US 2005O244462A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0244462 A1 Farooq (43) Pub. Date: Nov. 3, 2005

(54) DEVICES AND METHODS FOR TREATING A (57) ABSTRACT MAMMALIAN EYE (75) Inventor: Sidiq Farooq, Newark, CA (US) Devices and methods for delivering a therapeutically active ocular implant into an eye are provided. Such a device Correspondence Address: generally includes a hollow sleeve having an open proximal STOUT, UXA, BUYAN & MULLINS LLP end, a distal end, a Substantially uniform inner diameter and 4 VENTURE, SUITE 300 a Substantially uniform outer diameter extending between IRVINE, CA 92618 (US) the proximal end and the open distal end. In addition, the device includes a plunger element having an angled con (73) ASSignee: Allergan, Inc., Irvine, CA figuration and sized to be slidably received within the sleeve for urging an implant from the distal end of the sleeve and (21) Appl. No.: 10/836,908 into an eye. Systems for performing ocular research are (22) Filed: Apr. 30, 2004 provided which include a plurality of such hollow sleeves cut from a Single flouroplastic tube, and a plurality of Publication Classification plunger elements cut from a Single wire. The devices, Systems and methods are especially useful for facilitating

(51) Int. Cl...... A61F 2/00 implantation of relatively fragile, for example brittle, ocular (52) ... 424/427 implants in an intact condition. Patent Application Publication Nov. 3, 2005 Sheet 1 of 2 US 2005/0244462 A1

FIG. 1

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112 112 ". 114 S. T 114

142 116 116

142

142 FIG. 2 Patent Application Publication Nov. 3, 2005 Sheet 2 of 2 US 2005/0244462 A1

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FIG. 3 US 2005/0244462 A1 Nov. 3, 2005

DEVICES AND METHODS FOR TREATING A and describes implanting microcapsules comprising hydro MAMMALIAN EYE cortisone Succinate into the posterior Segment of the eye. 0009 Wong, U.S. Pat. No. 5,164,188 discloses encapsu BACKGROUND lated agents for introduction into the Suprachoroid of the 0001. The present invention generally relates to systems eye, and describes placing microcapsules and plaques com and methods for treating eyes and more Specifically relates prising hydrocortisone into the pars plana. to Systems and methods for delivering delivery 0010 Wong et al., U.S. Pat. Nos. 5,443,505 and 5,766, implants into eyes, for example, mammalian eyes. 242 disclose implants comprising active agents for intro 0002 Solid pharmaceutically active implants that pro duction into a Suprachoroidal Space or an avascular region of vide controlled release, for example, Sustained release, of an the eye, and describes placing microcapsules and plaques active ingredient are able to provide a relatively uniform comprising hydrocortisone into the parS plana. concentration of active ingredients in the body. Implants are 0011 Wong et al., U.S. Pat. No. 5,869,079 discloses particularly useful for providing a high local concentration combinations of hydrophilic and hydrophobic entities in a at a particular target Site for extended periods of time. biodegradable Sustained release implant, and describes a Additionally, Sustained release forms may reduce the num polylactic acid polyglycolic acid (PLGA) copolymer ber of doses of the drug required to be effective in treatment implant comprising dexamethasone. of a condition, and often reduce the occurrence of Side 0012 Wong, U.S. Pat. No. 5,824,072 discloses implants effects and/or inconsistency in drug concentration found for introduction into a Suprachoroidal Space or an avascular with traditional drug therapies. region of the eye, and describes a methylcellulose (i.e. 0.003 Various sites exist in the eye for implantation of a non-biodegradable) implant comprising dexamethasone. drug delivery device or implant, Such as the Vitreous of the 0013 Zhou et al. disclose a multiple-drug implant com eye, anterior or posterior chambers of the eye, or other areas prising 5-fluorouridine, triamcinolone, and human recombi of the eye including intraretinal, Subretinal, intrachoroidal, nant tissue plasminogen activator for intraocular manage Suprachoroidal, intrascleral, episcleral, Subconjunctival, ment of proliferative vitreoretinopathy. Zhou, T., et al. intracorneal or epicorneal Spaces. Wherever the desired “Development of a multiple-drug delivery implant for location of implantation, typical methods of implantation all require relatively invasive Surgical procedures, pose a risk of intraocular management of proliferative vitreoretinopathy', excessive trauma to the eye, and require excessive handling Journal of Controlled Release 55: pp. 281-295. of the implant. For example, in a typical method for place 0014 Heller, “Biodegradable Polymers in Controlled ment in the Vitreous, an incision is made through the Sclera, Drug Delivery”, in: CRC Critical Reviews in Therapeutic and the implant is inserted into and deposited at the desired Drug Carrier Systems, Vol. 1, (CRC Press, Boca Raton, Fla., location in the Vitreous, using forceps or other like manual 1987), pp.39-90, describes encapsulation for controlled drug grasping device. Once deposited, the forceps (or grasping delivery. Heller, in: Hydrogels in Medicine and Pharmacy, device) is removed, and the incision is Sutured closed. N. A. Peppes ed., Vol. III, (CRC Press, Boca Raton, Fla., 1987), pp 137-149, describes bioerodible polymers. 0004. There are many drawbacks of such techniques for intraocular implant delivery. Extensive handling of the 0.015 Anderson et al., Contraception 13:375, (1976), and implant is necessitated in these techniques, creating a risk Miller et al., J. Biomed. Materials Res. 11:711, (1977) that the implant will be damaged in the process. Many Such describe various properties of poly(dL-lactic acid). implants, particularly bioerodible implants, are polymer 0016 Brine, U.S. Pat. No. 5,075,115 discloses controlled based and are relatively fragile. If portions of Such implants release formulations with lactic acid polymers and co are damaged and broken-off, the effective therapeutic dose polymers. delivered by the implant once placed will be significantly altered. In addition, it becomes inherently difficult using 0017 Di Colo, Biomaterials 13:850-856 (1992) these methods to achieve reproducible placement from describes controlled drug release from hydrophobic poly patient to patient. CS. 0005 There thus remains a need for a more convenient, 0018 Olejnik, et al. U.S. Pat. No. 6,074,661 discloses an leSS invasive, and leSS traumatic means for delivering implantable device for treatment of an eye, wherein the implants into the eye, for example, into the Vitreous of the device incorporates a retinoid for improving the biocompat eye. There also remains a need for a more controlled means ability of the device in eye tissue. of delivering implants into the eye. 0019 Wong, U.S. Pat. No. 6,699,493 discloses a method for reducing or preventing transplant rejection in the eye and 0006 The following patents and additional publications intraocular implants for use therefor. include disclosure which is relevant to and/or helpful in understanding the present invention. 0020. Other documents that are also relevant or otherwise helpful in understanding the present invention are U.S. 0007 Weber et al., U.S. patent application Ser. No. patent application Ser. No. 09/693,008, filed on Jul. 5, 2000; 10/246,884, filed on Sep. 18, 2002, having Pub. No. U.S. Ser. No. 10/327,018, filed on Dec. 20, 2002 and Ser. No. 2004/00543.74 A1, describes apparatus and methods for 10/340,237, filed on Jan. 9, 2003. delivering ocular implants into an eye of a patient. 0021. The entire disclosure of each of the documents 0008 Wong, U.S. Pat. No. 4,997,652 discloses biode cited hereinabove is incorporated herein in its entirety by gradable ocular implants, including encapsulated agents, this reference. US 2005/0244462 A1 Nov. 3, 2005

SUMMARY 0028 Preferably, the step of introducing the implant into 0022. The present invention provides new devices, sys the eye includes advancing a plunger element, for example tems and methods for placing a drug delivery implant into an a relatively thin, elongated filament or wire, into the open eye, for example, to achieve one or more desired therapeutic proximal end of the hollow sleeve and passing the plunger effects. The present apparatus and methods are useful for element through the hollow sleeve in a distal direction in placing drug delivery implants, for example, Substantially order to pass or urge the implant out of the distal end of the biodegradeable drug delivery implants, into an eye, Such that hollow sleeve. For example, the plunger element may be the implant remains Substantially intact during the place held in a relatively fixed position while the hollow sleeve is ment procedure, for example, without causing any Substan gently drawn in a proximal direction out of the eye. Thus, tial breakage or other damage to the implant. For example, the plunger element functions to hold the implant in place the devices, Systems and methods of the invention are while the hollow sleeve is withdrawn. The plunger element Suitable for use in implanting drug delivery implants that are is then gently withdrawn from the eye, thereby leaving the relatively non-flexible, rigid, fragile, and/or otherwise prone implant in place within the eye. to damage or breakage. For example, the present methods 0029. Typically, the present invention is directed toward, and Systems are highly effective in delivering an implant in but not limited to, treatment of a mammalian eye, for an intact condition into an eye wherein the implant has a example an animal or a human eye. In other aspects of the degree of brittleness that would typically contribute to invention, ocular research Systems and methods are pro breakage thereof in the event the same implant had been Vided that can be incorporated into research and testing of Subjected to a conventional Surgical implantation procedure. drug delivery implants in animal Studies. It is also contem 0023 For example, in a preferred embodiment of the plated that the Systems and methods of the present invention invention, the hollow sleeve is structured to accommodate are particularly advantageous for clinical treatment of large the implant in a Substantially frictionless manner, meaning animals, for example, large wild or domestic animals. Such as that a degree of friction between the implant and the inner horses. wall of the sleeve is in effect negligible. Advantageously, in 0030. In some embodiments of the invention, the implant Some embodiments of the invention, the hollow sleeve is is placed in one of the anterior chamber or the posterior made of a fluoroplastic material, or other like material In chamber of the eye. In other embodiments of the invention, these embodiments, the device is Structured Such that fric the implant is placed in a structure of the eye Selected from tional forces generated upon movement between the rela the group consisting of the retina, the vitreous, the cornea, tively delicate, brittle implant and the sleeve will not be and the scleral of the eye. In other embodiments of the Sufficient to cause any Substantial damage to the implant as invention the implant is passed into a structure of the eye the implant is passed through the hollow Sleeve and into the consisting of the meningeal Space, the optic nerve, and the eye. intraoptic nerve. 0024. In a broad aspect of the invention, methods for treating an eye are provided. Such methods generally com 0031. The systems and methods of the invention are prise providing a device comprising a hollow sleeve having especially useful for implanting therapeutically active an open proximal end, a distal end, a Substantially uniform implants for example therapeutically active implants that are inner diameter and a Substantially uniform outer diameter at least partially biodegradable or bioerodible. In some extending between the proximal end and the open distal end. embodiments of the invention in which the implant is The method further comprises placing an implant, for substantially entirely biodegradable or bioerodible, removal example, a bioerodible or biodegradable therapeutic of the implant, after Substantially complete active compo implant, in the hollow sleeve, preferably at or near the distal nent release, is not required. end thereof. The method further comprises advancing the 0032. In one broad aspect of the invention, the devices, distal end of the hollow sleeve through the surface of the eye Systems and methods of the present invention include and passing the implant out of the distal end of the hollow implanting into an eye a biodegradable or bioerodible con sleeve. The hollow sleeve is then withdrawn from the eye, trolled release drug delivery implant, including a therapeutic leaving the implant in place within the eye. component, Sometimes referred to elsewhere herein as an 0.025 Advantageously, the method may be performed “active component' or a “therapeutically active compo without provision of an initial incision. For example, the nent', and a matrix component, for example a polymeric Step of advancing the distal end through the Surface of the matrix material. eye may comprise placing a distal edge of the hollow sleeve 0033. It will be appreciated that the implant compositions adjacent the Surface of the eye, puncturing the eye with the will vary according to the ocular condition being treated, the distal edge, and passing the distal end into the eye at a preferred drug release profile, the particular active agent desired location within the eye. used, and the medical history of the patient. 0026. In some embodiments of the invention, withdrawal 0034) For example, in some embodiments of the present of the device from the eye leaves a puncture or perforation invention, the implant advantageously comprises a thera wound that is Self-sealing in that no Suturing or other like peutic component admixed with one or more matrix mate means for closing the wound is required. rials, for example, one or more polymeric materials, for 0.027 Preferably, the method of the present invention is example one or more biodegradable polymeric materials. performed by direct manual manipulation of the hollow The implant may be structured to provide a controlled rate sleeve, particularly by direct manual manipulation of the of release of the active agent therefrom upon erosion or proximal end of the hollow sleeve, without use or provision degradation of an inactive, bioerodible or biodegradable of a handpiece, housing, or other Structure fixed to the material, for example polymeric material mixed with the hollow sleeve. therapeutic agent. US 2005/0244462 A1 Nov. 3, 2005

0035. The devices, systems and methods of the present deliver an amount of active agent that is therapeutic for the invention can be used to deliver any desired therapeutic intended medical condition of the eye. agent, or combination of therapeutic agents, including an 0038. The upper limit for the implant size will be deter antibiotic agent, an antiviral agent, an antifungal agent, an mined by factorS Such as the desired release kinetics, tol anti-cancer agent, an antiglaucoma agent, an antiinflamma eration for the implant at the site of implantation, Size tory agent, an analgesic, an immunomodulatory agent, a limitations on insertion, and ease of handling. For example, macro-molecule, or a mixture thereof. the vitreous chamber is able to accommodate relatively large 0.036 Therapeutic, active agents that may be used in the rod-shaped implants, generally having diameters of about Systems and methods of the present invention include, but 0.05 mm to 3 mm and a length of about 0.5 to about 10 mm. are not limited to ace-inhibitors, endogenous cytokines, In one variation, the rods have diameters of about 0.1 mm to agents that influence basement membrane, agents that influ about 1 mm. In another variation, the implants comprise ence the growth of endothelial cells, or rods having diameters of about 0.3 mm to about 0.75 mm. blockers, agonists or blockers, aldose reductase In yet a further variation, other implants having variable inhibitors, analgesics, anesthetics, antiallergics, anti-inflam geometries but approximately similar volumes may also be matory agents, antihypertensives, pressors, antibacterials, used. antivirals, antifungals, antiprotozoals, anti-infectives, anti 0039 The devices, systems and methods of the invention tumor agents, antimetabolites, antiangiogenic agents, may comprise introducing a plurality of biodegradable drug tyrosine kinase inhibitors, antibiotics Such as aminoglyco delivery implants into the same or different chambers or the SideS Such as gentamycin, kanamycin, neomycin, and van Same or different Structures of the eye. comycin; amphenicols Such as chloramphenicol; cepha losporins, Such as cefazolin HCl, penicillins Such as 0040. The implant may include a single therapeutic agent ampicillin, penicillin, carbenicillin, oxycillin, methicillin; or a plurality of different therapeutic agents depending upon lincosamides Such as lincomycin; polypeptide antibiotics the nature of the condition or conditions of the eye being Such as polymixin and bacitracin, tetracyclines Such as treated. The Site of implantation can vary depending upon tetracycline, quinolones Such as ciproflaxin, etc., Sulfona the ocular condition being treated and the desired course of mides Such as chloramine T, and Sulfones Such as Sulfanilic treatment. acid as the hydrophilic entity, anti-Viral , e.g. acyclovir, 0041. For example, the present devices, systems and gancyclovir, Vidarabine, azidothymidine, dideoxyinosine, methods may be designed to be effective in treating an dideoxycytosine, dexamethasone, ciproflaxin, water Soluble inflammation mediated condition, for example, uveitis. In antibiotics, Such as acyclovir, gancyclovir, Vidarabine, azi this case, an implant is provided including a therapeutic dothymidine, dideoxyinosine, dideoxycytosine, epineph component comprising an anti-inflammatory agent, and a rine, isoflurphate, adriamycin, bleomycin, mitomycin, ara method of the invention may include placing the implant C; actinomycin D; Scopolamine; and the like, analgesics, proximal to the uveal Structures. Such as codeine, morphine, keterolac, naproxen, etc., an anesthetic, e.g. lidocaine; beta.-adrenergic blocker or beta.- 0042. In another example, the present devices, systems adrenergic , e.g. ephidrine, epinephrine, etc.; aldose and methods may be structured for treatment of glaucoma. reductase inhibitor, e.g. epalrestat, ponalrestat, Sorbinil, tol An implant may be provided which is structured to provide restat; antiallergic, e.g. cromolyn, beclomethasone, dexam Sustained release of one or more neuroprotective agents that ethasone, and flunisolide; colchicine, anihelminthic agents, protect cells from excitotoxic damage. The implant may be e.g. iVermectin and Suramin Sodium; antiamebic agents, e.g. alternatively or additionally structured to be effective in chloroquine and chlortetracycline; and antifungal agents, delivering one or more beta-blockers, for example Timolol e.g. amphotericin, etc., anti-angiogenesis compounds Such Maleate, to the eye on a Substantially consistent basis. Other as anecortave acetate, retinoids Such as Tazaroteine, anti agents include -methyl-D-aspartate (NMDA) antagonists, glaucoma agents, Such as brimonidine (Alphagan and cytokines, and neurotrophic factors. The methods and Alphagan P), acetozolamide, bimatoprost (Lumigan), devices are designed and Structured to deliver one of more Timolol, mebefunolol, memantine; alpha-2 adrenergic Such implants deep into the Vitreous. agonists, 2ME2; anti-neoplastics, Such as vinblas tine, Vincristine, interferons, alpha., beta. and gamma., 0043. In yet another example, the present devices, sys antimetabolites, Such as folic acid analogs, purine analogs, tems and methods may be structured for treatment of dia and pyrimidine analogs, immunosuppreSSants Such as aza betic retinopathy. The therapeutic component may comprise thiprine, cycloSporine and mizoribine, miotic agents, Such as one or more anti-angiogenic agents and/or one or more carbachol, mydriatic agents Such as atropine, etc., protease neurotropic agents, and the implant may be placed within the inhibitorS Such as aprotinin, camoStat, gabexate, vasodilators Vitreous using the devices or methods of the invention. Such as bradykinin, etc., and various growth factors, Such 0044) In yet another example, the present devices, sys epidermal growth factor, basic fibroblast growth factor, tems and methods may be structured for treating age-related nerve growth factors, and the like. macular degeneration. For example, the devices, Systems and methods are useful for delivering implants including one 0037. The devices, systems and methods of the present or more neurotrophic factors preferably to the Vitreous, invention are generally useful for implanting drug delivery and/or one or more anti-angiogenic factors intraocularly or implants in the form of fibers, rods, filaments, pellets, periocularly, preferably periocularly, most preferably to the granules, and the like, or may be of any size or shape compatible with the Selected Site of implantation, as long as Sub-Tenon's region. the implants can be received within and passed through the 004.5 Each and every feature described herein, and each hollow sleeve and have the desired release kinetics and and every combination of two or more of Such features, is US 2005/0244462 A1 Nov. 3, 2005 included within the Scope of the present invention provided ocular region or site Such as choroid or Sclera (in a position that the features included in Such a combination are not posterior to a plane through the posterior wall of the lens mutually inconsistent. capsule), Vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascu 0.046 Additional aspects and advantages of the present larize or innervate a posterior ocular region or site. Thus, a invention are set forth in the following description and posterior ocular condition can include a disease, ailment or claims, particularly when considered in conjunction with the condition, Such as for example, macular degeneration (Such accompanying drawings in which like parts bear like refer as non-exudative age related macular degeneration and ence numerals. exudative age related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macu DRAWINGS lar edema (Such as cystoid macular edema and diabetic 0047 FIG. 1 shows a cross sectional view of a device macular edema); Behcet's disease, retinal disorders, diabetic useful for performing a method of the present invention. retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlu 0.048 FIG. 2 shows an embodiment of the present inven Sion; uveitic retinal disease; retinal detachment, ocular tion comprising a plurality of hollow sleeves and a plurality trauma which affects a posterior ocular site or location; a of plunger elements, useful for performing a method of the posterior ocular condition caused by or influenced by an present invention. ocular laser treatment; posterior ocular conditions caused by 0049 FIG. 3 shows a cross-sectional view of an eye. or influenced by a photodynamic therapy; photocoagulation; radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion; anterior ischemic optic neu DESCRIPTION ropathy; non-retinopathy diabetic retinal dysfunction, retini 0050. The invention provides devices and methods for tis pigmentosa and glaucoma. Glaucoma can be considered delivering biodegradable ocular implants into a region of an a posterior ocular condition because the therapeutic goal is eye, for example a vitreous, an anterior chamber, a posterior to prevent the loSS of or reduce the occurrence of loSS of chamber, or other location within an eye. The present Vision due to damage to or loSS of retinal cells or optic nerve devices and methods are Suitable for treatment of ocular cells (i.e. neuroprotection). conditions, Such as an anterior ocular condition, a posterior 0054 Referring now to FIG. 1, a device for treating eyes, ocular condition, or an ocular condition which can be characterized as both an anterior ocular condition and a for example mammalian eyes, in accordance with the posterior ocular condition. present invention, is shown generally at 10. 0055. The device 10 generally comprises a hollow sleeve 0051 AS used herein, and as generally understood by 12 having an open proximal end 14, a distal end 16, a those of skill in the art, an ocular condition can include a Substantially uniform inner diameter defining a lumen 18, disease, aliment or condition which affects or involves the and a Substantially uniform Outer diameter extending eye or one of the parts or regions of the eye. Broadly between the proximal end 14 and the distal end 16, the Speaking, the eye includes the eyeball and the tissues and hollow sleeve 12 terminating at the proximal end 14. The fluids which constitute the eyeball, the periocular muscles hollow sleeve 12 may further comprise a beveled distal tip (Such as the oblique and rectus muscles) and the portion of 2O. the optic nerve which is within or adjacent to the eyeball. 0056. When the device 10 is used to perform a method of 0.052 An anterior ocular condition is a disease, ailment or the invention, an implant or element, for example a biode condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, Such as a periocular gradable implant 26 is placed in the lumen 18, for example, muscle, an eye lid or an eye ball tissue or fluid which is proximally the beveled distal tip 20 as shown. located anterior to the posterior wall of the lens capsule or 0057 The implant 26 generally includes a therapeutic ciliary muscles. Thus, an anterior ocular condition primarily component 28 and preferably a matrix component 32, and is affects or involves, the conjunctiva, the cornea, the conjunc sized to be received, for example, Slidably received, within tiva, the anterior chamber, the iris, the posterior chamber the sleeve lumen 18. Even more preferably, the implant 26 (behind the retina but in front of the posterior wall of the lens is structured, for example sized, to be received within the capsule), the lens or the lens capsule and blood vessels and lumen 18 with negligible frictional contact between an inner nerve which vascularize or innervate an anterior ocular wall 34 of the hollow sleeve 12 and an outer Surface 36 of region or Site. An anterior ocular condition can include a the implant 26. disease, ailment or condition, Such as for example, aphakia; 0058 As used herein, “implants” refers to ocular pseudophakia, astigmatism; blepharospasm; cataract; con implants or drug delivery devices which can be implanted junctival diseases, conjunctivitis, corneal diseases, corneal into any number of locations in an eye and which are ulcer, dry eye Syndromes, eyelid diseases, lacrimal appara designed Such that a controlled amount of desired drug or tus diseases, lacrimal duct obstruction; myopia; presbyopia; therapeutic agent can be released over time. Such implants pupil disorders, refractive disorders and Strabismus. Glau are biocompatible, and in many cases are formed of a coma can also be considered to be an anterior ocular bioerodible substance, such as a bioerodible polymer. Such condition because a clinical goal of glaucoma treatment can implants may have a Sufficiently Small cross-sectional area be to reduce a hypertension of aqueous fluid in the anterior that they can be delivered by the devices, methods and chamber of the eye. Systems of the present invention in Such a manner that 0.053 A posterior ocular condition is a disease, ailment or results in Self-sealing of the eye at the puncture Site asso condition which primarily affects or involves a posterior ciated with the delivery procedure. In other words, methods US 2005/0244462 A1 Nov. 3, 2005

of delivering implants into the eye in accordance with Some implant 26 are then advanced into the Vitreous to an appro embodiments of the invention, do not require a Suture or priate position within the eye. Determination of the depth of other like closing means at the puncture Site. Such methods the distal end 16 within eye can be facilitated by Suitable in accordance with the invention tend to minimize initial indicia or markings placed on the Sleeve at Specific spaced leakage at the puncture Site to a degree that a Surgeon, or apart intervals. The sleeve 12 may then be withdrawn from another perSon equally skilled in the art, in his or her good the eye while the plunger element 42 is used to hold the clinical judgment, would not be compelled to Suture or implant 26 in a Substantially Stationary position within the otherwise provide other like closure means to the puncture eye. The plunger element 42 may then be withdrawn from Site. the eye, thereby leaving the implant 26 in place. The 0059. In particular, such implants, also sometimes more puncture wound may be Self-sealing as described elsewhere Specifically referred to herein as “microimplants' have herein, or may be Sutured or otherwise closed. dimensions such that they are deliverable through a hollow 0064. Advantageously, it can be appreciated that the Sleeve having a size equivalent to a 21 gauge or 22 gauge or device 10 is structured to enable use thereof by means of Smaller needle or cannula. Thin walled versions of 22 gauge direct manual manipulation of the hollow sleeve 12 and needles or cannulas can have inner diameters of less than plunger element 42. For example, no additional Structure, about 0.028 inches, and thus cylindrical microimplants Such as a housing, handpiece, holder or like Structure is deliverable through such similarly sized hollow sleeves will necessary for effective use of the present invention. have outer diameters of less than about 0.028 inches. Thin walled versions of 22 gauge needles or cannulas can have 0065 Turning now to FIG. 2, another embodiment of the inner diameters of up to about 0.023 inches, and thus invention is shown. More particularly, the present invention cylindrical microimplants with diameters of less than about may further provide an ocular research system 100 com 0.023 inches can be delivered through similarly sized hollow prising a plurality of hollow Sleeves 112, Sized to be inserted sleeves. into an eye, for example a vitreous of an eye. Each sleeve 112 may be substantially identical to each other sleeve 112. 0060. The hollow sleeve 12 may comprise any suitable Each sleeve 112 includes an open proximal end 114, a distal material, for example, Stainless Steel. More preferably, the end 116, and a Substantially uniform inner diameter and a hollow sleeve comprises a polymeric material, for example, Substantially uniform Outer diameter extending between the a fluoroplastic material. In Some embodiments of the inven proximal end 114 and the distal end 116. The plurality of tion, the hollow sleeve comprises a material Selected from hollow sleeves 112 may be produced by cutting a single tube the group consisting of polytetrafluoroethylene, polyper fluoroalkoxyl, ethylene propylene, polyfluorinated ethylene of material, at preferably equally spaced apart intervals. propylene, and combinations thereof. 0066. As shown, the system 100 further comprises a 0061 The device 10 may further comprise a plunger plurality of plunger elements 142, wherein each plunger element 42 structured to be slidably received within the element 142 is structured to be slidably received within one hollow Sleeve 12, and structured to urge the implant 26 out of the hollow sleeves 112. from the distal end 16 of the hollow sleeve 12. For example, 0067 Except as expressly described herein, each sleeve the plunger element 42 may comprise a thin filament, or 112 and each plunger element 142 in system 100 is sub other elongated element, for example, a bendable wire for Stantially identical to sleeve 12 and plunger element 42, example, a Stainless Steel wire, having an outer diameter leSS respectively, of device 10 shown in FIG. 1. Features of than the inner diameter of the hollow sleeve 12. In the sleeve 112 and plunger element 142 which correspond to particular embodiment of the invention shown in FIG. 1, the features of Sleeve 12 and plunger element 42 are designated plunger element 42 includes a distal portion 46 with a length by the corresponding reference numerals increased by 100. about equal to a length of the hollow sleeve 12, for example, no greater than the length of the hollow Sleeve 12, and a 0068. In some embodiments of the present invention, a proximal portion 48 disposed at an angle, for example an kit is provided. More particualry, for example, an equal angle of about 90 degrees, with respect to the distal portion number of hollow sleeves 112 and plunger elements 142 46. AS shown, the plunger element 42 may have a Substan may be packaged in a Sterile material and provided, as a kit, tially uniform diameter extending along the proximal por to research and development facilities for performing ocular tion 48 and the distal portion 46. research trials and tests. 0.062. In use, the distal end 16 of the hollow sleeve 12, 0069. The system 100 may further comprise a plurality of having the implant 26 disposed therein, is passed through a ocular implants (not shown in FIG. 2), for example, a surface of an eye, for example, such as the eye 300 shown plurality of Substantially biodegradable ocular implants each in FIG. 3. The implant 26 is then introduced into the eye at ocular implant including a therapeutic component and a a desired location within the eye by passing the implant 26 matrix component and being sized to be slidably received out of the distal end 16 of the hollow sleeve 12. The hollow within one of the hollow sleeves 112. sleeve 12 is withdrawn from the eye, and the implant is left 0070 The system 100 is especially useful for performing in place therein. ocular research in animal Studies, particularly in animal 0.063 More specifically, the distal portion 46 of the Studies for testing biodegradable ocular implants. Polymer plunger element 42 is passed into the open proximal end 14 based implants that are relatively fragile, brittle non-flexible of the sleeve 12 until the far distal edge of the plunger or rigid are difficult to implant, especially in an intact element 46 abuts the implant 26. This may be accomplished condition, into an eye, particularly into a posterior Section of by puncturing the eye through the Sclera with the Sharp an eye. The present Systems are designed to maintain the beveled tip 20 of the hollow sleeve 12. The sleeve 12 and implants in an intact condition during implantation proce US 2005/0244462 A1 Nov. 3, 2005

dure, reduce trauma to the eye, promote more consistent test 0079. In the present context, a biodegradable or bioerod results, and generally facilitate these types of animal ible material is one which degrades into physiologically research Studies. acceptable degradation products under physiological condi tions in the eye, or erodes into physiologically acceptable EXAMPLE materials under physiological conditions in the eye. 0.071) A plurality of hollow sleeves 112 were made from a single, Standard wall, 28 grade, 0.015 inch inner diameter 0080. The implants may be structured such that the Teflon(E) tube. The tube was marked and cut into increments biodegradable polymer matrix may comprise at least about of about 4.0 cm each increment. Using a Suitable Surgical 10 percent, at least about 20 percent, at least about 30 blade, each increment was made into a sharpened hollow percent, at least about 40 percent, at least about 50 percent, sleeve 112 by cutting one edge of each increment at a 45 at least about 60 percent, at least about 70 percent, at least degree angle, to form a Sharp edge, or distal tip 120, having about 80 percent, at least about 90 percent of the implant. about a 2.5 mm to about a 3.0 mm bevel. Each of the 0081 Biodegradable polymers which can be used in the Sharpened edges was marked for convenience. implants include, but are not limited to, polymers made of 0.072 A plurality of plunger elements 142 were made monomerS Such as organic esters or ethers, which when from a Single piece of StainleSS Steel wire that was marked degraded result in physiologically acceptable degradation and cut at increments of about 5.5 cm. Using pliers, indi products. Anhydrides, amides, orthoesters, or the like, by vidual StainleSS Steel plunger elements 142 were formed by themselves or in combination with other monomers, may bending each wire increment at a 90 degree angle with a also be used. The polymers are generally condensation proximal portion measuring about 1.5 cm, and a distal polymers. The polymers can be crosslinked or non portion measuring about 4.0 cm. crosslinked. If crosslinked, they are usually not more than lightly crosslinked, and are less than 5% crosslinked, usually 0073. These devices, each device comprising one of the less than 1% crosslinked. hollow sleeves 112 and one of the plunger elements 142, were used in rabbit model animal Studies for testing biode 0082 For the most part, besides carbon and hydrogen, the gradable intraocular implants having cross-sectional diam polymers will include oxygen and nitrogen, particularly eters of less than 0.015 inches, and comprising the anti oxygen. The oxygen may be present as oxy, e.g., hydroxy or inflammatory Steroid dexamethasone, and a co-polymer ether, carbonyl, e.g., non-oxo-carbonyl, Such as carboxylic matrix of lactic acid and glycolic acid. The devices were acid ester, and the like. The nitrogen can be present as amide, used to implant the intraocular implants into the vitreous, of cyano, and amino. An exemplary list of biodegradable one eye of each rabbit in the study. polymers that can be used are described in Heller, “Biode 0.074. In other embodiments of the invention, the devices, gradable Polymers in Controlled Drug Delivery', in: CRC Systems and methods are useful for effective clinical treat Critical Reviews in Therapeutic Drug Carrier Systems, Vol. ment of an eye of a domestic animal, for example an equine 1. (CRC Press, Boca Raton, Fla., 1987). eye. The present Systems and methods can provide effective 0083) Of particular interest are polymers of hydroxy means of quickly delivering a drug into a posterior chamber aliphatic carboxylic acids, either homo- or copolymers, and of an eye of Such an animal with minimal trauma and little polysaccharides. Included among the polyesters of interest or no significant injury being inflicted on the eye of the are homo- or copolymers of D-lactic acid, L-lactic acid, animal. It is contemplated that the present Systems and racemic lactic acid, glycolic acid, caprolactone, and combi methods are particularly advantageous for use in treatment nations thereof. Copolymers of glycolic and lactic acid are of a posterior chamber condition, for example, but not of particular interest, where the rate of biodegradation is limited to, treatment of a detached retina in a horse or other controlled by the ratio of glycolic to lactic acid. The percent large animal. of each monomer in poly(lactic-co-glycolic)acid (PLGA) 0075 Implants useful with the present invention include copolymer may be 0-100%, about 15-85%, about 25-75%, therapeutically active implants comprising a therapeutic or about 35-65%. In certain variations, 25/75 PLGA and/or component and a polymeric matrix component. 50/50 PLGA copolymers are used. In other variations, PLGA copolymers are used in conjunction with polylactide 0.076 Suitable polymeric materials or compositions for polymers. use in the implants include those materials which are com patible, that is biocompatible, with the eye So as to cause no 0084 Biodegradable polymer matrices that include mix Substantial interference with the functioning or physiology tures of hydrophilic and hydrophobic ended PLGA may also of the eye. be employed, and are useful in modulating polymer matrix degradation rates. Hydrophobic ended (also referred to as 0077. The matrix component may comprise materials capped or end-capped) PLGA has an ester linkage hydro which are at least partially, for example, are Substantially phobic in nature at the polymer terminus. Typical hydro completely, biodegradable or bioerodible, when exposed to phobic end groups include, but are not limited to alkyl esters the ocular environment. Once implanted in the eye, the and aromatic esters. Hydrophilic ended (also referred to as matrix material degrades within the eye, releasing the thera uncapped) PLGA has an end group hydrophilic in nature at peutic component into the eye, and providing Substantially the polymer terminus. PLGA with a hydrophilic end groups consistent, for example, Substantially constant therapeutic at the polymer terminus degrades faster than hydrophobic benefit thereto. ended is PLGA because it takes up water and undergoes 0078. In other embodiments of the invention, the matrix hydrolysis at a faster rate (Tracy et al., Biomaterials component 26 is made of materials that are not biodegrade 20:1057-1062 (1999)). Examples of suitable hydrophilic end able, or are not Substantially biodegradable, when exposed groups that may be incorporated to enhance hydrolysis to the ocular environment. include, but are not limited to, carboxyl, hydroxyl, and US 2005/0244462 A1 Nov. 3, 2005 polyethylene glycol. The Specific end group will typically Such as cross-linked poly(Vinyl acetate) and the like. Also of result from the initiator employed in the polymerization particular interest are ethylene-Vinyl ester copolymerS hav process. For example, if the initiator is water or carboxylic ing an ester content of 4 to 80% such as ethylene-vinyl acid, the resulting end groups will be carboxyl and hydroxyl. acetate (EVA) copolymer, ethylene-Vinyl hexanoate copoly Similarly, if the initiator is a monofunctional alcohol, the mer, ethylene-Vinyl propionate copolymer, ethylene-Vinyl resulting end groups will be ester or hydroxyl. butyrate copolymer, ethylene-Vinyl pentantoate copolymer, 0085. The composition of the implants may be mono ethylene-Vinyl trimethyl acetate copolymer, ethylene-Vinyl lithic, that is, having the therapeutic component Substantially diethyl acetate copolymer, ethylene-Vinyl 3-methyl uniformly distributed throughout the matrix component, for butanoate copolymer, ethylene-vinyl 3-3-dimethyl example, throughout the polymeric material present in the butanoate copolymer, and ethylene-Vinyl benzoate copoly implant, or the implants may have encapsulated reservoirs mer, Ethylene-Vinyl ester copolymers including ethylene for example, particles and/or other relatively concentrated Vinyl acetate copolymers for the manufacture of diffusional forms, of therapeutic component interspersed throughout the ocular drug delivery devices where the drug dissolves in and implant, for example, throughout the polymeric material in passes through the polymer by diffusion are described in the implant. U.S. Pat. Nos. 4,052,505 and 4,144,317. 0092 Additional exemplary naturally occurring or syn 0.086 Among the useful polysaccharides are, without thetic non-biodegradable polymeric materials include poly limitation, calcium alginate, and functionalized celluloses, (methylmethacrylate), poly(butylmethacrylate), plasticized particularly carboxymethylecellulose esters characterized poly(Vinylchloride), plasticized poly(amides), plasticized by being water insoluble, a molecular weight of about kD to nylon, plasticized Soft nylon, plasticized poly(ethylene 500 kD, etc. terephthalate), natural rubber, Silicone, poly(isoprene), poly 0087. Other polymers of interest include, without limita (isobutylene), poly(butadiene), poly(ethylene), poly(tet tion, polyvinyl alcohol, polyesters, polyethers and combi rafluoroethylene), poly(-vinylidene chloride), poly(acryloni nations thereof which are biocompatible and may or may not trile), croSS-linked poly(Vinylpyrrolidone), be biodegradable and/or bioerodible. poly(trifluorochloroethylene), chlorinated poly(ethylene), poly(4,4'-isopropylidene diphenylene carbonate), vinylidene 0088. Some preferred characteristics of the polymers or chloride-acrylonitrile copolymer, vinyl chloridediethyl polymeric materials for use in the present invention may fumarate copolymer, Silicone, Silicone rubbers (especially include biocompatibility, compatibility with the therapeutic the medical grade), poly(dimethylsiloxanes), ethylene-pro component, ease of use of the polymer in making the drug pylene rubber, Silicone-carbonate copolymers, Vinylidene delivery systems of the present invention, a halflife in the chloride-vinyl chloride copolymer, Vinyl chloride-acryloni physiological environment of at least about 6 hours, pref trile copolymer, Vinylidene chloride-acrylonitrile copoly erably greater than about one day, not significantly increas mer, poly(olefins), poly(Vinyl-olefins), poly(styrene), poly ing the Viscosity of the Vitreous, and water insolubility. (halo-olefins), poly(Vinyls), poly(acrylate), 0089. The biodegradable polymeric materials are desir poly(methacrylate), poly(oxides), poly(esters), poly(a- ably subject to enzymatic or hydrolytic instability. Water mides), and poly(carbonates). soluble polymers may be cross-linked with hydrolytic or 0093 Biodegradable or non-biodegradable hydrogels biodegradable unstable croSS-links to provide useful water may also be employed in the implants of the Subject inven insoluble polymers. The degree of stability can be varied tion. Hydrogels are typically a copolymer material, charac widely, depending upon the choice of monomer, whether a terized by the ability to imbibe a liquid. Exemplary non homopolymer or copolymer is employed, employing mix biodegradable hydrogels which may be employed and tures of polymers, where the polymers may be employed as methods of making these hydrogels are described in U.S. varying layerS or mixed. Pat. Nos. 4,959,217 and 4,668,506, herein incorporated by 0090 Alternatively or additionally, various non-biode reference. gradable polymeric compositions may be employed in the 0094. In addition to the controlled porosity of the implants. The non-biodegradable polymeric composition implant, in Some embodiments of the invention which employed may allow for release of the drug by, for example, employ a non-biodegradable polymer, the rate of release of Solution/diffusion or leaching mechanisms. The non-biode the drug will be solution/diffusion controlled. The rate of gradable polymeric compositions employed may be varied diffusion of drug through the non-biodegradable polymer according to the compatibility of the polymer with the drug may be affected by drug Solubility, polymer hydrophilicity, or other active agent to be employed, ease of manufacture, extent of polymer cross-linking, expansion of the polymer the desired rate of release of the drug, desired density or upon water absorption So as to make the polymer more porosity, and the like. Various non-biodegradable polymers permeable to the drug, and the like. which may be employed are described in U.S. Pat. Nos. 4,303,637; 4,304,765; 4,190,642, 4,186,184; 4,057,619; 0095 The therapeutic component useful in the present 4,052,505; 4,281,654; 4.959,217; 4,014,335; 4,668,506; invention may include any Suitable pharmacologically 4,144,317. The non-biodegradable polymers may be active agent or therapeutic agent which is beneficial when homopolymers, copolymers, Straight, branched-chain, or placed within the eye, for example, an agent of which extended, delayed, or otherwise controlled release thereof in croSS-linked derivatives. the eye, is desirable. Pharmacologic or therapeutic agents 0.091 Exemplary biocompatible, non-biodegradable which may find use in the present Systems, include, without polymers of particular interest include polycarbamates or limitation, those disclosed in U.S. Pat. No. 4,474,451, col polyureas, particularly polyurethanes, polymers which may umns 4-6 and U.S. Pat. No. 4,327,725, columns 7-8, which be croSS-linked to produce non-biodegradable polymers disclosures are incorporated herein by reference. US 2005/0244462 A1 Nov. 3, 2005

0.096 Pharmacological or therapeutic agents of interest agents that may be used include, but are not limited to, include hydrocortisone (5-20 mcg/l as plasma level), gen aspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac, tamycin (6-10 mcg/ml in serum), 5-fluorouracil (about 0.30 naproxen, and Suprofen. In a further variation, the anti mg/kg body weight in serum), sorbinil, IL-2, TNF, Phakan-a inflammatory agent is a Steroidal anti-inflammatory agent. (a component of glutathione), thioloa-thiopronin, Bendazac, 0100. The steroidal anti-inflammatory agents that may be acetylsalicylic acid, trifluorothymidine, interferon (alpha., used in the implants include, but are not limited to, 21-ac beta. and gamma.), immune modulators, e.g. lymphokines, etoxypregnenolone, alclometaSone, algestone, amcinonide, monokines, and growth factors, etc. beclomethasone, betamethasone, budesonide, chloropred 0097 Pharmacological or therapeutic agents of particular nisone, clobetaSol, clobetasone, clocortolone, cloprednol, interest include, without limitation, anti-glaucoma drugs, corticosterone, cortisone, cortivaZol, deflazacort, desonide, Such as the beta-blockers, Such as timolol maleate, betaxolol deSoximetasone, dexamethasone, diflorasone, diflucor and metipranolol, mitotics, Such as pilocarpine, acetylcho tolone, difluprednate, enoXolone, fluazacort, flucloronide, line chloride, isofluorophate, demacarium bromide, flumethasone, flunisolide, fluocinolone acetonide, fluocino iodide, phospholine iodide, carbachol, and nide, fluocortin butyl, fluocortolone, fluorometholone, flu phySOstigimine, epinephrine and Salts, Such as diplivefrin perolone acetate, fluprednidene acetate, fluprednisolone, flu hydrochloride; and dichlorphenamide, acetazolamide and randrenolide, fluticasone propionate, formocortal, methazolamide; anti-cataract and anti-diabetic retinopathy halcinonide, halobetasol propionate, halometasone, halopre drugs, Such as aldose reductase inhibitors, Such as tolrestat, done acetate, hydrocortamate, hydrocortisone, loteprednol lisinopril, enalapril, and Statil; thiol croSS-linking drugs other etabonate, maZipredone, medrySone, meprednisone, meth than those considered previously; anti-cancer drugs, Such as ylprednisolone, mometasone furoate, paramethasone, pred retinoic acid, methotrexate, adriamycin, bleomycin, triam nicarbate, prednisolone, prednisolone 25-diethylamino-ac cinoline, mitomycin, cis-platinum, Vincristine, vinblastine, etate, prednisolone Sodium phosphate, prednisone, actinomycin-D, ara-c, bisantrene, CCNU, activated cytoxan, prednival, prednylidene, rimeXolone, tiXocortol, triamcino DTIC, HMM, melphalan, mithramycin, procarbazine, lone, triamcinolone acetonide, triamcinolone benetonide, VM26, VP16, and tamoxifen; immune modulators, other triamcinolone hexacetonide, and any of their derivatives. than those indicated previously; anti-clotting agents, Such as tissue plasminogen activator, urokinase, and Streptokinase; 0101. In one aspect of the invention, cortisone, dexam anti-tissue damage agents, Such as Superoxide dismutase; ethasone, fluocinolone, hydrocortisone, methylpredniso proteins and nucleic acids, Such as mono- and polyclonal lone, prednisolone, prednisone, and triamcinolone, and their antibodies, enyzmes, protein hormones and genes, gene derivatives, are preferred Steroidal anti-inflammatory agents. fragments and plasmids, Steriods, particularly anti-inflam In another aspect of the invention, the Steroidal anti-inflam matory or anti-fibrous drugs, Such as cortisone, hydrocorti matory agent is dexamethasone. In another aspect of the Sone, prednisolone, prednisome, dexamethasone, peogester invention, the biodegradable implant includes a combination one-like compounds, medrysone (HMS) and of two or more Steroidal anti-inflammatory agents. fluorometholone; non-Steroidal anti-inflammatory drugs, 0102) The therapeutic component, for example, the active Such as ketrolac tromethamine, dichlofenac Sodium and agent, can comprise from about 10% to about 90% by Suprofen; antibiotics, Such as loridine (cephaloridine), weight of the implant. In one variation, the active agent is chloramphenicol, clindamycin, amikacin, tobramycin, from about 40% to about 80% by weight of the implant. methicillin, lincomycin, oxycillin, penicillin, amphotericin B, polymyxin B, cephalosporin family, amplicillin, bacitra 0103). Other agents may be employed in the formulation cin, carbenicillin, cepholothin, colistin, erythromycin, Strep for a variety of purposes. For example, buffering agents and tomycin, neomycin, Sulfacetamide, Vancomycin, Silver preservatives may be employed. Preservatives which may be nitrate, Sulfisoxazole diolamine, and tetracycline; other used include, but are not limited to, Sodium bisulfite, Sodium antipathogens, including anti-Viral agents, Such as idoxuri bisulfate, Sodium thiosulfate, benzalkonium chloride, chlo dine, trifluorouridine, Vidarabine (adenine arabinoside), acy robutanol, thimerosal, phenylmercuric acetate, phenylmer clovir (acycloguanosine), pyrimethamine, trisulfapyrimi curic nitrate, methylparaben, polyvinyl alcohol and phenyl dine-2, clindamycin, nyStatin, flucytosine, natamycin, ethyl alcohol. Examples of buffering agents that may be miconazole and piperazie derivatives, e.g. diethylcarbam employed include, but are not limited to, Sodium carbonate, azine, cycloplegic and mydriatic agents, Such as atropine, Sodium borate, Sodium phosphate, Sodium acetate, Sodium cyclogel, Scopolamine, homatropine and mydriacyl, and the bicarbonate, and the like, as approved by the FDA for the desired route of administration. Electrolytes Such as Sodium like and mixtures thereof. chloride and potassium chloride may also be included in the 0098. Other agents useful in the systems of the present formulation. invention include, without limitation, , anti coagulants, antifibrinolytic agents, , antima 0104. The implants can also include hydrophilic or larials, antitoxins, chelating agents, hormones, immunoSup hydrophobic compounds that accelerate or retard release of pressives, thrombolytic agents, Vitamins, Salts, desensitizing the active agent. Additionally, release modulatorS Such as those described in U.S. Pat. No. 5,869,079 can be included agents, prostaglandins, amino acids, metabolites, antialler in the implants. The amount of employed genics, and the like and mixtures thereof. will be dependent on the desired release profile, the activity 0099. In one embodiment of the invention, the active of the modulator, and on the release profile of the gluco agent is methotrexate. In another embodiment, the active corticoid in the absence of modulator. Where the buffering agent is a retinoic acid. In another embodiment, the active agent or release enhancer or modulator is hydrophilic, it may agent is an anti-inflammatory agent Such as a nonsteroidal also act as a release accelerator. Hydrophilic additives act to anti-inflammatory agent. Nonsteroidal anti-inflammatory increase the release rates through faster dissolution of the US 2005/0244462 A1 Nov. 3, 2005

material Surrounding the drug particles, which increases the tug/ml dexamethasone may be maintained for an extended Surface area of the drug exposed, thereby increasing the rate period of time (e.g., at least about three weeks or longer). of drug diffusion. Similarly, a hydrophobic buffering agent The preferred concentration levels of therapeutic component or enhancer or modulator can dissolve more slowly, slowing or drug in the Vitreous may vary according to the inflam the exposure of drug particles, and thereby slowing the rate matory mediated condition being treated. For example, for of drug diffusion. treating uveitis, a concentration equivalent of at least about 0105. In a particularly advantageous embodiment of the 0.01 to 0.1 lug/ml dexamethasone is preferred. invention, devices, Systems and methods Suitable for treating inflammation-mediated conditions of the eye are provided. 0110. In one embodiment, the concentration or therapeu The term “inflammation-mediated condition of the eye” is tic component is maintained for least about four weeks. In meant to include any condition of the eye which may benefit other embodiments, the concentration is maintained for at from treatment with an anti-inflammatory agent, and is least about five weeks, or at least about Six weeks, or at least meant to include, but is not limited to, uveitis, macular about Seven weeks, or at least about eight weeks, or at least edema, acute macular degeneration, retinal detachment, about nine weeks, or at least about 10 weeks, or at least ocular tumors, fungal or viral infections, multifocal chor about 12 weeks or longer. The preferred duration of thera oiditis, diabetic uveitis, proliferative vitreoretinopathy peutic component or drug release may be determined by the (PVR), Sympathetic opthalmia, Vogt Koyanagi-Harada inflammatory mediated condition being treated. For treating (VKH) syndrome, histoplasmosis, and uveal diffusion. uveitis, a drug release duration of at least about three weeks 0106 For example, the devices, systems and methods is preferable, more preferably at least about four weeks. In may comprise an implant, Structured for being implanted one embodiment, more than one implant or element 20 may into the Vitreous of the eye wherein the therapeutic compo be sequentially implanted into the Vitreous in order to nent comprises a Steroidal anti-inflammatory agent, for maintain therapeutic component or drug concentrations for example but not limited to, dexamethasone, and copolymer even longer periods. matrix of lactic acid and glycolic acid. The implant prefer 0111. The formulation of the implants in accordance with ably delivers the agent to the vitreous in an amount Sufficient the present invention may vary according to the desired to reach a concentration equivalent to at least about 0.05 therapeutic component release profile, the particular thera tug/ml dexamethasone within about 48 hours and maintains peutic component used, the condition being treated, and the a concentration equivalent to at least about 0.03 ug/ml medical history of the patient. dexamethasone for at least about three weeks. In another embodiment of the invention, the element 20 preferably 0112 Parameters which determine the release kinetics delivers the agent to the vitreous in an amount Sufficient to from the implant include the Size of the therapeutic compo reach a concentration equivalent to at least about 0.2 tug/ml nent or drug particles entrapped in the element, the water dexamethasone within about 6 hours and maintains a con Solubility of the therapeutic component or drug, the ratio of centration equivalent to at least about 0.01 lug/ml dexam therapeutic component or drug to polymer, the method of ethasone for at least about three weeks. manufacture, the amount of Surface area of the element exposed, the erosion rate of the polymer present in the 0107 “A concentration equivalent to dexamethasone”, as element. used herein, refers to the concentration of a Steroidal anti inflammatory agent necessary to have approximately the 0113 Preferably, the steroidal anti-inflammatory agent is Same efficacy in Vivo as a particular dose of dexamethasone. Selected from the group consisting of 21-acetoxypreg For example, hydrocortisone is approximately twentyfive nenolone, alclometasone, algestone, amcinonide, beclom fold less potent than dexamethasone, and thus a 25 mg dose ethasone, betamethasone, budeSonide, chloroprednisone, of hydrocortisone would be equivalent to a 1 mg dose of clobetasol, clobetaSone, clocortolone, cloprednol, corticos dexamethasone. One of ordinary skill in the art would be terone, cortisone, cortivaZol, deflazacort, desonide, des able to determine the concentration equivalent to dexam Oximetasone, dexamethasone, diflorasone, diflucortolone, ethasone for a particular Steroidal anti-inflammatory agent difluprednate, enoXolone, fluazacort, flucloronide, flumetha from one of several standard tests known in the art. Relative Sone, flunisolide, fluocinolone acetonide, fluocinonide, fluo potencies of Selected corticosteroids may be found, for cortin butyl, fluocortolone, fluorometholone, fluperolone example, in Gilman, A. G., et al., eds. (1990). Goodman and acetate, fluprednidene acetate, fluprednisolone, flurandreno Gilman's. The Pharmacological Basis of Therapeutics. 8th lide, fluticaSone propionate, formocortal, halcinonide, halo Edition, Pergamon Press: New York, p. 1447, which is betasol propionate, halometasone, halopredone acetate, incorporated herein by this specific reference. hydrocortamate, hydrocortisone, loteprednol etabonate, maZipredone, medrySone, meprednisone, methylpredniso 0108. In other embodiments, the implant delivers the lone, mometasone furoate, paramethasone, prednicarbate, agent to the Vitreous in an amount Sufficient to reach a prednisolone, prednisolone 25-diethylamino-acetate, pred concentration equivalent to at least about 0.3 ug/ml, or at nisolone Sodium phosphate, prednisone, prednival, pred least about 0.5 lig/ml, or at least about 0.75 ug/ml, or at least nylidene, rimeXolone, tiXocortol, triamcinolone, triamcino about 1.0 lig/ml, or at least about 2.0 ug/ml dexamethasone lone acetonide, triamcinolone benetonide, triamcinolone within about 4 hours, or within about 6 hours, or within hexacetonide and the like and mixtures thereof. In a pre about 8 hours, or within about 10 hours, or within about 24 ferred embodiment, the Steroidal anti-inflammatory agent is hours. Selected from the group consisting of cortisone, dexametha 0109) A concentration equivalent to at least about 0.01 Sone, hydrocortisone, methylprednisolone, prednisolone, tug/ml, or at least about 0.02 ug/ml, or at least about 0.03 prednisone, triamcinolone and the like and mixtures thereof. lug/ml, or at least about 0.05 lug/ml, or at least about 0.07 In a more preferred embodiment, the Steroidal anti-inflam US 2005/0244462 A1 Nov. 3, 2005 matory agent is dexamethasone. In another embodiment, the 0121 MACULOPATHIES/RETINAL DEGENERA bioerodible implant comprises more than one Steroidal anti TION: Non-Exudative Age Related Macular Degeneration inflammatory agent. (ARMD), Exudative Age Related Macular Degeneration (ARMD), Choroidal Neovascularization, Diabetic Retin 0114. The amount or concentrations of therapeutic com opathy, Acute Macular Neuroretinopathy, Central Serous ponent employed in the element will vary depending on the Chorioretinopathy, Cystoid Macular Edema, Diabetic Macu effective dosage required and rate of release. lar Edema. 0115 For embodiments of the invention employing ste roidal anti-inflammatory agents, the polymers may com 0122) UVEITIS/RETINITIS/CHOROIDITIS: Acute prise, for example, polymers of hydroxyaliphatic carboxylic Multifocal Placoid Pigment Epitheliopathy, Behcet’s Dis acids, either homo- or copolymers, and polysaccharides. ease, Birdshot Retinochoroidopathy, Infectious (Syphilis, Included among the polyesters of interest are polymers of Lyme, Tuberculosis, Toxoplasmosis), Intermediate Uveitis D-lactic acid, L-lactic acid, racemic lactic acid, glycolic (Pars Planitis), Multifocal Choroiditis, Multiple Evanescent acid, polycaprolactone, and combinations thereof. By White Dot Syndrome (MEWDS), Ocular Sarcoidosis, Pos employing the L-lactate or D-lactate, a slowly biodegrading terior Scleritis, Serpignous Choroiditis, Subretinal Fibrosis polymer is achieved, while degradation is Substantially and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome. enhanced with the racemate. 0123 VASCULAR DISEASES/EXUDATIVE DIS 0116 Copolymers of glycolic and lactic acid are of EASES: Retinal Arterial Occlusive Disease, Central Retinal particular interest, where the rate of biodegradation is con Vein Occlusion, Disseminated Intravascular Coagulopathy, trolled by the ratio of glycolic to lactic acid. The % of Branch Retinal Vein Occlusion, Hypertensive Fundus polylactic acid in the polylactic acid polyglycolic acid Changes, Ocular Ischemic Syndrome, Retinal Arterial (PLGA) copolymer can be 0-100%, preferably about Microaneurysms, Coat's Disease, Parafoveal Telangiectasis, 15-85%, more preferably about 35-65%. In a particularly Hemi-Retinal Vein Occlusion, Papillophlebitis, Central preferred embodiment, a 50/50 PLGA copolymer is used. Retinal Artery Occlusion, Branch Retinal Artery Occlusion, The most rapidly degraded copolymer has roughly equal Carotid Artery Disease (CAD), Frosted Branch Angitis, amounts of glycolic and lactic acid, where either homopoly Sickle Cell Retinopathy and other Hemoglobinopathies, mer is more resistant to degradation. The ratio of glycolic Angioid Streaks, Familial Exudative Vitreoretinopathy, acid to lactic acid will also affect the brittleness of in the Eales Disease. element, where a more flexible element is desirable for larger geometries. 0124 TRAUMATIC/SURGICAL: Sympathetic Oph 0117 Other agents may be employed in the element 20 thalmia, Uveitic Retinal Disease, Retinal Detachment, for a variety of purposes. In addition to the therapeutic Trauma, Laser, PDT, Photocoagulation, Hypoperfusion Dur component 23, effective amounts of buffering agents, pre ing Surgery, Radiation Retinopathy, Bone Marrow Trans servatives and the like may be employed. Suitable water plant Retinopathy. soluble preservatives include Sodium bisulfite, sodium thio 0125 PROLIFERATIVE DISORDERS: Proliferative Sulfate, ascorbate, benzalkonium chloride, chlorobutanol, Vitreal Retinopathy and Epiretinal Membranes, Proliferative thimerosal, phenylmercuric borate, parabens, benzyl alco Diabetic Retinopathy. hol, phenylethanol and the like and mixtures thereof. These agents may be present in amounts of from 0.001 to about 5% 0126 INFECTIOUS DISORDERS: Ocular Histoplas by weight and preferably 0.01 to about 2% by weight. mosis, Ocular Toxocariasis, Presumed Ocular Histoplasmo Suitable water soluble buffering agents include, without sis Syndrome (POHS), Endophthalmitis, Toxoplasmosis, limitation, alkali and alkaline earth carbonates, phosphates, Retinal Diseases Associated with HIV Infection, Choroidal bicarbonates, citrates, borates, acetates, Succinates and the Disease ASSociated with HIV Infection, Uveitic Disease like, Such as Sodium phosphate, citrate, borate, acetate, ASSociated with HIV Infection, Viral Retinitis, Acute Reti bicarbonate, carbonate and the like. These agents advanta nal Necrosis, Progressive Outer Retinal Necrosis, Fungal geously present in amounts Sufficient to maintain a pH of the Retinal Diseases, Ocular Syphilis, Ocular Tuberculosis, Dif system of between about 2 to about 9 and more preferably fuse Unilateral Subacute Neuroretinitis, Myiasis. about 4 to about 8. AS Such, the buffering agent may be as much as about 5% by weight of the total implant or element O127 GENETIC DISORDERS: Retinitis Pigmentosa, Systemic Disorders with Accosiated Retinal Dystrophies, 2O. Congenital Stationary Night Blindness, Cone Dystrophies, 0118. Although the system 10 shown in FIG. 1 comprises Stargardt's Disease and Fundus Flavimaculatus, Best's Dis hollow sleeve 12 and implant 26 both having corresponding ease, Pattern Dystrophy of the Retinal Pigmented Epithe Substantially cylindrical croSS-Sectional forms, it is to be lium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy, appreciated that the Sleeve 12 and implant 26 may have other Benign Concentric Maculopathy, Bietti's Crystalline Dys croSS-Sectional forms, for example triangular, rectangular, trophy, pseudoxanthoma elasticum. elliptical cross-sectional forms, are also included within the Scope of the present invention. 0128) RETINAL TEARS/HOLES: Retinal Detachment, 0119) The implant 26 may comprise an extruded filament Macular Hole, Giant Retinal Tear. having a size of between about 5 um and about 2 mm, or 0129. TUMORS: Retinal Disease Associated with between about 10 um and about 1 mm. Tumors, Congenital Hypertrophy of the RPE, Posterior 0120 Among the diseases/conditions which can be Uveal Melanoma, Choroidal Hemangioma, Choroidal treated or addressed in accordance with the present inven Osteoma, Choroidal Metastasis, Combined Hamartoma of tion include, without limitation, the following: the Retina and Retinal Pigmented Epithelium, Retinoblas US 2005/0244462 A1 Nov. 3, 2005

toma, Vasoproliferative Tumors of the Ocular Fundus, Reti Sone, methylprednisolone, prednisolone, prednisone, triam nal Astrocytoma, Intraocular Lymphoid Tumors. cinolone, and mixtures thereof. 14. The method of claim 1 wherein the therapeutic 0130 MISCELLANEOUS: Punctate Inner Choroidopa component comprises dexamethasone. thy, Acute Posterior Multifocal Placoid Pigment Epitheli 15. The method of claim 1 wherein the implant further opathy, Myopic Retinal Degeneration, Acute Retinal Pig includes a polymeric component. ment Epithelitis and the like. 16. The method of claim 11 wherein the polymeric 0131 Each and every feature described herein, and each component is Selected from the group of polymeric compo and every combination of two or more of Such features, is nents consisting of lactic acid polymers, glycolic acid poly included within the Scope of the present invention provided mers, copolymers of lactic acid and glycolic acid, and that the features included in Such a combination are not combinations thereof. mutually inconsistent. 17. The method of claim 1 effective in treating an inflam mation-mediated condition of the eye. We claim: 18. The method of claim 17 wherein the inflamation 1. A method for treating an eye, the method comprising mediated condition of the eye is Selected from the group the Steps of: consisting of uveitis, macular edema, acute macular degen eration, retinal detachment, ocular tumors, fungal infections, providing a device comprising a hollow sleeve having an Viral infections, multifocal choroiditis, diabetic uveitis, pro open proximal end, a distal end, a Substantially uniform liferative Vitreoretinopathy, Sympathetic ophthalmia, Vogt inner diameter and a Substantially uniform outer diam Koyanagi Harada Syndrome, histoplasmosis, uveal diffu eter extending between the proximal end and the distal Sion, and combinations thereof. end, the hollow Sleeve terminating at the proximal end; 19. The method of claim 1 wherein the implant comprises placing a Substantially bioerodible implant including a a generally cylindrically shaped implant configured to fit therapeutic component and sized for placement in an within the hollow sleeve. eye, in the hollow sleeve; 20. The method of claim 19 wherein the inner diameter of the hollow sleeve is greater than an outer diameter of the passing the distal end of the hollow sleeve through a implant. Surface of an eye; 21. The method of claim 1 wherein the hollow sleeve is introducing the implant into the eye at a location within Structured to accommodate the implant in a Substantially the eye by passing the implant out of the distal end of frictionless manner in order to maintain the implant Sub the hollow sleeve; and Stantially intact while the implant passes through the hollow sleeve and into the eye. withdrawing the hollow sleeve from the eye. 22. The method of claim 1 wherein the hollow sleeve 2. The method of claim 1 wherein the step of introducing comprises a fluoroplastic material. the implant includes advancing a plunger element through 23. The method of claim 1 wherein the hollow sleeve the hollow sleeve in a distal direction in order to urge the includes a material Selected from the group consisting of implant out of the distal end of the hollow sleeve. polytetrafluoroethylene, polyperfluoroalkoxyl, ethylene pro 3. The method of claim 1 wherein the eye is a mammalian pylene, polyfluorinated ethylene propylene, and combina eye. tions thereof. 4. The method of claim 1 wherein the eye is a non-human 24. A method of treating an inflammation-mediated con animal eye. dition of an eye comprising the Steps of: 5. The method of claim 1 wherein the eye is an equine eye. providing a device including a hollow Sleeve having a 6. The method of claim 1 wherein the eye is a human eye. distal end; 7. The method of claim 1 wherein the step of introducing comprises introducing the implant into an anterior chamber placing an implant sized for placement in an eye, in the of the eye. hollow sleeve, the implant being Substantially non 8. The method of claim 1 wherein the step of introducing flexible and including a therapeutic component and a comprises introducing the implant into a posterior chamber polymeric component; of the eye. passing the distal end of the hollow Sleeve through a 9. The method of claim 1 wherein the step of introducing Surface of the eye and into the eye; comprises introducing the implant into a structure of the eye Selected from the group consisting of the retina, the Vitreous, introducing the implant into a vitreous of the eye by the cornea, and the Scleral of the eye. passing the implant out of the distal end of the hollow 10. The method of claim 1 wherein the step of introducing sleeve, and comprises introducing the implant into a structure of the eye withdrawing the hollow sleeve from the eye. Selected from the group consisting of the meningeal Space, 25. The method of claim 24 wherein the step of introduc the optic nerve, and the intraoptic nerve. ing the implant includes advancing a plunger element 11. The method of claim 1 wherein the therapeutic com through the hollow sleeve in a distal direction in order to ponent comprises an anti-inflammatory agent. urge the implant out of the distal end of the sleeve and into 12. The method of claim 1 wherein the therapeutic the vitreous. component comprises a Steroid component. 26. The method of claim 24 wherein the therapeutic 13. The method of claim 1 wherein the therapeutic component comprises a Steroid component. component comprises a Steroid component Selected from the 27. The method of claim 26 wherein the steroid compo group consisting of cortisone, dexamethasone, hydrocorti nent is Selected from the group consisting of cortisone, US 2005/0244462 A1 Nov. 3, 2005 12 dexamethasone, hydrocortisone, methylprednisolone, pred 34. The system of claim 32 further comprising a plurality nisolone, prednisone, triamcinolone and combinations of plunger elements, each plunger element being Structured thereof. to be slidably received within one of the hollow sleeves. 28. The method of claim 26 wherein the steroid compo 35. The system of claim 32 further comprising a plurality nent comprises dexamethasone. of ocular implants, each ocular implant including a thera 29. The method of claim 24 wherein the polymeric peutic component and a matrix component and being sized component is Selected from the group consisting of lactic to be slidably received within one of the hollow sleeves. acid polymers, glycolic acid polymers, copolymers of lactic 36. The system of claim 32 wherein each sleeve is sized acid and glycolic acid, and combinations thereof. to be inserted into a vitreous of a rabbit eye. 30. The method of claim 24 wherein the implant is 37. The system of claim 32 wherein each of the hollow effective in treating an inflamation mediated condition of the sleeves includes a beveled tip on the distal end of the hollow eye Selected from the group consisting of uveitis, macular sleeve. edema, acute macular degeneration, retinal detachment, 38. A device for delivering an ocular implant into an eye, ocular tumors, fungal infections, Viral infections, multifocal the device consisting essentially of choroiditis, diabetic uveitis, proliferative vitreoretinopathy, Sympathetic ophthalmia, Vogt Koyanagi Harada Syndrome, a hollow Sleeve including an open proximal end, a distal histoplasmosis, uveal diffusion, and combinations thereof. end, a beveled tip distal to the distal end, a Substantially 31. The method of claim 24 wherein the hollow sleeve uniform inner diameter and a Substantially uniform comprises a fluoroplastic material. Outer diameter extending between the proximal end and 32. An ocular research System comprising: the distal end, the device terminating at and not extend a plurality of hollow sleeves, wherein each sleeve is ing beyond the proximal end, and sized to receive an Substantially identical to each other sleeve, is sized to therapeutic implant; and be inserted into a vitreous of an eye, and includes a a plunger element Structured to be slidably received proximal end, a distal end, a Substantially uniform inner within the hollow sleeve; diameter and a Substantially uniform outer diameter extending between the proximal end and the distal end. the device being structured to be directly manually 33. The system of claim 32 wherein the plurality of manipulable when used to introduce a biodegradable hollow sleeves are produced by cutting a Substantially implant into a vitreous of an eye. uniform tube at approximately equally Spaced apart inter vals.