Patent Grant
9522082
The present invention relates to improved delivery devices and methods of use. More particularly, the present invention relates to minimally invasive, refillable, sustained release delivery devices particularly suitable for the delivery of therapeutic agents to limited access regions, such as the posterior chamber of the eye.
The delivery of drugs to the eye presents many challenges. The ocular absorption of systemically administered pharmacologic agents is limited by the blood ocular barrier, namely the tight junctions of the retinal pigment epithelium and vascular endothelial cells. High systemic doses can penetrate this blood ocular barrier in relatively small amounts, but expose the patient to the risk of systemic toxicity. Topical delivery of drugs often results in limited ocular absorption due to the complex hydrophobic/hydrophilic properties of the cornea and sclera. Additionally, topical agents are mechanically removed by the blink mechanism such that only approximately 15% of a single drop is absorbed. Diffusion of topically administered drugs to the posterior chamber occurs, but often at sub-therapeutic levels. Intravitreal injection of drugs is an effective means of delivering a drug to the posterior segment in high concentrations. However, these repeated intraocular injections carry the risk of infection, hemorrhage and retinal detachment. Patients also find this procedure somewhat difficult to endure.
Local sustained delivery of therapeutics to the posterior chamber is critical in managing several chronic diseases of the eye. To address this need, several drug delivery devices have been developed for intraocular insertion into the vitreous region of the eye.
U.S. Pat. No. 4,300,557, for example, describes an intraocular implant in the form of a silicone capsule which can be filled with a drug to be delivered. The capsule is inserted in the vitreous region of the eye by making an incision in the eye, inserting the capsule and closing the incision. The capsule remains in place for a period of time and may be removed by making a second surgical incision into the eye and retrieving the device. The capsule has an attached tube which passes through the surface of the eye and extends outward from the eye useful for the subsequent injection of a drug. While in the vitreous, the device is not anchored and may move about freely.
U.S. Pat. No. 5,378,475 (often referred to as Vitrasert) describes a device 15 which has been developed for insertion in the vitreous region of the eye, and is described in T. J. Smith et al., Sustained-Release Ganciclovir, Arch. Ophthalmol, 110, 255-258 (1992) and G. E. Sanborn, et al., Sustained-Release Ganciclovir Therapy for Treatment of Cytomegalovirus Retinitis. Use of an Intravitreal Device, Arch. Ophthalmol, 110, 188-195 (1992). This device consists of an inner core of pharmacologic agent surrounded by two coatings with different permeabilities. Drug diffuses through a small opening in one of these coatings achieving near-order release kinetics. It is implanted in the region of the pars plana through a 3.5-5.0 mm scleral incision. The implant must be removed and replaced every 6 months in the operating room as the drug becomes depleted. There is an approximately 25% complication rate from these procedures. The device is membrane diffusion drug delivery system that relies on EVA/PVA polymers to mediate release rate. Thus, many agents cannot be effectively delivered from such a system because their permeation rate through the rate controlling material of the system is too small to produce a useful effect. Other agents cannot be satisfactorily delivered by diffusional devices because of a particular chemical characteristic of the agent. This includes salts, because of their ionic character, and unstable polar compounds that cannot be formulated into a composition suitable for storage and delivery from such systems.
U.S. Pat. No. 5,098,443 describes a series of C-shaped rings that are inserted through incisions made in the eye wall or sutured around the globe of the eye. These rings may be formed from biodegradable polymers containing microparticles of drug. Alternatively, the implant may be in the form of a hollow flexible polymeric cocoon with the drug disposed therewithin for slow release by osmosis. No anchoring device is described.
U.S. Pat. No. 5,466,233 describes a tack for intraocular drug delivery. This device has an end that is positioned in the vitreous cavity while the head remains external to the eye and abuts the scleral surface. The drug is contained in the vitreous end of the device and could be contained within a biodegradable or nonbiodegradable scaffold. Alternatively, the device may have a hollow core filled with a drug that could diffuse through the wall of the tack into the eye. This core could be refillable. The head of the tack may further have a suture hole for anchoring the sclera.
While intraocular devices exist which allow delivery of therapeutic agents to the eye, a need still remains for a device which accomplishes controlled, sustained delivery to the posterior chamber, is implantable and removable without requiring long full thickness scleral incisions, does not cause undue patient irritation or discomfort, is stable within the vitreous region of the eye, is refillable and dose titratable, and is capable of delivering a wide range of small molecule, gene and protein therapeutics.
The present invention provides a delivery device and methods of use. More particularly, the present invention relates to a sustained release delivery device that is minimally invasive and refillable. The delivery device of the present invention is particularly suitable for the delivery of therapeutic agents to the posterior chamber of the eye and other limited access regions.
An exemplary embodiment of the delivery device includes a reservoir having an inlet port at its proximal end for insertion of the agent. A scleral hub, or similar fixation element, may further be located near the proximal end for suturing or otherwise securing the device at a desired location. The agent inserted into the reservoir through the inlet port is delivered to a treatment area by a delivery mechanism located along the reservoir and/or at the distal end of the reservoir. For example, in one embodiment, the agent may be delivered through the reservoir by, for example, forming the reservoir of a material that is permeable to the agent or, for example, providing one or more apertures in the reservoir through which the agent may flow. In another embodiment, the delivery mechanism is located at the distal end of the reservoir by, for example, forming the distal end of the reservoir of a semi-permeable membrane or providing one or more apertures in the distal end of the reservoir. The reservoir is preferably fabricated of a pliable material that allows the reservoir to be compressed for insertion through a small incision. Once inside the incision, the reservoir may automatically unfold and/or as agent is injected through the inlet port, the reservoir may unfold as it is filled with the agent.
The drug delivery device may further include a hollow body or tube inside the reservoir, wherein the proximal end of the hollow body or tube forms the inlet port. In this embodiment, hollow body or tube may provide structural rigidity that facilitates insertion of the device through a small incision. The reservoir covers at least a portion of the length of the hollow body or tube and is preferably pliable so that it may be folded, rolled and/or compressed about the hollow body or tube to enable insertion of the device through a small incision not much larger than the size of the hollow body or tube. At least one aperture in the hollow body or tube provides communication between the contents of the hollow body or tube and the reservoir such that, as the agent is inserted through the inlet port, it travels through the hollow body or tube, through the aperture(s) and into the reservoir. As the agent fills the reservoir, the reservoir unfolds. In one embodiment, the distal end of the hollow body or tube extends outside the reservoir and forms a delivery port through which the agent is delivered to the patient. In another embodiment, the therapeutic agent is delivered to the patient through the reservoir by, for example, forming the reservoir of a material that is permeable to the agent or, for example, providing one or more apertures in the reservoir through which agent may flow. A scleral hub, or similar fixation element, may further be located near the proximal end of the hollow body or tube for suturing or otherwise securing the device at a desired location.
Methods for the delivery of an agent are also disclosed. In particular, the methods involve delivery of agents to the eye to treat a variety of ocular conditions such as, for example, retinal detachment, vascular occlusions, proliferative retinopathy, diabetic retinopathy, inflammations such as uveitis, choroiditis and retinitis, degenerative disease, vascular diseases and various tumors including neoplasms.
The methods comprise making a small incision in the eye to provide access to the treatment site. The delivery device is provided in an “empty” state, with the reservoir empty and preferably compressed tightly as shown in
Depending on the particular application, the device may be designed to deliver a desired dose of agent at a particular rate, for example, by providing various sized reservoirs, reservoirs with various permeabilities to the agent, delivery apertures or ports with smaller or larger diameters and delivery ports with rate controlling covers.
The present delivery device and methods of use are minimally invasive. In particular, the delivery device has a small profile that allows it to be inserted through a small opening. Such an insertion procedure eliminates the risks associated with more invasive surgery, and, further, enables such procedures to take place in an office setting. Also, the device can be removed from a small insertion site, requiring few or no sutures for scleral closure. This is a dramatic improvement over state of the art technologies which require surgery for both implantation and removal.
Further, while many existing devices for ocular delivery incorporate the therapeutic agent into the structure of the implant for release via diffusion or bioerosion of the carrier, the delivery device of the present invention is a refillable device easily filled and refilled by injection. This feature allows the physician to easily titrate dosage to the need of the individual patient. Additionally, a single device may be used with a wide range of agents, because the present device avoids implantation of the agent into the structure of the device during the manufacturing process.
Still further, because release of the agent using the present delivery device is not necessarily membrane diffusion regulated, the present device lends itself to the delivery of agents that do not readily permeate through polymeric membranes, such as ionic drugs or proteins.
Other aspects and embodiments of the invention are discussed infra.
Referring now to the various figures of the drawing, wherein like reference characters refer to like parts, there is shown various views of a delivery device 1, in accordance with the invention.
As shown in
The delivery device 1 may further include a hollow body or tube 10 housed at least partially within the reservoir 2. The hollow body or tube 10 has a proximal end 11 and a distal end 12. Preferably, the proximal end 11 of the hollow body or tube 10 extends outside the reservoir 2, as shown in
The materials used in fabricating the reservoir 2 are not particularly limited, provided these materials are biocompatible and preferably insoluble in the body fluids and tissues that the device comes into contact with. In some embodiments, it is further preferred that the materials used in fabricating the reservoir 2 are pliable materials that allows the reservoir 2 to be folded, rolled and/or compressed for insertion through a small incision that requires few or no sutures for closure. Once inside the incision, the reservoir 2 may automatically unfold or unroll to some extent. Additionally, as agent is injected through the inlet port 5 into the reservoir 2, the reservoir 2 may unfold or unroll and expand as it is filled with the agent.
In one preferred embodiment, the reservoir 2 is in the form of a balloon and is fabricated of an elastic material. As the agent is injected into the inlet port 5, the agent passes into the expandable reservoir 2 or balloon, thereby inflating and expanding the reservoir 2 or balloon. Pressure of the elastic material against the agent within the reservoir 2 provides a driving force for delivery of agent through the delivery mechanism 6. Suitable materials for use in forming an elastic reservoir are well known and may be readily determined by one of skill in the art. For example, some suitable include thin-walled nondistensible materials, such as PET, and more elastomeric materials, such as polyurethane. When the reservoir 2 is fabricated of a material such as PET, flow through the delivery mechanism 6 is primarily driven by diffusion and/or intraocular pressure force. When the reservoir 2 is fabricated of a material such as polyurethane, delivery of the agent may be driven, a least in part, by the spring-like properties of the material forming the reservoir 2.
In one embodiment, the delivery mechanism comprises at least a portion of the reservoir 2. For example, this may be accomplished by fabricating at least a portion of the reservoir 2 of a material that is permeable to the agent. Such materials may vary depending on the particular application and the agent to be delivered and may be readily determined by one of skill in the art. For example, this may be accomplished by fabricating at least a portion of the reservoir 2 of a material that is permeable to the agent. Such materials may vary depending on the particular application and the agent to be delivered and may be readily determined by one of skill in the art. By way of example, some suitable permeable materials may include polycarbonates, polyolefins, polyurethanes, copolymers of acrylonitrile, copolymers of polyvinyl chloride, polyamides, polysuiphones, 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.
The particular material may be chosen to provide a particular rate of delivery of the agent, which may be readily determined by one of skill in the art. The rate of delivery of an agent may also be increased or decreased by varying the percentage of the reservoir 2 formed of the material permeable to the agent. Preferably, to provide a slower rate of delivery, the reservoir 2 may be fabricated of 50% or less permeable material. For example, the reservoir 2 may be fabricated of 1%, 5%, 10%, 20%, 30%, 40% or 50% of permeable material. For a faster rate of delivery, the reservoir may be fabricated of greater than 50% of permeable material. For example, the reservoir 2 may be fabricated of 51%, 55%, 60%, 70%, 80%, 90% or 100% of permeable material.
In another embodiment, for example, as shown in
When the delivery device 1 includes a hollow body or tube 10, the distal end 12 of the hollow body or tube 10 may extend outside the reservoir 2, as shown in
In a preferred embodiment, the distal end 12 of the hollow body or tube 10 is designed to provide controlled delivery of agent from the device. This may be achieved by, for example, providing a distal end 12 with small holes and/or, for example, placing a covering or lining (not shown) over the distal end 12, wherein the covering or lining has a particular porosity to the agent or wherein the covering or lining is fabricated of a diffusion or rate-limiting membrane, matrix material or similar material.
In another embodiment, wherein the distal end 12 of the hollow body or tube 10 extends outside the reservoir 2, it is also possible to design the device such that both the distal end 12 and the reservoir 2 form the delivery mechanism 6. Thus, for example, the distal end 12 may be designed as set out above to deliver the agent and, for example, the reservoir 2 may be fabricated of a permeable material or one or more apertures 7 may be formed in the reservoir 2. Still further, it is possible to have the distal end 12 of the hollow body or tube 10 extend outside the reservoir 2, wherein the distal end 12 is closed off and does not serve as a delivery mechanism but, rather, the reservoir 2 serves as the delivery mechanism 6 by, for example, fabricating the reservoir 2 of a permeable material or forming one or more apertures 7 in the reservoir 2.
In another embodiment wherein the delivery device 1 includes a hollow body or tube 10, the distal end 12 of the hollow body or tube 10 may be contained within the reservoir 2, as shown in
The hollow body or tube 10 is preferably rigid and provides structural support beneath the reservoir 2 for easier implantation of the device 1 through the incision. As such, the hollow body or tube 10 may be formed of rigid materials including, for example, stainless steel, titanium, nitinol, polymers and other similar materials. As shown in
The reservoir 2 is bonded to the hollow body or tube 10 forming a fluid-tight seal that does not separate from the hollow body or tube 10 during use, thereby preventing leakage of agent out of the device between the hollow body or tube 10 and reservoir 2. Thus may be accomplished by using a variety of adhesives and epoxies.
The inlet port 5 of the delivery device 1 is designed such that the needle of a syringe, or similar injection mechanism, may be inserted through the inlet port 5 and the agent housed within the syringe or injection mechanism may be injected through the inlet port 5 and into the reservoir 2. The inlet port 5 preferably forms a snug seal about the needle of the syringe or injection mechanism to prevent leakage of the agent out of the inlet port around the syringe needle or injection mechanism and to provide sterile injection of agent into the delivery device 1. If desired, fittings or collars (not shown), through which a syringe needle or injection mechanism may be inserted and which form a snug seal about the syringe needle or injection mechanism, may be mounted on the inlet port 5.
Upon injection of the agent into the drug delivery device 1, the needle of the syringe or the injection mechanism is removed from the inlet port 5 and the inlet port 5 sealed. This may be accomplished by providing a removable cover (not shown) on the inlet port 5 that may be removed for injection of the agent and replaced when the agent has been injected. In a preferred embodiment, the inlet port 5 is composed of an injectable self-sealing material through which the needle or injection mechanism may be inserted and which seals off automatically when the needle or injection mechanism is removed. Such materials are known and include, for example, silicone rubber, silicone elastomers and polyolefin.
As shown in
As shown in
In some embodiments, it may also be desirable to deliver the agent through both the reservoir 2 and the tube 14. In such embodiments, for example, in addition to a tube 14 extending from the distal end 4 of the reservoir 2 or the distal end 12 of the hollow body or tube 10, at least a portion of the reservoir 2 may be fabricated of a material permeable to the agent or the reservoir 2 may have one or more apertures 7 through which the agent may be delivered from the reservoir 2 as discussed above.
The dimensions of the delivery device 1 will depend on the intended application of the device, and will be readily apparent to those having ordinary skill in the art. By way of example, when the delivery device 1 is used to deliver therapeutic agents to the eye, the device is designed for insertion through a small incision, preferably ranging from about 0.25 mm to about 1 mm in diameter, more preferably less than 0.5 mm in diameter, thereby requiring few or no sutures for scleral closure at the conclusion of the procedure. As such, the cross-section of the device 1 with the reservoir 2 compressed preferably ranges from about 0.25 mm to about 1 mm in diameter, and, more preferably, is no greater than 0.5 mm. Preferably, the hollow body or tube 10 has diameter ranging from about 0.5 to about 1.0 mm, and the reservoir 2 may be compressed to the hollow body or tube 10 so as to provide an overall cross section no greater than 1.0 mm. If the hollow body or tube 10 is not tubular, the largest dimension of the cross section can be used to approximate the diameter for this purpose. When used to deliver agents to the posterior chamber of the eye, the device 1 preferably has a length ranging from about 0.5 cm to about 1.5 cm such that when the fixation mechanism 8 is sutured or otherwise secured to the sclera in the region of the pars plana, the delivery mechanism 6 is positioned near the posterior chamber of the eye.
When included in the device 1, the dimensions of the tube 14 will depend on the intended application of the device, and will be readily apparent to those having ordinary skill in the art. By way of example, when used to deliver an agent to the choroids and retinal pigment epithelial cells of the eye, the tube 14 is preferably sized so as to limit delivery rate, to minimize trauma to the retina, and to minimize leaking of agent. As such, the tube 14 preferably has a length ranging from about 1 cm to about 2.5 cm, an outer diameter less than about 0.1 mm, and an inner diameter ranging from about 0.001 mm to about 0.007 mm, and more preferably, from about 0.005 mm to about 0.001.
The use of the delivery device 1 of the present invention can be further understood from the following discussion relating to a method for treating chronic diseases of the eye by sustained release of therapeutic agent to the eye and with reference to
The delivery device 1 is generally used by the following procedure: the delivery device 1 is prepared with the reservoir 2 empty and preferably compressed, as shown in
An incision is made to provide access to the treatment site. For example, when used to deliver therapeutic agent to the posterior chamber of the eye, a sclerotomy is created for insertion of the delivery device 1. Conventional techniques may be used for the creation of the sclerotomy. Such techniques require the dissection of the conjunctiva 44 and the creation of pars plana scleral incisions through the sclera 46. As shown in
Alternatively, the creation of the sclerotomy may be accomplished by use of an alignment device and method, such as that described in U.S. Ser. No. 09/523,767 the teachings of which are incorporated herein by reference, that enables sutureless surgical methods and devices therefore. In particular, such methods and devices do not require the use of sutures to seal the openings through which instruments are inserted. The alignment devices are inserted through the conjunctiva and sclera to form one or more entry apertures. Preferably, the alignment devices are metal or polyimide cannulas through which the surgical instruments used in the procedure are inserted into the eye.
The delivery device 1 is then inserted through the incision either by hand or using a variety of insertion devices, e.g. syringe-like devices, known to those of skill in the art. Once safely inside the eye, if the tube 14 is utilized in the application, microforceps or similar positioning mechanisms may be used to position the tube 14 at the treatment location.
The fixation mechanism 8 may then be sutured or otherwise secured to the sclera to hold the delivery device 1 in place. If a cover is used to close the inlet port 5, it is removed at this time, and, if used, a collar for providing a snug fit about the syringe or other injection mechanism is mounted on the inlet port 5. The syringe or other injection mechanism is then connected to the inlet port 5 for injection of the agent into the delivery device 1. If the inlet port 5 is composed of an injectable self-sealing material through which the needle of a syringe or other injection mechanism may be inserted and which seals off automatically when the needle other injection mechanism is removed, the needle or other injection mechanism is simply inserted through the inlet port 5 and the agent injected. Following injection, the conjunctiva may be adjusted to cover the distal end of the device.
When the device is used to deliver agents to the eye for the treatment of a variety of ocular conditions such as, for example, retinal detachment, occlusions, proliferative retinopathy, diabetic retinopathy, inflammations such as uveitis, choroiditis and retinitis, degenerative disease, vascular diseases and various tumors including neoplasms, some agents suitable for delivery to the eye may include, for example, antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin, and erythromycin and penicillin; antifungals such as amphotericin B and miconazole; antibacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals, such as idoxuridine trifluorotymidine, acyclovir, ganciclovir and interferon; antibacterial agents such as nitrofurazone and sodium propionate; antiallergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine, pyrilamine and prophenpyridamine; anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, 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; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; miotics and anti-cholinesterase such as pilocarpine, salicylate, carbachol, acetylcholine chloride, physostigmine, eserine, diisopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics 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; inhibitors of angiogenesis such as angiostatin, anecortave acetate, thrombospondin, and anti-VEGF antibody; and other therapeutic agents such as prostaglandins, antiprostaglandins and prostaglandin precursors.
In some applications, additives may further be included in the agent and, for example, some suitable additives may include water, saline, dextrose, carriers, preservatives, stabilizing agents, wetting agents, emulsifying agents or other similar materials.
In one embodiment, wherein the delivery device 1 comprises a reservoir 2 having an inlet port 5 located near the proximal end 3 of the reservoir 2, the agent injected through the inlet port 5 travels into the reservoir 2. If the reservoir 2 is fabricated of an elastic material, the reservoir 2 inflates/expands as it is filled. When the agent has been injected, the needle or other injection mechanism is removed from the inlet port 5 and the inlet port 5 sealed. The agent in the reservoir 2 is then delivered gradually via the delivery mechanism 6. If tube 14 is included, the agent is delivered through the tube 14 and/or reservoir 2. Once the therapeutic agent had been delivered to the treatment area, the delivery device 1 may be refilled for further delivery or removed if the required dose of agent has been delivered for treatment of the condition. If required, an aspirating device or similar mechanism (not shown) may be used to further compress the reservoir 2, thereby enabling removal of the delivery device 1 through a small incision that requires few or no sutures are required for sclera' closure.
In the embodiment that further comprises a hollow body or tube 10, the agent injected through the inlet port 5 travels through the hollow body or tube 10 and into the reservoir 2 through either the one or more apertures 13 in the hollow body or tube 10 or the distal end 12 of the hollow body or tube. The needle or other injection mechanism is then removed from the inlet port 5 and the inlet port 5 sealed. The agent in the reservoir 2 is then delivered to the treatment area gradually through the reservoir 2 and/or through the distal end 12 of the hollow body or tube 10. If tube 14 is included, the agent is delivered through the tube 14 and/or reservoir 2. Once the therapeutic agent had been delivered to the treatment area, the delivery device 1 may be refilled for further delivery or removed if the required dose of agent has been delivered for treatment of the condition. If required, an aspirating device or similar mechanism (not shown) may be used to further compress the reservoir 2 about the hollow body or tube 10, thereby enabling removal of the delivery device 1 through a small incision that requires few or no sutures are required for scleral closure.
The invention is not be limited to ocular applications, and is particularly useful in other limited access regions such as the inner ear.
The present invention also includes kits that comprise one or more device of the invention, preferably packaged in sterile condition. Kits of the invention also may include, for example, one or more tubes 14, one or more reservoirs 2, means for suturing or securing the fixation mechanism 8 to the sclera, etc. for use with the device, preferably packaged in sterile condition, and/or written instructions for use of the device and other components of the kit.
All documents mentioned herein are incorporated by reference herein in their entirety.
The foregoing description of the invention is merely illustrative thereof, and it is understood that variations and modifications can be effected without departing from the scope or spirit of the invention as set forth in the following claims.
The present application is a Continuation of U.S. patent application Ser. No. 14/268,723, filed May 2, 2014, which is a continuation of U.S. patent application Ser. No. 13/942,610, filed Jul. 15, 2013, which is a continuation of U.S. patent application Ser. No. 12/979,185, filed Dec. 27, 2010, now U.S. Pat. No. 8,486,052, issued Jul. 16, 2013, which is a Divisional of U.S. patent application Ser. No. 10/171,406, filed Jun. 12, 2002, now U.S. Pat. No. 7,883,717, issued Feb. 8, 2011, which claims the benefit of U.S. provisional application Ser. No. 60/297,499, filed Jun. 12, 2001. The priority of the filing dates is hereby claimed, and the disclosures of each of the above-mentioned patent applications are hereby incorporated by reference in their entirety.
| 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 |
| 3826258 | Abraham | Jul 1974 | 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 |
| 3986510 | Higuchi et al. | Oct 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 |
| 4634427 | Hannula et al. | Jan 1987 | A |
| 4673405 | Guittard et al. | Jun 1987 | A |
| 4693886 | Ayer | Sep 1987 | A |
| 4710167 | Lazorthes | Dec 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 |
| 4781680 | Redmond et al. | Nov 1988 | A |
| 4840615 | Hancock et al. | Jun 1989 | 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 |
| 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 |
| 5516522 | Peyman et al. | May 1996 | A |
| 5554132 | Straits et al. | Sep 1996 | A |
| 5562915 | Lowe et al. | Oct 1996 | A |
| 5576480 | Hopkins et al. | Nov 1996 | A |
| 5578042 | Cumming | Nov 1996 | A |
| 5681572 | Seare, Jr. | Oct 1997 | A |
| 5702414 | Richter et al. | Dec 1997 | A |
| 5704915 | Melsky et al. | Jan 1998 | 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 |
| 5830492 | Usala | 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 |
| 5968008 | Grams | Oct 1999 | A |
| 5972369 | Roorda et al. | Oct 1999 | A |
| 5985328 | Chu et al. | Nov 1999 | A |
| 5989216 | Johnson et al. | Nov 1999 | A |
| 5993414 | Haller | Nov 1999 | A |
| 6001386 | Ashton et al. | Dec 1999 | A |
| 6096070 | Ragheb et al. | Aug 2000 | 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 |
| 6331523 | Kljavin 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 |
| 6551291 | de Juan, Jr. et al. | Apr 2003 | 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 |
| 7094222 | Siekas et al. | Aug 2006 | B1 |
| 7094226 | Yaacobi | Aug 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 |
| 7384648 | Olejnik et al. | Jun 2008 | B2 |
| 7468065 | Weber et al. | Dec 2008 | B2 |
| 7476510 | Kapur et al. | Jan 2009 | B2 |
| 7621907 | Rodstrom | Nov 2009 | B2 |
| 7883717 | Varner et al. | Feb 2011 | B2 |
| 7914442 | Gazdzinski | Mar 2011 | B1 |
| 7973068 | Demopulos et al. | Jul 2011 | B2 |
| 8096972 | Varner et al. | Jan 2012 | B2 |
| 8486052 | Varner et al. | Jul 2013 | 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 |
| 20040024371 | Plicchi et al. | Feb 2004 | A1 |
| 20040029832 | Zeldis | Feb 2004 | A1 |
| 20040092911 | Yaacobi | May 2004 | A1 |
| 20040106906 | Yaacobi | Jun 2004 | A1 |
| 20040131654 | Yaacobi | Jul 2004 | A1 |
| 20040131655 | Yaacobi | Jul 2004 | A1 |
| 20040171997 | Wilson et al. | Sep 2004 | A1 |
| 20040199128 | Morris et al. | Oct 2004 | A1 |
| 20040208910 | Ashton et al. | Oct 2004 | A1 |
| 20050112175 | Yaacobi | May 2005 | A1 |
| 20050113806 | De Carvalho et al. | May 2005 | A1 |
| 20050119737 | Bene et al. | Jun 2005 | A1 |
| 20060246112 | Snyder et al. | Nov 2006 | A1 |
| 20070088432 | Solovay et al. | Apr 2007 | A1 |
| 20080161741 | Bene et al. | Jul 2008 | A1 |
| 20090061071 | McMorrow et al. | Mar 2009 | A1 |
| 20100022945 | Rodstrom | Jan 2010 | A1 |
| 20100100043 | Racenet | Apr 2010 | A1 |
| 20100221309 | Myers et al. | Sep 2010 | A1 |
| 20110208122 | Shekalim | Aug 2011 | A1 |
| 20120184905 | Shekalim | Jul 2012 | A1 |
| 20130304031 | Varner et al. | Nov 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 0033042 | Aug 1984 | EP |
| 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 |
| 1385452 | Sep 2006 | EP |
| 1409065 | Jan 2007 | EP |
| 1337284 | Dec 2007 | EP |
| 01-149716 | Jun 1989 | JP |
| 01-197429 | Aug 1989 | JP |
| 2001-518880 | Oct 2001 | JP |
| 2004-516889 | Jun 2004 | JP |
| 2004-524866 | Aug 2004 | JP |
| 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-9843611 | Oct 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-0217831 | Mar 2002 | WO |
| WO-02053128 | Jul 2002 | WO |
| WO-02100318 | Dec 2002 | WO |
| WO-03028765 | Apr 2003 | WO |
| WO-03077972 | Sep 2003 | WO |
| WO-03082188 | Oct 2003 | WO |
| WO-2007035473 | Mar 2007 | WO |
| Entry |
|---|
| 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. |
| ASTM Designation: E 128-99. Standard Test Method for Maximum Pore Diameter and Permeability of Rigid Porous Alters for Laboratory Use. Aug. 1999. Retrieved Jul. 4, 2014. |
| 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. |
| Breslin, C.W., et al., “Chapter 7. Slow Release Artificial Tears”, Symposium on Ocular Therapy pp. 77-83, 1977. |
| Carbonaro, et al. “Nano-pore silicon membrane characterization by diffusion and electrical resistance.” Journal of Membrane Science. 241 (2004):249-255. |
| Chirila et al., “The Vitreous Humor” in Handbook of Biomaterial Properties, eds. Black & Hastings. Chapman & Hall, London, 1998; pp. 125-131. |
| European Search Report: Form EPO1503 for Application No. 10184729.1-2319, dated Mar. 4, 2011, 1 page. |
| 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. |
| International Search Report: Form PCT/ISA210, for Application No. PCT/US2002/18642, dated May 23, 2003, 3 pages. |
| Jornitz et al. “Filter Integrity Testing in Liquid Applications, Revisited; Part 1.” Pharmaceutical Technology. Oct. 2001. pp: 34-50. |
| Kang et al., “Inhibitory effects of anti-inflammatory drugs on interleukin-6 bioactivity,” Biol Pharm Bull. Jun. 2001;24(6):701-703. |
| Katz, I.M., et al., “A Soluble Sustained-Release Ophthalmic Delivery Unit”, 8:5 (May 1977) pp. 728-734. |
| Lamberts, D.W., M.D., et al., “A Clinical Study of Slow-Releasing Artificial Tears”, Ophthalmology 85 (1978) pp. 794-800. |
| Lee, D.A., et al., “Glaucoma Filtration Surgery in Rabbits Using Bioerodible Polymers and 5-Fluorouracil”, Ophthalmology 94:12 (1987) pp. 1523-1530. |
| Lee, D.A., et al., “The Use of Bioerodible Polymers and 5-Fluorouracil in Glaucoma Filtration Surgery”, Investigative Ophthalmology & Visual Science 29-11 (1988) pp. 1692-1697. |
| Miller, DP, et al., Thermophysical Properties of Trehalose and Its Concentrated Aqueous Solutions,Pharmaceutical Research, vol. 14, No. 5, 1997, pp. 578-590. |
| Millipore. “Filter Integrity Test Methods.” Millipore Corporation. 1999. |
| Moritera, T., et al., “Microspheres of Biodegradable Polymers as a Drug-Delivery System in the Vitreous”, Investigative Ophthalmology & Visual Science 32-6 (1991) pp. 1785-1790. |
| Saline (medicine)—Wikipedia, the free encyclopedia. http://web.archive.org/web/20110205192937/http://en.wikipedia.org/wiki/Saline—(medicine). Apr. 27, 2012. |
| 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. |
| Weiner, A.L., “Chapter 13: Polymeric Drug Delivery Systems for the Eye”, Polymeric Site-Specific Pharmacotherapy, pp. 315-346, Edited by A.J. Domb (1994) John Wiley & Sons Ltd. |
| Wright, P., et al. “Slow-Release Artificial Tear Inserts in the Treatment of Dry Eyes Resulting from the Oculomucocutaneous Syndrome”, British Journal of Ophthalmology 67 (1983) pp. 393-397. |
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