CA2830555A1 - Intraocular drug delivery device and associated methods - Google Patents
Intraocular drug delivery device and associated methods Download PDFInfo
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- CA2830555A1 CA2830555A1 CA2830555A CA2830555A CA2830555A1 CA 2830555 A1 CA2830555 A1 CA 2830555A1 CA 2830555 A CA2830555 A CA 2830555A CA 2830555 A CA2830555 A CA 2830555A CA 2830555 A1 CA2830555 A1 CA 2830555A1
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- Prior art keywords
- active agent
- eye
- delivery device
- bioerodible
- matrix
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
Abstract
Devices, systems, and methods for delivery of an active agent into the eye of a subject can include an intraocular active agent delivery device including an active agent dispersed within a biodegradable active agent matrix. The active agent includes dexamethasone and the delivery device is adapted to fit within a lens capsule or ciliary sulcus of an eye. The delivery device can be inserted into the lens capsule or ciliary sulcus of an eye during cataract surgery or for treatment of uveitis.
Description
INTRAOCULAR DRUG DELIVERY DEVICE AND ASSOCIATED METHODS
RELATED APPLICATIONS
None.
FIELD OF THE INVENTION
The present invention relates to systems, methods, and devices for the sustained and targeted (local) delivery of a pharmaceutical active agent into an eye of a subject.
Accordingly, the present invention involves the fields of polymer chemistry, material science, polymer science, drug delivery, formulation science, pharmaceutical sciences, and medicine, particularly ophthalmology.
BACKGROUND
Age-related macular degeneration (AMD) and glaucoma are two of the leading causes of blindness in the United States and across the world. Present glaucoma therapies generally require polypharmacy, where subjects are often prescribed several topical agents that must be applied to the eye with varying frequencies, in some cases up to 3 or 4 times a day. These =
dosing regimens are often difficult for subjects to consistently follow, and many individuals progress to needing surgical treatments such as intraocular shunts or trabeculectomies, which have significant attendant complications.
Subjects having macular degeneration are often required to have monthly intravitreal injections. Such injections are painful and may lead to retinal detachment, endophthalmitis, and other complications. Furthermore, these injections are generally performed only by retinal surgeons, a small fraction of the ophthalmic community, producing a bottleneck in eye care delivery and increased expense.
Postoperative surgery inflammation is associated with raised intraocular pressure (lOP), and increases the likelihood of cystoid macular edema (CME), synechial formation, posterior capsule opacification (PCO), and secondary glaucoma. Patient compliance is of concern in the management of postoperative inflammation because multiple eye drops must be taken multiple times per day at regular intervals over the course of weeks.
Poor compliance compromises the efficacy of topical drugs, which are further limited by corneal absorption and have highly variable intraocular concentrations during the therapeutic course.
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea"
but in common usage may refer to any inflammatory process involving the interior of the eye.
Uveitis is estimated to be responsible for approximately 10% of the blindness in the United States.
Postoperative cataract surgery inflammation can be well controlled by improving patient compliance. Available literature and experience shows penetration of the drug after topical administration is poor and higher systemic concentration means frequent systemic adverse events. All of these factors highlight the need for sustained intraocular delivery for pharmaceutical active agents to effectively control inflammation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top view of an active agent delivery device in the shape of a disc.
FIG. 2 is a side view of an active agent delivery device in the shape of a disc.
FIG. 3 is a graphical representation of the amount of an active agent present in various eye tissues following implantation of an intraocular device in accordance with a further aspect of the present invention.
FIG. 4 is a photograph showing a bioerodible dexamethasone implant (BDI).
FIG. 5 is a graph of in-vitro release kinetics of the BDI-1 implant. Data are presented as mean SD (n=3).
FIG. 6 is a time vs. concentration profile of BDI-1 implant with 120 to 160 lig of dexamethasone (DXM) in aqueous and vitreous humor of New Zealand White (NZW) rabbits.
FIG. 7 is a time vs. concentration profile of BDI-1 implant with 120 to 160 lig of DXM in iris/ciliary body and retina/choroid of NZW rabbits.
FIG. 8 is a graph of in vitro release kinetics of dexamethasone from BDI-2 implants (containing 300 1.ig of DXM). Data are presented as Mean SD (n=3) [Form. A:
PLGA
50:50, M.W. 7,000-17000; Form. B: PLGA 65:35, M.W. 17000-32000; Form. C: PLGA
50:50, M.W. 7,000-17000 (50%), PLGA 65:35, M.W. 17000-32000 (50%); Form. D:
PLGA
50:50, M.W. 7,000-17000 with 10% hydroxypropyl methylcellulose (HPMC)].
FIG. 9 is a graph of time vs. concentration profile of BDI-2 implant and topical drops in aqueous humor of New Zealand white rabbits.
FIG. 10 is a graph of time vs. concentration profile of BDI-2 implant and topical drops in vitreous humor of New Zealand white rabbits.
FIG. 11 is a graph of time vs. concentration profile of BDI-2 implant and topical drops in retina/choroid of New Zealand white rabbits.
FIG. 12 is a graph of time vs. retinal thickness of New Zealand white rabbits in four
RELATED APPLICATIONS
None.
FIELD OF THE INVENTION
The present invention relates to systems, methods, and devices for the sustained and targeted (local) delivery of a pharmaceutical active agent into an eye of a subject.
Accordingly, the present invention involves the fields of polymer chemistry, material science, polymer science, drug delivery, formulation science, pharmaceutical sciences, and medicine, particularly ophthalmology.
BACKGROUND
Age-related macular degeneration (AMD) and glaucoma are two of the leading causes of blindness in the United States and across the world. Present glaucoma therapies generally require polypharmacy, where subjects are often prescribed several topical agents that must be applied to the eye with varying frequencies, in some cases up to 3 or 4 times a day. These =
dosing regimens are often difficult for subjects to consistently follow, and many individuals progress to needing surgical treatments such as intraocular shunts or trabeculectomies, which have significant attendant complications.
Subjects having macular degeneration are often required to have monthly intravitreal injections. Such injections are painful and may lead to retinal detachment, endophthalmitis, and other complications. Furthermore, these injections are generally performed only by retinal surgeons, a small fraction of the ophthalmic community, producing a bottleneck in eye care delivery and increased expense.
Postoperative surgery inflammation is associated with raised intraocular pressure (lOP), and increases the likelihood of cystoid macular edema (CME), synechial formation, posterior capsule opacification (PCO), and secondary glaucoma. Patient compliance is of concern in the management of postoperative inflammation because multiple eye drops must be taken multiple times per day at regular intervals over the course of weeks.
Poor compliance compromises the efficacy of topical drugs, which are further limited by corneal absorption and have highly variable intraocular concentrations during the therapeutic course.
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea"
but in common usage may refer to any inflammatory process involving the interior of the eye.
Uveitis is estimated to be responsible for approximately 10% of the blindness in the United States.
Postoperative cataract surgery inflammation can be well controlled by improving patient compliance. Available literature and experience shows penetration of the drug after topical administration is poor and higher systemic concentration means frequent systemic adverse events. All of these factors highlight the need for sustained intraocular delivery for pharmaceutical active agents to effectively control inflammation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top view of an active agent delivery device in the shape of a disc.
FIG. 2 is a side view of an active agent delivery device in the shape of a disc.
FIG. 3 is a graphical representation of the amount of an active agent present in various eye tissues following implantation of an intraocular device in accordance with a further aspect of the present invention.
FIG. 4 is a photograph showing a bioerodible dexamethasone implant (BDI).
FIG. 5 is a graph of in-vitro release kinetics of the BDI-1 implant. Data are presented as mean SD (n=3).
FIG. 6 is a time vs. concentration profile of BDI-1 implant with 120 to 160 lig of dexamethasone (DXM) in aqueous and vitreous humor of New Zealand White (NZW) rabbits.
FIG. 7 is a time vs. concentration profile of BDI-1 implant with 120 to 160 lig of DXM in iris/ciliary body and retina/choroid of NZW rabbits.
FIG. 8 is a graph of in vitro release kinetics of dexamethasone from BDI-2 implants (containing 300 1.ig of DXM). Data are presented as Mean SD (n=3) [Form. A:
PLGA
50:50, M.W. 7,000-17000; Form. B: PLGA 65:35, M.W. 17000-32000; Form. C: PLGA
50:50, M.W. 7,000-17000 (50%), PLGA 65:35, M.W. 17000-32000 (50%); Form. D:
PLGA
50:50, M.W. 7,000-17000 with 10% hydroxypropyl methylcellulose (HPMC)].
FIG. 9 is a graph of time vs. concentration profile of BDI-2 implant and topical drops in aqueous humor of New Zealand white rabbits.
FIG. 10 is a graph of time vs. concentration profile of BDI-2 implant and topical drops in vitreous humor of New Zealand white rabbits.
FIG. 11 is a graph of time vs. concentration profile of BDI-2 implant and topical drops in retina/choroid of New Zealand white rabbits.
FIG. 12 is a graph of time vs. retinal thickness of New Zealand white rabbits in four
- 2 -groups: standard control, topical drops, BDI, and normal control.
These drawings merely depict exemplary embodiments of the present invention and they are, therefore, not to be considered limiting of its scope. It will be readily appreciated that the components of the present invention, as generally described and illustrated in the figures herein, could be arranged, sized, and designed in a wide variety of different configurations.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description of exemplary embodiments of the invention makes reference to the accompanying drawings, which form a part hereof and in which are shown, by way of illustration, exemplary embodiments in which the invention may be practiced.
While these exemplary embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, it should be understood that other embodiments may be realized and that various changes to the invention may be made without departing from the spirit and scope of the present invention. Thus, the following more detailed description of the embodiments of the present invention is not intended to limit the scope of the invention, as claimed, but is presented for purposes of illustration only and not limitation to describe the features and characteristics of the present invention, to set forth the best mode of operation of the invention, and to sufficiently enable one skilled in the art to practice the invention.
Accordingly, the scope of the present invention is to be defmed solely by the appended claims.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drug" includes reference to one or more of such drugs, "an excipient" includes reference to one or more of such excipients, and "loading" refers to one or more of such steps.
Definitions In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
As used herein, "active agent," "bioactive agent," "pharmaceutically active agent,"
and "drug," may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount. These terms of art are well-known in the pharmaceutical and medicinal arts.
These drawings merely depict exemplary embodiments of the present invention and they are, therefore, not to be considered limiting of its scope. It will be readily appreciated that the components of the present invention, as generally described and illustrated in the figures herein, could be arranged, sized, and designed in a wide variety of different configurations.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description of exemplary embodiments of the invention makes reference to the accompanying drawings, which form a part hereof and in which are shown, by way of illustration, exemplary embodiments in which the invention may be practiced.
While these exemplary embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, it should be understood that other embodiments may be realized and that various changes to the invention may be made without departing from the spirit and scope of the present invention. Thus, the following more detailed description of the embodiments of the present invention is not intended to limit the scope of the invention, as claimed, but is presented for purposes of illustration only and not limitation to describe the features and characteristics of the present invention, to set forth the best mode of operation of the invention, and to sufficiently enable one skilled in the art to practice the invention.
Accordingly, the scope of the present invention is to be defmed solely by the appended claims.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drug" includes reference to one or more of such drugs, "an excipient" includes reference to one or more of such excipients, and "loading" refers to one or more of such steps.
Definitions In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
As used herein, "active agent," "bioactive agent," "pharmaceutically active agent,"
and "drug," may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount. These terms of art are well-known in the pharmaceutical and medicinal arts.
- 3 -As used herein, "bioerodible" and "biodegradable" may be used interchangeably to refer to materials that can be broken down over time in the body of a subject organism, especially in a lens capsule or a ciliary sulcus of an eye of a subject. A
bioerodible material can be a solid matrix that dissolves slowly, releasing any active agents that have been incorporated into the bioerodible material. A bioerodible implant can eventually dissolve completely so that the implant does not need to be removed from the subject.
As used herein, "formulation" and "composition" may be used interchangeably herein, and refer to a combination of two or more elements, or substances. In some embodiments a composition can include an active agent, an excipient, or a carrier to enhance delivery, depot formation, etc.
As used herein, "subject" refers to a mammal that may benefit from the administration of a composition or method as recited herein. Examples of subjects include humans, and can also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, aquatic mammals, etc.
As used herein, the terms "reservoir" and "active agent reservoir" may be used interchangeably, and refer to a body, a mass, or a cavity that can contain an active agent. As such, a reservoir can include any structure that may contain a liquid, a gelatin, a sponge, a semi-solid, a solid or any other form of active agent known to one of ordinary skill in the art.
In some aspects a reservoir can also contain an active agent matrix. Such matrixes are well known in the art. A reservoir is not necessarily a physical structure that encloses another material inside itself. In some cases a reservoir can simply be a specific volume of an active agent matrix without any external containing structure.
As used herein, the term "intraocular lens" refers to a lens that is utilized to replace a lens in the eye of a subject. Such intraocular lenses can be synthetic or biological in nature.
Furthermore, in some aspects the term "intraocular lens" can also refer to the original natural lens that is associated with the eye.
As used herein, the term "ciliary sulcus" refers to the space between the posterior root of the iris and the ciliary body of the eye.
As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, 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
bioerodible material can be a solid matrix that dissolves slowly, releasing any active agents that have been incorporated into the bioerodible material. A bioerodible implant can eventually dissolve completely so that the implant does not need to be removed from the subject.
As used herein, "formulation" and "composition" may be used interchangeably herein, and refer to a combination of two or more elements, or substances. In some embodiments a composition can include an active agent, an excipient, or a carrier to enhance delivery, depot formation, etc.
As used herein, "subject" refers to a mammal that may benefit from the administration of a composition or method as recited herein. Examples of subjects include humans, and can also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, aquatic mammals, etc.
As used herein, the terms "reservoir" and "active agent reservoir" may be used interchangeably, and refer to a body, a mass, or a cavity that can contain an active agent. As such, a reservoir can include any structure that may contain a liquid, a gelatin, a sponge, a semi-solid, a solid or any other form of active agent known to one of ordinary skill in the art.
In some aspects a reservoir can also contain an active agent matrix. Such matrixes are well known in the art. A reservoir is not necessarily a physical structure that encloses another material inside itself. In some cases a reservoir can simply be a specific volume of an active agent matrix without any external containing structure.
As used herein, the term "intraocular lens" refers to a lens that is utilized to replace a lens in the eye of a subject. Such intraocular lenses can be synthetic or biological in nature.
Furthermore, in some aspects the term "intraocular lens" can also refer to the original natural lens that is associated with the eye.
As used herein, the term "ciliary sulcus" refers to the space between the posterior root of the iris and the ciliary body of the eye.
As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, 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
- 4 -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. For example, a composition that is "substantially free of' particles would either completely lack particles, or so nearly completely lack particles that the relevant effect would be the same as if it completely lacked particles. In other words, 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.
As used herein, 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.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims unless otherwise stated.
Means-plus-function or step-plus-function limitations will only be employed where for a specific claim limitation all of the following conditions are present in that limitation: a) "means for" or "step for" is expressly recited; and b) a corresponding function is expressly recited. The structure,
As used herein, 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.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims unless otherwise stated.
Means-plus-function or step-plus-function limitations will only be employed where for a specific claim limitation all of the following conditions are present in that limitation: a) "means for" or "step for" is expressly recited; and b) a corresponding function is expressly recited. The structure,
- 5 -material or acts that support the means-plus function are expressly recited in the description herein. Accordingly, the scope of the invention should be determined solely by the appended claims and their legal equivalents, rather than by the descriptions and examples given herein.
Intraocular Drug Delivery Device An intraocular drug delivery device can provide improved ophthalmic drug delivery by alleviating the need for multiple injections or complex eyedrop regimens by providing an intra-capsular reservoir which is implantable and biodegrades such that subsequent surgery is often unnecessary. Further, the device can deliver a variety or combination of different medicines.
A novel intraocular drug delivery device, system, and associated methods for providing sustained release of ocular active agents for extended periods of time are disclosed and described. One problem with many eye diseases such as Age-related Macular Degeneration (AMD) is the constant need for a subject to receive painful ocular injections, which have significant risks of retinal detachment, vitreous hemorrhage, and endophthalmitis.
The intraocular drug delivery device allows for sustained release of an active agent over time, thus eliminating the need for frequent ocular injections.
In some aspects, the device can be implantable during cataract surgery, essentially "piggybacking" on the cataract extraction, and thus eliminating the need for additional surgical procedures. One benefit to "piggybacking" on the cataract extraction is the ability to deliver steroids, antibiotics, and various non-steroidal agents directly to the eye after surgery, thus helping to minimize complications such as cystoid macular edema. In other aspects, the device can be implanted in a surgery that is separate from a cataract procedure, e.g., subsequent to a previous cataract extraction with reopening of the lens capsule.
It should be noted that neovascularization is a key pathobiological process in a variety of eye diseases, such as AMD, proliferative diabetic retinopathy, vascular occlusive disease, and radiation retinopathy. Additionally, the incidence of glaucoma is increasing worldwide.
Many other disorders, including severe uveitis and geographic atrophy in AMD, can be treated using such an intraocular drug delivery device. Such an anterior segment drug delivery device thus has great potential to improve the quality of life for subjects.
The drug delivery device can continuously deliver dexamethasone or other anti-inflammatory agents with near zero order kinetics for up to two weeks.
Treatment of uveitis needs long term (6-8 weeks) sustained delivery of anti-inflammatory agents.
The biggest disadvantage with topical drops is negligible concentrations of drugs will reach the posterior
Intraocular Drug Delivery Device An intraocular drug delivery device can provide improved ophthalmic drug delivery by alleviating the need for multiple injections or complex eyedrop regimens by providing an intra-capsular reservoir which is implantable and biodegrades such that subsequent surgery is often unnecessary. Further, the device can deliver a variety or combination of different medicines.
A novel intraocular drug delivery device, system, and associated methods for providing sustained release of ocular active agents for extended periods of time are disclosed and described. One problem with many eye diseases such as Age-related Macular Degeneration (AMD) is the constant need for a subject to receive painful ocular injections, which have significant risks of retinal detachment, vitreous hemorrhage, and endophthalmitis.
The intraocular drug delivery device allows for sustained release of an active agent over time, thus eliminating the need for frequent ocular injections.
In some aspects, the device can be implantable during cataract surgery, essentially "piggybacking" on the cataract extraction, and thus eliminating the need for additional surgical procedures. One benefit to "piggybacking" on the cataract extraction is the ability to deliver steroids, antibiotics, and various non-steroidal agents directly to the eye after surgery, thus helping to minimize complications such as cystoid macular edema. In other aspects, the device can be implanted in a surgery that is separate from a cataract procedure, e.g., subsequent to a previous cataract extraction with reopening of the lens capsule.
It should be noted that neovascularization is a key pathobiological process in a variety of eye diseases, such as AMD, proliferative diabetic retinopathy, vascular occlusive disease, and radiation retinopathy. Additionally, the incidence of glaucoma is increasing worldwide.
Many other disorders, including severe uveitis and geographic atrophy in AMD, can be treated using such an intraocular drug delivery device. Such an anterior segment drug delivery device thus has great potential to improve the quality of life for subjects.
The drug delivery device can continuously deliver dexamethasone or other anti-inflammatory agents with near zero order kinetics for up to two weeks.
Treatment of uveitis needs long term (6-8 weeks) sustained delivery of anti-inflammatory agents.
The biggest disadvantage with topical drops is negligible concentrations of drugs will reach the posterior
- 6 -segment of the eye and especially the retina/choroid. The designed and disclosed drug delivery device can deliver dexamethasone continuously with near zero order kinetics both to the anterior and posterior chamber thus effectively controlling the inflammation.
Therefore, the opportunity exists to improve management of AMD, postoperative surgery inflammation and uveitis patients undergoing cataract surgery by sustained release of pharmaceutical active agent(s). Accordingly, the present invention provides systems, devices, and associated methods for the delivery of active agents into the eye of a subject. In one aspect, as is shown in FIG. 1, an ocular active agent delivery device 100 can include a biodegradable active agent matrix 110. The ocular active agent delivery device can be sized and designed to fit inside of a lens capsule. In one aspect, the device can be sutureless. A
sutureless device can be defined as a device or structure that can be inserted and retained within a lens capsule without the need for a suture to hold the device in place. The device can stay in place without obstructing a line of sight of the eye.
The active agent delivery device can optionally contain one or more additional/separated reservoirs for the delivery of additional active agents or other desired therapeutically beneficial substances. In one aspect, for example, the device can include a primary active agent reservoir comprising a bioerodible active agent matrix containing a primary active agent, and secondary active agent reservoir comprising a bioerodible active agent matrix containing a secondary active agent. The secondary active agent reservoir can occupy a region within the device, such as a layer of bioerodible matrix material disposed within the primary active agent reservoir. It should be noted that the secondary active agent reservoir can contain an active agent that is the same or different from the active agent contained in the primary active agent reservoir. Secondary active agent reservoirs can also comprise different matrix materials from the primary active agent reservoir.
For example, a matrix material with a different dissolution rate can be used to control the rate of drug delivery from the primary and secondary reservoirs. Individual reservoirs can be segregated by impermeable walls or merely by providing an adjacent drug matrix.
In one aspect, as shown in FIG. 1 and FIG. 2, the active agent delivery device 100 can have an optional secondary active agent reservoir 120 within the device. In this particular embodiment, the device is a disc shape with secondary reservoir comprising a secondary active agent matrix in the center surrounded by the primary active agent matrix on the outside. This configuration can be manufactured by coextruding the primary and secondary matrix materials to form a core of the secondary matrix material surrounded by the primary matrix material. In other embodiments, an active agent delivery device can be disc-shaped as
Therefore, the opportunity exists to improve management of AMD, postoperative surgery inflammation and uveitis patients undergoing cataract surgery by sustained release of pharmaceutical active agent(s). Accordingly, the present invention provides systems, devices, and associated methods for the delivery of active agents into the eye of a subject. In one aspect, as is shown in FIG. 1, an ocular active agent delivery device 100 can include a biodegradable active agent matrix 110. The ocular active agent delivery device can be sized and designed to fit inside of a lens capsule. In one aspect, the device can be sutureless. A
sutureless device can be defined as a device or structure that can be inserted and retained within a lens capsule without the need for a suture to hold the device in place. The device can stay in place without obstructing a line of sight of the eye.
The active agent delivery device can optionally contain one or more additional/separated reservoirs for the delivery of additional active agents or other desired therapeutically beneficial substances. In one aspect, for example, the device can include a primary active agent reservoir comprising a bioerodible active agent matrix containing a primary active agent, and secondary active agent reservoir comprising a bioerodible active agent matrix containing a secondary active agent. The secondary active agent reservoir can occupy a region within the device, such as a layer of bioerodible matrix material disposed within the primary active agent reservoir. It should be noted that the secondary active agent reservoir can contain an active agent that is the same or different from the active agent contained in the primary active agent reservoir. Secondary active agent reservoirs can also comprise different matrix materials from the primary active agent reservoir.
For example, a matrix material with a different dissolution rate can be used to control the rate of drug delivery from the primary and secondary reservoirs. Individual reservoirs can be segregated by impermeable walls or merely by providing an adjacent drug matrix.
In one aspect, as shown in FIG. 1 and FIG. 2, the active agent delivery device 100 can have an optional secondary active agent reservoir 120 within the device. In this particular embodiment, the device is a disc shape with secondary reservoir comprising a secondary active agent matrix in the center surrounded by the primary active agent matrix on the outside. This configuration can be manufactured by coextruding the primary and secondary matrix materials to form a core of the secondary matrix material surrounded by the primary matrix material. In other embodiments, an active agent delivery device can be disc-shaped as
- 7 -shown in FIG. 1 and FIG. 2, but without a secondary reservoir in the center.
Therefore the entire active agent delivery device can be one homogeneous matrix material.
Bioerodible matrices can include a variety of polymeric and non-polymeric materials.
Specific non-limiting examples of suitable matrix materials include biodegradable polymers (e.g. PLGA, albumin), colloidal suspensions, nanoparticles, microparticles, microspheres, nanospheres, hydrogels, purites, polycarbophil, solid matrix, and the like.
Although numerous active agents are known for the treatment of various eye conditions, a few examples used in the treatment or prophylaxis of eye diseases such as AMD
(neovascular form or atrophic form), glaucoma, diabetic retinopathy, Retinopathy of Prematurity, uveitis, corneal transplant rejection, capsular fibrosis, posterior capsule opacification, retinal vein occlusions, infections, and the like, can be treated with non-limiting active agents such as dexamethasone, bevacizumab (Avastin0), Timolol, Latanoprost, Brimonidine, Nepafenac, and ranibizumab (LucentisS). Other non-limiting examples of active agents include antibiotics, prednisolone, fluocinolide, and the like.
Treatment regimens can additionally include anti-VEGF aptamers such as pegaptanib (Macugen0), anti-VEGF Fab fragments such as ranibizumab (Lucentis 0), integrin antagonists, various photodynamic therapies, and the like.
Yet another aspect of the present invention provides a method of delivering an active agent into an eye of a subject. Such a method can include performing a cataract removal surgery on the eye of the subject, further including removing an existing lens from the eye of the subject, inserting an intraocular lens into the eye of the subject, and associating a device as described herein with the intraocular lens. The delivery device may be attached or detached from the intraocular lens. The delivery device can be associated by actual contact or sufficient proximity to allow effective diffusion of active agent to target areas of the eye. The delivery device can itself be a biodegradable matrix or a reservoir system. A
biodegradable system would have value in routine cataract surgery to enable short-term/time-limited delivery of postoperative medicines which would otherwise require eyedrop usage by the patient. The lens that is removed can be the original natural lens of the eye, or it can be a lens that was previously inserted into the eye as a result of a prior procedure.
Numerous methods of associating the device into the eye are contemplated. For example, in one aspect, the device can be associated with the intraocular lens prior to inserting the intraocular lens into the eye. In such cases it would be necessary to configure the device to comply with any requirements of the surgical procedure. For example, cataract surgeries are often performed through a small incision. One standard size incision is about
Therefore the entire active agent delivery device can be one homogeneous matrix material.
Bioerodible matrices can include a variety of polymeric and non-polymeric materials.
Specific non-limiting examples of suitable matrix materials include biodegradable polymers (e.g. PLGA, albumin), colloidal suspensions, nanoparticles, microparticles, microspheres, nanospheres, hydrogels, purites, polycarbophil, solid matrix, and the like.
Although numerous active agents are known for the treatment of various eye conditions, a few examples used in the treatment or prophylaxis of eye diseases such as AMD
(neovascular form or atrophic form), glaucoma, diabetic retinopathy, Retinopathy of Prematurity, uveitis, corneal transplant rejection, capsular fibrosis, posterior capsule opacification, retinal vein occlusions, infections, and the like, can be treated with non-limiting active agents such as dexamethasone, bevacizumab (Avastin0), Timolol, Latanoprost, Brimonidine, Nepafenac, and ranibizumab (LucentisS). Other non-limiting examples of active agents include antibiotics, prednisolone, fluocinolide, and the like.
Treatment regimens can additionally include anti-VEGF aptamers such as pegaptanib (Macugen0), anti-VEGF Fab fragments such as ranibizumab (Lucentis 0), integrin antagonists, various photodynamic therapies, and the like.
Yet another aspect of the present invention provides a method of delivering an active agent into an eye of a subject. Such a method can include performing a cataract removal surgery on the eye of the subject, further including removing an existing lens from the eye of the subject, inserting an intraocular lens into the eye of the subject, and associating a device as described herein with the intraocular lens. The delivery device may be attached or detached from the intraocular lens. The delivery device can be associated by actual contact or sufficient proximity to allow effective diffusion of active agent to target areas of the eye. The delivery device can itself be a biodegradable matrix or a reservoir system. A
biodegradable system would have value in routine cataract surgery to enable short-term/time-limited delivery of postoperative medicines which would otherwise require eyedrop usage by the patient. The lens that is removed can be the original natural lens of the eye, or it can be a lens that was previously inserted into the eye as a result of a prior procedure.
Numerous methods of associating the device into the eye are contemplated. For example, in one aspect, the device can be associated with the intraocular lens prior to inserting the intraocular lens into the eye. In such cases it would be necessary to configure the device to comply with any requirements of the surgical procedure. For example, cataract surgeries are often performed through a small incision. One standard size incision is about
- 8 -2.75 mm; although this device can be compatible with smaller or larger incision sizes as well.
As such, the intraocular lens assembly can be shaped to allow insertion through this small opening. Thus the active agent delivery device must also be configured to be inserted with the intraocular lens assembly, e.g. by shape and choice of resilient and flexible material for the device. Additionally, the active agent delivery device can also be physically coupled or decoupled to the intraocular lens assembly prior to insertion of the assembly into the eye. In another aspect, the device can be associated with the intraocular lens assembly following insertion of the lens into the eye. The capsular bag can be readily reopened for a patient having prior cataract surgery. Thus, the insertion of the delivery device can be performed immediately prior to insertion of an intraocular lens or later in time as a separate procedure.
Consistent with the principles set forth above, another optional configuration includes the use of a homogeneous delivery device formed of an active agent matrix and the active agent. The ocular active agent delivery device can be configured to fit within a lens capsule or ciliary sulcus of an eye. The delivery device can be shaped in any geometry which allows for insertion into the lens capsule or ciliary sulcus. Although dimensions can vary, typical dimensions can range from about 0.5 mm to about 4 mm width and about 0.2 mm to about 1 mm thickness. Although the total mass of the delivery device can vary, most often the total mass can be from 0.2 mg to 4 mg. For example, about 2 mg total mass can provide effective active agent volume, while also balancing overall size to fit within the target tissue areas.
An active agent delivery device comprising a biodegradable polymer matrix can contain one or several excipients depending on the duration of active agent delivery. The device can be in the following dimensions as shown in FIG. 4, e.g. 2 to 2.5 mm in diameter and 1.0-1.5 mm in thickness. Placement of the device can be inferior to the intraocular lens (TOL) and implanted during cataract surgery. The ocular active agent delivery device can be configured to fit within a lens capsule or ciliary sulcus of an eye. The delivery device can be shaped in any geometry which allows for insertion into the lens capsule or ciliary sulcus. The device can be in the shape of a disc, pellet, rod, square shape, crescent, donut shape, or other shapes. Depending on the dosage requirement one or two devices can be implanted per eye.
Suitable active agent matrices can include dexamethasone or those listed previously as active agent carriers. Non-limiting examples of active agent matrix materials can include polymeric and non-polymeric materials. Specific non-limiting examples of suitable matrix materials include biodegradable polymers such as PLGA (different ratios of lactic to glycolide content and end groups such as acid or ester termination), PVA, PEG, PLA, PGA, HPMC, hydroxypropylcellulose, sodium carboxymethylcellulose, croscarmellose sodium,
As such, the intraocular lens assembly can be shaped to allow insertion through this small opening. Thus the active agent delivery device must also be configured to be inserted with the intraocular lens assembly, e.g. by shape and choice of resilient and flexible material for the device. Additionally, the active agent delivery device can also be physically coupled or decoupled to the intraocular lens assembly prior to insertion of the assembly into the eye. In another aspect, the device can be associated with the intraocular lens assembly following insertion of the lens into the eye. The capsular bag can be readily reopened for a patient having prior cataract surgery. Thus, the insertion of the delivery device can be performed immediately prior to insertion of an intraocular lens or later in time as a separate procedure.
Consistent with the principles set forth above, another optional configuration includes the use of a homogeneous delivery device formed of an active agent matrix and the active agent. The ocular active agent delivery device can be configured to fit within a lens capsule or ciliary sulcus of an eye. The delivery device can be shaped in any geometry which allows for insertion into the lens capsule or ciliary sulcus. Although dimensions can vary, typical dimensions can range from about 0.5 mm to about 4 mm width and about 0.2 mm to about 1 mm thickness. Although the total mass of the delivery device can vary, most often the total mass can be from 0.2 mg to 4 mg. For example, about 2 mg total mass can provide effective active agent volume, while also balancing overall size to fit within the target tissue areas.
An active agent delivery device comprising a biodegradable polymer matrix can contain one or several excipients depending on the duration of active agent delivery. The device can be in the following dimensions as shown in FIG. 4, e.g. 2 to 2.5 mm in diameter and 1.0-1.5 mm in thickness. Placement of the device can be inferior to the intraocular lens (TOL) and implanted during cataract surgery. The ocular active agent delivery device can be configured to fit within a lens capsule or ciliary sulcus of an eye. The delivery device can be shaped in any geometry which allows for insertion into the lens capsule or ciliary sulcus. The device can be in the shape of a disc, pellet, rod, square shape, crescent, donut shape, or other shapes. Depending on the dosage requirement one or two devices can be implanted per eye.
Suitable active agent matrices can include dexamethasone or those listed previously as active agent carriers. Non-limiting examples of active agent matrix materials can include polymeric and non-polymeric materials. Specific non-limiting examples of suitable matrix materials include biodegradable polymers such as PLGA (different ratios of lactic to glycolide content and end groups such as acid or ester termination), PVA, PEG, PLA, PGA, HPMC, hydroxypropylcellulose, sodium carboxymethylcellulose, croscarmellose sodium,
- 9 -polycaprolactone, hyaluronic acid, albumin, sodium chloride block copolymers thereof, and the like. Specific copolymers such as polylactic-polyglycolic acid block copolymers (PLGA), polyglycolic acid-polyvinyl alcohol block copolymers (PGA/PVA), hydroxypropylmethylcellulose (HPMC), polycaprolactone-polyethylene glycol block copolymers, croscarmellose, and the like can be particularly effective. In one aspect, the active agent matrix can be a PLGA having about 45-80% PLA and 55-20% PGA such as about 65% PLA and 35% PGA. In another alternative embodiment, the ratios of PLGA, dexamethasone and Croscarmellose sodium can be 60-90/5-25/5-25 or 50-75/10-ratios.
Homogeneous delivery devices can be formed, for example, by mixing a polymer material with a loading amount of active agent to form a matrix dispersion.
The loading amount can be chosen to correspond to the desired dosage during diffusion.
Loading amount can take into account diffusion characteristics of the polymer and active agent, residual active agent, delivery time, and the like. The matrix dispersion can then be formed into the device shape using any suitable technique. For example, the matrix dispersion can be cast, sprayed and dried, extruded, stamped or the like. Such configurations will most often be formed using a biodegradable matrix, although non-biodegradable materials can also be used.
For example, in one embodiment the matrix dispersion can be extruded through a die with a circular cross section, and then the extruded matrix dispersion can be sliced to create disc-shaped implants.
In one alternative formulation, the device can be formed in situ from a suspension of the active agent within a biodegradable polymer matrix precursor. Upon delivery into the target site, the biodegradable polymer matrix precursor can form (via precipitation and/or polymerization) the biodegradable active agent matrix in situ.
With the above homogeneous delivery device, particular efficacy can be provided for treatment of uveitis and post-operative cataract surgery inflammation. For example, dexamethasone can be dispersed within a biodegradable active agent matrix.
Although dexamethasone dosage amounts can vary, generally from about 100 mcg to about 400 mcg can be effective for these indications. More specifically, some patients can be categorized as low risk while others can be categorized as high risk due to various factors such as age, secondary complications, pre-existing conditions, etc. Most often, a low risk patient can benefit from a low dosage of about 100 mcg to about 150 mcg. In contrast, a high risk individual can be administered a high dosage of about 250 mcg to about 350 mcg. One particular embodiment of an active agent delivery device, the "BDI-1 implant,"
has been specifically designed and tested for the treatment of postoperative surgery inflammation and
Homogeneous delivery devices can be formed, for example, by mixing a polymer material with a loading amount of active agent to form a matrix dispersion.
The loading amount can be chosen to correspond to the desired dosage during diffusion.
Loading amount can take into account diffusion characteristics of the polymer and active agent, residual active agent, delivery time, and the like. The matrix dispersion can then be formed into the device shape using any suitable technique. For example, the matrix dispersion can be cast, sprayed and dried, extruded, stamped or the like. Such configurations will most often be formed using a biodegradable matrix, although non-biodegradable materials can also be used.
For example, in one embodiment the matrix dispersion can be extruded through a die with a circular cross section, and then the extruded matrix dispersion can be sliced to create disc-shaped implants.
In one alternative formulation, the device can be formed in situ from a suspension of the active agent within a biodegradable polymer matrix precursor. Upon delivery into the target site, the biodegradable polymer matrix precursor can form (via precipitation and/or polymerization) the biodegradable active agent matrix in situ.
With the above homogeneous delivery device, particular efficacy can be provided for treatment of uveitis and post-operative cataract surgery inflammation. For example, dexamethasone can be dispersed within a biodegradable active agent matrix.
Although dexamethasone dosage amounts can vary, generally from about 100 mcg to about 400 mcg can be effective for these indications. More specifically, some patients can be categorized as low risk while others can be categorized as high risk due to various factors such as age, secondary complications, pre-existing conditions, etc. Most often, a low risk patient can benefit from a low dosage of about 100 mcg to about 150 mcg. In contrast, a high risk individual can be administered a high dosage of about 250 mcg to about 350 mcg. One particular embodiment of an active agent delivery device, the "BDI-1 implant,"
has been specifically designed and tested for the treatment of postoperative surgery inflammation and
- 10 -can deliver pharmaceutical active agent up to 2 weeks. The "BDI-2 implant" is designed and tested for the treatment of postoperative surgery inflammation and uveitis and can deliver active agent up to 6-8 weeks. Depending on the severity of the inflammation one or two implants can be implanted during surgery per eye.
As previously mentioned, the delivery device herein is targeted for a relatively short delivery duration, and in most cases less than eight weeks. In one alternative, the active agent has a delivery duration of about two weeks to about six weeks. Delivery duration can be a function of the type of polymer used in the matrix, copolymer ratios, and other factors.
Although other biodegradable polymers can be suitable such as those listed previously, particularly suitable polymers can include at least one of poly(lactic-co-glycolide), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose, polycaprolactone, eudragit L100, eudragit RS100, poly(ethylene glycol) 4000, poly(ethylene glycol) 8000 and poly(ethylene glycol) 20,000. The biodegradable active agent matrix can comprise poly(lactic-co-glycolide) having a copolymer ratio from 52/48 to 90/10. In one specific example, the copolymer ratio can be 52-78/48-22 and in another specific example from 60-90/40-10. Although degradation rates can be dependent on such proportions, additional alternative approaches can also be useful such as device coatings, particle encapsulation, and the like.
Examples:
Example 1:
A standard clear-corneal phacoemulsification with intraocular lens (Acrysof SA6OAT;
Alcon) implantation was performed on 35 rabbits. At the time of each surgery, an intraocular device containing an active agent was inserted into a lens capsule of each rabbit. The rabbits were divided into 4 groups, depending on the active agent in the intraocular device. Devices were loaded with 5-15 mg of either Avastin, Timolol, Brimonidine, or Latanoprost. Each group was evaluated to determine the intraocular device and lens stability, capsular fibrosis, and healing of cataract wounds and anterior segment. A subgroup of eyes was evaluated weekly for 4 weeks for inflammation and harvested at 1 month for histopathologic evaluation of capsular and CDR integrity.
Example 2:
The surgery and setup as described in Example 1 was repeated, with the exception that aqueous and vitreous taps were performed biweekly and assayed for drag concentrations with HPLC and/or ELISA. In each drag group, half of the eyes were harvested at one month
As previously mentioned, the delivery device herein is targeted for a relatively short delivery duration, and in most cases less than eight weeks. In one alternative, the active agent has a delivery duration of about two weeks to about six weeks. Delivery duration can be a function of the type of polymer used in the matrix, copolymer ratios, and other factors.
Although other biodegradable polymers can be suitable such as those listed previously, particularly suitable polymers can include at least one of poly(lactic-co-glycolide), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose, polycaprolactone, eudragit L100, eudragit RS100, poly(ethylene glycol) 4000, poly(ethylene glycol) 8000 and poly(ethylene glycol) 20,000. The biodegradable active agent matrix can comprise poly(lactic-co-glycolide) having a copolymer ratio from 52/48 to 90/10. In one specific example, the copolymer ratio can be 52-78/48-22 and in another specific example from 60-90/40-10. Although degradation rates can be dependent on such proportions, additional alternative approaches can also be useful such as device coatings, particle encapsulation, and the like.
Examples:
Example 1:
A standard clear-corneal phacoemulsification with intraocular lens (Acrysof SA6OAT;
Alcon) implantation was performed on 35 rabbits. At the time of each surgery, an intraocular device containing an active agent was inserted into a lens capsule of each rabbit. The rabbits were divided into 4 groups, depending on the active agent in the intraocular device. Devices were loaded with 5-15 mg of either Avastin, Timolol, Brimonidine, or Latanoprost. Each group was evaluated to determine the intraocular device and lens stability, capsular fibrosis, and healing of cataract wounds and anterior segment. A subgroup of eyes was evaluated weekly for 4 weeks for inflammation and harvested at 1 month for histopathologic evaluation of capsular and CDR integrity.
Example 2:
The surgery and setup as described in Example 1 was repeated, with the exception that aqueous and vitreous taps were performed biweekly and assayed for drag concentrations with HPLC and/or ELISA. In each drag group, half of the eyes were harvested at one month
- 11 -and the other half at two months. This was accomplished as follows:
immediately after sacrificing the rabbit and enucleating the eye, the eye was frozen in liquid nitrogen to prevent perturbation and redistribution of drug in eye tissues. The eye was then dissected into 3 parts (aqueous humor, vitreous and retina/choroid layer) to evaluate anatomic toxicity and tissue drug concentration. The intraocular device was retrieved and assessed for remaining drug amounts. The distribution profile of the intraocular device was compared with the conventional intravitreal injection of 2.5 mg/0.1 cc Avastin for direct comparison of the different delivery methods.
At 2 and 4 months, eyes from the remaining subgroups of rabbits were enucleated, fixed by 10% formalin, embedded in paraffin, step sectioned, stained by hematoxyline and eosin (H & E), and examined for histological changes.
Example 3:
Three intraocular devices were implanted into eyes of New Zealand white rabbits under general anesthesia after lens extraction (phacoemulsification technique). Two of the devices were loaded with Avastin and one was loaded with the contrast agent Galbumin as a control. Proper intraocular device position was verified by MRI as well as clinical examination.
The rabbits were sacrificed and the eyes are removed and assayed after 1 week post implantation. Avastin was detected by ELISA in the retina and vitreous at concentrations of 24-48 mcg/mL, and was not present in the control rabbit eye. FIG. 3 shows the amount of Avastin assayed per ocular region at 1 week post implantation.
Example 4:
To confirm that placement of implant in the capsular bag and delivers drugs both to the front and back of the eye for short and long term, microparticles were prepared using PLGA [poly(d,l-lactide-co-glycolide), MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose (HPMC) and dexamethasone. Dexamethasone loaded PLGA
microspheres were prepared using standard oil-in-water (o/w) emulsion-solvent extraction method. An amount of 160 mg PLGA was dissolved in 4 mL methylene chloride and 1 mL
acetonitrile.
An amount of 40 mg dexamethasone and 10 mg of HPMC was dispersed in the PLGA
solution by vortexing for 5 min. This organic phase was then emulsified in 20 mL of a 2%
(w/v) PVA (MW 90 kDa) solution and homogenized. The resultant emulsion was poured into 200 mL of a 2.0% (w/v) PVA (MW 90 kDa) solution and stirred in an ice bath for 6 min. The contents were stirred for 8 hr at room temperature to evaporate the dichloromethane and acetonitrile to form a turbid microparticulate suspension. The microparticles were separated
immediately after sacrificing the rabbit and enucleating the eye, the eye was frozen in liquid nitrogen to prevent perturbation and redistribution of drug in eye tissues. The eye was then dissected into 3 parts (aqueous humor, vitreous and retina/choroid layer) to evaluate anatomic toxicity and tissue drug concentration. The intraocular device was retrieved and assessed for remaining drug amounts. The distribution profile of the intraocular device was compared with the conventional intravitreal injection of 2.5 mg/0.1 cc Avastin for direct comparison of the different delivery methods.
At 2 and 4 months, eyes from the remaining subgroups of rabbits were enucleated, fixed by 10% formalin, embedded in paraffin, step sectioned, stained by hematoxyline and eosin (H & E), and examined for histological changes.
Example 3:
Three intraocular devices were implanted into eyes of New Zealand white rabbits under general anesthesia after lens extraction (phacoemulsification technique). Two of the devices were loaded with Avastin and one was loaded with the contrast agent Galbumin as a control. Proper intraocular device position was verified by MRI as well as clinical examination.
The rabbits were sacrificed and the eyes are removed and assayed after 1 week post implantation. Avastin was detected by ELISA in the retina and vitreous at concentrations of 24-48 mcg/mL, and was not present in the control rabbit eye. FIG. 3 shows the amount of Avastin assayed per ocular region at 1 week post implantation.
Example 4:
To confirm that placement of implant in the capsular bag and delivers drugs both to the front and back of the eye for short and long term, microparticles were prepared using PLGA [poly(d,l-lactide-co-glycolide), MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose (HPMC) and dexamethasone. Dexamethasone loaded PLGA
microspheres were prepared using standard oil-in-water (o/w) emulsion-solvent extraction method. An amount of 160 mg PLGA was dissolved in 4 mL methylene chloride and 1 mL
acetonitrile.
An amount of 40 mg dexamethasone and 10 mg of HPMC was dispersed in the PLGA
solution by vortexing for 5 min. This organic phase was then emulsified in 20 mL of a 2%
(w/v) PVA (MW 90 kDa) solution and homogenized. The resultant emulsion was poured into 200 mL of a 2.0% (w/v) PVA (MW 90 kDa) solution and stirred in an ice bath for 6 min. The contents were stirred for 8 hr at room temperature to evaporate the dichloromethane and acetonitrile to form a turbid microparticulate suspension. The microparticles were separated
- 12 -by centrifugation, washed twice, resuspended in deionized water, and freeze-dried to obtain lyophilized particles. The prepared microparticles were characterized and pelleted using bench top pellet press with 2 mm die set to form an implant.
These implants were sterilized, implanted in the capsular bag of rabbit's eyes. Two dose groups were used (300 and 600 p.g), two rabbits were sacrificed from each of low and high dose group at 1, 2, 4, 6 weeks and various tissue samples (aqueous humor, vitreous humor, IOL, iris/ciliary body and retina/choroid) were collected and samples were analyzed by a validated LC/MS/MS method. Microspheres were in the range of 6 2 }un as confirmed by Zetasizer nano and SEM photomicrographs. Drug loading in the microparticles was >99%
and the final yield was 60% (i.e. encapsulation efficiency). Drug loading was determined as percent drug loading = (weight of drug loaded/weight of microspheres) x100.
Dose related pharmacokinetics with near zero order kinetics was observed in rabbits up to 6 weeks.
Further, dexamethasone flow was bidirectional from the endocapsular space into both the anterior and posterior chambers. There were also no cells or formation of fibrin in the anterior and posterior chambers of the eye. Histological examinations revealed all the tissues examined were normal and showed no signs of inflammation.
All the study animals were acquainted to study room conditions once they are out of quarantine and randomized. All the positive control group and implantation groups underwent phacoemulsification and insertion of an intraocular lens (IOL) in both the eyes.
Group III and IV received one and two implants per eye respectively.
Group I: Normal control group; n=6 Group II: Phacoemulsification and inserting IOL; DXM drops (up to 4 weeks with tapering) and antibiotic drops (up to 2 days); positive control group; n=6 Group-III: Phacoemulsification and inserting IOL; BDI implant low dose (one implant per eye) and antibiotic drops up to 2 days (b.i.d.) after surgery; n=8 Group-IV: Phacoemulsification and inserting IOL; BDI implant high dose (two implants per eye) and antibiotic drops up to 2 days (b.i.d.) after surgery, n=8 Results of in vitro release kinetics are presented in FIG. 8. All the batches exhibited biphasic release pattern with initial burst release on day-1 and thereafter slow and sustained release. The burst effect was slightly higher with implants containing HPMC.
A total of 16 animals (32 eyes) received the implant. Dexamethasone concentrations are presented in FIG. 9 through FIG. 11. The implants degraded slowly over 4 weeks and by week 6 were completely disappeared. Therapeutic concentrations of DXM was found up to week 6 with minimal systemic exposure (<40 ng/mL with high dose), whereas, with
These implants were sterilized, implanted in the capsular bag of rabbit's eyes. Two dose groups were used (300 and 600 p.g), two rabbits were sacrificed from each of low and high dose group at 1, 2, 4, 6 weeks and various tissue samples (aqueous humor, vitreous humor, IOL, iris/ciliary body and retina/choroid) were collected and samples were analyzed by a validated LC/MS/MS method. Microspheres were in the range of 6 2 }un as confirmed by Zetasizer nano and SEM photomicrographs. Drug loading in the microparticles was >99%
and the final yield was 60% (i.e. encapsulation efficiency). Drug loading was determined as percent drug loading = (weight of drug loaded/weight of microspheres) x100.
Dose related pharmacokinetics with near zero order kinetics was observed in rabbits up to 6 weeks.
Further, dexamethasone flow was bidirectional from the endocapsular space into both the anterior and posterior chambers. There were also no cells or formation of fibrin in the anterior and posterior chambers of the eye. Histological examinations revealed all the tissues examined were normal and showed no signs of inflammation.
All the study animals were acquainted to study room conditions once they are out of quarantine and randomized. All the positive control group and implantation groups underwent phacoemulsification and insertion of an intraocular lens (IOL) in both the eyes.
Group III and IV received one and two implants per eye respectively.
Group I: Normal control group; n=6 Group II: Phacoemulsification and inserting IOL; DXM drops (up to 4 weeks with tapering) and antibiotic drops (up to 2 days); positive control group; n=6 Group-III: Phacoemulsification and inserting IOL; BDI implant low dose (one implant per eye) and antibiotic drops up to 2 days (b.i.d.) after surgery; n=8 Group-IV: Phacoemulsification and inserting IOL; BDI implant high dose (two implants per eye) and antibiotic drops up to 2 days (b.i.d.) after surgery, n=8 Results of in vitro release kinetics are presented in FIG. 8. All the batches exhibited biphasic release pattern with initial burst release on day-1 and thereafter slow and sustained release. The burst effect was slightly higher with implants containing HPMC.
A total of 16 animals (32 eyes) received the implant. Dexamethasone concentrations are presented in FIG. 9 through FIG. 11. The implants degraded slowly over 4 weeks and by week 6 were completely disappeared. Therapeutic concentrations of DXM was found up to week 6 with minimal systemic exposure (<40 ng/mL with high dose), whereas, with
- 13 -dexamethasone drops systemic exposure was higher (>150 ng/mL during week 1).
Mean PK
parameters for BDI-2 implant and positive control group in aqueous humor, vitreous humor, retina/choroid, and iris/ciliary body are shown in Table 1 and 2.
Table 1: Pharmacokinetics in aqueous humor and vitreous humor Low dose: 300 jag High dose: 600 p.g Dexamethasone Drops Parameter Aqueous Vitreous Aqueous Vitreous Aqueous Vitreous humor humor humor humor humor humor Cmax (ng/mL) 650 109 892 151 62 24 3 0 Tmax (day) 19 8 28 0 7 0 28 0 14 0 16 11 AUCo-t 15231 18317 28202 32933 1023 (day*ng/mL) 361 2435 3369 4027 320 Ciast (ng/mL) 8 3 2 1 52 18 85 23 6 2 2 1 Table 2: Pharmacokinetics in retina/choroid and iris/ciliary body Low dose: 300 1.1g High dose: 600 j.tg Dexamethasone Drops Parameter Retina/ Retina/ Retina/
Iris/CB Iris/CB Iris/CB
Choroid Choroid Choroid Cmax (givi) 21 4 35 5 117 40 209 24 3 1 3 Tmax (day) 14 0 7 0 23 8 14 0 14 0 9 4 AUCo-t 2226 (day*Ilm) 1105 Ciast (I.LN) 1.3 0.6 1.5 0.5 12 8 13 10 0.2 0.1 0.5 0.3 Intraocular pressure was normal in all the groups. Further, there were no signs of anterior or posterior chamber inflammation as assessed with Slit lamp biomicroscopy and confirmed by histological examination. There was a trend in increase in retinal thickness in animals treated with dexamethasone drops whereas, implants maintained retinal thickness.
The PLGA polymer degrades in to lactic and glycolic acid through hydrolysis, then further degrades in to carbon dioxide and water before eliminating from the body. Implants did not migrate to the center to obstruct the visual field.
BDI-1 implant was manufactured by following partial solvent casting method with
Mean PK
parameters for BDI-2 implant and positive control group in aqueous humor, vitreous humor, retina/choroid, and iris/ciliary body are shown in Table 1 and 2.
Table 1: Pharmacokinetics in aqueous humor and vitreous humor Low dose: 300 jag High dose: 600 p.g Dexamethasone Drops Parameter Aqueous Vitreous Aqueous Vitreous Aqueous Vitreous humor humor humor humor humor humor Cmax (ng/mL) 650 109 892 151 62 24 3 0 Tmax (day) 19 8 28 0 7 0 28 0 14 0 16 11 AUCo-t 15231 18317 28202 32933 1023 (day*ng/mL) 361 2435 3369 4027 320 Ciast (ng/mL) 8 3 2 1 52 18 85 23 6 2 2 1 Table 2: Pharmacokinetics in retina/choroid and iris/ciliary body Low dose: 300 1.1g High dose: 600 j.tg Dexamethasone Drops Parameter Retina/ Retina/ Retina/
Iris/CB Iris/CB Iris/CB
Choroid Choroid Choroid Cmax (givi) 21 4 35 5 117 40 209 24 3 1 3 Tmax (day) 14 0 7 0 23 8 14 0 14 0 9 4 AUCo-t 2226 (day*Ilm) 1105 Ciast (I.LN) 1.3 0.6 1.5 0.5 12 8 13 10 0.2 0.1 0.5 0.3 Intraocular pressure was normal in all the groups. Further, there were no signs of anterior or posterior chamber inflammation as assessed with Slit lamp biomicroscopy and confirmed by histological examination. There was a trend in increase in retinal thickness in animals treated with dexamethasone drops whereas, implants maintained retinal thickness.
The PLGA polymer degrades in to lactic and glycolic acid through hydrolysis, then further degrades in to carbon dioxide and water before eliminating from the body. Implants did not migrate to the center to obstruct the visual field.
BDI-1 implant was manufactured by following partial solvent casting method with
-14-subsequent evaporation and removing the residual solvent by drying the product under high vacuum for 3 days. Various implants were prepared using PLGA [poly(d,l-lactide-co-glycolide), MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose (HPMC), croscarmellose sodium (cross linked sodium carboxymethylcellulose), hydroxypropyl cellulose and dexamethasone in several different compositions.
The dried particles were directly pelleted using bench top pellet press with a 2 mm die set to form an implant.
The selected BDI-1 implants (from in-vitro release studies, FIG. 5) were sterilized, implanted in the capsular bag of rabbit's eyes. Two implants with different composition and dose were tested in-vivo in NZW rabbits to establish pharmacokinetics. Two rabbits were sacrificed at 2, 6, 10, 15 days and various tissue samples (aqueous humor, vitreous humor, IOL, iris/ciliary body and retina/choroid) were collected and samples were analyzed by a validated LC/MS/MS method. Pharmacokinetics with near zero order kinetics was observed in rabbits up to 15 days. Further, dexamethasone flow was bidirectional from the endocapsular space into both the anterior and posterior chambers. There were also no cells or formation of fibrin in the anterior and posterior chambers of the eye.
Histological examinations revealed all the tissues examined were normal and showed no signs of inflammation.
Results of in vitro release kinetics are presented in FIG. 5. All the batches exhibited smooth release pattern with initial burst release on day-1 and thereafter slow and sustained release. The burst effect was slightly higher with implants containing HPMC.
A total of 8 animals (16 eyes) received the implant containing 120 g of DXM.
DXM
concentrations are presented in FIG. 6 and FIG. 7. The implants eroded slowly over 10 days and reaching trough concentrations of DXM by day 15. The implants are degraded by 80% of its mass by day 15 and expected to fully degrade by day 20. Therapeutic concentrations of DXM was found up to day 15 with minimal systemic exposure (<23 ng/mL), whereas, with dexamethasone drops systemic exposure was higher (>150 ng/mL during week 1, in-house data).
Example 5:
Microparticles containing DXM were prepared with PLGA [poly(lactide-co-glycolide)] and hydroxypropyl methylcellulose (HPMC) as reported previously by our group.
The BDI was placed in the inferior fornix of the capsular bag after intravitreal injection of Concanavalin A (Con-A) and subsequent phacoemulsification in New Zealand White (NZW) rabbits (n=18). All eyes were assessed clinically using slit lamp biomicroscopy and graded
The dried particles were directly pelleted using bench top pellet press with a 2 mm die set to form an implant.
The selected BDI-1 implants (from in-vitro release studies, FIG. 5) were sterilized, implanted in the capsular bag of rabbit's eyes. Two implants with different composition and dose were tested in-vivo in NZW rabbits to establish pharmacokinetics. Two rabbits were sacrificed at 2, 6, 10, 15 days and various tissue samples (aqueous humor, vitreous humor, IOL, iris/ciliary body and retina/choroid) were collected and samples were analyzed by a validated LC/MS/MS method. Pharmacokinetics with near zero order kinetics was observed in rabbits up to 15 days. Further, dexamethasone flow was bidirectional from the endocapsular space into both the anterior and posterior chambers. There were also no cells or formation of fibrin in the anterior and posterior chambers of the eye.
Histological examinations revealed all the tissues examined were normal and showed no signs of inflammation.
Results of in vitro release kinetics are presented in FIG. 5. All the batches exhibited smooth release pattern with initial burst release on day-1 and thereafter slow and sustained release. The burst effect was slightly higher with implants containing HPMC.
A total of 8 animals (16 eyes) received the implant containing 120 g of DXM.
DXM
concentrations are presented in FIG. 6 and FIG. 7. The implants eroded slowly over 10 days and reaching trough concentrations of DXM by day 15. The implants are degraded by 80% of its mass by day 15 and expected to fully degrade by day 20. Therapeutic concentrations of DXM was found up to day 15 with minimal systemic exposure (<23 ng/mL), whereas, with dexamethasone drops systemic exposure was higher (>150 ng/mL during week 1, in-house data).
Example 5:
Microparticles containing DXM were prepared with PLGA [poly(lactide-co-glycolide)] and hydroxypropyl methylcellulose (HPMC) as reported previously by our group.
The BDI was placed in the inferior fornix of the capsular bag after intravitreal injection of Concanavalin A (Con-A) and subsequent phacoemulsification in New Zealand White (NZW) rabbits (n=18). All eyes were assessed clinically using slit lamp biomicroscopy and graded
- 15 -with Draize scoring scale. Retinal thickness measurements were also performed.
The BDI
was effective at preventing retinal thickening. Retinal thickness measurements were carried out using SD-OCT (Spectral Domain Optical Coherence Tomography; Heidelberg Engineering GmbH, Heidelberg, Germany). Rabbits were anesthetized and dilated as above.
At least 4 measurements were taken from each eye. Readings were reported as mean SD.
Retinal thickness was defined as the distance between the inner retinal boundary (vitreous¨
retina interface) and the outer retinal boundary (retina¨retinal pigment epithelium interface).23 Baseline mean retinal thickness was 130 5 m in all study rabbits as measured by SD-OCT. In the standard control group, retinal edema increased progressively and architectural disruption was seen in n=4 eyes by week 4 (Fig. 6). Retinal thickness in the BDI
group was controlled effectively and was close to normal at all time points.
However, in the topical drops group, retinal thickness increased significantly (P<0.05) by week 1 which persisted up to week 6 in comparison to both normal control and BDI groups.
Results are presented in FIG. 12.
It should be understood that the above-described arrangements are only illustrative of application of the principles of the present invention. Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention. Thus, while the present invention has been described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that numerous modifications, including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.
The BDI
was effective at preventing retinal thickening. Retinal thickness measurements were carried out using SD-OCT (Spectral Domain Optical Coherence Tomography; Heidelberg Engineering GmbH, Heidelberg, Germany). Rabbits were anesthetized and dilated as above.
At least 4 measurements were taken from each eye. Readings were reported as mean SD.
Retinal thickness was defined as the distance between the inner retinal boundary (vitreous¨
retina interface) and the outer retinal boundary (retina¨retinal pigment epithelium interface).23 Baseline mean retinal thickness was 130 5 m in all study rabbits as measured by SD-OCT. In the standard control group, retinal edema increased progressively and architectural disruption was seen in n=4 eyes by week 4 (Fig. 6). Retinal thickness in the BDI
group was controlled effectively and was close to normal at all time points.
However, in the topical drops group, retinal thickness increased significantly (P<0.05) by week 1 which persisted up to week 6 in comparison to both normal control and BDI groups.
Results are presented in FIG. 12.
It should be understood that the above-described arrangements are only illustrative of application of the principles of the present invention. Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention. Thus, while the present invention has been described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that numerous modifications, including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.
- 16 -
Claims (16)
1. An intraocular active agent delivery device, comprising:
an active agent dispersed within a bioerodible active agent matrix, said active agent including dexamethasone and said delivery device being configured to fit within a lens capsule or ciliary sulcus of an eye.
an active agent dispersed within a bioerodible active agent matrix, said active agent including dexamethasone and said delivery device being configured to fit within a lens capsule or ciliary sulcus of an eye.
2. The device of claim 1, wherein the active agent is present at from about 100 mcg to about 400 mcg.
3. The device of claim 1, wherein the active agent is present at a low dosage of about 100 mcg to about 150 mcg.
4. The device of claim 1, wherein the active agent is present at a high dosage of about 250 mcg to about 350 mcg.
5. The device of claim 1, wherein active agent has a delivery duration of about two weeks to about 6 weeks.
6. The device of claim 1, wherein the bioerodible active agent matrix comprises at least one of poly(lactic-co-glycolide), polylactic-polyglycolic acid block copolymers (PLGA), hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol, croscarmellose sodium, hydroxypropylcellulose, sodium carboxymethylcellulose, polyglycolic acid-polyvinyl alcohol block copolymers (PGA/PVA), hydroxypropylmethylcellulose (HPMC), and polycaprolactone-polyethylene glycol block copolymers.
7. The device of claim 1, wherein the bioerodible active agent matrix comprises poly(lactic-co-glycolide) having a copolymer ratio from 52/48 to 90/10.
8. The device of claim 1, wherein the delivery device is shaped as a disc or pellet.
9. The device of claim 1, wherein the device is in the form of a suspension of the active agent within a bioerodible polymer matrix precursor, the bioerodible polymer matrix precursor forming the bioerodible active agent matrix in situ.
10. The device of claim 1, further comprising at least one secondary active agent reservoir disposed within the biodegradable active agent matrix.
11. The device of claim 1, wherein the delivery device has a total mass of 0.2 mg to 4 mg.
12. A method of treating an eye condition, comprising administering the active agent to the eye using the delivery device of Claim 1 by inserting the delivery device into the lens capsule or ciliary sulcus of the eye, wherein the eye condition is at least one of post-operative cataract surgical inflammation and uveitis.
13. The method of claim 14, wherein the inserting is performed during a cataract surgery.
14. The method of claim 14, wherein the inserting is performed after a cataract surgery to treat post-operative cataract surgical inflammation.
15. The method of claim 14, wherein the eye condition is uveitis.
16. The method of claim 14, wherein the delivery device is in the form of a suspension of the active agent within a bioerodible polymer matrix precursor, and inserting includes injecting the suspension into the lens capsule or ciliary sulcus such that the bioerodible polymer matrix precursor forms the bioerodible active agent matrix in situ.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2830555A CA2830555A1 (en) | 2013-10-18 | 2013-10-18 | Intraocular drug delivery device and associated methods |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2830555A CA2830555A1 (en) | 2013-10-18 | 2013-10-18 | Intraocular drug delivery device and associated methods |
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| Publication Number | Publication Date |
|---|---|
| CA2830555A1 true CA2830555A1 (en) | 2015-04-18 |
Family
ID=53002901
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2830555A Abandoned CA2830555A1 (en) | 2013-10-18 | 2013-10-18 | Intraocular drug delivery device and associated methods |
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| CA (1) | CA2830555A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110337296A (en) * | 2016-12-27 | 2019-10-15 | 犹他大学研究基金会 | Intraocular drug delivery device and correlation technique |
| US10813789B2 (en) | 2009-05-18 | 2020-10-27 | Dose Medical Corporation | Drug eluting ocular implant |
| US11253394B2 (en) | 2013-03-15 | 2022-02-22 | Dose Medical Corporation | Controlled drug delivery ocular implants and methods of using same |
| US11318043B2 (en) | 2016-04-20 | 2022-05-03 | Dose Medical Corporation | Bioresorbable ocular drug delivery device |
| US11559430B2 (en) | 2013-03-15 | 2023-01-24 | Glaukos Corporation | Glaucoma stent and methods thereof for glaucoma treatment |
| US11564833B2 (en) | 2015-09-25 | 2023-01-31 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
| US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
-
2013
- 2013-10-18 CA CA2830555A patent/CA2830555A1/en not_active Abandoned
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10813789B2 (en) | 2009-05-18 | 2020-10-27 | Dose Medical Corporation | Drug eluting ocular implant |
| US11253394B2 (en) | 2013-03-15 | 2022-02-22 | Dose Medical Corporation | Controlled drug delivery ocular implants and methods of using same |
| US11559430B2 (en) | 2013-03-15 | 2023-01-24 | Glaukos Corporation | Glaucoma stent and methods thereof for glaucoma treatment |
| US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
| US11564833B2 (en) | 2015-09-25 | 2023-01-31 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
| US11318043B2 (en) | 2016-04-20 | 2022-05-03 | Dose Medical Corporation | Bioresorbable ocular drug delivery device |
| CN110337296A (en) * | 2016-12-27 | 2019-10-15 | 犹他大学研究基金会 | Intraocular drug delivery device and correlation technique |
| EP3562489A4 (en) * | 2016-12-27 | 2020-07-29 | University of Utah Research Foundation | Intraocular drug delivery device and associated methods |
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