drug delivery device.
  • Non-limiting examples can include a steroid, an antimicrobial agent, an immunosuppressive agent, a non-steroidal anti-inflammatory agent, an anti- angiogenic agent, a vasoconstrictive agent, an antihistamine, a glaucoma agent (e.g.
  • the non-invasive ocular delivery device can be adapted as an active delivery device. Otherwise, the non-invasive ocular delivery device can generally be a passive delivery device. As such, in some examples, the non-invasive ocular delivery device does not include an electrode or other electrical components used in an active delivery device. In some specific examples, the non-invasive ocular delivery device does not include an electrode or other electrical components adapted specifically for iontophoretic administration of the active agent.
  • the non-invasive ocular drug delivery device can include an electrode and/or other electrical components to adapt the device for active administration of the active agent, such as iontophoretic delivery, electroporation, sonoporation, the like, or combinations thereof.
  • the active agent can be or include a steroid.
  • the active agent can include fluocinolone, difluprednate, fluorometholone, loteprednol, dexamethasone, prednisolone, medrysone, triamcinolone, rimexolone, the like, a salt thereof, an ester thereof, a hydrate thereof, derivatives thereof, or a combination thereof.
  • the active agent can be or include dexamethasone sodium phosphate (DSP).
  • the active agent can be or include triamcinolone acetonide sodium phosphate.
  • the active agent can be or include an antimicrobial agent.
  • the active agent can include an antibacterial agent, such as besifloxacin, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, gatifloxacin, tobramycin, gentamicin, polymyxin B, trimethoprim, bacitracin, neomycin, gramicidin, azithromycin, erythromycin, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • an antibacterial agent such as besifloxacin, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, gatifloxacin, tobramycin, gentamicin, polymyxin B, trimethoprim, bacitracin, neomycin, gramicidin, azithromycin, erythromycin, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can include an antiviral agent, such as fluorometholone, ganciclovir, trifluridine, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can include an antifungal agent, such as clotrimazole, econazole, ketoconazole, miconazole, bifonazole, isoconazole, neticonazole, sertaconazole, fluconazole, fosfluconazole, itraconazole, posaconazole, voriconazole, thiabendazole, nystatin, amphotericin B, natamycin, terbinafine, butenafine, amorolfine, caspofungin, micafungin, anidulafungin, flucytosine, gresiofulvin, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can be or include an immunosuppressive agent.
  • the active agent can include cyclophosphamide, chlorambucil, azathioprine, methotrexate, mycophenolic acid, cyclosporine, tacrolimus, infliximab, adalimumab, rapamycin, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can be or include a non-steroidal antiinflammatory agent.
  • the active agent can include ketorolac tromethamine, flurbiprofen, diclofenac, bromfenac, nepafenac, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can be or include an anti-angiogenic agent.
  • the active agent can include ranibizumab, bevacizumab, pegaptanib, aflibercept, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can include a vasoconstrictive agent.
  • the active agent can include naphazoline, tetrahydrozoline, phenylethylamine, epinephrine, norepinephrine, dopamine, dobutamine, colterol, ethylnorepinephrine, isoproterenol, isotharine, metaproterenol, terbutaline, metearaminol, phenylephrine, tyramine, hydroxy amphetamine, ritodrine, prenalterol, methoxyamine, albuterol, amphetamine, methamphetamine, benzphetamine, ephedrine, phenylpropanolamine, methentermine, phentermine, fenfluramine, propylhexedrine, diethylpropion, phenmetrazine, phendimetrazine, the like, salts thereof, esters thereof, a hydrate thereof, derivatives
  • the active agent can be or include an antihistamine.
  • the antihistamine can include emedastine difumarate, epinastine, azelastine, ketotifen, olopatadine, bepotastine, alcaftadine, cetirizine, chlorpheniramine maleate, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can be or include a glaucoma agent.
  • the glaucoma agent can include timolol, brimonidine, brinzolamide, travoprost, tafluprost, dorzolamide, apraclonidine, latanoprost, bimatoprost, levobunolol, betaxolol, carbachol, epinephrine, physostigmine, carbachol, pilocarpine, acetylcholine, carbachol, carteolol, metipranolol, echothiophate iodide, dipivefrin, unoprostone, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can be or include an anesthetic.
  • the anesthetic can include lidocaine, proparacaine, tetracaine, bupivacaine, benoxinate, the like, salts thereof, esters thereof, a hydrate thereof, derivatives thereof, or combinations thereof.
  • the active agent can be or include an analgesic.
  • the analgesic can include a steroid listed above, a non-steroidal antiinflammatory agent listed above, an immunomodulator (e.g. cyclosporine, dapsone, tacrolimus, sirolimus, mitomycin, antilymphocyte serum, anti-T cell antibody, gamma globulin, cyclophosphamide, chlorambucil, methotrexate, 5-fluorouracil, azathioprine, or the like), an opioid (e.g.
  • the active agent can be present in the active agent composition in various amounts, depending on the desired dosage, the specific active agent being employed, the condition to be treated, etc. In some examples, the active agent can be present in the active agent composition in an amount from about 0.005 w/v% to about 25 w/v%. In other examples, the active agent can be present in the active agent composition in an amount from about 0.0001 w/v% to about 1 w/v%. In yet other examples, the active agent can be present in the active agent composition in an amount from about 0.01 w/v% to about 10 w/v%.
  • the active agent can be present in the active agent composition in an amount from about 1 w/v% to about 10 w/v%, from about 5 w/v% to about 15 w/v%, or from about 10 w/v% to about 20 w/v%.
  • the active agent composition can also vary depending on the particular active agent being administered.
  • the active agent composition can be a hydrophilic composition.
  • the active agent composition can be a lipophilic composition.
  • the active agent composition can be an emulsion, such as an oil-in-water emulsion or a water-in-oil emulsion.
  • the active agent composition can include micelles, liposomes, molecular carriers that are charged or soluble in water but that can be loaded with water- insoluble active agents (e.g. cyclodexrins, etc.), the like, or combinations thereof.
  • the active agent composition can include water.
  • the active agent composition can be substantially free of solvents other than water.
  • the active agent composition can include a lubricant such as polyethylene glycol (PEG) (e.g. PEG-200, PEG-300, PEG-400), propylene glycol, glycerin, mineral oil, the like, or combinations thereof.
  • PEG polyethylene glycol
  • the active agent composition can include a preservative, such as benzalkonium chloride, cetrimonium, chlorbutanol, polyquaternium-1, polyhexamethylene biguanide, sodium perborate, stabilized oxychloro complex, the like, or combinations thereof.
  • the active agent composition can include a chelating agent, such as edetate disodium dihydrate, edetic acid, ethylene diamine, porphine, the like, or combinations thereof.
  • the active agent composition can include phosphate-buffered saline (PBS), Dulbecco's PBS, Alsever's solution, Tris- buffered saline (TBS), water, balanced salt solutions (BSS), such as Hank's BSS,
  • PBS phosphate-buffered saline
  • Dulbecco's PBS Dulbecco's PBS
  • Alsever's solution Tris- buffered saline
  • BSS balanced salt solutions
  • the active agent composition can generally have a pH of from about 5 to about 8. In some specific examples, the active agent composition can have a pH of from about 6 to about 8, or from about 6.5 to about 7.5.
  • Suitable pH adjusters can be used to adjust the pH, which can include a number of acids, bases, and combinations thereof, such as hydrochloric acid, phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like
  • the active agent composition can typically have a tonicity of from about 200 milliosmoles (mOsm)/kilogram (kg) to about 750 mOsm/kg. In some specific examples, the active agent composition can have a tonicity of from about 250 mOsm/kg to about 450 mOsm/kg, or from about 450 mOsm/kg to about 750 mOsm/kg. In some additional examples, the active agent composition can have a tonicity of from about 250 mOsm/kg to about 350 mOsm/kg, or from about 277 mOsm/kg to about 310 mOsm/kg.
  • the active agent composition can include a tonicity agent, such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, mannitol, sorbitol, dextrose, glycerin, propylene glycol, ethanol, trehalose, the like, or combinations thereof.
  • a tonicity agent such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, mannitol, sorbitol, dextrose, glycerin, propylene glycol, ethanol, trehalose, the like, or combinations thereof.
  • the active agent composition can typically be particulate-matter-free or substantially particulate-matter-free.
  • the term "particulate-matter- free” or its grammatical equivalents such as “particle free” refer to the state in which the active agent composition meets the USP requirements for particulate matter in ophthalmic compositions. See for example, USP, Chapter 789.
  • the ophthalmic composition can include less than or equal to 50 particles per milliliter (mL) having a particle diameter greater than or equal to 10 ⁇ .
  • the ophthalmic composition can include less than or equal to 5 particles per mL having a particle diameter greater than or equal to 25 ⁇ . These values can be determined using the Light Obscuration Particle Count Test, the Microscopic Particle Count Test, or both, as described in USP, Chapter 789.
  • the active agent composition can be free or substantially free of a preservative.
  • preservatives can include benzalkonium chloride, benzethonium chloride, parahydroxybenzoates, phenylmercuric acetate, cetrimonium, chlorobutanol, phenylethylalcohol, polyquaternium-1, polyhexamethylene biguanide, sodium perborate, stabilized oxychloro complex, and the like.
  • the active agent composition is free or substantially free of an antioxidant.
  • Non-limiting examples of antioxidants can include sodium metabisulphite, sodium formaldehyde sulphoxylate, sodium sulphite, N-acetylcarnosine, L-camosine, L-glutathione, cysteine ascorbate, L-cysteine, and the like.
  • the active agent composition can be free or substantially free of a buffering agent, such as phosphate-buffered saline, TRIS- buffered saline, and the like.
  • the active agent composition can be free or substantially free of a polymer (e.g. a thickening agent, a gelling agent, or the like), such as cellulosic compounds (e.g.
  • the active agent composition does not include a surface-active agent or surfactant.
  • surface-active agents can include non-ionic surfactants (e.g. sorbitan oleates, polysorbates, polyoxyethylene ethers, etc.), anionic surfactants, and cationic surfactants.
  • the active agent composition does not include a cyclodextrin, or the like. In some examples, the active agent composition does not include a hydrocarbon, a sterol (e.g. cholesterol), or both. In some examples, the active agent composition does not include one or more of a preservative, an antioxidant, a buffering agent, a polymer, a surface-active agent, a cyclodextrin, a hydrocarbon, or a sterol. In some examples, the active agent composition does not include two or more of a preservative, an antioxidant, a buffering agent, a polymer, a surface-active agent, a cyclodextrin, a hydrocarbon, or a sterol.
  • the active agent composition does not include three or more of a preservative, an antioxidant, a buffering agent, a polymer, a surface-active agent, a cyclodextrin, a hydrocarbon, or a sterol. In some examples, the active agent composition does not include one or more of a polymer, a dendrimer, a micelle, a liposome, a nanoparticle, a surface-active agent, or the like.
  • the active agent composition or ophthalmic composition can include dexamethasone phosphate, or a salt thereof (e.g. sodium salt, for example). Additionally, the ophthalmic composition can include dexamethasone. However, dexamethasone is typically not present in an amount greater than 0.5 wt% relative to dexamethasone phosphate, or a salt thereof.
  • the active agent composition can also include water. The pH of the active agent composition can typically be from about 5 to about 8 and the tonicity can typically be from about 200 mOsm/kg to about 760 mOsm/kg.
  • the dexamethasone phosphate, or salt thereof can typically be present in the composition in a variety of amounts.
  • the dexamethasone phosphate, or salt thereof can be present in the composition in an amount from about 1 wt% to about 25 wt%.
  • the dexamethasone phosphate, or salt thereof can be present in the composition in an amount greater than 4 wt%.
  • the dexamethasone phosphate, or salt thereof can be present in the composition in an amount greater than 10 wt%.
  • the dexamethasone phosphate, or salt thereof can be present in the composition in an amount from about 1 wt% to about 3 wt%. In other examples, the dexamethasone phosphate, or salt thereof, can be present in the composition in an amount from about 3 wt% to about 6 wt%. In some other examples, the dexamethasone phosphate, or salt thereof, can be present in the composition in an amount from about 6 wt% to about 10 wt%. In still other examples, the dexamethasone phosphate, or salt thereof, can be present in the composition in an amount from about 10 wt% to about 15 wt%. In yet other examples, the dexamethasone phosphate, or salt thereof, can be present in the composition in an amount from about 12 wt% to about 18 wt%.
  • the carrier of the active agent composition can provide good stability for the dexamethasone phosphate, or salt thereof.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage at ambient temperature for a period of 3 months or less.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage at ambient temperature for a period of 3 months or less.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage at ambient temperature for a period of 6 months or less. In some examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage at ambient temperature for a period of 6 months or less. In other examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage at ambient temperature for a period of 9 months or less.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2°
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 6 months or less. In other examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 12 months or less. In some examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2°
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 18 months or less. In some examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 18 months or less.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 24 months or less. In some examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 24 months or less.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 36 months or less. In some examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 36 months or less.
  • the amount of dexamethasone present in the active agent composition does not exceed or is not more than 0.5 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 49 months or less. In some examples, the amount of dexamethasone present in the active agent composition does not exceed or is not more than 1.0 wt% relative to dexamethasone phosphate, or salt thereof, after storage a temperature of from about 2° C to about 8° C for a period of 49 months or less.
  • the active agent composition including dexamethasone phosphate, or a salt thereof can generally have a pH of from about 5 to about 8. However, in some examples, the active agent composition can have a pH of from about 6 to about 9. In other examples, the pH can be from about 6.5 or 6.6 to about 7.4 or 7.5. In some examples, the active agent composition can include a suitable pH adjuster, such as hydrochloric acid, phosphoric acid, sodium hydroxide, the like, or a combination thereof.
  • a suitable pH adjuster such as hydrochloric acid, phosphoric acid, sodium hydroxide, the like, or a combination thereof.
  • the tonicity of the active agent composition including dexamethasone phosphate, or a salt thereof can be influenced by a number of factors, such as the amount of dexamethasone phosphate, or salt thereof, present in the composition, the presence of a tonicity agent, etc.
  • the tonicity of the active agent composition can typically be from about 200 mOsm/kg to about 760 mOsm/kg. In some specific examples, the tonicity can be from about 200 mOsm/kg to about 300 mOsm/kg. In other examples, the tonicity can be from about 300 mOsm/kg to about 350 mOsm/kg.
  • the tonicity of the composition can be from about 325 mOsm/kg to about 375 mOsm/kg or 400 mOsm/kg. In still other examples, the tonicity can be from about 400 mOsm/kg to about 500 mOsm/kg. In yet additional examples, the tonicity can be from about 500 mOsm/kg to about 600 mOsm/kg.
  • the composition can include a tonicity agent, such as those described elsewhere herein. In some examples, where the active agent is dexamethasone sodium phosphate (DSP), the amount of DSP present in the composition can provide the desired tonicity without the need for an additional tonicity agent. As such, in some examples, the composition does not include a tonicity agent.
  • the composition including dexamethasone phosphate, or a salt thereof can further include a chelating agent.
  • a chelating agent can include edetate disodium dihydrate, edetic acid, ethylene diamine, porphine, the like, or combinations thereof.
  • a chelating agent is included in the active agent composition, it can typically be present in an amount of from about 0.001% w/v to about 0.1 % w/v, or from about 0.005% w/v to about 0.05% w/v.
  • the composition does not include a chelating agent.
  • dexamethasone, or salt thereof can be sourced or prepared to have a very low concentration of metal ions.
  • the container can impart a very low amount of metal ions to the composition.
  • the container can be a plastic container, a glass container with an interior plastic coating, or the like, that does not impart significant amounts of metal ions.
  • a chelating agent is not always desirable or necessary.
  • the active agent composition including dexamethasone phosphate, or a salt thereof can be an active agent solution.
  • the active agent composition is not a gel, an ointment, a suspension, an emulsion, or the like.
  • the active agent composition can include limited amounts of excipients.
  • an "excipient" refers to components in the active agent composition other than the active agent (e.g. dexamethasone phosphate, or salt thereof) and the predominant carrier (e.g. water).
  • the total amount of excipients in the ophthalmic composition can be less than 10% w/v.
  • the total amount of excipients in the ophthalmic composition can be less than 5% w/v, less than 3% w/v, or less than l % w/v.
  • the ophthalmic composition can consist of, or consist essentially of, dexamethasone phosphate, or a salt thereof, a chelating agent, water, optionally a tonicity agent, and optionally a pH adjuster.
  • the chelating agent can be disodium edetate.
  • the composition can include dexamethasone sodium phosphate (DSP).
  • the active agent composition can be supplied in an enclosed container, which can be a sterile container. Where this is the case, the container can include any suitable container.
  • the container can be made of a material such as glass, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, the like, or a combination thereof.
  • the container can have a volume of from about 0.1 ml to about 10 ml, from about 0.5 ml to about 5 ml, or from about 0.75 ml to about 1.5 ml.
  • the amount of active agent composition supplied in the container can include from about 1 mg to about 2500 mg active agent (e.g. dexamethasone phosphate, for example). In other examples, the amount of active agent composition supplied in the container can include from about 10 mg to about 50 mg, from about 50 mg to about 500 mg, from about 500 mg to about 1000 mg, or from about 1000 mg to about 2000 mg active agent.
  • active agent e.g. dexamethasone phosphate, for example.
  • the amount of active agent composition supplied in the container can include from about 10 mg to about 50 mg, from about 50 mg to about 500 mg, from about 500 mg to about 1000 mg, or from about 1000 mg to about 2000 mg active agent.
  • the concentration of active agent in the composition or solution can cause the composition or solution to turn from substantially colorless to colored.
  • the color of the solution with an active agent e.g. dexamethasone phosphate
  • the composition or solution can have a color with a wavelength ranging from about 560 nm to about 590 nm.
  • the composition or solution can have a color with a frequency interval ranging from about 510 THz to about 540 THz.
  • the composition or solution can have color properties falling within both of the above-recited wavelength and frequency ranges, including any point or specific number in either and any combination thereof.
  • the active agent composition can be further supplied with or in the ocular drug delivery device described herein.
  • some or all of the composition can be included in the ocular drug delivery device, the container, or a combination thereof.
  • a portion of the active agent composition can be pre-loaded into the ocular drug delivery device, and another portion can be loaded into the container for use in re-loading the ocular drug delivery device after administration of the pre-loaded portion.
  • the active agent composition can be initially contained within the container for subsequent transfer to load the ocular drug delivery device.
  • the ocular drug delivery device can be pre-loaded with the active agent composition and supplied without a separate container including additional active agent composition.
  • the device can include at least 50 ⁇ , at least 100 ⁇ , or at least 150 of the active agent composition pre-loaded therein. In some examples, the device can include from about 50 to about 5000 ⁇ of the active agent composition pre-loaded therein. In other examples, the device can include from about 100 ⁇ to about 1000 ⁇ of the active agent composition pre-loaded therein. In yet other examples, the device can include from about 150 ⁇ to about 500 ⁇ of the active agent composition pre-loaded therein. In some specific examples, the device can include from about 120 ⁇ to about 300 ⁇ of the active agent composition preloaded therein.
  • the non-invasive ocular drug delivery device and/or the active agent composition can be sterile.
  • a number of sterilization procedures can be used to sterilize the device and/or the active agent composition.
  • Non-limiting examples of sterilization procedures can include EtO sterilization, gamma sterilization, E-beam sterilization, x-ray sterilization, vaporized hydrogen peroxide (VHP) sterilization, steam sterilization, dry-heat sterilization, filtration, the like, or combinations thereof.
  • the active agent composition can be preloaded into the non-invasive ocular delivery device. Where this is the case, it is possible to terminally sterilize the device and the composition.
  • the active agent composition can be pre-loaded into the device, but the composition and the device can be individually or aseptically sterilized. In yet other examples, the active agent composition can be loaded into the device at the time of use. In such examples, the composition and device are typically sterilized individually or aseptically.
  • the device can include a loading base or dock.
  • the loading base can be shaped to removably mate with or engage the housing of the device to facilitate loading of the active agent composition into the active agent matrix.
  • the loading base can include a port to introduce the active agent composition into or onto the loading base.
  • the loading base can include a reservoir, basin, or channel fluidly connected to the port to collect and hold the active agent composition prior to and/or during loading of the active agent composition into the non-invasive ocular drug delivery device.
  • the reservoir, basin, or channel can be positioned to interface with the active agent matrix to facilitate passive absorption of the active agent composition into the active agent matrix of the device.
  • the present disclosure also describes a method of manufacturing a noninvasive ocular drug delivery device.
  • the method can include preparing a housing that is adapted to couple to an eye of a subject.
  • the method can further include forming an active agent matrix from an electrospun material.
  • the active agent matrix can have a combination of a density, a thickness, and an ocular surface area configured to hold and retain an active agent composition prior to application of the device to the eye. Further, the combination of the density, the thickness, and the ocular surface area can be configured to deliver an effective dose of the active agent within 30 minutes of application of the device to the eye.
  • the active agent matrix can be coupled to the housing in any suitable way.
  • the present disclosure also describes a method of treating a subject with an ocular condition.
  • the method can include coupling a non-invasive ocular drug delivery device, as described herein, to an eye of a subject.
  • the method can further include passively administering an active agent from the device to an eye of the subject during a continuous dosing period to provide a threshold dose of the active agent to the eye within 30 minutes of coupling the device to the eye.
  • the method of treating a subject can be used to treat a variety of ocular conditions.
  • any ocular disease or condition that can be reasonably treated with the present device and method is considered within the scope of the present disclosure.
  • Non-limiting examples can include uveitis, age-related macular degeneration (AMD), macular edema, a cataract, diabetic retinopathy, glaucoma, dry eye, post-operation inflammation, eye infection, allergic conjunctivitis, presbyopia, corneal wound healing, ocular pain, the like, or combinations thereof.
  • the device can be adapted to continuously deliver active agent to the eye during the entire duration of the continuous dosing period.
  • the active agent matrix can typically include an excess of the active agent composition and active agent, although this is not required.
  • the method can be adapted to terminate passive delivery of the threshold dose at a predetermined time point by removing the non-invasive ocular drug delivery device from the eye.
  • the threshold dose can include a sufficient amount of the active agent to deliver the active agent to the posterior segment of the eye, such as the retina, choroid, vitreous humor, optic nerve, or a combination thereof. Therefore, the method can be adapted to deliver active agent to both the anterior and posterior segments of the eye via topical, passive administration of the active agent to the surface of the eye.
  • passive administration can deliver the active agent to the eye via the sclera. In some examples, passive administration can minimize delivery of the active agent to the eye via the cornea.
  • the method can also include administering an anesthetic to the eye concurrently with or prior to coupling the non-invasive ocular drug delivery device to the eye of the subject. In some cases, this can increase the comfort of the subject during treatment.
  • suitable anesthetics can be used. Non-limiting examples can include lidocaine, proparacaine, tetracaine, the like, or combinations thereof.
  • a method for treating a subject with an ocular condition responsive to steroid therapy, but that minimizes an increase in IOP.
  • the method can include administering a threshold dose of a steroid to an eye of the subject in a therapeutically effective regimen that minimizes an intraocular pressure (IOP) increase above a baseline level.
  • IOP intraocular pressure
  • the present method can be used to administer steroids to an eye of a subject, such as a glaucoma patient, a pre-glaucoma patient, or other patient with IOP concerns, without substantially increasing the IOP in the treated eye.
  • the present method can be used to treat any ocular condition that is responsive to steroid therapy.
  • Non-limiting examples can include uveitis, age- related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, dry eye, post-operative inflammation, eye infection, allergic conjunctivitis, corneal trauma, infiltrative keratitis, staphylococcal marginal keratitis, posterior blepharitis, ocular herpetic disease, cystoid macular edema (CME), diabetic retinopathy, Behcet's disease, ocular pain, or a combination thereof.
  • any one, or a combination, of these conditions can be treated in a subject, even where IOP is a concem, because the present methods can be used to administer steroids to the eye without substantially increasing IOP.
  • administration of the steroid can be performed non-invasively via topical administration to the eye.
  • Topical administration can be performed in a number of ways.
  • the steroid can be topically applied to the eye via a solution, a suspension, an emulsion, a gel, an ointment, a film, a contact lens, a device, the like, or a combination thereof.
  • topical administration of the steroid can include administering the threshold dose of the steroid to the sclera of the eye while minimizing topical administration to the cornea.
  • this can be accomplished by employing a fluidic seal and/or barrier around the cornea of the eye so as to minimize or eliminate direct topical administration of the steroid to the cornea such that the steroid is not delivered to the eye via the cornea.
  • the steroid can be administered via active or passive administration techniques. In either case, the steroid can be delivered to both the anterior segment and posterior segment of the eye.
  • the present method can include non-invasive topical administration of a steroid to an eye of a subject to deliver the steroid to both the anterior segment and the posterior segment of the eye.
  • the anterior segment of the eye can include the cornea, the iris, the ciliary body, the lens, the sclera, the conjunctiva, etc.
  • the posterior segment can include the vitreous humor, the retina, the choroid, the optic nerve, etc.
  • the administration of the steroid can be performed via passive administration.
  • the steroid can be topically administered to the eye and allowed to passively diffuse into the eye.
  • passive administration can employ penetration enhancers or other suitable delivery aids to increase the rate at which the steroid is delivered to the eye.
  • passive administration does not employ penetration enhancers or the like.
  • Passive administration can also be non-invasive administration that excludes the use of devices configured to pierce or puncture an outer surface of the eye, or similar.
  • the administration of the steroid can be performed via active administration. Active administration can employ iontophoresis, electroporation, ultrasound, microneedles, the like, or a combination thereof to actively deliver the steroid to the eye.
  • administration can be non-invasive.
  • Non-invasive administration excludes the use of microneedles and other devices configured to pierce or puncture an outer surface of the eye, or similar.
  • drug delivery methods employing iontophoresis, electroporation, ultrasound, or microneedles are generally known in the art, such methods will not be discussed in detail. However, it is to be understood that such methods, and other similar methods, are considered within the scope of the present disclosure.
  • active administration can include iontophoretic administration of the steroid and/or other active agent to the eye.
  • active administration can include electroporation or electroporation- facilitated delivery of the steroid and/or other active agent to the eye.
  • active administration can include ultrasound or ultrasound-facilitated delivery of the steroid and/or other active agent to the eye.
  • active administration can employ microneedles to facilitate delivery of the steroid and/or other active agent to the eye.
  • the steroid can typically be administered during a continuous administration period. More specifically, each administration event in the therapeutically effective regimen is typically performed for a continuous or consecutive period.
  • the continuous or consecutive period can be a sufficient period of time to deliver the threshold dose of the steroid to the eye. Generally, the continuous period is less than one week. In some additional examples, the continuous period is less than or equal to 5 days, less than or equal to 3 days, or less than or equal to 1 day (i.e. 24 hours). In some specific examples, the consecutive period can be a period of from about 1 minute to about 30 minutes.
  • the consecutive period can be a period of from about 2 minutes to about 20 minutes, from about 3 minutes to about 15 minutes, from about 4 minutes to about 10 minutes, or from about 5 minutes to about 8 minutes. It is noted that the continuous or consecutive period can be adjusted based on the concentration of the therapeutic agent. For example, where a longer administration event or administration period is desired, a lower concentration of the steroid can be used. Conversely, where a shorter administration event or administration period is desired, a greater concentration of the steroid can be used.
  • each administration event can be a sufficient continuous period of time to introduce the threshold dose of the steroid to the eye.
  • the threshold dose can be considerably higher than an amount administered via an eye drop.
  • the threshold dose can deliver at least about 5 times more steroid to the eye than an eye drop.
  • the threshold dose can depend on the specific steroid being administered, the type and severity of the condition being treated, the specific individual being treated, etc.
  • the threshold dose can be an amount from about 0.1 mg to about 30 mg of the steroid, or from about
  • the threshold dose can be an amount from about 0.2 mg to about 10 mg of the steroid. In still other examples, the threshold dose can be an amount from about 0.5 mg to about 5 mg of the steroid. In some specific examples, the threshold dose can be an amount from about 0.1 mg to about 0.5 mg of the steroid. In other specific examples, the threshold dose can be an amount from about 0.2 mg to about 1 mg, about 0.3 mg to about 2 mg, or about 0.25 mg to about 1.5 mg of the steroid. In yet other specific examples, the threshold dose can be an amount from about 1 mg to about 8 mg, about 2 mg to about 6 mg, about 0.5 mg to about 4 mg, about 5 mg to about 12 mg, about 10 mg to about 20 mg, or about 15 to about 25 mg.
  • steroids can be used.
  • Non-limiting examples can include fluocinolone, difluprednate, fiuorometholone, loteprednol, dexamethasone, prednisolone, medrysone, triamcinolone, rimexolone, the like, a salt thereof, an ester thereof, a hydrate thereof, or a combination thereof.
  • the steroid can include dexamethasone, a salt thereof, an ester thereof, a hydrate thereof, or a combination thereof.
  • the steroid can include dexamethasone phosphate, dexamethasone sodium phosphate, other esters of dexamethasone, other salts of dexamethasone, a hydrate thereof, or a combination thereof.
  • the steroid can include triamcinolone, a salt thereof, an ester thereof, a hydrate thereof, or a combination thereof.
  • the steroid can include triamcinolone acetonide, triamcinolone acetonide phosphate, triamcinolone acetonide sodium phosphate, other esters of triamcinolone, other salts of triamcinolone, a hydrate thereof, or a combination thereof.
  • Administration of the threshold dose of the steroid can typically be followed by a recovery period.
  • the recovery period can be sufficient to prevent a substantial increase in IOP above a baseline level.
  • the recovery period can be at least 1 day.
  • the recovery period can be at least 2 days.
  • the recovery period can be at least 3 days.
  • the recovery period can be at least 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days.
  • the therapeutically effective regimen can include a dosing frequency of from about one administration event every 2 days to about one administration event every 10 days.
  • the therapeutically effective regimen can include a dosing frequency of from about one administration event every 3 days to about one administration event every 7 days.
  • the therapeutically effective dosing regimen can include a dosing frequency of from about one administration event every 3 days to about one administration event every 5 days for the first one or two weeks of steroid therapy.
  • a maintenance dosing period can be initiated with a dosing frequency of from one administration event about every two weeks to one administration event about every month (or four weeks), or one administration event about every 7 days to one administration event about every 10 days during the therapeutically effective dosing regimen, for example.
  • the therapeutically effective regimen can be considered a pulsatile dosing regimen.
  • the therapeutically effective dosing regimen can provide periodic threshold doses of the steroid interspersed with an adequate recovery period that minimizes an increase in an average IOP level above a baseline level or pre-dose level.
  • the therapeutically effective dosing regimen can provide an average IOP value of less than or equal to 2 mmHg above a baseline level or pre-dose level.
  • the therapeutically effective dosing regimen can provide an average IOP value of less than or equal to 1 mmHg above a baseline level or pre-dose level.
  • the therapeutically effective dosing regimen can provide an average IOP value of less than or equal to the baseline level or pre- dose level.
  • the baseline level can be the IOP level of the eye prior to commencement of the therapeutically effective regimen. It is noted that this does not necessarily mean that the IOP level never exceeds the specified levels during the therapeutically effective dosing regimen so long as the average IOP level during the regimen remains equal to or below the specified levels.
  • the therapeutically effective regimen can temporarily or transiently increase the IOP above a baseline level or pre-dose level.
  • the temporary or transient IOP increase can typically return to a level less than or equal to a baseline or pre-dose level within 48 hours or 24 hours of a single continuous administration event or a cessation of a single continuous administration event.
  • the temporary or transient IOP increase can return to level less than or equal to 1 mmHg above a baseline or pre-dose level within 48 hours or 24 hours of a single continuous administration event or a cessation of a single continuous administration event.
  • a temporary or transient IOP increase can return to a level less than or equal to a baseline or pre-dose level within about 30 minutes, 60 minutes, or 90 minutes of a single continuous administration event or a cessation of a single continuous administration event.
  • a temporary or transient IOP increase can return to a level less than or equal to 1 mmHg above a baseline or pre-dose level within about 30 minutes, 60 minutes, or 90 minutes of a single continuous administration event or a cessation of a single continuous administration event.
  • the average IOP level during the therapeutically effective dosing regimen can still remain within the ranges disclosed above.
  • a non-steroidal active agent in addition to administering a steroid, it can be beneficial to further administer a non-steroidal active agent.
  • the nonsteroidal active agent can be co-administered with the steroid in the therapeutically effective regimen.
  • the non-steroidal active agent can be administered via an alternative dosing regimen.
  • a variety of non-steroidal active agents are described elsewhere herein.
  • any suitable nonsteroidal active agent listed herein, or other suitable non-steroidal active agent can be further administered with the steroid.
  • the active agent matrix 120 includes two semicircle segments, but can include a single segment or other suitable number of segments.
  • the housing 100 includes a corneal dome 130 shaped to cover a cornea of an eye. Additionally, the housing includes a corneal seal 140 positioned about a perimeter of the corneal dome 130 to form a fluidic seal against the eye when in use to minimize fluid transport into the corneal dome 130.
  • the housing also includes a scleral flange 115 positioned to cover a portion of the sclera of an eye without covering the cornea.
  • a scleral lip or scleral seal 1 17 is disposed about a perimeter of the scleral flange 1 15.
  • Figs. 2a, 2b, and 2c illustrate an alternative example of a non-invasive ocular drug delivery device 200 having a housing 210 and an active agent matrix 220 coupled thereto.
  • the housing 200 does not include a corneal dome.
  • the cornea of the eye can be exposed to ambient conditions during use of this particular example of the device 200. Nonetheless, the device 200 still includes a corneal seal 240 to minimize fluid transport across the surface of the eye to the cornea. This can minimize surface contact of the active agent with the sensitive cornea.
  • the device 200 can also include a scleral lip or scleral seal 217 adapted to contain topical delivery of the active agent between the corneal seal 240 and the scleral seal 217.
  • Figs. 3a, 3b, 3c, and 3d illustrate yet another example of a non-invasive ocular delivery drug device 300.
  • the device 300 includes a housing 310 with an active agent matrix 320 coupled thereto. Additionally, a pressure regulator
  • the pressure regulator 350 can be marked, or include instructions, for applying device 300 to the eye and removing the device 300 from the eye.
  • segment 352 of the pressure regulator 350 can be marked for placement of device 300 on the eye, whereas segment 354 can be marked for removal of device 300 from the eye.
  • the segment 352 can form a lesser volume of the pressure regulator 350 than segment 354.
  • Fig. 4 illustrates an example of the device 300 coupled to an eye.
  • a gap 362 can be maintained between an inner surface 332 of the housing and the cornea 360 so as to minimize contact of the housing 310 with the cornea 360.
  • a distance 364 can be maintained between the perimeter of the cornea 360 and the corneal seal 340 so as to maintain a fluidic seal about the cornea and minimize fluid transport across the surface of the eye to the cornea 360.
  • Figs. 5a and 5b illustrate one example of a loading base 570 to facilitate loading of a non-invasive ocular drug delivery device 300.
  • the loading base 570 can include an injection or infusion port 572 in fluid communication with a loading reservoir 576 via channel 574.
  • the active agent composition can thus be loaded into the loading reservoir 576 by injecting the composition into the loading base 570 at the injection port 572.
  • the loading base 570 can include a guide post 579 and/or docking basin 578 to facilitate placement of the non-invasive ocular drug delivery device 300 on the loading base.
  • the docking basin 578 can mate with an ocular-interfacing portion of the non-invasive ocular drug delivery device 300 so as to facilitate loading of the active agent composition to the active agent matrix 320. Further, in some examples, the loading reservoir 576 can also flood upward into the docking basin 578 to expedite loading of the active agent matrix 320. In some examples, where the non-invasive ocular drug delivery device 300 includes a pressure regulator 350 or a port for attachment of a pressure regulator, the guide post 579 to mate with the pressure regulator 350 or associated port to facilitate intended positioning of the non-invasive ocular drug delivery device 300 on the loading base 570.
  • a non-invasive ocular drug delivery device comprising a housing configured to couple to an eye of a subject and an active agent matrix coupled to the housing, said active agent matrix comprising an electrospun material having a combination of a density, a thickness, and an ocular surface area configured to hold and retain an active agent composition prior to application of the device to the eye, and deliver an effective dose of an active agent within 30 minutes of application of the device to the eye.
  • the noninvasive ocular drug delivery device is a passive drug delivery device.
  • the housing is a monolithic unit.
  • the monolithic unit is formed from a molded elastomeric material.
  • the housing is formed from a translucent material.
  • the portion of the housing that interfaces with the eye, or otherwise faces the eye during use has an elliptical geometry.
  • the elliptical geometry has an aspect ratio (width to height) of from about 1.05: 1 to about
  • the housing comprises a corneal dome shaped to cover a cornea of the eye.
  • the corneal dome is further shaped to maintain a gap between a portion of the comea and an inner surface of the corneal dome.
  • the gap between the cornea and the inner surface of the corneal dome is at least 100 ⁇ . In some examples of the non-invasive ocular drug delivery device, the portion of the comea is at least 50% of the corneal surface area.
  • the housing comprises a corneal seal disposed about a periphery of the corneal dome to circumscribe the cornea and form a fluidic seal against the eye to minimize fluid transport into the corneal dome when in use.
  • the corneal seal is shaped to maintain a distance from a perimeter of the comea of from about 50 ⁇ to about 5000 ⁇ .
  • the housing comprises a scleral flange extending radially outward from the corneal seal.
  • the device can further include a pressure regulator operatively connected to the housing and adapted to induce negative pressure between the housing and the eye to couple the housing to the eye when in use.
  • the pressure regulator forms part of the housing.
  • the pressure regulator is adapted to reduce a pressure between the housing and the eye by an amount from about 0.1 atmospheres (atm) to about 3 atm relative to atmospheric pressure.
  • the active agent matrix is positioned to interface with a sclera of the eye, but not a cornea of the eye.
  • the active agent matrix is coupled to the housing via an adhesive.
  • the adhesive is a member selected from the group consisting of: a silicone adhesive, an epoxy adhesive, an acrylic adhesive, a polyurethane adhesive, and combinations thereof.
  • the electrospun material is a hydrophobic material.
  • the electrospun material is a hydrophilic material.
  • the electrospun material is a polyurethane material.
  • the active agent matrix is solvent-swellable to a weight of from about 2 times to about 9 times the dry weight of the active agent matrix.
  • the density of the active agent matrix is from about 0.15 grams/cubic centimeter (cc) to about 0.4 grams/cc prior to loading.
  • the thickness of the active agent matrix is from about 250 ⁇ to about 600 ⁇ prior to loading.
  • the ocular surface area of the active agent matrix is from about 50 mm 2 to about 300 mm 2 .
  • the active agent matrix has a loading capacity to hold and retain from about 50 to about 5000 of the active agent composition prior to application.
  • the active agent matrix is configured to passively absorb at least 100 ⁇ of the active agent composition within 10 minutes.
  • the active agent matrix is configured to deliver the effective dose of the active agent within 20 minutes of application of the device to the eye. In some examples of the non-invasive ocular drug delivery device, the effective dose is from about 5 wt% to about 50 wt% of the active agent loaded into the active agent matrix.
  • the effective dose is an amount from about 0.01 mg to about 100 mg of the active agent.
  • the device can further include the active agent composition.
  • the active agent is a member selected from the group consisting of: a steroid, an antimicrobial agent, an immunosuppressive agent, a non-steroidal anti-inflammatory agent, an anti- angiogenic agent, a vasoconstrictive agent, an antihistamine, a glaucoma agent, and combinations thereof.
  • the active agent is dexamethasone sodium phosphate (DSP).
  • the active agent is present in the active agent composition in an amount from about 0.005 w/v% to about 25 w/v%.
  • the active agent composition has a pH of from about 5 to about 8.
  • the active agent composition has a tonicity of from about 200 mOsm/kg to about 750 mOsm/kg.
  • the active agent composition is substantially particulate matter free.
  • the device is sterile.
  • the device does not include an electrode.
  • the device further includes a loading base shaped to removably mate with the housing and facilitate loading of the active agent composition into the active agent matrix.
  • a method of manufacturing a non- invasive ocular drug delivery device comprising preparing a housing that is adapted to couple to an eye of a subject, forming an active agent matrix from an electrospun material, said active agent matrix having a combination of a density, a thickness, and a ocular surface area configured to hold and retain an active agent composition prior to application of the device to the eye, and deliver an effective dose of an active agent within 30 minutes of application of the device to the eye, and coupling the active agent matrix to the housing to form the non-invasive ocular drug delivery device.
  • the housing is prepared as a monolithic unit.
  • the monolithic unit is formed of a molded elastomeric material.
  • the elastomeric material is a member selected from the group consisting of: ethylene propylene diene monomer (EPDM), a fluoroelastomer, an acrylonitrile-butadiene rubber, a silicone, and combinations thereof.
  • the electrospun material is a hydrophilic material.
  • the electrospun material is a member selected from the group consisting of: polyamides, polyurethanes, polycarbonates, polyvinyl alcohols, polylactic acids, polyglycolic acids, polyethylene-co-vinyl acetate, polyethylene oxide, polystyrene, collagen, polyvinyl pyrrolidone, polyethylene, polypropylene, and combinations thereof.
  • the active agent matrix is coupled to the housing with an adhesive. In some examples of the method of manufacturing a non-invasive ocular drug delivery device, the method further includes loading the active agent composition into the active agent matrix.
  • the method further includes terminally sterilizing the non-invasive active agent delivery device.
  • the method further includes aseptically sterilizing the active agent composition and the non-invasive active agent delivery device.
  • an ophthalmic composition comprising dexamethasone phosphate, or a salt thereof, present in the composition in an amount from about 1 wt% to about 25 wt%, dexamethasone present, but in an amount not greater than 1.0 wt% relative to the amount of dexamethasone phosphate, or the salt thereof, and water, wherein the composition has a pH of from about 5 to about 8, and wherein the composition has a tonicity of from about 200 mOsm/kg to about 760 mOsm/kg.
  • the dexamethasone phosphate is dexamethasone sodium phosphate.
  • the dexamethasone phosphate, or the salt thereof is present in an amount from about 4 wt% to about 18 wt%.
  • dexamethasone is present, but in an amount not more than 0.5 wt% relative to dexamethasone phosphate, or the salt thereof.
  • dexamethasone is present, but in an amount not more than 0.5 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at ambient temperature for a period of 3 months or less.
  • dexamethasone is present, but in an amount not more than 1.0 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at ambient temperature for a period of 3 months or less. In some examples of the ophthalmic composition, dexamethasone is present, but in an amount not more than 0.5 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at ambient temperature for a period of 6 months or less.
  • dexamethasone is present, but in an amount not more than 1.0 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at ambient temperature for a period of 6 months or less.
  • dexamethasone is present, but in an amount not more than 0.5 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at a temperature of from about 2° C to about 8° C for a period of 36 months or less.
  • dexamethasone is present, but in an amount not more than 1.0 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at a temperature of from about 2° C to about 8° C for a period of 36 months or less. In some examples of the ophthalmic composition, dexamethasone is present, but in an amount not more than 0.5 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at a temperature of from about 2° C to about 8° C for a period of 49 months or less.
  • dexamethasone is present, but in an amount not more than 1.0 wt% relative to dexamethasone phosphate, or the salt thereof, after storage at a temperature of from about 2° C to about 8° C for a period of 49 months or less.
  • the pH is from about 6.5 to about 7.5. In some examples of the ophthalmic composition, the tonicity is from about
  • the tonicity is from about 500 mOsm/kg to about 600 mOsm/kg. In some examples of the ophthalmic composition, the composition is substantially particulate matter free.
  • the composition further comprises a pH adjuster. In some examples of the ophthalmic composition, the composition further comprises a chelating agent.
  • the chelating agent is a member selected from the group consisting of: edetate disodium dihydrate, edetic acid, ethylene diamine, porphine, and combinations thereof.
  • the composition does not include a preservative or an antioxidant.
  • the composition does not include a polymer.
  • the composition does not include a cyclodextrin.
  • the composition does not include a surface-active agent.
  • the composition does not include a hydrocarbon. In some examples of the ophthalmic composition, the composition does not include a buffering agent.
  • an ophthalmic system comprising an ophthalmic composition as described herein disposed in a container and an ocular drug delivery device configured to couple to an eye of a subject.
  • the ophthalmic composition comprises an amount of dexamethasone phosphate, or the salt thereof, of from about 0.1 mg to about 2500 mg.
  • the container is a sterile container.
  • the sterile container has a volume of from about 0.5 ml to about 10 ml.
  • a portion of the ophthalmic composition is preloaded into the ocular drug delivery device.
  • the portion of the ophthalmic composition that is preloaded into the ocular drug delivery device is an amount of from about 50 to about 500 ⁇ .
  • the ocular drug delivery device is configured to couple to the eye via negative pressure.
  • a method of treating an ophthalmic condition responsive to dexamethasone phosphate, or a salt thereof, in a subject comprising administering a dexamethasone phosphate composition as described herein to an eye of the subject.
  • the ophthalmic condition comprises uveitis, age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, dry eye, post-operative inflammation, eye infection, allergic conjunctivitis, corneal trauma, infiltrative keratitis, staphylococcal marginal keratitis, posterior blepharitis, ocular herpetic disease, cystoid macular edema (CME), diabetic retinopathy, Behcet's disease, ocular pain, or a combination thereof.
  • AMD age-related macular degeneration
  • diabetic retinopathy diabetic macular edema
  • dry eye post-operative inflammation
  • eye infection allergic conjunctivitis
  • corneal trauma infiltrative keratitis
  • staphylococcal marginal keratitis staphylococcal marginal keratitis
  • posterior blepharitis ocular herpetic disease
  • cystoid macular edema (CME) cyst
  • administering is performed for a continuous administration period.
  • administration period is from about 1 minute to about 30 minutes.
  • administering is performed via an ophthalmic device that is adapted to couple to the eye.
  • the ophthalmic device is configured to couple to the eye via negative pressure.
  • administering is noninvasive administration.
  • administering is passive administration.
  • administering is active administration.
  • administering delivers a threshold dose of dexamethasone phosphate, or a salt thereof, to the eye of the subject in an amount of from about 0.1 mg to about 10 mg.
  • a method of treating a subject with an ocular condition comprising coupling a device as described herein to an eye of a subject and passively administering an active agent from the device to an eye of the subject during a continuous dosing period to provide a threshold dose of the active agent to the eye within 30 minutes of coupling the device to the eye.
  • the ocular condition includes uveitis, age-related macular degeneration (AMD), macular edema, a cataract, diabetic retinopathy, glaucoma, dry eye, post-operation inflammation, eye infection, allergic conjunctivitis, presbyopia, corneal wound healing, ocular pain, or combinations thereof.
  • AMD age-related macular degeneration
  • macular edema a cataract, diabetic retinopathy, glaucoma, dry eye, post-operation inflammation, eye infection, allergic conjunctivitis, presbyopia, corneal wound healing, ocular pain, or combinations thereof.
  • coupling comprises inducing negative pressure between the device and the eye of the subject.
  • the active agent is a member selected from the group consisting of: a steroid, an antimicrobial agent, an immunosuppressive agent, a non-steroidal anti-inflammatory agent, an anti-angiogenic agent, a vasoconstrictive agent, an antihistamine, a prostaglandin, a beta-blocker, an alpha-adrenergic agonist, a carbonic anhydrase inhibitor, an anesthetic, an analgesic, and combinations thereof.
  • the threshold dose is from about 5 wt% to about 50 wt% of the active agent loaded into the active agent matrix.
  • the threshold dose is an amount from about 0.01 mg to about 100 mg of the active agent.
  • the threshold dose is passively delivered to the eye within 5 minutes of coupling the device to the eye.
  • the threshold dose is sufficient to deliver the active agent to the posterior segment of the eye.
  • the posterior segment includes the retina.
  • the method further includes terminating passive administration by removing the device from the eye.
  • passively administering comprising administering the threshold dose to the eye via the sclera of the eye while minimizing administration via the cornea.
  • a method of treating a subject with an ocular condition responsive to steroid therapy comprising administering a threshold dose of a steroid to an eye of the subject in a therapeutically effective regimen that minimizes an intraocular pressure (IOP) increase above a baseline level.
  • IOP intraocular pressure
  • the ocular condition includes uveitis, age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, dry eye, post-operative inflammation, eye infection, allergic conjunctivitis, corneal trauma, infiltrative keratitis, staphylococcal marginal keratitis, posterior blepharitis, ocular herpetic disease, or a combination thereof.
  • AMD age-related macular degeneration
  • diabetic retinopathy diabetic macular edema
  • dry eye post-operative inflammation
  • eye infection allergic conjunctivitis
  • corneal trauma infiltrative keratitis
  • staphylococcal marginal keratitis staphylococcal marginal keratitis
  • posterior blepharitis ocular herpetic disease
  • administering is performed via passive administration.
  • administering is performed via active administration.
  • administering is performed via topical administration.
  • the topical administration is performed via topical administration of the threshold dose to the sclera while minimizing topical administration to the cornea.
  • administering is performed for a consecutive period of from about 1 minute to about 30 minutes.
  • the threshold dose is from 0.1 mg to 30 mg.
  • the steroid includes fluocinolone, difluprednate, fluorometholone, loteprednol, dexamethasone, prednisolone, medrysone,
  • the steroid is dexamethasone phosphate or a salt thereof.
  • the steroid is triamcinolone acetonide phosphate or a salt thereof.
  • the therapeutically effective regimen includes a dosing frequency of from once about every 2 days to once about every 7 days.
  • the therapeutically effective regimen includes a dosing frequency of from once about every 3 days to once about every 5 days.
  • the therapeutically effective regimen includes a dosing frequency of from once about every 7 days to once about every 4 weeks.
  • the therapeutically effective regimen provides an average IOP of less than or equal to 2 mmHg above the baseline level.
  • the therapeutically effective regimen provides an average IOP of less than or equal to 1 mmHg above the baseline level.
  • the therapeutically effective regimen provides an average IOP of less than or equal to the baseline level.
  • a transient increase in IOP above the baseline level returns to a level less than or equal to 2 mmHg above the baseline level within 90 minutes of administering.
  • a transient increase in IOP above the baseline level returns to a level less than or equal to 1 mmHg above the baseline level within 90 minutes of administering.
  • a transient increase in IOP above the baseline level returns to a baseline level within 90 minutes of administering.
  • the method can further include administering a nonsteroidal active agent.
  • the non-steroidal active agent is a member of the group consisting of: an antimicrobial, an immunosuppressive agent, a non-steroidal antiinflammatory agent, an anti-angiogenic agent, a vasoconstrictive agent, an antihistamine, an analgesic, an anesthetic, and combinations thereof.
  • the non-steroidal active agent is co-administered with the steroid in the therapeutically effective regimen.
  • the non-steroidal active agent is administered via an alternative dosing regimen.
  • Example 1 Manufacture of a Non-Invasive Ocular Drug Delivery Device
  • a housing for the ocular delivery device was prepared as a monolithic unit by molding a medical grade silicone material.
  • the housing included a corneal dome, corneal seal, and vacuum bulb as a single monolithic unit.
  • the housing had the general appearance of that illustrated in FIGs. 3a-3d.
  • An active agent matrix was formed by electrospinning a hydrophilic polyether-based thermoplastic polyurethane material to form polymer fibers.
  • the polymer fibers were used to form a non-woven pad having a dry thickness of about 0.4 mm, a dry density of about 0.25 g/cc, and a surface area of about 150 mm 2 .
  • Pads were manufactured to have a crescent shape so that two pads could be positioned adjacent one another about the corneal seal to deliver active agent to the sclera without contacting the cornea.
  • the individual segments of the active agent matrix were coupled to the housing using a medical grade silicone adhesive.
  • the active agent matrix was loaded with an aqueous based 15 w/v% dexamethasone sodium phosphate solution (DSP).
  • DSP dexamethasone sodium phosphate solution
  • the active agent matrix was able to passively absorb greater than 240 of the solution within 2 minutes.
  • the active agent matrix did not leak, drip, or otherwise prematurely release the active agent composition.
  • Fig. 6 illustrates an in-vitro drug release profile provided by this exemplary device.
  • Intraocular pressures were similar for untreated and treated eyes within each group. Intraocular pressures were also similar for the test article groups compared to the control group at each measured time point. IOP measurements were within normal reference ranges except for a few individual animals in all groups on days 1 and 2. Intra-ocular pressures are affected by a number of variables, including circadian rhythm effects, stress, location, environmental conditions, physical restraint, eye position, systemic blood pressure, water consumption, sedation or anesthesia. The few readings obtained on dose days 1 and 2 that were outside of the normal limits were likely caused by the stress of restraint, dosing and handling. As animals became acclimated to handling, restraint and dosing procedures, IOP measurements became more consistent and were within the normal limits. This suggests that there were no IOP effects related to dosing observed in this study.
  • NZW New Zealand White
  • DSP dexamethasone sodium phosphate
  • the Group 1 (male) IOP for the treated eye changed after a 15-minute continuous treatment, but returned to a pre-dose value within one half hour following treatment.
  • the IOP for the male left eye (no treatment) did not change after treatment.
  • the male right eye (DSP Treatment) IOP went up by 8 mmHg after treatment, and returned to normal within one half hour after treatment.
  • the IOP increased by an absolute value of 8 mmHg immediately after treatment, but quickly returned to normal.
  • the Group 2 (female) IOP for the treated eye changed after a 15-minute continuous treatment, and returned to a pre-dose/baseline range within about one hour of treatment.
  • the IOP for the left eye (no treatment) went up by 5 mmHg after treatment, which may be due to stress.
  • the IOP returned to a normal range within 1 hour of treatment.
  • the female right eye (DSP Treatment) IOP went up by 8 mmHg after treatment, and returned to a normal range within one half hour after treatment.
  • the IOP increased by an absolute value of 3 mmHg immediately after application.
  • the Group 1 (male) IOP for the treated eye changed after a 5-minute continuous treatment, but returned to normal within one hour following treatment.
  • the IOP for the male left eye (no treatment) went up by 2 mmHg after treatment, which perhaps is an indication of a rise in IOP due to stress.
  • the IOP dropped to a slightly lower value than the pre-dose/baseline range within 1 hour of application.
  • the male right eye (DSP Treatment) IOP went up by 6 mmHg after treatment, and dropped to a 4 mmHg change in IOP within one hour after treatment.
  • the IOP increased by an absolute value of 2 mmHg immediately after application.
  • the Group 2 (female) IOP for the treated eye changed after a 5-minute continuous treatment, but dropped to a low IOP within one half hour following treatment.
  • the IOP for the female left eye (no treatment) also dropped to lower than the baseline after treatment.
  • the female right eye (DSP Treatment) IOP went up by 5 mmHg after treatment, and returned to below baseline IOP within one half hour after treatment.
  • the IOP increased by an absolute value of 5 mmHg immediately after application.
  • a total of 44 human subjects were divided into three treatment groups. Each treatment group was simultaneously subjected to 2 separate dosing regimens. Specifically, each treatment group received both a pulsatile administration of an active composition or placebo in addition to daily active or placebo eye drop administration.
  • the pulsatile administration consisted of administration for a continuous period of approximately 5 minutes on days 1, 3, and 8, followed by maintenance dosing every seven days thereafter for a total period of about 1 month.
  • Daily eye drop administration consisted of 1-2 drops twice daily during the same treatment period of about 1 month.
  • Treatment group 1 received an 8 w/v% dexamethasone sodium phosphate composition in a pulsatile manner as described above and placebo (i.e. saline) eye drops for daily administration.
  • Treatment group 2 received a 15 w/v% dexamethasone sodium phosphate composition in a pulsatile manner as described above and placebo (i.e. saline) eye drops for daily administration.
  • Treatment group 3 received a saline composition in a pulsatile manner as described above and PRED FORTE ® eye drops for daily administration.
  • the intraocular pressure (I OP) values for each of the test subjects were checked periodically for the period of about 1 month to determine how these different steroid treatment modalities would affect IOP levels in the subjects. The results are illustrated in Fig. 7. As illustrated in Fig. 7, the pulsatile administration of steroids described herein provided an average IOP level that was approximately equivalent to or below baseline levels. In contrast, daily administration of steroid via eye drops increased IOP values by approximately 2 mmHg during the treatment period.
  • Example 4 Treatment of Experimental Uveitis in Rabbits
  • DSP Dexamethasone sodium phosphate USP grade was obtained from Letco Products (Decatur, AL). The concentrations of DSP solution were 4.0%, 8.0%, and 15.0% w/v. All DSP formulations contained 0.01% w/v of EDTA (Sigma-Aldrich, St. Louis, MO) with pH adjusted to 7.0 with 1M hydrochloric acid (LabChem, Zelienople, PA) and were freshly prepared in doubly deionized water on the day of dosing using an aseptic technique. The applicator for use in rabbit studies was fabricated from medical grade silicone rubber, which incorporated a customized active agent matrix (3-5mm wide).
  • mice Twenty-three animals were randomly assigned into 6 groups according to Table 4 after uveitis induction of the right eye. Left eyes were not induced with uveitis to provide some vision in the animals throughout the study.
  • the DSP treatment was on the affected eye (right eye).
  • the first dose occurred -30 minutes after the uveitis induction on Day 1. Ocular examinations and clinical observation were performed during the weekday before and after each dosing. Following the final observations on Day 29, animals were anesthetized with a 2.5 mL intramuscular injection containing 5 mg ketamine and 30 mg xylazine per mL. Depth of anesthesia was confirmed by absence of corneal blink reflex or toe pinch response to ensure humane euthanasia.
  • the animal was then sacrificed by an intracardiac injection of 2 mL of saturated KC1 with a 3 mL syringe and 18GA x 1" needle.
  • the eyes were collected and processed for histological evaluation.
  • the severity of the uveitic conditions limited the number of rabbits per group to 3 in the first part of the study. With the successful experience of the first part of the study, the same number of animals per group was kept for the rest of the study.
  • the study was conducted in 3 parts, and each time a control group was evaluated with the treatment group(s). Then, the results were pooled for analysis. Table 4 - Study Design
  • mice were preimmunized by subcutaneous injections of 0.5mL FCA H37Ra, a suspension of Mycobacterium tuberculosis H37Ra antigen in FCA.
  • the Freund's Complete Adjuvant H37Ra containing 20 mg/mL of antigen was prepared by mixing dried M. tuberculosis H37Ra antigen with the FCA.
  • the preimmunized injections were in the dorsal area of the animal's neck and occurred at 19 and 12 days before induction of uveitis. Then uveitis was induced on Day 1 by 100 mL IVT injection of a suspension containing 33 mg of the M.
  • DSP administration One drop of sterile proparacaine hydrochloride ophthalmic solution, a local anesthetic, was given to the right eye of each rabbit ⁇ 5 min before dose administration.
  • DSP solution 250 ⁇ was loaded into the applicator using an Eppendorf pipettor. The drug solution saturated the carrier matrix uniformly within a minute. Then, the applicator containing the drug formulation was gently applied to the scleral surface of the right eye of each rabbit. The position of the applicator was checked to ensure that the drug matrix was in immediate contact with the white scleral part of the eye, but not the cornea. Digital laboratory timers were used for accurate application times (treatment duration) of 5, 10, or 15 min.
  • the tissues were processed, embedded in paraffin wax, sectioned by microtomy, and stained. Histopathology of the tissues was conducted on slides stained with hematoxylin and eosin. The pathologist who evaluated the tissues had no prior knowledge of the specific pharmacologic activity or formulation of the test articles.
  • Standardized toxicologic pathology criteria and nomenclature for the rabbit were used to categorize microscopic tissue changes.
  • posterior section the vitreous, choroid, and retina were also scored from 0 (normal) to 4 (marked) for signs of inflammatory cell infiltration.
  • Vitreous All animals in the control group (Group 1) reached a severe uveitic state (i.e. scores of 3 or 4 for the vitreous), which remained on average above a score of 3 throughout the 28 days of study. Vitreous opacity increased steadily for the first 4 days after initiation of uveitis in all 5 groups. The opacity in Group 1 (control) increased the most. Scores for Group 1 animals decreased slightly around Day 13, but remained on average above a score of 3 throughout the experiment. By Day 4, Groups 2, 3, and 4 had reached the highest scores they would attain and began to decrease steadily thereafter. Group 5 scores began a steady decrease on Day 8, while those for
  • Group 6 began to decrease on Day 10. There were clear decreases in vitreous opacity scores in all treatment groups, while the control group scores remained high. Group 2 animals showed a steady decrease in vitreous opacity scores until reaching zero on Day 10 and remaining at zero throughout the remainder of the study. Group 3 (15% DSP, 10 min, 1 dose) reached zero on Day 15, Group 5 (8% DSP, 10 min, 4 doses) on Day 10.
  • Conjunctival injection Mild to moderate conjunctival injection was present in all animals and was observed throughout the study. Averaged group scores over the course of treatment are presented in Table 5. All treatment groups except Group 5 showed slightly lower average conjunctiva scores over the course of study than the control group (Group 1). The average conjunctiva scores of Group 5 were equal to the control group. There were day to day variations as well as an overall downward trend over the entire experiment in all groups (i.e. the average score ranged from 0 to 3 in the first 2 weeks and from 0 to 1 in the last 2 weeks). In Group 1, conjunctival injection declined slowly over the course of the experiment, but was still present until the end. Some irritation from placement of the DSP was observed in the DSP treatment groups.
  • Chemosis Mild chemosis was found in all groups. Overall chemosis was minor, with no group having an average chemosis score greater than 1 at any point. In Group 1 animals (controls), chemosis decreased slowly, although with variation, throughout the study. Chemosis increased slightly after DSP treatment, a trend similar to that seen with conjunctival injection. Groups 2 and 5 showed mild chemosis immediately after each dosing, but resolving to 0 generally within a day. Groups 4 and 6 showed some variations in chemosis scores and reached 0 after Day 11, with Group 6 showing a slight reoccurrence on Days 16 through 18. Neither Group 3 rabbits displayed any significant chemosis. Conjunctival discharge. Discharge was noted in all groups in a random manner. Discharge never exceeded a score of 1. There was an undistinguishable trend between the treatment regimens and the control.
  • Cornea A low grade of cornea cloudiness, mostly with scores of ⁇ 1, was found in some rabbits in all groups (untreated control group and treatment groups). The corneal haze observed in all rabbits faded with time. Overall, the incidence and severity of corneal haze in treatment groups appeared to be lower than the control group.
  • Histopathology of uveitis eyes The eyes were collected at the end of the study on Day 29 for histopathology evaluation. The average inflammation scores for both anterior and posterior sections of the eyes graded by a veterinarian pathologist are presented in Table 6.
  • the inflammatory cell infiltrations into the anterior section of the eye were less in all DSP treatment groups compared to the control. This was reflected by the lower of inflammatory cell infiltration scores of the treatment groups compared to the control group. However, there was no obvious efficacy-concentration relationship among the treatment groups. All animals in Group 1 (untreated) had inflammatory cell infiltrations to the conjunctiva, cornea, AC, trabecular meshwork, iris, and/or ciliary body with the average inflammatory cell infiltration score of 0.7 for the whole anterior section. In contrast, the average inflammatory cell infiltration score of Group 2 (15% DSP, 15 min, 4 doses) was 0.0.
  • Figs. 9a and 9b The differences in the photoreceptor layer appearance between the untreated eye (Group 1) and the eye from the highest dose regimen (Group 2) can be seen in Figs. 9a and 9b.
  • the posterior tissues of the treated eye appeared to be healthy with minimal inflammation, where it appeared to be completely impaired in the untreated eye. Histopathology of Group 3 (15% DSP, 10 min, 1 dose), Group 4 (8% DSP, 10 min, 1 dose), and Group 5 (8% DSP, 5 min, 4 doses) showed minimal to mild inflammation with the average infiltration scores of 1.8, 1.2, and 1.9, respectively. All animals in the lowest dosing group (Group 6) had posterior section inflammation nearly identical to the control group.
  • Example 5 Ocular Drug Distribution and Safety of Dexamethasone Phosphate Administered with Non-Invasive Ocular Drug Delivery System
  • DSP Dexamethasone sodium phosphate USP grade was supplied from Letco Products (Decatur, AL). The concentrations of DSP solution were 4.0%, 8.0%, 15.0%, and 25.0% w/v. All DSP solutions containing 0.01% w/v of EDTA (Sigma- Aldrich, St. Louis, MO) with the pH adjusted to 7.0 using 1.0 M hydrochloric acid (LabChem, Zelienople, PA) were freshly prepared in double deionized water on the day of dosing using an aseptic technique. The non-invasive ocular drug delivery device for use in this study was fabricated from medical grade silicone rubber and a proprietary sponge material.
  • Ketamine hydrochloride injectable USP 100 mg/mL and sodium chloride 0.9% USP were from Hospira, Inc. (Lake Forest, IL); proparacaine hydrochloride ophthalmic solution was from Bausch & Lomb (Tampa, FL); cyclopentolate hydrochloride ophthalmic solution was from Alcon Laboratories (Fort Worth, TX); xyrazine and potassium chloride (KC1) were from Sigma- Aldrich
  • test parameters included four DSP concentrations (i.e., 4%, 8%, 15%, and 25% w/v) and three application times (i.e., 5, 10, and 20 minutes). Each group received a single DSP concentrations (i.e., 4%, 8%, 15%, and 25% w/v) and three application times (i.e., 5, 10, and 20 minutes). Each group received a single DSP concentrations (i.e., 4%, 8%, 15%, and 25% w/v) and three application times (i.e., 5, 10, and 20 minutes). Each group received a single DSP concentrations (i.e., 4%, 8%, 15%, and 25% w/v) and three application times (i.e., 5, 10, and 20 minutes). Each group received a single DSP concentrations (i.e., 4%, 8%, 15%, and 25% w/v) and three application times (i.e., 5, 10, and 20 minutes). Each group received a single DSP concentrations (i.e., 4%, 8%
  • DSP treatment via the non-invasive ocular drug delivery device at a pre-specified concentration and application time on both eyes concurrently (within 10-20 seconds apart).
  • the rabbits were sacrificed immediately after dosing (generally within 5 minutes).
  • the eyes were then enucleated and analyzed for DSP and DEX using HPLC. A total of 6 eyes were used for averaging the amount of the drug in each group.
  • the rationale for this study was to answer whether or not a single application of the non-invasive ocular drug delivery device can deliver a meaningful amount of DSP into the deeper eye tissues.
  • the target concentration of DSP in each eye tissue (immediately after the application) that is considered meaningful was arbitrarily set at 1 ⁇ g/g. This was based on the fact that 1 ⁇ g/mL DEX was the quantification limit of the HPLC assay in this study. This number can very well be on the high side as even a concentration of DEX at 10 "7 M ( ⁇ 40 ng/mL) can inhibit prostaglandin release from rabbit coronary microvessel endothelium.
  • the longest application time of interest 20 minutes, was selected for testing safety and tolerability of the four DSP concentrations.
  • Each rabbit received a weekly DSP administration via application of the non-invasive ocular drug delivery device (i.e., 4%, 8%, 15%, or 25% DSP concentrations) for 20 minutes in one eye (right eye) leaving the other (left eye) as an untreated control.
  • the total exposure was 12 doses over the period of 12 weeks.
  • Clinical observations were performed on weekdays, and before and after each dosing. Following the final observations (i.e., one week after the last dose), the rabbits were sacrificed and the eyes were processed for histological evaluation.
  • the animals received a 2.5 mL intramuscular injection containing 5mg ketamine and 30 mg xylazine per mL as general anesthetic.
  • the depth of anesthesia was confirmed by absence of corneal blink reflex or toe pinch response to ensure humane euthanasia.
  • the animal was then sacrificed by an intracardiac injection of 2 mL of saturated KC1 with a 3 mL syringe and 18GA X I" needle. The eyes were collected and processed for drug analysis or histological evaluation.
  • Each rabbit was placed in a rabbit restrainer to limit movement during administration of DSP via the non-invasive ocular drug delivery device.
  • One drop of sterile proparacaine hydrochloride (a local anesthetic) was put on the eye (to be treated) 5 minutes before dose administration.
  • DSP solution 250 ⁇ was loaded onto the annular active agent matrix of the non-invasive ocular drug delivery device using an Eppendorf pipettor. Then, the non-invasive ocular drug delivery device containing the DSP solution was gently applied to the scleral surface of the eye of each rabbit. The position of the device was checked to ensure that the active agent matrix was in immediate contact with the white part of the eye but not the cornea. Digital timers were used for accurate application times (i.e., 5, 10, or 20 minutes). After the given application duration, the applicator was carefully removed from the eye.
  • the eyes were dissected into seven tissue sections: anterior chamber, lens, retina-choroid, cornea, vitreous, conjunctiva, and sclera.
  • the anterior chamber consists of iris, ciliary muscles, and aqueous humor.
  • the drug was extracted from each tissue overnight with 5 mL of the extraction solvent (60% chloroform-40% methanol).
  • the tissue was then separated from the extraction solution by centrifuge at 3400 rpm for 10 minutes.
  • the extraction solutions were concentrated by evaporation of the solvent in a water bath at 50 °C, using nitrogen gas, and then reconstituted in 1 mL of the reconstitution solvent (95% methanol/5% 1M HC1).
  • the amounts of total DSP and DEX in the eye tissues were then determined by HPLC analysis.
  • the enucleated eyes were stored in Davidson's solution (i.e., 34.7% deionized water, 11.1% glacial acetic acid, 32.0% ethanol, and 22.2% formalin) for 24 hours and then transferred to plastic conical tubes containing 20 mL of 70% ethanol in water. The eyes were sent for histopathological processing and evaluation at Colorado Histo-Prep (Fort Collins, CO).
  • Davidson's solution i.e., 34.7% deionized water, 11.1% glacial acetic acid, 32.0% ethanol, and 22.2% formalin
  • Blood was collected at predose (-20 minutes), 5, 30, 60, 120, 240, and 360 minutes, and 24, 48, 72, and 168 hours after DSP application via the non-invasive ocular drug delivery device. Approximately 1 mL of blood was collected by direct venipuncture of the jugular vein with a 3 mL syringe and 21 GA X 1" needle. Blood was immediately transferred into anticoagulant (potassium EDTA) coated microcentrifuge tubes. Blood was then centrifuged for five minutes at 3000 X G at 4 °C. Plasma was immediately separated into another microcentrifuge tube then kept in -20 °C freezer for LC-MS analysis. The amounts of DSP and DEX in the eye tissues were determined by HPLC analysis.
  • HPLC system used was Waters 2695 separation module equipped with Waters 2487 dual wavelength detector (Waters Corporation, Milford, MA) and Kinetex C18 column 2.6 ⁇ 100 X 4.6 mm (Phenomenex, Torrance, CA). All the chemical reagents for making HPLC mobile phases were HPLC grade from Sigma-
  • DSP and Dex standard curves of 0.2 to 200 ng/mL were generated.
  • the limit of quantitation (LOQ) of this method was 1 ng/mL.
  • Toxicokinetic data analysis was based on standard noncompartmental pharmacokinetic methods.
  • Plasma concentration of DSP equivalent was used in the analysis to express systemic exposure of DSP and DEX as a single entity.
  • the DSP equivalent was calculated by converting DEX to DSP using 392.5 g of DEX equivalent to 516.4 g of DSP.
  • the maximum observed plasma concentration (Cmax) was determined by visual estimation from the data plot.
  • Area under the plasma concentration vs. time curve from 0 to the time of the last measurable concentration (AUC) was calculated by the linear trapezoidal method.
  • Elimination half-life (t1 ⁇ 2) was calculated as ln(2)/ke, where ke is the elimination rate constant determined by linear regression of the last three analytically measured points on the plasma concentration vs. time curve.
  • Body weights of the animal were taken upon arrival, and then monthly. All animals (both left and right eyes) were examined by indirect ophthalmoscopy of the cornea, conjunctiva, anterior chamber, vitreous, posterior chamber, and sclera. One to two drops each of phenylephrine hydrochloride and cyclopentolate hydrochloride were used as mydriatics. Observations on the anterior and posterior segments of the eye were made, graded, and recorded. A modified McDonald-Shadduck scale was used for grading eye irritation and ocular toxicity.
  • the histopathological processing and evaluation were conducted at Colorado Histo-Prep (Fort Collins, CO). Briefly, a central cut of the eye globe was taken, as well as two cuts on either side of the central cut (calottes) at trim. For each eye, the central cut was placed into one cassette, and the two calottes were placed together into a separate cassette. The tissues were processed, embedded in paraffin wax, sectioned by microtome, and stained. Histopathology of the tissues was conducted on slides stained with hematoxylin and eosin. A pathologist who evaluated the tissues had no knowledge of the specific pharmacologic activity or formulation of the test articles. Standardized toxicological pathology criteria and nomenclature for the rabbit were used to categorize microscopic tissue changes.
  • DSP and DEX were found in all the tissues.
  • a typical rank order of DSP amounts in the eye tissue is sclera, conjunctiva, cornea, retina-choroid, anterior chamber, vitreous, and lens.
  • the total amount of drugs in each tissue except vitreous and lens appears to be correlated well with the DSP concentration and application time of the non-invasive ocular drug delivery device.
  • the total amount of DSP delivered by the non-invasive ocular drug delivery device was calculated by the sum of DSP and DEX in ⁇ for a purpose of drug deliver) ' - analysis.
  • a higher DSP formulation concentration yielded a higher amount of DSP in the eye.
  • a longer application duration of the non-invasive ocular drug delivery device yielded a higher amount of DSP in the eye.
  • the concentration of DSP in each tissue was also calculated in ⁇ g/g and summarized in Table 7 for potential efficacy evaluation of the non-invasive ocular drug delivery device. As discussed earlier, the concentration of 1 ⁇ g/g or higher in the tissue is considered as a potential therapeutic level. With exception of the lens and vitreous samples in a few cases, most of the ocular tissue concentrations of DSP are significantly higher than 1 ⁇ g/g.
  • Table 7 DSP-equivalent concentrations in ocular tissues (mean ⁇ SD, ⁇ g/g).
  • the animals treated with 15% DSP had typical conjunctival injection scores immediately after treatment of ⁇ 1 for the first four weeks, and then 2 at Week 8 until the end of study.
  • the animals treated with 25% DSP had typical conjunctival injection scores immediately after treatment of ⁇ 1 for the first four weeks, and then 2 or 3 at Week 8 until the end of study.
  • Chemosis on the conjunctiva was also observed immediately after DSP administration via the non-invasive ocular drug delivery device. Although chemosis tends to increase in severity with the DSP concentration and with repeated application, the occurrence of chemosis appeared to be sporadic. Conjunctival discharge was noted occasionally but appears to be irrespective of DSP concentration and not related to infection. Table 8 - Clinical Observations
  • Cornea appeared normal after each DSP administration via the noninvasive ocular drug delivery device in all rabbits except in one case with a rabbit in the 15% DSP group from Week 4 to Week 8. Corneal haze on the treated eye was immediately observed in this rabbit after the DSP administration on Week 4. The lesion covered about 40% of the corneal surface. The haze was identified as a result of an off center applicator placement. This caused the drug reservoir to be in direct contact with the cornea during the DSP administration via the non-invasive ocular drug delivery device. The corneal haze grew fainter over time and it was not visible by Week 8.
  • Body Weight There were no significant weight changes in the 4% or 8% DSP treated rabbits. However, the animals in the 15% and 25% DSP groups showed trends of decreasing body weight. The consistent decline in body weights of the animals in these two groups indicate that long term exposure at these levels of DSP dosing (i.e., 15% and 25% DSP for 20 min) may have significant systemic side effects on rabbit.
  • DSP and DEX were found in plasma for all four treatment regimens (i.e., 5 or 20 minute applications of 4% or 15% of DSP).
  • the plasma concentrations of DSP and DEX after single applications of the non-invasive ocular drug delivery device are shown in Fig. 11a. Tmax of DSP was reached at the first blood draw (5 minutes after device application) whereas Tmax of DEX was reached later at 30 minutes.
  • the maximum plasma concentration (Cmax) of both DSP and DEX increased with increasing DSP concentration and with longer application time. It appears that the concentration affected the systemic exposure more than the application time; the 4% DSP applied for 20 minutes yielded a lower plasma concentration than the 15% DSP applied for 5 minutes.
  • the drug plasma concentrations of all groups were approaching or under the lowest detection limit of 1 ng/mL.
  • DSP equivalent is defined as the sum of DSP and DEX in gram equivalent, with 392.5 g of DEX equivalent to 516.4 g of DSP.
  • the pharmacokinetic profiles of DSP equivalent from all four treatment regimens are shown in Fig. l ib and the key toxicokinetic parameters are presented in Table 9.
  • the half-life of the drug in the rabbit is approximately 2-3 hours.
  • Cmax and AUC increased with increased concentration of DSP and increased application time.
  • the highest dose (15% DSP, 20 minutes) of DSP administered via the non-invasive ocular drug delivery device are 2 and 25 ng/mL, respectively.
  • DSP dexamethasone sodium phosphate
  • Example 7 Aging Study for Non-Invasive Ocular Drug Delivery Device A non-invasive ocular drug delivery device was prepared as described in
  • Example 1 The device was sterilized using electron beam irradiation and subsequently stored at 25 °C/60% RH for 24 months. At various time points the device was examined to determine uptake of 190 ⁇ 10 of 15% dexamethasone sodium phosphate (DSP) in aqueous vehicle within 120 seconds. Subsequently, the device was evaluated to determine the amount of absorbed DSP released over 10 minutes. Additionally, intentional and unintentional separation force of the device were measured at each time point. Specifically, the upper portion of the bulb was squeezed and the device was pressed lightly onto a corneal seal fixture until the bulb began to visually compress such that an annular vacuum seal was formed around the corneal seal of the device.
  • DSP dexamethasone sodium phosphate
  • an open end of a separation fixture was positioned around a portion of the applicator and the other end of the separation fixture was connected to a tensile testing machine.
  • the tensile strain rate of the tensile testing machine was set to 400 mm/min and was run until the device had completely separated from the corneal seal fixture. The peak load required to create the separation was recorded. It is noted that with the intentional separation model, the device bulb was directly secured to the tensile testing machine such that jaws of the machine compressed the bulb to expel the vacuum without dislodging the device from the comeal seal fixture. Otherwise, the test was the same. Further, a "Force at Break" test was performed at each time point.

Abstract

Dispositif d'administration de médicament oculaire non invasive pouvant comprendre un boîtier conçu pour être accouplé à un œil d'un sujet. Une matrice d'agent actif peut être accouplée au boîtier. La matrice d'agent actif peut comprendre un matériau électrofilé ayant une combinaison d'une densité, d'une épaisseur, et d'une superficie oculaire conçue pour contenir et retenir un agent actif avant l'application du dispositif à l'œil, et délivrer une dose efficace d'un agent actif dans les 30 minutes de l'application du dispositif à l'œil.
PCT/US2018/055080 2017-10-06 2018-10-09 Dispositifs d'administration de médicament oculaire non invasive WO2019071275A1 (fr)

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US201762569430P 2017-10-06 2017-10-06
US15/727,452 US20190105194A1 (en) 2017-10-06 2017-10-06 Methods of treating a subject with an ocular condition responsive to steroid therapy
US15/727,529 2017-10-06
US62/569,430 2017-10-06
US15/727,452 2017-10-06
US15/727,529 US20190105264A1 (en) 2017-10-06 2017-10-06 Non-invasive ocular drug delivery devices

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058100A1 (en) * 2006-10-13 2012-03-08 Shastri V Prasad Modulation of drug release rate from electrospun fibers
US20140031766A9 (en) * 2007-10-04 2014-01-30 John W. Higuchi Intrascleral Drug Delivery Device and Associated Methods
US20170157147A1 (en) * 2014-08-13 2017-06-08 The Johns Hopkins University Glucocorticoid-loaded nanoparticles for prevention of corneal allograft rejection and neovascularization

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058100A1 (en) * 2006-10-13 2012-03-08 Shastri V Prasad Modulation of drug release rate from electrospun fibers
US20140031766A9 (en) * 2007-10-04 2014-01-30 John W. Higuchi Intrascleral Drug Delivery Device and Associated Methods
US20170157147A1 (en) * 2014-08-13 2017-06-08 The Johns Hopkins University Glucocorticoid-loaded nanoparticles for prevention of corneal allograft rejection and neovascularization

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