Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
  • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
  • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
  • A61M39/02—Access sites
  • A61M39/0208—Subcutaneous access sites for injecting or removing fluids

Definitions

• an implantable therapeutic device to treat a patient.
• the device includes a hollow refillable housing for implantation within the posterior segment of an eye through a penetration in the sclera of the eye.
• the housing has a proximal end region.
• a proximal retention structure protrudes outward from the proximal end region and has an access portion opening.
• a penetrable barrier is positioned at least in part within the access portion opening and is configured to be repeatedly penetrated.
• a rigid porous structure is positioned within a region of the housing away from the access portion opening.
• a reservoir chamber extends along an axis between the penetrable barrier and the porous structure.
• the reservoir chamber includes a volume sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time.
• the access portion opening opens into the reservoir chamber.
• a cover is coupled to at least an upper surface of the proximal retention structure.
• the access portion opening can be over-molded by the cover.
• the cover can encapsulate and bond the proximal retention structure and an upper surface of the penetrable barrier can be positioned within the access portion opening.
• the cover can encapsulate and bond to at least an upper surface of the proximal retention structure.
• the cover can encapsulate and bond to a lower surface of the proximal retention structure.
• the cover can maintain a seal of the reservoir chamber volume.
• the cover and the proximal retention structure can have the same shape profile.
• the cover and the penetrable barrier can be penetrated during filling of the reservoir chamber.
• the cover and the penetrable barrier can be configured to reseal after penetration of the reservoir chamber.
• the proximal retention structure can include one or more through-holes.
• the penetrable barrier can be pre-molded and the cover can be over-molded.
• the penetrable barrier can be a soft, high strength material and the cover can be a high durometer material.
• the cover can be a translucent material.
• the device can further include an anchor positioned within the access portion opening and in contact with at least a portion of the penetrable barrier.
• the penetrable barrier can further include a distal region that is flared and positioned within a proximal end region of the reservoir chamber.
• an implantable therapeutic device to treat a patient having a hollow refillable housing for implantation within the posterior segment of an eye through a penetration in the sclera of the eye.
• the housing has a proximal end region.
• a proximal retention structure is protruding outward from the proximal end region and includes an access portion opening.
• a penetrable barrier is positioned at least in part within the access portion opening. The penetrable barrier is configured to be repeatedly penetrated.
• a rigid porous structure is positioned within a region of the housing away from the access portion opening.
• a reservoir chamber extends along an axis between the penetrable barrier and the porous structure.
• the reservoir chamber has a volume sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time.
• the access portion opening opens into the reservoir chamber.
• An anchor is positioned within the access portion opening and in contact with at least a portion of the penetrable barrier.
• the penetrable barrier can be pre-molded with soft, high strength material.
• the anchor can be formed of a high durometer material that resists deformation.
• the penetrable barrier can be bonded to the anchor creating a single septum structure.
• the anchor can engage an undercut feature in the proximal end of housing.
• the penetrable barrier can apply radial compression to the anchor.
• the device can further include a cover covering an upper surface of the proximal retention structure.
• the device can further include a sealing element positioned within a proximal end region of the reservoir chamber and coupled to the penetrable barrier.
• FIG. 1 is a cross-sectional, schematic view of a portion of the human eye
• FIG. 2 is a cross-sectional, schematic view of a portion of the human eye having an implementation of a therapeutic device implanted therein;
• FIG. 3A is an exploded, perspective view of an
• FIGs. 3B-3C are exploded, side views of the therapeutic device of FIG. 3A;
• FIGs. 3D-3E are top and bottom views, respectively, of the therapeutic device of FIG. 3A;
• FIG. 3F is a side, cross-sectional view of the therapeutic device of FIG. 3A;
• FIGs. 4A-4B are perspective and cross-sectional partial views, respectively, of an implementation of a therapeutic device
• FIG. 5 is a side, cross-sectional partial view of an implementation of a therapeutic device
• FIG. 6. is a side, cross-sectional partial view of an implementation of a therapeutic device.
• implantable devices, systems and methods of use for the delivery of one or more therapeutics for the treatment of diseases can deliver therapeutics to select regions and structures of the body over a variety of periods of time.
• the devices and systems described herein have improved penetrable access portions for the repeated injection and long-term treatment and implantation of the device. It should be appreciated that the penetrable access portions 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. No. 8,399,006; U.S. Pat. No. 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.
• FIG. 1 is a cross-sectional, schematic view of a portion of the human eye showing the anterior chamber, posterior chamber and vitreous body of the eye.
• the eye 10 is generally spherical and is covered on the outside by the sclera 24.
• the retina 26 lines the inside posterior segment of the eye 10 and includes the macula 32.
• the retina 26 registers the light and sends signals to the brain via the optic nerve.
• the bulk of the eye 10 is filled and supported by the vitreous body (vitreous humor) 30, a clear, jelly-like substance disposed between the lens 22 and the retina 26.
• 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, a posterior flat area approximately 4 mm long.
• the pars plana region 25 is an example of a region of the eye suitable for placement and retention of the devices described herein.
• the eye 10 can include an insertion of the tendon of the superior rectus muscle to couple the sclera 24 of the eye to the superior rectus muscle.
• the devices described herein can be positioned in many locations of the pars plana region 25, for example 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.
• FIG. 2 shows an implementation of the therapeutic device 100 implanted at the pars plana region 25.
• the device 100 can be positioned so as to extend from the pars plana region 25 through the sclera 24 into the posterior segment of the eye including the vitreous body 30 so as to release the therapeutic agent into the vitreous body 30.
• the therapeutic device 100 can include a proximal, retention structure 120, such as a smooth protrusion at a proximal end region of the device 100, configured for placement along the sclera 24.
• the retention structure 120 can be positioned under the conjunctiva 16 such that the conjunctiva 16 can cover the therapeutic device and protect the therapeutic device 100.
• the conjunctiva 16 may be lifted away, incised, or punctured with a needle to access the therapeutic device 100.
• 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.
• tissue intraocular, intravascular, intraarticular, intrathecal, pericardial, intraluminal and intraperitoneal.
• 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.
• 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 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. No. 8,399,006; U.S. Pat. No. 8,623,395; PCT Pat. Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047; and PCT Pat. Publication No. WO 2012/065006.
• the septum features described herein may be used with any of the various implementations of a device or system.
• the device 100 can include a housing 130, a penetrable barrier 140 and a porous structure 150.
• the housing 130 can be a rigid, hollow refillable housing for implantation within an interior chamber of the eye, such as the posterior segment of an eye through a penetration in the sclera of the eye.
• the housing 130 can have a proximal end region and a distal end region.
• the housing 130 can have an inner surface that defines, at least in part, a reservoir chamber 160 for holding a therapeutic material or agent(s) (see FIG. 3F).
• the penetrable barrier 140 can be positioned within a proximal end region of the housing 130 such as within an opening 180 in an access portion of the device that leads into a reservoir chamber 160 of the device.
• the porous structure 150 can be positioned within another region of the housing 130 a distance away from the penetrable barrier 140 such as within an opening 152 leading out of the reservoir chamber 160 of the device.
• the porous structure 150 can be positioned near a distal end region of the housing 130 opposite the location of the more proximal penetrable barrier 140.
• the reservoir chamber 160 can have a volume sized to deliver therapeutic amounts of therapeutic agent to the eye for an extended period of time and the porous structure 150 can be configured to release therapeutic agent contained within the reservoir chamber 160 over the extended period of time.
• the housing 130 can include a retention structure 120 that can protrude outward from the proximal end region of the housing 130.
• the access portion opening 180 can be an opening in the device 100 that extends into the reservoir chamber 160.
• the penetrable barrier 140 can be positioned, at least in part, within the access portion opening 180 such that it forms a seal with the proximal end region of the housing 130.
• the devices described herein can also include a cover 1 10 coupled to at least a region of the device such as the retention structure 120.
• the cover 1 10 can cover, coat, cap, encapsulate, bond or otherwise couple to at least the penetrable barrier 140 of the device.
• the cover 1 10 can be configured to improve the integrity of the penetrable barrier 140 and its sealing engagement within the access portion opening 180 for repeated injection and long-term implantation.
• a distal end region of the housing 130 can include another opening 152, for example opposite the proximal access portion opening 180 into the reservoir chamber 160, that extends between the inside of the reservoir chamber 160 out of the housing 130.
• the porous structure 150 can be coupled to or positioned, at least in part, within the opening 152. It should be appreciated that the porous structure 150 can be coupled to or positioned within other regions besides the distal end region of the housing 130.
• the porous structure 150 can be affixed within an opening 152 in distal end of housing 130, for example with glue or other material(s).
• the distal end of the housing 130 can include an inner diameter sized to receive the porous structure 150, and the housing 130 can include a stop to position the porous structure 150 at a predetermined location on the distal end so as to define a predetermined size of reservoir chamber 160.
• the reservoir chamber 160 within the housing 130 of the device 100 can extend along axis 100A between the penetrable barrier 140 positioned proximally within the access portion opening 180 to the location of the porous structure 150.
• Therapeutic formulations injected into device 100 can be released from the reservoir chamber 160 in accordance with the volume of the reservoir chamber 160 and a release characteristic or release rate index of the porous structure 150.
• the volume of the reservoir chamber 160 can be sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time.
• the volume of the reservoir chamber 160 can be substantially determined by an inner cross sectional area of the housing 130, such as the distance between the proximal, penetrable barrier 140 and the porous structure 150.
• the release rate index (RRI) can be used to determine the release of the therapeutic from the device 100.
• RRI encompasses (PA/FL) where P comprises the porosity, A comprises an effective area, F comprises a curve fit parameter corresponding to an effective length and L comprises a length or thickness of the porous structure 150. Additional details regarding release characteristics of the porous structure 150 that can be used in the various devices described herein can be found, for example, in PCT Publication No. WO 2012/065006, which is incorporated herein by reference in its entirety.
• the housing 130 can have a dimension such that its length generally exceeds its width or diameter.
• the housing 130 can have a diameter sized within a range, for example, from at least about 0.5 mm to at least about 4 mm, from at least about 1 mm to at least about 3 mm. In some implementations the diameter of the housing 130 at its widest point can be about 2 mm, for example.
• the housing 130 can have a length sized so as to extend from the conjunctiva 16 to the vitreous body 30 along axis 100A to release the therapeutic agent into the vitreous body 30.
• the housing 130 can have a length sized within a range, for example, from at least about 2 mm to at least about 14 mm, from at least about 4 mm to at least about 10 mm. In some implementations, the length of the housing 130 can be about 7 mm, for example.
• the above dimensions are provided as example dimensions and are not intended to be limiting. It should be appreciated that a variety and combination of dimensions are to be considered herein.
• the housing 130 and reservoir chamber 160 can each (although not necessarily both) have an elliptical or oval cross-sectional shape, for example.
• This elongation of the device along one direction can allow for increased drug in the reservoir chamber 160 with a decrease interference in vision, for example, as the major axis of the ellipse can be aligned substantially with the circumference of the pars plana region 25 of the eye extending substantially around the cornea 12 of the eye, and the minor axis of the ellipse can be aligned radially with the eye so as to decrease interference with vision as the short axis of the ellipse extends toward the optical axis of the eye corresponding to the patient's line of sight through the pupil.
• One or more regions of the housing 130 of the devices described herein can be formed of a substantially rigid, biocompatible material.
• the walls of the housing 130 including at least the proximal retention structure 120 down to and including the porous structure 150 are substantially rigid such that the reservoir chamber 160 has a substantially constant volume when the therapeutic agent is released from the device so as to maintain a stable release rate profile, for example when the patient moves.
• the reservoir chamber 160 can remain substantially rigid and have a substantially constant volume even during injection of the therapeutic agent into the device, for example a device already implanted in the eye.
• One or more regions of the housing 130, one or more regions of the retention structure 120 as well as other portions of the devices described herein, alone or in combination, can be formed of one or more of many biocompatible materials including, but not limited to materials such as acrylates, polymethylmethacrylate, siloxanes, metals, titanium stainless steel, polycarbonate, polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate (PET), polyimide, polyamide-imide, polypropylene, polysulfone, polyurethane, polyvinylidene fluoride, polyphenylene polyphenylsulfone or PTFE, and others.
• biocompatible materials including, but not limited to materials such as acrylates, polymethylmethacrylate, siloxanes, metals, titanium stainless steel, polycarbonate, polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate (PET), polyimide, polyamide-imide, polypropylene, polysulfone, polyurethane,
• one or more portions of the devices described herein, such as the housing 130 can be formed at least in part from an optically transmissive material such that the housing 130 can be translucent or transparent, such that when the device 100 is loaded with therapeutic agent the reservoir chamber 160 can be visualized outside the patient prior to implantation, for example when injected with a formulation of therapeutic agent prior to implantation in the physician's office.
• visualization of the reservoir chamber 160 can be helpful to ensure that the reservoir chamber 160 is properly filled with therapeutic agent by the treating physician or assistant prior to implantation.
• transparency can enable visualization, for example, using an indirect ophthalmoscope, of the contents of the reservoir chamber 160 of an implanted device allowing one to confirm that no air is trapped in the device and/or verify the clarity of the device contents.
• a cloudy appearance for example, may indicate that some degree of contamination, microbial or otherwise, has occurred.
• biocompatible, optically transmissive materials can include one or more of acrylate, polyacrylate, methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate, glass or siloxane.
• the porous structure 150 can include one or more of a release control element, a release control mechanism, permeable membrane, a semi-permeable membrane, a material having at least one hole disposed therein, channels formed in a rigid material, straight channels, nano-channels, nano-channels etched in a rigid material, laser drilled holes, laser etched nano-channels, a capillary channel, a plurality of capillary channels, one or more tortuous channels, sintered material, sintered rigid material, sintered glass, sintered ceramic, sintered metal, sintered titanium, tortuous micro- channels, sintered nano-particles, an open cell foam or a hydrogel such as an open cell hydrogel.
• Porous structures considered herein are described in U.S. Pat. No. 8,399,006; U.S. Pat. No. 8,623,395; PCT Publication No.
• the retention structure 120 can protrude outward from the proximal end region of the housing 130. At least a first surface of the retention structure 120 can be configured to contact the sclera 24 and, in some implementations, can be configured to contact the conjunctiva 16 on at least a second surface of the retention structure 120. For example, at least a portion of the underside of the retention structure 120 can contact the sclera 24 and at least a portion of the upper side of the retention structure 120 can contact the conjunctiva 16.
• the retention structure 120 can be configured to contact the sclera 24 such that the retention structure 120 is at least partially embedded within the thickness of the sclera 24 and does not necessarily sit on an upper surface of the sclera or the conjunctiva.
• the retention structure 120 can include a narrowed portion 121 and a wider, flanged portion 122 extending proximally from the narrowed portion 121 .
• the narrowed portion 121 can have a cross-section sized to fit in an elongate incision or a puncture through the pars plana region 25 without causing gaping of the tissue near either end of the incision.
• an incision can be made with a device having a straight, flat blade, for example a 3.2 mm blade. Penetrating the sclera with such a blade can result in exposed scleral tissue that may need to be sealed (e.g. 6.4 mm or 2 x 3.2 mm).
• a cross-sectional region of an implant positioned within the cut region of the sclera could open the wound such that there would be relatively large voids on either side of the device, for example about 2.2 mm between either side of the device and the farthest aspects of the exposed sclera. These voids can result in cut portions of the sclera remaining exposed and unsealed.
• the geometry of the narrowed portion 121 of the devices described herein can be designed to minimize the length of cut scleral tissue that remains exposed and/or unsealed.
• the narrowed portion 121 can have a first cross-sectional distance across, or first dimensional width, and a second cross-sectional distance across, or second dimensional width, in which the first cross- sectional distance across is greater than the second cross-sectional distance across providing the narrowed portion 121 with an elongate cross-sectional profile.
• the elongate cross section of the narrowed portion 121 can be sized in many ways to fit the incision.
• the elongate cross section can have a first dimension longer than a second dimension and can have one or more of many shapes such as dilated slit, dilated slot, lentoid, oval, ovoid, or elliptical.
• the narrowed portion 121 can have other cross sectional shapes, for example, a circular shape, if desired.
• the dilated slit shape and dilated slot shape can correspond to the shape assumed by the scleral tissue when cut and dilated.
• the lentoid shape can correspond to a biconvex lens shape.
• the elongate cross-section of the narrowed portion 121 can include a first curve along a first axis and a second curve along a second axis that is different than the first curve.
• the narrowed portion 121 can be sized and configured to receive the sclera 24 upon implantation in the eye 10 when the flanged portion 122 is positioned between the sclera 24 and the conjunctiva 16 and the distal end of the housing 130 extends into the vitreous body 30.
• Flanged portion 122 of the retention structure 120 can include a first distance across and a second distance across.
• the first distance across can be greater than the second distance across (see FIGs. 3B and 3C, for example).
• the first distance across can result in the flanged portion 122 having a diameter greater than a largest diameter of the housing 130 (see e.g., FIG. 3B) whereas the second distance across can result in the flanged portion 122 having a diameter equal to or less than a largest diameter of the housing 130 (see e.g., FIG. 3C).
• the flanged portion 122 can have a variety of shapes, such as rectangular, square, oval, elliptical, circular, teardrop, polygonal or other shape.
• the flanged portion 122 can be formed as a smooth protrusion configured for placement along a portion of the sclera 24. In some implementations, the flanged portion 122 is positioned under the conjunctiva 16, such that the conjunctiva 16 covers and protects the device 100.
• the flanged portion 122 can be formed from a translucent material such that the physician can visualize tissue under the flanged portion 122 to assess the patient and to decrease appearance of the device 100 when implanted.
• the penetrable barrier 140 can be positioned, at least in part, within access portion opening 180 sealing the reservoir chamber 160 on a proximal end region of the device 100.
• the penetrable barrier 140 can be a septum configured to receive and be repeatedly penetrated by a sharp object such as a needle for injection of the therapeutic agent into the reservoir chamber 160.
• the penetrable barrier 140 can be configured to re-seal when the sharp object is removed.
• the penetrable barrier 140 can be a pre-molded soft, high strength material.
• the penetrable barrier 140 can be formed from one or more elastic materials such as siloxane, rubber, or another liquid injection molding silicone elastomer such as NUSIL MED-4810 (NuSil Silicone
• the penetrable barrier 140 can include an opaque material and/or a colored material such that it can be visualized by the treating physician.
• the penetrable barrier 140 can be positioned within a proximal end region of the housing 130 at least in part within an opening of the access portion 180.
• the overall shape of the external surface of the penetrable barrier 140 can correspond generally to the shape of the surface(s) near the access portion opening 180 against which the penetrable barrier 140 contacts to mate and seal. It should be appreciated that the points of contact between the penetrable barrier 140 and the housing 130 can vary.
• the penetrable barrier 140 can make contact, for example sealing contact, with at least one or more surfaces or regions of the upper end of the reservoir chamber, the housing 130, the retention structure 120, the narrowed portion 121 , the flanged portion 122, the access portion opening 180, and/or a combination thereof.
• the penetrable barrier 140 can have an upper region 144, a middle region 141 , and a distal region 142.
• the upper region 144 can be sized to reside within and mate with at least a portion of the flanged portion 122.
• the upper region 144 can form an upper surface of the penetrable barrier 140 available through the access region opening 180 of the device.
• the outer surface of the upper region 144 can be beveled to correspond with the shape of and provide optimum mating engagement with an inner surface of the retention structure 120 that can also be beveled (see FIG. 3F).
• the middle region 141 can be sized to reside within and mate with an inner surface of the narrowed portion 121 of the retention structure 120. As such, the middle region 141 can be a reduced diameter region or form a "waist" in the penetrable barrier 140. Alternatively, the middle region 141 can be relatively annular and have a generally planar outer surface configured to contact a corresponding planar surface forming the opening of the access region 180.
• the distal region 142 can have a diameter that is the same as or greater than the narrowed portion 121 of the retention structure 120 such that the distal region 142 helps to prevent withdrawal of the penetrable barrier 140 out of the access region 180.
• the distal region 142 can have one or more tabs, a flared skirt, flange, rib or other feature of enlarged diameter compared to the middle and/or upper regions 141 , 144 and sized to reside within and mate with at least a portion of the retention structure 120 located distal to the narrowed portion 121 and/or an upper region of the reservoir chamber 160 such as with an inner wall of the housing 130.
• the flange can have an upper surface configured to contact an inner wall surface near the upper end of the reservoir chamber 160 that surrounds the opening 180 of the access portion.
• the features of the distal region 142 having an enlarged diameter compared to the middle or upper regions 144, 141 , such as the one or more tabs can also aid in forming a seal and retaining the penetrable barrier 140 within the access portion opening 180. For example, as best shown in FIG.
• the distal region 142 of the penetrable barrier 140 can include a first tab 142a positioned on a first region of the penetrable barrier 140 and a second tab 142b positioned on a second region of the penetrable barrier 140, such as a side opposite or a distance away from the first region.
• the tabs 142a, 142b can project away from the longitudinal axis 100A providing a cross-sectional diameter of the penetrable barrier 140 in at least one direction that is greater that the cross-sectional diameter of the middle region 141 .
• the cross-sectional diameter of the penetrable barrier 140 distal to the middle region 141 in at least a first direction can be equal to, more or less than the cross-sectional diameter of the upper region 144.
• the distal region 142 can have one, two, three, four, or more tabs spaced around the wall of the penetrable barrier 140. It should also be appreciated that the entire distal region 142 of the penetrable barrier 140 can be flared away from the longitudinal axis 100A of the penetrable barrier 140 as shown in FIG. 4B to better engage an upper region of the housing 130 near the access region 180. In further implementations, the distal region 142 of the penetrable barrier 140 can be include a flange of an enlarged diameter. It should be appreciated that the distal region 142 as well as the entire penetrable barrier 140 itself can have a variety of shapes and features that act to improve retention within the upper end of the reservoir chamber 160. The features of one implementation of the penetrable barrier 140 can be used in combination or in the alternative with one or more implementations of the devices described herein.
• the penetrable barrier 140 can be adhered within the device 100, for example, in at least a portion of the access portion opening 180 of the retention structure 120. Alternatively, the penetrable barrier 140 can be positioned into a proximal region of the device 100 in an adhesion-free manner and rely on the mating features between the external surface of the penetrable barrier 140 with the corresponding surfaces of the access portion opening 180 against which the penetrable barrier 140 abuts and seals.
• the devices described herein can be coupled to a cover 1 10 that can be configured to improve the integrity of the penetrable barrier 140 and its sealing engagement with the access portion opening 180 for repeated injection and long-term implantation. This provides a benefit to a device intended to be implanted long-term and re-filled while implanted, such as those described herein.
• the cover 1 10 can cap, coat, bond, encapsulate, cover, or otherwise couple to one or more components of the devices described herein.
• a proximal end region of the device 100 including one or more combinations of the upper surface of the penetrable barrier 140 positioned within the opening of the access portion 180, an upper surface of the proximal retention structure 120 including the flanged portion 122, a lower surface of the proximal retention structure 120 including the flanged portion 122, the narrowed portion 121 of the retention structure 120, and at least a portion of an outer surface of the housing 130 near the proximal end region.
• FIG. 4A-4B show an implementation of a device in which the access portion opening 180, the penetrable barrier 140 and the retention structure 120 can be over-molded by the cover 1 10 such that the cover 1 10 can encapsulate and bond the access portion opening 180 and the upper surface of the penetrable barrier 140 positioned within the access portion opening 180.
• the cover 1 10 can encapsulate and bond to at least an upper surface of the proximal retention structure 120 as well as the lower surface of the proximal retention structure 120 (see, for example, FIG. 4B).
• the cover 1 10 can also encapsulate the flanged portion 122 such that the cover 1 10 bonds to at least the upper surface and also the lower surface of the flanged portion 122.
• the penetrable barrier 140 can be exposed or accessible on a proximal end region.
• the cover 1 10 can extend across the entire proximal end region of the device 100 such that it bonds to the flanged portion 122 and to the proximal end region of the penetrable barrier 140 positioned therein. As such, the cover 1 10 can supplement the bond between the penetrable barrier 140 and the inner surfaces of the device near the access portion opening 180 such as within the flanged region 120 and the inner surfaces of the proximal end region of the housing 130.
• the cover 1 10 can maintain or help to maintain a seal of the reservoir chamber volume. In some
• the cover 1 10 maintains the seal of the penetrable barrier 140 within the access portion opening 180 such that the seal of the reservoir chamber 160 need not rely on bonding between the surfaces of the housing 130 and the surfaces of the penetrable barrier 140. In some implementations, the cover 1 10 eliminates any need for a bond between the housing 130 and the penetrable barrier 140. Certain surface treatments can also be used during manufacturing of the devices described herein to enhance bonding between various components, including for example but not limited to, bonding primer agents such as NUSIL MED 161 or other surface activation techniques such as plasma treatment of the surfaces to be bonded.
• the cover 1 10 and the proximal retention structure 120 can have corresponding shape profiles.
• the thickness of the over-molded cover 1 10 can vary from approximately 0.007" to approximately 0.025".
• the cover 1 10 can extend beyond the outer diameter of the flanged portion 122 as best shown in FIGs. 4A and 4B.
• the cover 1 10 can also extend upward from the upper surface of the flanged portion 122 and provide a slightly thicker and slightly higher profile to the access portion under the conjunctiva.
• the needle can extend through the cover 1 10 as it penetrates the barrier 140.
• the cover 1 10, like the penetrable barrier 140, can be configured to re-seal when the needle or other sharp object is withdrawn.
• the proximal retention structure 120 can include one or more through-holes, apertures, indentations or other features.
• the flanged portion 122 can include one or more apertures 125 extending therethrough.
• the apertures 125 can create mechanical struts of the over-molded cover material that extend through one or more regions of the flanged portion 122.
• the mechanical struts of over-molded cover material can provide some anchoring support as well as facilitating good filling of the over-mold.
• the apertures 125 can also allow for a thin, uniform layer of over-mold material to form on the underside of the flanged portion 122 or other another region of the retention structure during over-molding. It should be appreciated, however, that mechanical struts of the over-molded material can be formed by over-molded material extending only partially through apertures in the flanged portion 122. Further, instead of apertures 125, the flanged portion 122 can include only partial-thickness holes or indentations in the flanged portion 122. The indentations can be on an external surface of the flanged portion 122 such as in the upper and/or lower surfaces of the flanged portion 122.
• the external surfaces of the flanged portion 122 can also be textured such that the over- molded material of the cover 1 10 can penetrate and fill additional indented regions of the flanged portion 122 to provide a better coupling between the flanged portion 122 and the material of the cover 1 10.
• the cover 1 10 can be an over-molded, high durometer material such as a translucent, liquid silicone rubber like MED-4880 or MED- 4860 (NuSil Silicone Technology, Carpinteria, CA).
• the penetrable barrier 140 positioned within the proximal end region of the housing 130 can be a pre-molded soft, high strength material such as a liquid injection molding silicone elastomer such as MED-4810 (NuSil Silicone Technology,
• FIG. 5 illustrates another implementation of a device that can include, alternatively or in combination with the cover 1 10, an anchor 250 to secure the septum structure within the access portion of the housing 130.
• the anchor 250 can provide further support to the penetrable barrier 140 as well as providing perimeter seal and added physical integrity useful during repeated penetration of the barrier 140 to refill the device.
• the anchor 250 can be an annular element encircling at least a portion of the penetrable barrier 140.
• An inner surface of the anchor 250 can contact and encircle at least a portion of the outer surface of the penetrable barrier 140.
• the anchor 250 encircles the upper region 144, the middle region 141 , the distal region 142 or a combination of one or more of the upper, middle and distal regions of the penetrable barrier 140.
• the upper region 144 of the penetrable barrier 140 can be beveled such that the outer diameter of the upper region 144 is larger than the outer diameter of the middle region 141 of the penetrable barrier 140.
• the shape of the inner surface of the anchor 250 can be beveled to match the shape of the outer surface of the penetrable barrier 140.
• the inner surface of the anchor 250 can be shaped to match the outer surface of the distal region 142 of the penetrable barrier 140, which can be straight or flared or have one or more tabs or flanged regions as described above.
• the outer surface of the anchor 250 can have a geometry that matches at least a portion of the geometry of the housing 130 at the access portion.
• the outer surface of the 250 can engage with an undercut feature 252 in the proximal end of the housing 130.
• the anchor 250 can be, but is not necessarily, annular or ring-shaped.
• the anchor 250 can be any of a variety of shapes and can include one or more features that can be bonded to at least a region of the penetrable barrier.
• the outer surface of the anchor 250 can have any of a variety of shapes, including, but not limited to the rounded shape as shown in FIG.
• the anchor 250 can have sufficient physical robustness so as to translate to a secure mechanical interference with internal aspects of the rigid, body device in the area of the penetrable barrier.
• the penetrable barrier 140 can be pre-molded with a soft, high strength material such as a liquid injection molding silicone elastomer such as MED-4810 (NuSil Silicone Technology, Carpinteria, CA).
• the anchor 250 can be formed of a higher durometer material such as a translucent, liquid silicone rubber like MED-4880 (NuSil Silicone Technology, Carpinteria, CA).
• the pre-mold penetrable barrier 140 can be bonded to the annular anchor 250 creating a single septum structure for insertion within the proximal end of the housing 130.
• the pre-mold penetrable barrier 140 and anchor 250 can be bonded together within the housing 130 or can be bounded outside the device and loaded into positioned once a single septum structure is formed.
• the higher durometer of the anchor 250 can resist deformation and create a mechanical lock fixing the location of the septum in the housing 130.
• the pre- mold penetrable barrier 140 can apply radial compression to the outer anchor 250 and housing 130 to maintain septum seal performance.
• the radial compression of the penetrable barrier 140 can encourage re-sealing after penetration following filling or re-filling of the reservoir chamber, for example re-sealing of a needle track upon removal of the needle.
• the radial compression of the penetrable barrier 140 can be provided by the pre-mold penetrable barrier 140 being larger in dimension relative to the access portion of the housing 130 in which it is positioned and the access portion of the housing 130 being formed of a more rigid material than the softer, pre-mold penetrable barrier 140.
• FIG. 6 illustrates an interrelated implementation of a device that can include, alternatively or in combination with the cover 1 10, an anchor 250.
• the anchor 250 can secure the septum structure within the access portion opening 180 of the housing 130.
• the anchor 250 can provide further support to the penetrable barrier 140 as well as providing perimeter seal and added physical integrity.
• the anchor 250 can be an annular element encircling at least a portion of the penetrable barrier 140.
• An inner surface of the anchor 250 can contact and encircle at least a portion of the outer surface of the penetrable barrier 140.
• the inner surface of the anchor 250 can have a shape that corresponds to the outer surface of the penetrable barrier 140 and the outer surface of the anchor 250 can have a shape that corresponds to the inner surface of the access portion opening 180 of the housing 130, for example such that it engages an undercut feature 252 in the proximal end of the housing 130.
• the anchor 250 can be formed of a high durometer material to provide further support to the penetrable barrier 140 as well as providing perimeter seal and added physical integrity as described above.
• the penetrable barrier 140 can be a pre-molded, low durometer material also as described above. Further, the penetrable barrier 140 can be oversized such that the penetrable barrier 140 provides radial compression to the anchor 250 to provide improved needle track sealing as described above.
• the penetrable barrier 140 can include a distal region 142 having a flared, flanged or otherwise enlarged diameter compared to the middle region 141 and/or upper region 144 of the penetrable barrier 140.
• the enlarged distal region 142 can be positioned within the access portion opening 180, for example, where the access portion opening 180 opens into the reservoir chamber 160 at a proximal end region of the reservoir chamber 160.
• the penetrable barrier 140 can also include a sealing element 254 near its distal end region that is flared and/or creates a "skirt" within a proximal end region of the reservoir chamber 160.
• the sealing element 254 can be positioned in a proximal end of the reservoir chamber 160 of the housing 130 to provide a secondary seal and to prevent withdrawal of the penetrable barrier 140 in a proximal direction.
• the sealing element 254 can be a separate element coupled to the penetrable barrier 140, for example to the distal region 142 of the penetrable barrier 140.
• the sealing element 254 can be integral with the penetrable barrier 140 such as the flared distal end region 142 shown in FIG. 4B.
• the sealing element 254 can be a low durometer material that is the same as or different from the material of the penetrable barrier 140.
• the variations described above, such as the cover 1 10 can also be incorporated with the implementation shown in FIG. 6. It should be appreciated that the one or more of the components described herein can optionally be included in any feasible combination with the various implementations described herein.
• the housing 130 can be machined from a piece of material, or injection molded, so as to form the retention structure 120, flange 122 and/or the narrowed portion 121 .
• the penetrable barrier 140 can be pre-molded and the cover 1 10 can be over-molded.
• the cover 1 10 can be pre-molded and bonded to the pre-molded penetrable barrier 140.
• the penetrable barrier 140 and cover 1 10 can be the same material and over-molded around the flange 122 using a single step injection molding process.
• the penetrable barrier 140 or cover 1 10 can be two different materials and over molded around the flange and cured in two independent steps.
• the anchor 250 and/or sealing element 254 can be pre-molded and bonded to pre-molded penetrable barrier 140.
• the anchor 250 and/or sealing element 254 can be casted in the housing and the pre-penetrable barrier 140 can be compressed into the housing and bonded to the anchor 250 and/or sealing element 254.
• the sealing element 254 can be formed by a distal flared portion of the pre- molded penetrable barrier 140.
• Initial filling of the device 100 with one or more therapeutic agents can occur prior to insertion or after insertion in a patient's eye.
• the penetrable barrier 140 as well as the cover 1 10, if present, can be penetrated with a needle or access device attached to a syringe or injection device containing therapeutic agent.
• the cover 1 10 and the penetrable barrier 140 can be penetrated during filling and/or refilling of the reservoir chamber 160.
• the needle or access device can be inserted through the penetrable barrier 140 until a distal opening of the needle enters the reservoir chamber 160.
• the contents of the syringe or injection device can be injected into the reservoir chamber 160 and the needle or access device can be removed from the penetrable barrier 140.
• the cover 1 10 and the penetrable barrier 140 can be configured to reseal after penetration during filling and/or refilling of the reservoir chamber 160.
• the penetrable barrier 140 can reseal around the path created by the needle or access device upon its removal.
• the device 100 also can be periodically refilled with therapeutic agent following surgical placement as needed by accessing the implanted device 100 and without necessitating device removal.
• the conjunctiva 16 can be lifted or incised away. Alternatively, the conjunctiva can be pierced with the needle or access device used to fill the device 100 such that a single penetration is performed through each of the conjunctiva, cover 1 10 (if present), and penetrable barrier 140.
• the therapeutic devices described herein can be implanted in the eye to treat the eye for as long as is helpful and beneficial to the patient.
• the device can be implanted for at least about 1 year, 2 years, 3 years, 4 year, 5 years and up to permanently for the life of the patient.
• the device can be removed when no longer helpful or beneficial for treatment of the patient.
• the device can be implanted for at least about 4 years to 10 years, for example a duration of treatment period for a chronic disease such as diabetic macular edema or age-related macular degeneration.
• the device can be periodically refilled in the physician's office with new therapeutic agent as indicated by disease progression.
• diseases such as age-related macular
• the device can be refilled as frequently as once every week, biweekly, monthly, bi-monthly, every 3 months, every 4 to 6 months, every 3 to 9 months, every 12 months, or any other period as indicated to treat a disease.
• glaucoma macular degeneration, retinal disease, proliferative vitreoretinopathy, diabetic retinopathy, uveitis, keratitis, cytomegalovirus retinitis, cystoid macular edema, herpes simplex viral and adenoviral infections and other eye diseases
• eye infections including, but not limited to, infections of the skin, eyelids, conjunctivae, and/or lacrimal excretory system
• orbital cellulitis dacryoadenitis, hordeolum, blepharitis, conjunctivitis, keratitis, corneal infiltrates, ulcers, endophthalmitis, panophthalmitis, viral keratitis, fungal keratitis herpes zoster ophthalmicus, viral conjunctivitis,
• the devices can deliver drugs for the treatment of inflammation, infection, cancerous growth. It should also be appreciated that any number of drug combinations can be delivered using any of the devices and systems described herein.
• therapeutic agent is an agent or agents that ameliorate the symptoms of a disease or disorder or ameliorate the disease or disorder including, for example, small molecule drugs, proteins, nucleic acids, polysaccharides, and biologies or combination thereof.
• 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.
• Therapeutic agents include, but are not limited to, moieties that inhibit cell growth or promote cell death, that can be activated to inhibit cell growth or promote cell death, or that activate another agent to inhibit cell growth or promote cell death.
• the therapeutic agent can exhibit or manifest additional properties, such as, properties that permit its use as an imaging agent, as described elsewhere herein.
• Exemplary therapeutic agents include, for example, cytokines, growth factors, proteins, peptides or peptidomimetics, bioactive agents, photosensitizing agents, radionuclides, toxins, antimetabolites, signaling modulators, anti-cancer antibiotics, anti-cancer antibodies, angiogenesis inhibitors, radiation therapy, chemotherapeutic compounds or a combination thereof.
• the drug may be any agent capable of providing a therapeutic benefit.
• the drug is a known drug, or drug combination, effective for treating diseases and disorders of the eye.
• the drug is an antiinfective agent (e.g., an antibiotic or antifungal agent), an anesthetic agent, an anti-VEGF agent, an anti-inflammatory agent, a biological agent (such as RNA), an intraocular pressure reducing agent (i.e., a glaucoma drug), or a combination thereof.
• an antiinfective agent e.g., an antibiotic or antifungal agent
• an anesthetic agent e.g., an anesthetic agent
• an anti-VEGF agent e.g., an anti-VEGF agent
• an anti-inflammatory agent e.g., a biological agent (such as RNA), an intraocular pressure reducing agent (i.e., a glaucoma drug), or a combination thereof.
• a biological agent such as RNA
• an intraocular pressure reducing agent i.e., a glaucoma drug
• the therapeutic agent can include a macromolecule, for example an antibody or antibody fragment.
• the therapeutic macromolecule can include a VEGF inhibitor, for example commercially available LucentisTM.
• the VEGF (Vascular Endothelial Growth Factor) inhibitor can cause
• VEGF inhibitors include LucentisTM AvastinTM, MacugenTM, and VEGF Trap.
• the therapeutic agent can include small molecules such as of a corticosteroid and analogues thereof.
• the therapeutic corticosteroid can include one or more of trimacinalone, trimacinalone acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate, or analogues thereof.
• the small molecules of therapeutic agent can include a tyrosine kinase inhibitor comprising one or more of axitinib, bosutinib, cediranib, dasatinib, eriotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, or vatalanib, for example.
• the therapeutic agent can include an anti-VEGF therapeutic agent.
• Anti-VEGF therapies and agents can be used in the treatment of certain cancers and in age-related macular degeneration.
• anti-VEGF therapeutic agents suitable for use in accordance with the embodiments described herein include one or more of monoclonal antibodies such as bevacizumab (AvastinTM) or antibody derivatives such as ranibizumab (LucentisTM), or small molecules that inhibit the tyrosine kinases stimulated by VEGF such as lapatinib (TykerbTM), sunitinib (SutentTM), sorafenib (NexavarTM), axitinib, or pazopanib.
• the therapeutic agent can include a therapeutic agent suitable for treatment of dry AMD such as one or more of SirolimusTM (Rapamycin), CopaxoneTM (Glatiramer Acetate), OtheraTM, Complement C5aR blocker, Ciliary
• the therapeutic agent can include a therapeutic agent suitable for treatment of wet AMD such as one or more of REDD14NP (Quark), SirolimusTM (Rapamycin), ATG003;
• the therapeutic agent can include a kinase inhibitor such as one or more of bevacizumab (monoclonal antibody), BIBW 2992 (small molecule targeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (small molecule), trastuzumab (monoclonal antibody), gefitinib (small molecule), ranibizumab (monoclonal antibody), pegaptanib (small molecule), sorafenib (small molecule), dasatinib (small molecule), sunitinib (small molecule), erlotinib (small molecule), nilotinib (small molecule), lapatinib (small molecule), panitumumab
• bevacizumab monoclonal antibody
• BIBW 2992 small molecule targeting EGFR/Erb2
• cetuximab monoclonal antibody
• imatinib small molecule
• VEGFR2A/EGFR2 small molecule commercially available from Esai, Co.
• a variety of therapeutic agents can be delivered using the drug delivery implants described herein, including: anesthetics, analgesics, cell transport/mobility impending agents such as colchicine, vincristine, cytochalasin B and related compounds; antiglaucoma drugs including beta- blockers such as timolol, betaxolol, atenolol, and prostaglandins, lipid-receptor agonists or prostaglandin analogues such as bimatoprost, travoprost, latanoprost, unoprostone etc; alpha-adrenergic agonists, brimonidine or dipivefrine, carbonic anhydrase inhibitors such as acetazolamide,
• methazolamide methazolamide, dichlorphenamide, diamox; and neuroprotectants such as nimodipine and related compounds.
• antibiotics such as
• tetracycline chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin;
• antibacterials such as sulfonamides, sulfacetamide, sulfamethizole and sulfisoxazole
• anti-fungal agents such as fluconazole, nitrofurazone, amphotericin B, ketoconazole, and related compounds
• anti-viral agents such as trifluorothymidine, acyclovir, ganciclovir, DDI, AZT, foscamet, vidarabine, trifluorouridine, idoxuridine, ribavirin, protease inhibitors and anti- cytomegalovirus agents
• antiallergenics such as methapyriline;
• anti-inflammatories such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and triamcinolone; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; miotics, muscarinics and anti-cholinesterases such as pilocarpine, carbachol, di-isopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine; sympathomimetics such as epinephrine and vasoconstrictors and vasodilators; Ranibizumab,
• Antiinflammatories such as non-steroidal antiinflammatories (NSAIDs) may also be delivered, such as cyclooxygenase-1 (COX-1 ) inhibitors (e.g., acetylsalicylic acid, for example ASPIRIN from Bayer AG, Leverkusen, Germany; ibuprofen, for example ADVIL from Wyeth, Collegeville, Pa.; indomethacin; mefenamic acid), COX-2 inhibitors
• COX-1 cyclooxygenase-1
• MMP metalloproteinase
• Anticlotting agents such as heparin, antifibrinogen, fibrinolysin, anti clotting activase, etc., can also be delivered.
• Antidiabetic agents that may be delivered using the disclosed implants include acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, insulin, aldose reductase inhibitors, etc.
• Some examples of anti-cancer agents include 5-fluorouracil, adriamycin, asparaginase, azacitidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin,
• mercaptopurine methotrexate, mitomycin, mitotane, pentostatin, pipobroman, plicamycin, procarbazine, sargramostin, streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard, vinblastine, vincristine and vindesine.
• Hormones, peptides, steroids, nucleic acids, saccharides, lipids, glycolipids, glycoproteins, and other macromolecules can be delivered using the present implants.
• examples include: endocrine hormones such as pituitary, insulin, insulin-related growth factor, thyroid, growth hormones; heat shock proteins; immunological response modifiers such as muramyl dipeptide, cyclosporins, interferons (including ⁇ , ⁇ , and ⁇ interferons), interleukin-2, cytokines, FK506 (an epoxy-pyrido-oxaazcyclotricosine-tetrone, also known as Tacrolimus), tumor necrosis factor, pentostatin, thymopentin, transforming factor beta2, erythropoetin; antineogenesis proteins (e.g., anti- VEGF,
• Interferons among others and anticlotting agents including anticlotting activase.
• Further examples of macromolecules that can be delivered include monoclonal antibodies, brain nerve growth factor (BNGF), ciliary nerve growth factor (CNGF), vascular endothelial growth factor (VEGF), and monoclonal antibodies directed against such growth factors.
• Additional examples of immunomodulators include tumor necrosis factor inhibitors such as
• nucleic acids can also be delivered wherein the nucleic acid may be expressed to produce a protein that may have a variety of pharmacological, physiological or immunological activities.
• the above list of drugs is not meant to be exhaustive.
• a wide variety of drugs or agents may be used in the present invention, without restriction on molecular weight, etc.
• Other agents include anti-coagulant, an anti-proliferative, imidazole antiproliferative agent, a quinoxaline, a phsophonylmethoxyalkyl nucleotide analog, a potassium channel blocker, and/or a synthetic oligonucleotide, 5-[1 -hydroxy-2-[2-(2-methoxyphenoxyl) ethylamino] ethyl]-2- methylbenzenesulfonannide, a guanylate cyclase inhibitor, such as methylene blue, butylated hydroxyanisole, and/or N-methylhydroxylamine, 2-(4- methylaminobutoxy) diphenylmethane, apradonidine, a doprostenol analog or a fluprostenol analog, a crosslinked carboxy-containing polymer, a sugar, and water, a non-corneotoxic serine-threonine kinase inhibitor, a
• acetylcholinesterase inhibitors include sympathomimetics (e.g., epinephrine and dipivalylepinephxine), beta-blockers (e.g., betaxolol, levobunolol and timolol), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), and prostaglandins (e.g., metabolite derivatives of
• arachidonic acid or any combination thereof.
• phrases such as "at least one of or "one or more of may occur followed by a conjunctive list of elements or features.
• the term “and/or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features.
• the phrases “at least one of A and ⁇ ;” “one or more of A and ⁇ ;” and “A and/or B” are each intended to mean "A alone, B alone, or A and B together.”
• a similar interpretation is also intended for lists including three or more items.
• phrases "at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” are each intended to mean "A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.”

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• Health & Medical Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
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• Biomedical Technology (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Ophthalmology & Optometry (AREA)
• Vascular Medicine (AREA)
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• 2014
  • 2014-03-27 CN CN201480030878.8A patent/CN105246438B/zh active Active
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