Patent Grant
11110001
Diseases that affect vision can be treated with a variety of therapeutic agents, but the delivery of drugs to the eye continues to be challenging. Injections of therapeutic via the eye can be painful, involve some risk of infection, hemorrhage and retinal detachment. Depending on the frequency, intra-ocular injections can be time-consuming for both patient and physician. Consequently, in at least some instances the drug may be administered less often than the prescribed frequency resulting in sub-optimal treatment benefit. Further, bolus intra-ocular injections may not provide the ideal pharmacokinetics and pharmacodynamics. A bolus injection of drug into the vitreous humor of a patient can result in a peak drug concentration several times higher than the desired therapeutic amount and then before the patient is able to get the next injection drop to a drug concentration that is far below therapeutic effectiveness.
In one aspect, disclosed is a drug delivery device configured to be at least partially implanted in an eye. The device includes a retention structure positioned near a proximal end region of the device; a penetrable element coupled to and extending within at least a portion of the retention structure; a porous drug release mechanism positioned in fluid communication with an outlet of the device; and a reservoir having a volume configured to contain one or more therapeutic agents and to be in fluid communication with the outlet through the porous drug release mechanism. The device is configured to be at least partially inserted into the eye along an axis of insertion. The reservoir is configured to enlarge from an insertion configuration having a first three-dimensional shape to an expanded configuration having a second three-dimensional shape. The second three-dimensional shape is eccentrically positioned relative to the axis of insertion.
A portion of the volume of the reservoir in the expanded configuration can enlarge away from the lens of the eye and can be greater than a remaining portion of the volume. The first portion and the remaining portion can each remain outside the visual axis of the eye. The reservoir can be formed of a non-compliant material. The non-compliant material of the reservoir can expand from the first three-dimensional shape to the second three-dimensional shape, but does not stretch beyond the second three-dimensional shape. A proximal end of the reservoir can be separated a distance from one or more internal tissue surfaces surrounding penetration site of the eye when in the expanded configuration. The device can remain outside the visual axis in the expanded configuration.
The device can further include a central core element extending from the proximal end region of the device to a distal end region of the device. The drug release mechanism can be coupled to the central core element near the distal end region of the device and the retention structure can be coupled to the central core element near the proximal end region of the device. The central core element can include an inner lumen and one or more openings extending through a wall of the central core element. The inner lumen of the central core element can be in fluid communication with the reservoir volume through the one or more openings. The one or more openings can direct flow of material injected into the device into the reservoir volume. The central core element can have a cylindrical geometry and further include a flow director to direct flow through the one more openings. The flow director can include a first cylindrical region coupled to a second cylindrical region by a funnel shaped region. The first cylindrical region can have a larger cross-sectional diameter than the second cylindrical region. The flow director can include a penetrable barrier positioned within the inner lumen of the central core element. The penetrable barrier can seal the inner lumen.
The retention structure can include a proximal flange element configured to extend outside a sclera of the eye and a neck. The neck can have a proximal region configured to extend through a penetration site in the sclera of the eye and a distal extension extending inside the sclera of the eye. The distal extension of the neck can surround a portion of the central core element near the proximal end of the device providing stabilization of the neck to maintain a position of the reservoir. The distal extension of the neck can prevent contact between the reservoir and internal surfaces of the eye adjacent the penetration site. An upper surface of the proximal flange element can indicate orientation of the reservoir in the expanded configuration. The upper surface of the flange element can include an orientation indicator visible to a user from outside the eye. The orientation indicator can be a shape of the flange element or a mark on the upper surface of the flange element. The distal extension of the neck can provide stabilization of the neck to maintain a position of the reservoir as indicated by the orientation indicator.
In an interrelated implementation, described is a drug delivery device that includes a proximal end region of the device having a retention structure and a penetrable element coupled to and extending within at least a portion of the retention structure; and a distal end region of the device configured to be at least partially implanted into an eye. The distal end region can include a porous drug release mechanism positioned in fluid communication with an outlet of the device; and a reservoir having a volume configured to contain one or more therapeutic agents and to be in fluid communication with the outlet through the porous drug release mechanism. The reservoir is configured to enlarge from an insertion configuration to an expanded configuration. After at least partial implantation in the eye along an axis of insertion, the device is configured to be changed from a first shape in which the distal end region of the device is aligned with the axis of insertion to a second shape in which the distal end region of the device is not aligned with the axis of insertion. The second shape can be a curvilinear shape that remains outside the visual axis of the eye and avoids contact with internal surfaces of the eye adjacent a penetration site. The expanded configuration of the reservoir can include a symmetrical expansion. The expanded configuration of the reservoir can be an asymmetrical expansion.
In an interrelated implementation, described is a drug delivery device configured to be at least partially implanted in an eye that includes a reservoir formed of non-compliant material forming a volume configured to contain one or more therapeutic agents. The device includes a central core element extending through the volume between a proximal end region of the reservoir and a distal end region of the reservoir. The central core element has a wall surrounding a lumen, an inlet to the lumen, an outlet from the lumen, and one or more openings extending through the wall of the central core element between the inlet and the outlet. The lumen is in fluid communication with the volume of the reservoir via the one or more openings. The device includes a porous drug release mechanism positioned within the outlet and configured to release the one or more therapeutic agents from the volume through the porous drug release mechanism. The non-compliant material of the reservoir is collapsed around the central core element forming a first three-dimensional shape prior to filling the volume with the one or more therapeutic agents when the device is in an insertion configuration. The non-compliant material of the reservoir is enlarged away from the central core element forming a second three-dimensional shape upon filling the volume with the one or more therapeutic agents when the device is in an expanded configuration.
The device can further include a retention structure positioned near a proximal end region of the device and a penetrable element coupled to and extending within at least a portion of the retention structure. The device can further include a flow director positioned within the lumen of the central core element. The flow director can be configured to facilitate filling of the reservoir volume. The flow director can include a first cylindrical region coupled to a second cylindrical region by a funnel-shaped region to direct flow through the one or more openings in the central core element. The first cylindrical region can have a larger cross-sectional diameter than the second cylindrical region.
In some variations, one or more of the following can optionally be included in any feasible combination in the above methods, apparatus, devices, and systems. More details of the devices, systems and methods are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings.
These and other aspects will now be described in detail with reference to the following drawings. Generally speaking the figures are not to scale in absolute terms or comparatively but are intended to be illustrative. Also, relative placement of features and elements may be modified for the purpose of illustrative clarity.
Described herein are implantable devices, systems and methods of use for the delivery of one or more therapeutics for the treatment of diseases. The devices and systems described herein maximize reservoir volume and capacity while minimizing overall device invasiveness and impact on eye anatomy and vision. In some implementations, the devices described herein include an expandable reservoir that can be compressed into a first configuration for minimally-invasive delivery into the eye, for example, through the sclera and expanded into a second, enlarged configuration upon filling with therapeutic agent following implantation in the eye. When in the second configuration, the reservoir can avoid interfering with the visual axis of the eye as well as remain a safe distance away from certain anatomical structures of the eye so as to avoid damage and impacting vision. As will be described herein, in some implementations the expandable reservoir in the expanded configuration takes on a shape that is eccentric, asymmetrical, or otherwise off-set from the axis of placement of the device into the eye tissue, for example an axis of insertion through the sclera. This off-set can result in a majority of the expanded volume of the reservoir being directed away from certain critical structures of the anterior segment of the eye, for example, the lens, the ciliary body, the choroid, the retina, as well as the sclera and surrounding internal tissue layers through which the device was inserted. In other implementations, the expandable reservoir in the expanded configuration can remain symmetrical or coaxial with a central axis of the device, but can be shaped such that at least a portion of the device is curved, angled, or otherwise off-set relative to the axis of insertion. For example, the expanded reservoir can be shaped into an arc or other curvilinear shape relative to the axis of insertion. Alternatively, the expanded reservoir can be shaped to form an angle relative to the axis of insertion. In these implementations, the overall length of the device can be increased while still remaining outside the visual axis or significantly impacting the visual field. These and other features of the devices described herein will be described in more detail below.
It should be appreciated that the devices and systems described herein can incorporate any of a variety of features described herein and that elements or features of one implementation of a device and system described herein can be incorporated alternatively or in combination with elements or features of another implementation of a device and system described herein as well as the various implants and features described in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047; and PCT Pat. Publication No. WO 2012/065006; the entire disclosures of which are incorporated herein by reference thereto. For example, the expandable reservoirs described herein may be used with any of the various implementations of a device or system. For the sake of brevity, explicit descriptions of each of those combinations may be omitted although the various combinations are to be considered herein. Additionally, described herein are different methods for implantation and access of the devices. The various implants can be implanted, filled, refilled etc. according to a variety of different methods and using a variety of different devices and systems. Provided are some representative descriptions of how the various devices may be implanted and accessed, however, for the sake of brevity explicit descriptions of each method with respect to each implant or system may be omitted.
It should also be appreciated that the devices and systems described herein can be positioned in many locations of the eye and need not be implanted specifically as shown in the figures or as described herein. The devices and systems described herein can be used to deliver therapeutic agent(s) for an extended period of time to one or more of the following tissues: intraocular, intravascular, intraarticular, intrathecal, pericardial, intraluminal and intraperitoneal. Although specific reference is made below to the delivery of treatments to the eye, it also should be appreciated that medical conditions besides ocular conditions can be treated with the devices and systems described herein. For example, the devices and systems can deliver treatments for inflammation, infection, and cancerous growths. Any number of drug combinations can be delivered using any of the devices and systems described herein.
The materials, compounds, compositions, articles, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein. Before the present materials, compounds, compositions, articles, devices, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific methods or specific reagents, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the invention(s) belong. All patents, patent applications, published applications and publications, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there are pluralities of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information is known and can be readily accessed, such as by searching the internet and/or appropriate databases. Reference thereto evidences the availability and public dissemination of such information.
As used herein, relative directional terms such as anterior, posterior, proximal, distal, lateral, medial, sagittal, coronal, transverse, etc. are used throughout this disclosure. Such terminology is for purposes of describing devices and features of the devices and is not intended to be limited. For example, as used herein “proximal” generally means closest to a user implanting a device and farthest from the target location of implantation, while “distal” means farthest from the user implanting a device in a patient and closest to the target location of implantation.
As used herein, a disease or disorder refers to a pathological condition in an organism resulting from, for example, infection or genetic defect, and characterized by identifiable symptoms.
As used herein, treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the devices described and provided herein.
As used herein, amelioration or alleviation of the symptoms of a particular disorder, such as by administration of a particular pharmaceutical composition, refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
As used herein, an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease. Such an amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. The amount can cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Repeated administration can be required to achieve the desired amelioration of symptoms. Pharmaceutically effective amount, therapeutically effective amount, biologically effective amount and therapeutic amount are used interchangeably herein to refer to an amount of a therapeutic that is sufficient to achieve a desired result, i.e. Therapeutic effect, whether quantitative or qualitative. In particular, a pharmaceutically effective amount, in vivo, is that amount that results in the reduction, delay, or elimination of undesirable effects (such as pathological, clinical, biochemical and the like) in the subject.
As used herein, sustained release encompasses release of effective amounts of an active ingredient of a therapeutic agent for an extended period of time. The sustained release may encompass first order release of the active ingredient, zero order release of the active ingredient, or other kinetics of release such as intermediate to zero order and first order, or combinations thereof. The sustained release may encompass controlled release of the therapeutic agent via passive molecular diffusion driven by a concentration gradient across a porous structure.
As used herein, a subject includes any animal for whom diagnosis, screening, monitoring or treatment is contemplated. Animals include mammals such as primates and domesticated animals. An exemplary primate is human. A patient refers to a subject such as a mammal, primate, human, or livestock subject afflicted with a disease condition or for which a disease condition is to be determined or risk of a disease condition is to be determined.
As used herein, a therapeutic agent referred to with a trade name encompasses one or more of the formulation of the therapeutic agent commercially available under the tradename, the active ingredient of the commercially available formulation, the generic name of the active ingredient, or the molecule comprising the active ingredient. As used herein, a therapeutic or therapeutic agents are agents that ameliorate the symptoms of a disease or disorder or ameliorate the disease or disorder. Therapeutic agent, therapeutic compound, therapeutic regimen, or chemotherapeutic include conventional drugs and drug therapies, including vaccines, which are known to those skilled in the art and described elsewhere herein. Therapeutic agents include, but are not limited to, moieties that are capable of controlled, sustained release into the body.
As used herein, a composition refers to any mixture. It can be a solution, a suspension, an emulsion, liquid, powder, a paste, aqueous, non-aqueous or any combination of such ingredients.
As used herein, fluid refers to any composition that can flow. Fluids thus encompass compositions that are in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams and other such compositions.
As used herein, a kit is a packaged combination, optionally, including instructions for use of the combination and/or other reactions and components for such use.
Eye Anatomy
The elastic lens 22 is located near the front of the eye 10. The lens 22 provides adjustment of focus and is suspended within a capsular bag from the ciliary body 20, which contains the muscles that change the focal length of the lens 22. A volume in front of the lens 22 is divided into two by the iris 18, which controls the aperture of the lens 22 and the amount of light striking the retina 26. The pupil is a hole in the center of the iris 18 through which light entering anteriorly passes. The volume between the iris 18 and the lens 22 is the posterior chamber. The volume between the iris 18 and the cornea 12 is the anterior chamber. Both chambers are filled with a clear liquid known as aqueous humor.
The cornea 12 extends to and connects with the sclera 24 at a location called the limbus 14 of the eye. The conjunctiva 16 of the eye is disposed over the sclera 24 and the Tenon's capsule (not shown) extends between the conjunctiva 16 and the sclera 24. The eye 10 also includes a vascular tissue layer called the choroid 28 that is disposed between a portion of the sclera 24 and the retina 26. The ciliary body 20 is continuous with the base of the iris 18 and is divided anatomically into pars plica and pars plana 25, a posterior flat area approximately 4 mm long.
The devices described herein can be positioned in many locations of the eye 10, for example in the pars plana region away from tendon of the superior rectus muscle and one or more of posterior to the tendon, anterior to the tendon, under the tendon, or with nasal or temporal placement of the therapeutic device. As shown in
Treatment Devices
The devices described herein are referred to as drug delivery devices, treatment devices, therapeutic devices, port delivery systems, and the like. It should be appreciated that these terms are used interchangeably herein and are not intended to be limiting to a particular implementation of device over another. The devices and systems described herein can incorporate any of a variety of features described herein and the elements or features of one implementation of a device and system described herein can be incorporated alternatively or in combination with elements or features of another implementation of a device and system described herein as well as the various implants and features described in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047; and PCT Pat. Publication No. WO 2012/065006. For the sake of brevity, explicit descriptions of each of those combinations may be omitted although the various combinations are to be considered herein. Additionally, described herein are different methods for implantation and access of the devices. The various implants can be implanted, filled, refilled etc. according to a variety of different methods and using a variety of different devices and systems. Provided are some representative descriptions of how the various devices may be implanted and accessed, however, for the sake of brevity explicit descriptions of each method with respect to each implant or system may be omitted.
The porous structures (also referred to herein as a drug release mechanism, release control element, RCE, or frit) as described herein can be used with a number of various different implantable therapeutic devices including one or more of those devices described U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047; and PCT Pat. Publication No. WO 2012/065006; the entire disclosures of which are incorporated herein by reference thereto.
The drug release mechanism 120 can be positioned in a variety of locations within the device 100 such that the volume of the reservoir 130 is in fluid communication with the drug release mechanism 120. For example, the drug release mechanism 120 can be positioned near a distal end region of the device 100 such as within an outlet 125 of the device 100, for release of the one or more therapeutic agents contained within the reservoir 130 into the eye. The drug release mechanism 120 can also be positioned in a region of the device proximal of the distal end region. The drug release mechanism 120 can also be positioned towards a particular area to be treated, such as the retina.
The device 100 can be implanted in the eye such that at least a portion of the device 100, for example the reservoir 130, the drug release mechanism 120 and one or more outlets 125, are positioned intraocularly. In some implementations, the device 100 can be positioned so as to extend through the sclera 24 from the pars plana region so as to release the therapeutic agent into the vitreous body 30. As mentioned above, the device 100 can be positioned in the eye along an axis of insertion A (see
As best shown in
As mentioned above, the neck of the retention structure 105 can also include a distal extension 117. The distal extension 117 of the neck can extend inside the eye a distance away from the inner surface of the sclera 24 at the penetration site. As described above and as best shown in
The distal extension 117 of the neck can provide stabilization to the penetrable region of the device 100 while eliminating contact between the expandable reservoir 130 and inner surfaces of the eye adjacent the proximal end of the device 100.
As mentioned above, the devices described herein can include one or more drug release mechanisms 120. The drug release mechanism 120 can be positioned adjacent and/or within the one or more outlets 125 such that the drug release mechanism 120 can control or regulate the delivery of the one or more therapeutic agents from the reservoir 130 through the one or more outlets 125. The contents of the reservoir 130 can be delivered according to slow diffusion rather than expelled as a fluid stream. In some implementations, the one or more drug release mechanisms 120 can be disposed within a region of the reservoir 130, such as a distal end region, or a region proximal to the distal end region of the device. In some implementations, the drug release mechanism 120 can be a covering or lining having a particular porosity to the substance to be delivered and can be used to provide a particular rate of release of the substance. The drug release mechanism 120 can be a release control mechanism, including but not limited to a wicking material, permeable silicone, packed bed, small porous structure or a porous frit, multiple porous coatings, nanocoatings, rate-limiting membranes, matrix material, a sintered porous frit, a permeable membrane, a semi-permeable membrane, a capillary tube or a tortuous channel, nano-structures, nano-channels, sintered nanoparticles and the like. The drug release mechanism 120 can have a porosity, a cross-sectional area, and a thickness to release the one or more therapeutic agents for an extended time from the reservoir. The porous material of the drug release mechanism 120 can have a porosity corresponding to a fraction of void space formed by channels extending through the material. The void space formed can be between about 3% to about 70%, between about 5% to about 10%, between about 10% to about 25%, or between about 15% to about 20%, or any other fraction of void space. The drug release mechanism 120 can be selected from any of the release control mechanisms described in more detail in U.S. Pat. No. 8,277,830, which is incorporated by reference herein.
As mentioned above, the devices described herein include a reservoir 130 configured to enlarge from a generally minimally-invasive insertion configuration to an expanded configuration with an increased volume. The insertion configuration of the devices described herein has a three-dimensional shape that is relatively low profile such that the device 100 can be inserted at least partially into the eye using a small gauge device, or directly into the eye through a small incision. Many of the devices described herein can be inserted using an incision or puncture that is minimally-invasive, for example in a range of about 1 mm to about 5 mm. In some implementations, the incision is a 3.2 mm incision. It should also be appreciated that in some implementations, the device 100 can have column strength sufficient to permit the device 100 to pierce through eye tissue without an internal structural support member or members. The device can be inserted through the sclera 24 without a prior incision or puncture having been made in the eye. For example, the device can be inserted using a needle cannula member extending through an interior of the device and the drug release mechanism 120 pressed or secured inside at a distal tip of the cannula member.
Generally, when in the insertion configuration the portion of the device 100 configured to penetrate the eye (e.g. the reservoir 130) can have a smaller cross-sectional diameter compared to the cross-sectional diameter of the portion of the device 100 configured to remain external to the eye (e.g. the flange element 110). In some implementations, the cross-sectional diameter of the reservoir 130 (e.g. collapsed around a central core element 135 as will be described in more detail below) in the insertion configuration can be about 1.3 mm to about 1.5 mm in diameter, the diameter of the proximal portion 116 of the neck can be about 2.7 mm long and about 1.5 mm wide, and the flange element 110 can be about 4.5 mm long and about 3.8 mm wide. In some implementations, the device 100 can be approximately 25 gauge such that the device 100 can be inserted through a needle bore. In this implementation, the flange element 110 can be of a resilient material (such as shape memory or a flexible silicone) such that it can be housed in the needle bore during implantation and released out the distal end of the needle bore at which point the flange element 110 can retake its shape. Further, the cross-sectional shape of the eye-penetrating portion of the device 100 when in the insertion configuration can vary including circular, oval, or other cross-sectional shape. Also, when in the insertion configuration the device 100 can have a substantially uniform diameter along its entire length or the cross-sectional dimension and shape can change along the length of the device 100. In some implementations, the shape of the device 100 in the insertion configuration can be selected to facilitate easy insertion into the eye. For example, the device 100 can be tapered from the proximal end region to the distal end region.
The length of the device 100 can vary depending on where and how the device 100 is to be implanted in the eye. Generally, the length is selected so as not to impact or enter the central visual field or cross the visual axis 27 of the eye upon implantation and filling of the device 100. In some implementations, the total length of the device can be between about 2 mm to about 10 mm. In some implementations, the total length of the device can be between about 3 mm to about 7 mm. In some implementations, the length of the intraocular region of the device is about 4 mm to about 5 mm long.
The reservoir 130 of the devices described herein can expand into a particular contour or shape that can maximize its overall capacity while minimizing its impact on the internal eye anatomy. The insertion configuration of the reservoir 130 can have a first three-dimensional shape and the expanded configuration can have a second three-dimensional shape that is different from the first. Again with respect to
The expandability of the reservoir 130 from a low profile dimension for insertion to an expanded profile dimension after insertion allows for the device to be inserted in a minimally-invasive manner and also have an increased reservoir capacity. This increased reservoir capacity, in turn, increases the duration of drug delivery from the device such that the device 100 need not be refilled as frequently, and/or can reach the targeted therapeutic concentration of drug in the eye. In some implementations, the volume of the reservoir 130 can be between about 0.5 to about 100 μL. In some implementations, the volume of the reservoir 130 can be at least about 1 μL, 2 μL, 3 μL, 4 μL, 5 μL, 10 μL, 15 μL, 20 μL, 25 μL, 30 μL, 35 μL, 40 μL, 45 μL, 55 μL, 60 μL, 65 μL, 70 μL, 75 μL, 80 μL, 85 μL, 90 μL, 95 μL, 96 μL, 97 μL, 98 μL, or 99 μL or other volume.
An outer wall of the reservoir 130 can be formed of a substantially non-compliant material that is expandable yet rigid and/or non-distensible material. As such, the reservoir 130 can be filled into the expanded configuration, but the material of the reservoir 130 is configured to maintain its shape and does not stretch so as to avoid an unintentional driving force created by the memory of the wall material of the reservoir 130. In other implementations, the outer wall of the reservoir 130 can be a compliant material such that a controllable pressure can be provided by the compliant wall of the reservoir 130 up to the point of pressure equalization, for example, to provide a small initial boost of drug delivery from the reservoir after filling. Examples of expandable, non-distensible, substantially non-compliant materials are provided herein, including but not limited to PET, Nylon, and acrylics. Examples of expandable, compliant materials are also provided herein, including but not limited to silicone, urethane, and acrylics.
In some implementations, the volume of the reservoir 130 and the shape of the reservoir 130 in the expanded configuration are selected to maximize the payload capacity as well as maximizing the distance away from the lens 22 and/or the sclera 24 adjacent the penetration site. For example, in some implementations, the volume of the reservoir 130 can be 60 μL and the shape of the reservoir 130 in the expanded configuration can be D-shaped, C-shaped, elliptical, eccentric, or other shape that can extend away from the insertion axis A of the device (see
As best shown in
The one or more openings 139 in the wall of the central core element 135 allow for fluid communication between the inner lumen 137 of the central core element 135 and the reservoir 130. Material introduced through the penetrable element 115 such as via a delivery element can be injected within the lumen 137 and the flow of fluid directed through the one or more openings 139 into the reservoir 130. The introduction of material into the reservoir 130 expands the inner volume of the reservoir 130 and causes the pliable walls of the reservoir 130 to move away from the longitudinal axis of the device and/or move away from the central core element 135. Expansion of the reservoir volume changes the reservoir from the initial, insertion configuration to the expanded configuration, which will be described in more detail below. Optimizing the size of the one or more openings 139 in relation to the diameter of the inner lumen 137 can help to direct flow through the central core element 135 through the one or more openings 139 into the reservoir 130. The central core element 135 can also include a flow director 140 to facilitate filling of the reservoir 130 and increase efficiency of filling (see
As mentioned above, the treatment devices described herein can be held by an insertion tool and inserted through the puncture or incision into the target region. As such, the distal end region of the devices can be shaped in order to ease initial wound entry. A distal end region of the device having a larger diameter and/or a flatter distal tip can be more difficult to find and insert through an incision or puncture as small as 3.2 mm. Further, abrupt edges in the outer contour of the device due to bonding between structural elements of the device (e.g. where a distal edge of the reservoir material bonds to the central core element) can negatively impact tissue entry. In some implementations, the distal end region of the treatment device is beveled, tapered or has a bullet-point tip or other element such that it smoothly penetrates the tissue during implantation.
In some implementations, the distal end of the treatment device can have a sleeve 131 associated with it, for example inserted over it or inside a region of the distal end (see
In other implementations, the sleeve 131 can insert over a distal end region of the treatment device 100 (see
In a further implementation, the sleeve 131 can insert over the distal end of the treatment device 100 as described above (see
As mentioned above, the central core element 135 can be bonded at a proximal end to an upper portion of the reservoir 130 and at a distal end to a lower portion of the reservoir 130. The bond between the central core element 135 and the reservoir 130 as well as the central core element 135 and the drug release mechanism 120 can be achieved by adhesives such as a two-part epoxy like Epotech 301. In some implementations, thermal fusing between the components is used. For example, if the central core element 135 and the reservoir material can both be made from thermally bondable materials, such as nylon or polysulfone (PSU), the two may be thermally bonded together using heat and compression providing a simpler manufacturing process and more reliable bond than adhesive. The central core element 135 also can be formed of a metal material and designed to accept the flow of plastic such that it can be joined to the reservoir using heat and compression despite not be formed of the same thermally bondable material. In some implementations, the distal and/or proximal region of the central core element 135 can incorporate a plurality of small holes to accept the flow of a polymer material such as a small hole pattern laser drilled into the core. If the reservoir material and the central core element are made from similar materials or the core has features designed to accept the flow of a polymer material an ultrasonic welding process can be used to provide energy required to create the bond between them. In further implementations, the central core element 135 can be formed of a thermoplastic that can allow for the development of an over-molding process between the drug release mechanism 120 to create a bond joint between the drug release mechanism 120 and the central core element 135 at the distal end of the device.
It should be appreciated that the devices described herein need not include a flow director 140 or a central core element 135. For example,
As discussed above, the device can include a proximal retention structure 105 having a smooth protrusion or flange element 110 configured to remain generally external to the eye to aid in retention of the device 100 when the remainder of the device 100 is implanted intraocularly. In some implementations, the flange element 110 can be designed to provide an identifiable orientation of the device 100 for implanting in the eye such that the direction of expansion of an eccentrically expanding reservoir 130 is predictable and according to a desired orientation. The reservoir 130 once implanted within the vitreous 30 may not be directly visualized. Thus, an orientation indicator 150 on a portion of the device 100, such as the flange element 110, that can be visualized from outside the eye allows a user to know the expansion of the reservoir 130 will be in the correct plane. For example,
The devices described herein can incorporate expanding reservoirs that are also symmetrically distributed in the expanded configuration. As previously shown in
Methods of Use
It should be appreciated that the treatment devices described herein can be used in a variety of locations and implanted in a variety of ways. The implantation method and use of the treatment devices described herein can vary depending on the type of treatment device being implanted and the intended location and drug for treatment. As will be described in more detail below, the treatment devices described herein can be primed, implanted, filled, refilled, and/or explanted using one or more devices.
In one implementation of treatment device implantation, a sclerotomy is created according to conventional techniques. The sclerotomy can be created posterior to an insertion site of the treatment device through the sclera 24 or the sclerotomy can be created directly above the insertion site of the post through the sclera 24. The conjunctiva 16 can be dissected and retracted so as to expose an area of the sclera 24. An incision in the conjunctiva 16 can be made remote from the intended insertion site of the treatment device. A scleral incision or puncture can be formed. The scleral incision or puncture can be made with a delivery device tool or using a distal tip of the treatment device, as described above. In some implementations, the treatment device is implanted using sutureless surgical methods and devices. In other implementations, the treatment device can be positioned sub-sclerally such as under a scleral flap. The post can be inserted into the eye (such as within the vitreous or the anterior chamber, etc.) until at least one of the outlets is positioned within or near the target delivery site and, if a flange element is present, until the inner-facing surface of the flange element can abut an outer surface of the eye. An additional fixation element can be used such as a suture or other element if needed following implantation of the treatment device in the eye. The treatment device can remain in position to deliver the one or more therapeutic agents to the eye for a period of time including, but not limited to 1, 2, 3, 4, 5, 10, 15, 20, 25 days or any number of days, months and year, up to at least about 3 years. After the therapeutic agent has been delivered for the desired period of time, the treatment device can be refilled for further delivery or removed.
Generally, the implementations of the treatment devices described herein contain drug solutions, drug suspensions and/or drug matrices. The treatment devices described herein can also contain therapeutic agents formulated as one or more solid drug core or pellets formulated to deliver the one or more therapeutic agents at therapeutically effective amounts for an extended period of time. The period of time over which the treatment device delivers therapeutically effective amounts can vary. In some implementations, the treatment device is implanted to provide a therapy over the effective life of the device such that refill of the device is not necessary.
As described herein the treatment device can have an expandable reservoir formed of a generally non-compliant material. The reservoir can be folded down so that it fits within the internal volume of a delivery element and deployed reliably upon expansion.
The treatment devices described herein can be primed and inserted using one or more devices described in U.S. Publication No. 2015/0080846, which is incorporated by reference herein. In some implementations, the folded down treatment device 2100 can be held within a priming tool 2200.
The priming tool 2200 can further include a channel 2220 between the clamshells 2210 (see
The treatment device 2100 can be primed using a priming needle. The priming needle can be part of an insertion tool or can be a separate priming needle of a separate tool. The priming needle can penetrate the septum of the treatment device 2100 constrained within the cavity 2215 between the opposing clamshells 2210 of the priming tool 2200. The priming needle can be coupled to a syringe filled with an amount of priming fluid. The syringe can be actuated such as via a plunger to inject fluid into the constrained device to purge air out of the device 2100. The air can be purged through a porous structure in the treatment device 2100, such as the drug release mechanism at a distal end of the treatment device 210, as the injected priming fluid is injected into the reservoir 2130 of the device 2100. The priming fluid can be a fluid such as saline or can be a drug solution to be delivered to the patient. Because the treatment device 2100 is constrained between the clamshells 2210 priming does not discernibly expand the reservoir 2130.
Again with respect to
Although the treatment device 2100 held by the insertion tool 2300 can be inserted through a puncture or an incision in the target region in a known manner, the orientation of the treatment device 2100 can be rotationally adjusted once inserted, if desired. In some implementations, the insertion tool 2300 can incorporate one or more features designed specifically to rotate the treatment device 2100 around the axis of insertion A. As mentioned above, the insertion tool 2300 can include a seating element 2325 configured to urge the treatment device 2100 through the incision. The seating element 2325 can have a distal end 2320 shaped to mate with and apply torque to the treatment device 2100. As best shown in
The seating element 2325 and/or the needle post 2310 can be movable relative to the handle 2305, for example, rotated as described above, advanced in a distal direction, and/or withdrawn in a proximal direction. Alternatively, the seating element 2325 and needle post 2310 can be fixed relative to the handle 2305 such that the entire insertion tool 2300 is moved by the operator in a clockwise, counter-clockwise, distal or proximal direction relative to a patient to seat the therapeutic device. Once the treatment device 2100 is properly oriented within the target treatment location, the seating element 2325 can be used to seat the treatment device 2100 into its final position in the incision with a single advancing motion.
In some implementations, the seating element 2325 can have an outer surface that is shaped to engage an inner surface of the end effectors 2350 to urge them in an outward direction as the seating element 2325 is advanced distally through the end effectors 2350 to seat the treatment device 2100. As best shown in
The reservoir 2130 can be filled and expanded following implantation and seating of the device. However, it should be appreciated that the reservoir 2130 can be filled prior to, during, or after final seating the treatment device 2100 fully within the incision as will be described in more detail below. In some implementations, the fill needle 2500 can be a 30 gauge needle that has a hub providing visual feedback via its fluid return path when the treatment device 2100 has been filled (see
In some implementations, the fill needle 2500 can be the same as the prime needle used to prime and purge air from the treatment device as described above. The fill needle 2500 can also be the same as the needle on the insertion device 2300 used to hold and deliver the treatment device into position as described above. It should be appreciated that the priming needle, needle post 2310, and fill needle 2500 can each be separate devices such that three penetrations of the septum in the treatment device 2100 occurs during prime, insertion and filling. It should be appreciated that the priming needle, needle post 2310, and fill needle 2500 can be the same needle such that a single penetration of the septum is performed during prime, insertion and filling. Alternatively, the prime needle and needle post 2310 can be the same component and the fill needle 2500 separate component or the prime needle a separate component and the needle post 2310 and the fill needle 2500 the same component such that only two penetrations are needed to prime, insert, and fill the therapeutic device initially. It should also be appreciated that the treatment devices described herein can be refilled after a period of time. The septum of the treatment device can be penetrated during refill with a refill needle, for example such as that described in U.S. Pat. No. 9,033,911 or in U.S. Publication No. 2013/0165860, which are each incorporated by reference herein. The refill needle and the fill needle can be the same type of needle or can be distinct from one another. For example, the fill needle may or may not incorporate features to visualize filling whereas the refill needle does incorporate such features.
Once the expanded volume of the implanted reservoir is achieved, the device can be refilled at predictable intervals (e.g. every 3, 4, 5, 6 months or as along as every 12 months). However, changing the volume of the expanded device once implanted in the eye may not be desirable (e.g. movement in the eye once implanted may lead to potential trauma to surrounding structures or fluctuations in intraocular pressure) and is thus something to be avoided. The treatment devices described herein once implanted and expanded can maintain a consistent volume such that the outer diameter or contour of the reservoir does not change substantially throughout the use of the device and regardless of fill status. Further, the treatment devices described herein can maintain the same expanded shape even while fluid is being injected into the reservoir and/or while fluid is being removed from the reservoir (e.g. using the refill needle with or without flow directors). For example, drug passively diffuses through the porous drug delivery mechanism and out of the expanded reservoir over time. Despite this drug release into the eye, the expanded reservoir can remain filled with fluid, for example, fluid that enters the reservoir from the vitreous and drug formulation fluid remaining in the reservoir. The reservoir material can be formed of a substantially non-compliant material that tends to maintain its physical structure regardless of whether the interior of the reservoir is filled with drug. Further, refill of the treatment devices described herein can be performed such that a negative pressure and/or a positive pressure does not build within it. The refill and exchange devices used can incorporate features to avoid aspirating or evacuating the fluid within the reservoir and instead exchange the fluid while maintaining a substantially constant internal pressure. The treatment devices as well can incorporate one or more features to encourage this pressure-neutral exchange. For example, the treatment device can incorporate a central core element extending through the volume of the reservoir that has a wall surrounding a lumen, an inlet to the lumen, an outlet from the lumen, and one or more openings extending through the wall of the central core element between the inlet and the outlet. The lumen can be in fluid communication with the volume of the reservoir via the one or more openings. In some implementations, the one or more openings are located along the wall of the central core element to encourage exchange of new drug formulation fluid with the fluid remaining within the reservoir. For example, a first opening can be located near a distal end region of the central core element such that upon insertion of the refill/exchange needle through the inlet new drug formulation is delivered near this first opening. At least a second opening can be located near a proximal end region of the central core element. The fluid remaining within the reservoir that is to be exchanged for the new drug formulation can exit the reservoir volume through the second opening(s). An outlet lumen of the refill/exchange needle can be positioned near this second opening such that the fluid is removed from the treatment device through the outlet lumen. This arrangement of inlet and outlet openings in the central core element can encourage exchange of fluids (e.g. new formulation for old formulation) without mixing and without impacting the pressure within the reservoir volume that could impact the outer diameter or contour of the expandable reservoir. Further, the central core element can protect the material of the reservoir as the refill needle is inserted through the inlet of the central core element. The insertion configuration of the treatment device is when the non-compliant material of the reservoir is collapsed around the central core and forms a first three-dimensional shape prior to filling the volume with the one or more therapeutic agents. The non-compliant material of the reservoir is enlarged away from the central core element forming a second three-dimensional shape upon filling the volume with the one or more therapeutic agents when in an expanded configuration. This second three-dimensional shape achieved upon filling is then maintained throughout the life of the treatment device regardless of fill status or whether or not fluid is being added to the reservoir or taken from the reservoir.
The treatment devices described herein need not be removed and can remain in place indefinitely so long as therapeutically effective and beyond. However, the treatment device 2100 can be explanted (i.e. removed from the target location). Because the reservoir 2130 is expanded to a profile that is greater than the insertion profile, the reservoir 2130 is preferably unexpanded prior to removal. An aspiration needle can be connected, such as by tubing or other connector, to an aspiration device. The aspiration device can be a vacuum-lock syringe that creates a vacuum and provides suction for aspiration from the reservoir 2130. The syringe can be actuated by a luer lock lever, for example, to aspirate the reservoir 2130 of the treatment device 2100 and remove remaining contents. This system can be used to aspirate the contents of the reservoir 2130 for refill of the device and/or for removal of the device. The contents aspirated can be made visible through the aspiration device for visual feedback on completion of the aspiration process. Aspiration can collapse the expanded reservoir to a low profile such that the device 2100 can be explanted through the incision cavity. Smaller profile can reduce the removal force required as well as limit contact with internal tissues that can cause bleeding and damage. The aspirated and collapsed treatment devices described herein can be removed according to the methods and using the devices described in U.S. Patent Publication No. 2015/0080846, which is incorporated by reference herein. A long cannula or stylet can aid in stabilizing the therapeutic device during explanation, for example, if the device 2100 has no central core element 135, during evacuation of the reservoir 130 to a smaller outer diameter for ease of removal during explant.
Indications
The treatment devices described herein can be used to treat and/or prevent a variety of other ocular conditions besides glaucoma, including but not limited to dry or wet age-related macular degeneration (AMD), neuroprotection of retinal ganglion cells, cataract or presbyopia prevention, cancers, angiogenesis, neovascularization, choroidal neovascularization (CNV) lesions, retinal detachment, proliferative retinopathy, proliferative diabetic retinopathy, degenerative disease, vascular diseases, occlusions, infection caused by penetrating traumatic injury, endophthalmitis such as endogenous/systemic infection, post-operative infections, inflammations such as posterior uveitis, retinitis or choroiditis and tumors such as neoplasms and retinoblastoma. Still further conditions that can be treated and/or prevented using the devices and methods described herein, include but are not limited to hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditary diseases such as cerebrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Graves' disease, systemic lupus erythematosus and rheumatoid arthritis, shock and wasting disorders, cystic fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel disease, gastrointestinal or other cancers, degenerative diseases, trauma, multiple systemic conditions such as anemia.
Therapeutics
Examples of therapeutic agents that may be delivered by the treatment devices described herein and/or are described in the applications incorporated by reference herein are provided below and in Table 1, which is incorporated herein in its entirety.
Therapeutics that can be delivered from the devices described herein include but are not limited to Triamcinolone acetonide, Bimatoprost (Lumigan) or the free acid of bimatoprost, latanoprost or the free acid or salts of the free acid of latanoprost, Ranibizumab (Lucentis™) Travoprost (Travatan, Alcon) or the free acid or salts of the free acid of travoprost, Timolol (Timoptic, Merck), Levobunalol (Betagan, Allergan), Brimonidine (Alphagan, Allergan), Dorzolamide (Trusopt, Merck), Brinzolamide (Azopt, Alcon). Additional examples of therapeutic agents that may be delivered by the therapeutic device include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol kanamycin, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin and penicillin; antifungals such as amphotericin B and miconazole; anti-bacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals such as idoxuridine, trifluorotymidine, acyclovir, ganciclovir and interferon; antiallergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine; anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, and triamcinolone; non-steroidal anti-inflammatories such as salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen and piroxicam; decongestants such as phenylephrine, naphazoline and tetrahydrozoline; miotics and anticholinesterases such as pilocarpine, salicylate, acetylcholine chloride, physostigmine, eserine, carbachol, diisopropyl fluorophosphate, phospholine iodide and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics such as epinephrine; antineoplastics such as carmustine, cisplatin and fluorouracil; immunological drugs such as vaccines and immune stimulants; hormonal agents such as estrogens, estradiol, progestational, progesterone, insulin, calcitonin, parathyroid hormone and peptide and vasopressin hypothalamus releasing factor; beta adrenergic blockers such as timolol maleate, levobunolol HCl and betaxolol HCl; growth factors such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, somatotropin and fibronectin; carbonic anhydrase inhibitors such as dichlorophenamide, acetazolamide and methazolamide and other drugs such as prostaglandins, antiprostaglandins and prostaglandin precursors. Other therapeutic agents known to those skilled in the art which are capable of controlled, sustained release into the eye in the manner described herein are also suitable for use in accordance with embodiments of the devices described herein.
The therapeutic agent can also include one or more of the following: Abarelix, Abatacept, Abciximab, Adalimumab, Aldesleukin, Alefacept, Alemtuzumab, Alpha-1-proteinase inhibitor, Alteplase, Anakinra, Anistreplase, Antihemophilic Factor, Antithymocyte globulin, Aprotinin, Arcitumomab, Asparaginase, Basiliximab, Becaplermin, Bevacizumab, Bivalirudin, Botulinum Toxin Type A, Botulinum Toxin Type B, Capromab, Cetrorelix, Cetuximab, Choriogonadotropin alfa, Coagulation Factor IX, Coagulation factor VIIa, Collagenase, Corticotropin, Cosyntropin, Cyclosporine, Daclizumab, Darbepoetin alfa, Defibrotide, Denileukin diftitox, Desmopressin, Dornase Alfa, Drotrecogin alfa, Eculizumab, Efalizumab, Enfuvirtide, Epoetin alfa, Eptifibatide, Etanercept, Exenatide, Felypressin, Filgrastim, Follitropin beta, Galsulfase, Gemtuzumab ozogamicin, Glatiramer Acetate, Glucagon recombinant, Goserelin, Human Serum Albumin, Hyaluronidase, Ibritumomab, Idursulfase, Immune globulin, Infliximab, Insulin Glargine recombinant, Insulin Lyspro recombinant, Insulin recombinant, Insulin, porcine, Interferon Alfa-2a, Recombinant, Interferon Alfa-2b, Recombinant, Interferon alfacon-1, Interferonalfa-n1, Interferon alfa-n3, Interferon beta-1b, Interferon gamma-1b, Lepirudin, Leuprolide, Lutropin alfa, Mecasermin, Menotropins, Muromonab, Natalizumab, Nesiritide, Octreotide, Omalizumab, Oprelvekin, OspA lipoprotein, Oxytocin, Palifermin, Palivizumab, Panitumumab, Pegademase bovine, Pegaptanib, Pegaspargase, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant, Pramlintide, Ranibizumab, Rasburicase, Reteplase, Rituximab, Salmon Calcitonin, Sargramostim, Secretin, Sermorelin, Serum albumin iodonated, Somatropin recombinant, Streptokinase, Tenecteplase, Teriparatide, Thyrotropin Alfa, Tositumomab, Trastuzumab, Urofollitropin, Urokinase, or Vasopressin.
The therapeutic agent can include one or more of compounds that act by binding members of the immunophilin family of cellular proteins. Such compounds are known as “immunophilin binding compounds” Immunophilin binding compounds include but are not limited to the “limus” family of compounds. Examples of limus compounds that may be used include but are not limited to cyclophilins and FK506-binding proteins (FKBPs), including sirolimus (rapamycin) and its water soluble analog SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779 (Wyeth), AP23841 (Ariad), and ABT-578 (Abbott Laboratories). The limus family of compounds may be used in the compositions, devices and methods for the treatment, prevention, inhibition, delaying the onset of, or causing the regression of angiogenesis-mediated diseases and conditions of the eye, including choroidal neovascularization. The limus family of compounds may be used to prevent, treat, inhibit, delay the onset of, or cause regression of AMD, including wet AMD. Rapamycin may be used to prevent, treat, inhibit, delay the onset of, or cause regression of angiogenesis-mediated diseases and conditions of the eye, including choroidal neovascularization. Rapamycin may be used to prevent, treat, inhibit, delay the onset of, or cause regression of AMD, including wet AMD.
The therapeutic agent can include one or more of: pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors; proteosome inhibitors such as Velcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) and other antibodies directed to the same target; pegaptanib (Macugen™); vitronectin receptor antagonists, such as cyclic peptide antagonists of vitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrin antagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinediones such as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran and metal coordination; pigment epithelium derived factor (PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortave acetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA interference (RNAi) of angiogenic factors, including ribozymes that target VEGF expression; Accutane™ (13-cis retinoic acid); ACE inhibitors, including but not limited to quinopril, captopril, and perindozril; inhibitors of mTOR (mammalian target of rapamycin); 3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and (E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthase modulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor; potassium channel blockers; endorepellin; purine analog of 6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase; epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGF trap molecules; apoptosis inhibiting agents; Visudyne™, snET2 and other photo sensitizers, which may be used with photodynamic therapy (PDT); inhibitors of hepatocyte growth factor (antibodies to the growth factor or its receptors, small molecular inhibitors of the c-met tyrosine kinase, truncated versions of HGF e.g. NK4).
The therapeutic agent can include inhibitors of VEGF receptor kinase; inhibitors of VEGFA, VEGFC, VEGFD, bFGF, PDGF, Ang-2, PDGFR, cKIT, FGF, BDGF, mTOR, αvβ3, αvβ 5, α5β1 integrin, and alpha2 adrenergic receptor; inhibitors of complement factor B (e.g. TA106), complement factor D (CFD) (Lampalizumab/TNX-234), C3 (e.g. APL-2, novel compstatin analogs), C5 (e.g. Eculizumab, Zimura, ARC1905, ALN-CC5), C5a (e.g. JPE-1375), and tubulin; AAV-CD56 The therapeutic agent can also include Complement Factor H (CFH), engineered mini-CFH, or recombinant CFH (rCFH).
The therapeutic agent can include a combination with other therapeutic agents and therapies, including but not limited to agents and therapies useful for the treatment of angiogenesis or neovascularization, particularly CNV. Non-limiting examples of such additional agents and therapies include pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitors such as Velcade™ (bortezomib, for injection; ranibizumab (Lucentis™) and other antibodies directed to the same target; pegaptanib (Macugen™); vitronectin receptor antagonists, such as cyclic peptide antagonists of vitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrin antagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinediones such as rosiglitazone or troglitazone; interferon, including .gamma-interferon or interferon targeted to CNV by use of dextran and metal coordination; pigment epithelium derived factor (PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortave acetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA interference (RNAi) of angiogenic factors, including ribozymes that target VEGF expression; Accutane™ (13-cis retinoic acid); ACE inhibitors, including but not limited to quinopril, captopril, and perindozril; inhibitors of mTOR (mammalian target of rapamycin); 3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and (E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthase modulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor; potassium channel blockers; endorepellin; purine analog of 6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase; epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGF trap molecules; inhibitors of hepatocyte growth factor (antibodies to the growth factor or its receptors, small molecular inhibitors of the c-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosis inhibiting agents; Visudyne™, snET2 and other photo sensitizers with photodynamic therapy (PDT); and laser photocoagulation.
Prostaglandin analogues (PGAs) can be used to increase outflow of aqueous through the ciliary body and/or the trabecular meshwork including travaprost (0.004%), bimatoprost (0.03%, 0.01%), tafluprost (0.0015%), and latanoprost (0.005%). Beta blockers can be used to reduce aqueous fluid production by the ciliary body. Drugs in this class include timolol (0.5%). Carbonic anhydrase inhibitors can be used to reduce aqueous fluid production by the ciliary body as well. Drugs in this class include brinzolamide (1%), methazolamide, dorzolamide (2%), and acetazolamide. Alpha antagonists can be used to reduce aqueous fluid production by the ciliary body and increase outflow through the trabecular meshwork. Thus, the drug targets tissues located in both the anterior chamber and the posterior chamber and as such the devices can be implanted in either location to achieve a therapeutic result. Drugs in this class include brimonidine (0.1%, 0.15%) and apraclonidine (0.5%, 1.0%). Commercially available combinations of therapeutics considered herein include COMBIGAN® (brimonidine tartrate/timolol maleate ophthalmic solution; Allergan), and COSOPT® (dorzolamide hydrochloride-timolol maleate ophthalmic solution; Merck). Further, other sustained release therapeutics considered herein include subconjunctival latanoprost (Psivida/Pfizer), intracameral bimatoprost (Allergan), and intravitreal brimonidine (Allergan).
Various pharmaceutically acceptable carriers for the therapeutic agents described herein can include such as, for example, solids such as starch, gelatin, sugars, natural gums such as acacia, sodium alginate and carboxymethyl cellulose; polymers such as silicone rubber; liquids such as sterile water, saline, dextrose, dextrose in water or saline; condensation products of castor oil and ethylene oxide, liquid glyceryl triester of a lower molecular weight fatty acid; lower alkanols; oils such as corn oil, peanut oil, sesame oil, castor oil, and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide such as lecithin, polysorbate 80, and the like; glycols and polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose, sodium hyaluronate, sodium alginate, poly(vinyl pyrrolidone) and similar compounds, either alone, or with suitable dispensing agents such as lecithin, polyoxyethylene stearate and the like. The carrier may also contain adjuvants such as preserving, stabilizing, wetting, emulsifying agents or other related materials
Materials
Generally, the components of the devices described herein are fabricated of materials that are biocompatible and preferably insoluble in the body fluids and tissues that the device comes into contact with. The materials generally do not cause irritation to the portion of the eye that it contacts. Materials may include, by way of example, various polymers including, for example, silicone elastomers and rubbers, polyolefins, polyurethanes, acrylates, polycarbonates, polyamides, polyimides, polyesters, and polysulfones. One or more components of the devices described herein can be fabricated of a permeable material including, but not limited to, polycarbonates, polyolefins, polyurethanes, copolymers of acrylonitrile, copolymers of polyvinyl chloride, polyamides, polysulphones, polystyrenes, polyvinyl fluorides, polyvinyl alcohols, polyvinyl esters, polyvinyl butyrate, polyvinyl acetate, polyvinylidene chlorides, polyvinylidene fluorides, polyimides, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polyethers, polytetrafluoroethylene, polychloroethers, polymethylmethacrylate, polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, gelatin, silicone rubbers and porous rubbers. One or more components of the devices described herein can be fabricated of a nonbiodegradable polymer, including but not limited to polymethylmethacrylate, a silicone elastomer, or silicone rubber. Other suitable non-erodible, biocompatible polymers which may be used in fabricating the devices described herein may include polyolefins such as polypropylene and polyethylene, homopolymers, and copolymers of vinyl acetate such as ethylene vinyl acetate copolymer, polyvinylchlorides, homopolymers and copolymers of acrylates such as polyethylmethacrylate, polyurethanes, polyvinylpyrrolidone, 2-pyrrolidone, polyacrylonitrile butadiene, polycarbonates, polyamides, fluoropolymers such as polytetrafluoroethylene and polyvinyl fluoride, polystyrenes, homopolymers and copolymers of styrene acrylonitrile, cellulose acetate, homopolymers and copolymers of acrylonitrile butadiene styrene, polymethylpentene, polysulfones, polyesters, polyimides, natural rubber, polyisobutylene, polymethylstyrene and other similar non-erodible biocompatible polymers.
One or more of the components of the devices described herein can be fabricated of a substantially non-compliant material that can be expanded to a particular shape. One or more of the components of the devices described herein can be fabricated of a rigid, non-pliable material. One or more of the components of the devices described herein can be fabricated of a shape memory material and/or superelastic material including, but not limited to shape memory alloys (SMA) like Nitinol (Ni—Ti alloy) and shape memory polymers (SMP) like AB-polymer networks based on oligo(e-caprolactone) dimethacrylates and n-butyl acrylate. Shape memory alloys generally have at least two phases: (1) a martensite phase, which has a relatively low tensile strength and which is stable at relatively low temperatures, and (2) an austenite phase, which has a relatively high tensile strength and which is stable at temperatures higher than the martensite phase. The shape memory characteristics are imparted on the material by heating the material to a temperature above the temperature at which the austenite phase is stable. While the material is heated to this temperature, the device is held in the “memory shape”, which is shape that is desired to be “remembered”.
While this specification contains many specifics, these should not be construed as limitations on the scope of what is claimed or of what may be claimed, but rather as descriptions of features specific to particular embodiments. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. Only a few examples and implementations are disclosed. Variations, modifications and enhancements to the described examples and implementations and other implementations may be made based on what is disclosed. The claimed subject matter has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the claimed subject matter of the appended claims.
This application is a continuation of U.S. application Ser. No. 14/937,754, filed Nov. 10, 2015, now U.S. Pat. No. 10,500,091, which claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 62/077,829, entitled “Expandable Drug Delivery Devices and Methods of Use,” filed Nov. 10, 2014. Priority of the filing date is hereby claimed and the full disclosures are hereby incorporated by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2564977 | Hu et al. | Aug 1951 | A |
| 2585815 | McLintock | Feb 1952 | A |
| 3232117 | Gilmont | Feb 1966 | A |
| 3416530 | Ness | Dec 1968 | A |
| 3618604 | Ness | Nov 1971 | A |
| 3641237 | Gould et al. | Feb 1972 | A |
| 3828777 | Ness | Aug 1974 | A |
| 3831583 | Edmunds, Jr. et al. | Aug 1974 | A |
| 3845201 | Haddad et al. | Oct 1974 | A |
| 3902495 | Weiss et al. | Sep 1975 | A |
| 3914402 | Shell | Oct 1975 | A |
| 3916899 | Theeuwes et al. | Nov 1975 | A |
| 3926188 | Baker et al. | Dec 1975 | A |
| 3949748 | Malmin | Apr 1976 | A |
| 3949750 | Freeman | Apr 1976 | A |
| 3961628 | Arnold | Jun 1976 | A |
| 3977404 | Theeuwes | Aug 1976 | A |
| 3995635 | Higuchi et al. | Dec 1976 | A |
| 4008719 | Theeuwes et al. | Feb 1977 | A |
| 4014333 | McIntyre | Mar 1977 | A |
| 4014334 | Theeuwes et al. | Mar 1977 | A |
| 4014335 | Arnold | Mar 1977 | A |
| 4034756 | Higuchi et al. | Jul 1977 | A |
| 4034758 | Theeuwes | Jul 1977 | A |
| 4077407 | Theeuwes et al. | Mar 1978 | A |
| 4111201 | Theeuwes | Sep 1978 | A |
| 4111203 | Theeuwes | Sep 1978 | A |
| 4135514 | Zaffaroni et al. | Jan 1979 | A |
| 4160452 | Theeuwes | Jul 1979 | A |
| 4164559 | Miyata et al. | Aug 1979 | A |
| 4179497 | Cohen et al. | Dec 1979 | A |
| 4186184 | Zaffaroni | Jan 1980 | A |
| 4200098 | Ayer et al. | Apr 1980 | A |
| 4220152 | Dresback | Sep 1980 | A |
| 4220153 | Dresback | Sep 1980 | A |
| 4256108 | Theeuwes | Mar 1981 | A |
| 4298000 | Thill et al. | Nov 1981 | A |
| 4300557 | Refojo et al. | Nov 1981 | A |
| 4309776 | Berguer | Jan 1982 | A |
| 4326525 | Swanson et al. | Apr 1982 | A |
| 4327725 | Cortese et al. | May 1982 | A |
| 4343787 | Katz | Aug 1982 | A |
| 4439196 | Higuchi | Mar 1984 | A |
| 4439198 | Brightman, II et al. | Mar 1984 | A |
| 4475916 | Himmelstein | Oct 1984 | A |
| 4484922 | Rosenwald | Nov 1984 | A |
| 4519801 | Edgren | May 1985 | A |
| 4609374 | Ayer | Sep 1986 | A |
| 4627850 | Deters et al. | Dec 1986 | A |
| 4634418 | Binder | Jan 1987 | A |
| 4673405 | Guittard et al. | Jun 1987 | A |
| 4693886 | Ayer | Sep 1987 | A |
| 4712550 | Sinnett | Dec 1987 | A |
| 4730013 | Bondi et al. | Mar 1988 | A |
| 4737150 | Baeumle et al. | Apr 1988 | A |
| 4774091 | Yamahira et al. | Sep 1988 | A |
| 4777049 | Magruder et al. | Oct 1988 | A |
| 4781675 | White | Nov 1988 | A |
| 4851228 | Zentner et al. | Jul 1989 | A |
| 4853229 | Theeuwes | Aug 1989 | A |
| 4863457 | Lee | Sep 1989 | A |
| 4865846 | Kaufman | Sep 1989 | A |
| 4883459 | Calderon | Nov 1989 | A |
| 4959217 | Sanders et al. | Sep 1990 | A |
| 4979938 | Stephen et al. | Dec 1990 | A |
| 5049142 | Herrick et al. | Sep 1991 | A |
| 5053030 | Herrick et al. | Oct 1991 | A |
| 5084021 | Baldwin | Jan 1992 | A |
| 5098443 | Parel et al. | Mar 1992 | A |
| 5128145 | Edgren et al. | Jul 1992 | A |
| 5141748 | Rizzo | Aug 1992 | A |
| 5147647 | Darougar | Sep 1992 | A |
| 5164188 | Wong | Nov 1992 | A |
| 5171270 | Herrick | Dec 1992 | A |
| 5174999 | Magruder et al. | Dec 1992 | A |
| 5213576 | Abiuso et al. | May 1993 | A |
| 5238687 | Magruder et al. | Aug 1993 | A |
| 5277912 | Lowe et al. | Jan 1994 | A |
| 5282829 | Hermes | Feb 1994 | A |
| 5300114 | Gwon et al. | Apr 1994 | A |
| 5322691 | Darougar et al. | Jun 1994 | A |
| 5334189 | Wade | Aug 1994 | A |
| 5336175 | Mames | Aug 1994 | A |
| 5378475 | Smith et al. | Jan 1995 | A |
| 5413572 | Wong et al. | May 1995 | A |
| 5443505 | Wong et al. | Aug 1995 | A |
| 5466233 | Weiner et al. | Nov 1995 | A |
| 5476511 | Gwon et al. | Dec 1995 | A |
| 5554132 | Straits et al. | Sep 1996 | A |
| 5562915 | Lowe et al. | Oct 1996 | A |
| 5578042 | Cumming | Nov 1996 | A |
| 5681572 | Seare, Jr. | Oct 1997 | A |
| 5702414 | Richter et al. | Dec 1997 | A |
| 5725493 | Avery et al. | Mar 1998 | A |
| 5766242 | Wong et al. | Jun 1998 | A |
| 5770076 | Chu et al. | Jun 1998 | A |
| 5773019 | Ashton et al. | Jun 1998 | A |
| 5797898 | Santini, Jr. et al. | Aug 1998 | A |
| 5807581 | Rosenblatt et al. | Sep 1998 | A |
| 5824072 | Wong | Oct 1998 | A |
| 5830173 | Avery et al. | Nov 1998 | A |
| 5830546 | Ehret et al. | Nov 1998 | A |
| 5836935 | Ashton et al. | Nov 1998 | A |
| 5868697 | Richter et al. | Feb 1999 | A |
| 5902598 | Chen et al. | May 1999 | A |
| 5904144 | Hammang et al. | May 1999 | A |
| 5916584 | O'Donoghue et al. | Jun 1999 | A |
| 5928662 | Phillips | Jul 1999 | A |
| 5951512 | Dalton | Sep 1999 | A |
| 5972369 | Roorda et al. | Oct 1999 | A |
| 5985328 | Chu et al. | Nov 1999 | A |
| 5993414 | Haller | Nov 1999 | A |
| 6001386 | Ashton et al. | Dec 1999 | A |
| 6123861 | Santini, Jr. et al. | Sep 2000 | A |
| 6183461 | Matsuura et al. | Feb 2001 | B1 |
| 6196993 | Cohan et al. | Mar 2001 | B1 |
| 6251090 | Avery et al. | Jun 2001 | B1 |
| 6303290 | Liu et al. | Oct 2001 | B1 |
| 6306426 | Olejnik et al. | Oct 2001 | B1 |
| 6331313 | Wong et al. | Dec 2001 | B1 |
| 6375972 | Guo et al. | Apr 2002 | B1 |
| 6395300 | Straub et al. | May 2002 | B1 |
| 6413540 | Yaacobi | Jul 2002 | B1 |
| 6416777 | Yaacobi | Jul 2002 | B1 |
| 6420399 | Graff et al. | Jul 2002 | B1 |
| 6472162 | Coelho et al. | Oct 2002 | B1 |
| 6605066 | Gravagna et al. | Aug 2003 | B1 |
| 6663668 | Chaouk et al. | Dec 2003 | B1 |
| 6669950 | Yaacobi | Dec 2003 | B2 |
| 6685940 | Andya et al. | Feb 2004 | B2 |
| 6713081 | Robinson et al. | Mar 2004 | B2 |
| 6719750 | Varner et al. | Apr 2004 | B2 |
| 6740077 | Brandau et al. | May 2004 | B1 |
| 6756049 | Brubaker et al. | Jun 2004 | B2 |
| 6756058 | Brubaker et al. | Jun 2004 | B2 |
| 6932983 | Straub et al. | Aug 2005 | B1 |
| 6976982 | Santini, Jr. et al. | Dec 2005 | B2 |
| 6986900 | Yaacobi | Jan 2006 | B2 |
| 7009039 | Yayon et al. | Mar 2006 | B2 |
| 7026329 | Crain et al. | Apr 2006 | B2 |
| 7074426 | Kochinke | Jul 2006 | B2 |
| 7077848 | de Juan, Jr. et al. | Jul 2006 | B1 |
| 7083803 | Peyman | Aug 2006 | B2 |
| 7087237 | Peyman | Aug 2006 | B2 |
| 7090681 | Weber et al. | Aug 2006 | B2 |
| 7094226 | Yaacobi | Aug 2006 | B2 |
| 7117870 | Prescott | Oct 2006 | B2 |
| 7141023 | Diermann et al. | Nov 2006 | B2 |
| 7141152 | Le Febre | Nov 2006 | B2 |
| 7181287 | Greenberg | Feb 2007 | B2 |
| 7195774 | Carvalho et al. | Mar 2007 | B2 |
| 7195778 | Fleshner-Barak et al. | Mar 2007 | B2 |
| 7211272 | Renner et al. | May 2007 | B2 |
| 7276050 | Franklin | Oct 2007 | B2 |
| 7384648 | Olejnik et al. | Jun 2008 | B2 |
| 7468065 | Weber et al. | Dec 2008 | B2 |
| 7476510 | Kapur et al. | Jan 2009 | B2 |
| 7585517 | Cooper et al. | Sep 2009 | B2 |
| 7615141 | Schwartz et al. | Nov 2009 | B2 |
| 7621907 | Rodstrom | Nov 2009 | B2 |
| 7625927 | Klimko et al. | Dec 2009 | B2 |
| 7678078 | Peyman et al. | Mar 2010 | B1 |
| 7686016 | Wharton et al. | Mar 2010 | B2 |
| 7709049 | Chappa | May 2010 | B2 |
| 7883717 | Varner et al. | Feb 2011 | B2 |
| 7893040 | Loftsson et al. | Feb 2011 | B2 |
| 7906136 | Wong et al. | Mar 2011 | B2 |
| 7909800 | Cazzini | Mar 2011 | B2 |
| 7914442 | Gazdzinski | Mar 2011 | B1 |
| 7939094 | Schwarz et al. | May 2011 | B2 |
| 7973068 | Demopulos et al. | Jul 2011 | B2 |
| 7998497 | de Juan, Jr. et al. | Aug 2011 | B2 |
| 8034369 | Anderson et al. | Oct 2011 | B2 |
| 8038650 | Shekalim | Oct 2011 | B2 |
| 8096972 | Varner et al. | Jan 2012 | B2 |
| 8231608 | Pang et al. | Jul 2012 | B2 |
| 8231609 | Pang et al. | Jul 2012 | B2 |
| 8277830 | de Juan, Jr. et al. | Oct 2012 | B2 |
| 8308755 | Cronin et al. | Nov 2012 | B2 |
| 8348877 | Tu et al. | Jan 2013 | B2 |
| 8348897 | Shih et al. | Jan 2013 | B2 |
| 8399006 | de Juan, Jr. et al. | Mar 2013 | B2 |
| 8486052 | Varner et al. | Jul 2013 | B2 |
| 8623395 | de Juan, Jr. et al. | Jan 2014 | B2 |
| 8795711 | de Juan, Jr. et al. | Aug 2014 | B2 |
| 8821474 | Shekalim | Sep 2014 | B2 |
| 8864703 | LaBelle | Oct 2014 | B2 |
| 8992503 | Shekalim | Mar 2015 | B2 |
| 9033911 | de Juan, Jr. et al. | May 2015 | B2 |
| 9084662 | Gifford, III et al. | Jul 2015 | B2 |
| 9883968 | Doud et al. | Feb 2018 | B2 |
| 20020026176 | Varner et al. | Feb 2002 | A1 |
| 20020086051 | Viscasillas | Jul 2002 | A1 |
| 20020106395 | Brubaker | Aug 2002 | A1 |
| 20020110591 | Brubaker et al. | Aug 2002 | A1 |
| 20020110592 | Brubaker et al. | Aug 2002 | A1 |
| 20020110635 | Brubaker et al. | Aug 2002 | A1 |
| 20030003129 | Yaacobi | Jan 2003 | A1 |
| 20030005945 | Onishi et al. | Jan 2003 | A1 |
| 20030014036 | Varner et al. | Jan 2003 | A1 |
| 20030118649 | Gao et al. | Jun 2003 | A1 |
| 20030119177 | Gruber et al. | Jun 2003 | A1 |
| 20030176854 | Rodstrom | Sep 2003 | A1 |
| 20030185872 | Kochinke | Oct 2003 | A1 |
| 20030212383 | Cote et al. | Nov 2003 | A1 |
| 20030235603 | Schwarz et al. | Dec 2003 | A1 |
| 20040011651 | Becker et al. | Jan 2004 | A1 |
| 20040019325 | Shekalim | Jan 2004 | A1 |
| 20040092911 | Yaacobi | May 2004 | A1 |
| 20040106906 | Yaacobi | Jun 2004 | A1 |
| 20040131654 | Yaacobi | Jul 2004 | A1 |
| 20040131655 | Yaacobi | Jul 2004 | A1 |
| 20040209359 | Yayon et al. | Oct 2004 | A1 |
| 20040230183 | Breegi et al. | Nov 2004 | A1 |
| 20040260380 | Marco et al. | Dec 2004 | A1 |
| 20040260381 | Marco et al. | Dec 2004 | A1 |
| 20050064010 | Cooper et al. | Mar 2005 | A1 |
| 20050074497 | Schultz | Apr 2005 | A1 |
| 20050112175 | Yaacobi | May 2005 | A1 |
| 20050112759 | Radisic et al. | May 2005 | A1 |
| 20050113806 | De Carvalho et al. | May 2005 | A1 |
| 20050119737 | Bene et al. | Jun 2005 | A1 |
| 20050143363 | De Juan et al. | Jun 2005 | A1 |
| 20050154399 | Weber et al. | Jul 2005 | A1 |
| 20050163711 | Nycz et al. | Jul 2005 | A1 |
| 20050181018 | Peyman | Aug 2005 | A1 |
| 20050244467 | Nivaggioli et al. | Nov 2005 | A1 |
| 20050244469 | Whitcup et al. | Nov 2005 | A1 |
| 20050255144 | Schultz | Nov 2005 | A1 |
| 20050256499 | Pettis et al. | Nov 2005 | A1 |
| 20050271703 | Anderson et al. | Dec 2005 | A1 |
| 20050271706 | Anderson et al. | Dec 2005 | A1 |
| 20050276837 | Anderson et al. | Dec 2005 | A1 |
| 20050277802 | Larsen et al. | Dec 2005 | A1 |
| 20050281861 | Hughes et al. | Dec 2005 | A1 |
| 20050281863 | Anderson et al. | Dec 2005 | A1 |
| 20050287188 | Anderson et al. | Dec 2005 | A1 |
| 20060013835 | Anderson et al. | Jan 2006 | A1 |
| 20060020253 | Prescott | Jan 2006 | A1 |
| 20060039952 | Yaacobi | Feb 2006 | A1 |
| 20060052754 | Fields | Mar 2006 | A1 |
| 20060057277 | Chappa | Mar 2006 | A1 |
| 20060073182 | Wong et al. | Apr 2006 | A1 |
| 20060104969 | Oray et al. | May 2006 | A1 |
| 20060110428 | deJuan et al. | May 2006 | A1 |
| 20060129215 | Helmus et al. | Jun 2006 | A1 |
| 20060154981 | Klimko et al. | Jul 2006 | A1 |
| 20060172941 | Rastelli et al. | Aug 2006 | A1 |
| 20060182783 | Hughes et al. | Aug 2006 | A1 |
| 20060200097 | Humayun et al. | Sep 2006 | A1 |
| 20060233858 | Tzekov et al. | Oct 2006 | A1 |
| 20060246112 | Snyder et al. | Nov 2006 | A1 |
| 20060257450 | Mudumba et al. | Nov 2006 | A1 |
| 20060258000 | Allen et al. | Nov 2006 | A1 |
| 20060258994 | Avery | Nov 2006 | A1 |
| 20070020336 | Loftsson et al. | Jan 2007 | A1 |
| 20070021357 | Tobia et al. | Jan 2007 | A1 |
| 20070026037 | Kloke et al. | Feb 2007 | A1 |
| 20070059336 | Hughes et al. | Mar 2007 | A1 |
| 20070071756 | Peyman | Mar 2007 | A1 |
| 20070072933 | Peyman | Mar 2007 | A1 |
| 20070088414 | Campbell et al. | Apr 2007 | A1 |
| 20070119450 | Wharton et al. | May 2007 | A1 |
| 20070128644 | Munenaka | Jun 2007 | A1 |
| 20070131610 | Peng et al. | Jun 2007 | A1 |
| 20070131611 | Peng et al. | Jun 2007 | A1 |
| 20070134305 | Zilberman | Jun 2007 | A1 |
| 20070141111 | Suokas et al. | Jun 2007 | A1 |
| 20070191863 | De Juan et al. | Aug 2007 | A1 |
| 20070197491 | Robin et al. | Aug 2007 | A1 |
| 20070203174 | Klimko et al. | Aug 2007 | A1 |
| 20070212397 | Roth | Sep 2007 | A1 |
| 20070233037 | Gifford et al. | Oct 2007 | A1 |
| 20070235331 | Simpson et al. | Oct 2007 | A1 |
| 20070243230 | de Juan et al. | Oct 2007 | A1 |
| 20070260201 | Prausnitz et al. | Nov 2007 | A1 |
| 20070269487 | de Juan et al. | Nov 2007 | A1 |
| 20080003219 | Peyman | Jan 2008 | A1 |
| 20080004329 | Jamieson et al. | Jan 2008 | A1 |
| 20080020045 | Chappa et al. | Jan 2008 | A1 |
| 20080038316 | Wong et al. | Feb 2008 | A1 |
| 20080057561 | Takahashi et al. | Mar 2008 | A1 |
| 20080066739 | LeMahieu et al. | Mar 2008 | A1 |
| 20080066741 | LeMahieu et al. | Mar 2008 | A1 |
| 20080069854 | Xiao et al. | Mar 2008 | A1 |
| 20080089923 | Burkstrand et al. | Apr 2008 | A1 |
| 20080111282 | Xie et al. | May 2008 | A1 |
| 20080124372 | Hossainy et al. | May 2008 | A1 |
| 20080139674 | Archambeau et al. | Jun 2008 | A1 |
| 20080145406 | Asgharian et al. | Jun 2008 | A1 |
| 20080146679 | Archambeau et al. | Jun 2008 | A1 |
| 20080147021 | Jani | Jun 2008 | A1 |
| 20080152694 | Lobl et al. | Jun 2008 | A1 |
| 20080154241 | Burkstrand et al. | Jun 2008 | A1 |
| 20080161741 | Bene et al. | Jul 2008 | A1 |
| 20080167600 | Peyman | Jul 2008 | A1 |
| 20080172014 | Whitcup et al. | Jul 2008 | A1 |
| 20080181930 | Rodstrom et al. | Jul 2008 | A1 |
| 20080207502 | Rastelli et al. | Aug 2008 | A1 |
| 20080213611 | Asgari | Sep 2008 | A1 |
| 20080216736 | David | Sep 2008 | A1 |
| 20080228127 | Burns et al. | Sep 2008 | A1 |
| 20080233053 | Gross et al. | Sep 2008 | A1 |
| 20080233171 | Whitcup et al. | Sep 2008 | A1 |
| 20080233172 | Whitcup et al. | Sep 2008 | A1 |
| 20080233173 | Whitcup et al. | Sep 2008 | A1 |
| 20080241219 | Whitcup et al. | Oct 2008 | A1 |
| 20080241220 | Whitcup et al. | Oct 2008 | A1 |
| 20080241221 | Whitcup et al. | Oct 2008 | A1 |
| 20080241222 | Whitcup et al. | Oct 2008 | A1 |
| 20080241223 | Nivaggioli et al. | Oct 2008 | A1 |
| 20080249501 | Yamasaki | Oct 2008 | A1 |
| 20080286338 | Rosenthal et al. | Nov 2008 | A1 |
| 20080292679 | Lyons et al. | Nov 2008 | A1 |
| 20080293691 | Brigandi et al. | Nov 2008 | A1 |
| 20090005864 | Eggleston | Jan 2009 | A1 |
| 20090036827 | Cazzini | Feb 2009 | A1 |
| 20090043253 | Podaima | Feb 2009 | A1 |
| 20090047335 | Rastelli et al. | Feb 2009 | A1 |
| 20090082631 | Cronin et al. | Mar 2009 | A1 |
| 20090087494 | Kompella et al. | Apr 2009 | A1 |
| 20090092654 | de Juan, Jr. et al. | Apr 2009 | A1 |
| 20090093752 | Richard et al. | Apr 2009 | A1 |
| 20090099626 | de Juan, Jr. et al. | Apr 2009 | A1 |
| 20090104243 | Utkhede et al. | Apr 2009 | A1 |
| 20090105749 | de Juan et al. | Apr 2009 | A1 |
| 20090124997 | Pettis et al. | May 2009 | A1 |
| 20090192493 | Meng et al. | Jul 2009 | A1 |
| 20090214601 | Chappa et al. | Aug 2009 | A1 |
| 20090224064 | Brodbeck et al. | Sep 2009 | A1 |
| 20090234449 | De Juan, Jr. et al. | Sep 2009 | A1 |
| 20090240215 | Humayun et al. | Sep 2009 | A1 |
| 20090247458 | Watson et al. | Oct 2009 | A1 |
| 20090258069 | Burnier et al. | Oct 2009 | A1 |
| 20090263346 | Taft et al. | Oct 2009 | A1 |
| 20090263495 | Watson et al. | Oct 2009 | A1 |
| 20090274730 | Watson et al. | Nov 2009 | A1 |
| 20090274771 | Watson et al. | Nov 2009 | A1 |
| 20090280470 | Fare et al. | Nov 2009 | A1 |
| 20090324686 | Cooper et al. | Dec 2009 | A1 |
| 20090324687 | Cooper et al. | Dec 2009 | A1 |
| 20090324688 | Cooper et al. | Dec 2009 | A1 |
| 20090324689 | Cooper et al. | Dec 2009 | A1 |
| 20090324690 | Cooper et al. | Dec 2009 | A1 |
| 20090326448 | Huo et al. | Dec 2009 | A1 |
| 20100003333 | Watson et al. | Jan 2010 | A1 |
| 20100004189 | Watson et al. | Jan 2010 | A1 |
| 20100008997 | Watson et al. | Jan 2010 | A1 |
| 20100009008 | Watson et al. | Jan 2010 | A1 |
| 20100010452 | Paques et al. | Jan 2010 | A1 |
| 20100011888 | Pawliszyn et al. | Jan 2010 | A1 |
| 20100015157 | Andya et al. | Jan 2010 | A1 |
| 20100016786 | Drews et al. | Jan 2010 | A1 |
| 20100021464 | Archambeau et al. | Jan 2010 | A1 |
| 20100022943 | Mauch et al. | Jan 2010 | A1 |
| 20100022945 | Rodstrom | Jan 2010 | A1 |
| 20100023033 | Mauch et al. | Jan 2010 | A1 |
| 20100028442 | Archambeau et al. | Feb 2010 | A1 |
| 20100028443 | Watson et al. | Feb 2010 | A1 |
| 20100030136 | Dacquay et al. | Feb 2010 | A1 |
| 20100034870 | Sim et al. | Feb 2010 | A1 |
| 20100083963 | Wharton et al. | Apr 2010 | A1 |
| 20100100054 | Cormier et al. | Apr 2010 | A1 |
| 20100114017 | Lenker | May 2010 | A1 |
| 20100114309 | de Juan, Jr. et al. | May 2010 | A1 |
| 20100168535 | Robinson et al. | Jul 2010 | A1 |
| 20100174272 | Weiner | Jul 2010 | A1 |
| 20100185205 | Novakovic et al. | Jul 2010 | A1 |
| 20100197512 | Trinkle et al. | Aug 2010 | A1 |
| 20100216702 | Szkudlinski et al. | Aug 2010 | A1 |
| 20100221309 | Myers et al. | Sep 2010 | A1 |
| 20100223979 | Ploehn et al. | Sep 2010 | A1 |
| 20100255061 | de Juan, Jr. et al. | Oct 2010 | A1 |
| 20100256597 | Prausnitz et al. | Oct 2010 | A1 |
| 20100266664 | Asgharian et al. | Oct 2010 | A1 |
| 20100286121 | Rohrs et al. | Nov 2010 | A1 |
| 20100286791 | Goldsmith | Nov 2010 | A1 |
| 20100297046 | Schwartz et al. | Nov 2010 | A1 |
| 20100297120 | Beliveau et al. | Nov 2010 | A1 |
| 20100297193 | Archambeau et al. | Nov 2010 | A1 |
| 20100303917 | Watson et al. | Dec 2010 | A1 |
| 20100303918 | Watson et al. | Dec 2010 | A1 |
| 20100310664 | Watson et al. | Dec 2010 | A1 |
| 20100310665 | Watson et al. | Dec 2010 | A1 |
| 20100316723 | Watson et al. | Dec 2010 | A1 |
| 20100330146 | Chauhan et al. | Dec 2010 | A1 |
| 20110009571 | Taft et al. | Jan 2011 | A1 |
| 20110014264 | Helmus et al. | Jan 2011 | A1 |
| 20110033933 | Gharib et al. | Feb 2011 | A1 |
| 20110034448 | Chang et al. | Feb 2011 | A1 |
| 20110081384 | Archambeau et al. | Apr 2011 | A1 |
| 20110098686 | Varner et al. | Apr 2011 | A1 |
| 20110104155 | Rekik | May 2011 | A1 |
| 20110108025 | Fink et al. | May 2011 | A1 |
| 20110111006 | Wong et al. | May 2011 | A1 |
| 20110112188 | Tobia et al. | May 2011 | A1 |
| 20110117083 | Bais et al. | May 2011 | A1 |
| 20110125178 | Drews et al. | May 2011 | A1 |
| 20110159073 | deJuan et al. | Jun 2011 | A1 |
| 20110206646 | Alfonso et al. | Aug 2011 | A1 |
| 20110208122 | Shekalim | Aug 2011 | A1 |
| 20120028918 | Gupta | Feb 2012 | A1 |
| 20120029445 | de Juan, Jr. et al. | Feb 2012 | A1 |
| 20120029470 | Juan, Jr. et al. | Feb 2012 | A1 |
| 20120095439 | de Juan, Jr. | Apr 2012 | A1 |
| 20120183799 | Steele et al. | Jul 2012 | A1 |
| 20120184905 | Shekalim | Jul 2012 | A1 |
| 20120209077 | Racenet | Aug 2012 | A1 |
| 20130116664 | Tai et al. | May 2013 | A1 |
| 20130165860 | Doud et al. | Jun 2013 | A1 |
| 20130204209 | de Juan, Jr. et al. | Aug 2013 | A1 |
| 20130218081 | Roth | Aug 2013 | A1 |
| 20130245544 | de Juan, Jr. et al. | Sep 2013 | A1 |
| 20130245573 | de Juan, Jr. et al. | Sep 2013 | A1 |
| 20130274691 | de Juan, Jr. et al. | Oct 2013 | A1 |
| 20130274692 | Alster et al. | Oct 2013 | A1 |
| 20130289482 | Meng et al. | Oct 2013 | A1 |
| 20130289497 | Humayun et al. | Oct 2013 | A1 |
| 20130296810 | Humayun et al. | Nov 2013 | A1 |
| 20130304031 | Varner et al. | Nov 2013 | A1 |
| 20130324918 | de Juan, Jr. et al. | Dec 2013 | A1 |
| 20130324942 | de Juan, Jr. et al. | Dec 2013 | A1 |
| 20140031769 | de Juan, Jr. et al. | Jan 2014 | A1 |
| 20140031833 | Novakovic et al. | Jan 2014 | A1 |
| 20140033800 | Farinas et al. | Feb 2014 | A1 |
| 20140073714 | Reich et al. | Mar 2014 | A1 |
| 20140121609 | de Juan, Jr. et al. | May 2014 | A1 |
| 20140221941 | Erickson et al. | Aug 2014 | A1 |
| 20140243795 | Varner et al. | Aug 2014 | A1 |
| 20140276482 | Astafieva et al. | Sep 2014 | A1 |
| 20140296800 | Erickson et al. | Oct 2014 | A1 |
| 20140328894 | de Juan, Jr. et al. | Nov 2014 | A1 |
| 20140336619 | Stankus et al. | Nov 2014 | A1 |
| 20140358125 | de Juan, Jr. et al. | Dec 2014 | A1 |
| 20150080846 | de Juan, Jr. et al. | Mar 2015 | A1 |
| 20150133896 | Benner et al. | May 2015 | A1 |
| 20150202079 | Shekalim | Jul 2015 | A1 |
| 20150224200 | de Juan, Jr. et al. | Aug 2015 | A1 |
| 20150231265 | Gupta | Aug 2015 | A1 |
| 20150250647 | de Juan, Jr. et al. | Sep 2015 | A1 |
| 20150282983 | Benner et al. | Oct 2015 | A1 |
| 20150297402 | de Juan, Jr. et al. | Oct 2015 | A1 |
| 20150351796 | Richard et al. | Dec 2015 | A1 |
| 20160038488 | Horvath et al. | Feb 2016 | A1 |
| 20160101046 | Reich et al. | Apr 2016 | A1 |
| 20160128867 | Bachelder et al. | May 2016 | A1 |
| 20160184134 | Varner et al. | Jun 2016 | A1 |
| 20160258855 | Farinas et al. | Sep 2016 | A1 |
| 20160270955 | Shekalim | Sep 2016 | A1 |
| 20160302965 | Erickson et al. | Oct 2016 | A1 |
| 20170165108 | Bianchi et al. | Jun 2017 | A1 |
| 20170165110 | Erickson et al. | Jun 2017 | A1 |
| 20170172794 | Varner et al. | Jun 2017 | A1 |
| 20170258634 | de Juan, Jr. et al. | Sep 2017 | A1 |
| 20180147204 | Horvath et al. | May 2018 | A1 |
| 20180161202 | de Juan, Jr. et al. | Jun 2018 | A1 |
| 20180243130 | Doud et al. | Aug 2018 | A1 |
| 20180243131 | Erickson et al. | Aug 2018 | A1 |
| 20180289542 | de Juan, Jr. et al. | Oct 2018 | A1 |
| 20180292403 | de Juan, Jr. et al. | Oct 2018 | A1 |
| 20190336335 | de Juan, Jr. et al. | Nov 2019 | A1 |
| 20190350754 | Bianchi et al. | Nov 2019 | A1 |
| 20190365757 | Horvath et al. | Dec 2019 | A1 |
| 20200030142 | Erickson et al. | Jan 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 1538826 | Oct 2004 | CN |
| 101052435 | Oct 2007 | CN |
| 1019698970 | Feb 2011 | CN |
| 102596097 | Jul 2012 | CN |
| 0 228 185 | Nov 1986 | EP |
| 0498471 | Aug 1992 | EP |
| 0500143 | Aug 1992 | EP |
| 0671165 | Sep 1995 | EP |
| 0295248 | Apr 1999 | EP |
| 0944658 | Jun 2003 | EP |
| 1671624 | Jun 2006 | EP |
| 1385452 | Sep 2006 | EP |
| 1409065 | Jan 2007 | EP |
| 1337284 | Dec 2007 | EP |
| 1911481 | Apr 2008 | EP |
| 1521572 | Mar 2009 | EP |
| 01-149716 | Jun 1989 | JP |
| 01-197429 | Aug 1989 | JP |
| 2414199 | Mar 2011 | RU |
| WO-8804573 | Jun 1988 | WO |
| WO-9007545 | Jul 1990 | WO |
| WO-9528984 | Nov 1995 | WO |
| WO-9729850 | Aug 1997 | WO |
| WO-9825982 | Jun 1998 | WO |
| WO-9911244 | Mar 1999 | WO |
| WO-0048660 | Aug 2000 | WO |
| WO-0126714 | Apr 2001 | WO |
| WO-0150943 | Jul 2001 | WO |
| WO-0168016 | Sep 2001 | WO |
| WO-02100318 | Dec 2002 | WO |
| WO-03077972 | Sep 2003 | WO |
| WO-03082188 | Oct 2003 | WO |
| WO-2004000267 | Dec 2003 | WO |
| WO-2004112653 | Dec 2004 | WO |
| WO-2005016401 | Feb 2005 | WO |
| WO-2005027906 | Mar 2005 | WO |
| WO-2005028006 | Mar 2005 | WO |
| WO-2005091922 | Oct 2005 | WO |
| WO-2005107705 | Nov 2005 | WO |
| WO-2005110362 | Nov 2005 | WO |
| WO-2005110436 | Nov 2005 | WO |
| WO-2005110473 | Nov 2005 | WO |
| WO-2005117780 | Dec 2005 | WO |
| WO-2006014484 | Feb 2006 | WO |
| WO-2006015385 | Feb 2006 | WO |
| WO-2006023530 | Mar 2006 | WO |
| WO-2006031358 | Mar 2006 | WO |
| WO-2006031388 | Mar 2006 | WO |
| WO-2006044614 | Apr 2006 | WO |
| WO-2006050221 | May 2006 | WO |
| WO-2006068838 | Jun 2006 | WO |
| WO-2006071554 | Jul 2006 | WO |
| WO-2006082588 | Aug 2006 | WO |
| WO-2006108054 | Oct 2006 | WO |
| WO-2006127962 | Nov 2006 | WO |
| WO-2006138609 | Dec 2006 | WO |
| WO-2007012974 | Feb 2007 | WO |
| WO-2007035621 | Mar 2007 | WO |
| WO-2007038453 | Apr 2007 | WO |
| WO-2007044534 | Apr 2007 | WO |
| WO-2007047744 | Apr 2007 | WO |
| WO 2007066339 | Jun 2007 | WO |
| WO 2007084582 | Jul 2007 | WO |
| WO-2007084765 | Jul 2007 | WO |
| WO-2007101204 | Sep 2007 | WO |
| WO-2007117394 | Oct 2007 | WO |
| WO-2007131050 | Nov 2007 | WO |
| WO-2007133761 | Nov 2007 | WO |
| WO-2007133762 | Nov 2007 | WO |
| WO-2008003043 | Jan 2008 | WO |
| WO-2008005240 | Jan 2008 | WO |
| WO-2008011125 | Jan 2008 | WO |
| WO-2008033924 | Mar 2008 | WO |
| WO-2008040062 | Apr 2008 | WO |
| WO-2008045272 | Apr 2008 | WO |
| WO-2008052145 | May 2008 | WO |
| WO-2008060359 | May 2008 | WO |
| WO-2008061043 | May 2008 | WO |
| WO-2008076544 | Jun 2008 | WO |
| WO-2008094989 | Aug 2008 | WO |
| WO-2008115290 | Sep 2008 | WO |
| WO-2008116165 | Sep 2008 | WO |
| WO-2008144340 | Nov 2008 | WO |
| WO-2008144919 | Dec 2008 | WO |
| WO-2009012075 | Jan 2009 | WO |
| WO-2009023615 | Feb 2009 | WO |
| WO-2009046164 | Apr 2009 | WO |
| WO-2009055620 | Apr 2009 | WO |
| WO-2009055671 | Apr 2009 | WO |
| WO-2009055729 | Apr 2009 | WO |
| WO-2009055824 | Apr 2009 | WO |
| WO-2009061607 | May 2009 | WO |
| WO-2009073192 | Jun 2009 | WO |
| WO-2009086112 | Jul 2009 | WO |
| WO-2009089409 | Jul 2009 | WO |
| WO-2009094466 | Jul 2009 | WO |
| WO-2009112878 | Sep 2009 | WO |
| WO-2009117112 | Sep 2009 | WO |
| WO-2009124096 | Oct 2009 | WO |
| WO-2009128932 | Oct 2009 | WO |
| WO-2009134929 | Nov 2009 | WO |
| WO-2009137777 | Nov 2009 | WO |
| WO-2010008424 | Jan 2010 | WO |
| WO-2010021993 | Feb 2010 | WO |
| WO-2010047753 | Apr 2010 | WO |
| WO-2010062628 | Jun 2010 | WO |
| WO-2010066714 | Jun 2010 | WO |
| WO-2010075565 | Jul 2010 | WO |
| WO-2010078063 | Jul 2010 | WO |
| WO-2010088548 | Aug 2010 | WO |
| WO-2010093945 | Aug 2010 | WO |
| WO-2010095940 | Aug 2010 | WO |
| WO-2010125416 | Nov 2010 | WO |
| WO-2010126908 | Nov 2010 | WO |
| WO-2010135369 | Nov 2010 | WO |
| WO-2010141729 | Dec 2010 | WO |
| WO-2010147661 | Dec 2010 | WO |
| WO-2011008896 | Jan 2011 | WO |
| WO-2011008897 | Jan 2011 | WO |
| WO-2011028850 | Mar 2011 | WO |
| WO-2011034627 | Mar 2011 | WO |
| WO-2011079232 | Jun 2011 | WO |
| WO-2012019047 | Feb 2012 | WO |
| WO-2012019136 | Feb 2012 | WO |
| WO-2012065006 | May 2012 | WO |
| WO-2014160884 | Oct 2014 | WO |
| WO-2015059680 | Apr 2015 | WO |
| Entry |
|---|
| U.S. Appl. No. 13/814,466, filed Jun. 28, 2013, 2013/0274691. |
| U.S. Appl. No. 14/753,574, filed Jun. 29, 2015, 2015/0297402. |
| U.S. Appl. No. 15/102,191, filed Jun. 6, 2016, 2016/0302965. |
| U.S. Appl. No. 15/606,647, filed May 26, 2017, 2017/0258634. |
| U.S. Appl. No. 15/807,396, filed Nov. 8, 2017, 2018/0292403. |
| U.S. Appl. No. 15/877,146, filed Jan. 22, 2018, 2018/0243130. |
| U.S. Appl. No. 16/004,085, filed Jun. 8, 2018, 2018/0289542. |
| U.S. Appl. No. 16/091,493, filed Oct. 4, 2018, 2019/0117454. |
| U.S. Appl. No. 16/380,786, filed Apr. 10, 2019, 2019/0350754. |
| U.S. Appl. No. 16/386,854, filed Apr. 17, 2019, 2019/0336335. |
| U.S. Appl. No. 16/434,966, filed Jun. 7, 2019, 2019/0365757. |
| U.S. Appl. No. 16/540,617, filed Aug. 14, 2019, 2020/0030142. |
| PCT/US2018/61262, Nov. 15, 2018, WO 2019/10396. |
| Andrews, “Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa,” Am J Physiol. Apr. 1994. 266(4 Pt 1):G657-664. |
| Avery et al., “Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy,” Ophthalmology. Oct. 2006, 113(10):1695-1705.e6. |
| Bakri et al., “The effect of intravitreal triamcinolone acetonide on intraocular pressure,” Ophthalmic Surgery, Lasers and Imaging, Sep./Oct. 2003; 34(5): 386-390. |
| Bird et al., Transport Phenomena, John Wiley & Sons, Inc., New York, 1960, pp. 196-201. |
| Block et al., “Solubility and dissolution of triamcinolone acetonide,” Journal of Pharmaceutical Sciences, Apr. 1973; 62(4):617-621. |
| Castro et al., “Effect of COX inhibitors on VEGF-induced retinal vascular leakage and experimental corneal and choroidal neovascularization,” Exp Eye Res. Aug. 2004; 79(2):275-285. |
| Chirila et al., “The Vitreous Humor” in Handbook of Biomaterial Properties, eds. Black & Hastings. Chapman & Hall, London, 1998; pp. 125-131. |
| Cousins et al., “Program # 1251—Targeting Complement Factor 5 in Combination with Vascular Endothelial Growth Factor (VEGF) Inhibition for Neovascular Age Related Macular Degeneration (AMD): Results of a Phase 1 Study,” [Presentation Abstract], AMD Clinical Trials Session # 220, May 3, 2010. 2 pages. |
| Deissler et al., “VEGF-induced effects on proliferation, migration and tight junctions are restored by ranibizumab (Lucentis) in microvascular retinal endothelial cells,” Br J Ophthalmol 2008;92:839-843. |
| Donoso et al., “The role of inflammation in the pathogenesis of age-related macular degeneration,” Surv Ophthalmol. Mar.-Apr. 2006;51(2):137-52. |
| European Medicine Agency, Scientific Discussion; retrieved from the Internet; <http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf>, EMEA 2007, 54 pages total. 2007. |
| Funatsu et al. “Association of vitreous inflammatory factors with diabetic macular edema,” Ophthalmology 2009;116:73-79. |
| Gaudreault et al., “Preclinical Pharmacokinetics of Ranibizumab (rhuFabV2) after a Single Intravitreal Administration,” Investigative Ophthalmology and Visual Science. 2005;46:726-733. Retrieved from the Internet: <<http://www.iovs.org/cgi/reprint/46/2/726>>. |
| Gillies et al., “Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial,” Ophthalmology. Sep. 2006;113(9):1533-1538. |
| Hastedt & Wright, “Diffusion in porous materials above the percolation threshold,” Pharm. Res. Sep. 1990; 7(9):893-901 (1990). |
| Heier et al, “Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema,” Ophthalmology. Nov. 2000;107(11):2034-2038 ;discussion 2039. |
| Jena et al., “A Novel Technique for Surface Area and Particle Size Determination of Components of Fuel Cells and Batteries,” Porous Materials, Inc., Dec. 2006, 3 pages total. Downloaded from the Internet: <<http://www.pmiapp.com/publications/docs/A_Novel_technique_for_surface_area.pdf>>. |
| Kang et al., “Inhibitory effects of anti-inflammatory drugs on interleukin-6 bioactivity,” Biol Pharm Bull. Jun. 2001;24(6):701-703. |
| Lopez-Armada et al., “Modulation of cell recruitment by anti-inflammatory agents in antigen-induced arthritis,” Ann Rheum Dis Nov. 2002;61(11):1027-1030. |
| Luncentis, INN-Ranibizumab, “Scientific Discussion,” European Medicines Agency ; retrieved from the Internet:<http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Assessment_Report_-_Variation/human/000715/WC500101009.pdf>. Oct. 21, 2010. 32 pages. |
| Metal Powder Industries Federation, Porous Metal Design Guidebook, 2007, 24 pages total. Downloaded from the Internet: <<http://www.mpif.org/DesignCenter/porous.pdf>>. |
| MOTT Corporation, “Sintered Metal Powder Media,” American Filtration & Separation Society 2007, 2 pages total. Downloaded from the Internet:<<http://www.afssociety.org/education/0907oneminute.htm>>. |
| Navarro, “The Optical Design of the Human Eye: a Critical Review,” J Optom, Jan.-Mar. 2009 2(1): 3-18. |
| Okabe et al., “Intraocular tissue distribution of betamethasone after intrascleral administration using a non-biodegradable sustained drug delivery device,” Investigative Ophthalmology and Visual Science. 2003;44:2702-2707. Downloaded from the Internet: <<http://www.iovs.org/cgi/reprint/44/6/2702>>. |
| Rosenfeld, “The Latest Research: Intravitreal Bevacizumab for Proliferative Diabetic Retinopathy,” Review of Ophthalmology's Retina Online, Feb. 2006. 2 pages. Retrieved from the Internet: http://www.revophth.com/archive/newsletter/0206_retina.htm. |
| Sanborn G.E., et al., Sustained-Release Ganciclovir Therapy for Treatment of Cytomegalovirus Retinitis, Use of an Intravitreal Device, Arch. Ophthalmol, vol. 110, 188-195 (Feb. 1992). |
| Smith et al., “Spectrophotometric determination of pKa values for fluorescein using activity coefficient corrections,” WaterSA 2002; 28(4):395-402. |
| Smith, T.J., et al., “Intravitreal Sustained-Release Ganciclovir”, Arch. Ophthamol 110 (1992) pp. 255-258. |
| Soheilian et al., “Pilot Study of Intravitreal Injection of Diclofenac for Treatment of Macular Edema of Various Etiologies,” Retina, Mar. 2010; 30(3): 509-515. |
| Theodossiadis et al., “Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration,” Am J Ophthalmol. May 2009;147(5):825-830. |
| Williams et al., “Treating Diabetic Macular Edema With Ocular NSAIDs,” Retinal Physician, Nov. 2007; retrieved from the Internet Nov. 11, 2007. http://www.retinalphysician.com/article.aspx?article=101096>, 5 pages total. |
| Number | Date | Country | |
|---|---|---|---|
| 20200060874 A1 | Feb 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62077829 | Nov 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14937754 | Nov 2015 | US |
| Child | 16671749 | US |
