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US 20110159073A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0159073 A1 de Juan et al. (43) Pub. Date: Jun. 30, 2011

(54) METHODS AND DEVICES FOR THE Publication Classification TREATMENT OF OCULAR CONDITIONS (51) Int. Cl. (76) Inventors: Eugene de Juan, LaCanada, CA A6F 2/00 (2006.01) (US); Signe E. Varner, Los (52) U.S. Cl...... 424/427 Angeles, CA (US); Laurie R. Lawin, New Brighton, MN (US) (57) ABSTRACT Featured is a method for instilling one or more bioactive (21) Appl. No.: 12/981,038 agents into ocular tissue within an eye of a patient for the treatment of an ocular condition, the method comprising con (22) Filed: Dec. 29, 2010 currently using at least two of the following bioactive agent delivery methods (A)-(C): (A) implanting a Sustained release Related U.S. Application Data delivery device comprising one or more bioactive agents in a (63) Continuation of application No. 1 1/175,850, filed on posterior region of the eye so that it delivers the one or more Jul. 5, 2005, now abandoned. bioactive agents into the vitreous humor of the eye; (B) instill ing (e.g., injecting or implanting) one or more bioactive (60) Provisional application No. 60/585,236, filed on Jul. 2, agents Subretinally; and (C) instilling (e.g., injecting or deliv 2004, provisional application No. 60/669,701, filed on ering by ocular iontophoresis) one or more bioactive agents Apr. 8, 2005. into the vitreous humor of the eye. Patent Application Publication Jun. 30, 2011 Sheet 1 of 22 US 2011/O159073 A1

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METHODS AND DEVICES FOR THE sive treatment. The procedure generally needs to be repeated TREATMENT OF OCULAR CONDITIONS every three months for at least two years, with approximate total cost of S12,250. CROSS-REFERENCE TO RELATED 0006. A number of angiostatic agents are currently under APPLICATIONS investigation for the treatment of AMD. , for example, is known to be a powerful angiostatic agent. Its 0001. This application is a continuation of U.S. applica systemic side effects, however, include peripheral neuropa tion Ser. No. 1 1/175,850, filed Jul. 5, 2005, entitled “METH thy, central nervous system depression, and embryotoxicity. ODS AND DEVICES FOR THE TREATMENT OF OCU In addition, these systemic side effects have limited the dos LAR CONDITIONS, which claims the benefit of U.S. age administered to patients for the treatment of Subretinal Provisional Application Ser. No. 60/585,236, filed Jul. 2, neovascularization. Systemic inhibition of angiogenesis in 2004, entitled “METHODS, DEVICES AND SYSTEMS older patients can also interfere with the development of FORTREATMENT OF OCULARDISEASES AND CON collateral circulation, which has a role in the prevention of DITIONS, and U.S. Provisional Application Ser. No. central nervous system as well as cardiac ischemic events. 60/669,701, filed Apr. 8, 2005, entitled “SUSTAINED 0007. A number of techniques or methodologies have DELIVERY DEVICES FOR THE CHOROID AND been developed to deliver to the various tissues or RETINA AND METHODS FOR SUBRETINAL ADMIN structure that make up the mammalian eye, as described here ISTRATION OF BIOACTIVE AGENTS TO TREAT AND/ inafter, to treat a wide range of disorders or diseases of the OR PREVENT RETINAL DISEASES.” which applications eye. However, delivery of drugs, proteins and the like to the are incorporated herein by reference in their entirety. eye(s) of mammals in order to achieve the desired therapeutic or medical effect, especially to the retina and/or the choroid, FIELD has proved to be challenging, owing in large part to the geometry, delicacy and/or behavior of the eye and its compo 0002. The invention relates to methods and devices for the nents. A brief description of various conventional methods or treatment of ocular conditions. techniques for delivering drugs to the tissues of the eye and the shortcomings thereof is Summarized. BACKGROUND 0008 Oral ingestion of a drug or injection of a drug at a site other than the eye can provide a drug systemically, how 0003. There are a number of vision-threatening disorders ever such a systemic administration does not provide effec or diseases of the eye of a mammal including, but not limited tive levels of the drug specifically to the eye. In many oph to diseases of the retina, retinal pigment epithelium (RPE) thalmic disorders involving the retina, posterior tract, and and choroid. Such vision threatening diseases include ocular optic nerve, adequate levels of the drug cannot be achieved or neovascularization, ocular inflammation and retinal degen maintained by oral or parenteral routes of administration. erations. Examples of these disease states include diabetic Thus, further and repeated administration of the drug would retinopathy, chronic glaucoma, retinal detachment, sickle cell be necessary to achieve the desired or adequate levels of retinopathy, age-related macular degeneration, retinal concentration of the drug. Such further and repeated admin neovascularization, Subretinal neovascularization; rubeosis istrations of Such drugs may produce undesired systemic iritis inflammatory diseases, chronic posterior and pan uvei . tis, neoplasms, retinoblastoma, pseudoglioma, neovascular 0009 Ophthalmic conditions have also been treated using glaucoma; neovascularization resulting following a com drugs applied directly to the eye in either liquid or ointment bined vitrectomy-2 and lensectomy, vascular diseases, retinal form. This route of administration (i.e., topical administra ischemia, choroidal vascular insufficiency, choroidal throm tion) is only effective in treating problems involving the bosis, neovascularization of the optic nerve, diabetic macular superficial surface of the eye and diseases that involve the edema, cystoid macular edema, macular edema, retinitis pig cornea and anterior segment of the eye, Such as conjunctivitis. mentosa, retinal vein occlusion, proliferative vitreoretinopa Topical administration of drugs is not effective in achieving thy, angioid streak, and retinal artery occlusion, and neovas adequate concentrations of a drug(s) in the Sclera, vitreous, or cularization due to penetration of the eye or ocular injury. posterior segment of the eye. In addition, topical eye drops 0004 Age-related macular degeneration (AMD) is the may drain from the eye through the nasolacrimal duct and into leading cause of irreversible severe central vision loss in the systemic circulation, further diluting the and Caucasians fifty years old and older in the United States. risking unwanted systemic side effects. Furthermore, deliv According to the 1990 U.S. census, approximately 750,000 ery of drugs in the form of topical eye drops is also of little people over 65 years of age were estimated as severe visual utility because the drug cannot cross the cornea and be made impairment in one or both eyes from AMD. Also, the number available to the vitreous, retina, or other subretinal structures of cases of AMD has been predicted to increase from 2.7 such as the retinal pigment epithelium (“RPE) or choroidal million in 1970 to 7.5 million by the year 2030. vasculature. Some drugs are highly unstable and therefore not 0005 Roughly 80 percent of the AMD cases involve non easily formulated for topical delivery. Moreover, data also neovascular conditions, for which there are no effective treat indicate that it is not unusual for up to 85% of topically ments. For the remaining cases involving neovascularization, applied agents to he removed by the eye's blink mechanism/ currently available treatments are sub-optimal. Perhaps the reflex. best known therapy is photodynamic therapy (PDT), how 0010 Direct delivery of drugs to the eye by a topical insert ever, while this therapy has received significant attention in has also been attempted, however, this method is not desir both the ophthalmic and financial investment communities, it able. Such topical inserts require patient self-administration is useful in only about 20 percent of neovascular AMD cases. and thus education on their insertion into and removal from In addition, this particular therapy is not a simple or inexpen the eye. Consequently, this technique demands a certain US 2011/O 159073 A1 Jun. 30, 2011

degree of manual dexterity that can be problematic for geri that is in communication with the vitreous and which is con atric patients who are particularly Susceptible to certain eye figured so as to provide a release over time into the vitreous of disorders that appear age related (e.g., age related macular the contained drug. Examples of Such controlled release degeneration). In many instances such topical inserts may devices are described in U.S. Pat. Nos. 6,217,895; 5,773,019; cause eye irritation and Such inserts are prone to inadvertent 5,378.475; and U.S. Patent Application Publication No. loss due to eyelid laxity. In addition, these devices provide a 20O2/OO61327. Source of drug only to the cornea and anterior chamber, and 0015. A common feature of the techniques/instruments thus do not provide any pharmacologic advantage over topi described in these references, is that a Surgical incision is cal eye drops or ointments. Such devices therefore have lim required at the outset of a procedure so that the implant, ited, if any at all, utility for providing an effective source of capsule or other such device can be inserted through the eye drugs to the vitreous or tissues located in the posterior seg and located in the vitreous. These methods and techniques ment of the eye. also necessarily involve the use of sutures following comple 0011 Consequently, most methods for treating eye disor tion of the procedure to seal or close the incision in order to ders or diseases in the posterior segment, or the back-of-the prevent loss of vitreous material. As is known to those skilled eye, involve intravitreal delivery of the drug. One such tech in the art, maintaining the Volume of the posterior segment or nique for intravitreal delivery is accomplished by intraocular vitreous is necessary to maintaining the shape and optical injection of the drug or microspheres containing the drug arrangement of the eye. Such a course of treatment also directly into the vitreous or by locating a device or capsule increases the duration and cost as well as the realistic risks of containing the drug in the vitreous, Such as that described in corneal ulceration, cataract formation, intraocular , U.S. Pat. No. 5,770.589. Intravitreal injection of a drug is an and/or vitreous loss that accompany these procedures. effective means of delivering the drug to the posterior seg 0016 U.S. Pat. Nos. 5.273,530 and 5,409,457 describe an ment of the eye in high concentrations, but it is not without its instrument and methodology to transplant donor cells, more shortcomings. It is well known that drugs that are initially specifically donor retina cells, in the Subretinal space. The located within the vitreous are removed from the vitreous instrument is also described as useful for injecting or remov over time via the anterior segment of the eye. If the ocular ing material from the vitreous. According to the described condition is anything other than acute, this technique neces methodology, the instrument is shaped and dimensioned so it sarily requires follow-up injections in order to maintain an can be inserted into an eye orbit along an insertion path that adequate therapeutic concentration within the vitreous. This, extends along the periphery of the eye in order to place the tip in turn, presents problems because each additional intraocu adjacent to the retina or sub-retinal region. The tip is then lar injection carries with it a realistic risk of infection, hem moved generally in the medial direction so that the tippierces orrhage and/or retinal detachment. the exterior of the eye and resides in the sub-retinal region or 0012. It also is well known that many therapeutic drugs in the vitreous, depending upon how much the tip is moved. In cannot easily diffuse across the retina. The dose being admin order to prevent over-insertion of the tip, a collar is provided istered and maintained in the vitreous has to take into account about the tip in order to limit the distance the tip can be the amount that can diffuse across the retinal boundary as well inserted into the eye. as how long the drug is retained in effective amounts within (0017 U.S. Patent Application Publication 2002/0055724 the vitreous. It has been observed from animal studies that 72 describes an instrument for Sub-retinal transplantation of reti hours after injection of , less than 1% of the nal cells, epithelium and choroid within their normal planar triamcinolone present in the vitreous is associated with other configuration as a graft into the Sub-retinal region of an eye. tissues including the retina, pigment epithelium, and Sclera. The described instrument is inserted into an opening in the 0013. In addition to concerns relating to the relative effec eye using either a transcorneal Surgical approach or a trans tiveness of drug delivery across the barrier, complications or choroidal and Scleral Surgical approach. According to this side effects have been observed when using a direct injection technique, the instrument is advanced under the retina to into vitreous technique with some therapeutics. For example, detach the retina So that the graft can be inserted. As noted in compounds, such as triamcinolone, can effec U.S. Pat. No. 5.273,530, the penetration of the anterior part or tively treat Some forms of neovascularization Such as corneal segment of the eye, using the transcorneal or the transscleral neovasularization. When these compounds are used to treat route creates the risk of corneal ulceration, cataract formation neovascularization of the posterior segment by direct injec and other anterior penetration problems. Also using either tion, undesirable side effects can be caused in many patients. approach, a Surgical incision is created at the outset of a The adverse affects or undesirable side effects included eleva procedure so that the instrument can be inserted and Sutures tions in intraocular pressure and the formation of, or accel are used following completion of the procedure to seal or eration of the development of cataracts. Elevations in close the incision inn order to prevent loss of vitreous material intraocular pressure are of particular concern in patients who (i.e., aqueous humor). are already Suffering from elevated intraocular pressure. Such 0018. The delivery of drugs to the eye presents significant as glaucoma patients. Moreover, there is a risk in using cor challenges. The ocular absorption of systemically adminis ticosteroids in patients with normal intraocular pressure tered pharmacologic agents is limited by the blood ocular because of elevations in pressure that can result in damage to barrier, namely the tight junctions of the retinal pigment ocular tissue. Since therapy with is frequently epithelium and vascular endothelial cells. High systemic long term, i.e., several days or more, a potential exists for doses of therapeutic drugs can penetrate this blood ocular significant damage to ocular tissue as a result of prolonged barrier in relatively small amounts, but may expose the elevations in intraocular pressure attributable to that therapy. patient to the risk of systemic toxicity. Topical delivery of 0014 Consequently, investigations in the area of intravit drugs often results in limited ocular absorption due to the real delivery also have focused on developing a Sustained complex hydrophobic/hydrophilic properties of the cornea release implant, capsule or other Such device or mechanism and Sclera. Additionally, topical agents are mechanically US 2011/O 159073 A1 Jun. 30, 2011

removed by the blink mechanism such that only approxi be formed from biodegradable polymers containing micro mately 15% of a single drop is absorbed. Diffusion of topi particles of drug. Alternatively, the implant may be in the cally administered drugs to the posterior chamber occurs, but form of a hollow flexible polymeric cocoon with the drug often at sub-therapeutic levels. Intravitreal injection of drugs disposed therewithin for slow release by osmosis. No anchor is an effective means of delivering a drug to the posterior ing device is described. segment in high concentrations. However, repeated intraocu 0023 U.S. Pat. No. 5,466.233 describes a certain tack for lar injections carry the risk of infection, hemorrhage and intraocular drug delivery. This device has an end that is posi retinal detachment. Patients also find this procedure some tioned in the vitreous cavity while the head remains external what difficult to endure, resulting in high rates of noncompli to the eye and abuts the Scleral Surface. The tack contains a aCC. fixation portion to attempt to retain attachment within the eye. 0019. Local sustained delivery of therapeutics to the pos Because the overall shape of the capsule is linear, the amount terior chamber is particularly critical in managing several of drug that may be held by the device and the surface area chronic diseases of the eye. In attempts to address this need, through which the drug may be delivered is limited. If the several drug delivery devices have been developed for width of the capsule is increased, excessive sized incisions intraocular insertion into the vitreous region of the eye. will be required for insertion of the device. If the length of the 0020 U.S. Pat. No. 4.300,557, for example, describes an capsule is increased to greater than 1 cm, the implant will pass intraocular implant in the form of a silicone capsule, which into the central visual field of the eye, thereby causing blind can be filled with a drug to be delivered. The implant is spots in the patient's eyes well as increase risk of damage to inserted through an incision into the vitreous region of the the retinal tissue and lens capsule. eye. After insertion of the implant, the incision is closed and 0024. In view of the above, it would be desirable to provide the capsule remains in place for a period of time. Attached to additional methods and devices for treating the eye, particu the implant is a tube that passes through the Surface of the eye. larly treating retinal and/or choroidal conditions. The tube may be used for subsequent injection of a drug while the implant is in the eye. The implant may be removed by SUMMARY making a second Surgical incision into the eye and retrieving 0025. In one aspect, the invention provides a method for the implant. While in the vitreous, the device is not anchored instilling one or more bioactive agents into ocular tissue and may move about freely. Because the overall shape of the within an eye of a patient for the treatment of an ocular capsule is linear, the amount of drug held by the device and condition, the method comprising concurrently using at least delivered over the Surface area of the device is limited. If the two of the following bioactive agent delivery methods (A)- width of the capsule is increased, excessive sized incisions (C): will be required for insertion of the device. If the length of the 0026 (A) implanting a sustained release delivery capsule is increased to greater than 1 cm, the implant will pass device comprising one or more bioactive agents in a into the central visual field of the eye, causing blind spots in posterior region of the eye so that it delivers the one or the patient’s eye as well as increased risk of damage to the more bioactive agents into the vitreous humor of the eye; retinal tissue and lens capsule. 0027 (B) instilling (e.g., injecting or implanting) one or 0021 U.S. Pat. No. 5,378.475 describes a device which more bioactive agents Subretinally; and has been developed for insertion in the vitreous region of the 0028 (C) instilling (e.g., injecting or delivering by ocu eye, and is described in T. J. Smith et al., Sustained Release lar iontophoresis) one or more bioactive agents into the Ganciclovir, Arch. Ophthalmol, 110, 255-258 (1992) and G. vitreous humor of the eye. E. Sanborn, et al., Sustained-Release Ganciclovir Therapy for 0029. In one embodiment of the method, method (A) is Treatment of Cytomegalovirus Retinitis: Use of an Intravit used concurrently with method (B). In this embodiment, one real Device, Arch. Ophthalmol, 110, 188-195 (1992). This or more bioactive agents are released to the vitreous humor of device consists of an inner core of pharmacologic agent Sur the eye from a sustained release delivery device implanted in rounded by two coatings with different permeabilities. Drug the posterior region of the eye; and one or more bioactive diffuses through a small opening in one of these coatings agents are instilled (e.g., injected or implanted) Subretinally. achieving near Zero-order release kinetics. It is implanted in The one or more bioactive agents delivered by the sustained the region of the pars plana through a 3.55.0 mm scleral release delivery device may be the same as or may be different incision. The implant must be removed and replaced every 6 than the one or more bioactive agents delivered subretinally. months in the operating room as the drug becomes depleted. In another embodiment of the method, method (A) is used There is an approximately 25% complication rate from these concurrently with method (C). In this embodiment, one or procedures. The device is a membrane diffusion drug delivery more bioactive agents are released to the vitreous humor of system that relies on EVA/PVA polymers to mediate release the eye from a sustained release delivery device implanted in rate. However, many agents cannot be effectively delivered the posterior region of the eye; and one or more bioactive from Such a system because their permeation rate through the agents are instilled (e.g., injected or delivered by ocular rate controlling material of the system is too small to produce tophoresis) into the vitreous humor of the eye. In this embodi a useful effect. Other agents cannot be satisfactorily delivered ment, the one or more bioactive agents released by the Sus by diffusional devices because of a particular chemical char tained release delivery device of method (A) may be the same acteristic of the agent. This includes salts, because of their as or different than the one or more bioactive agents instilled ionic character, and unstable polar compounds that cannot be (e.g., injected or delivered by ocular iontophoresis) by formulated into a composition Suitable for storage and deliv method (C). In yet another embodiment, method (B) is used ery from Such systems. concurrently with method (C). In this embodiment, one or 0022 U.S. Pat. No. 5,098.443 describes certain specific more bioactive agents are instilled (e.g., injected or implants that are inserted through incisions made in the eye implanted) Subretinally and one or more bioactive agents are wall or Sutured around the globe of the eye. These rings may instilled (e.g., injected or delivered by ocular iontophoresis) US 2011/O 159073 A1 Jun. 30, 2011

into the vitreous humor of the eye. In this embodiment, the (meth)acrylates), and poly(alkoxyaryl (meth)acrylates). Poly one or more bioactive agents delivered by method (B) may be (alkyl(meth)acrylates) include poly(n-butyl methacrylate), the same as or different than the one or more bioactive agents poly(n-butyl methacrylate-co-methyl methacrylate), poly(n- delivered by method (C). In yet another embodiment, method butyl methacrylate-co-isobutyl methacrylate), and poly(t-bu (A) is used concurrently with both method (B) and method tyl methacrylate). In one embodiment, the first polymer is (C) to instill one or more bioactive agents into ocular tissue in poly(butylmethacrylate) and the second polymer is poly(eth the eye. In this embodiment, the one or more bioactive agents ylene-co-vinyl ). delivered by one method may be the same as or different than 0036. In some embodiments, the intraocular sustained the one or more bioactive agents delivered by the other meth release delivery device of method (A) comprises a nonlinear ods. body member having a direction of extension, a longitudinal 0030. In some embodiments, method (B) comprises axis along the direction of extension, and a proximal end and instilling (e.g., injecting or implanting) one or more bioactive a distal end, wherein at least a portion of the body member agents Subretinally. The bioactive agent(s) may be injected deviates from the direction of extension, and wherein the subretinally when provided, for example, in the form of a body member includes the one or more bioactive agents, and liquid or it may be implanted subretinally when provided in a polymer matrix. The body member may be coil-shaped. In the form of a Solid (e.g., a Sustained release delivery device). Some embodiments, the Sustained delivery device includes a In some embodiments, method (B) comprises (a) forming a cap positioned at the proximal end of the body member. In localized retinal detachment to define a Subretinal space; and Some embodiments the body member includes a lumen. instilling one or more bioactive agents in the Subretinal space 0037. In some embodiments, the sustained release deliv formed by localized retinal detachment. ery device has a total diameter of no greater than about 1000 0031. In some embodiments, method (C) comprises um and a length of no greater than about 6 mm. injecting one or more bioactive agents into the vitreous humor 0038. In some embodiments, the sustained release deliv of the eye using a needle. In another embodiment, the one or ery devices have a bioactive agent elution rate of at least more bioactive agents are instilled by ocular iontophoresis, 0.0001 ug per day or greater. for example, transscleral iontophoresis. 0039 Methods of the invention may deliver one or more 0032. In some embodiments, the one or more bioactive bioactive agents, for example, antiproliferative agents, anti agents are provided in a Sustained release delivery device that inflammatory agents, anti-angiogenic agents, , is configured for implantation in the Subretinal space. The neurotrophic factors, or combinations thereof. sustained release delivery device may be a solid in the form of 0040. As used herein, a “coating composition” refers to a capsule, pellet, rod, sheet, or film. In some embodiments, one or more vehicles (for example, Solutions, mixtures, emul the sustained release delivery device may be in the form of a sions, dispersions, blends, and the like) used to effectively flexible rod, thin film, foldable disc, biodegradable polymer coat a surface. A “coated composition” refers to the combi with the bioactive agent embedded within, bioactive agent nation of one or more bioactive agent and a polymer on a eluting polymer coating over a rigid scaffold, compressed surface of the device. The coated composition can be formed pellet of one or more bioactive agents, or one or more bioac from one or more coating compositions, or in one or more tive agents encapsulated in a semi-permeable membrane. The layers, as will be apparent from the teaching herein. Sustained release delivery device may be tapered at a proxi 0041 As used herein, “biocompatible” means the ability mal end, a distal end, or both the proximal and distal ends. of an object to be accepted by and to function in a recipient 0033. In another embodiment, the sustained release deliv without eliciting a significant foreign body response (such as, ery device is in the form of a biocompatible polymer capsule for example, an immune, inflammatory, thrombogenic, or the comprising (a) a core comprising one or more bioactive like response). For example, when used with reference to one agents; and (b) a jacket Surrounding the core comprising a or more of the polymers of the invention, biocompatible membrane that is biocompatible and that permits diffusion of refers to the ability of the polymer (or polymers) to be the one or more bioactive agents. accepted by and to function in its intended manner in a recipi 0034. In another embodiment, the sustained release deliv ent ery device comprises a core having an outer Surface; and a 0042. As used herein, “therapeutically effective amount coating layer of a polymer matrix and at least one bioactive refers to that amount of a bioactive agent alone, or together agent applied over at least a portion of the outer Surface of the with other substances (as described herein), that produces the core. The coating layer may be provided on a portion of the desired effect (Such as treatment of a medical condition Such outer Surface of the core (e.g., an intermediate portion) or it as a disease or the like, or alleviation of pain) in a patient. may cover the entire outer Surface of the core. The coating During treatment, such amounts will depend upon Such fac layer may include a proximal transition segment, a distal tors as the particular condition being treated, the severity of transition segment, or both a proximal and a distal transition the condition, the individual patient parameters including segment. Representative examples of core materials include age, physical condition, size and weight, the duration of the titanium alloys, nickel-cobalt base alloys, stainless steel, treatment, the nature of the particular bioactive agent thereof cobalt-chromium alloys, and biodegradable employed and the concurrent therapy (ifany), and like factors alloys. within the knowledge and expertise of the health practitioner. 0035. In some embodiments, the polymer matrix com A physician or Veterinarianofordinary skill can readily deter prises a first polymer and a second polymer wherein the first mine and prescribe the effective amount of the bioactive agent polymer is a poly(alkyl(meth)acrylate) or a poly(aromatic required to treat and/or prevent the progress of the condition. (meth)acrylate) and wherein the second polymer is poly(eth 0043. The term “implantation site' refers to the site within ylene-co-vinyl acetate). Poly(aromatic(meth)acrylates) a patient's body at which the implantable device is placed include poly(aryl(meth)acrylates), poly(aralkyl(meth)acry according to the invention. In turn, a “treatment site' includes lates), poly(alkaryl (meth)acrylates), poly(aryloxyalkyl the implantation site as well as the area of the body that is to US 2011/O 159073 A1 Jun. 30, 2011 receive treatment directly or indirectly from a device compo 0063 FIG. 15 is a flow diagram of a method of instilling nent. For example, bioactive agent can migrate from the one or more bioactive agents Subretinally. implantation site to areas Surrounding the device itself. 0064 FIG. 16 is a schematic view illustrating the localiza thereby treating a larger area than simply the implantation tion of the operable end of a subretinal bioactive agent deliv site. The term “incision site' refers to the area of the patient's ery device. body (the skin and transdermal area) at which an incision or 0065 FIG. 17 is a schematic view illustrating the subreti Surgical cut is made to implant the device according to the nal instillation of a bioactive agent using a Subretinal bioac invention. The incision site includes the Surgical cut, as well tive agent delivery device. as the area in the vicinity of the Surgical cut, of the patient. 0.066 FIG. 18 is a detail view of an embodiment of an 0044. The term “instill means to deliver one or more operable end of the subretinal bioactive agent delivery device bioactive agents using various delivery means and/or mecha of FIG. 16. nisms. 0045. The term “treatment course' refers to the dosage 0067 FIG. 19 is a flow diagram of a method of instilling rate over time of one or more bioactive agents, to provide a one or more bioactive agents Subretinally. therapeutically effective amount to a patient. Thus, factors of 0068 FIG. 20 is a schematic depiction of the filament a treatment course include dosage rate and time course of preparation process in accordance with one embodiment of treatment (total time during which the bioactive agent(s) is the present invention. administered). 0069 FIG.21 shows fundus photography (Rabbit 4) of the implanted polycaprolactone? (PCL/ BRIEF DESCRIPION OF THE DRAWING TA) filament at 4 weeks post Surgery. 0070 FIG. 22 shows fluorescein angiography (Rabbit 4) 0046 For a fuller understanding of the nature and desired of the implanted PCL/TA filament at 4 weeks post surgery. objects of the present invention, reference is made to the following detailed description taken in conjunction with the 0071 FIG. 23 shows optical coherence tomography of the accompanying drawing figures wherein like reference char retinal thickness Surrounding the implant site for the polyca acter denote corresponding parts throughout the several prolactone (PCL) filaments (Rabbit 1 and 2) at 4 weeks post views and wherein: Surgery. 0047 FIG. 1 shows a perspective view of an implantable 0072 FIG. 24 shows in vitro cumulative elution data for a device configured for intraocular placement according to one 70:30 PCLFTA filament. embodiment of the invention. 0073 FIG. 25 shows invitro cumulative elution data for a 0.048 FIG.2 shows a view from the bottom of the embodi 60:40 PCLFTA filament. ment illustrated in FIG. 1. 0074 FIG. 26 shows in vitro cumulative elution data for a 0049 FIG. 3 shows a perspective view of an implantable 50:50 PCLFTA filament. device configured for intraocular placement according to 0075 FIG. 27 shows optical image and magnification of another embodiment of the invention. the subretinal PCL/TA implant (Rabbit 5) following 4 weeks 0050 FIG.4 shows a view form the bottom of the embodi implantation where A) shows the optic nerve location, B) ment illustrated in FIG. 3. marks the implant location, C and D) shows the site of the 0051 FIG. 5 shows transcleral placement of an implant retinotomy, E) is the outer sclera surface, and F) outlines the able device according to one embodiment of the invention. region of damage to the proximal end of the filament during 0.052 FIG. 6 shows and illustration of a subretinal sus micro forceps insertion. tained release delivery device in accordance with one (0076 FIG. 28 shows histology (H&E staining) of a 150 embodiment of the invention. um PCL filament (no drug) following 4 weeks implantation 0053 FIG. 7 shows an illustration of a side view of a (Rabbit 1) where A) marks the device location, B) shows the subretinal sustained release delivery device. RPE, C) shows the nerve fiberlayer, D) shows the choroid and 0054 FIG. 7A shows a longitudinal cross-sectional view E) shows the sclera. of the subretinal sustained release delivery device of FIG. 7. (0077 FIG. 29 shows histology (H&E staining) of a 150 0055 FIG. 8 shows an illustration of a side view of a um PCL/TA filament subretinal delivery system following 4 Sustained release delivery device in accordance with one weeks implantation (Rabbit 5) where A) marks the device embodiment of the invention. location, B) shows the RPE, C) shows the nerve fiberlayer, D) 0056 FIG. 8A shows a longitudinal cross-sectional view shows the choroid, E) shows the sclera and F) identifies the of the subretinal sustained release delivery device of FIG.8. region of vacuolated spaces. 0057 FIG.9 is a schematic diagram of a spray stream as it passes through a focal point. (0078 FIG. 30 shows explanted PCL/TA filament. 0058 FIG. 10 is a schematic diagram of a spray stream 007.9 FIG. 31 shows in vivo detection of triamcinolone that expands continuously as it moves away from the spray acetonide (TA) following a 4-week subretinal drug delivery head. implantation (PCL/TA 60:40) for rabbit 4. 0059 FIG. 11 is a schematic view of a grid-like coating 0080 FIG. 32 shows a photo of RS1, one (1) week post pattern useful in coating devices of the invention. Surgery, photo and fluorescein angiography. 0060 FIG. 12 is a schematic view of a grid-like coating I0081 FIG. 33 shows a photo of RS1, two (2) weeks post pattern Superimposed over a core material. Surgery, photo and fluorescein angiography. 0061 FIG. 13 is a schematic view of series of first trans I0082 FIG. 34 shows a photo of RS1, four (4) weeks post verse Sweeps Superimposed over a core material. Surgery, photo and fluorescein angiography. 0062 FIG. 14 is a flow diagram of a method of instilling I0083 FIG. 35 shows a photo of RS5, four (4) weeks post one or more bioactive agents Subretinally. Surgery, photo and fluorescein angiography. US 2011/O 159073 A1 Jun. 30, 2011

0084 FIG.36 shows a photo of RS3, 4 weeks post surgery, of ocular conditions, for example, retinal detachment; occlu photo, fluorescein angiography and optical coherence tomog sions; proliferative retinopathy; proliferative vitreoretinopa raphy. thy; diabetic retinopathy; inflammations such as uveitis, chor I0085 FIG. 37 shows a histology photo of RS1. oiditis, and retinitis; degenerative disease (such as age-related macular degeneration, also referred to as AMD); vascular DETAILED DESCRIPTION diseases; and various tumors including neoplasms. I0086. The present invention is directed to methods and 0095. The methods and devices useful to deliver one or devices for treating ocular conditions (e.g., ocular diseases more bioactive agents according to the method of the inven and disorders). The methods and devices provide flexibility in tion are now described in detail below. treatment of ocular conditions, including flexibility in the combination of bioactive agent(s) and delivery methods Method A: Intraocular Sustained Release Delivery Device: employed. 0096 Embodiments of the invention comprise the use an 0087. In one aspect, the invention provides a method for intraocular Sustained release delivery device in order to con instilling one or more bioactive agents to ocular tissue within trollably release one or more bioactive agents to the vitreous an eye of a patient for the treatment of an ocular condition, the humor of the eye. Representative examples of intraocular method comprising concurrently using at least two of the sustained release delivery devices are described, for example, following bioactive agent delivery methods (A)-(C): in U.S. Pat. No. 6,719,750 B2 (“Devices for Intraocular Drug I0088 (A) implanting a sustained release delivery Delivery.” Varneret al.); U.S. Publication Nos. 2005/0019371 device comprising one or more bioactive agents in a A1 (“Controlled Release Bioactive Agent Delivery Device.” posterior region of the eye so that it delivers the one or Anderson et al.), 2004/0133155A1 (“Devices for Intraocular more bioactive agents into the vitreous humor of the eye; Drug Delivery.” Varner et al.), 2005/0059956 A1 (“Devices I0089 (B) instilling (e.g., injecting or implanting) one or for Intraocular Drug Delivery. Varner et al.), and 2003/ more bioactive agents Subretinally; and 0014036A1 (“Reservoir Device for Intraocular Drug Deliv 0090 (C) instilling one or more bioactive agents into ery. Varner et al.); and related applications. the vitreous humor. (0097. Referring now to FIGS. 1-5, a sustained release 0091. In one embodiment of the invention, the method delivery device according to one embodiment is illustrated. comprises using method A concurrently with method B. In Generally speaking, the device illustrated in FIGS. 1-5 pro another embodiment, the method of the invention comprises vides a controlled release bioactive agent delivery device using method A concurrently with method C. In another comprising a body member having a direction of extension, a embodiment, the method comprises using method B concur longitudinal axis along the direction of extension, and a rently with method C. In yet another embodiment, the method proximal end and a distal end, wherein at least a portion of the of the invention comprises using method A concurrently with body member deviates from the direction of extension, the both method Band method C. body member including a polymer matrix comprising a bio 0092. In each of the above-described embodiments, the active agent. As shown in FIG. 1, the device includes a body individual methods may be used to deliver the same bioactive member 2 having a proximal end 4 and a distal end 6. FIG. 1 agent(s) or to deliver different bioactive agent(s) to the eye. illustrates the body member in a coil configuration. For example, if method A is used in conjunction with method 0098. The distal end 6 of the body member 2 can be posi C, the bioactive agent(s) delivered by method A may be the tioned at any desirable location relative to the longitudinal same or different than the bioactive agent(s) delivered by axis of the body member. As shown in FIGS. 1-2, the distal method C. end 6 of the body member according to one embodiment of 0093 Advantageously, the method of the invention may the invention can include a tip 10 that is spaced from the be used to simultaneously instill bioactive agents that may not longitudinal axis. This configuration is similar to a standard be readily delivered by one method and/or by one device. For “corkscrew' type configuration. In use, the device is inserted example, bioactive agents that are different in molecular through the incision site and then twisted until the controlled weight, hydrophobicity, polarity, physical state (e.g., Solid or delivery device is properly positioned at the treatment site. liquid) and/or stability may be simultaneously instilled using 0099. Another embodiment is shown in FIGS. 3-4, the method of the present invention. In one embodiment, a wherein the distal end 6 of the body member includes tip 10 first bioactive agent is delivered subretinally from a sustained that is positioned at the longitudinal axis of the body member release delivery device and a second bioactive agent that is 2. In some embodiments, placement of the tip 10 of the body different from the first bioactive agent in molecular weight, member 2 at the longitudinal axis can provide advantages, hydrophobicity, polarity, and/or stability is delivered to the such as ease of insertion of the device at the distal end. It will vitreous humor. In addition, the method of the invention may be readily apparent that various other configurations of the be used to provide a bioactive agent delivery profile that may distal end of the body member can be provided, depending not be readily obtainable using a single delivery method. For upon the desired application. example, a sustained release delivery device of method A or B 0100 Further, the proximal end 4 of the body member 2 may be used concurrently with method C in order to provide can also be positioned at any desirable location relative to the both a high initial concentration of a bioactive agent in the longitudinal axis of the body member. FIGS. 1 and 3 illustrate vitreous humor and Sustained delivery (e.g., vitreal or Sub the proximal end 4 of the body member as spaced from the retinal) of the bioactive agent over an extended period of time. longitudinal axis. However, the proximal end 4 of the body In another embodiment, methods A and B may be used con member can be provided at the longitudinal axis as well (not currently to provide sustained vitreal and subretinal delivery shown in the FIGS.). In some embodiments, placement of the of one or more bioactive agents. proximal end 4 of the body member 2 at the longitudinal axis 0094 Methods and devices of the invention can be used to can provide advantages, such as ease of fabrication of the instill one or more bioactive agents to the eye for the treatment device, increased mechanical strength, improved translation US 2011/O 159073 A1 Jun. 30, 2011

of force (since a uniform force can be applied and translated 0105. In some embodiments, the deviations from the to the body member, with less risk of bending or other defor direction of extension can be provided in the form of rings. mation of the body member), and the like. Such individual rings can be concentric (that is, having a common axis, or being coaxial about the longitudinal axis) or 0101. According to the intraocular embodiments of the eccentric (deviating from a circular path). According to these invention, the coil shape of the body member allows the embodiments, the individual rings are noncontiguous along device to be screwed or twisted into the body through an the body member length, thereby forming individual ribs at incision approximately the same size as the outer diameter of positions along the direction of extension of the body mem the material forming the body member 2. Still further, the coil ber. shape of the body member can act as an anchoring mechanism 0106 Preferred configurations of the body member are to maintain the controlled delivery device within the implan coiled or spiral. Generally, in a coil configuration, the indi tation site, and can prevent unwanted movement of the device vidual rings of the coil rotate about the longitudinal axis, and and unwanted ejection of the device from the implantation the overall coil is substantially symmetrical about the longi site and/or the body. As a result of the coil shape, the con tudinal axis. A preferred coil is composed of multiple rings trolled delivery device is twisted and unscrewed out of the that are substantially similar in circumference along the body during removal of the device. length, from proximal to distal, of the device. In some pre 0102 Generally speaking, the body member of the ferred embodiments, the rings form a spiral pattern, wherein implantable device is the portion of the controlled release the circumference of the rings changes over the length of the device that is inserted into a patient. The body member can be device. Preferably, the circumference of the rings decreases described as including a proximal end (which is located, upon toward the distal direction of the device, so that the largest implantation, towards the exterior of the body), a distal end ring circumference is located at the proximal region of the (which is located, upon implantation, towards the interior of device, and the Smallest ring circumference is located at the the body), and a longitudinal axis. In use, at least a portion of distal region of the device. the body member is inserted into a patient's body. For 0107 Inclusion of deviating portions of the body member example, in Some embodiments, it can be preferable to posi provides an increased surface area for delivery of a bioactive tion less than 100% of the body member inside the patient’s agent to an implantation site as compared to a linear device body. The amount of the body member positioned within the having the same length and/or width. This can provide advan body can be determined by the interventionalist, based upon tages during use of the device, since this configuration allows such factors as desired treatment parameters, the particular a greater surface area to be provided in a smaller length and/or configuration of the device, the implantation site, and the like. width of the device. For example, in Some applications, it can 0103) The body member further includes a direction of be desirable to limit the length of the device. For example, as extension, and in preferred embodiments, at least a portion of will be discussed in more detail herein, it is desirable to limit the body member deviates from the direction of extension. In the length of implants in the eye to prevent the device from preferred embodiments, the body member includes at least entering the central visual field of the eye and to minimize risk two, three, four, five, six, seven, eight, nine, ten, or more of damage to the eye tissues. By providing a body member deviations from the direction of extension. In some alterna that has at least a portion of the body member deviating from tive embodiments, where the body does not include multiple the direction of extension, the device of the invention has deviations from the direction of extension, the body member greater Surface area (and thus can hold a greater Volume of can be provided in a “J” or a hook-type configuration. bioactive agent) per length of the device without having to 0104. The deviations from the direction of extension can make the cross section of the device, and thus the size of the be provided in any suitable configuration. Exemplary insertion incision, larger. embodiments of such deviations will be described herein for 0.108 Still further, in certain embodiments, the shape of illustrative purposes only, and without intending to be bound the body member can provide a built-in anchoring system that by any particular embodiment described herein. The devia reduces unwanted movement of the device and unwanted tions need not be rounded or arcuate. For example, in some ejection of the device out of the patient's body, since the shape embodiments, the body member is provided with a Z-shaped of the body member requires manipulation to remove it from configuration, Such that the deviations are angular. Moreover, an incision. For example, for a coil-shaped body member, the the deviations need not be in a regular pattern, but can alter device would require twisting, and a Z-shaped body member natively be provided in a random manner. Such that the body would require back and forth movement, to remove the device member contains random curls or turns. In some embodi from the implantation site. According to Some preferred ments, the deviations are provided in a patterned configura embodiments, the device does not require additional anchor tion about the longitudinal axis. Examples of these patterned ing mechanisms (such as Suturing) to the body tissues, as a embodiments include coils, spirals, or patterned Z-shaped result of the self-anchoring characteristics of the device itself. turns in the body. Alternatively, the deviations can be pro As described in more detail herein, inclusion of a cap 8 on the vided in a random or non-patterned configuration about the device can provide further anchoring features of the device. longitudinal axis. According to these particular non-patterned 0109. In some embodiments, when the body member embodiments, the distance of the individual deviations from includes two or more deviations from the direction of exten the longitudinal axis to the outermost periphery of the body Sion, the spacing of the individual deviations can be selected member can be selected to provide a desired overall profile of to provide an optimum combination of Such features as the body member, depending upon the application of the increased Surface area available for coating, overall dimen device. For example, it can be desirable, in some applications, sions of the device, and the like. For example, when the body to provide an overall profile of the body member having an member is provided in the form of a coil that includes two or hourglass shape, alternating ring circumference shapes, and more deviations from the direction of extension, the distance the like. between the individual coils can be selected to be equal to or US 2011/O 159073 A1 Jun. 30, 2011 greater than the diameter of the material forming the body sharp or pointed tip. In one preferred embodiment, the distal member. In Sonic aspects, if the distance between coils is less end 6 of the body member has a ramp-like angle. Preferably, than the diameter of the material forming the body member, the device according to this embodiment can be utilized to the amount of surface area available for coating of the body make an incision in the body, rather than requiring separate member can decrease, since it can be more difficult to access equipment and/or procedures for making the incision site. If portions of the surface area of the body member with the the distal end 6 of the body member 2 is used to pierce the coating compositions. In one illustrative embodiment of this body during insertion, at least the distal end 6 is preferably aspect of the invention, the body member is formed of a fabricated of a rigid, non-pliable material suitable for piercing material having a diameter of 0.5 mm, and the distance between each coil of the body member is at least 0.5 mm. the body. Such materials are well known and can include, for These principals can be applied to any configuration of the example, polyimide and similar materials. In one Such pre body member and is not limited to coiled configurations. ferred embodiment, the distal end 6 of the body member 2 is 0110. The overall dimensions of the implantable device utilized to pierce the eye for insertion of the controlled deliv can be selected according to the particular application. For ery device in the interior of the eye. example, the length and/or width of the device can be selected 0114. In another preferred embodiment, the distal end 6 of to accommodate the particular implantation site. Some fac the body member 2 can be shaped or bent to form a portion tors that can affect the overall dimensions of the implantable (for example, the distal-most portion of the body member) device include the potency of any bioactive agent to be deliv that is parallel to the longitudinal axis. In one embodiment ered (and thus the volume of bioactive agent required, which illustrated in FIGS. 3 and 4, for example, the distal end 6 impacts the Surface area of the device, as discussed herein), includes a sharp or pointed tip that is parallel to the longitu the location of the implantation site within the body (for dinal axis. According to this particular embodiment, the tip example, how far within the body the implantation site is located at the distal end 6 of the body member is perpendicu located), the size of the implantation site (for example, a small lar to the plane of incision, thus providing a self-starting tip of area such as the eye orinner ear, or a larger area, such as a joint the device. While the figures illustrate a sharp tip of the body or organ area), the tissue Surrounding the implantation site member, it is understood that any Suitable configuration of the (for example, vascular tissue or hard, calcinous tissue. Such as distal tip can be provided, utilizing the teaching herein. bone), and the like. 0115 The body member 2 can be fabricated from a solid 0111. By way of example, the device is preferably material (a material that does not contain a lumen) or a mate designed for insertion through a small incision that requires rial containing a lumen, as desired. In the embodiment illus few or no sutures for scleral closure at the conclusion of the trated in FIGS. 1 to 4, for example, the body member 2 is Surgical procedure. As such, the device is preferably inserted fabricated from a solid material that is shaped into a coil. through an incision that is no more than about 1 mm in Alternatively, the body member 2 can be fabricated from a cross-section, for example, in the range of about 0.25 mm to tubular material that includes alumen. The choice of a solidor about 1 mm in diameter, preferably in the range of about 0.25 lumen-containing material is not critical to the invention and mm to about 0.5 mm in diameter. As such, the cross-section of can be determined based upon availability of materials and the material forming the body member 2 is preferably no processing considerations. more than about 1 mm, for example, in the range of about 0.25 0116. When included, the lumen(s) can extend along the mm to about 1 mm in diameter, preferably in the range of length of the body member 2 or only a portion of the length of about 0.25 mm to about 0.5 mm in diameter. When the mate the body member 2, as desired. In some embodiments, the rial forming the body member 2 is not cylindrical, the largest lumen(s) can serve as a delivery mechanism for delivery of a dimension of the cross-section can be used to approximate the desired Substance to the implantation site. The Substance diameter of the body member for this purpose, for example, delivered via the lumen can comprise any of the bioactive when the body member cross-section is square. agents described herein. The substance delivered via the 0112 The body member of the controlled release device lumen can be the same or different bioactive agent(s) from preferably has a total length from its proximal end to its distal that included in the polymer matrix. Further, the substance end that is less than about 1 cm, for example, in the range of can be provided in addition to the bioactive agent of the about 0.25 cm to about 1 cm. Upon implantation, the body polymer matrix, or in place of the bioactive agent. For member is positioned within the eye, such that the portion of example, in one embodiment, one or more substances can be the controlled delivery device that delivers bioactive agent to delivered via the lumen, and one or more bioactive agents can the eye chamber is positioned near the posterior segment of be provided to the implantation site from the polymer matrix. the eye. When the controlled delivery device includes a cap 8. 0117. In some embodiments, the lumen can contain a the cap is preferably provided with a thickness of less than polymer matrix as described herein. According to these par about 1 mm, more preferably less than about 0.5 mm. Accord ticular embodiments, the body member of the device can be ing to this particular embodiment, the total length of the provided with or without a coating on its external Surface. In controlled delivery device is less than about 1.1 cm, prefer some such embodiments, the lumen can be utilized to deliver ably less than about 0.6 cm. the bioactive agent(s) to the implantation site. For example, 0113. The distal end 6 of the body member can include any the lumen can contain the polymer matrix, including bioac Suitable configuration, depending upon the application of the tive agent. According to this particular embodiment, the body device and the site of the body at which the device is to be member can be provided with a coating on an external Surface implanted. For example, in some embodiments, the distal end comprising a suitable polymer only (that is, lacking any bio 6 can be blunt or rounded. In preferred embodiments, the active agent). Thus, the bioactive agent is provided to the distal end 6 of the body member is configured to pierce the implantation site in this embodiment principally via the body during implantation of the device into the body. For lumen of the body member. In other embodiments, the lumen example, the distal end 6 of the body member can include a can include the inventive polymer matrix (including biode US 2011/O 159073 A1 Jun. 30, 2011

gradable polymer and bioactive agent), and the body member of the substance (when provided) and can be readily deter is not provided with a coated composition on its external mined by one of skill in the art. The apertures are preferably Surface. designed such that the substance to be delivered is slowly 0118. The lumen can contain any combination of ele diffused rather than expelled as a fluid stream from the device. ments, as desired. For example, in Some embodiments, the For example, when the device is implanted in the eye, it is lumen can include only the substance to be delivered. In other preferable to deliver the substance through slow diffusion embodiments, the lumen can include the Substance to be rather than expulsion of the Substance as a fluid stream, which delivered, as well as the polymer matrix. The particular com can damage the delicate tissues of the eye. In some embodi bination of elements to be included in the lumen can be ments, the polymer matrix in contact with the body can pro selected depending upon the desired application of the vide a particular porosity to the Substance and can assist in device. controlling the rate of diffusion of the substance from the 0119 When the lumen is to be provided with a substance lumen. When included in the device, the particular location of and/or polymer matrix, the lumen can be filled with the the apertures can be situated so as to deliver the Substance at desired Substance and/or polymer matrix prior to inserting the a particular location once the device is implanted into the device into the body, or after the device has been inserted into body. the body. When it is desired to fill the device with the sub I0123. In another embodiment, when the body member 2 stance after insertion into the body, a port can be provided includes alumen for delivery of an additional substance to the near the proximal end 4 of the body member 2 for such implantation site, the material forming the body member 2 purpose. The port is in fluid communication with the lumen(s) can be chosen to be permeable (or semi-permeable) to the of the body member and can also be used for refilling the substance to be delivered from the lumen. According to this device with the substance and/or polymer matrix before and/ particular embodiment, the material can be chosen depending or after implantation, when desired. upon the particular application of the device and the Sub 0120 When the device includes a port, the port is prefer stance to be delivered and can be readily determined by one of ably designed Such that the needle of an injection mechanism skill in the art. Examples of suitable permeable materials (for example, a syringe) can be inserted into the port and the include polycarbonates, polyolefins, polyurethanes, copoly material to be included in the lumen injected by the injection mers of acrylonitrile, copolymers of polyvinyl chloride, mechanism. Thus, the material can travel through the port and polyamides, polysulphones, polystyrenes, polyvinyl fluo into the lumen(s) of the body member. The port preferably rides, polyvinyl , polyvinyl esters, polyvinyl forms a Snug seal about the needle of the injection mechanism butyrate, polyvinyl acetate, polyvinylidene chlorides, poly to prevent leakage of the material out of the port around the vinylidene fluorides, polyimides, polyisoprene, polyisobuty injection mechanism and to provide sterile injection of mate lene, polybutadiene, polyethylene, polyethers, polytetrafluo rial into the lumen(s). If desired, fittings or collars (not roethylene, polychloroethers, polymethylmethacrylate, shown), through which an injection mechanism can be polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, inserted and which form a Snug seal about the injection gelatin, silicone rubbers, porous fibers, and the like. mechanism, can be mounted on the port. Upon injection of the 0.124. According to these particular embodiments, the material into the delivery device, the needle of the injection material used to fabricate the body member 2 can be chosen to mechanism is removed from the port and the port sealed. provide a particular rate of delivery of the substance, which Sealing can be accomplished by providing a removable cover can be readily determined by one of skill in the art. Further, (not shown) on the port that can be removed for injection of the rate of delivery of the substance can be controlled by the substance and replaced when the material has been varying the percentage of the body member 2 formed of the injected. In a preferred embodiment, the port is fabricated of permeable (or semi-permeable) material. Thus, for example, a self-sealing material through which the injection mecha to provide a slower rate of delivery, the body member 2 can be nism can be inserted and which seals off automatically when fabricated of 50% or less permeable material. Conversely, for the injection mechanism is removed. Such materials are a faster rate of delivery, the body member 2 can be fabricated known and include, for example, silicone rubber, silicone of greater than 50% of permeable material. When one or more elastomers, polyolefin, and the like. portions of the body member 2, rather than the whole body 0121. In further embodiments, when the device includes member 2, is fabricated of a permeable or semi-permeable more than one lumen, the device can include more than one material, the location of the permeable or semi-permeable port. For example, each lumen can be in fluid communication material can be situated so as to deliver the Substance at a with a plurality of ports. These ports are similar to the single particular location once the device is implanted at the implan port described above. If desired, the lumens and ports can be tation site. arranged such that each lumen can be filled with a different 0.125. In another embodiment, the lumen of the body material through a corresponding port (for example, each member 2 can include impermeable dividers located along lumen has its own dedicated port). It can be desirable to the length of the lumen. Thus, the lumen of the body member include more than one lumen when it is desirable to deliver can containa plurality of compartments, each of which can be more than one additional material to the implantation site. filled with a different substance, as desired. These compart 0122. In embodiments where it is desired to deliver one or ments could be filled prior to insertion through an injection more additional Substances to the implantation site via one or port located, for example, in the side of each compartment. In more lumens, the individual lumens can include one or more another embodiment, the device can be filled after it is apertures to allow Such delivery. In one embodiment, Such implanted by providing a plurality of conduits, each conduit apertures are provided at the distal end 6 of the device. In in fluid communication with a corresponding compartment. other embodiments, the apertures are provided along the These conduits can be provided within the wall of the body length of the body member 2. The number and size of the member 2, along the circumference of the body member 2. apertures can vary depending upon the desired rate of delivery The substances could then be injected through a plurality of US 2011/O 159073 A1 Jun. 30, 2011 ports, each port in fluid communication with a corresponding characteristics of the device, without Substantially increasing conduit. Thus, a substance could be injected into the first the overall profile of the device upon implantation. In some compartment just below the cap 8 by a port in the center of the embodiments, for example, the cap can be covered by a flap of cap 8, which delivers the substance directly into the first tissue at the incision site upon implantation, to further reduce compartment. A Substance injected into the second port, potential irritation and/or movement of the device at the would flow through conduit and would flow through an aper implantation and/or incision sites. One illustrative example ture in the wall of body member 2 into second compartment, described in more detail elsewhere herein is the covering of and so on. The substance(s) to be delivered can be delivered to the cap with a Scleral cap upon implantation of the device in the implantation site via any of the methods described herein the eye. for the lumen(s). I0131 Further, while the cap 8 is illustrated with a circular 0126. In another embodiment, each lumen or compart shape, the cap can be of any shape, for example, circular, ment (as desired) can be designed for selected "opening” or rectangular, triangular, square, and the like. In order to mini activation by a laser (via heat or photodisruption). For mize irritation to the incision site, the cap preferably has example, a laser could be used to create apertures in the walls rounded edges. The cap 8 is designed Such that it remains of the desired lumen and/or compartment when the particular outside the implantation site and, as such, the cap 8 is sized so substance is to be delivered. As such, release of each sub that it will not pass into the implantation site through the stance could be controlled upon demand by an intervention incision through which the device is inserted. alist. Preferably, when a laser is utilized to create such aper 0.132. As described herein, inclusion of a cap 8 in the tures, the wavelength and temperature are controlled to device can provide additional anchoring features to the device minimize any effects on the polymeric coating composition. itself. However, in some embodiments, it can be desirable to 0127. In preferred embodiments, the body member 2 can further secure the device to provide additional anchoring or befabricated in a way that further increases the surface area of securing features at the implantation site. Thus, when desired, the body member, preferably without increasing the overall the cap 8 can be further designed such that it can be easily dimensions of the device. For example, in one embodiment, Sutured or otherwise secured to the Surface Surrounding the the device can be fabricated of multiple strands of material incision and can, for example, contain one or more holes (not that are entwined or twisted around each other to form the shown) through which Sutures can pass. body member 2 (for example, multiple strands of wire can be I0133. The materials used to fabricate the cap 8 are not twisted around each other to form the body member). Accord particularly limited and include any of the materials previ ing to these particular embodiments, any number of indi ously described for fabrication of the body member 2. Pref vidual strands can be utilized to form the body member, for erably, the materials are insoluble in body fluids and tissues example, 2, 3, 4, or more strands. The number of individual with which the device comes in contact. Further, it is pre strands twisted to form the body member can be selected ferred that the cap 8 is fabricated of a material that does not depending upon Such factors as, for example, the desired cause irritation to the portion of the body that it contacts (such diameter of the material forming the body member and/or the as the area at and Surrounding the incision site). For example, overall body member diameter, the desired flexibility or rigid when the device is implanted into the eye, the cap 8 is pref ity of the device during insertion and/or implantation, the size erably fabricated from a material that does not cause irritation of the implantation, the desired incision size, the material to the portion of the eye that it contacts. As such, preferred used to form the body member, and the like. materials for this particular embodiment include, by way of 0128. As shown in FIG. 1, the body member 2 is prefer example, various polymers (such as silicone elastomers and ably cylindrical in shape, with a circular cross-section. How rubbers, polyolefins, polyurethanes, acrylates, polycarbon ever, the cross-sectional shape of the body member 2 is not ates, polyamides, polyimides, polyesters, polysulfones, and limited and, for example, can alternatively have square, rect the like), as well as metals (such as those described previously angular, octagonal or other desired cross-sectional shapes. for the body member). 0129. As shown in FIGS. 1 and 3, a preferred embodiment I0134. In some embodiments, the cap 8 can be fabricated can include a cap 8 positioned at the proximal end 4 of the from the same material as the body member 2. Alternatively, body member 2. When included in the device, the cap 8 can the cap 8 can be fabricated from a material that is different assist in stabilizing the device once implanted in the body, from the body member 2. The cap 8 can be fabricated sepa thereby providing additional anchoring features of the device. rately from the body member 2, and subsequently attached to Preferably, the device is inserted into the body through an the body member 2, using any suitable attachment mecha incision until the cap 8 abuts the incision on the exterior of the nism (such as, for example, Suitable adhesives or Soldering body. If desired, the cap 8 can then be sutured to the body at materials). For example, the cap 8 can be fabricated to include the incision site to further stabilize and prevent the device an aperture, into which the body member 2 is placed and from moving once it is implanted in its desired location. thereafter soldered, welded, or otherwise attached. In alter When the device is implanted in the eye, for example, the native embodiments, the cap 8 and body member 2 are fab device can be inserted into the eye through an incision until ricated as a unitary piece, for example, utilizing a mold that the cap 8 abuts the incision. If desired, the cap 8 can then be includes both components (the body member 2 and cap 8) of sutured to the eye, to provide further stabilization as dis the device. The precise method of fabricating the device can cussed above. be chosen depending upon Such factors as availability of 0130. The overall size and shape of the cap 8 is not par materials and equipment for forming the components of the ticularly limited, provided that irritation to the body at the device. incision site is limited. Preferably, the cap 8 is sized such that I0135) In some aspects, and particularly when the body it provides a low profile. For example, the dimensions of the member is fabricated of a biodegradable material, the cap can cap 8 are preferably selected to provide a small surface area to be fabricated of a nondegradable material or a material that accomplish Such desired features as additional anchoring degrades more slowly than the degradable material forming US 2011/O 159073 A1 Jun. 30, 2011

the body member. This can be desirable, for example, to in FIG. 3. According to this embodiment, the sharp tip 10 can maintain the features provided by the cap (such as anchoring be utilized to pierce the body and thereby create the incision features) for a period of time at least as long as the time the site and access to the implantation site. In this case, no con body member retains some structural integrity at the implan junctival Surgery or extraneous alignment device is necessary. tation site. This can reduce risk of a significant intact portion 0.141. In further embodiments, the conjunctival tissue can of the body member breaking off the cap and losing an be dissected to expose a portion of the pars plana region, and anchoring point at the implantation site. a needle Stick can be made into the Sclera in the exposed 0136. In some embodiments, the cap 8 can be provided region. A self-starting coil that includes a sharp tip is then with a polymeric coating. According to these particular inserted through the pars plana at the site of the needle Stick, embodiments, the polymeric coating provided in connection and the coil is rotated through the sclera until the cap of the with the cap 8 can be the same as, or different from, the device abuts the sclera. In some preferred embodiments, the polymeric coating provided in connection with the body needle stick is smaller than the diameter of the body member member 2. For example, the particular bioactive agent of the implantable device (for example, a 30-gauge needle included in the polymeric coating for the cap 8 can be varied Stick can be used with an implantable device having a body to provide a desired therapeutic effect at the incision site. member with a diameter of 0.5 mm or less). The conjunctival Exemplary bioactive agents that could be desirable at the tissue is then pulled over the cap, to provide a flap or “seal incision site include antimicrobial agents, anti-inflammatory over the device, thus minimizing irritation of the implantation agents, and the like, to reduce or otherwise control reaction of site, foreign body sensation, and the like. Optionally, the the body at the incision site. It will be readily apparent upon conjunctival tissue can be further secured by a single suture. review of this disclosure that the first polymer and second In some embodiments the suture is biodegradable. polymer can also be selected for the polymeric coating com 0142. In some embodiments, it can be preferable to create position provided in connection with the cap 8, to provide a an incision site that is slightly larger than the dimensions of desired polymeric coating specific for the cap, when desired. the proximal portion of the body member. For example, when 0.137 In some embodiments, the cap 8 can include a poly the device includes a cap 8 and is implanted into the eye, it can meric coating that is the same as the polymer coating pro be preferable to create an incision that is larger than the largest vided in connection with the body member 2. According to diameter of the cap 8, such that the cap sits below the outer these embodiments, the polymeric coating can be applied in Surface of the Sclera. For example, a partial incision in the one step to the entire controlled delivery device (body mem Sclera can be made to create a Scleral flap. Once the device has ber and cap), if desired. Alternatively, the polymeric coating been implanted, and the cap 8 is placed so that it abuts the can be applied to the cap 8 in a separate step, for example, incision site, the scleral flap can be folded back over the when the cap 8 is manufactured separately, and Subsequently device, thus providing a covering over the cap. Alternatively, attached to the body member 2. when the proximal end of the body member does not include 0138 For intraocular delivery of one or more bioactive a cap 8, a flap-like cover can still be utilized to cover the agents, the following procedure may be used. A sclerotomy proximal end of the device, in accordance with the descrip can be created for insertion of the device into the posterior tion above. Preferably, these embodiments minimize the con portion of the eye. Conventional techniques can be used for tact of the proximal end (for example, the cap 8) of the device the creation of the sclerotomy. As shown in FIG. 5, such with other body tissues, thereby reducing Such risks as irrita techniques include the dissection of the conjunctiva 32 and tion of body tissues, and/or translation of movement of the the creation of pars plana Scleral incisions through the Sclera eye to the device, thereby potentially damaging eye tissues. 28. The dissection of the conjunctiva 32 typically involves This can provide one or more advantages, such as reduced pulling back the conjunctiva 32 about the eye so as to expose tendency for movement of the eye to be translated to the large areas of the Sclera 28, and the clipping or securing of the controlled delivery device, since the proximal end of the conjunctiva 32 in that pulled back State (the normal position device will not be sitting at the surface of the eye and thus in of the conjunctiva is shown in phantom). In other words, the contact with other body tissues; and reduced irritation of Sclera 28 is exposed only in the areas where the pars plana Surrounding tissues. Scleral incisions are to be made. Surgical instruments used in 0143. The body member 2 is then inserted into the eye. For the procedure are then passed through these incisions. Thus, example, in embodiments wherein the body member 2 has a the incisions should be made large enough to accommodate coil shape, the body member 2 is inserted into the eye by the instruments required for the procedure. rotating or twisting the body member 2 into the eye until the 0.139. Alternatively, the creation of the sclerotomy can be cap 8 abuts the outer surface of the eye. In embodiments accomplished by use of an alignment device and method, wherein the body member 2 is fabricated of a shape memory such as that described in U.S. patent application Ser. No. material, the shape memory material is first cooled to a tem 09/523,767, that enables sutureless surgical methods and perature at which the martensite phase is stable and the device devices thereof. In particular, Such methods and devices do is deformed, for example, into a linear shape. The device is not require the use of Sutures to seal the openings through then inserted into the eye. To return the device to its memory which instruments are inserted. The alignment devices are shape, the device is left unrestrained and is simply allowed to inserted through the conjunctiva and Sclera to form one or reach a temperature (for example, by heating the device) more entry apertures. Preferably, the alignment devices are above the martensite phase temperature. For example, the metal or polyimide cannulas through which the Surgical shape memory material can be heated by a laser to return the instruments used in the procedure are inserted into the eye. device to a temperature above the martensite phase tempera 0140. In further embodiments, the device can be ture. The shape memory material can also be selected Such implanted directly through a self-starting transconjunctival that the martensite phase temperature is below body tempera trans-scleral “needle stick. For example, the body member 2 ture so that the material is simply cooled to below body of the device can include a sharp tip 10, such as that illustrated temperature, deformed to a linear shape, and inserted into the US 2011/O 159073 A1 Jun. 30, 2011

eye. Then, as the material warms up within the eye to body the related discussion in U.S. Pat. No. 6,217,895. The capsule temperature, the device can return to its remembered shape. or other structure forming the solid or the sustained release As discussed herein, when laser application is utilized, con delivery device may be any suitable configuration, including ditions are preferably controlled to maintain such parameters cylindrical, rectangular, disk-shaped, patch-shaped, ovoid, as wavelength and temperature, to minimize adverse effect on Stellate, or spherical. It is desirable, however, to use a con the polymeric coated composition. figuration that does not tend to lead to migration from the 014.4 FIG. 5 illustrates a controlled delivery device Subretinal space so as to minimize the potential for migration according to one embodiment of the invention that is of the instilled bioactive agent from the targeted tissue site. implanted in the eye. When implanted into the eye, it is 0150. In some embodiments, sustained release delivery desirable to limit the length Lof controlled delivery devices to devices include, but are not limited to, flexible rods, thin prevent the controlled delivery device from entering the cen films, foldable discs, biodegradable polymer with one or tral visual field. If the device enters the central visual field, more bioactive agents embedded within, a bioactive agent this can result in blind spots in the patient's vision and can eluting polymer coating over a rigid scaffold, a compressed increase the risk of damage to the retinal tissue and lens pellet of one or more bioactive agents, or one or more bioac capsule. Thus, for example, when the controlled delivery tive agents encapsulated in a semi-permeable membrane. device is inserted at the pars plana (as shown in FIG. 5), the 0151. In some embodiments, the subretinal sustained distance from the implantation site on the pars plana to the delivery device is in the form of a biocompatible polymer central visual field is preferably less than about 1 cm. capsule. Biocompatible polymer capsules contemplated for 0145 Optionally, after the device is implanted into the use with the methods of the invention comprise: (a) a core eye, the cap 8 can then be sutured or otherwise secured to the which contains one or more bioactive agents, either Sus sclera to maintain the controlled delivery device in place. In pended in a liquid medium or immobilized within a biocom preferred embodiments, no further manipulation of the device patible matrix, and (b) a Surrounding jacket comprising a is required for delivery of one or more bioactive agents to the material that is biocompatible and permits diffusion of the interior of the eye. The conjunctiva can be adjusted to cover bioactive agent to the tissues proximal the Subretinal space. the cap 8 of the device, when desired, and the Surgical proce The core may comprise a biocompatible matrix of a hydrogel dure is completed. or other biocompatible matrix material that stabilizes the 0146 In other embodiments, when a lumen is included in position of the bioactive agent. The jacket may be manufac the device for delivery of one or more additional substances to tured from various polymers and polymer blends including, the interior of the eye, further steps can be included as fol for example, polyacrylates (including acrylic copolymers), lows. If a cover is used to close the port(s), it is removed at this polyvinylidenes, polyvinyl chloride copolymers, polyure time, and if used, a collar for providing a Snug fit about the thanes, polystyrenes, polyamides, cellulose , cellu injection mechanism (such as a Syringe) is provided. The lose nitrates, polysulfones (including polyether Sulfones), injection mechanism is then connected with the port(s) for polyphosphaZenes, polyacrylonitriles, poly(acrylonitrile/ injection of one or more substances to the controlled delivery covinyl chloride), as well as derivatives, copolymers, and device. If the port(s) are composed of a self-sealing material mixtures thereof. through which the needle of an injection mechanism can be 0152. In some embodiments, the subretinal sustained inserted and which seals off automatically when the injection delivery device comprises a polymer matrix containing one or mechanism is removed, the injection mechanism is simply more bioactive agents. Referring to FIG. 6, an embodiment of inserted through the port and the substance injected. Follow a sustained delivery device 50 is shown. Sustained delivery ing injection, the conjunctiva can be adjusted to cover the cap device 50 comprises polymer matrix 52 which is embedded 8 of the device, if desired. with one or more bioactive agents 54. Sustained delivery device 50 has proximal end 56 and distal end 58. In the Method B. Subretinal Instillation: embodiment of FIG. 6, distal end 58 is beveled to facilitate 0147 In some embodiments, the invention includes sub subretinal insertion. Alternatively, distal end 58 may be blunt, retinal instillation (e.g., injection or implantation) of one or rounded, tapered, pointed, or other desired shape. Proximal more bioactive agents in order to localize action of the bio end 56 may have the same end treatment as distal end 58 or it active agent(s) at the desired treatment site of the choroid may have a different end treatment. For example, in the and/or retina. The bioactive agent(s) that are delivered sub embodiment of FIG. 6, proximal end 56 is beveled and distal retinally or in the subretinal space may be provided in any of end 58 is blunt. Sustained delivery device 50 may have any a number of forms, for example, fluid Solutions, Solids, Sus desirable cross-sectional shape. For example, as shown in tained release formulations, and Sustained release delivery FIG. 6, the cross-sectional shape of sustained delivery device devices. is circular. Alternatively, the cross-sectional shape may be 0148 Representative examples of formulations for deliv triangular, Square, rectangular, pentagaonal, octagonal, oval, ery of the bioactive agent into the Subretinal space include, and the like. Sustained delivery device 50 may be linear, as but are not limited to, injectable hydrogels, cyclodextrin shown in FIG. 6, or may be non-linear. Examples of non “solubilized' and micronized solutions. linear shapes include curved (e.g., “C” or “S” shaped), Zig 0149. In embodiments where the bioactive agent(s) is ini Zag (e.g., “Z” shaped), spiral, circular, and the like. tially provided in the form of a solid, such solids may be in the 0153. In another embodiment, the device comprises a bio form of a capsule, pellet, rod, sheet, film, or hydrogel. Such compatible core material that is coated with a coating layer of Solids can be configured and arranged so as to comprise a a polymer matrix and one or more bioactive agents. Referring sustained release device for controllably releasing the bioac to FIGS. 7-7A, one embodiment of a device of the type that tive agent to the tissues of the eye over an extended period of has a core is shown. Device 70 includes core 72, having time. Examples of Sustained release devices are found, for proximal end 77 and distal end 79, and coating layer 74 example, in U.S. Pat. Nos. 5,378.475 and 5,773,019. See also comprising polymer matrix and one or more bioactive agents. US 2011/O 159073 A1 Jun. 30, 2011

In the embodiment of FIGS. 7-7A, the coating layer 74 of embodiments 100 um or less. Typically, the diameter (or polymer matrix and one or more bioactive agents is coated maximum cross-sectional dimension) ranges from about 200 over the entire length of core 72. The coating layer 74 um to about 500 Lum. includes proximal transition segment 76, distal transition seg 0158. In some embodiments, the length of the sustained ment 78, and centerportion80. In this embodiment, proximal release delivery device is about 5.0 mm or less, in other transition segment 76 and distal transition segment 78 have embodiments about 4.5 mm or less, in other embodiments been feathered (i.e., a sloped transition segment). about 4.0 mm or less, in other embodiments about 3.5 mm or 0154. In another embodiment, as shown in FIGS. 8-8A, less. In a specific embodiment, the device is about 3.0 mm or device 90 includes core 92, having proximal end 93 and distal less in length as Such lengths have been found to provide the end 95. A coating layer 94 of polymer matrix-bioactive mate additional benefit of coming to a resting point in the eye that rial is coated over a portion of the length “1” of core 92. does not cross multiple tissue layers. However, it is possible to resulting in coated portion 96 and uncoated portion 98. The provide devices longer than about 3.0 mm that can be inserted uncoated portion 98 may be useful to provide a handling with special care so as to minimize multiple tissue layer portion by which the device may be grasped or docked with a crossing. In other embodiments, the length of the device is 2.9 Surgical instrument (e.g. by microSurgical instruments) to mm or less, in other embodiments about 2.8 mm or less, in prevent any potential damage to the coating layer 94 upon other embodiments about 2.7 mm or less, in other embodi handling. In one embodiment, the uncoated portion 98 of the ments about 2.6 mm or less, in other embodiments about 2.5 device 90 could be left periretinal for easy retrieval in follow mm or less, in other embodiments about 2.4 mm or less, in up surgery. In the embodiment of FIGS. 8-8A, proximal tran other embodiments about 2.3 mm or less, in other embodi sition segment 100 and distal transition segment 102 of ments about 2.2 mm or less, in other embodiments about 2.1 coated portion 96 have been feathered (i.e., a sloped transition mm or less, in other embodiments about 2.0 mm or less. In segment). Without being bound by theory, it is believed that Some embodiments, the length of the device ranges from feathering the distal and proximal ends of the device may about 2.0 to about 3.0 mm. enhance the uniformity, processing reproducibility, and ease 0159. As the device becomes smaller in diameter (or maxi of implantation. mum cross-sectional dimension) or in length, the insertion 0155 The cross-sectional shape of the core may be any and handling of the device may become more difficult and the desired shape, but is typically circular. The diameter of the amount of bioactive agent contained in the device will typi core (or maximum cross-sectional dimension, if not circular) cally be reduced. Such factors may be taken into account is typically less than about 200 um, in some embodiments when determining the diameter and/or length of the device. ranging from about 10 um to about 200 um. The size, geom 0160 The core may be a polymer matrix material as etry and materials used informing the core may be selected to described herein or may be a non-polymer based material. provide desired characteristics to the device. For example, the Representative examples of non-polymer based materials material forming the core and the diameter (or maximum include titanium-nickel alloy wire (e.g., Nitinol wire, com cross-sectional dimension) of the core may be selected to mercially available from Nitinol Devices and Components, provide the desired rigidity and flexibility to the device. For Freemont Calif.), titanium alloys, nickel-cobalt base alloys, example, a thin (i.e., Small diameter) core material may be stainless steel, cobalt-chromium alloys, and biodegradable used if a less rigid device is desired. Thin core materials also magnesium alloys. It is to be understood that the core material allow for thicker coating layers, thereby maximizing the Vol is not limited to the examples provided herein and can be any ume of bioactive agent(s) that may be contained in the device. conventional material used in implant devices. In some The core material may also be selected to facilitate the ability embodiments, the core comprises titanium-nickel wire. In of the polymer layer to adhere as a coating. For example, the one embodiment, the core is titanium-nickel wire having a Surface of the core material may be primed, roughened, or diameter of about 80 um (or the smallest commercially avail chemically modified to facilitate adhesion of the polymer able diameter), in order to maximize the volume of bioactive layer to the core material. agent in the device. 0156. In some embodiments, the subretinal sustained 0.161 Subretinal sustained release delivery devices may delivery device (with or without the core material) may fur be prepared by the steps of: (a) dissolving one or more poly ther include a layer of material that modifies the bioactive mers in a solvent to form a complex fluid; (b) adding one or agent release rate characteristics. For example, a thin layer of more bioactive agents to the complex fluid to produce a polycaprolactone can be coated on the device. Such a poly homogeneous solution of the one or more bioactive agents caprolactone layer can also provide a degradation rate-con and/or a solution with a dispersed phase of one or more trolling barrier, protection of the bioactive agent from envi bioactive agents; (c) optionally drying the complex fluid to a ronmental degradation prior to implantation, or even delay Solid form; (d) optionally heating the solid form to a tempera the time point of release of the drug. ture just below the melting point of the polymer(s); and (e) 0157. In some embodiments, the outer diameter (or maxi forming the device out of the solution of (b) or the solid form mum cross-sectional dimension) of the Sustained release of (c). delivery device is no greater than about 1000 um in order to 0162. In some embodiments, the method comprises a low minimize retinal detachments and hemorrhaging. In other temperature process (e.g., from about 20°C. to about 100°C., embodiments, the outer diameter (or maximum cross-sec more preferably from about 50° C. to about 90° C.). In one tional dimension) of the device is 900 um or less, in other embodiment, the method comprises a process that involves embodiments 800 um or less, in other embodiments 700 um homogenously mixing the polymer and one or more bioactive or less, in other embodiments 600 um or less, in other embodi agents in solvent, drying, and melt-extrusion-drawing the ments 500 um or less, in other embodiments 400 um or less, prepared solid-form into the device shape. More specifically, in other embodiments 300 um or less, in other embodiments the method comprises: dissolving one or more polymers in a 200 um or less, in other embodiments 100 um or less, in other Suitable solvent solution to produce a complex fluid; adding US 2011/O 159073 A1 Jun. 30, 2011

one or more bioactive agents to the complex fluid to produce Ser. No. 1 1/102,465, filed Apr. 8, 2005, and entitled “Medical a homogeneous solution of one or more bioactive agents Devices and Methods for Producing Same.” and/or a solution with a dispersed phase of one or more 0167. In some embodiments, a core (e.g., a TiNi wire) to bioactive agents; drying the solution to a solid form; heating be coated is mounted in a pin Vise, or other device that is the solid form to a temperature below the melting point of the capable of rotating the core about its longitudinal axis. The polymer (e.g., about 1° C. to about 5° C. below the melting pin vice is rotated and an ultrasonic spray head is passed back point); forming the device out of this semi Solid; and shaping and forth relative to the rotating core. Ultrasonic coating the filament into the desired shape by drawing it into a lengthy systems can produce a spray stream that narrows down as it filament and mechanically sectioning it into a fixed length. moves away from the coating head. Referring now to FIG.9. Bending the device can add curvature. In other embodiments spray stream 120 narrows as it travels away from the coating the complex fluid is not dried to a solid form. In these embodi head 122 before passing through a focal point 124 (or point of ments, heating may not be required during the forming step Smallest spray stream diameter) before starting to expand. In an embodiment, the focal point has a cross-sectional diameter because of the presence of the solvent in the complex fluid. of about 0.5 mm to about 1.0 mm. In contrast, other types of 0163 The steps of forming the subretinal sustained release spray systems frequently produce a spray stream that continu delivery device and shaping the filament into the desired ously expands in diameter as the stream leaves the spray head. shape can be accomplished by a variety of conventional meth For example, referring now to FIG. 10, the spray stream 130 ods for forming and shaping a device out of a solid. For continues to get wideras it travels away from the coating head example, the Solid form may be processed by melt-extrusion 132. drawing (applying tensile force) to form the Solid into the 0168 Ultrasonic coating systems may be used to coat a desired shape and thickness. The length can be modified by core with a large degree of accuracy, particularly where the cutting the device with any conventional cutting tool. The core to be coated is positioned at or near the focal point of the distal and/or proximal ends of the device can be shaped by spray stream. This is because the spray stream has a relatively cutting, Sanding, and other methods for forming tapered, Small cross-sectional area at or near the focal point because rounded, beveled and other desired end shapes. the spray stream has a relatively small amount of spray drop 0164 Referring to FIG. 20 a schematic depiction of an lets that are outside of the focal point. As the spray stream has embodiment of a Sustained release delivery device prepara a relatively small cross-sectional area, the position of the tion process 400 is shown. As depicted in the figure, the spray stream with respect to the core must be moved if a device may be fabricated by: solubilizing polycaprolactone broader area of the core is to be coated with a coating layer. 401 in a solvent 403 at a temperature below boiling under still Either the core or the spray head may be moved in order to or continuous stirring conditions; adding one or more bioac coat a broader area. tive agents 405 to the solution in a ratio that preferably ranges 0169. In an embodiment, the ultrasonic spray head is from 1:99 to 70:30 (weight bioactive agent: weight polymer) moved back and forth over the rotating core in a grid-like (step 402); allowing the solvent 403 to evaporate under still or pattern. By way of example, an exemplary grid-like pattern stirring conditions after the solution becomes translucent or 140 is shown in FIG. 11. The grid-like pattern starts at point dispersed (step 404); transferring the solid-form of the loaded 143 and ends at point 145. The grid-like pattern has a series of polymer 407 to an extrusion device 409 (step 406); heating transverse Sweeps 142 and longitudinal movements 144. the extrusion device 409 to about 50° C. to about 90° C., Depending upon the length of the longitudinal movements depending on the molecular weight of the polycaprolactone 144, any number of transverse Sweeps can be used to cover the (M3,000 to 120,000), such that the polymer temperature length of a given coating layer. In embodiments of the inven approaches the melt temperature (but does not exceed it); tion, the grid-like pattern 140 includes between 3 and 100 drawing the solid-form of the loaded polymer 407 to its transverse sweeps 142. In embodiments of the invention, the desired geometry once the extrusion device reaches the grid-like pattern 140 includes between 3 and 100 longitudinal desired sub melt temperature (step 408); and shaping the movements 144. The desired length of the longitudinal move resulting device 411 to the desired implantation length (“1”) ments will depend upon a number of factors including the and shape after the temperature of the drawn implant falls diameter of the spray pattern and the relative spray density of (step 410). various parts of the spray pattern. 0165. In embodiments where the device includes a core, 0170 Referring now to FIG. 12, grid-like pattern 140 is the device may be fabricated by applying a coating composi Superimposed over an exemplary core material 146 having tion comprising one or more polymers and one or more bio distal end 147 and proximal end 149 to illustrate how core active agents over at least a portion of the outer Surface of the material 146 would be coated with reference to the grid-like core. The coating composition can be applied to the outer pattern 140. Surface of the core using any suitable method. For example, 0171 In some embodiments, the ultrasonic coating head the coating composition may be applied by dipping, spraying, follows the grid-pattern multiple times (that is, multiple and other known methods for applying coating compositions passes) in order to deposita coating layer onto a core. On each to substrates. The suitability of the coating composition for pass, an amount of the coating layer is deposited. Thus, the use on a particular material can be evaluated by those skilled precise number of passes made by the ultrasonic coating head in the art. can be varied depending upon the total coating thickness 0166 In some embodiments, the coating composition is desired. In some embodiments, the mass of the coating layer applied to the core utilizing a precision coating system comprises between about 10 ug and about 1000 ug dry wherein the coating material is atomized ultrasonically (an weight. In other embodiments, the mass of the coating layer ultrasonic coating system). Exemplary ultrasonic coating comprises between about 50 ug to about 300 ug dry weight. systems and methods are described in U.S. Published Appli 0172. In some embodiments, the same longitudinal start cation 2004/0062875 (Chappa et al.) and in U.S. application ing position is used with respect to the core for each pass of US 2011/O 159073 A1 Jun. 30, 2011

the ultrasonic coating head. For example, for each pass, the can be applied to the core under conditions of increased or ultrasonic coating head would start at the same longitudinal decreased relative humidity as compared to ambient humid point and follow the same pattern. In other embodiments, the ity. longitudinal starting position of the ultrasonic coating head 0176 According to the invention, humidity can be con may change with each additional pass. Referring to FIG. 13, trolled in any suitable manner, including at the time of pre the first transverse Sweep of the first pass may start at point paring and/or applying the coating composition to the body 150. Then, the first transverse sweep of the second pass may member. For example, when humidity is controlled at the start at an offset position 152 that is offset at a distance 151 time of preparing the coating composition, the water content from starting point 150. Similarly, the first transverse sweep of the coating composition can be adjusted, before and/or of the third pass and fourth pass begin at points 154 and 156, after the coating composition is applied to the body member. respectively. This technique of moving the starting position in When humidity is controlled at the time of applying the the direction of arrow 158 can be used to extend the distance coating composition, the coating composition can be applied over which the coating builds up to its full thickness thereby to the body member in a confined chamber or area adapted to controlling the slope of the transition segment of the coating provide a relative humidity that differs from ambient humid layer. By way of example, the offset distance between suc ity. Generally, it has been found that applying coating com cessive passes could be 0.5 mm. This would generally result positions under conditions of increased humidity will typi in a longer transition segment with a lower slope in compari cally accelerate release of the bioactive agent, while applying son with a coating layer that was applied with an offset coating compositions under conditions of decreasing humid between Successive passes of less than 0.5 mm, for example ity levels will tend to decelerate release of the bioactive agent. 0.2 mm. The slope of the transition segment may be desirably As contemplated in the invention, even ambient humidity can low (e.g., less than about 1.0) when the device will undergo be considered “controlled humidity if it has been correlated stresses (for example, frictional stresses) that may result in with and determined to provide a corresponding controlled delamination or failure of the coating. The slope of the tran release of the bioactive agent. sition segment may be desirably high (e.g., greater than about 0177. The bioactive agent to be administered may be con 1.0) where it is desired to maximize the amount of the coating centrated to minimize the volume to be administered subreti layer on the device. The proximal and distal transition seg nally or into the subretinal space. After the liquid and the ments of the coating layer may have slopes that are the same bioactive agent is administered or instilled subretinally, the or different. For example, in some embodiments, the distal Surrounding tissues absorb the liquid and the bioactive agent transition segment has a slope that is less than the proximal resides Subretinally (e.g., as a solid) and diffuses or otherwise transition segment. is absorbed by the surrounding tissues of the eye over time. In 0173. In some embodiments, the coating comprises at this way, the methods of the invention provide a localized least two layers, wherein each layer comprises the same com subretinal deposit of the bioactive agent within the eye. In position, or a different composition. In one such embodiment, addition, the action of the deposit or depot of the bioactive a first layer having either bioactive agent alone, or bioactive agent also is localized at the retina and the choroid. agent together with one or more of the biodegradable poly 0.178 The bioactive agent may include a pharmaceutically mers is applied, after which one or more additional layers are acceptable carrier or excipient and/or one or more accessory applied, each with or without one or more bioactive agents. molecules which may be suitable for diagnostic or therapeu These different layers, in turn, can cooperate in the resultant tic use in vitro or in vivo. The term “pharmaceutically accept composite coating to provide an overall release profile having able carrier as used herein encompasses any of the standard certain desired characteristics, and is particularly preferred pharmaceutical carriers, such as a phosphate buffered for use with bioactive agents having high molecular weight. Solution, water, and emulsions, such as an oil/water or water/ According to the invention, the composition of individual oil emulsion, and various types of wetting agents. The bioac layers of the coating can include any one or more of the tive agent may also include Stabilizers and preservatives. For following: one or more bioactive agents, and/or a biodegrad examples of carriers, stabilizers and adjuvants, see Martin able polymer, as desired. Remington's Pharm. Sci., 15th Ed. (Mack Publ. Co., Easton 0.174 Preferably, the coating composition is applied to the (1975)). core of the device in one or more applications. The method of 0.179 For subretinal instillation of one or more bioactive applying the coating composition to the body member is agent(s), the following procedure may be used. With refer typically governed by Such factors as the geometry of the ence to FIG. 14, the step of instilling the bioactive agent(s) device and other process considerations. The coated compo (Step 200) includes forming a limited or localized retinal sition can be subsequently dried by evaporation of the Sol detachment (e.g., a bleb detachment) using any of a number vent. The drying process can be performed at any Suitable of devices and/or techniques known to those skilled in the art temperature, (for example, room temperature or elevated (Step 202), thereby defining or forming a subretinal space and temperature), and optionally with the assistance of vacuum. instilling (i.e., injecting or implanting) bioactive agent(s) into 0.175. In some embodiments, the coating composition is the subretinal space formed by the retinal detachment (Step applied to the core under conditions of controlled relative 204). The limited or local subretinal detachment is created in humidity. As used herein, “relative humidity” is the ratio of Such a fashion that the detachment itself generally does not the water vapor pressure (or water vapor content) to the Satu have an appreciable or noticeable long-term effect on the ration vapor pressure (or the maximum vapor content) at a vision of the patient. In more particular embodiments, the given temperature of the air. The saturation vapor pressure in bioactive agentis instilled Subretinally or in a Subretinal space the air varies with air temperature: the higher the temperature, that is proximal to a given site or locus of particular tissues of the more water vapor it can hold. When saturated, the relative the eye that require Such treatment or are an appropriate humidity in the air is 100% relative humidity. According to pathway for effective delivery of the bioactive agent to tissues Some embodiments of the invention, the coating composition requiring treatment or prevention of the disease or disorder. In US 2011/O 159073 A1 Jun. 30, 2011

this way, the action of the bioactive agent is localized at the the opening in the Sclera with Sutures to prevent leaking of the choroid and the retina and also minimizes the drug action at aqueous humor because as indicated above Such an opening other tissue. or wound in the Sclera is self-sealing. In addition, with the 0180 Methods of the invention bypass the mechanisms or transconjunctical approach, the Surgeon does not have to deal barriers that may limit the effective delivery of bioactive with reattaching the dissected conjunctiva. Thus, further sim agents when injected only directly into the vitreous, thereby plifying the Surgical procedure as well as reducing if not permitting more Sustained therapy to the target tissue. Locat eliminating the Suturing required under the Surgical proce ing the bioactive agent Subretinally also minimizes the loss or dure. removal of the bioactive agent from the eye Such as expiration 0185. After the insertable portion of the instrument is of the bioactive agent via the anterior segment of the eye after inserted into the eye, the operable end thereof is localized to being initially located or injected in the vitreous. Subretinal the targeted site (Step 304) including the tissues that are being locating of the bioactive agent minimizes the need for follow targeted for treatment. As is known to those skilled in the art, up injections, as typically needed with injections into the Surgical personnel typically mount a lens assembly (not vitreous in order to maintain an adequate therapeutic concen shown) onto the cornea of the eye in accordance with known tration within the vitreous as well as minimizing the risks and accepted practices and techniques. This lens assembly is attendant with such injections to the vitreous. Further, provided so that the surgeon can view the interior of the eye as because the bioactive agent is delivered directly to the sub well as any instruments inserted therein. In addition, a light retinal space, it follows that higher concentrations of the transmitting apparatus as is known in the art also is inserted bioactive agent is delivered to the choroidal vessels and reti into the vitreous So as to be capable of providing a source of nal pigment epithelial cells as compared to intravitreal injec light therein for the Surgeon. Accordingly, the Surgeon would tion and intraocular implants that introduce drugs into the determine the positioning of the operable end of the instru vitreous humor. ment by viewing the interior of the eye using the lens assem 0181. Now referring to FIG. 15, there is shown a flow bly and being illuminated by the light transmitting apparatus. diagram of an eye treatment methodology according to one 0186. After localizing the operable end of the instrument embodiment of the invention, which methodology includes to the target site, for example the Surface of the retina proxi inserting a delivery device or delivery instrument into the eye mal the target site, the Surgeon forms the limited retinal to be treated (Step 302). The instrument being inserted can be detachment (Step 306). In an illustrative exemplary embodi any of a number of instruments known to those skilled in the ment, the Surgeon forms the limited retinal detachment by art that can be used to form a retinal detachment. More par injecting a fluid, such as liquid or gas, from the instrument’s ticularly, the instrument is configured and arranged so as to be operable end. More specifically, the fluid is injected from the capable of forming a limited or localized retinal detachment instrument's operable end in Such a manner that the injected and to minimize the area of the retinal detachment such that fluid is disposed between the retina and the choroid thereby there is no long-term apparent loss in visual acuity. causing the retina to detach therefrom. In more specific 0182. In some embodiments, the step of inserting (Step embodiments, the instrument's operable end is positioned 302) includes inserting a portion of the delivery instrument or such that the stream of fluid flowing from the operable end of device, such as the exemplary delivery device illustrated in the instrument is directed towards the targeted site of the U.S. Patent Application No. 2004/0133155 (Varner et al.), retina and the stream of fluid pierces the retina and flows into the eye in a minimally invasive manner. This methodol beneath the retina. ogy also yields a technique that can be implemented in an 0187. Referring to FIG. 16, the sharp distal end 18 of the outpatient clinic setting. According to this embodiment, a piercing member 12' is localized to a desired location on the delivery instrument or device is provided, a portion of which surface of the conjunctiva or the sclera 104" of the eye 100'. A is configured and arranged Such that when the instrument is pressure or force is applied to the device 10' such that the inserted into the eye, the opening formed in the Sclera to sharp distal end 18 of the piercing member 12 penetrates the receive the instrument is Small enough so as to not require sclera 104 of the eye 100" or both the conjunctiva and sclera Sutures to seal or close the opening in the Sclera. In other of the eye and the distal end is within the vitreous humor 102 words, the opening is Small enough that the wound or opening of the eye 100'. This also thus creates a continuous passage is self-sealing, thereby preventing the aqueous humor from way (not shown) between the device 10' and the vitreous leaking out of the eye. humor 102 of the eye 100" providing a pathway for the sur 0183 In addition, the step of inserting further includes geon to gains access to the vitreous humor. inserting the insertable portion of the delivery instrument or 0188 The piercing member 12" also has a length such that device transconjunctivally so the operable end thereof is once its proximal end 16' is in contact with a portion of the within the vitreous. In this regard, transconjunctival shall be outer periphery of the sclera or the conjunctiva of the eye, the understood to mean that the instrument's operable end is distal end 18 of the piercing member is within the vitreous inserted through both the conjunctiva and through the Sclera humor 102 of the eye 100'. Once inserted the piercing mem into the vitreous. More particularly, inserting the insertable ber 12" can be angled by gently tilting or manipulating any portion that forms an opening in the Sclera and the conjunctiva portion of the device that lies outside of the eye 100'. In this that is Small enough so as to not require Sutures or the like to way, the device 10" can be localized to multiple target sites seal or close the opening in the Sclera. In conventional Surgi within the eye without necessitating multiple, separate inser cal techniques for the posterior segment of the eye, the con tions of the device into the eye. junctiva is routinely dissected to expose the Sclera, whereas 0189 Once a passageway into the eye 100' is thus created, according to the methodology of this embodiment, the con the cannula 44' and attached tubing 32", is advanced into and junctiva need not be dissected nor pulled back. through the device 10' and localized to a treatment/target site. 0184 Consequently, when the instrument is removed from As illustrated in FIG. 17, the target site is the retina 110' of the the eye (step 310), the surgeon does not have to seal or close eye 100'. The cannula 44' is guided through the device 10' US 2011/O 159073 A1 Jun. 30, 2011

until a distal portion 46 of the cannula emerges from the the Sclera Small enough so as to be self sealing, Suturing may guiding member 12, and into the vitreous humor 102 and the not be required and for the transconjunctival technique, re cannula is further advanced within the eye 100' until the distal attachment of the conjunctiva should not be required. portion 46' of the cannula enters the retina 110'. (0194 Referring now to FIG. 19, there is shown a flow (0190. An operator of the device 10' is able to determine diagram of an eye treatment methodology according to yet that the distal portion 46 of the cannula 44 has entered, but another embodiment of the invention, which methodology not traveled completely through, the retina 48' by virtue of includes inserting a device or instrument into the eye to be techniques generally known in the art. For example, once an treated (Step 352). The instrument being inserted can be any operator estimates that the distal portion 46' of the cannula is of a number of instruments known to those skilled in the art approaching the retina, S/he can inject an agent through the that can be used to pierce the tissues of the retina and forman cannula 44'. In order to simplify this estimation, the cannula opening or aperture therein so as to provide access to the area 44' can include one or more markings that serve as visual or region between the retina and choroids. In a particular and/or tactile indicators of the relative position of the cannula illustrative embodiment of the invention, the opening or with respect to the retina. If, following this injection, the through aperture is formed by a small gauge needle that is formation of a retinal detachment is observed, the operator disposed within the vitreous and manipulated by the Surgeon can safely deduce that the distal portion 46' of the cannula 44 So as to pierce the tissues of the retina. For example, a Surgeon has entered, and still remains within, the retina 110' and can can use micro-forceps as is known to those skilled in the art halt the distal advancement of the cannula. that the Surgeon would use to grip and manipulate the needle. (0191 Referring now to FIG. 15, after forming the local 0.195 As previously described, the inserted instrument is ized or limited retinal detachment (e.g., a bleb detachment), localized to the targeted site (Step 354) that includes the the bioactive agent is instilled (i.e., injected or implanted) in tissues that are being targeted for treatment. As is known to the subretinal spaced defined by the limited retinal detach those skilled in the art, Surgical personnel typically mount a ment (Step 308). In the case, where the bioactive agent is in a lens assembly (not shown) onto the cornea of the eye in liquid form or formulation, the instrument forming the retinal accordance with known and accepted practices and tech detachment can be used to inject the bioactive agent into the niques. This lens assembly is provided so that the Surgeon can retinal detachment. Alternatively, a fluid including the bioac view the interior of the eye as well as any instruments inserted tive agent can be used to form the retinal detachment and therein. In addition, a light-transmitting apparatus as is thereby simultaneously form the detachment and inject the known in the art also is inserted into the vitreous so as to be bioactive agent. Thus, the forming of the detachment (Step capable of providing a source of light therein for the surgeon. 308) and the injection of the bioactive agent (step 310) are Accordingly, the Surgeon would determine the positioning of performed essentially simultaneously, thereby further simpli the operable end of the instrument by viewing the interior of fying the procedure or process. the eye using the lens assembly and being illuminated by the (0192 Referring now to FIG. 18, in the case where the light transmitting apparatus. bioactive agent is in a solid or implantable form or formula 0196. After localizing the operable end of the instrument tion, the operable end 902 of the instrument may be further to the tissues of the retina proximal the target site, the Surgeon configured and arranged so to include a cannula 904 or lumen. manipulates the instrument to penetrate or pierce the tissues The bioactive agent in its implantable form 910 such as a of the retina as herein described (Step 356). As indicated capsule, rod or sheet is disposed in the cannula or lumen prior hereinabove, this action preferably creates or forms an open to it being deployed there from subretinally. Thus, after form ing or through aperture in the retina of Small diameter that ing the limited retinal detachment, the Surgeon or medical provides access the area or region between the retina and the personnel manipulates the instrument so that the bioactive choroids. Preferably the opening or through aperture created agent in its implanted form 910 is dispensed from the end of or formed by Such action generally does not have an appre the cannula 904 in the instrument's operable end 902 into the ciable or noticeable long-term effect on the vision of the subretinal space formed by the limited retinal detachment. person. Alternatively, the Surgeon or medical personnel can manipu 0.197 After forming the opening or aperture (Step 356), late the implantable form of the bioactive agent so as to insert the Surgeon then manipulates the form the bioactive agent is the bioactive agent at the same time as forming the retinal in so that the form of the bioactive agent is passed through the detachment. Such dispensing can be accomplished by opening in the tissues of the retina and slide between the mechanical action on the implantable form of the drug (e.g., tissues of the choroid and the retina. In more particular a rod acting on the capsule form of the drug) or by fluid or embodiments, the bioactive agent is provided in the form of a hydraulic action on the implantable form. sustained release device or other delivery device and the 0193 After completing such injection or implanting, the sustained release device or delivery device is manipulated by instrument is removed from the eye (Step 310). Prior to seal the Surgeon so as it passes through the opening or aperture in ing or closing the opening formed in the eye, one or more the tissues of the retina and so it is slide subretinally between bioactive agent(s) may be injected into the vitreous humor the tissues of the retina and the choroids (Step 358). After using a small gauge needle and Syringe (Step 312). Such completion of the instilling of the bioactive agent(s), the bioactive agent(s) may be the same as the bioactive agents Surgeon removes the Surgical instruments from the vitreous instilled subretinally or may be different than such bioactive (Step 360). Optionally, the surgeon may inject one or more agent(s). Following this, in the case where an incision was bioactive agents into the vitreous humor using a small gauge made in the sclera to insert the instrument, sutures would be needle and Syringe (Step 362). Such bioactive agent(s) may used to close the incision. In addition, if the particular tech be the same as or different from the bioactive agent(s) nique also involved dissection of the conjunctiva, the con instilled subretinally. As indicated herein, the process of junctiva would be re-attached to the eye. As indicated herein, inserting the instruments into the vitreous and removal pref if the technique used to form the opening yields an opening in erably are accomplished using techniques whereby an open US 2011/0159073 A1 Jun. 30, 2011 ing(s) formed in the sclera for admission of the instruments treatment, the type of bioactive agent(s) being injected, the into the vitreous is self-sealing. In addition, the technique concentration of the bioactive agent(s), disease state, location used for inserting the instruments into the vitreous also is of disease and affected tissue. Typically the volume of the more particularly a transconjunctival technique whereby the injection will be up to about 500 ul, more typically from instruments are inserted through both of the conjunctiva and about 50 uL to 500 ul. Additional details regarding intravit the sclera. real injections can be found, for example, in Lloyd P. Aiello, 0198 In further embodiments, the bioactive agent is MD et al., Evolving Guidelines For Intravitreous Injections, inserted or implanted through the retinal tissues semi-perma The Journal of Retinal and Vitreous Diseases, Vol. 24, No. 5 nently or temporarily. Thus, in such further embodiments the (2004). methodology further includes inserting a withdrawal instru 0201 The methodologies of the invention are contem ment (e.g., micro-forceps) into the vitreous following plated as being practiced alone, or in combination with other completion of the treatment phase and localizing the operable therapies or treatments. For example, where laser treatment of end of the withdrawal instrument proximal the target site. an eye is indicated, the method of the invention can be prac more particularly proximal the tissues containing the device. ticed before and/or after the laser treatment. Thereafter, the surgeon manipulates the withdrawal instru ment so as to withdraw the bioactive agent, for example, Bioactive Agents: withdrawing the bioactive agent delivery device from the 0202 As used herein, “bioactive agent” refers to an agent subretinal region. The bioactive agent is withdrawn from the that affects physiology of biological tissue. Bioactive agents vitreous along with any instruments. In yet further particular useful according to the invention include virtually any Sub embodiments, the methodology of the invention contem stance that possesses desirable therapeutic and/or prophylac plates insertion of another depot of bioactive agent, for tic characteristics for application to the implantation site. example insertion of another delivery device with a fresh 0203) While reference may be made to a “bioactive agent. charge of bioactive agent, into the subretinal region following it will be understood that the invention can provide any num such withdrawal of the used device or bioactive agent. ber of bioactive agents to a treatment site. Thus, reference to the singular form of “bioactive agent” is intended to encom Method C Intravitreal Delivery: pass the plural form as well. (0199. In some embodiments, the method of the invention (0204 Exemplary bioactive agents include, but are not lim includes instilling one or more bioactive agents into the Vit ited to, thrombin inhibitors; antithrombogenic agents; throm reous humor of the eye. The intravitreal delivery will typically bolytic agents (such as plasminogen activator, or TPA; and be performed after implantation of the intraocular sustained streptokinase); fibrinolytic agents; vasospasm inhibitors; cal release delivery device (see, Method A) and/or after instilla cium channel blockers; vasodilators; antihypertensive agents: tion of the bioactive agent(s) subretinally (see, Method B). clotting cascade factors (for example, protein S); anti-coagul Typically, the intravitreal delivery will be accomplished by lant compounds (for example, heparin and nadroparin, or low direct intravitreal injection of the one or more bioactive molecular weight heparin); antimicrobial agents, such as agents, for example, using a 27 to 30-gauge needle (or antibiotics (such as , chlortetracycline, , smaller) having a length of about 0.5 to about 0.62 inches. , , , cephalexin, oxytetracy Alternatively, the intravitreal delivery may be accomplished cline, chloramphenicol, , , tobramy using transscleral iontophoresis as discussed, for example, in cin, gentamycin, , , sulfonamides, Sul Ashim K. Midra; Ophthalmic Drug Delivery System; 2" fadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, Edition (2004) at Chapter 12 (Marvin E. Myles et al., Ocular , propionate, minocycline, doxycy Inotophoresis). Iontophoresis is the direct transport of ion cline, , kanamycin, such as ized substances through tissue by application of an external cephalothin, cephapirin, , cephalexin, cephardine, electric current. Bioactive agents having one or more pKa , , , , , values either below pH 6 or above pK8 may be suitable for , , cefitaxime, moxalactam, cetizoxime. iontophoresis because these bioactive agents will be in their , ), geldanamycin and analogues. ionized form at the physiological pH of the eye. The salt form (such as and ), and of the bioactive agent may also be preferred. The bioactive antivirals (such as idoxuridine trifluorothymidine, acyclovir, agent is driven into the ocular tissue with an electrode carry gancyclovir, interferon, O-methyl-P- methy ing the same charge ionized form as the bioactive agent. In lamine, hydroxy-ethoxymethyl-guanine, adamantanamine, transscleral iontophoresis the electrical current is applied 5-iodo-deoxyuridine, trifluorothymidine, interferon, adenine through the pars plana. Specifically, for transscleral ionto arabinoside); inhibitors of surface glycoprotein receptors: phoresis the bioactive agent is contained in a tube within an antiplatelet agents (for example, ticlopidine); antimitotics: eyecup held to the conjunctiva by Suction. The tube is placed microtubule inhibitors; anti-secretory agents; active inhibi over the pars plana to avoid current damage to the retina. tors; remodeling inhibitors; antisense nucleotides (such as Devices for iontophoresis are commercially available from a morpholino phosphorodiamidate oligomer); anti-metabo number of sources, for example, Iomed, Inc. (Salt Lake City, lites; antiproliferatives (including antiangiogenesis agents. Utah): Life-Tech, Inc. (Stafford, Tex.); General Medical Co. taxol, (rapamycin), analogues of rapamycin (“rapa (Los Angeles, Calif); and Fischer Co., Inc. (Glendale Calif.). logs”), , ABT-578 from Abbott, everolimus, pacli 0200. The one or more bioactive agents instilled into the taxel, taxane, vinorelbine); anticancer chemotherapeutic vitreous humor may be the same as the one or more bioactive agents; anti-inflammatories (such as , hydro agents in the intraocular device (Method A) or instilled sub acetate, 21-phosphate, fluocino retinally (Method B), or the bioactive agent(s) may be differ lone, , , ent. The bioactive agent(s) are typically injected as liquids. 21-phosphate, , fluoromethalone, The volume will depend, for example, on the method of , triamcinolone, triamcinolone acetonide); US 2011/O 159073 A1 Jun. 30, 2011

non-steroidal anti-inflammatories (such as Salicylate, methyltyrosine, L(-)alpha methyltyrosine, D.L(-)cetazola indomethacin, , , , piroxi mide, dichlorophenamide, 6-hydroxy-2- cam); antiallergenics (such as sodium chromoglycate, anta , and allopurinol. Zoline, methapyriline, chlorpheniramine, cetrizine, pyril 0207 Another group of useful bioactive agents are anti amine, prophenpyridamine); anti-proliferative agents (such pyretics and antiinflammatory agents. Examples of Such as 1.3-cis retinoic acid); (such as phenyleph agents include (), indomethacin, sodium rine, , tetrahydrazoline); miotics and anti-cho indomethacintrihydrate, , , colchicine, linesterase (such as , salicylate, , acetyl , , , diclofenac, indoprofen and chloride, , eserine, diisopropyl Sodium salicylamide. Local are Substances that fluorophosphate, phospholine iodine, demecarium ); have an effect in a localized region. Examples of mydriatics (such as , , , Such anesthetics include , , and , , eucatropine, hydroxyamphet dibucaine. amine); sympathomimetics (such as epinephrine); antine 0208. Other bioactive agents include abamectin, abundia oplastics (such as carmustine, cisplatin, fluorouracil); immu Zole, , acabrose, , , acebu nological drugs (such as vaccines and immune ); tolol, acecainide, , , , hormonal agents (such as , , progesterol, , acediasulfone, acedoben, , acefur , insulin, calcitonin, parathyroid hormone, pep tiamine, acefylline clofibrol, acefylline , acegla tide and vasopressin hypothalamus releasing factor); beta tone, , aceglutamide , , blockers (such as maleate, acenocoumarol, aceperone, , , HCl, HCl); immunosuppressive agents, growth aceduinoline, acesulfame, acetaminophen, acetaminosalol, hormone antagonists, growth factors (such as epidermal , acetarSone, , acetiamine, acetiro mate, , acetohydroxamic acid, acetomeroctol, growth factor, fibroblast growth factor, platelet derived , , acetosulfone, acet: oZate, growth factor, transforming growth factor beta, Somatotropin, acetryptine, acetylcolchinol, , acetyldigitoxin, fibronectin, insulin-like growth factor (IGF)); carbonic anhy acetylleucine, acetylsalicyclic acid, acevaltrate, acexamic drase inhibitors (such as dichlorophenamide, , acid, acifran, acipimox, acitemate, acitretin, acivicin, aclan methazolamide); inhibitors of angiogenesis (such as tate, aclarubicin, aclatonium napadisilate, acodazole, aco angiostatin, anecortave acetate, thrombospondin, anti-VEGF niazide, , acoXatrine, , acrihellin, acrisor antibody such as anti-VEGF fragment—ranibizumab (Lu cin, , acrocinide, acronine, actinoquinol, centis)); ; radiotherapeutic agents; pep actodigin, , adamexine, ademetionine, adenosine tides; proteins; ; nucleic acids and nucleic acid frag phosphate, adibendan, adicillin, , , ments; extracellular matrix components; ACE inhibitors; free adiphenine, aditeren, aditoprim, , adrenalone, aflo radical scavengers; chelators; antioxidants; anti-poly qualone, , aganodine, , aklomide, alacepril, merases; photodynamic therapy agents; gene therapy agents; alafosfalin, mustard, alanosine, , alaza and other therapeutic agents such as , antipros nine triclofenate, , albendazole oxide, albuterol, taglandins, precursors, and the like. , alclofenac, alcometasone dipropionate, alcloxa, 0205 Another group of useful bioactive agents are anti , aldioxa, , alepride, ale septics. Examples of include Sulfadiazine, tamine, alexidine, alfacalcidol, alfadex, , alfapros tol, , , , acetonide, , , peracetic acid, sodium , alibendol, aliconazole, aliifedrine, hypochlorite, , phenolic compounds, iodophor com , , alinidine, alipamide, alitame, , pounds, quaternary ammonium compounds, and chlorine allantoin, , , , allocupre compounds. ide, allomethadione, allopurinol, , allyl isothicy 0206. Another group of useful bioactive agents are anate, , allylthiourea, almadrate Sulfate, almasi inhibitors. Examples of enzyme inhibitors include late, , , alminoprofen, , chrophonium chloride, N-methylphysostigmine, neostig , alonacic, alonimid, aloxistatin, aloZafone, alp mine bromide, physostigmine Sulfate, HCL, tacrine, ertine, , alphameprodine, , 1-hydroxymaleate, iodotubercidin, p-bromotetramisole, 10 alphaprodine, alpha-Vinylaziridinoethyl acetate, , (C-diethylaminopropionyl)- hydrochloride, alpiropride, , , alprostadil, alrestatin, calmidazolium chloride, hemicholinium-3,3,5-dinitrocat , altapizone, alteconazole, althiazide, , echol, diacylglycerol kinase inhibitor 1, diacylglycerol altretamine, aluminium acetate, aluminium clofibrate, alu kinase inhibitor II, 3-phenylpropargylamine, N-monom minium Subacetate, alverine, acetate, amafolone, ethyl-L-arginine acetate, , 3-hydroxybenzylhydra amanozine, , amantanium bromide, amantocillin, zine HCl, HCl, clorgyline HCl, deprenyl HCl, ambasilide, ambazone, ambenonium chloride, ambenoxan, L(-)deprenyl HCl, phosphate, 6-MeO-tetrahydro , ambruticin, ambucaine, ambucetamide, ambu 9H-pyrido-indole, , HCl, quinacrine HCl, phylline, ambuside, , , HCl, HCl, N,N-diethylami , , amdinocillin, amdinocillin pivoxil, noethyl-2,2-diphenylvalerate hydrochloride, 3-isobutyl-1- , , ametantrone, , amezinium methylxanthine, papaverine HCl, indomethacin, 2-cyclooc metilsulfate, amfenac, , , amfluti tyl-2-hydroxyethylamine hydrochloride, 2,3-dichloro-O- Zole, , amicarbalide, amicibone, amicloral, methylbenzylamine (DCMB), 8,9-dichloro-2,3,4,5- amicycline, amidantel, amidapsone, , ami tetrahydro-1H-2- hydrochloride, flamine, amifloverine, amifloxacin, amifostine, , p-, p-aminoglutethimide tartrate, R(+) amikhelline, , aminacrine, amindocate, , p-aminoglutethimide tartrate, S(-)-3-iodotyrosine, alpha aminobenzoic acid, aminocaproic acid, aminoethyl nitrate, US 2011/O 159073 A1 Jun. 30, 2011 20 aminoglutethimide, aminohippuric acid, aminometradine, Zetimide, benzilonium bromide, benzindopyrine, aminopentamide, , aminopromazine, aminop , benzmalecene, , , terin, aminopyrine, aminoquinol, aminoquinuride, , , benzoclidine, benzoctamide, benzodepa, ben aminosalicyclic acid, aminothiadiazole, aminothiazole, Zododecinium chloride, , benzoin, , , amiperone, amipheaZole, amipiZone, ami benzopyrronium bromide, benzoquinium chloride, benzot prilose, amiquinsin, amisometradine, , amiterol, ript, benzoxiduine, , benzoyl peroxide, amithioZone, , , , amix benzoylpas, , benzpiperylon, benzpyrinium etrine, amlexanox, , , , bromide, benzquercin, , benzthiazide, benz amogastrin, amolanone, amonofide, amoproxan, amopyro tropine, , , benzylsulfamide, quin, amorolfine, amocanate, , amotriphene, beperidium iodide, bephenium naphtoate, bepiastine, bepri , amoxecaine, , amoxydramine camsi dil, beraprost, berberine sulfate, bermastine, bermoprofen, late, , amphecloral, amphenidone, , berythromycin, besulpamide, beslunide, beta carotene, beta amphotalide, amplicillin, ampiroXicam, amprolium, ampy cetylmethadol, , betaine, betameprodine, rimine, ampyZine, amduinate, aminone, amsacrine, amygda , , betamethasone acibu lin, amylene, amylmetacresol, amyl nitrite, tate, , betamethasone dipropionate, acetate, anagrelide, anaxirone, , anazolene, , , betami , ancitabine, androstanediol, androstanol propi cin, betaprodine, , chloride, bethani onate, androstenetrione, androstenonol propionate, , dine, betiatide, betoxycaine, , metilsul anguidine, anidoxime, anilamate, , aniline, anilo fate, bezafibrate, , bialamicol, bibenzonium pam, , aniracetam, anirolac, anisacril, anisindione, bromide, bibrocathol, bici fadine, biclodil, biclofibrate, biclo anisopirol, anisoylbromacrylic acid, , anpirtoline, tymol, bicoZamycin, bidimazium iodine, bietamiverine, , antafenite, antazonite, anthelmycin, anthi , , bifepramide, , bifona olimine, anthralin, , antienite, antimony potas Zole, binedaline, binfloxacin, binfibrate, bioallethrin, biores sium tartrate, antimony thioglycollate, antipyrine, antrafe methrin, biotin, bipenamol, , biphenamine, biriper nine, apalcillin, apaZone, apicycline, , one, bisacodyl, bisantrene, bis(aziridinyl) butanediol. apovincamine, , apramycin, , aprobar bisbendazole, bisbentiamine, bisfenazone, bisfentidine, bis bital, aprofene, , aptocaine, arabinosylmercap muth betanaphthol, bismuth-triglycollamate, bismuth sub topurine, aranotin, arbaprostil, arbekacin, arclofenin, gallate, bismuth Subsalicylate, bisorbin, , bisorcic, , arginine, arginine glutamat, arildone, . bioxatin acetate, bispyrithione magsulfex, , bithion aronixil, , arpinocid, arpromidine, arsanilic acid, oloxide, bitipaZone, bitoterol, bitoscantate, bleomycin, , , , asaley, ascorbic acid, ascor bluensomycin, bofumustine, dipropionate, bolas byl palmitate, asocainol, aspartame, aspartic acid, asperlin, terone, , undecylenate, , bolman aspoxicillin, , , , , talate, bometolol, , , . , atolide, , atromepine, atropine bornelone, botiacrine, boxidine, bralobarbital, brazergoline, oxide, auranofin, aurothoiglucose, aurothioglycanide, avila , , brequinar, tosylate, brin mycin-A, pyridine, axamozide, azabon, azabuperone, azaci doxime, brivundine, brobactam, broclepride, brocresine, bro todine, azaclorzine, azaconazole, azacosterol, , crinat, brodimoprim, , brofezil, brofoxine, bro aZaftozine, azaguanidine, azaloxan, azamethonium bromide, laconazole, brolamfetamine, bromacrylide, , aZamulin, azanator, , ; azapicyl, aza bromamid, , bromchlorenone, bromebric acid, procin, azaquinzole, azaribine, azarole, azaserine, azaspirium , brometenamine, , , bro chloride, azastene, azastrptonigrin, azatodine, azathioprine, mindione, bromisovalum, bromociclen, , bro aZauridine, , azepexole, , azetepa, modiphenhydramine, bromofenofos, , bromox aZidamfenicol, , azimexon, azintamide, andide, , bromperidol decanoate, , azithromycin, , azolimine, azosemide, , bronopol, , broperamole, aZotomycin, , and azumolene. bropirimine, broquinaldol, broSotamide, broSuximide, bro 0209. Also, , , bacmecillinam, bal tianide, , brovanexine, brovincamine, broxaldine, Salazide, , , bamethan, bamifylline, , broxitalamic acid, broXuridine, , , bamnidazole, baduiloprim, , , bruceantin, brucine, bucainide, , buciclovir, bucil barucainide, batilol, , becanthone, , lamine, , bucladesine, , buclosamide, beclobrate, beclomethasone dipropionate, beclotiamine, bucloxic acid, bucolome, bucricaine, bucromarone, bucry befiperide, , , bekanamycin, belarizine, late, , , budipine, budotitane, budrala beloxamide, bemarinone, , bemetizide, bemitra Zine, bufenadrine, bufeniode, , bufexamac, buf dine, , benafentrine, benanserin, benapry Zine, eZolac, , bufogenin, buformin, bufrolin, , benaxibine, benazepril, bencianol, bencisteine, benclonidine, bumadizone, bumecaine, bumepidil, , bumetri , bendamustine, bendazac, bendazol, benderizine, Zole, , bunamidine, bunamiodyl, bunaprolast, bendroflumethiazide, benethamide penicillin, benexate, ben , , bunolol, buparvaquone, , florex, benfosformin, benfotiamine, benfurodil hemisucci , , , , nate, benhepaZone, , , benolizime, beno buquineran, buquinolate, buquiterine, buramate, burodiline, rilate, , benoxafos, , benoximate, , buSulfan, , , butacetin, , , benrixate, bensalan, , , butadiazamide, butafosfan, butalamine, butalbi bensuldazic acid, , bentemazole, bentiamine, tal, , , butamisole, butamoxane, bentipimine, bentiromide, benurestat, benzaldehyde, benza diol cyclic Sulfite, , butanixin, butanserin, Ikonium chloride, benzaprinoxide, benzarone, benzbromar butantrone, , butaprost, butaverine, butedronate, one, , , , ben buterizine, butetamate, butethamine, buthiazide, butibufen, US 2011/O 159073 A1 Jun. 30, 2011

, butikacin, butilfenin, , , ine, , chlorozotocin, chlorphenesin, chlorphen butirosin, butixirate, butobendine, butoconazole, butoprolol. esin , chlorphenoctium amSOnate, butoctamide, , butonate, butopamine, butopiprine, , , , butoprozine, butopyrammonium iodide, , butox chlorproguanil, , , chlorpro amine, butoxylate, , butropium bromide, buty thixene, , chlortetracycline, chlorthalidone, lated hydroxyanisole, butylated hydroxytoluene, butylpara chlorthenoxazine, chlorZoaxaZone, chloecalciferol, cholic ben, butynamine, and buZepide metiodide. acid, choline chloride, choline glycerophosphate, chro 0210 Also, cabastine, , , cafami mocarb, chrornonar, ciadox, ciamexon, cianergoline, ciani nol, , , calcifediol, calcitrol, citrate, dol, , ciapilome, cicaprost, cicarperone, ciclac calcium dobesilate, calcium glubionate, calcium gluceptate, tate, , , cicletanine, ciclomenol, calcium gluconate, calcium glycerophosphate, calcium ciclonicate, ciclonium bromide, ciclopiroX, , hypophosphite, calcium lactate, calcium lactobionate, cal cicloprofen, , ciclosidomine, , ciclo cium levulinate, calcium mandelate, calcium pantothenate, tropium bromide, cicloxilic acid, cicloxolone, , calcium phosphate dibasic, calcium phophate tribasic, cal cicrotic acid, , cifenline, cifostodine, , cium saccharate, calcium Stearate, , , ciheptolane, , cilastatin, cilaZapril, cilaZaprilat, cilo cambendazole, camiverine, camostast, camphotamide, bamine, cillofungin, cilostamide, cilostaZol, ciltoprazine, camptothecin, , canbisol, cannabinol, canrenoic , , cimepanol, , cimetropium acid, , cantharidine, capobenic acid, , bromide, , cinchonine, cinchophen, cinecromen, , , captamine, , captopril, cinepaXadil, , , , cinfenine, capuride, caracemide, , , carbadox, car cinfenoac, cinflumide, , , cinmetacin, cin baldrate, , carbamide peroxide, carbantel lau namaverine, , , cinnarizine clofi ryl Sulfate, carbaril, carbarSone, carbaspirin calcium, carbaz brate, cinnofuradione, cincotramide, cinodine, , eran, carbazochrome, carbazachrome salicylate, cinoquidox, cinoaxin, cinoxate, cinoXolone, cinooxopazide, carbazachrome Sulfonate, , carbeniciltin, carbe cinperene, cinprazole, cinpropazide, cinromide, cintaZone, nicillin indanyl, carbencillin phenyl, , carben cintriamide, cinperone, ciprafamide, ciprafaZone, , Zide, carbestrol, carbetapentane, carbidopa, carbimazole, , ciprofibrate, cipropride, ciprocquaZone, cipros , carbiphene, carbocloral, carbocysteine, car tene, , , , cisconazole, cismadi bofenotion, carbol-fuschin, carbomycin, carboplatin, carbo none, cistinexine, , citatepine, citenamide, citena prost, carboprost methyl, carboquone, , , Zone, , , clamidoxic acid, clamoxyquin, , , , carcainiurn chloride, clanfenur, clanobutin, clantifen, , clavulanic carebastine, , carfimate, , carmanta acid, , clazolimine, claZuril, , , dine, carmetizide, carmofur, camidazole, carnitine, carocam , clemeprol, , , clenpirin, ide, , , carperidine, caperone, car cletoquine, clibucaine, clidafidine, clidanac, clidinum bro , , carpiramine, carprofen, carpronium mide, , climbazole, climiqualine, , chloride, carsalam, , , carubicin, caru clindamycin palmitate, clindamycin phosphate, clinofibrate, monam, , carzenide, carzolamide, , cathi clinolamide, cliquinol, clioxamide, clipoxamine, cliprofen, none, cefaloniurm, cefaloram, cefamandole naftate, cefap , clobenoside, , , clobenz arole, , , , cefazolin, tropine, propionate, butyrate, clobuti , cefcanel, cefcanel daloxate, cefedrolor, nol, clobuZarit, clocanfamide, , clociguanil, cefempidone, , , cefetrizole, cefvitril, , acetate, , clo , cefimenoXime, cefimepidium chloride, cefimetazole, coumarol, clodacaine, clodanolene, clodazon, clodoxopone, cefninox, , cefonizid, , , clodronic acid, , clofenamic acid, clofenamide, , cefoxazole, , , ce?pirome, , clofenetamine, clofenoxyde, clofenVinfos, , cefpodoxime proxetil, cefauinome, cefrotil, clofeverine, clofexamide, clofeZone, clofibrate, clofibric , , cefsumide, , , acid, clofibride, clofilium phosphate, cloflucarban, clofoctol, , , , ceftioxide, , cefu , clofurac, acetate, cloguanamil, clomac racetime, cefuraxime axetil, cefurzonam, , ceph ran, acetate, clometacin, clometherone, clom acetrile, cephaloglycin, , cephradine, cetaben, ethiazole, clometocillin, , , clomi , cethexonium chloride, cetiedil, , cetocy phene, , clomocycline, clomoxir, , cline, cetohexazine, cetophenicol, cetotiamine, cetoxime, clonazoline, , , clonitrate, clonixeril, , chaulmosulfone, chendiol, , chlophedi clonixin, clopamide, , , cloperidone, , , betaine, , chloral clopidogrel, clopidol, , clopipazan, clopirac, clo ose, chlorambucil, chloramine, chloramphenicol palmitate, ponone, , cloprostenol, cloprothiazole, cloquinate, chloramphenicol Succinate, chlorazanil, , cloquinozine, cloracetadol, , , clore chlorbetamide, , chlordantoin, chlordiazep thate, clorexolone, cloricromen, , clorindanic acid, oxide, chlordimorine, chlorhexadol, chlorhexidine, chlo clorindione, clormecaine, cloroperone, clorophene, cloro rhexidine phosphanilate, chlorindanol, qualone, , clorprenaline, clorSulon, , chloride, acetate, chlormerodrin, chlormeza closantel, none, chlormidazole, chloronaphazine, chloroaZodin, chlo closiramine, , clothiapine, clothixamide, clotiaz robutanol, chlorocresol, chlorodihydroxyandrostenone, chlo epam, propionate, clotioxone, , clo roethyl mesylate, 5-chloro-3'-fluoro-2'3-dideoxyuridine, Voxamine, cloxacepride, , cloxacillin benzathine, chloroguanide, chlorophenothane, acetate, , , cloximate, , , , chloroquine, chloroserpi cloxypendyl, cloxyquin, , cobamide, , dine, , chlorothiazide, chlorotriansene, chloroX cocarboxylase, , , cofisatin, , US 2011/O 159073 A1 Jun. 30, 2011 22 colchicine, colestolone, colfenamate, , , con ride, dibucaine, dibuprol, dibupyrone, dibusadol, dicarbine, essine, conorphone, copper gluconate, cormethasone acetate, dicarfen, dichlorallyl lawsone, acetate, dichlo , , , . rmeZanone, dichlorofluorimethane, dichlorom, ethotrexate, cortodoxone, cotarnine chloride, , , cou dichlorophen, dichlorophenarsine, dichlorotetrafluoroet maphos, coumaZoline, coumermycin, coumetarol, creatinol hane, dichloroxylenol, dichlorphenamide, , dici fosfate, crisinatol, croconazole, , cromitrile, cro ferron, , , , diclofurime, molyn, cropropamide, crospovidone, crotamiton, diclometide, diclonixin, , dicobalt edetate, crotetamide, crotoniazide, cruformate, cuprimyxin, cuproXo dicolinium iodide, dicresulene, dicumarol, dicyclomine, line, cyacetacide, , cyanocobalamine, cyclacil didemnin, dideoxycytidine, didrovaltrate, , dienes lin, cyclandelate, , , , trol, , diethadione, diethazine, diethylpropion, cyclexanone, cyclindole, cycliramine, , cyclobar , diethylstilbestrol diphosphate, diethylstil bital, cyclobendazole, , cyclobutoic acid, bestrol dipropionate, , diethyltoluamide, , , cycloguanil, cloheximide, cycloleu dietifen, , , difemetorex, difenami cine, cyclomenol, cyclomethicone, , cyclo Zole, difencloxazine, difenoximide, , , , cyclopenthiazide, cyclopenazine, cyclophospha difeterol, diacetate, difloxacin, difluanine, diflu mide, cyclopregnol, cyclopyrronium bromide, , cortolone, diflurcortolone pivalate, diflumidone, diflunisal, cyclosporine, , cyclovalone, cyclotiamine, , diftalone, digalloyl trioleate, , cycrimine, cyheptamide, cyheptropine, cynarine, cype digoxin, , , dihydroaZacytidine, namine, cypothrin, , cyprenophine, , , dihydrolenperone, dihydrostreptomy , cyprolidol, cyproduinate, cin, dihydrotachysterol, dihydroxyfluoroprogestrone, diiso acetate, cyproximide, cystine, and cytarabine. promine, diisopropanolamine, , dilevalol, dilimefone, 0211 Also, dacarbazine, dacemazine, dacisteine, dacino , , dimabefylline, dimecamine, dime mycin, , dagapamil, , colonium iodide, dimecrotic acid, dimefadane, dimefline, , daltroban, dametralast, damotepine, , dani dimelazine, , , , tracen, danosteine, danthron, , , dap dimeheptanol, dimepranol, , dimeproZan, Sone, , darenZepine, , datelliptium , dimeSna, , , dimetamfe chloride, dunorubicin, daZadrol, dazepinil, dazidamine, tamine, dimethadione, dimethaminostyrylquinoline, dimet daZmegrel, dazolicine, , dazoquinast, dacoxiben, hazan, dimethindene, dimethiodal, dimethisoquin, dimethis deanolaceglumate, deanolacetaminobenzoate, deazauridine, terone, dimetholizine, , deboxamet, debrisoquin, bromide, deci dimethylhydroxytestosterone, dimethylnorandrostadienone, memide, decitropine, declaben, declenperone, decloxizine, dimethylnortestosterone, dimethylstilbestrol, dimethyl, dim decominol, decoquinate, deditonium bromide, deferoxam ethylthiambutene, dimethyltubocurarinium chloride, ine, , defosfamide, dehydroacetic acid, dehydro dimetipirium bromide, , dimetridazole, dimina , dehydro-7-, , dela Zene, dimoxamine, dimoxaprost, dimoxyline, dimpylate, pril, delergotrile, delfantrine, acetate, dinaline, dinaZafone, diniprofylline, dinitolmide, dinoprost, delmetacin, delmopinol, , deloxone, delproste dinoprostone, dinsed, dioSmin, dioxadillol, dioxadrol, diox nate, dembrexine, demeclocycline, , demecy amate, , dioxethedrin, dioxifedrine, cline, , demelverine, , democona dioxybenzone, dipenine bromide, diperodon, diphemanil Zole, , denaverine, denbufylline, denipride, methylsulfate, diphenadione, diphenan, , , denpidazone, denZimol, deoxyspergualin, diphendiol, , diphenylpraline, diphoxazide, , , deprostil, , derpanicate, , dipipoverine, dipliverin, , diprenor desacetylcolchicine tartrate, desaspidin, desiclovir, descino phine, diprobutine, diprofene, diprogulic acid, diproleando lone acetonide, , , deslanoside, des mycin, diprocqualone, , diprotriozate, diproxa methylcolchicine, desmethylmisonidazole, desmethylmora dol, dipyridamole, dipyrithione, dipyrocetyl, dipyrone, mide, desocriptine, , , , dirithromycin, disobutamide, disofenin, disogluside, disopy , desoxycorticosterone acetate, desoxycorti ramide, disoxaril, bromide, disulergine, disulfa costerone pivalate, desoxypyridoxine, detajmium bitartrate, mide, disulfuram, disuprazole, ditazole, ditercalinium chlo detanosal, , , detorubicin, detrothronine, ride, dithiazanine iodide, ditiocarb, ditiomustine, ditolamide, , dexamethasone, , dex ditophal, divabuterol, dixanthogen, dizatrifone, , amethasone acetate, dexamethasone dipropionate, dexami dobupride, , docarpamine, doconazole, , sole, , , dex doliracetam, domazoline, , domiphen bromide, clamol, , dexetoZoline, , domipizone, , domoxin, , don, deximafen, dexindoprofen, dexivacaine, dexlofexidine, donetidine, dopamantine, dopamine, , dopropi , dexoxadrol, dexpanthenol, dexpropra dil, doqualast, dorastine, doreptide, dosergoside, , nolol, dex.proxibutene, deXecoverine, dextilidine, dextroam dotefonium bromide, dothiepin, , phetamine, dextrofemine, , dextromora aminol, doxapram, doxaprost, , , dox mide, , dextrothyroxine, deZaguanine, , enitoin, , , doxifluridine, doxofylline, diacerein, diacetamate, , diacetylmorphine, diam doxorubicin, , , dramedilol, draqui fenetide, diaminomethylphenazinium chloride, diamocaine, nolol, deaZidox, dribendazole, drindene, drobuline, drocino , diamthazole, dianhydrogalactitol, diapamide, nide, droclidinium bromide, drocode, , , diarbarone, diathymosulfone, diatrizoic acid, diaveridine, drometrizole, dromostanolone, dromostanolone propionate, , diaziquone, diazoacetylglycine , diazou dronabinol, dropempine, , droprenilamine, dro racil, , dibekacin, dibemethine, dibenamine, diben propizine, drotaverine, , droxacin, droxicamide, Zepin, , dibromsalan, dibrospidium chlo droxicam, , , dulofibrate, duloZafone, US 2011/O 159073 A1 Jun. 30, 2011 duometacin, duoperone, dupracetam, durapatite, dyclonine, 0213 Also, fallintolol, fallpamil, famiraprinium chloride, , dymanthine, and dyphylline. , famotine, famiprofaZone, , fantridone, 0212. Also, , , ebselen, , echi , fazaribine, febantel, , nomycin, iodide, ecipramidil, , februpol, febuverine, feclemine, feclobuZone, , fel eclaZolast, econazole, ectylurea, edelfosine, edetic acid, ede bamate, felbinac, felipyrine, , , fen tol, edifolone, , edoxudine, edrophonicum chlo abutene, fenacetinol, fenaclon, , fenaptic acid, ride, , efetozole, , , efrotomycin, femalamide, fenalcomine, fenamifuril, penamole, fenaper elantrine, elanzepine, elderfield's pyrimidine mustard, elf one, , fenbencillin, fenbufen, , fen azepam, , elliptinium acetate, elmustine, elnad camfamine, fencibutirol, fenclexoniurn metilsulfate, fen ipine, eltenac, , elucaine, elziverine, , clofenac, , fenclorac, fenlozic acid, , , , emetine, emiglitate, fendosal, feneritrol, , , , fen emilium tosylate, emopanil, emorfaZone, , enala etradil, fenflumizole, , fenfluthrin, , pril, enalaprilat, enbucrilate, encamide; , enclo fenharmane, fenimide, feniodium chloride, fenipentol, miphene, encyprate, endomide, , endrysone, fenirofibrate, , , , enefexine, , enfenamic acid, , eniclobrate, fenobam, fenocinol, fenoctimine, fenofibrate, , enilconazole, , enisoprost, enocitabine, enoli fenoprofen, , fenoverine, , fenoxedil, cam, enoxacin, enoxamast, enoXimone, , enipra , , femperate, fenipalone, fenipra Zole, eniproline, , enprofylline, empromate, mide, feniprane, fempiverinium bromide, fenprinast, fenpro , enrofloxacin, entisulfon Sodium, , envi porex, fenprostalene, fenguizone, fenretinide, , radene, epalretat, , , , epicamide, , fentiazac, , fenticonazole, fentonium bro , , , , , epi mide, fenyripol, fepentolic acid, fepitrizol, fepradinol, fepra nephryl borate, epipropidine, epirizole, epiroprim, epirubi Zone, fepromide, , ferriclate calcium, ferrotre cin, epithiazide, , epoprostenol, epostane, eprazi nine, ferrous fumarate, ferrous gluconate, fetoxylate, none, eprovafen, eproXindine, eproZinol, epsiprantel, fexicaine, , fezatione, , fiacitabine, eptaloprost, , , , ergocalciferol, fibracillin, , filipin, fifexide, flamenol, flavamine, fla mesylates, ergonovine, ergosterol, , eri Vodic acid, flavodil, flavoneactic acid, , flazalone, colol, erizepine, erocamide, erythrityl tetranitrate, erythro flecamide, flerobuterol, fleroxacin, , , fle mycin acistrate, erythromycin ethylsuccinate, erythromycin tazepam, , , , florantyrone, propionate, erythrosine, esaprazole, esculamine, eseridine, flordipine, floredil, florfenicol, florifenine, floseduinan, esflurbiprofen, esmolol, esorubicin, esproquin, , flotrenizine, floverine, floxacillin, floxacrine, floxuridine, , , estradiol dipropi , fluialamide, fluianisone, , flubanilate, onate, estradiolenanthate, , estradiol val flubendazole, flubepride, flucabril, flucetorex, , flu erate, , , , ciprazine, flucloronide, fluconazole, flucrylate, flucytosine, , , , , estrone hydrogen Sul fludalanine, fludarabine phosphate, fludazonium chloride, fate, , , etabenzarone, etacepride, , fluidorex, fludoxopone, acetate, , , etamestrol, etamiline, etamiphyllin, , flufenisal, flufosal, flufylline, fluindarol, flu etamocycline, etanidazole, etanterol, , etasuline, indione, , flumecinol, -17-acetate, , , etebenecid, , etersalate, flumequine, flumeridone, flumethasone, flumethasone piv ethacridine, ethacrynic acid, , ethamivan, etham alate, flumethiazide, flumetramide, , , Sylate, ethanolamine oleate, ethaverine, , , , , flunamine, , , ethazide, ethidium chloride, , ethi flunidazole, , flunisolide acetate, flunitrazepan, nyl estradiol, ethiofos, , ethsterone, ethohep flunixin, flunoprost, flunoxaprofen, acetonide, tazine, ethomoxane, ethonam, ethopropazine, , , flourcortin butyrate, , fluocor , ethoxazene, ethoxazorutoside, , tolone caproate, fluorescein, fluoresone, fluoroadenosine, ethyybenztropine, ethyl biscoumacetate, , 3-fluoroandrostanol, fluorodopane, fluorohydroxyandroster ethyl cartrizoate, ethyl , , one, acetate, fluorosalan, 6-fluorotestoster diamine, , ethylhydrocupreine, ethyl loflaze one propionate, 9-fluoroxotestenololactone, 9-fluoroxotest pate, , , 9-ethyl-6- ololacetone, , , , mercaptopurine, ethyl nitrite, ethylnorepinephrine, , , fluperamide, , fluper ethylparaben, ethylphenacemide, ethylstibamine, ethyner olone acetate, , fluiphenazine enanthate, flupi one, ethynodiol diacetate, ethypicone, etibendazole, eticlo mazine, , flupranone, , , flu pride, , , etidronic acid, etifelmine, prednisolone, Valerate, fluprofen, etifenin, , , , etillefrine piv fluprofylline, fluproduaZone, fluprostenol, fluguaZone, flura alate, etintidine, etiochlanolone, etipirium iodide, etiproston, doline, flurandrenoline, flurantel, , flurbiprofen, , etiroXate, etisazole, etisomicin, etisulergine, eti fluretofen, flurithromycin, fluorocitabine, fluorofamide, fluo Zolam, etocarlide, etocrylene, , etodroXZine, etofa rogestone acetate, fluorothyl, fluoroxene, , fluspip mide, etofenamate, etofemproX, etofibrate, etoformin, eto erone, , , , , flu furadine, etofylline, etoglucid, etolorex, etolotifen, tiazin, propionate, flutizenol, flutonidine, etoloxamine, , etomidoline, etomoxir, , , flutroline, flutropiurn bromide, , , etoposide, etoprindole, etoprine, , eto fluzinamide, fluzoperine, folescutol, folic acid, fomidacillin, salamide, etoxadrol, , etoZolin, etrabamine, etreti , fomocaine, fonazine, fopiirtoline, forfenimex, nate, etryptamine, , eucalyptol, eugenol, eupro , formetorex, formintrazole, , for cin, evandamine, , exalamide, exametazine, moterol, fosarilate, , foScarnet, foscolic acid, fos , exepanol, exifone, and exiproben. enazide, fosfocreatine, , foSfonet, fosfosal, fosi US 2011/O 159073 A1 Jun. 30, 2011 24 napril, foSmenic acid, fosmidomycin, forpirate, , cortisone Valerate, hydroflumethiazide, , fostriecin, fotemustine, fotreamine, frabuprofen, frentizole, , , hydroquinone, hydroxin fronepidil, froxiprost, ftaxilide, ftivazide, forafur, dasate, hydroxindasol, hydroxyoxocobalamin, hydroxychlo roquine, hydroxydimethandrostadienone, Suc formetazine, forpropazine, fubrogonium iodide, fuchsin, cinate, hydroxymethylandrostanone, , fumoXcillin, fuprazole, furacrinic acid, furafyl 10-hydroxynorehisterone, , hydroxyphe line, furalazine, furaltadone, furaprofen, , furazoli namate, hydroxyprocaine, hydroxyprogeserone, hydrox done, furazolium chloride, furbucillin, furcloprofen, furegre yprogesterone caproate, hydroxypyridine tartrate, hydrox late, , , furidarone, furmethoxadone, yStilbamidine, 7-hydroxytestololacetone, furobufen, furodazole, furofenac, furomazine, , hydroxytestosterone propionate, hydroxytetracaine, , fursalan, fursultiamine, furtherene, furtretho hydroxytoluic acid, hydroxyurea, hydroxy Zine, hymec nium iodide, fusidic acid, and fuzlocillin. romone, , and hypericin. 0214. Also, , gabexate, , galan 0216. Also, ibacitabine, ibafloxacin, , ibopam tamine, gallamine triethodide, , galosemide, gal ine, ibrotamide, ibudilast, ibufenac, ibuprofen piconol, ibu tifenin, gampexine, gamolenic acid, ganglefene, gapicomine, proxam, ibuterol, ibuverine, icazepam, icosipiramide, icoti gapromidine, , , gemcadiol, gemeprost, dine, idarubicin, idaverine, , idebenone, idenast, gemfibrozil, gentian violet, , , geroquinol, idralfidine, idrocilamide, , , ifosfa , gestadienol, , , mide, , ilmofosine, iloprost, imafen, imanixil, ima , giparmen, gitaloxin, gitoformate, , Zodan, imcarbofos, imexon, imiclopazine, salicy glaziovine, gliamilide, glibomuride, glibutimine, glicara late, imidazopyrazole, imidecyl iodine, imidocarb, imidoline, mide, glicetanile, geroquinol, gestaclone, gestadienol, imidurea, , iminophendimide, , imi gestodene, gestonorone caproate, gestrinone, giparmen, pramine, , imirestat, , imoxiterol, gitaloxin, gitoformate, glafenine, glaziovine, gliamilide, gli impacarzine, , improSulfan, imuracetam, ina bomuride, glibutimine, , glicetanile, , perisone, indacrinone, , indanazoline, , glicondamide, glidaZamide, gliflumide, , glipen , indapamide, , indacamide, indelox tide, , , glisamuride, glisindamide, gliso azine, , indicine-N-oxide, indigotindisulfonic acid, lamide, , gloxazone, gloximonam, glucametacin, indobufen, indocate, indocyanine green, indolapril, indol glucosamine, glucosulfamide, glucosulfone, glucurolactone, idan, , indopine, indoprofen, , glucuronamide, glunicate, glutamic acid, glutaral, glutarim , indoxole, indriline, inicarone, , ide, glutaurine, , glyburide, glybuthiazol, glybu inosine, inosine dialdehyde, inositol niacinate, inproduone, Zole, glyceryl monostearate, glycidyl methacrylate, , intrazole, , iobenzamic acid, iobutic acid, iocar , glybiarsol, glycopyrrolate, glycyclamide, mic acid, iocetamic acid, iodamide, iodecimol, iodetryl, iodi glyhexamide, glymidine, glyoctamide, glypinamide, glypro pamide, iodixanol, iodoalphionic acid, iodol, iodophthalein, thiazol, glySobuzole, gold thiomalate, gold Sodium thiosul iodoquinol, iodothiouracil, iodoxamic acid, ioglicic acid, fate, , , guabenXan, guacetisal, guaf ioglucol, ioglucomide, ioglunide, ioglycamic acid, iogula ecainol, guaiactamine, guaiapate, guaietolin, , mide, iohexyl, iodlidonic acid, iolixanic acid, iomeglamic guaimeSal, guaisteine, guaithylline, guamecycline, guana acid, iomeprol, iomorinic acid, iopamidol, iopanoic acid, benz, guanacline, , , guanazole, guan iopentol, iophendylate, iophenoxic acid, ioprocemic acid, clofine, guancydine, , , guanisoquin, iopromide, iopronic acid, iopydol, iopydone, iosarcol, iose guanoclor, guanoctine, , , and guan famic acid, io.seric acid, iosimide, ioSulamide, ioSumetic acid, oxyfen. iotasul, iotetric acid, iothalamic acid, iotranic acid, iotrizoic 0215. Also, hadacidin, , , , acid, iotrolan, iotroXic acid, ioVersol, ioXabrolic acid, ioxaglic halethazole, halocortolone, halofantrine, halofenate, acid, ioxitalamic acid, ioxotrizoic acid, ioZomic acid, ipexi halofluginone, , halonamine, halopemide, dine, ipodic acid, ipragratine, ipramidil, ipratropium bro halopenium chloride, , , mide, , ipriflavone, , iprocinodine, haloperidone acetate, , , hal , , iprofenin, , iproniazid, othane, , haloxon, halquinols, hedaquinium iproidazole, iproplatin, iprotiazem, iproxamine, iprozil chloride, hepronicate, heptabarbital, , heptaver amine, ipsalazide, , iquindamine, irindalone, ine, heptolamide, , , hetaflur, heteronium irloxacin, irolapride, irsogladine, isamfaZone, isamoltan, bromide, , , hexacyprone, isamoxole, isaxonine, isbogrel, isepamicin, , iso hexadiline, hexadimethrine bromide, hexafluorenium bro bromindione, , isobutamben, , iso mide, bromide, , hexapradol, conazole, isocromil, isoetharine, isofeZolac, hexaprofen, , hexasonium iodide, hexacarba acetate, , isofluorophate, isoleucine, isomazole, choline bromide, hexedine, , hexetidine, hexobar isomerol, isometamidium, , , bital, , methylsulfate, hexoprena isomylamine, , isonixin, isopraZone, , line, hexopyrronium bromide, , hexylene glycol, isoprofen, isoprofamide iodide, isopropicillin, isopropyl hexylresorcinol, , , homarylamine, myristate, isopropyl palmitate, isoproterenol, isosorbide, homatropine methylbromide, homidium bromide, homo , , isospalglumic chlorcyclizine, homofenazine, homoharringtonine, acid, isosulfan blue, isosulpride, , isotic, iso homopipramol, homosalate, homotestosterone propionate, tiquimide, isotretinoin, , isoxepac, , isox , , hoquizil, hycanthone, Suprine, , itanoxone, itaZigrel, , itroca hydracarbazine, hydrargaphen, hydrobentizide, hydrochlor mide, bib, and ivoqualine. , , , hydrocortisone ace 0217. Also, josamycin. ponate, , , 0218. Also, kainic acid, kalafungin, kebuZone, keracya hydrocortisone-phosphate, hydrocortisone Succinate, hydro nin, , , , , kethoxal, US 2011/O 159073 A1 Jun. 30, 2011

ketipramine, , , ketocainol, ketocona Soprol, acetate, meletimide, melinamide, Zole, , , , , ketotrexate, , melizame, , , melphalan, khellin, khelloSide, and kitasamycin. , memotine, , menadiol, menadiol 0219. Also, , , lactalfate, lactose, lactu diphosphate, menadiol disulfate, menadione, menadione lose, , lamtidine, lanatoside, lapachol, lapinone, Sodium bisulfite, menatetrenone, menbutone; menfegol, lapyrium chloride, , laudexium methyl sulfate, lau menglytate, , menoctone, menogaril, , ralkonium chloride, laureth, laurixamine, laurocapram, lau meobentine, meparfynol, mepazine, bromide, roguadine, laurolinium acetate, lauryl isoquinolinium, lefe meperidine, , , , tamine, leflunomide, leiopyrrole, lemidosul, lenampicillin, mephenylon, mephobarbital, , , leniquinsin, lemperone, leptacline, , letimide, leto mepiroXol, , , mepixanox, mepra Steine, leucine, leucinocaine, leucocianidol, leucovorin, midil, , , meproscillarin, levacecamine, , levamfetamine, , lev meproxitol, , , medulidox, meduinol, , levisoprenaline, levlofexidine, , meduitazine, meralein, meralluride, merbarone, , levocarnitine, levodopa, levofacetoperane, levofenfluramine, mercaptamine, mercaptomerin, mercaptopurine, mercudera levofluraltadone, levoglutamide, levomenol, , mide, mercufenol chloride, mercumatilin, mercurobutol, levomethadyl acetate, , levometiomeprazine, mergocriptine, merophan, mersalyl, , levomopranol, levomoramide, levonantradol, levonordeprin, mesalamine, meseclaZone, , , meso-hex , levophenacyl morphan, , estrol, , mesipirenone, , mester olone, , meSudipine, , mesulfamide, levopropylcillin, levopropylhexedrine, levoprotiline, levorin, meSulfen, meSuprine; metabromsalan, metacetamol, meta , , levoxadrol, lexofenac, libecil clazepam, , , metamelfalan, lide, libenzapril, lidamidine, lidocaine, lidofenin, , metamfaZone, , , metanixin, lifibrate, , limaprost, lincomycin, , linsi , metaproterenol, , metaterol, domine, iothyronine, liroldine, lisinopril, , , metazamide, metazide, , metbufen, carbonate, , , lividomycin, lixazinone, meteneprost, , metergotamine, metescufylline, , lobendazole, lobenzarit, lobuprofen, locicortone, metesculetol, , metformin, lodaxaprine, lodacezarlodinixil, lodiperone, , chloride, methacycline, , methadyl acetate, meth lodoxamide ethyl, lofemizole, , , allenestril, methallibure, methalthiazide, , , , loflucarban, lombazole, lomefloxa , methandrostenolone, , methanthe cin, lometraline, lomevactone, lomifylline, lomofungin, line bromide, , , , lomustine, lonapalene, lonaprofen, lonazolac, , methastyridone, , methenamine, methenolone , loperamide oxide, , , acetate, methenolone enanthate, , , loprodiol, , lorapride, , , lor methetoin, , methimazole, methiodal Sodium, bamate, lorcainide, lorcinadol, , , methioguanine, methiomeprazine, methionine, methisaZone, , lorZafone, losindole, losulazine, lotifazole, lot , methixene, , , rifen, lotucaine, , loxanast, , loxiglumide, methopholine, methoserpidine, methotrexate, methotrime prazine, , methoXSalen, , meth , loXtidine, lozilurea, lucanthone, lucartamide, oxyphedrine, , methoxypromazine, lucimycin, , , luprostiol, luxabendazole, methScopolamine bromide, methSuximide, methyllothiazide, lyapolate sodium, lycetamine, lydimycin, lymecycline, N-methyladrealone hcl. methyl , , lysergide, and . nitrate, methylbenactyzium bromide, methylbenzethonium, 0220 Also, , maduramicin, mafenide, mafopra methylchromone, , methyldihydromor Zine, mafosfamide, magnesium citrate, magnesium glucon phine, , methyldopate, , meth ate, , , malethamer, malic ylphedrine, methylergonovine, methylformamide, methyl acid, malotilate, , manganese gluconate, manni nicotinate, 2-methyl-19-nortestosterone, 2-methyl-11-oxo tol, hexanitrate, mannomustine, mannosulfan, progestrone, methyl palmoxirate, methylparaben, meth manoZodil, , maridomycin, mariptiline, maroX ylphendiate, methylprednisolone aceponate, methylpred epin, maytansine, , , , meba nisolone acetate, methylprednisolone hemisuccinate, nazine, mebendazole, mebenoside, , mebeZo methylprednisolone phosphate, methylprednisolone Sulep nium iodide, , mebiquine, , tanate, , methylstreptonigrin, 4-methyltest mebrofenin, , mebutizide, , osterone, 7-methyltestosterone, 17-methyltestosterone, mecarbinate, mecetronium ethylsulfate, mechlorethamine, 7-methyltesosterone propionate, methylthionosine, 16-meth , mecinarone, , meclocycline, meclocy ylthioprogestone, methylthiouracil, methynodiol diacetate, cline Sulfosalicylate, , , , , , , metiaz , , mecloralurea, inic acid, metibride, meticrane, metildigoxin, metindizate, dibutyrate, mecloxamine, mecobalamin, mecrylate, mecys metioprim, metioxate, metipirox, , metiprena teine, , medazomide, , mediba line, , , metkephamid, metochalcone, Zine, , medorinone, medorubicin, medroge metocinium iodide, , iodide; stone, medronic acid, , medroxyprogestrone, metofenazate, , metolaZone, , metopi medroxyprogestrone acetate, , mefeclorazine, mazine, , metoprine, , metoquizine, , mefenidil, mefenidramium metilsulfate, metoserpate, metostilenol, metoxepin, metrafazoline, metral , mefeserpine, , , mefru indole, metrazifone, metrenperone, , metri side, megalomicin, acetate, meglitimide, megucy fonate, metrifudil, metrizamide, metrizoic acid, metronida cline, meglumine, meglutol, , melarsonyl, melar Zole, meturedepa, , metyridine, metyrosine, US 2011/O 159073 A1 Jun. 30, 2011 26 , mexafylline, , mexenone, , timox, nifurtoinol, nifurvidine, nifurzide, , nihy mexiprostil, mexoprofen, mexrenoate, meZacopride, draZone, , nileprost, nilprazole, , meZepine, mezilamine, , , , , , nimaZone, , micinicate, micronomicin, , midaglizole, midalcip , nimidane, , , nimustine, ran, midamaline, midazogrel, , midecamycin, niometacin, , nipradillol, niprofaZone, niridazole, , mifentidine, , mifobate, miglitol, nisbuterol, , , , mikamycin, millacemide, milemperone, millipertine, miloxa acetate, nitarSone, , nithiamide, nitracrine, cin, milrinone, milverine, mimbane, , , nitrafudam, nitralamine, nitramisole, nitraquaZone, mindolilol, mindoperone, minepentate, minocromil, minoxi , nitrefazole, , nitricholine, nitrochlo dil, mioflazine, mipimazole, mirincamycin, miristalkonium fene, nitrocycline, nitrodan, nitrofurantoin, nitroglycerin, chloride, miroprofen, mirosamicin, misonidazole, misopros , nitromide, , nitroscanate, nitrosul tol, mitindomide, mitobronitol, mitoclomine, mitoguaZone, fathiazole, nitroXinil, nitroxoline, nivaZol. nivimeldone, mitolactol, mitomycin, mitonafide, mitopodozide, mitoqui nixylic acid, , nizofenone, noberastine, nocloprost, done, , mitotenamine, mitoxantrone, mitoZolomide, nocodazole, nofecamide, nogalamycin, nolinium bromide, , mixidine, , mitindomide, , nomelidine, , nonabine, nonaper mitobronitol, mitoclomine, mitoguaZone, mitolactol, mito one, nonapyrimine, nonoxynol-4, nonoxynol-9, noracymeth mycin, mitonafide, mitopodozide, mitoquidone, mitotane, adol, norbolethone, norbudrine, , , mitotenamine, mitoxantrone, mitoZolomide, mivacurium , nordefrin, , , nore chloride, mixidine, mizoribine, mobecarb, mob enzoxamine, mocimycin, mociprazine, , moctamide, thandrolone, norethindrone, norethindrone acetate, nor , modaline, mofebutaZone, mofloverine, mofoXime, ethynodrel, noreximide, , norfloxacin, norfloxa molfarnate, molinaZone, , molracetam, molsidom cin Succinil, norflurane, , , ine, furoate, monalaZone disodium, monensin, , , , norletimol, nor monobenzone, monoethanolamine, monometacrine, mono levorphanol, , , , phosphothiamine, monothioglycerol, monoxerutin, montire , nortestosterone propionate, , lin, , mopidamol, mopidralazine, . , , nosantine, , nosihep moduizone, , , , , tide, novobiocin, , noxytiolin, nuclomedone, moricizine, morinamide, morniflumate, morocromen, nuclotixine, nufenoXole. nuvenZepine, nylestriol, nylidrin, moroxydine, , , morSuximide, mot and nystatin. apiZone, , motretinide, moveltipril, moxadolen, 0222 Also, , ocilitide, ocrylate, octabenzone, moxaprindine, , moXaverine, , moX octacaine, octafonium chloride, , octamylamine, estrol, moxicoumone, moxipraquine, , moXnida octanoic acid, octapinol, octastine, octaverine, octaZamide, Zole, moxonidine, , murabutide, murocamide, octenidine, octenidine saccharin, octicizer, octimibate, octo muZolimine, mycophenolic acid, my fadol, myralact, myro rylene, , , octotiamine, octoxynol-9, phine, and myrtecaine. , octrizole, , oftormine, oftasceine, 0221. Also, nabazenil, , nabitan, naboctate, nabu olaflur, olaquindox, oleanomycin, oletimol, oleyl alcohol, metone, nadide, , , naepaine, nafamo.stat, olivomycin a, olimidine, olpimedone, olSalazine, oltipraz. nafazatrom, nafcaproic acid, , nafenodone, olvanil, , omidoline, omoconazole, omonasteine, nafenopin, nafetolol, nafimidone, nafiverine, , nafo , , ontianil, opiniazide, . mine, nafoxadol, , nafronyl, naftalofos, naftaZone, oraZamide, orbutopril, orconazole, orestrate, ormetoprim, naftifine, , naftoxate, naftypramide, , , ornipressin, ornithine, omoprostil, orotic acid, nalidixic acid, , , , naltrex orotirelin, orpanoxin, , , osalmid, one, naminterol, namoXyrate, nanaprocin, cyclo osmadizone, , otimerate Sodium, ouabain, tate, , nandrolone phenpropionate, cipionate, oXabrexine, oxaceprol, , oxa nanofin, nantradol, napactadine, napamezole, naphthonone, dimedine, , oxaflumazine, oxagrelate, Oxalinast, naprodoxime, naproxen, naproXol, , narasin, natamy oxaliplatin, oXamarin, oxametacin, oxamisole, oxamniquine, cin, naxagolide, naxaprostene, , nebidrazine, , , oxantel, oxapadol, , , nebracetam, , , neflu oxapropanium iodide, , , oxarbazole, mozide, , neleZaprine, neoarsphenamine, neocin , oxazafone, , oxazidione, , chophen, nequinate, neraminol, nerbacadol, nesapidil, nesos oxazorone, , oxdralazine, , oxen teine, netilmicin, netobimin, neutramycin, , , dolone, Oxepinac, oxetacillin, oxethazaine, , niacinamide, nialamide, , nibroxane, nicafenine, oxfendazole, Oxfenicine, oxibendazole, OXibetaine, oxicona nicainoprol, nicametate, nicarbazin, nicarpidine, , Zole, , oxidronic acid, , oxifungin, niceritrol, niceverine, niclofolan, niclosamide, nicoboxil, , oximonam, OXindanac, oxiniacic acid, oxipero nicoclonate, nicocodine, , , nicofi mide, , oxiramide, oxisopred. Oxisuran, oxitefo brate, nicofuranose, nicofurate, nicogrelate, nicomol, nico nium bromide, oxitriptan, , , morphine, nicopholine, , nicothiaZone, nicotinyl , , phenpropionate, oxola alcohol, nicoXamat, nictiazem, nictindole, nodroxyZone, mine, , , Oxonazine, oxophenars , nifemalol, , , nifluridide, ine, oxoprostol, , oXprenoate potassium, nifuradene, nifuraldeZone, nifuralide, nifuratel, nifuratrone, , oxtriphylline, oxybenzone, , oxy nifurdazil, nifurethazone, nifurfoline, nifurimide, nifurizone, chlorosene, oxycinchophen, oxyclozanide, , oxy nifurmazole, nifurmerone, nifuroquine, nifuroxazide, dipentonium chloride, , , oxymeta nifuroxime, nifurpipone, nifurpirinol, nifurprazine, Zoline, , , oxypendyl. nifurquinazole, nifusemizone, nifursol, nifurthiazole, nifur , oxyphenbutaZone, , oxy US 2011/O 159073 A1 Jun. 30, 2011 27 purinol, oxypyrronium bromide, oxyquinoline, oxyridazine, tremide, , , pimondiazole, , oxysonium iodide, oxytiocin, oZagrel, and oZolinone. , pinadoline, pinafide, , 0223 Also, pacrinolol, pactamycin, padimate, . , pincamide, , pinolcaine, , palatrigine, paldimycin, palmidrol, palmoxiric acid, pam pioglitaZone, pipacycline, pipamazine, pipaperone, abrom, pamaquine, , pamidronic acid, pancuro pipazethate, pipebuZone, , pipemidic nium bromide, panidazole, , patenicate, pan acid, bromide, , , pip thenol, , , papaverine, eracillin, piperamide, piperazine, piperazinedione, piperidol papaveroline, parachlorophenol, paraflutizide, , ate, piperilate, , , , pipobro , acetate, paranyline, parap man, pipoctanone, , piposulfan, enzolate bromide, parapropamol, pararosaniline, pararosa palmiate, , pipoxolan, pipradimadol, pipradol, niline embonate, , parbendazole, parconazole, pipramadol, pipratecol, piprinhydrinate, piprocurarium pareptide, parethoxycaine, pargeverine, , pargyline, iodide, piprofurol, piprozolin, , piquizil, pirac paridocaine, parodilol, , , paroX etam, , pirarubicin, piraxelate, piraZmonam, ypropione, parsalmide, partricin, parvaquone, pasiniazid, piraZolac, pirbenicillin, , pirdonium bromide, paulomycin, paxamate, paZelliptine, paZOxide, pcnu, pecilo pirenoxine, piremperone, , pirepolol, , cin, pecocycline, pefloxacin, , pelretin, pelrinone, pirfenidone, , piridicillin, , piridoxilate, pemedolac, pemerid, , , , piridironic acid, pirifibrate, pirindazole, pirinixic acid, pirin , pendecamaine, , penflutizide, pengi ixil, piriprost, piriqualone, , , piritr toxin, penicillamine, procaine, penicillin, penimepicycline, exim, pirlimycin, , pirmagrel, pirmenol, pirnabine, penimocycline, penirolol, , penoctonium bro piroctone, pirogliride, , , pirolazamide, mide, penprostene, , pentacynium chloride, pen piromidic acid, piroXantrone HCL, cinnamate, taerythritol tetranitrate, , pentagastrin, pentag piroxicillin, piroXimone, pirozadil, pirprofen, pirquinoZol. estrone, pentalamide, pentamethonium bromide, pirralkonium bromide, pirtenidine, pitenodil, pitofenone, pentamethylmelamine, , pentamoxane, pentam pituxate, , pivenfrine, pivopril, , ustine, pentapiperide, pentapiperium methylsulfate, pen pizotyline, plafibride, plaunotol, pleuromulin, , taquine, , pentetate calcium trisodium, pentetic podilfen, podophylloxoxin, methylsulfate, poli acid, bromide, penthrichloral, pentiapine male docanol, polythiazide, ponalrestat, ponfibrate, porfiromycin, ate, pentifylline, pentigetide, pentisomicin, pentisomide, poskine, potassium , potassium nitraze pentizidone, , tartrate, , pate, potassium sodium tartrate, potassium sorbate, potas pentopril, , pentosan polysulfate Sodium, pentosta sium thiocyanate, , prajmalium, chlo tin, pentoxifylline, pentrinitrol, pentylenetrazole, peplomy ride, , pramiracetam, pramiverine, pramoxime, cin, pepstatin, peraclopone, peradoxime, , peralo prampine, pranolium chloride, pranoprofen, pranosal, pras pride, peraquinsin, perastine, peratizole, perbufylline, terone, pravastatin, praxadine, , prazepine, praZiqu perfluamine, perflunafene, , perhexylene, periciaZ antel, , prazocillin, , preclamol, , ine, perimetazine, perindopril, perindoprilat, perisoxal, per , , , , lapine, , , persilic acid, , prednisolone, prednisolone hemisuccinate, prednisolone pexantel, phanquone, , , , Steaglate, , , prednival, pred phenact tropinium chloride, , . nylidene, prefenamate, , pregnenolone Succi phenamaZoline, , phenarsone Sulfoxylate, nate, , , prenisteine, prenoverine, , , phencarbamide, phencyclid , , pretarnazium iodide, pretiadil, ine, , , , phenesterin, pribecaine, , prideperone, , prifelone, pri penethicillin, phenformin, , phenicarbazide, finium bromide, prifuroline, , primaperone, pri , phenindione, , pheniraminie, maquine, , , primycin, prinomide, pris phenisonone, , , phenobutiodil, tinamycin, prizidilol, , , , phenolphtalein, phenolsulfonphthalein, , phe probicromil, probucol, , procaine, procarba noperidine, phenothiazine, , , Zine, , , , , , , phenprocoumon, phen proclonol, procodazole, , , prodeco promethamine, , , , nium bromide, , prodipine, prodolic acid, profa , phenylaminosalicylate, phenylbutaZone, phe dol, profeXalone, proflavine, , , proglu nylethyl alcohol, phenylmercuric acetate, phenylmercuric metacin, , , , proline, borate, phenylmercuric chloride, phenylmercuric nitrate, , prolonium iodide, , , phenylmethylbarbituric acid, , phe , , promolate, , pron nylthildne, , phenyramidol, phenyloin, etalol, , , , , phethafbital, , , phosphoramide mus propanocaine, , proparacaine, pro tard, , phthalofyne, phthalysulfacetamide, phthalyl patyl nitrate, propazolamide, propendiazole, propentofylline, Sulfamethizole, phthalylsulfathiazole, phytic acid, phytona propenZolate, , propetamide, , propi diol diphosphate, phytonadione, pibecarb, pibenZimol, cillin, propikacin, propinetidine, propiolactone, propiom pibecarb, pibenZimol, , picafibrate, picartamide, azine, propipocaine, , propisergide, , , , piclonidine, piclopastine, picloxydine, , , , , pro picobenzide, picodralazine, picolamine, piconol, picoperine, poxyphene, , propyl docetrizoate, propylene gly picoprazole, picotamide, picotrin diolamine, picumast, col, propylene glycol monostearate, propyl gallate, propyl pidolic acid, pifamine, pilfenate, pifexole, piflutiXole, hexedrine, propyliodone, propylparaben, propylthiouracil, pifoXime, piketoprofen, , pimoclone, pimefhyl propyperone, , propyromazine bromide, line, pimelautde, pimetacin, , pimetime, pime produaZone, produinolate, , proroxan, US 2011/O 159073 A1 Jun. 30, 2011 28 proscillaridin, prospidium chloride, prostalene, proSulpride, traline, , SetaZindol, , , Sevit prosultiamine, proterguride, protheobromine, . ropium mesilate, , Sevopramide, siagoside, prothixene, protiofate, protionamide, protirelin, protizinic , siccanin, , , silicristin, silidi acid, , protoveratine, , proxazole, anin, silver Sulfadiazine, simetride, Simfibrate, simtraZene, proxibarbal, proxibutene, proXicromil, proxifeZone, proXor , sineflungin, sintropium bromide, Sisomicin, phan, proxyphylline, proZapine, , psilocy Sitalidone, sitofibrate, sitogluside, sodium benzoate, sodium bine, pumiteba, puromycin, pyrabrom, pyran copolymer, pyr dibunate, sodium ethasulfate, sodium formaldehyde sulfoxy antel, pyrathiazine, , pyrazofurin, pyricarbate, late, Sodium gentisate, sodium gualenate, Sodium nitrite, pyridarone, pyridofylline, bromide, pyridox Sodium nitroprusside, , sodium phenylac ine, pyrimethamine, pyrimitate, pyrinoline, pyrithione , etate, sodium picofosfate, Sodium picosulfate, Sodium stib , pyritidium bromide, , pyronine, ocaptate, , sodium tetradecyl sulfate, pyrophenindane, , pyroxamine, , Sodium thiosulfate, , Solasulfone, Solpecainol, pyrrocaine, pyrroliphene, pyrrolnitrin, pyrvinium chloride, Solypertine. Somantadine, Sopitazine, Sopromidine, Soqui and pytamine. nolol, Sorbic acid, Sorbinicate, Sorbinil, Sorbitan monolaurate, 0224. Also, , , quatacaine, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan , quaZinone, quaZodine, quaZolast, , monostearate, Sorbitan trioleate, Sorbitan tristearate, Sorbitol, quillifoline, quinacainol, quinacillin, quinacrine, quinaldine Sorndipine, , Soterenol, spaglumic acid, sparfosic acid, blue, quinapril, quinaprilat, , , quincar sparsomycin, , spectinomycin, spiclamine, spiclo bate, quindecamine, quindonium bromide, quindoxin, mazine, , , , spiramycin, Spi , , quinethaZone, quinetolate, quineza rapril, spiraprilat, , spirgetine, spirilene, spirofyl mide, quinfamide, acetate, , quin line, Spirogermanium, spiromustine, , dine, , quinocide, , quinterenol, quintiofos, spiroplatin, , spirotriazine, , SpiroX quinuclium bromide, , , and quisul atrine, SpiroXepin, Spizofurone, stallimycin, stanolone, stan tazine. Zolol, , Stearyl alcohol, Stearylsulfamide, Steffimy 0225. Also, racefemine, racemethionine, racemethor cin, acetate, , Stercuronium iodide, phan, racemetirosine, , , rafoxanide, Stevaladil, Stibamine glucoside, Stibophen, Stilbamidine, stil ralitoline, , ramciclane, ramefenaZone, ramipril, bazium iodide, stilonium iodide, Stirimazole, , Sti ramiprilat, ramixotidine, ramnodignin, ranimustine, ranimy rocamide, Stirifos, , streptonicozid, streptoni cin, , , rapamycin, rathyronine, raZinodil, grin, Streptovarycin, Streptozocin, Strinoline, , raZobazam, raZOxane, , recainam, , , Subathizone, Subendazole. Succimer, Succinylcho relomycin, , , rentiapril, repirinast, line chloride, Succinylsulfathiazole, Succisulfone, repromicin, , recimetol, rescinnamine, , Suclofenide, . Sucrose octaacetate, Sudexanox, resorantel, resorcinol, resorcinol monoacetate, retelliptine, Sudoxicam, , Sufosfamide, , , , revenast, ribavirin, riboflavin, riboflavin 5'-phos , Sulbactam pivoxil, , Sulbenox, Sul phate, riboprine, ribostamycin, , ridiflone, , bentine, Sulbutiamine, Sulclamide, Sulconazole, Sulfabenz, rifamide, rifampin, , , , rilap Sulfabenzamide, Sulfacarbamide, Sulfacecole, Sulfachlorpy ine, , rillmenidine, rilopiroX, riloZarone, rimanta ridazine, Sulfachrysoidine, Sulfaclomide, Sulfaclorazole, Sul dine, metilsulfate, , , rimit faclozine, Sulfacytine, Sulfadicramide, Sulfadimethoxine, Sul erol, rimoprogin, , rioprostil, , , fadoxine, Sulfaethidole, Sulfaguandide, Sulfaguanole, , ristianol, ristocetin, , ritiometan, rito Sulfalene, Sulfaloxic acid, SulfamaZone, Sulfamerazine, Sul drine, ritropirronium bromide, ritrosulfan, robenidine, rocas fameter, Sulfamethazine, Sulfamethoxazole, Sulfamethoxy tine, , rodocaine, rodorubicin, rofelodine, roflu pyridazine, Sulfamethoxypyridazine acetyl, Sulfametomi rante, rokitamycin, roletamide, rolgamidine, , dine, Sulfametrole, Sulfamonomethoxine, Sulfamoxole, rolicyprine, rolipram, rollitetracycline, rolodine, rolzirac Sulfanil amide, Sulfanitran, Sulfaperin, Sulfaphenazole, Sul etam, romifenone, , ronactolol, ronidazole, ronifi faproxyline, Sulfapyridine, Sulfaquinoxaline, Sulfarsphe brate, ronipamil, ronnel, ropitoin, , ropizine, namine, Sulfasalazine, Sulfasomizole, SulfaSuccinamide, Sul roquinimex, rosaprostol, rosaramicin, rosaramicin butyrate, fasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, rosaramicin propionate, rosoxacin, rosterolone, rotamicillin, Sulfatroxazole, SulfatroZole, Sulfazamet, , Sulfin rotoxamine, rotraxate, roXarsone, , roxi pyrazone, Sulfuram, Sulfisomidine, Sulfisoxazole, Sulfobro bolone, , , roXolonium metilsulfate, mophthalein, Sulfonethylmethane, , Sul roXoperone, rufloxacin, rutamycin, rutin, and ruvaZone. fonterol, , Sulfoxone sodium, Sullicrinat, 0226. Also, sabeluzole, saccharin, salacetamide, Salafi Sulindac, Sulisatin, Sulisobenzone, Sulmarin, Sulmazole, Sul brate, salantel, salaZodine, Salazossulfadimedine, Salazosul mepride, Sulinidazole, Sulocarbilate, Suloctidil, Sulosemide, famide, Salazosulfathiazole, Salethamide, Salfluverine, Sali Sulotroban, Suloxifen, , Sulprosal, Sulprostone, Sul cin, Salicyl alcohol, Salicylamide, Salicylanilide, salicylic tamicillin, Sulthiame, , Sultosilic acid, Sultropo acid, Salinazid, salinomycin, Salmefanol, , Salm nium, Sulverapride, Sumacetamol, , Sumetizide, isteine, Salprotoside, , salverine, Sancycline, Sangi Sunagrel, Suncillin, Supidimide, , , vamycin, Saperconazole, sarcolysin, , Sarmoxicil , Suricamide, , Suxemerid, SuXethonium lin, Sarpicillin, saterinone, satranidazole, Savoxepin, Scarlet chloride, SuxibuZone, Symclosene, Symetine, , and red, scopafungin, seclaZone, , , sec Syrisingopine. overine, , sedecamycin, Seganserin, seglitide, sel 0227. Also, taclamine, taglutimide, , talas egiline, selenium sulfide, selprazine, sematilide, Semustine, tine, , , , , talisomycin, tal sepazonium chloride, Seperidol, sequifenadine, serfibrate, metacin, talmetoprim, talniflumate, , talosalate, , serine, Sermetacin, , Sertaconazole, ser taloXimine, , taltrimide, tameridone, tameticillin, US 2011/O 159073 A1 Jun. 30, 2011 29 , tarnitinol, tamoxipen, , , utamide, tolciclate, toldimfos, tolfamide, , taprostene, tartaric acid, tasuldine, taurocholic acid, tauroli , , tolindate, toliodium chloride, tolip dine, tauromustine, tauroselcholic acid, taurultam, tazad rolol, tolmesoxide, , , tolnapersine, olene, taZanolast, tazaburate, taZeprofen, tazifylline, tolnidamine, toloconium metilsulfate, , tolonium taZiprinone, , tebatizole, tebuquine, teclothiazide, chloride, , toloxychlorinol, tolpadol, tolpentam , , tefazoline, tefenperate, tefludazine, teflu ide, , toliprazole, tolpronine, , rane, teflutiXol, tegafur, , temafloxacin, temaro tolpyrramide, tolduinzole, tolrestat, toltraZuril, , tene, , , temelastine, , temodox, tolycaine, tomelukast, tomoglumide, tomoxetine, tomox temozolomide, temurtide, tenamfetamine, , iprole, , , toprilidine, tonazocine, topi , tenilsetam, teniposide, , tenoni ramate, toprilidine, , toguizine, torasemide, toe trozole, , tenylidone, teopranitol, teoprolol, tepir bafylline, , tosifen, to Sufloxacin, toSulur, indole, tepoxalin, , terbinafine, terbucromil, terbufi toyocamycin, toyomycin, traboxepine, , , brol, terbuficin, terbuprol, , terciprazine, , , trandolapril, tranexamic acid, tra , , , , , nilast, transcainide, trantelinium bromide, tranylcypromine, ternidazole, , terofenamate, teroxalene, teroxirone, trapencaine, , traxanox, trazilitine, esilate, tra hydrate, , tesicam, tesimide, , tes Zodone, traZolopride, trebenzomine, trecadrine, treloxinate, tosterone, cypionate, , tes acetate, , trenizine, troSulfan, trepibu tosterone ketolaurate, testosterone phenylacetate, testoster tone, , trepirium iodide, treptilamine, trequensin, one propionate, , , tetracaine, acetate, trethinium tosilate, trethocanoic acid, tre tetrachloroethylene, tetradonium bromide, tetraethylammo tinoin, , triacetin, triafungin, triamcinolone nium chloride, tetramethrin, tetramisole, , tetran acetonide-phosphate, triamcinolone benetonide, triamcino toin, , tetriprofen, tetronasin 5930, tetroquinone, lone diacetate, , triamcinolone tetroxoprim, tetrydamine, texacromil, thalicarpine, thalido hexacetonide, triampyZine, , triazinate, triazi mide, , , , thenium closylate, the quone, , tribendilol, tribenoside, , nyldiamine, , , theofibrate, theo tribromsalan, tribuZone, triacetamide, trichlormethiazide, phylline, thiabendazole, thiacetarsamide, , trichlormethine, trichloroacetic acid, , tric thiambutosine, thiamine, thiamiprine, , thia ribine phosphate, triclabendazole, triclacetamol, triclazate, mylal, thiazesim, thiazinamium chloride, thiazolsulfone, thi triclobisonicum chloride, , triclodazol, tri ethyperazine, thihexinol methylbromide, thimerfonate, clofenol, piperazine, , triclofylline, , tri thimerosal, thiocarbanidin, thiocarzolamide, thiocolchioside, closan, tricyclamol chloride, chloride, trientine, thiofuradene, thioguanine, thioguanine alpha-deoxyriboside, triethylenemelamine, triethylenephosphoramide, trifenagrel, thioguanine beta-deoxyriboside, thioguanosine, thiohexam trifezolac, triflocin, , triflumidate, trifluomepra ide, thioinosine, thiopental, , , zine, , , , trifluri , thiosalan, thiotepa, , thiothix dine, triflusal, trigevolol, , triletide, trilos ene, thiouracil, thiphenamil, thiphencillin, thiram, thonzo tane, , , , trimedoxime nium bromide, , , threonine, thymi bromide, , trimeprazine, , tri dine, , thymol iodide, thymopentin, thyromedan, methadione, trimethamide, trimethaphan camsylate, trime thyropropic acid, tiacrilast, tiadenol, tiafibrate, , thidinium methosulfate, , trimethoprim. tiametonium iodide, tiamulin, tianafac, , tiapamil, , , trimexiline, , trimo tiapirinol, , , tiaprost, tiaramide, tia prostil, trimoxamine, , trioXSalen, tripamide, tri Zoflurin, tiaZuril, tibalosin, tibenalast sodium, tibenzate, tib paranol, , tripotassium dicitratobismuthate, eZonium iodide, , tibric acid, tibrofan, tic-mustard, , tritioZine, , trityl , trixolane, propionate, ticarbodine, , ticarcillin trizoxime, trocimine, troclosene potassium, trofosfamide, cresyl, ticlatone, ticrynafen, , tiemoium iodide, tieno , , tromantadine, tromethamine, carbine, tienopramine, , tifemoxone, tiflamizole, tropabazate, , tropapride, , tropen tiflorex, , tiflucarbine, tiformin, tifurac, tigemonam, Ziline bromide, tropigline, tropiprine, tropodifene, trospecto , tigloidine, , , , tiliq mycin, , troXerutin, , troXolamide, uinol, , tilmicosin, tilomisole, tillorone, tilozepine, til troxonium tosilate, troxypyrrolium tosilate, troxypyrrolium Suprost, timefurone, timegadine, timelotem, timepidium bro tosilate, truXicurium iodide, truXipicurium iodide, tryparsa mide, , acetate, timofibrate, mide, , tryptophane mustard, , timonacic, , tinabinol, tinazoline, timidazole, tubercidine, , tubulozole, , tinisulpride, tinofedrine, tinoridine, tiocarlide, tioclomarol, tulobutrol, tuvatidine, , tylocrebin, tylosin, tioconazole, tioctilate, , tiodonium chloride, , tyropanic acid, and . tiomergine, , tioperidone, tiopinac, tiopronin, 0228. Also, , ubidecarenone, ubisindine, ufe tiopropamine, , tiotidine, tioxacin, tioXamast, tioX namate, ufiprazole, , , undecoylium aprofen, tioxidazole, tioXolone, tipentosin, , chloride, undecyclenic acid, uracil mustard, , urea, tipetropium bromide, tipindole, , , tipri uredepa, uredofos, urefibrate, urethane, uridine, urSodeoxy nast, tipropidil, tiprostanide, tiprotimod, tiquinamide, tiqui , and urSucholic acid. Zium bromide, tiratricol, tiropramide, tisocromide, tisopu 0229. Also, Vadocaine, Valconazole, Valdetamide, val rine, tisoquone, tivandizole, tixadil, tiXanox, dipromide, Valine, , , , Val pivalate, tiZabrin, tianidine, tizolemide, tizoprolic acid, proate pivoxil, Valproic acid, , Valtrate, Vancomy tobuterol, tocamide, tocamphyl, tocofenoxate, tocofibrate, cin HCl, vaneprim, Vanillin, vanitolide, Vanyldisulfamide, tocophersolan, todralazine, , tofetridine, tofisoline, vapiprost, , Velnacrine maleate, ven , , , , tolboxane, tolb lafaxine, Veradoline, , , Verazide, Verilo US 2011/O 159073 A1 Jun. 30, 2011 30 pam, Verofylline, , Vetrabutine, Vidarabine, 0238. In some aspects, the concentration of bioactive Vidarabine phophate, , , , vinbar agent can be selected to provide a desired tissue concentration bital, vinblastine, , Vincamine, Vincanol, Vin of bioactive agent at the treatment site. Given the site-specific cantril, Vincofos, Vinconate, Vincristine, vindrburnol, Vin nature of the inventive devices, methods and systems, it will desine, Vindepidine, Vinformide, Vinglycinate, Vinpocetine, be apparent that the tissue concentration of bioactive agent Vinpoline, Vinrosidine, Vintiamol, Vintriptol, , will be greater at the treatment site than at areas within the vinylether, Vinzolidine, viomycin, Viprostol, Vidualine, Vicqui patient outside the treatment site. As discussed herein, this dil, Virginiamycin factors, ViroXime, Visnadine, Visnafylline, provides several benefits to the patient, such as reduced risk of Vitamine, and . toxic levels of the bioactive agent within the body, reduced 0230 Also, warfarin. risk of adverse affects caused by bioactive agent outside the 0231. Also, , Xanoxic acid, Xanthinol niacinate, treatment site, and the like. The location of the bioactive agent Xanthiol, Xantifibrate, Xantocillin, Xenalipin, Xenazoic acid, on or within the device and on or within the polymer can also Xenbucin, Xenipentone, Xenthiorate, Xenygloxal, Xenyhexenic affect tissue concentration of bioactive agent (for example, acid, Xenylropium bromide, , Xibornol, Xilobam, when substantially the entire device body includes bioactive Ximoprofen, Xinidamine, Xinomiline, Xipamide, . agent, or selected portion(s) of the device body include bio , , , Xylocoumarol. Xylometa active agent). Moreover, inclusion of optional coating layers Zoline, and Xyloxemine. that contain bioactive agent can also impact tissue concentra tion of bioactive agent. 0232 Also, yohimbic acid. 0239. The particular bioactive agent, or combination of 0233. Also, Zabicipril, , Zafiuleptine, Zaltidine, bioactive agents, can be selected depending upon one or more , Zaprinast, Zardaverine, mesylate, of the following factors: the application of the device (for Zepastine, , Zetidoline, Zidapamide, Zidometacin, example, Subretinal implant, intraocular implant, intraocular Zidovudine, Zilantel, Zimeldine, Zimidoben, Zinc acetate, Zinc injection, and the like), the amount of the device composed of phenolsulfonate, Zinc undecylenate, Zindotrine, , the polymer material, the condition to be treated, the treat Zinoconazole, , ZinviroXime, . Zocainone, ment method, the anticipated duration of treatment, charac Zofenopril, Zoficonazole, , , Zolenzepine, teristics of the implantation site, the number and type of Zollertine, Zolimidine, Zoliprofen, Zoloperone, , bioactive agents to be utilized, and the like. , , , , , 0240. The amount of the bioactive agent that is to be Zorubicin, , , Zuclomiphene, Zuclo delivered to the treatment site may be determined by one of phenthixol, and Zylofuramine. ordinary skill in the art and will vary depending on the con 0234. The bioactive agent can be present as a liquid, a dition to be treated and the particular treatment method. In finely divided solid, or any other appropriate physical form. addition, the amount also will depend upon the particular Typically, but optionally, the biodegradable composition will formulation of the bioactive agent. Further, the amount of the include one or more additives, such as diluents, carriers, bioactive agent to be delivered also takes into account the excipients, stabilizers, or the like. period of time expected for administration and/or treatment 0235. The particular bioactive agent, or combination of and/or the frequency or periodicity of Such administration bioactive agents, can be selected depending upon one or more and/or treatment. of the following factors: the application of the device (for 0241. In some embodiments, an intraocular or subretinal example, Subretinal implant or intraocular implant), the Sustained release delivery device has a bioactive agent elution amount of the device composed of the polymeric material (for rate of at least 0.0001 ug per day, in other embodiments at example, percentage of the device fabricated of degradable least 0.001 ug per day, in other embodiments at least 0.01 ug material, inclusion of a biodegradable material as a coating on per day, in other embodiments at least 0.1 ug perclay, in other a surface of the body member, as well as the amount of surface embodiments at least 1 lug per day, in other embodiments at provided with the coating), the condition to be treated, the least 10 ug per day. In some embodiments, an intraocular anticipated duration of treatment, characteristics of the device has an elution rate of at least 0.01 ug per day, in other implantation site, the number and type of bioactive agents to embodiments at least 0.1 ug per day, in other embodiments at be utilized, and the like. least 1 ug per day, in other embodiments at least 10 ug per day, 0236. The concentration of the bioactive agent in the poly in other embodiments at least 100 g per day, and in other meric material can be provided in the range of about 0.01% to embodiments at least 1000 ug per day. about 75% by weight, or about 0.01% to about 50% by 0242. The elution rate can vary and can be customized as weight, based on the weight of the final polymeric material. desired for each type of eye condition treated, the nature of the Preferably, the bioactive active agent is present in the poly ocular tissue being treated (for example, Subretinal versus meric material in an amount in the range of about 75% by intraocular), the treatment method, the selected bioactive weight or less, preferably about 50% by weight or less. The agent(s), the potency of bioactive agent(s), the size of the amount of bioactive agent in the polymeric material can be in bioactive agent(s), and the severity of the condition being the range of about 1 Jug to about 10 mg. or about 100 ug to treated. In some aspects, the elution rate can be customized about 1000 ug, or about 100 lug to about 500 g. depending upon any physiological barriers that may exist 0237. In some aspects, the concentration of bioactive between the implant site and the tissue to be treated. In gen agent can also be selected to provide a desired elution rate eral, it is desired to maximize the total bioactive agent(s) from the device. As discussed herein, some aspects of the loading while maintaining mechanical integrity of the device. invention provide methods including steps of selecting one or 0243 The sustained release delivery devices can be more bioactive agents to administer to a patient, determining implanted to release or deliver bioactive agent(s), more par a treatment course for a particular patient, and formulating the ticularly a therapeutic dosage of the bioactive agent(s), for a polymeric material to achieve the treatment course. sustained period of time, that is for example for about 1 month US 2011/O 159073 A1 Jun. 30, 2011

to about 20 years, such as from about 6 months to about 5 more preferably at least 93%, more preferably at least 94%, years and more specifically from about 3 months to 2 years. In more preferably at least 95%, more preferably at least 96%, Some embodiments the Sustained release device releases the more preferably at least 97%, more preferably at least 98%, bioactive agent(s) by pseudo Zero order release kinetics. more preferably at least 99%, more preferably all of the 0244. The devices can be utilized to deliver any desired bioactive agent delivered by the device is delivered to the bioactive agent or combination of bioactive agents to the eye, treatment site. As used herein, the terminology "does not such as the bioactive agents described herein. The amount of deliver any significant amount of bioactive agent to healthy bioactive agent(s) delivered over time is preferably within the tissues” is understood to mean that less than 95%, more therapeutic level, and below the toxic level. For example, a preferably less than 90%, more preferably less than 80%, preferred target dosage for intraocular delivery of triamcino more preferably less than 70%, more preferably less than lone acetonide for use in treating diseases or disorders of the 60%, more preferably less than 50%, more preferably less eye is preferably in the range of about 0.5 lug/day to about 10 than 40%, more preferably less than 30%, more preferably ug per day. Preferably, the treatment course is greater than 6 less than 20%, more preferably less than 15%, more prefer months, more preferably greater than one year. Thus, in pre ably less than 10%, more preferably less than 5%, more ferred embodiments, the bioactive agent is released from the preferably less than 4%, more preferably less than 3%, more coated composition in a therapeutically effective amount for preferably less than 2%, more preferably less than 1% of the a period of 6 months or more, or 9 months or more, or 12 total bioactive agent delivered by the device. months or more, or 36 months or more, when implanted in a 0248. This is in contrast to systemic, topical, and oral patient. delivery mechanisms that may have been used to treat dis 0245. In some aspects, the concentration of bioactive eases and disorders of the eye, as such mechanisms require agent(s) can also be selected to provide a desired elution rate the administration of significantly larger dosages of bioactive from the device. As discussed herein, some aspects of the agents systemically, topically, or orally so as to deliver a invention provide methods including steps of selecting one or therapeutically effective amount of bioactive agent to the more bioactive agents to administer to a patient, determining treatment site. a treatment course for a particular patient, and formulating the polymeric material to achieve the treatment course. Polymers 0246. In some aspects, the concentration of bioactive 0249 Polymers useful in the sustained release delivery agent can be selected to provide a desired tissue concentration devices (e.g., as cores and/or as coating layers) are biocom of bioactive agent at the treatment site. Given the site-specific patible and may be biodegradable or biostable (i.e., non nature of the devices and methods, it will be apparent that the biodegradable). Representative biostable polymers include tissue concentration of bioactive agent will be greater at the polyurethanes, silicones, polyesters, polyolefins (e.g., poly treatment site than at areas within the patient outside the ethylene or polypropylene), polyisobutylene, acrylic poly treatment site. As discussed herein, this provides several ben mers, vinyl halide polymers, polyvinyl ethers, polyvinyl efits to the patient, such as reduced risk of toxic levels of the methyl ether, polyvinylidene halides, polyacrylonitrile, poly bioactive agent within the body, reduced risk of adverse vinyl ketones, polyvinyl aromatics, polyvinyl esters (e.g., affects caused by bioactive agent outside the treatment site, poly(alkyl(meth)acrylates) such as poly(methyl)methacry and the like. The location of the bioactive agent on or within late) or poly((butyl)methacrylate)), polyvinyl amides, polya the device and on or within the polymer can also affect tissue mides, polycaprolactam, polycarbonates, polyoxymethyl concentration of bioactive agent (for example, when Substan enes, polyimides, polyethers, polyurethanes, rayon, rayon tially the entire device includes bioactive agent, or selected triacetate, cellulose acetate, cellulose butyrate, cellophane, portion(s) of the device include bioactive agent). Moreover, cellulose nitrate, cellulose propionate, cellulose ethers, car inclusion of optional coating layers that contain bioactive boxymethyl cellulose and copolymers (e.g., polyethylene agent can also impact tissue concentration of bioactive agent. vinyl acetate) and blends of the above polymers. 0247. In some embodiments, the invention provides for 0250 Representative examples of biodegradable poly the treatment of disorders or diseases of the choroid and the mers include poly(L-), polycaprolactone, poly(lac retina. As such, the bioactive agents may be instilled directly tide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybu in the choroid, the retina or Subretinal space, so as to deliver tyrate-co Valerate), polydioxanone, polyorthoesters, the bioactive agent precisely to the portion of the tissue being polyanhydrides, poly(glycolic acid), poly(D.L. lactic acid), treated. In some embodiments, the invention provides for the poly(glycolic acid-co-trimethylene carbonate), poly(phos treatment of disorders or diseases via intraocular routs, for phate esters), polyphosphoester urethanes, poly(amino example, using devices that are inserted and implanted in the acids), cyanoacrylates, poly(trimethylene carbonates), poly vitreous of the eye. Such localized delivery to various targeted carbonates, poly(iminocarbonates), polyesters, copoly(ether portions of the eye is efficient and delivers the bioactive agent esters), polyalkylene oxalates, polyphosphaZenes and substantially only to the portion of the eye being treated and copolymers and blends of the above polymers. Biodegradable does not deliver any significant amount of bioactive agent to materials such as fibrin, fibrinogen, cellulose, dextrans, healthy tissues. As used herein, the terminology delivery Sub polysaccharides, starch collagen, chromic gut, and hyalu stantially only to the portion of the eye being treated is under ronic acid could also be used. stood to mean that at least 5%, more preferably at least 10%, 0251 Selection of the polymers may depend, for example, more preferably at least 20%, more preferably at least 30%, on the desired properties of the sustained delivery device more preferably at least 40%, more preferably at least 50%, including the desired bioactive agent that is to be delivered by more preferably at least 60%, more preferably at least 70%, the device and the rate and duration of desired bioactive agent more preferably fit least 75%, more preferably at least 80% release. more preferably at least 85%, more preferably at least 90%, 0252. In some embodiments, the biocompatible polymer more preferably at least 91%, more preferably at least 92%, is made up, in whole or in part, of repeating caprolactone US 2011/O 159073 A1 Jun. 30, 2011 32 monomer units (e.g., poly(caprolactone) or co-polymers (such as adherence, durability, flexibility) and bioactive thereof). It has been found that polycaprolactone is well tol release characteristics as compared to the polymers when erated by the retinal tissue and can elute bioactive agents used alone or in admixture with other polymers previously without eliciting unacceptable inflammatory response or known. For example the polymeric material can include an complications. For example, polycaprolactone can elute Ste adherent polymer and a polymer having drug release charac roid for a period of at least 4 weeks without eliciting unac teristics. ceptable inflammatory response or complications. Thus, in 0258. In some aspects the adherent polymer preferably one embodiment, the device is formed using a biodegradable includes poly(alkyl(meth)acrylates) and poly(aromatic polycaprolactone polymer matrix. In another embodiment, (meth)acrylates), where “(meth) will be understood by those the device includes corticosteroid triamcinolone acetonide in skilled in the art to include such molecules in either the acrylic a biodegradable polycaprolactone polymer matrix. Such and/or methacrylic form (corresponding to the acrylates and/ embodiments may optionally include a core. or methacrylates, respectively). 0253) In some embodiments the polymer comprises a first 0259 Examples of suitable poly(alkyl (meth)acrylates) polymer and a second polymer. Suitable first polymers and include those with alkyl chain lengths from 2 to 8 carbons, second polymers can be prepared using conventional organic inclusive, and with molecular weights from 50 kilodaltons to synthesis procedures and/or are commercially available from 900 kilodaltons. In one preferred embodiment the polymeric a variety of sources. Preferably, such polymers are either material includes a poly(alkyl (meth)acrylate) with a molecu provided in a form suitable for in vivo use or are purified for lar weight of from about 100 kilodaltons to about 1000 kilo Such use to a desired extent (for example, by removing impu daltons, preferably from about 150 kilodaltons to about 500 rities) by conventional methods available to those skilled in kilodaltons, most preferably from about 200 kilodaltons to the art. about 400 kilodaltons. An example of a particularly preferred 0254 For application to a core, a coating composition can polymer is poly (n-butyl methacrylate). Examples of other be prepared to include a solvent, a first polymer and second preferred polymers are poly(n-butyl methacrylate-co-methyl polymer dissolved in the solvent, and one or more bioactive methacrylate, with a monomer ratio of 3:1, poly(n-butyl agents dispersed in the polymer/solvent. The solvent is pref methacrylate-co-isobutyl methacrylate, with a monomer erably one in which the polymers form a true solution. The ratio of 1:1 and poly(t-butyl methacrylate). Such polymers bioactive agent(s) can either be soluble in the solvent or may are available commercially (e.g., from Sigma-Aldrich, Mil form a dispersion in the solvent. In some embodiments, the waukee, Wis.) with molecular weights ranging from about solvent is (THF). Other solvents may also be 150 kilodaltons to about 350 kilodaltons, and with varying used, for example, alcohols (such as , butanol, pro inherent viscosities, solubilities and forms (e.g., as slabs, panol, isopropanol, and the like), alkanes (such as haloge granules, beads, crystals or powder). nated or unhalogenated alkanes such as hexane and cyclohex 0260 Examples of suitable poly(aromatic (meth)acry ane), amides (such as dimethylformamide), ethers (such as lates) include poly(aryl (meth)acrylates), poly(aralkyl (meth) ), ketones (such as methylketone), aromatic com acrylates), poly(alkaryl (meth)acrylates), poly(aryloxyalkyl pounds (such as and Xylene), acetonitrile, and esters (meth)acrylates), and poly (alkoxyaryl (meth)acrylates). (such as ethyl acetate). 0261 Examples of suitable poly(aryl (meth)acrylates) 0255. The coating layer formed from the coating compo include poly(9-anthracenyl methacrylate), poly(chlorophe sition is biocompatible. In addition, the layer is preferably nyl acrylate), poly(methacryloxy-2-hydroxybenzophenone), useful under a broad spectrum of both absolute concentra poly(methacryloxybenzotriazole), poly(naphthyl acrylate), tions and relative concentrations of the polymers. In the con poly(naphthylmethacrylate), poly-4-nitrophenylacrylate, text of the previous sentence, the physical characteristics of poly(pentachloro(bromo, fluoro) acrylate) and methacrylate, the coating layer (Such as tenacity, durability, flexibility and poly(phenyl acrylate) and poly(phenyl methacrylate). expandability) will typically be suitable over abroad range of Examples of suitable poly(aralkyl (meth)acrylates) include polymer concentrations. Furthermore, the ability to control poly(benzyl acrylate), poly(benzyl methacrylate), poly(2- the release rates of a variety of bioactive agents can preferably phenethyl acrylate), poly(2-phenethyl methacrylate) and be manipulated by varying the absolute and/or relative con poly(1-pyrenylmethyl methacrylate). Examples of suitable centrations of the polymers and/or the bioactive agent(s). poly(alkaryl(meth)acrylates include poly(4-sec-butylphenyl 0256 In one embodiment, the polymer matrix comprises a methacrylate), poly(3-ethylphenyl acrylate), and poly(2-me hydrogel. Representative examples of hydrogels include the thyl-1-naphthyl methacrylate). Examples of suitable poly dextran-based hydrogels described in WO 02/17884 (Hen (aryloxyalkyl (meth)acrylates) include poly(phenoxyethyl nink et al.). acrylate), poly(phenoxyethyl methacrylate), and poly(poly 0257. In one embodiment, the polymeric material com ethylene glycol phenyl ether acrylate) and poly(polyethylene prises a composition as described in U.S. Pat. No. 6,214,901 glycol phenyl ether methacrylate) with varying polyethylene (Chudzik et al.) and U.S. Publication No. 2002/0188037 A1 glycol molecular weights. Examples of Suitable poly (Chudzik et al.) (each commonly assigned to the assignee of (alkoxyaryl(meth)acrylates) include poly(4-methoxyphenyl the present invention). As described therein, the composition methacrylate), poly(2-ethoxyphenyl acrylate) and poly(2- comprises a plurality of polymers, including at least two methoxynaphthyl acrylate). polymer components, for example, primary and secondary 0262 Acrylate or methacrylate monomers or polymers polymer components. As used herein “primary and 'second and/or their parent alcohols are commercially available from ary' are used solely for designation of the polymer compo Sigma-Aldrich (Milwaukee, Wis.) or from Polysciences, Inc. nents are not intended to reflect the relative amounts of poly (Warrington, Pa.). mer components in the composition. The polymer 0263. One of the other polymer components in the mixture components are adapted to be mixed to provide a mixture that provides an optimal combination of similar properties, and exhibits an optimal combination of physical characteristics particularly when used in admixture with the primary poly US 2011/O 159073 A1 Jun. 30, 2011

mer component. Examples of Suitable secondary polymers Triamcinolone acetonide (Purity 99%, M., 434.5, are available commercially and include poly(ethylene-co CHFO, Sigma Aldrich Biochemicals, St. Louis, Mo.) vinyl acetate) having vinyl acetate concentrations in the range Prednisolone (Purity 99%, CHOs, M, 360.5, Sigma Ald of about 1% to about 50%, in the form of beads, pellets, rich Biochemicals, St. Louis, Mo.) granules, and the like. (purity 99.8%, CHCl, A.C.S. spectroscopic 0264. In some embodiments, the composition comprises at least one poly(alkyl)(meth)acrylate, as a primary, adherent grade, Sigma Aldrich Chemicals) polymeric component, and poly(ethylene-co-vinyl acetate) Ether (purity 99%, M, 74.12, (CH)O A.C.S. reagent, as a secondary polymeric component. Preferably, the poly Sigma Aldrich Chemicals) mer mixture includes mixtures of poly(butylmethacrylate) Balanced salt solution (Sterile, preservative free, Akorn, Inc., (PBMA) and poly(ethylene-co-vinyl acetate) (pVA). This Somerset, N.J.) mixture of polymers has proven useful with absolute polymer Bovine serum albumin (Molecular biology grade, Sigma Ald concentrations (total combined concentrations of both poly rich Biochemicals, St. Louis, Mo.) mers in the composition) in the range of about 0.25 to about 70% (by weight). It has furthermore proven effective with Abbreviations: individual polymer concentrations in the coating Solution in 0270 PCL: polycaprolactone biodegradable filament the range of about 0.05 to about 70% (by weight). In one TA: triamcinolone preferred embodiment, the polymer mixture includes poly PCL/TA: biodegradable triamcinolone loaded polycaprolac (n-butylmethacrylate) (PBMA) with a molecular weight in tone filaments the range of about 100 kD to 900 kD and a pBVA copolymer with a vinyl acetate content in the range of about 24 to 36% Filament Preparation: (by weight). In another preferred embodiment, the polymer mixture includes poly (n-butylmethacrylate) (PBMA) with a 0271 The filaments used in the example were prepared as molecular weight in the range of about 200 kD to 400 kD and follows. PCL was solubilized in chloroform at 35° C. over a pEVA copolymer with a vinyl acetate content in the range of night under continuous stirring conditions. Triamcinolone about 30 to 34% (by weight). According to these embodi acetonide (TA) was then added to the solution in a polymer/ ments, the concentration of the bioactive agent or agents drug weight ratio (w/w,) of 70:30, 60:40 or 50:50. Once the dissolved or Suspended in the coating mixture can be in the Solution became homogeneous, it was poured onto an evapo range of about 0.01 to 90%, by weight, based on the weight of rating tray and left in a fume hood for 72 hours to solidify. The the final coating composition. white Solid-form sheath of the TA loaded PCL was rolled into 0265. Other useful mixtures of polymers that can be a tight column and packed into a 10 mL syringe. The Syringe included in the coating composition are described in com was heated to 80° C. in a water bath to ensure even heat monly assigned U.S. Provisional Application Ser. No. distribution and to prevent high localized temperatures that 60/559,821, filed Apr. 6, 2004, and entitled “Coating Com could damage the drug or polymer. Although the polymer was positions For Bioactive Agents’. These blends include a first not fully in the melt state, the temperature was sufficiently polymer and a second polymer. The first polymer can be high to initiate the transition of this semi-crystalline closed selected from the group consisting of (i) poly(alkylene-co packed macromolecular polymer to a sufficiently viscous alkyl(meth)acrylates, (ii) ethylene copolymers with other state to be extruded. Additionally, it was noted that drug alkylenes, (iii) polybutenes, (iv) diolefin derived non-aro crystals within the polymeracted as a “flow enhancing plas matic polymers and copolymers, (v) aromatic group-contain ticizer when comparing the process to a PCL only filament ing copolymers, and (vi) epichlorohydrin-containing poly extrusion. mers. A second polymer can be selected from the group 0272. Once the syringe reached 80° C. it was rapidly consisting of poly(alkyl (meth)acrylates) and poly(aromatic removed from the water bath and 1 cm of material was (meth)acrylates). extruded from it. The extruded material was subsequently 0266 Other useful mixtures of polymers that can be drawn to a filament by imparting a tensile force. For the 70:30, included in the coating are described in U.S. Publication No. 60:40 or 50:50 w/w, formulations, ~150 um filament diam 2004/0047911. This publication describes polymer blends eters were achieved by a drawing length of approximately 20, that include poly(ethylene-co-methacrylate) and a polymer 15 and 10cm, respectively, while ~300 um filament diameters selected from the group consisting of a poly(vinylalkylate), a were achieved by a drawing length of approximately 15, 10 poly(vinyl alkyl ether), a poly(vinyl acetal), a poly(alkyl and/ and 5 cm, respectively. The formulation with the highest drug oraryl methacrylate) or a poly(alkyl and/oraryl acrylate); not load (50:50 w/w,) broke more frequently during the draw including pEVA. ing process. The drawn filament cooled rapidly and could be 0267. The polymeric material can also be a styrene Subsequently cut under a microscope to the desired implan copolymer, Such as poly(styrene-isobutylene-styrene); the tation length. preparation of medical devices having Such coatings that 0273 Filaments without drug were also prepared by include poly(styrene-isobutylene-styrene) is described in, for directly inserting the PCL pellets into the Syringe, heating example, U.S. Pat. No. 6,669,980. them to 80° C. and then extruding and drawing in a similar 0268. The invention will now be described with reference manner to that previously described. to the following non-limiting examples. 0274 Six pigmented rabbits underwent fluorescein angiography, fundus photography, and optical coherence Example 1 tomography (Zeiss Model 3000, ) at baseline and 4 Materials Used weeks after implantation. The rabbits were subdivided into 0269 Polycaprolactone (Average Mw 80,000, O(CH) the following groups: CO I, Melt index 125° C./0.3 MPa, Sigma Aldrich Bio (0275 Group 1: 2 rabbits with PCL only filaments (PCL, chemicals, St. Louis, Mo.) Rabbits 1 and 2); US 2011/O 159073 A1 Jun. 30, 2011 34

(0276 Group 2: 4 rabbits with PCL/TA 60:40 (w/w) 0281. After the final time period, the filaments were filaments (Rabbits 3-6). removed from the BSS/BSA solution and placed in tubes 0277 Both groups underwent standard pars plana vitrec containing 2 mL of ether for complete extraction of the tomy, and insertion of the drug delivery device into the sub remaining TA. Ether (2 mL) and a 50 uL of internal standard retinal space. Briefly, animals were anesthetized with an (prednisolone 2 mg/ml) were added to the remaining BSS/ intramuscular injection of 0.3 mL of ketaminehydrochloride BSA solutions. Each solution was vortexed for 2 minand then (100 mg/mL. Fort Dodge Lab., Iowa) and 0.1 mL of xylazine centrifuged for 3 min at 10,000 rpm to separate the ether and hydrochloride (100 mg/mL. Miles Inc., USA) per kilogram of BSS/BSA phases. The top layer ether phase was removed body weight. Pupils were dilated with 1 drop each of 2.5% using a glass syringe and added to a 2 mL capped microtube and 1% tropicamide. A 3-mm peritomy was for solvent evaporation in fume hood. Following complete made at the Superotemporal and Superonasal quadrant of the evaporation, 1 mL of 60% methanol was added to the micro right eye. Sclerotomies were created with a 20-gauge micro tube and vortexed. The solution was then transferred to a 1 mL vitreoretinal blade 1 to 2 mm posterior to the limbus in the Superotemporal and Superonasal quadrants. An infusion line glass shell high performance liquid chromatography (HPLC) was inserted and Sutured through the Superonasal sclerotomy vial for analysis. and a vitreous cutter (Bausch & Lomb, USA) was inserted through the Superotemporal Sclerotomy. The vitreous cutter In Vivo Elution and infusion line were used to perform a 2-port core vitrec (0282. Two rabbits (PCL/TA 60:40 filaments) were used tomy. The illumination provided by the operating microscope for analysis of in vivo drug elution. Rabbits were anesthetized (Zeiss, Germany) was sufficient for the operation. prior to the collection of aqueous (-0.3 mL) and blood into 0278. Using intraocular microscopic forceps (Bausch & lithium heparin tube (2 mL). Rabbits were then euthanized Lomb, USA), the filaments were inserted in the subretinal space through a small self-sealing retinotomy. The beveled tip and the eyes enucleated. The implanted device and Surround of the implant allowed easy insertion through the retina. The ing tissues (Sclera, choroid, retina, lens, and vitreous) were filament was left in position and the forceps was withdrawn dissected and separated into 2 mL micro tubes. Individual from the eye. No laser retinopexy was applied to seal the tissue was weighed and then homogenized in 0.5 mL BSS by retinal breaks. The infusion line was removed and the sclero sonication (1-2 pulse/sec at 50% power). Once completed, tomies and conjunctival openings were closed using Vycril samples were enriched with 50 uL internal standard (pred 7-0 (Ethicon, USA). During week 4, all rabbits underwent nisolone 2 mg/ml) and Vortexed. TA was extracted from the fundus examination and were then sacrified under anesthesia tissue sample by adding ether (0.5 mL), Vortexing and cen using an intracardiac injection of pentobarbital Sodium (An trifuging at 10,000 rpm for 10 min. The top ether layer was pro Pharmaceuticals, Oyster Bay, N.Y.). removed and placed in a new 2 mL microtube for evaporation and substitution of the solvent for methanol as previously Elution, Drug Extraction and Histology: described in the in vivo study. 0283. A Millennium high performance liquid chromato In Vitro Elution graph (Waters Corp., USA) equipped with a 515 pump. 2996 0279 For in vitro drug elution characterization, drug photodiode array detector and 717-plus autosampler injector loaded PCL filaments were prepared according to Table 1. was used in this study to process the in vitro and in vivo samples. The Millennium software provided with the high TABLE 1. performance liquid chromatograph (HPLC) was used for integration of chromatographic peaks. The Solvents were In vitro sample parameters linked to an in-line degasser. The samples were injected into Formulation Diameter Length reverse phase HPLC system consisting of stationary phase of Sample PCLTA (Lm) (mm) Nova-Pak C18 column (3.9x150 mm) and Nova-Pack guard 1 70:30 210 30 column (Waters Corp., USA); and an isocratic mobile phase 2 70:30 210 30 of 60% methanol. The peaks of TA and prednisolone were 3 70:30 250 30 eluted at a flow rate of 1 mL/min with detection at 245 nm. 4 70:30 250 30 Parallel 50 uL of prednisolone was chromatogramed under 5 70:30 360 30 the same HPLC condition to determine the extraction effi 6 60:40 150 30 7 60:40 150 30 ciency of TA. Further, the co-chromatography technique was 8 60:40 32O 30 adopted to validate the identification of both compounds. The 9 60:40 32O 30 calculation of TA concentration was based on the area peaks 10 50:50 150 30 and percentage recovery of prednisolone. The HPLC condi 11 50:50 150 30 12 50:50 32O 30 tion separated the peaks of triamcinolone and prednisolone 13 50:50 32O 30 with good resolution. The retention time of prednisolone was 3.46 minutes while that of triamcinolone was 5.2 minutes. 0280 Each filament was placed in a 15 mL capped tube Histology containing 10 mL of a 1% bovine serum albumin (BSA)/ balance salt solution (BSS). Tubes were incubated at 37°C. in 0284. The eyes of the four remaining rabbits (2 rabbits a shaking water bath (100 rpm). At each time increment of 2, with PCL only filaments; 2 rabbits with PCL/TA 60:40 fila 4, 8, 24, 72, 168,336, 504 and 672 hours, the filaments were ments) were enucleated and fixed in 4% paraformaldehyde removed from the BSS/BSA solution and placed into a new for 24 hours and then Bouin's fixative for a further 24 hours. 10 ml BSS/BSA Solution. The specimens were then embedded in paraffin, sectioned, US 2011/O 159073 A1 Jun. 30, 2011

and hematoxylin and (H & E) stained under standard mately 500 um. However, smaller sized retinotomies are pos histology laboratory conditions. sible with the use of custom implantation tools. 0289 Compared with the initial implant, the explanted Results filaments at four weeks post Surgery had a somewhat more 0285) Clinical examination using slit-lamp and indirect fibrous polymer microstructure, as shown in FIG.30, than the ophthalmoscopy at 1, 2, 3 and 4 weeks showed that there was initial implant. In some studies, only a flaky fibrous/porous no detectable accumulation of subretinal fluid, exudates, polymer microstructure remained once the entire drug was hemorrhage or fibrosis Surrounding the device at any of the extracted from the device during the in vitro elution studies. follow up points. Fundus photography showed that the fila The molecular number selected for this polymer was at the ment maintained its position without signs of inflammation or high end (M. 80,000) of the commercially available range. migration, as shown in FIG. 21 for a representative rabbit. PCL degrades by a reduction in M, so a longer degradation Fluorescein angiography demonstrated the absence of vascu time is expected with this high M. There was no indication lar leakage, pooling, retinal pigmented epithelium (RPE) that polymer degradation had begun during the follow-up abnormalities, or fibrosis at any of the follow-up points for a period. representative rabbit, as shown in FIG.22. Optical coherence tomography revealed the Successful placement of the implant 0290. Histology revealed that the implants, whether drug in the subretinal space of all the rabbit eyes, as shown in FIG. loaded or not, were encapsulated by one or two cell layers that 23. did not appear fibrotic in nature, as shown in FIGS. 28 and 29. 0286 The topographical effect of using different filament The nerve fiber layer (ganglion axles) above the filament diameters (150 um . 320 um) can also be seen in FIG. 23 by appeared intact, while the Support cells immediately over the the comparative increase in retinal thickness at the site of the filament location are clearly absent in the PCL only implant implant. No abnormalities were reported from increasing the and somewhat disrupted and thinned in the TA/PCL filament diameter. An increase in the filament diameter implanted eye. The Bruch's membrane appeared intact but merely resulted in a slightly more demanding Surgical proce there was evidence of thinning and disruption of the outer dure and a larger area of cellular disruption. nuclear and RPE layers adjacent to the filament. Due to the 0287. The in vitro elution rates for the different polymer lack of inflammatory response, PCL demonstrated excellent drug ratios and geometries into a BSS/BSA (1%) solution are compatibility with this tissue region and the bulk of the shown in FIGS. 24-26. In general, the elution rates showed an observed cellular changes were attributed to the mechanical early burstphase followed by a late first order phase. Without damage during the implantation. Other factors such as the being bound by a particular theory, it is believed that the impact of interfering with the nutritional source of these outer initial early rapid-release phase is attributed to the absorption cellular layers may also play a role in these cellular changes. of drug crystals in the Surface to Subsurface region of the 0291. It has been found that PCL degrades by random filament into the medium, preceding diffusion from the poly hydrolytic chain scission in subdermally implanted rabbits. mer core. This initial burst may be particularly useful if it is The degradation initially manifests by a progressive reduc desired to rapidly achieve local therapeutic dosage. For each tion in molecular weight as the chain Scission reactions of the different polymer-drug ratios, increasing the filament propagate. However, it has also been shown that the physical diameter or drug polymer ratio resulted in an increase in the weight of PCL does not change until the molecular weight has amount of drug eluted. Without being bound by theory, it is fallen to 5000 that is, there is no weight loss during the first believed that this change results from the increased drug phase of the degradation (Pitt CG. Polye caprolactone and its content and/or eluting surface area. For the larger (-300 um) copolymers. In Chassin MLanger R, editors, Biodegradable filaments, increasing the ratio of drug in the formulation from polymers as drug delivery systems, New York: Dekker; 1990. PCL/TA 70:30 to 50:50 also increased the drug elution rate, p 71-119). Thus, phagocytosis and of small PCL while a drug dumping effect occurs if both the drug ratio is fragments will not begin until the final phase of the degrada high (PCL/TA 50:50) and the filament diameter is small, as tion process. Further, PCL has shown excellent biocompat shown in FIG. 26. In this latter case, total drug release had ibility during the one-month follow up period. occurred during the initial burst, and the rate ofTA absorption 0292. The PCL/TA drug delivery system showed less dis by the subretinal tissue was most likely a limiting factor. The ruption to the RPE layer and less tissue layer thinning in the near superimposition of all the elution profiles during the first adjacent regions of the implant than the PCL only filament, as few hours of each study also indicated that it was the rate of shown in FIGS. 28 and 29. However, it is difficult to conclude TA absorption that was the limiting step during the first stage whether this could be attributed to the anti-inflammatory of elution. Polycaprolactone is hydrophobic and imperme effect of the or was simply due to variability in surgi able to enzyme diffusion; therefore swelling, bulk diffusion, cal procedure and positioning. The region of retinal cell layers or degradation is unlikely in a bodily environment. Without disruption where the implant resides extends for approxi intending to be bound by a particular theory, the TA elution mately 300 um in width and 2000 um in length. It has been profile that occurs after the initial surface to subsurface event found that the nerve fiber layer remains intact over the is believed to be the result of a microporous drug boundary implant, but is disrupted at the site of the retinotomy. Thus, layer being formed and moving deeper toward the core as the only a very focal region of vision loss is expected and one that TA crystals are progressively absorbed by the body. As a is certainly less invasive than laser photocoagulation therapy. result, the lower the drug loading, the Smaller the polymer 0293 HPLC confirmed the presence of TA four weeks porosity formed during drug absorption and the lower the rate after the implant in the posterior tissue samples (FIG.31). TA of TA elution. was not detected in the anterior structures or the blood. HPLC 0288 Illustrative images (optical and histology staining) peaks for TA are marked on the graphs shown in FIG.31. The of implanted filaments are shown in FIGS. 27 through 29. The additional peaks present indicate the internal standard pred size of the retinotomy shown in the optical images is approxi nisolone. US 2011/O 159073 A1 Jun. 30, 2011 36

0294 Based upon this initial investigation, it has been used to hold the end of the NIT wire. The NIT wire was held demonstrated that PCL has at least a one month elution capa perpendicular to the spray head at the focal point of the spray bility with TA. Drug levels in the tissue were shown to be (i.e., about 2-3 mm from the spray head) and was rotated at localized to the posterior eye segment. Histology showed no about 200 rpm. The spray head was moved longitudinally indication of inflammatory response from the presence of over the NIT wire to apply the coating composition. A grid PCL. Minor mechanical damage from the insert was observed like pattern as shown in FIGS. 11-12 was used for the coating and is believed to be the leading cause of changes in the with 0.1 mm longitudinal movements 144. The coating was cellular layers and structures PCL encapsulation was also dried by evaporation of the solvent at room temperature (ap evident and is expected for implanted materials. proximately 20°C. to 22°C.) overnight. The resulting coating was about 3.0 mm in total length, comprising a centerportion Example 2 of about 2.0 mm in length having a uniform thickness of about 300 and two segments of about 0.5 mm in length with tran Materials Used and Abbreviations sitional thickness on each side of the center portion. After Core: drying, the coated NIT wire was weighed to +/-0.003 ug using a microbalance (Type UMX2, from Metler-Toledo). 0295 NIT: 80 um etched Nitinol wire, commercially The implant coating weight was calculated by Subtracting the available from Nitinol Devices and Components (Freemont weight of the uncoated wire from the final weight of the Calif.). coated wire. The total amount of RAP in each implant was calculated by multiplying the coating weight by 0.50, which Bioactive Agent: represents the weight percent of RAP in the coating. The total 0296 RAP: Rapamycin, commercially available from LC amount of RAP in the polymer coating of the filament ranged Laboratories, Woburn Mass. from 26 to 89 ug (see, Table 2). 0302 Prior to implanting in rabbits, the implants were Polymers: trimmed to a length of between about 2.3 to 3.04 mm (see, 0297 pEVA: polyethylene vinyl acetate copolymer (33% Table 2). wit. vinyl acetate and 67% wt. polyethylene), commercially Implantation: available from Aldrich Chemical Co. pBMA: poly(n-butyl methacrylate), commercially available 0303 Experimental protocols were approved by the Insti from Aldrich Chemical Co. tutional Animal Care and Use Committee of the University of Southern California. Experiments were conducted in accor Solvent: dance with the ARVO Statement for the Use of Animals in Ophthalmic and Visual Research. 0298 CHCl: chloroform solvent, commercially available 0304 Six Dutch pigmented rabbits were given general from Burdick & Jackson. anesthesia by an intramuscular injection of 1-1.5 mL of a 4:1 mixture of ketamine hydrochloride (100 mg/mL.; Fort Dodge Implant Preparation: Labs. Fort Dodge, Iowa) and xylazine hydrochloride (100 Coating Solution Preparation: mg/mL, Miles, Inc., Shawnee Mission, Kans.). 0305. In all rabbits, surgery was performed on the right eye 0299. A coating solution was prepared by first adding 25.0 only. Pupillary dilation was achieved with topical 1% tropi pails pEVA and 25.0 parts pBMA to an aliquot of CHCl camide and 2.5% phenylephrine. After limited conjunctival solvent. In order to dissolve the pEVA, the components were peritomy in the Superior quadrant, stab incisions were made heated to 30° to 40° C. for approximately 1 hour. After the approximately 1 mm posterior to the limbus using a 20-gauge pEVA and pPMA had dissolved in the CHCl, the resulting microvitreoretinal blade. In three rabbits (RS1, RS3 and RS4) polymer/solvent Solution was allowed to cool to room tem no vitrectomy was performed. A vitreoretinal microforceps perature. Then, 50 parts of RAP was added to the polymer/ was used to grasp the end of a filament, and it was introduced solvent solution and the RAP was stirred into the polymer/ into the posterior chamber through the sclerotomy. The tip of solvent solution at room temperature for approximately 30 the filament was used to puncture the retina several millime minutes to form a coating Solution. The resulting coating ters inferior to the disc and the vascular arcades. The forceps solution was filtered using a 10um polypropylene filter (Gel were then used to slide the filament into the subretinal space man Sciences pall membrane Pail No. 61756). The final coat through this retinotomy. ing Solution contained about 40 mg/ml of Solids (i.e., pEVA, (0306. In three rabbits (RS3, RS5, and RS6), a vitrectomy pBMA, and RAP). was performed prior to filament insertion. In these eyes, one Sclerotomy was created Superiorly and another Superonasally. Coating Procedure: An infusion cannula was inserted through the Superonasal 0300 NIT wire was cut into lengths of approximately 1 cm Sclerotomy and Sutured into place. A vitreous cutter (Bausch each using a Scissors. The wire lengths were cleaned with a and Lomb Surgical, St. Louis, Mo.) was introduced through wipe (Alpha Wipe from Tex Wipe) that had been dampened the superior sclerotomy. After completion of a core vitrec with . Each wire length was then weighed to tomy, the vitrector was removed from the eye. In two of the +/-0.003 ug using a microbalance (Type UMX2, from rabbits having a vitrectomy (RS5 and RS6), a 25-gauge Metler-Toledo). needle was used to puncture the retina several millimeters 0301 The coating solution was sprayed onto the NIT wire inferior to the disc and the vascular arcades and raise a small using ultrasonic coater equipment that consisted of an ultra subretinal bleb by injecting approximately 0.1 mL of bal Sonic spray head (Sono-Tek, Milton, N.Y.) and Syringe pump anced salt solution into the subretinal space. With the micro system for the coating solution. A cylindrical pin vise was forceps, the filament was then inserted through the retino US 2011/O 159073 A1 Jun. 30, 2011 37 tomy into the Subretinal space in this location. In one of the low-up exams at weeks 2 and 4. Consequently, fluorescein rabbits (RS3) no subretinal bleb was raised; rather, the fila angiography (FA) and optical coherence tomography (OCT) ment was inserted directly beneath the retina after vitrectomy studies could not be performed at these visits. No retinal in the manner described above. detachment occurred in any of the four eyes that received 0307. In all rabbits, after the filament had been inserted, implants. the instruments were removed from the eye, and the sclero 0312. In three rabbits (RS1, RS3, and RS5), no signs of tomies were closed with 7-0 Vicryl sutures (Johnson and inflammation or toxicity were detected on follow-up exami Johnson, Piscataway, N.J.). The conjunctiva was left to close nation. In addition, the filaments did not migrate from their by secondary intention. Subconjunctival injection of gen initial implantation sites. In RS1, in which no bleb of subreti tamicin (0.2 mL of 40 mg/mL Solution, American Pharma nal fluid was raised prior to device insertion, at week 1 small ceutical Partners, Schaumberg, Ill.) was performed. amounts of residual Subretinal hemorrhage from the proce dure were still present adjacent to the filament, causing block Monitoring and Evaluation: age on fluorescein angiography (FIG. 32). This resolved with time, so that less blockage from Subretinal hemorrhage was 0308 Indirect ophthalmoscopic examination, fundus pho noted at week 2 (FIG.33) and none by week 4 (FIG.34). The tography, fluorescein angiography, and optical coherence angiogram otherwise showed only blockage by the device. tomography were performed on the right eye of each rabbitat OCT also confirmed the subretinal location of the device 1, 2, and 4 weeks post-operatively. After the week 4 studies (FIG. 34). There was no evidence of atrophy or damage to were completed, the rabbits were euthanized with an intrac adjacent retina or RPE. In RS5, in which a bleb of subretinal ardiac injection of sodium pentobarbital (Anpro Pharmaceu fluid was raised to assist with correct subretinal device place ticals, Arcadia, Calif.). The right eye of each rabbit was ment, there was no Subretinal hemorrhage noted at any time enucleated and placed in 4% paraformaldehyde for 24 hours. point. Fluorescein angiography showed a linear hypofluores The eyes were then transferred to Dulbecco's phosphate buff cent spot inferior to the device that was the site of instrument ered saline for storage at 4° C. until further dissection, at touch during Surgery. In addition, mild hypopigmentation which time they were sectioned down to a 2 cmx2 cm block could be seen around the device, corresponding to the area in of the retina-choroid-sclera complex at the posterior pole. which the subretinal bleb had been raised. This circular area This was embedded in paraffin, sectioned, and stained with appeared mildly hyperfluorescent on angiography (FIG. 35). hematoxylin and eosin using standard techniques. There was no indication of other damage to adjacent tissue by Implantation Results: the implant. 0313. In RS6, exams at weeks 1 and 2 showed that the 0309 Filaments were implanted into the subretinal space filament remained stable at the site of implantation, and the in three rabbits and into the sub-RPE space in one rabbit. (see, adjacent tissue appeared normal. Mild anterior chamber Table 2) In four eyes (RS1-RS4), no bleb of subretinal fluid inflammation and posterior Synechiae developed by week 2. was raised prior to implantation of the filament. In these so pupillary dilation was impaired, making photography dif cases, there was one Subretinal implantation (RS1), one Sub ficult. Indirect ophthalmoscopy showed no evidence of pos RPE implantation (RS3), and two unsuccessful attempts at terior chamber inflammation. implantation. In two cases (RS5 and RS6), ableb of subretinal 0314. In RS3, in which the device was implanted beneath fluid was raised before filament placement. In both of these the RPE, the filament also remained in a stable position and instances, the filament was inserted into the Subretinal space did not cause any visible abnormalities of adjacent areas. The without difficulty. implant could not be directly visualized on examination, but 0310. The presence or absence of the vitreous body over angiography showed blockage by it, and OCT appeared to the area of implantation was found to be a factor determining corroborate its location (FIG. 36). the ease of the procedure. In one of the cases in which no vitrectomy was performed (RS1), the surgeon was able to Histology Results: insert the filament into the subretinal space, and the filament remained in place upon removal of the forceps. However, two 0315. In eyes in which the filament was implanted subreti rabbits (RS2 and RS4), both of which did not undergo vitrec nally, sections of the posterior pole at the implantation site tomy prior to filament implantation, were sacrificed at the showed loss of photoreceptors overlying the device. Adjacent time of surgery because of the creation of multiple retinoto structures appeared normal. A histology photo of RS1 is mies during attempted implantation. In these two cases, the shown in FIG. 37. vitreous body prevented Successful implantation by adhering to the filament and causing it to egress from the Subretinal TABLE 2 space when the implantation forceps were withdrawn. By Filament Characteristics and Implantation Results contrast, when a vitrectomy had been performed prior to implantation (RS3, RS5, and RS6), it was possible to release Filament Total RAP the filament and withdraw the forceps without disturbing the Length Content position of the device. Rabbit No. Vitrectomy Bleb (mm) (ug) Outcome RS1 No No 2.3 28 Subretinal Implantation Tolerance of Filament Implants in the Rabbit Eye: RS2 No No 3.04 61.5 Sacrificed RS3 Yes No 2.54 88.S. Sub-RPE 0311 All scheduled follow-up exams were completed Implantation over a one-month time period for three of the four rabbits that RS4 No No 2.88. 28 Sacrificed received implants (RS1, RS3, and RS5). In one rabbit (RS6), RSS Yes Yes 2.7 26 Subretinal posterior synechiae developed between weeks 1 and 2, so Implantation adequate pupillary dilation could not be achieved on the fol US 2011/O 159073 A1 Jun. 30, 2011

9. The method of claim 7, wherein the sustained release TABLE 2-continued delivery device is a solid in the form of a capsule, pellet, rod, sheet, or film. Filament Characteristics and Implantation Results 10. The method of claim 7, wherein the sustained release Filament Total RAP delivery device comprises a core having an outer Surface; and Length Content a coating layer of a polymer matrix and a least one bioactive Rabbit No. Vitrectomy Bleb (mm) (ug) Outcome agent applied over at least a portion of the outer Surface of the RS6 Yes Yes 2.46 89 Subretinal COC. Implantation 11. The method of claim 10, wherein the coating layer is provided on a portion of the outer surface of the core. 0316. Other embodiments of this invention will be appar 12. The method of claim 10, wherein the coating layer is ent to those skilled in the art upon consideration of this speci provided on an intermediate portion of the core. fication or from practice of the invention disclosed herein. 13. The method of claim 10, wherein the core is selected Various omissions, modifications, and changes to the prin from titanium alloys, nickel-cobalt base alloys, stainless ciples and embodiments described herein may be made by steel, cobalt-chromium alloys, and biodegradable magne one skilled in the art without departing from the true scope sium alloys. and spirit of the invention which is indicated by the following 14. The method of claim 10, wherein the polymer matrix claims. All patents, patent documents, and publications cited comprises a first polymer and a second polymer wherein the herein are hereby incorporated by reference as if individually first polymer is a poly(alkyl(meth)acrylate) or a poly(aromat incorporated. ic(meth)acrylate) and wherein the second polymer is poly What is claimed is: (ethylene-co-vinyl acetate). 1. A method for instilling one or more bioactive agents into ocular tissue within an eye of a patient for the treatment of an 15. The method of claim 1, wherein the sustained release ocular condition, the method comprising concurrently using delivery device of (A) comprises: at least two of the bioactive agent delivery methods (A)-(C): a nonlinear body member having a direction of extension, (A) implanting a Sustained release delivery device com a longitudinal axis along the direction of extension, and prising one or more bioactive agents in a posterior region a proximal end and a distal end, of the eye so that it delivers the one or more bioactive wherein at least a portion of the body member deviates agents into a vitreous humor; from the direction of extension, (B) instilling one or more bioactive agents subretinally by and wherein the body member includes the one or more direct injection or by implantation of a delivery device bioactive agents, and a polymer matrix. comprising one or more bioactive agents; and 16. The method of claim 15, wherein the body member is (C) instilling one or more bioactive agents into the vitreous coil-shaped. humor by direct injection or by iontophoresis. 2. The method of claim 1, wherein method (A) is used 17. The method of claim 15, wherein the body member concurrently with method (B). includes a lumen. 3. The method of claim 1, wherein method (A) is used 18. The method of claim 15, wherein the polymer matrix concurrently with method (C). comprises a first polymer and a second polymer, wherein the 4. The method of claim 1, wherein method (B) is used first polymer is a poly(alkyl(meth)acrylate) or a poly(aromat concurrently with method (C). ic(meth)acrylate), and wherein the second polymer is poly 5. The method of claim 1, wherein method (A) is used (ethylene-co-vinyl acetate). concurrently with method (B) and with method (C). 19. The method of claim 1, wherein method (C) comprises 6. The method of claim 1, wherein method (B) comprises: injecting one or more bioactive agents into the vitreous humor (a) forming a localized retinal detachment to define a Subreti or comprises delivering one or more bioactive agents into the nal space; and (b) instilling one or more bioactive agents in vitreous humor using iontophoresis. the subretinal space formed by localized retinal detachment. 20. The method of claim 1, wherein the one or more bio 7. The method of claim 1 wherein the one or more bioactive active agents are selected from antiproliferative agents, anti agents are provided in a Sustained release delivery device that inflammatory agents, inhibitors of angiogenesis, antibiotics, is configured for implantation in the Subretinal space. hormonal agents, neurotropic factors, or combinations 8. The method of claim 7, wherein the sustained release thereof. delivery device is tapered at a proximal end, a distal end, or both the proximal and distal ends.