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Ocular therapeutic agent delivery devices and methods for making and using such devicesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Implant Or Insert, OcularOcular therapeutic agent delivery devices and methods for making and using such devices description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070190111, Ocular therapeutic agent delivery devices and methods for making and using such devices. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This patent application is a continuation of copending U.S. patent application Ser. No. 10/471,468, filed Sep. 12, 2003 [pending], which is a PCT national phase application of PCT/US0207836 filed Mar. 14, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 09/808,149, filed Mar. 15, 2001 [issued Mar. 30, 2004 as U.S. Pat. No. 6,713,081]. FIELD OF THE INVENTION [0002] The present invention generally relates to local therapies for the eye and, more particularly, to controlled-release ocular implant devices, including methods for making and using such devices, for delivery of therapeutic agents to the eye. BACKGROUND OF THE INVENTION [0003] In the treatment of many diseases and disorders of the eye, and especially in the case of degenerative or persistent conditions, implantable sustained-release delivery devices have been desired that would continuously administer a therapeutic agent to the eye for a prolonged period of time. [0004] Local ocular implants of a wide variety of constructions and placements have been proposed heretofore for dispensing a therapeutic drug to the eye. [0005] For instance, U.S. Pat. No. 4,014,335 describes an ocular drug delivery device placed in the cul-de-sac between the sclera and lower eyelid for administering the drug and acting as a reservoir. The ocular device is characterized therein as administering drug to the eye in a controlled, continuous dosage rate over a prolonged time. To accomplish this, the ocular device comprises a three-layered laminate of polymeric materials holding the drug in a central reservoir region of the laminate. The drug diffuses from the reservoir through at least on of the polymeric layers of the laminate. [0006] U.S. Pat. No. 5,773,021 describes bioadhesive ophthalmic inserts that are placed in the conjunctival sac, in which the inserts are prepared by extrusion, thermoforming, or heat compression of a polymeric material matrix and the drug to be delivered. The polymeric matrix comprises a water-soluble biocompatible polymer, such as hydroxyalkyl celluloses, maltodextrins, chitosans, modified starches or polyvinyl alcohols; a water-soluble biocompatible polymer such as an alkyl cellulose; and where applicable a bioadhesive polymer such as polyvinyl carboxlic acid type polymers or certain bioadhesive polysaccharides or derivates thereof. The ophthalmic inserts are characterized therein as intended for the prolonged and controlled release of a medicinal substance. [0007] U.S. Pat. No. 5,773,019 describes a continuous release drug delivery implant which, among other mentioned places, can be mounted either on the outer surface of the eye or within the eye. A drug core is covered by a polymer coating layer that is permeable to the low solubility agent without being release rate limiting. Descriptions include a coating of cyclosporine A (CsA) drug cores with one or multiple coatings of polyvinyl alcohol solution, followed by heating to 110, 104 or 120.degree. C., presumable to cross link and harden the coating(s) in place around the core. Also described is a implant prepared by fixing a pellet directly over a smaller hole formed in a silicone film, followed by a suture being placed around the pellet in a gapped relationship thereto, and then the entire assembly is coated again with silicone to form the implant. The ocular device is characterized therein as giving a continuous release to an affected area, once implanted, and producing long-term sustained tissue and vitreous levels at relatively low concentrations. [0008] U.S. Pat. No. 5,378,475 describes a sustained-release implant for insertion into the vitreous of the eye. The implant has a first impermeable coating, such as ethylene vinyl acetate, surrounding most, but not all, of a drug reservoir and a second permeable coating, such as a permeable crosslinked polyvinyl alcohol, disposed over the first coating including the region where the first coating does not cover the drug reservoir, to provide a location through which the drug can diffuse out of the implant. The implant also has a tab, which can be used to suture the device in place in the eye. The implant devices are prepared by applying coating solutions, such as by dipping, spraying or brushing, of the various coating layers around the drug reservoir. [0009] U.S. Pat. No. 5,725,493 describes an ocular implant device for providing drugs to the vitreous cavity over a period of time. The drug reservoir is attached to the outside of the eye with a passageway permitting medicament to enter the vitreous cavity of the eye. The above-listing of publications describing prior ocular implant systems is intended to be only illustrative in nature, and not exhaustive. [0010] Local ocular implants avoid the shortcomings and complications that can arise from systemic therapies of eye disorders. For instance, oral therapies for the eye fail to provide sustained-release of the drug into the eye. Instead, oral therapies often only result in negligible actual absorption of the drug in the ocular tissues due to low bioavailability of the drug. Ocular drug levels following systemic administration of the drugs is usually limited by blood/ocular barriers (i.e., tight junctions between the endothelial cells of the capillaries) limit drugs entering the eye via systemic circulation. In addition, variable gastrointestinal drug absorption and/or liver metabolism of the medications can lead to dose to dose and inter-individual variations in vitreous drug levels. Moreover, adverse side effects have been associated with systemic administration of certain drugs to the eyes. [0011] For instance, systemic treatments of the eye using the immune response modifier cyclosporine A (CsA) have the potential to cause nephrotoxicity or increase the risk of opportunistic infections, among other concerns. This is unfortunate since CsA is a recognized effective active agent for treatment of a wide variety of eye diseased and indications, such as endogenous or anterior uveitis, corneal transplantation, Behcet's disease, vernal or ligneous keratoconjunctivitis, dry eye syndrome, and so forth. In addition, rejection of corneal allografts and stem cell grafts occurs in up to 90% of patients when associated with risk factors such as corneal neovascularization. CsA has been identified as a possible useful drug for reducing the failure rate of such surgical procedures for those patients. Thus, other feasible delivery routes for such drugs that can avoid such drawbacks associated with systemic delivery are in demand. [0012] Apart from implant therapies, other local administration routes for the eye have included topical delivery, such as ophthalmic drops and topical ointments containing the medicament. Tight junctions between corneal epithelial cells limit the intraocular penetration of eye drops and ointments. Topical delivery to the eye surface via solutions or ointments can in certain cases achieve limited, variable penetration for the anterior chamber of the eye. However, therapeutic levels of the drug are not achieved and sustained in the middle or back portions of the eye. This is a major drawback, as the back (posterior) chamber of the eye is a frequent site of inflammation or otherwise the site of action where, ideally, ocular drug therapy should be targeted for many indications. [0013] Age-related macular degeneration (AMD) is a common disease associated with aging that gradually impairs sharp, central vision. There are two common forms of AMD: dry AMD and wet AMD. About ninety percent of the cases of AMD are the dry form, caused by aging and thinning of the tissues of the macula; a region in the center of the retina that allows people to see straight ahead and to make out fine details. Although only about ten percent of people with AMD have the wet form, it poses a much greater threat to vision. With the wet form of the disease, rapidly growing abnormal blood vessels known as choroidal neovascular membranes (CNVM) develop beneath the macula, leaking fluid and blood that destroy light sensing cells and causing a blinding scar tissue, with resultant sever loss of central vision. Wet AMD is the leading cause of legal blindness in the United States for people aged sixty-five or more with approximately 25,000 new cases diagnosed each year in the United States. Ideally, treatments of the indication would include inducing an inhibitory effect on the choroidal neovascularization (CNV) associated with AMD. However, in that the macula is located at the back of the eye, treatment of CNVM by topical delivery of pharmacological agents to the macula tissues is not possible. Laser photocoagulation, photodynamic therapy, and surgical removal is currently used to treat CNVM. Unfortunately, the recurrence rate using such methods exceeds 50% within a year of therapy. [0014] As an approach for circumventing the barriers encountered by local topical delivery, local therapy route for the eye has involved direct intravitreal injection of a treatment drug through the sclera (i.e., the spherical, collagen-rich outer covering of the eye). However, the intravitreal injection delivery route tends to result in a short half life and rapid clearance, without sustained release capability being attained. Consequently, daily injections are frequently required to maintain therapeutic ocular drug levels, with is not practical for many patients. [0015] Given these drawbacks, the use of implant devices placed in or adjacent to the eye tissues to delivery therapeutic drugs thereto should offer a great many advantages and opportunities over the rival therapy routes. Despite the variety of ocular implant devices which have been described and used in the past, the full potential of the therapy route has not been realized. Among other things, prior ocular implant devices deliver the drug to the eye tissues via a single mode of administration for a given treatment, such as via slow constant rate infusion at low dosage. However, in many different clinical situations, such as with CNVM in AMD, this mode of drug administration might be a sub-optimal ocular therapy regimen. [0016] Another problem exists with previous ocular implants, from a construction standpoint, insofar as preparation techniques thereof have relied on covering the drug pellet or core with a permeable polymer by multi-wet coating and drying approaches. Such wet coating approaches can raise product quality control issues such as an increased risk of delamination of the thinly applied coatings during subsequent dippings, as well as thickness variability of the polymer around the drug pellets obtained during hardening. Additionally, increased production costs and time from higher rejection rates and labor and increased potential for device contamination from additional handling are known problems with present implant technology. [0017] Accordingly, this invention provides local treatment of a variety of eye diseases. The present invention also provides a method for the delivery of pharmaceuticals to the eye to effectively treat eye disease, while reducing or eliminating the systemic side effects of these drugs. This invention also provides sustained-release ocular implants for administration of therapeutic agents to the eye for prolonged periods of time. Additionally, this invention provides multi-modal sustained-release ocular implants. The invention also provides methods for making ocular implants with reduced product variability. The invention also provides methods for making ocular implants well-suited for ocular treatment trials using animal models. Other advantages and benefits of the present invention will be apparent from consideration of the present specification. SUMMARY OF THE INVENTION [0018] The present invention provides ocular implant devices for the delivery of a therapeutic agent to an eye in a controlled manner. The invention also includes fabrication and implementation techniques associated with the unique ocular implant devices that are presented therein. [0019] In one embodiment of this invention, ocular implants are provided which administer a therapeutic drug to the eye according to dual mode release kinetics during a single treatment regimen. For instance, an ocular implant under this embodiment of this invention delivers drug continuously to the eye by initial delivery at a high release rate to eye tissues soon after placement of the implant in or near the eye, as a first administration mode, followed by drug delivery via a continuous, sustained lower release rate thereafter, as a second administration mode, and within the same treatment regimen using the same implant device. The delivery of drug is never interrupted during the regimen, as a smooth transition occurs in the changeover from the high to low release rate modes of drug delivery during the regimen. In this manner, the delivery of drug by the implant is dual mode or dual action in nature. Animal model studies have been performed, which are described elsewhere herein, that confirm this dual mode performance capability in local eye therapies for several embodiments of implants of this invention. As a consequence, no intervention is needed between initiation of the treatment, i.e., installing the ocular implant, and discontinuation of the treatment regimen, i.e., exhaustion of the drug reservoir after a prolonged period of time. [0020] Although not desiring to be bound to any particular theory, a large initial dosage is delivered at a relatively high release rate to the eye tissues via an ocular implant according to one embodiment of the present invention in a manner effective to substantially saturate the eye compartments, permitting an ensuing lower release rate, maintenance dosage delivered over a period of time by the same implant to more effectively reach the target site of treatment, even if located in posterior chamber of the eye. A dual mode implant according to the embodiment of this invention provides the sustained-release of the therapeutic agent for a prolonged period of time after the period of high release kinetics. 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