US 200601 10428A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 de Juan et al. (43) Pub. Date: May 25, 2006
(54) METHODS AND DEVICES FOR THE Publication Classification TREATMENT OF OCULAR CONDITIONS (51) Int. Cl. (76) Inventors: Eugene de Juan, LaCanada, CA (US); A6F 2/00 (2006.01) Signe E. Varner, Los Angeles, CA (52) U.S. Cl...... 424/427 (US); Laurie R. Lawin, New Brighton, MN (US) (57) ABSTRACT Correspondence Address: Featured is a method for instilling one or more bioactive SCOTT PRIBNOW agents into ocular tissue within an eye of a patient for the Kagan Binder, PLLC treatment of an ocular condition, the method comprising Suite 200 concurrently using at least two of the following bioactive 221 Main Street North agent delivery methods (A)-(C): Stillwater, MN 55082 (US) (A) implanting a Sustained release delivery device com (21) Appl. No.: 11/175,850 prising one or more bioactive agents in a posterior region of the eye so that it delivers the one or more (22) Filed: Jul. 5, 2005 bioactive agents into the vitreous humor of the eye; (B) instilling (e.g., injecting or implanting) one or more Related U.S. Application Data bioactive agents Subretinally; and (60) Provisional application No. 60/585,236, filed on Jul. (C) instilling (e.g., injecting or delivering by ocular ion 2, 2004. Provisional application No. 60/669,701, filed tophoresis) one or more bioactive agents into the Vit on Apr. 8, 2005. reous humor of the eye. Patent Application Publication May 25, 2006 Sheet 1 of 22 US 2006/0110428A1 R 2 2 C.6 Fig. 2 Y-6 10 Fig. 1
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FORM RETNAL DETACHMENT
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INSTILL BOACTIVE AGENT(S) IN SUBRETINAL SPACE
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INSERT INSTRUMENT(S)
LOCALIZE TO TARGET SITE 304
FORMRETINAL DETACHMENT 306
INSTILLBOACTIVE AGENT(S) IN SUBRETINAL SPACE
REMOVE INSTRUMENT(S) 310
OPTIONALLY INUECT BIOACTIVE AGENT(S) 312 INTO VITREOUS HUMOR Fig. 15 Patent Application Publication May 25, 2006 Sheet 8 of 22 US 2006/0110428A1
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Patent Application Publication May 25, 2006 Sheet 10 of 22 US 2006/0110428A1
INSTRUMENT(S)-352INSERT
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FORM OPENING IN RETNA 356
INSTAGENT(S) BOACTIVE-38 SUBRETINALLY
REMOVE 360 INSTRUMENT(S)
OPTIONALLY, INJECT ONEAGENTSNTOVRGOUS-362 ORMORE BOACTIVE HUMOR Fig. 19 Patent Application Publication May 25, 2006 Sheet 11 of 22 US 2006/0110428A1
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10 15 2O 25 30 Time (Days) Fig. 25 Patent Application Publication May 25, 2006 Sheet 15 of 22 US 2006/0110428A1
-0-150 un diameter -H 150 um diameter Total drug load: -A-320 um diameter 150pum diameter - 1.96 ug (s.d. 0.86) ->e-320 um diameter 320pum diameter - 11.62 ug (s.d. 0.77) 1
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METHODS AND DEVICES FOR THE TREATMENT example, is known to be a powerful angiostatic agent. Its OF OCULAR CONDITIONS systemic side effects, however, include peripheral neuropa 0001) This application claims the benefit of U.S. Provi thy, central nervous system depression, and embryotoxicity. sional Application Ser. No. 60/585,236, filed Jul. 2, 2004, In addition, these systemic side effects have limited the entitled “METHODS, DEVICES AND SYSTEMS FOR dosage administered to patients for the treatment of Subreti TREATMENT OF OCULAR DISEASES AND CONDI nal neovascularization. Systemic inhibition of angiogenesis TIONS,” and U.S. Provisional Application Ser. No. 60/669, in older patients can also interfere with the development of 701, filed Apr. 8, 2005, entitled “SUSTAINED DELIVERY collateral circulation, which has a role in the prevention of DEVICES FOR THE CHOROID AND RETINA AND central nervous system as well as cardiac ischemic events. METHODS FOR SUBRETINAL ADMINISTRATION OF 0007. A number of techniques or methodologies have BIOACTIVE AGENTS TO TREAT AND/OR PREVENT been developed to deliver drugs to the various tissues or RETINAL DISEASES,” which applications are incorpo structure that make up the mammalian eye, as described rated herein by reference in their entirety. hereinafter, to treat a wide range of disorders or diseases of the eye. However, delivery of drugs, proteins and the like to FIELD the eye(s) of mammals in order to achieve the desired therapeutic or medical effect, especially to the retina and/or 0002 The invention relates to methods and devices for the choroid, has proved to be challenging, owing in large the treatment of ocular conditions. part to the geometry, delicacy and/or behavior of the eye and its components. A brief description of various conventional BACKGROUND methods or techniques for delivering drugs to the tissues of 0003. There are a number of vision-threatening disorders the eye and the shortcomings thereof is Summarized. or diseases of the eye of a mammal including, but not limited 0008 Oral ingestion of a drug or injection of a drug at a to diseases of the retina, retinal pigment epithelium (RPE) site other than the eye can provide a drug systemically, and choroid. Such vision threatening diseases include ocular however Such a systemic administration does not provide neovascularization, ocular inflammation and retinal degen effective levels of the drug specifically to the eye. In many erations. Examples of these disease states include diabetic ophthalmic disorders involving the retina, posterior tract, retinopathy, chronic glaucoma, retinal detachment, sickle and optic nerve, adequate levels of the drug cannot be cell retinopathy, age-related macular degeneration, retinal achieved or maintained by oral or parenteral routes of neovascularization, Subretinal neovascularization; rubeosis administration. Thus, further and repeated administration of iritis inflammatory diseases, chronic posterior and pan uvei the drug would be necessary to achieve the desired or tis, neoplasms, retinoblastoma, pseudoglioma, neovascular adequate levels of concentration of the drug. Such further glaucoma; neovascularization resulting following a com and repeated administrations of Such drugs may produce bined vitrectomy-2 and lensectomy, vascular diseases, reti undesired systemic toxicity. nal ischemia, choroidal vascular insufficiency, choroidal thrombosis, neovascularization of the optic nerve, diabetic 0009 Ophthalmic conditions have also been treated macular edema, cystoid macular edema, macular edema, using drugs applied directly to the eye in either liquid or retinitis pigmentosa, retinal vein occlusion, proliferative ointment form. This route of administration (i.e., topical vitreoretinopathy, angioid streak, and retinal artery occlu administration) is only effective in treating problems involv Sion, and neovascularization due to penetration of the eye or ing the Superficial Surface of the eye and diseases that ocular injury. involve the cornea and anterior segment of the eye. Such as conjunctivitis. Topical administration of drugs is not effec 0004 Age-related macular degeneration (AMD) is the tive in achieving adequate concentrations of a drug(s) in the leading cause of irreversible severe central vision loss in Sclera, vitreous, or posterior segment of the eye. In addition, Caucasians fifty years old and older in the United States. topical eye drops may drain from the eye through the According to the 1990 U.S. census, approximately 750,000 nasolacrimal duct and into the systemic circulation, further people over 65 years of age were estimated as severe visual diluting the medication and risking unwanted Systemic side impairment in one or both eyes from AMD. Also, the effects. Furthermore, delivery of drugs in the form of topical number of cases of AMD has been predicted to increase eye drops is also of little utility because the drug cannot from 2.7 million in 1970 to 7.5 million by the year 2030. cross the cornea and be made available to the vitreous, 0005 Roughly 80 percent of the AMD cases involve retina, or other subretinal structures such as the retinal non-neovascular conditions, for which there are no effective pigment epithelium (“RPE) or choroidal vasculature. Some treatments. For the remaining cases involving neovascular drugs are highly unstable and therefore not easily formulated ization, currently available treatments are sub-optimal. Per for topical delivery. Moreover, data also indicate that it is not haps the best known therapy is photodynamic therapy unusual for up to 85% of topically applied agents to he (PDT), however, while this therapy has received significant removed by the eye's blink mechanism/reflex. attention in both the ophthalmic and financial investment 0010 Direct delivery of drugs to the eye by a topical communities, it is useful in only about 20 percent of insert has also been attempted, however, this method is not neovascular AMD cases. In addition, this particular therapy desirable. Such topical inserts require patient self-adminis is not a simple or inexpensive treatment. The procedure tration and thus education on their insertion into and generally needs to be repeated every three months for at least removal from the eye. Consequently, this technique two years, with approximate total cost of S12,250. demands a certain degree of manual dexterity that can be 0006. A number of angiostatic agents are currently under problematic for geriatric patients who are particularly Sus investigation for the treatment of AMD. Thalidomide, for ceptible to certain eye disorders that appear age related (e.g., US 2006/01 10428 A1 May 25, 2006
age related macular degeneration). In many instances Such release implant, capsule or other such device or mechanism topical inserts may cause eye irritation and Such inserts are that is in communication with the vitreous and which is prone to inadvertent loss due to eyelid laxity. In addition, configured so as to provide a release over time into the these devices provide a source of drug only to the cornea and vitreous of the contained drug. Examples of such controlled anterior chamber, and thus do not provide any pharmaco release devices are described in U.S. Pat. Nos. 6,217,895: logic advantage over topical eye drops or ointments. Such 5,773,019; 5,378.475; and U.S. Patent Application Publica devices therefore have limited, if any at all, utility for tion No. 2002/0061327. providing an effective source of drugs to the vitreous or tissues located in the posterior segment of the eye. 0015. A common feature of the techniques/instruments described in these references, is that a Surgical incision is 0011 Consequently, most methods for treating eye dis required at the outset of a procedure so that the implant, orders or diseases in the posterior segment, or the back-of capsule or other Such device can be inserted through the eye the-eye, involve intravitreal delivery of the drug. One such and located in the vitreous. These methods and techniques technique for intravitreal delivery is accomplished by also necessarily involve the use of Sutures following intraocular injection of the drug or microspheres containing completion of the procedure to seal or close the incision in the drug directly into the vitreous or by locating a device or order to prevent loss of vitreous material. As is known to capsule containing the drug in the vitreous, such as that those skilled in the art, maintaining the volume of the described in U.S. Pat. No. 5,770,589. Intravitreal injection posterior segment or vitreous is necessary to maintaining the of a drug is an effective means of delivering the drug to the shape and optical arrangement of the eye. Such a course of posterior segment of the eye in high concentrations, but it is treatment also increases the duration and cost as well as the not without its shortcomings. It is well known that drugs that realistic risks of corneal ulceration, cataract formation, are initially located within the vitreous are removed from the intraocular infection, and/or vitreous loss that accompany vitreous over time via the anterior segment of the eye. If the these procedures. ocular condition is anything other than acute, this technique necessarily requires follow-up injections in order to main 0016 U.S. Pat. Nos. 5.273,530 and 5,409,457 describe an tain an adequate therapeutic concentration within the vitre instrument and methodology to transplant donor cells, more ous. This, in turn, presents problems because each additional specifically donor retina cells, in the Subretinal space. The intraocular injection carries with it a realistic risk of infec instrument is also described as useful for injecting or remov tion, hemorrhage and/or retinal detachment. ing material from the vitreous. According to the described methodology, the instrument is shaped and dimensioned so 0012. It also is well known that many therapeutic drugs it can be inserted into an eye orbit along an insertion path cannot easily diffuse across the retina. The dose being that extends along the periphery of the eye in order to place administered and maintained in the vitreous has to take into the tip adjacent to the retina or Sub-retinal region. The tip is account the amount that can diffuse across the retinal bound then moved generally in the medial direction so that the tip ary as well as how long the drug is retained in effective pierces the exterior of the eye and resides in the sub-retinal amounts within the vitreous. It has been observed from region or in the vitreous, depending upon how much the tip animal studies that 72 hours after injection of triamcinolone, is moved. In order to prevent over-insertion of the tip, a less than 1% of the triamcinolone present in the vitreous is collar is provided about the tip in order to limit the distance associated with other tissues including the retina, pigment the tip can be inserted into the eye. epithelium, and Sclera. 0017 U.S. Patent Application Publication 2002/0055724 0013 In addition to concerns relating to the relative describes an instrument for Sub-retinal transplantation of effectiveness of drug delivery across the barrier, complica retinal cells, epithelium and choroid within their normal tions or side effects have been observed when using a direct planar configuration as a graft into the Sub-retinal region of injection into vitreous technique with some therapeutics. For an eye. The described instrument is inserted into an opening example, corticosteroid compounds, such as triamcinolone, in the eye using either a transcorneal Surgical approach or a can effectively treat Some forms of neovascularization Such trans-choroidal and Scleral Surgical approach. According to as corneal neovasularization. When these compounds are this technique, the instrument is advanced under the retina to used to treat neovascularization of the posterior segment by detach the retina so that the graft can be inserted. As noted direct injection, undesirable side effects can be caused in in U.S. Pat. No. 5.273,530, the penetration of the anterior many patients. The adverse affects or undesirable side part or segment of the eye, using the transcorneal or the effects included elevations in intraocular pressure and the transscleral route creates the risk of corneal ulceration, formation of or acceleration of the development of cata cataract formation and other anterior penetration problems. racts. Elevations in intraocular pressure are of particular Also using either approach, a Surgical incision is created at concern in patients who are already Suffering from elevated the outset of a procedure so that the instrument can be intraocular pressure, such as glaucoma patients. Moreover, inserted and Sutures are used following completion of the there is a risk in using corticosteroids in patients with normal procedure to seal or close the incision inn order to prevent intraocular pressure because of elevations in pressure that loss of vitreous material (i.e., aqueous humor). can result in damage to ocular tissue. Since therapy with corticosteroids is frequently long term, i.e., several days or 0018. The delivery of drugs to the eye presents significant more, a potential exists for significant damage to ocular challenges. The ocular absorption of systemically adminis tissue as a result of prolonged elevations in intraocular tered pharmacologic agents is limited by the blood ocular pressure attributable to that therapy. barrier, namely the tight junctions of the retinal pigment epithelium and vascular endothelial cells. High systemic 0014 Consequently, investigations in the area of intrav doses of therapeutic drugs can penetrate this blood ocular itreal delivery also have focused on developing a Sustained barrier in relatively small amounts, but may expose the US 2006/01 10428 A1 May 25, 2006
patient to the risk of systemic toxicity. Topical delivery of agent. This includes salts, because of their ionic character, drugs often results in limited ocular absorption due to the and unstable polar compounds that cannot be formulated complex hydrophobic/hydrophilic properties of the cornea into a composition Suitable for storage and delivery from and Sclera. Additionally, topical agents are mechanically Such systems. removed by the blink mechanism Such that only approxi mately 15% of a single drop is absorbed. Diffusion of 0022 U.S. Pat. No. 5,098.443 describes certain specific topically administered drugs to the posterior chamber implants that are inserted through incisions made in the eye occurs, but often at sub-therapeutic levels. Intravitreal injec wall or Sutured around the globe of the eye. These rings may tion of drugs is an effective means of delivering a drug to the be formed from biodegradable polymers containing micro posterior segment in high concentrations. However, repeated particles of drug. Alternatively, the implant may be in the intraocular injections carry the risk of infection, hemorrhage form of a hollow flexible polymeric cocoon with the drug and retinal detachment. Patients also find this procedure disposed therewithin for slow release by osmosis. No Somewhat difficult to endure, resulting in high rates of anchoring device is described. noncompliance. 0023 U.S. Pat. No. 5,466.233 describes a certain tack for intraocular drug delivery. This device has an end that is 00.19 Local sustained delivery of therapeutics to the positioned in the vitreous cavity while the head remains posterior chamber is particularly critical in managing several external to the eye and abuts the scleral surface. The tack chronic diseases of the eye. In attempts to address this need, contains a fixation portion to attempt to retain attachment several drug delivery devices have been developed for within the eye. Because the overall shape of the capsule is intraocular insertion into the vitreous region of the eye. linear, the amount of drug that may be held by the device and 0020 U.S. Pat. No. 4,300,557, for example, describes an the surface area through which the drug may be delivered is intraocular implant in the form of a silicone capsule, which limited. If the width of the capsule is increased, excessive can be filled with a drug to be delivered. The implant is sized incisions will be required for insertion of the device. inserted through an incision into the vitreous region of the If the length of the capsule is increased to greater than 1 cm, eye. After insertion of the implant, the incision is closed and the implant will pass into the central visual field of the eye, the capsule remains in place for a period of time. Attached thereby causing blind spots in the patient’s eyes well as to the implant is a tube that passes through the Surface of the increase risk of damage to the retinal tissue and lens capsule. eye. The tube may be used for Subsequent injection of a drug while the implant is in the eye. The implant may be removed 0024. In view of the above, it would be desirable to by making a second Surgical incision into the eye and provide additional methods and devices for treating the eye, retrieving the implant. While in the vitreous, the device is particularly treating retinal and/or choroidal conditions. not anchored and may move about freely. Because the SUMMARY overall shape of the capsule is linear, the amount of drug held by the device and delivered over the surface area of the 0025. In one aspect, the invention provides a method for device is limited. If the width of the capsule is increased, instilling one or more bioactive agents into ocular tissue excessive sized incisions will be required for insertion of the within an eye of a patient for the treatment of an ocular device. If the length of the capsule is increased to greater condition, the method comprising concurrently using at least than 1 cm, the implant will pass into the central visual field two of the following bioactive agent delivery methods of the eye, causing blind spots in the patient’s eye as well as (A)-(C): increased risk of damage to the retinal tissue and lens 0026 (A) implanting a sustained release delivery capsule. device comprising one or more bioactive agents in a 0021 U.S. Pat. No. 5,378.475 describes a device which posterior region of the eye so that it delivers the one or has been developed for insertion in the vitreous region of the more bioactive agents into the vitreous humor of the eye, and is described in T. J. Smith et al., Sustained Release eye; Ganciclovir, Arch. Ophthalmol, 110, 255-258 (1992) and G. E. Sanborn, et al., Sustained-Release Ganciclovir Therapy 0027 (B) instilling (e.g., injecting or implanting) one for Treatment of Cytomegalovirus Retinitis; Use of an or more bioactive agents Subretinally; and Intravitreal Device, Arch. Ophthalmol, 110, 188-195 (1992). 0028 (C) instilling (e.g., injecting or delivering by This device consists of an inner core of pharmacologic agent ocular iontophoresis) one or more bioactive agents into surrounded by two coatings with different permeabilities. the vitreous humor of the eye. Drug diffuses through a small opening in one of these coatings achieving near Zero-order release kinetics. It is 0029. In one embodiment of the method, method (A) is implanted in the region of the pars plana through a 3.55.0 used concurrently with method (B). In this embodiment, one mm Scleral incision. The implant must be removed and or more bioactive agents are released to the vitreous humor replaced every 6 months in the operating room as the drug of the eye from a sustained release delivery device becomes depleted. There is an approximately 25% compli implanted in the posterior region of the eye; and one or more cation rate from these procedures. The device is a membrane bioactive agents are instilled (e.g., injected or implanted) diffusion drug delivery system that relies on EVA/PVA subretinally. The one or more bioactive agents delivered by polymers to mediate release rate. However, many agents the Sustained release delivery device may be the same as or cannot be effectively delivered from such a system because may be different than the one or more bioactive agents their permeation rate through the rate controlling material of delivered subretinally. In another embodiment of the the system is too small to produce a useful effect. Other method, method (A) is used concurrently with method (C). agents cannot be satisfactorily delivered by diffusional In this embodiment, one or more bioactive agents are devices because of a particular chemical characteristic of the released to the vitreous humor of the eye from a sustained US 2006/01 10428 A1 May 25, 2006 release delivery device implanted in the posterior region of the core. The coating layer may be provided on a portion of the eye; and one or more bioactive agents are instilled (e.g., the outer Surface of the core (e.g., an intermediate portion) injected or delivered by ocular iontophoresis) into the vit or it may cover the entire outer surface of the core. The reous humor of the eye. In this embodiment, the one or more coating layer may include a proximal transition segment, a bioactive agents released by the sustained release delivery distal transition segment, or both a proximal and a distal device of method (A) may be the same as or different than transition segment. Representative examples of core mate the one or more bioactive agents instilled (e.g., injected or rials include titanium alloys, nickel-cobalt base alloys, stain delivered by ocular iontophoresis) by method (C). In yet less steel, cobalt-chromium alloys, and biodegradable mag another embodiment, method (B) is used concurrently with nesium alloys. method (C). In this embodiment, one or more bioactive 0035) In some embodiments, the polymer matrix com agents are instilled (e.g., injected or implanted) Subretinally prises a first polymer and a second polymer wherein the first and one or more bioactive agents are instilled (e.g., injected polymer is a poly(alkyl(meth)acrylate) or a poly(aromatic or delivered by ocular iontophoresis) into the vitreous humor (meth)acrylate) and wherein the second polymer is poly of the eye. In this embodiment, the one or more bioactive (ethylene-co-vinyl acetate). Poly(aromatic(meth)acrylates) agents delivered by method (B) may be the same as or include poly(aryl(meth)acrylates), poly(aralkyl(meth)acry different than the one or more bioactive agents delivered by lates), poly(alkaryl (meth)acrylates), poly(aryloxyalkyl method (C). In yet another embodiment, method (A) is used (meth)acrylates), and poly(alkoxyaryl (meth)acrylates). concurrently with both method (B) and method (C) to instill Poly(alkyl(meth)acrylates) include poly(n-butyl methacry one or more bioactive agents into ocular tissue in the eye. In late), poly(n-butyl methacrylate-co-methyl methacrylate), this embodiment, the one or more bioactive agents delivered poly(n-butyl methacrylate-co-isobutyl methacrylate), and by one method may be the same as or different than the one poly(t-butyl methacrylate). In one embodiment, the first or more bioactive agents delivered by the other methods. polymer is poly(butylmethacrylate) and the second polymer 0030. In some embodiments, method (B) comprises is poly(ethylene-co-vinyl acetate). instilling (e.g., injecting or implanting) one or more bioac 0036). In some embodiments, the intraocular sustained tive agents Subretinally. The bioactive agent(s) may be release delivery device of method (A) comprises a nonlinear injected subretinally when provided, for example, in the body member having a direction of extension, a longitudinal form of a liquid or it may be implanted subretinally when axis along the direction of extension, and a proximal end and provided in the form of a solid (e.g., a Sustained release a distal end, wherein at least a portion of the body member delivery device). In some embodiments, method (B) com deviates from the direction of extension, and wherein the prises (a) forming a localized retinal detachment to define a body member includes the one or more bioactive agents, and Subretinal space; and instilling one or more bioactive agents a polymer matrix. The body member may be coil-shaped. In in the subretinal space formed by localized retinal detach Some embodiments, the Sustained delivery device includes a ment. cap positioned at the proximal end of the body member. In 0031. In some embodiments, method (C) comprises Some embodiments the body member includes a lumen. injecting one or more bioactive agents into the vitreous humor of the eye using a needle. In another embodiment, the 0037. In some embodiments, the sustained release deliv one or more bioactive agents are instilled by ocular ionto ery device has a total diameter of no greater than about 1000 phoresis, for example, transscleral iontophoresis. um and a length of no greater than about 6 mm. 0032. In some embodiments, the one or more bioactive 0038. In some embodiments, the sustained release deliv agents are provided in a Sustained release delivery device ery devices have a bioactive agent elution rate of at least that is configured for implantation in the Subretinal space. 0.0001 ug per day or greater. The sustained release delivery device may be a solid in the 0039 Methods of the invention may deliver one or more form of a capsule, pellet, rod, sheet, or film. In some bioactive agents, for example, antiproliferative agents, anti embodiments, the sustained release delivery device may be inflammatory agents, anti-angiogenic agents, antibiotics, in the form of a flexible rod, thin film, foldable disc, neurotrophic factors, or combinations thereof. biodegradable polymer with the bioactive agent embedded within, bioactive agent-eluting polymer coating over a rigid 0040. As used herein, a “coating composition” refers to one or more vehicles (for example, Solutions, mixtures, scaffold, compressed pellet of one or more bioactive agents, emulsions, dispersions, blends, and the like) used to effec or one or more bioactive agents encapsulated in a semi tively coat a surface. A “coated composition” refers to the permeable membrane. The sustained release delivery device combination of one or more bioactive agent and a polymer may be tapered at a proximal end, a distal end, or both the on a Surface of the device. The coated composition can be proximal and distal ends. formed from one or more coating compositions, or in one or 0033. In another embodiment, the sustained release deliv more layers, as will be apparent from the teaching herein. ery device is in the form of a biocompatible polymer capsule 0041 As used herein, “biocompatible” means the ability comprising (a) a core comprising one or more bioactive of an object to be accepted by and to function in a recipient agents; and (b) a jacket Surrounding the core comprising a without eliciting a significant foreign body response (such membrane that is biocompatible and that permits diffusion as, for example, an immune, inflammatory, thrombogenic, or of the one or more bioactive agents. the like response). For example, when used with reference to 0034. In another embodiment, the sustained release deliv one or more of the polymers of the invention, biocompatible ery device comprises a core having an outer Surface; and a refers to the ability of the polymer (or polymers) to be coating layer of a polymer matrix and at least one bioactive accepted by and to function in its intended manner in a agent applied over at least a portion of the outer Surface of recipient. US 2006/01 10428 A1 May 25, 2006
0042. As used herein, “therapeutically effective amount 0052 FIG. 6 shows and illustration of a subretinal sus refers to that amount of a bioactive agent alone, or together tained release delivery device in accordance with one with other substances (as described herein), that produces embodiment of the invention. the desired effect (such as treatment of a medical condition Such as a disease or the like, or alleviation of pain) in a 0053 FIG. 7 shows an illustration of a side view of a patient. During treatment, such amounts will depend upon subretinal sustained release delivery device. Such factors as the particular condition being treated, the 0054 FIG. 7A shows a longitudinal cross-sectional view severity of the condition, the individual patient parameters of the subretinal sustained release delivery device of FIG. 7. including age, physical condition, size and weight, the duration of the treatment, the nature of the particular bio 0.055 FIG. 8 shows an illustration of a side view of a active agent thereof employed and the concurrent therapy (if Sustained release delivery device in accordance with one any), and like factors within the knowledge and expertise of embodiment of the invention. the health practitioner. A physician or veterinarian of ordi 0056 FIG. 8A shows a longitudinal cross-sectional view nary skill can readily determine and prescribe the effective of the subretinal sustained release delivery device of FIG. 8. amount of the bioactive agent required to treat and/or 0057 FIG. 9 is a schematic diagram of a spray stream as prevent the progress of the condition. it passes through a focal point. 0043. The term “implantation site' refers to the site 0058 FIG. 10 is a schematic diagram of a spray stream within a patient’s body at which the implantable device is that expands continuously as it moves away from the spray placed according to the invention. In turn, a “treatment site' includes the implantation site as well as the area of the body head. that is to receive treatment directly or indirectly from a 0059 FIG. 11 is a schematic view of a grid-like coating device component. For example, bioactive agent can migrate pattern useful in coating devices of the invention. from the implantation site to areas Surrounding the device itself, thereby treating a larger area than simply the implan 0060 FIG. 12 is a schematic view of a grid-like coating tation site. The term “incision site' refers to the area of the pattern Superimposed over a core material. patient’s body (the skin and transdermal area) at which an 0061 FIG. 13 is a schematic view of series of first incision or Surgical cut is made to implant the device transverse Sweeps Superimposed over a core material. according to the invention. The incision site includes the surgical cut, as well as the area in the vicinity of the surgical 0062 FIG. 14 is a flow diagram of a method of instilling cut, of the patient. one or more bioactive agents Subretinally. 0063 FIG. 15 is a flow diagram of a method of instilling 0044) The term “instill means to deliver one or more one or more bioactive agents Subretinally. bioactive agents using various delivery means and/or mechanisms. 0064 FIG. 16 is a schematic view illustrating the local ization of the operable end of a subretinal bioactive agent 0045. The term “treatment course' refers to the dosage delivery device. rate over time of one or more bioactive agents, to provide a therapeutically effective amount to a patient. Thus, factors of 0065 FIG. 17 is a schematic view illustrating the sub a treatment course include dosage rate and time course of retinal instillation of a bioactive agent using a Subretinal treatment (total time during which the bioactive agent(s) is bioactive agent delivery device. administered). 0066 FIG. 18 is a detail view of an embodiment of an operable end of the subretinal bioactive agent delivery BRIEF DESCRIPION OF THE DRAWING device of FIG. 16. 0046 For a fuller understanding of the nature and desired 0067 FIG. 19 is a flow diagram of a method of instilling objects of the present invention, reference is made to the one or more bioactive agents Subretinally. following detailed description taken in conjunction with the accompanying drawing figures wherein like reference char 0068 FIG. 20 is a schematic depiction of the filament acter denote corresponding parts throughout the several preparation process in accordance with one embodiment of views and wherein: the present invention. 0069 FIG. 21 shows fundus photography (Rabbit 4) of 0047 FIG. 1 shows a perspective view of an implantable the implanted polycaprolactone?triamcinolone acetonide device configured for intraocular placement according to (PCL/TA) filament at 4 weeks post surgery. one embodiment of the invention. 0070 FIG. 22 shows fluorescein angiography (Rabbit 4) 0048 FIG. 2 shows a view from the bottom of the of the implanted PCL/TA filament at 4 weeks post surgery. embodiment illustrated in FIG. 1. 0071 FIG. 23 shows optical coherence tomography of 0049 FIG. 3 shows a perspective view of an implantable the retinal thickness Surrounding the implant site for the device configured for intraocular placement according to polycaprolactone (PCL) filaments (Rabbit 1 and 2) at 4 another embodiment of the invention. weeks post Surgery. 0050 FIG. 4 shows a view form the bottom of the 0072 FIG. 24 shows in vitro cumulative elution data for embodiment illustrated in FIG. 3. a 70:30 PCLFTA filament. 0051 FIG. 5 shows transcleral placement of an implant 0.073 FIG. 25 shows in vitro cumulative elution data for able device according to one embodiment of the invention. a 60:40 PCLFTA filament. US 2006/01 10428 A1 May 25, 2006
0074 FIG. 26 shows in vitro cumulative elution data for 0091. In one embodiment of the invention, the method a 50:50 PCLFTA filament. comprises using method A concurrently with method B. In 0075 FIG. 27 shows optical image and magnification of another embodiment, the method of the invention comprises the subretinal PCL/TA implant (Rabbit 5) following 4 weeks using method A concurrently with method C. In another implantation where A) shows the optic nerve location, B) embodiment, the method comprises using method B con marks the implant location, C and D) shows the site of the currently with method C. In yet another embodiment, the retinotomy, E) is the outer sclera surface, and F) outlines the method of the invention comprises using method A concur region of damage to the proximal end of the filament during rently with both method B and method C. micro forceps insertion. 0092. In each of the above-described embodiments, the 0076 FIG. 28 shows histology (H&E staining) of a 150 individual methods may be used to deliver the same bioac um PCL filament (no drug) following 4 weeks implantation tive agent(s) or to deliver different bioactive agent(s) to the (Rabbit 1) where A) marks the device location, B) shows the eye. For example, if method A is used in conjunction with RPE, C) shows the nerve fiber layer, D) shows the choroid method C, the bioactive agent(s) delivered by method A may and E) shows the sclera. be the same or different than the bioactive agent(s) delivered by method C. 0077 FIG. 29 shows histology (H&E staining) of a 150 um PCL/TA filament subretinal delivery system following 4 0093 Advantageously, the method of the invention may weeks implantation (Rabbit 5) where A) marks the device be used to simultaneously instill bioactive agents that may location, B) shows the RPE, C) shows the nerve fiber layer, not be readily delivered by one method and/or by one D) shows the choroid, E) shows the sclera and F) identifies device. For example, bioactive agents that are different in the region of vacuolated spaces. molecular weight, hydrophobicity, polarity, physical State (e.g., Solid or liquid) and/or stability may be simultaneously 0078 FIG. 30 shows explanted PCL/TA filament. instilled using the method of the present invention. In one 0079 FIG. 31 shows in vivo detection of triamcinolone embodiment, a first bioactive agent is delivered subretinally acetonide (TA) following a 4-week subretinal drug delivery from a Sustained release delivery device and a second implantation (PCL/TA 60:40) for rabbit 4. bioactive agent that is different from the first bioactive agent in molecular weight, hydrophobicity, polarity, and/or stabil 0080 FIG. 32 shows a photo of RS1, one (1) week post ity is delivered to the vitreous humor. In addition, the Surgery, photo and fluorescein angiography. method of the invention may be used to provide a bioactive 0081 FIG.33 shows a photo of RS1, two (2) weeks post agent delivery profile that may not be readily obtainable Surgery, photo and fluorescein angiography. using a single delivery method. For example, a Sustained 0082 FIG. 34 shows a photo of RS1, four (4) weeks post release delivery device of method A or B may be used Surgery, photo and fluorescein angiography. concurrently with method C in order to provide both a high initial concentration of a bioactive agent in the vitreous 0083 FIG. 35 shows a photo of RS5, four (4) weeks post humor and Sustained delivery (e.g., vitreal or Subretinal) of Surgery, photo and fluorescein angiography. the bioactive agent over an extended period of time. In 0084 FIG. 36 shows a photo of RS3, 4 weeks post another embodiment, methods A and B may be used con Surgery, photo, fluorescein angiography and optical coher currently to provide sustained vitreal and subretinal delivery ence tomography. of one or more bioactive agents. 0085 FIG. 37 shows a histology photo of RS1. 0094 Methods and devices of the invention can be used DETAILED DESCRIPTION to instill one or more bioactive agents to the eye for the treatment of ocular conditions, for example, retinal detach 0.086 The present invention is directed to methods and ment; occlusions; proliferative retinopathy; proliferative vit devices for treating ocular conditions (e.g., ocular diseases reoretinopathy; diabetic retinopathy; inflammations such as and disorders). The methods and devices provide flexibility uveitis, choroiditis, and retinitis; degenerative disease (such in treatment of ocular conditions, including flexibility in the as age-related macular degeneration, also referred to as combination of bioactive agent(s) and delivery methods AMD); vascular diseases; and various tumors including employed. neoplasms. 0087. In one aspect, the invention provides a method for instilling one or more bioactive agents to ocular tissue 0.095 The methods and devices useful to deliver one or within an eye of a patient for the treatment of an ocular more bioactive agents according to the method of the condition, the method comprising concurrently using at least invention are now described in detail below. two of the following bioactive agent delivery methods Method A: Intraocular Sustained Release Delivery Device: (A)-(C): 0096 Embodiments of the invention comprise the use an 0088 (A) implanting a sustained release delivery intraocular sustained release delivery device in order to device comprising one or more bioactive agents in a controllably release one or more bioactive agents to the posterior region of the eye so that it delivers the one or vitreous humor of the eye. Representative examples of more bioactive agents into the vitreous humor of the intraocular sustained release delivery devices are described, eye; for example, in U.S. Pat. No. 6,719,750 B2 (“Devices for 0089 (B) instilling (e.g., injecting or implanting) one Intraocular Drug Delivery. Varner et al.); U.S. Publication or more bioactive agents Subretinally; and Nos. 2005/0019371 A1 (“Controlled Release Bioactive 0090 (C) instilling one or more bioactive agents into Agent Delivery Device.” Anderson et al.), 2004/0133155A1 the vitreous humor. (“Devices for Intraocular Drug Delivery. Varner et al.), US 2006/01 10428 A1 May 25, 2006
2005/0059956A1 (“Devices for Intraocular Drug Delivery,” device that is inserted into a patient. The body member can Vamer et al.), and 2003/0014036A1 (“Reservoir Device for be described as including a proximal end (which is located, Intraocular Drug Delivery. Vamer et al.); and related appli upon implantation, towards the exterior of the body), a distal cations. end (which is located, upon implantation, towards the inte 0097. Referring now to FIGS. 1-5, a sustained release rior of the body), and a longitudinal axis. In use, at least a delivery device according to one embodiment is illustrated. portion of the body member is inserted into a patient’s body. Generally speaking, the device illustrated in FIGS. 1-5 For example, in some embodiments, it can be preferable to provides a controlled release bioactive agent delivery device position less than 100% of the body member inside the comprising a body member having a direction of extension, patient’s body. The amount of the body member positioned a longitudinal axis along the direction of extension, and a within the body can be determined by the interventionalist, proximal end and a distal end, wherein at least a portion of based upon Such factors as desired treatment parameters, the the body member deviates from the direction of extension, particular configuration of the device, the implantation site, the body member including a polymer matrix comprising a and the like. bioactive agent. As shown in FIG. 1, the device includes a 0103) The body member further includes a direction of body member 2 having a proximal end 4 and a distal end 6. extension, and in preferred embodiments, at least a portion FIG. 1 illustrates the body member in a coil configuration. of the body member deviates from the direction of exten 0098. The distal end 6 of the body member 2 can be sion. In preferred embodiments, the body member includes positioned at any desirable location relative to the longitu at least two, three, four, five, six, seven, eight, nine, ten, or dinal axis of the body member. As shown in FIGS. 1-2, the more deviations from the direction of extension. In some distal end 6 of the body member according to one embodi alternative embodiments, where the body does not include ment of the invention can include a tip 10 that is spaced from multiple deviations from the direction of extension, the body the longitudinal axis. This configuration is similar to a member can be provided in a “J” or a hook-type configu standard “cork screw' type configuration. In use, the device ration. is inserted through the incision site and then twisted until the controlled delivery device is properly positioned at the 0.104) The deviations from the direction of extension can treatment site. be provided in any suitable configuration. Exemplary embodiments of such deviations will be described herein for 0099. Another embodiment is shown in FIGS. 3-4, illustrative purposes only, and without intending to be bound wherein the distal end 6 of the body member includes tip 10 by any particular embodiment described herein. The devia that is positioned at the longitudinal axis of the body tions need not be rounded or arcuate. For example, in some member 2. In some embodiments, placement of the tip 10 of embodiments, the body member is provided with a Z-shaped the body member 2 at the longitudinal axis can provide configuration, such that the deviations are angular. More advantages. Such as ease of insertion of the device at the over, the deviations need not be in a regular pattern, but can distal end. It will be readily apparent that various other alternatively be provided in a random manner, such that the configurations of the distal end of the body member can be body member contains random curls or turns. In some provided, depending upon the desired application. embodiments, the deviations are provided in a patterned 0100 Further, the proximal end 4 of the body member 2 configuration about the longitudinal axis. Examples of these can also be positioned at any desirable location relative to patterned embodiments include coils, spirals, or patterned the longitudinal axis of the body member. FIGS. 1 and 3 Z-shaped turns in the body. Alternatively, the deviations can illustrate the proximal end 4 of the body member as spaced be provided in a random or non-patterned configuration from the longitudinal axis. However, the proximal end 4 of about the longitudinal axis. According to these particular the body member can be provided at the longitudinal axis as non-patterned embodiments, the distance of the individual well (not shown in the FIGS.). In some embodiments, deviations from the longitudinal axis to the outermost placement of the proximal end 4 of the body member 2 at the periphery of the body member can be selected to provide a longitudinal axis can provide advantages, such as ease of desired overall profile of the body member, depending upon fabrication of the device, increased mechanical strength, the application of the device. For example, it can be desir improved translation of force (since a uniform force can be able, in Some applications, to provide an overall profile of applied and translated to the body member, with less risk of the body member having an hourglass shape, alternating ring bending or other deformation of the body member), and the circumference shapes, and the like. like. 0101 According to the intraocular embodiments of the 0105. In some embodiments, the deviations from the invention, the coil shape of the body member allows the direction of extension can be provided in the form of rings. device to be screwed or twisted into the body through an Such individual rings can be concentric (that is, having a incision approximately the same size as the outer diameter common axis, or being coaxial about the longitudinal axis) of the material forming the body member 2. Still further, the or eccentric (deviating from a circular path). According to coil shape of the body member can act as an anchoring these embodiments, the individual rings are noncontiguous mechanism to maintain the controlled delivery device within along the body member length, thereby forming individual the implantation site, and can prevent unwanted movement ribs at positions along the direction of extension of the body of the device and unwanted ejection of the device from the member. implantation site and/or the body. As a result of the coil 0106 Preferred configurations of the body member are shape, the controlled delivery device is twisted and coiled or spiral. Generally, in a coil configuration, the unscrewed out of the body during removal of the device. individual rings of the coil rotate about the longitudinal axis, 0102 Generally speaking, the body member of the and the overall coil is substantially symmetrical about the implantable device is the portion of the controlled release longitudinal axis. A preferred coil is composed of multiple US 2006/01 10428 A1 May 25, 2006 rings that are Substantially similar in circumference along member is at least 0.5 mm. These principals can be applied the length, from proximal to distal, of the device. In some to any configuration of the body member and is not limited preferred embodiments, the rings form a spiral pattern, to coiled configurations. wherein the circumference of the rings changes over the 0110. The overall dimensions of the implantable device length of the device. Preferably, the circumference of the can be selected according to the particular application. For rings decreases toward the distal direction of the device, so example, the length and/or width of the device can be that the largest ring circumference is located at the proximal selected to accommodate the particular implantation site. region of the device, and the Smallest ring circumference is Some factors that can affect the overall dimensions of the located at the distal region of the device. implantable device include the potency of any bioactive 0107 Inclusion of deviating portions of the body member agent to be delivered (and thus the volume of bioactive agent provides an increased surface area for delivery of a bioactive required, which impacts the Surface area of the device, as agent to an implantation site as compared to a linear device discussed herein), the location of the implantation site having the same length and/or width. This can provide within the body (for example, how far within the body the advantages during use of the device, since this configuration implantation site is located), the size of the implantation site allows a greater Surface area to be provided in a smaller (for example, a small area Such as the eye or inner ear, or a length and/or width of the device. For example, in some larger area, Such as a joint or organ area), the tissue Sur applications, it can be desirable to limit the length of the rounding the implantation site (for example, Vascular tissue device. For example, as will be discussed in more detail or hard, calcinous tissue. Such as bone), and the like. herein, it is desirable to limit the length of implants in the 0111. By way of example, the device is preferably eye to prevent the device from entering the central visual designed for insertion through a small incision that requires field of the eye and to minimize risk of damage to the eye few or no sutures for scleral closure at the conclusion of the tissues. By providing a body member that has at least a Surgical procedure. As such, the device is preferably inserted portion of the body member deviating from the direction of through an incision that is no more than about 1 mm in extension, the device of the invention has greater Surface cross-section, for example, in the range of about 0.25 mm to area (and thus can hold a greater Volume of bioactive agent) about 1 mm in diameter, preferably in the range of about per length of the device without having to make the cross 0.25 mm to about 0.5 mm in diameter. As such, the cross section of the device, and thus the size of the insertion section of the material forming the body member 2 is incision, larger. preferably no more than about 1 mm, for example, in the 0108 Still further, in certain embodiments, the shape of range of about 0.25 mm to about 1 mm in diameter, the body member can provide a built-in anchoring system preferably in the range of about 0.25 mm to about 0.5 mm that reduces unwanted movement of the device and in diameter. When the material forming the body member 2 unwanted ejection of the device out of the patient’s body, is not cylindrical, the largest dimension of the cross-section since the shape of the body member requires manipulation can be used to approximate the diameter of the body member to remove it from an incision. For example, for a coil-shaped for this purpose, for example, when the body member body member, the device would require twisting, and a cross-section is square. Z-shaped body member would require back and forth move 0.112. The body member of the controlled release device ment, to remove the device from the implantation site. preferably has a total length from its proximal end to its According to Some preferred embodiments, the device does distal end that is less than about 1 cm, for example, in the not require additional anchoring mechanisms (such as Sutur range of about 0.25 cm to about 1 cm. Upon implantation, ing) to the body tissues, as a result of the self-anchoring the body member is positioned within the eye, such that the characteristics of the device itself. As described in more portion of the controlled delivery device that delivers bio detail herein, inclusion of a cap 8 on the device can provide active agent to the eye chamber is positioned near the further anchoring features of the device. posterior segment of the eye. When the controlled delivery device includes a cap 8, the cap is preferably provided with 0109. In some embodiments, when the body member a thickness of less than about 1 mm, more preferably less includes two or more deviations from the direction of than about 0.5 mm. According to this particular embodi extension, the spacing of the individual deviations can be ment, the total length of the controlled delivery device is less selected to provide an optimum combination of Such fea than about 1.1 cm, preferably less than about 0.6 cm. tures as increased Surface area available for coating, overall dimensions of the device, and the like. For example, when 0113. The distal end 6 of the body member can include the body member is provided in the form of a coil that any Suitable configuration, depending upon the application includes two or more deviations from the direction of of the device and the site of the body at which the device is extension, the distance between the individual coils can be to be implanted. For example, in some embodiments, the selected to be equal to or greater than the diameter of the distal end 6 can be blunt or rounded. In preferred embodi material forming the body member. In some aspects, if the ments, the distal end 6 of the body member is configured to distance between coils is less than the diameter of the pierce the body during implantation of the device into the material forming the body member, the amount of Surface body. For example, the distal end 6 of the body member can area available for coating of the body member can decrease, include a sharp or pointed tip. In one preferred embodiment, since it can be more difficult to access portions of the Surface the distal end 6 of the body member has a ramp-like angle. area of the body member with the coating compositions. In Preferably, the device according to this embodiment can be one illustrative embodiment of this aspect of the invention, utilized to make an incision in the body, rather than requiring the body member is formed of a material having a diameter separate equipment and/or procedures for making the inci of 0.5 mm, and the distance between each coil of the body sion site. If the distal end 6 of the body member 2 is used to US 2006/01 10428 A1 May 25, 2006 pierce the body during insertion, at least the distal end 6 is 0118. The lumen can contain any combination of ele preferably fabricated of a rigid, non-pliable material suitable ments, as desired. For example, in some embodiments, the for piercing the body. Such materials are well known and lumen can include only the substance to be delivered. In can include, for example, polyimide and similar materials. other embodiments, the lumen can include the Substance to In one such preferred embodiment, the distal end 6 of the be delivered, as well as the polymer matrix. The particular body member 2 is utilized to pierce the eye for insertion of combination of elements to be included in the lumen can be the controlled delivery device in the interior of the eye. selected depending upon the desired application of the device. 0114. In another preferred embodiment, the distal end 6 of the body member 2 can be shaped or bent to form a 0119 When the lumen is to be provided with a substance portion (for example, the distal-most portion of the body and/or polymer matrix, the lumen can be filled with the member) that is parallel to the longitudinal axis. In one desired substance and/or polymer matrix prior to inserting embodiment illustrated in FIGS. 3 and 4, for example, the the device into the body, or after the device has been inserted distal end 6 includes a sharp or pointed tip that is parallel to into the body. When it is desired to fill the device with the the longitudinal axis. According to this particular embodi Substance after insertion into the body, a port can be pro ment, the tip located at the distal end 6 of the body member vided near the proximal end 4 of the body member 2 for such is perpendicular to the plane of incision, thus providing a purpose. The port is in fluid communication with the self-starting tip of the device. While the figures illustrate a lumen(s) of the body member and can also be used for sharp tip of the body member, it is understood that any refilling the device with the substance and/or polymer matrix suitable configuration of the distal tip can be provided, before and/or after implantation, when desired. utilizing the teaching herein. 0120 When the device includes a port, the port is pref 0115 The body member 2 can be fabricated from a solid erably designed Such that the needle of an injection mecha material (a material that does not contain a lumen) or a nism (for example, a Syringe) can be inserted into the port material containing a lumen, as desired. In the embodiment and the material to be included in the lumen injected by the illustrated in FIGS. 1 to 4, for example, the body member 2 injection mechanism. Thus, the material can travel through is fabricated from a solid material that is shaped into a coil. the port and into the lumen(s) of the body member. The port Alternatively, the body member 2 can be fabricated from a preferably forms a Snug seal about the needle of the injection tubular material that includes a lumen. The choice of a solid mechanism to prevent leakage of the material out of the port or lumen-containing material is not critical to the invention around the injection mechanism and to provide sterile injec and can be determined based upon availability of materials tion of material into the lumen(s). If desired, fittings or and processing considerations. collars (not shown), through which an injection mechanism can be inserted and which form a Snug seal about the 0116. When included, the lumen(s) can extend along the injection mechanism, can be mounted on the port. Upon length of the body member 2 or only a portion of the length injection of the material into the delivery device, the needle of the body member 2, as desired. In some embodiments, the of the injection mechanism is removed from the port and the lumen(s) can serve as a delivery mechanism for delivery of port sealed. Sealing can be accomplished by providing a a desired Substance to the implantation site. The Substance removable cover (not shown) on the port that can be delivered via the lumen can comprise any of the bioactive removed for injection of the substance and replaced when agents described herein. The substance delivered via the the material has been injected. In a preferred embodiment, lumen can be the same or different bioactive agent(s) from the port is fabricated of a self-sealing material through that included in the polymer matrix. Further, the substance which the injection mechanism can be inserted and which can be provided in addition to the bioactive agent of the seals off automatically when the injection mechanism is polymer matrix, or in place of the bioactive agent. For removed. Such materials are known and include, for example, in one embodiment, one or more Substances can be example, silicone rubber, silicone elastomers, polyolefin, delivered via the lumen, and one or more bioactive agents and the like. can be provided to the implantation site from the polymer matrix. 0.121. In further embodiments, when the device includes more than one lumen, the device can include more than one 0117. In some embodiments, the lumen can contain a port. For example, each lumen can be in fluid communica polymer matrix as described herein. According to these tion with a plurality of ports. These ports are similar to the particular embodiments, the body member of the device can single port described above. If desired, the lumens and ports be provided with or without a coating on its external Surface. can be arranged Such that each lumen can be filled with a In some such embodiments, the lumen can be utilized to different material through a corresponding port (for deliver the bioactive agent(s) to the implantation site. For example, each lumen has its own dedicated port). It can be example, the lumen can contain the polymer matrix, includ desirable to include more than one lumen when it is desir ing bioactive agent. According to this particular embodi able to deliver more than one additional material to the ment, the body member can be provided with a coating on implantation site. an external Surface comprising a suitable polymer only (that is, lacking any bioactive agent). Thus, the bioactive agent is 0122) In embodiments where it is desired to deliver one provided to the implantation site in this embodiment prin or more additional Substances to the implantation site via cipally via the lumen of the body member. In other embodi one or more lumens, the individual lumens can include one ments, the lumen can include the inventive polymer matrix or more apertures to allow such delivery. In one embodi (including biodegradable polymer and bioactive agent), and ment, such apertures are provided at the distal end 6 of the the body member is not provided with a coated composition device. In other embodiments, the apertures are provided on its external Surface. along the length of the body member 2. The number and size US 2006/01 10428 A1 May 25, 2006 of the apertures can vary depending upon the desired rate of responding compartment. These conduits can be provided delivery of the substance (when provided) and can be readily within the wall of the body member 2, along the circum determined by one of skill in the art. The apertures are ference of the body member 2. The substances could then be preferably designed such that the substance to be delivered injected through a plurality of ports, each port in fluid is slowly diffused rather than expelled as a fluid stream from communication with a corresponding conduit. Thus, a Sub the device. For example, when the device is implanted in the stance could be injected into the first compartment just eye, it is preferable to deliver the substance through slow below the cap 8 by a port in the center of the cap 8, which diffusion rather than expulsion of the substance as a fluid delivers the substance directly into the first compartment. A stream, which can damage the delicate tissues of the eye. In Substance injected into the second port, would flow through Some embodiments, the polymer matrix in contact with the conduit and would flow through an aperture in the wall of body can provide a particular porosity to the Substance and body member 2 into second compartment, and so on. The can assist in controlling the rate of diffusion of the Substance substance(s) to be delivered can be delivered to the implan from the lumen. When included in the device, the particular tation site via any of the methods described herein for the location of the apertures can be situated so as to deliver the lumen(s). Substance at a particular location once the device is implanted into the body. 0.126 In another embodiment, each lumen or compart ment (as desired) can be designed for selected "opening or 0123. In another embodiment, when the body member 2 activation by a laser (via heat or photodisruption). For includes a lumen for delivery of an additional substance to example, a laser could be used to create apertures in the the implantation site, the material forming the body member walls of the desired lumen and/or compartment when the 2 can be chosen to be permeable (or semi-permeable) to the particular substance is to be delivered. As such, release of substance to be delivered from the lumen. According to this each Substance could be controlled upon demand by an particular embodiment, the material can be chosen depend interventionalist. Preferably, when a laser is utilized to ing upon the particular application of the device and the create such apertures, the wavelength and temperature are substance to be delivered and can be readily determined by controlled to minimize any effects on the polymeric coating one of skill in the art. Examples of suitable permeable composition. materials include polycarbonates, polyolefins, polyure thanes, copolymers of acrylonitrile, copolymers of polyvinyl 0127. In preferred embodiments, the body member 2 can chloride, polyamides, polysulphones, polystyrenes, polyvi be fabricated in a way that further increases the surface area nyl fluorides, polyvinyl alcohols, polyvinyl esters, polyvinyl of the body member, preferably without increasing the butyrate, polyvinyl acetate, polyvinylidene chlorides, poly overall dimensions of the device. For example, in one vinylidene fluorides, polyimides, polyisoprene, polyisobu embodiment, the device can be fabricated of multiple tylene, polybutadiene, polyethylene, polyethers, polytet strands of material that are entwined or twisted around each rafluoroethylene, polychloroethers, other to form the body member 2 (for example, multiple polymethylmethacrylate, polybutylmethacrylate, polyvinyl strands of wire can be twisted around each other to form the acetate, nylons, cellulose, gelatin, silicone rubbers, porous body member). According to these particular embodiments, fibers, and the like. any number of individual strands can be utilized to form the body member, for example, 2, 3, 4, or more Strands. The 0.124. According to these particular embodiments, the number of individual strands twisted to form the body material used to fabricate the body member 2 can be chosen member can be selected depending upon such factors as, for to provide a particular rate of delivery of the substance, example, the desired diameter of the material forming the which can be readily determined by one of skill in the art. body member and/or the overall body member diameter, the Further, the rate of delivery of the substance can be con desired flexibility or rigidity of the device during insertion trolled by varying the percentage of the body member 2 and/or implantation, the size of the implantation, the desired formed of the permeable (or semi-permeable) material. incision size, the material used to form the body member, Thus, for example, to provide a slower rate of delivery, the and the like. body member 2 can be fabricated of 50% or less permeable material. Conversely, for a faster rate of delivery, the body 0128. As shown in FIG. 1, the body member 2 is pref member 2 can be fabricated of greater than 50% of perme erably cylindrical in shape, with a circular cross-section. able material. When one or more portions of the body However, the cross-sectional shape of the body member 2 is member 2, rather than the whole body member 2, is fabri not limited and, for example, can alternatively have square, cated of a permeable or semi-permeable material, the loca rectangular, octagonal or other desired cross-sectional tion of the permeable or semi-permeable material can be shapes. situated so as to deliver the Substance at a particular location 0129. As shown in FIGS. 1 and 3, a preferred embodi once the device is implanted at the implantation site. ment can include a cap 8 positioned at the proximal end 4 of 0125. In another embodiment, the lumen of the body the body member 2. When included in the device, the cap 8 member 2 can include impermeable dividers located along can assist in Stabilizing the device once implanted in the the length of the lumen. Thus, the lumen of the body body, thereby providing additional anchoring features of the member can contain a plurality of compartments, each of device. Preferably, the device is inserted into the body which can be filled with a different substance, as desired. through an incision until the cap 8 abuts the incision on the These compartments could be filled prior to insertion exterior of the body. If desired, the cap 8 can then be sutured through an injection port located, for example, in the side of to the body at the incision site to further stabilize and prevent each compartment. In another embodiment, the device can the device from moving once it is implanted in its desired be filled after it is implanted by providing a plurality of location. When the device is implanted in the eye, for conduits, each conduit in fluid communication with a cor example, the device can be inserted into the eye through an US 2006/01 10428 A1 May 25, 2006
incision until the cap 8 abuts the incision. If desired, the cap otherwise attached. In alternative embodiments, the cap 8 8 can then be sutured to the eye, to provide further stabili and body member 2 are fabricated as a unitary piece, for Zation as discussed above. example, utilizing a mold that includes both components 0130. The overall size and shape of the cap 8 is not (the body member 2 and cap 8) of the device. The precise particularly limited, provided that irritation to the body at the method of fabricating the device can be chosen depending incision site is limited. Preferably, the cap 8 is sized such upon Such factors as availability of materials and equipment that it provides a low profile. For example, the dimensions for forming the components of the device. of the cap 8 are preferably selected to provide a small 0.135) In some aspects, and particularly when the body Surface area to accomplish Such desired features as addi member is fabricated of a biodegradable material, the cap tional anchoring characteristics of the device, without Sub can be fabricated of a nondegradable material or a material stantially increasing the overall profile of the device upon that degrades more slowly than the degradable material implantation. In some embodiments, for example, the cap forming the body member. This can be desirable, for can be covered by a flap of tissue at the incision site upon example, to maintain the features provided by the cap (Such implantation, to further reduce potential irritation and/or as anchoring features) for a period of time at least as long as movement of the device at the implantation and/or incision the time the body member retains some structural integrity sites. One illustrative example described in more detail at the implantation site. This can reduce risk of a significant elsewhere herein is the covering of the cap with a Scleral cap intact portion of the body member breaking off the cap and upon implantation of the device in the eye. losing an anchoring point at the implantation site. 0131 Further, while the cap 8 is illustrated with a circular 0.136. In some embodiments, the cap 8 can be provided shape, the cap can be of any shape, for example, circular, with a polymeric coating. According to these particular rectangular, triangular, square, and the like. In order to embodiments, the polymeric coating provided in connection minimize irritation to the incision site, the cap preferably has with the cap 8 can be the same as, or different from, the rounded edges. The cap 8 is designed such that it remains polymeric coating provided in connection with the body outside the implantation site and, as such, the cap 8 is sized member 2. For example, the particular bioactive agent so that it will not pass into the implantation site through the included in the polymeric coating for the cap 8 can be varied incision through which the device is inserted. to provide a desired therapeutic effect at the incision site. Exemplary bioactive agents that could be desirable at the 0132) As described herein, inclusion of a cap 8 in the incision site include antimicrobial agents, anti-inflammatory device can provide additional anchoring features to the agents, and the like, to reduce or otherwise control reaction device itself. However, in some embodiments, it can be of the body at the incision site. It will be readily apparent desirable to further secure the device to provide additional upon review of this disclosure that the first polymer and anchoring or securing features at the implantation site. Thus, second polymer can also be selected for the polymeric when desired, the cap 8 can be further designed such that it coating composition provided in connection with the cap 8. can be easily sutured or otherwise secured to the surface to provide a desired polymeric coating specific for the cap, Surrounding the incision and can, for example, contain one when desired. or more holes (not shown) through which Sutures can pass. 0.137 In some embodiments, the cap 8 can include a 0133. The materials used to fabricate the cap 8 are not polymeric coating that is the same as the polymer coating particularly limited and include any of the materials previ provided in connection with the body member 2. According ously described for fabrication of the body member 2. to these embodiments, the polymeric coating can be applied Preferably, the materials are insoluble in body fluids and in one step to the entire controlled delivery device (body tissues with which the device comes in contact. Further, it is member and cap), if desired. Alternatively, the polymeric preferred that the cap 8 is fabricated of a material that does coating can be applied to the cap 8 in a separate step, for not cause irritation to the portion of the body that it contacts example, when the cap 8 is manufactured separately, and (such as the area at and Surrounding the incision site). For subsequently attached to the body member 2. example, when the device is implanted into the eye, the cap 0.138 For intraocular delivery of one or more bioactive 8 is preferably fabricated from a material that does not cause agents, the following procedure may be used. A Sclerotomy irritation to the portion of the eye that it contacts. As such, can be created for insertion of the device into the posterior preferred materials for this particular embodiment include, portion of the eye. Conventional techniques can be used for by way of example, various polymers (such as silicone the creation of the sclerotomy. As shown in FIG. 5, such elastomers and rubbers, polyolefins, polyurethanes, acry techniques include the dissection of the conjunctiva 32 and lates, polycarbonates, polyamides, polyimides, polyesters, the creation of pars plana Scleral incisions through the Sclera polysulfones, and the like), as well as metals (such as those 28. The dissection of the conjunctiva 32 typically involves described previously for the body member). pulling back the conjunctiva 32 about the eye so as to expose 0134. In some embodiments, the cap 8 can be fabricated large areas of the Sclera 28, and the clipping or securing of from the same material as the body member 2. Alternatively, the conjunctiva 32 in that pulled back state (the normal the cap 8 can be fabricated from a material that is different position of the conjunctiva is shown in phantom). In other from the body member 2. The cap 8 can be fabricated words, the sclera 28 is exposed only in the areas where the separately from the body member 2, and Subsequently pars plana Scleral incisions are to be made. Surgical instru attached to the body member 2, using any Suitable attach ments used in the procedure are then passed through these ment mechanism (such as, for example, Suitable adhesives incisions. Thus, the incisions should be made large enough or Soldering materials). For example, the cap 8 can be to accommodate the instruments required for the procedure. fabricated to include an aperture, into which the body 0.139. Alternatively, the creation of the sclerotomy can be member 2 is placed and thereafter soldered, welded, or accomplished by use of an alignment device and method, US 2006/01 10428 A1 May 25, 2006
such as that described in U.S. patent application Ser. No. has a coil shape, the body member 2 is inserted into the eye 09/523,767, that enables sutureless surgical methods and by rotating or twisting the body member 2 into the eye until devices thereof. In particular, Such methods and devices do the cap 8 abuts the outer surface of the eye. In embodiments not require the use of Sutures to seal the openings through wherein the body member 2 is fabricated of a shape memory which instruments are inserted. The alignment devices are material, the shape memory material is first cooled to a inserted through the conjunctiva and Sclera to form one or temperature at which the martensite phase is stable and the more entry apertures. Preferably, the alignment devices are device is deformed, for example, into a linear shape. The metal or polyimide cannulas through which the Surgical device is then inserted into the eye. To return the device to instruments used in the procedure are inserted into the eye. its memory shape, the device is left unrestrained and is simply allowed to reach a temperature (for example, by 0140. In further embodiments, the device can be heating the device) above the martensite phase temperature. implanted directly through a self-starting transconjunctival For example, the shape memory material can be heated by trans-scleral “needle stick.’ For example, the body member a laser to return the device to a temperature above the 2 of the device can include a sharp tip 10, such as that martensite phase temperature. The shape memory material illustrated in FIG. 3. According to this embodiment, the can also be selected Such that the martensite phase tempera sharp tip 10 can be utilized to pierce the body and thereby ture is below body temperature so that the material is simply create the incision site and access to the implantation site. In cooled to below body temperature, deformed to a linear this case, no conjunctival Surgery or extraneous alignment shape, and inserted into the eye. Then, as the material warms device is necessary. up within the eye to body temperature, the device can return 0141. In further embodiments, the conjunctival tissue can to its remembered shape. As discussed herein, when laser be dissected to expose a portion of the pars plana region, and application is utilized, conditions are preferably controlled a needle Stick can be made into the Sclera in the exposed to maintain Such parameters as wavelength and temperature, region. A self-starting coil that includes a sharp tip is then to minimize adverse effect on the polymeric coated compo inserted through the pars plana at the site of the needle Stick, sition. and the coil is rotated through the sclera until the cap of the 014.4 FIG. 5 illustrates a controlled delivery device device abuts the sclera. In some preferred embodiments, the according to one embodiment of the invention that is needle stick is smaller than the diameter of the body member implanted in the eye. When implanted into the eye, it is of the implantable device (for example, a 30-gauge needle desirable to limit the length L of controlled delivery devices stick can be used with an implantable device having a body to prevent the controlled delivery device from entering the member with a diameter of 0.5 mm or less). The conjunc central visual field. If the device enters the central visual tival tissue is then pulled over the cap, to provide a flap or field, this can result in blind spots in the patient’s vision and "seal' over the device, thus minimizing irritation of the can increase the risk of damage to the retinal tissue and lens implantation site, foreign body sensation, and the like. capsule. Thus, for example, when the controlled delivery Optionally, the conjunctival tissue can be further secured by device is inserted at the pars plana (as shown in FIG. 5), the a single suture. In some embodiments the Suture is biode distance from the implantation site on the pars plana to the gradable. central visual field is preferably less than about 1 cm. 0142. In some embodiments, it can be preferable to create 0145 Optionally, after the device is implanted into the an incision site that is slightly larger than the dimensions of eye, the cap 8 can then be sutured or otherwise secured to the the proximal portion of the body member. For example, sclera to maintain the controlled delivery device in place. In when the device includes a cap 8 and is implanted into the preferred embodiments, no further manipulation of the eye, it can be preferable to create an incision that is larger device is required for delivery of one or more bioactive than the largest diameter of the cap 8. Such that the cap sits agents to the interior of the eye. The conjunctiva can be below the outer surface of the sclera. For example, a partial adjusted to cover the cap 8 of the device, when desired, and incision in the Sclera can be made to create a Scleral flap. the Surgical procedure is completed. Once the device has been implanted, and the cap 8 is placed so that it abuts the incision site, the scleral flap can be folded 0146 In other embodiments, when a lumen is included in back over the device, thus providing a covering over the cap. the device for delivery of one or more additional substances Alternatively, when the proximal end of the body member to the interior of the eye, further steps can be included as does not include a cap 8, a flap-like cover can still be utilized follows. If a cover is used to close the port(s), it is removed to cover the proximal end of the device, in accordance with at this time, and if used, a collar for providing a Snug fit the description above. Preferably, these embodiments mini about the injection mechanism (such as a syringe) is pro mize the contact of the proximal end (for example, the cap vided. The injection mechanism is then connected with the 8) of the device with other body tissues, thereby reducing port(s) for injection of one or more Substances to the Such risks as irritation of body tissues, and/or translation of controlled delivery device. If the port(s) are composed of a movement of the eye to the device, thereby potentially self-sealing material through which the needle of an injec damaging eye tissues. This can provide one or more advan tion mechanism can be inserted and which seals off auto tages, such as reduced tendency for movement of the eye to matically when the injection mechanism is removed, the be translated to the controlled delivery device, since the injection mechanism is simply inserted through the port and proximal end of the device will not be sitting at the surface the Substance injected. Following injection, the conjunctiva of the eye and thus in contact with other body tissues; and can be adjusted to cover the cap 8 of the device, if desired. reduced irritation of Surrounding tissues. Method B. Subretinal Instillation: 0143. The body member 2 is then inserted into the eye. 0.147. In some embodiments, the invention includes sub For example, in embodiments wherein the body member 2 retinal instillation (e.g., injection or implantation) of one or US 2006/01 10428 A1 May 25, 2006
more bioactive agents in order to localize action of the delivery device 50 has proximal end 56 and distal end 58. In bioactive agent(s) at the desired treatment site of the choroid the embodiment of FIG. 6, distal end 58 is beveled to and/or retina. The bioactive agent(s) that are delivered facilitate subretinal insertion. Alternatively, distal end 58 subretinally or in the subretinal space may be provided in may be blunt, rounded, tapered, pointed, or other desired any of a number of forms, for example, fluid Solutions, shape. Proximal end 56 may have the same end treatment as Solids, Sustained release formulations, and Sustained release distal end 58 or it may have a different end treatment. For delivery devices. example, in the embodiment of FIG. 6, proximal end 56 is beveled and distal end 58 is blunt. Sustained delivery device 0148 Representative examples of formulations for deliv 50 may have any desirable cross-sectional shape. For ery of the bioactive agent into the Subretinal space include, example, as shown in FIG. 6, the cross-sectional shape of but are not limited to, injectable hydrogels, cyclodextrin sustained delivery device is circular. Alternatively, the cross “solubilized' and micronized solutions. sectional shape may be triangular, square, rectangular, 0149. In embodiments where the bioactive agent(s) is pentagaonal, octagonal, oval, and the like. Sustained deliv initially provided in the form of a solid, such solids may be ery device 50 may be linear, as shown in FIG. 6, or may be in the form of a capsule, pellet, rod, sheet, film, or hydrogel. non-linear. Examples of non-linear shapes include curved Such solids can be configured and arranged so as to com (e.g., “C” or “S” shaped), Zig-Zag (e.g., “Z” shaped), spiral, prise a Sustained release device for controllably releasing the circular, and the like. bioactive agent to the tissues of the eye over an extended period of time. Examples of Sustained release devices are 0153. In another embodiment, the device comprises a found, for example, in U.S. Pat. Nos. 5,378.475 and 5,773, biocompatible core material that is coated with a coating 019. See also the related discussion in U.S. Pat. No. 6,217, layer of a polymer matrix and one or more bioactive agents. 895. The capsule or other structure forming the solid or the Referring to FIGS. 7-7A, one embodiment of a device of the Sustained release delivery device may be any suitable con type that has a core is shown. Device 70 includes core 72, figuration, including cylindrical, rectangular, disk-shaped, having proximal end 77 and distal end 79, and coating layer 74 comprising polymer matrix and one or more bioactive patch-shaped, ovoid, Stellate, or spherical. It is desirable, agents. In the embodiment of FIGS. 7-7A, the coating layer however, to use a configuration that does not tend to lead to 74 of polymer matrix and one or more bioactive agents is migration from the Subretinal space so as to minimize the coated over the entire length of core 72. The coating layer 74 potential for migration of the instilled bioactive agent from includes proximal transition segment 76, distal transition the targeted tissue site. segment 78, and center portion 80. In this embodiment, 0150. In some embodiments, sustained release delivery proximal transition segment 76 and distal transition segment devices include, but are not limited to, flexible rods, thin 78 have been feathered (i.e., a sloped transition segment). films, foldable discs, biodegradable polymer with one or more bioactive agents embedded within, a bioactive agent 0154) In another embodiment, as shown in FIGS. 8-8A, eluting polymer coating over a rigid scaffold, a compressed device 90 includes core 92, having proximal end 93 and distal end 95. A coating layer 94 of polymer matrix-bioactive pellet of one or more bioactive agents, or one or more material is coated over a portion of the length “1” of core 92. bioactive agents encapsulated in a semi-permeable mem resulting in coated portion 96 and uncoated portion 98. The brane. uncoated portion 98 may be useful to provide a handling 0151. In some embodiments, the subretinal sustained portion by which the device may be grasped or docked with delivery device is in the form of a biocompatible polymer a Surgical instrument (e.g. by microSurgical instruments) to capsule. Biocompatible polymer capsules contemplated for prevent any potential damage to the coating layer 94 upon use with the methods of the invention comprise: (a) a core handling. In one embodiment, the uncoated portion 98 of the which contains one or more bioactive agents, either Sus device 90 could be left periretinal for easy retrieval in pended in a liquid medium or immobilized within a bio follow-up surgery. In the embodiment of FIGS. 8-8A, compatible matrix, and (b) a Surrounding jacket comprising proximal transition segment 100 and distal transition seg a material that is biocompatible and permits diffusion of the ment 102 of coated portion 96 have been feathered (i.e., a bioactive agent to the tissues proximal the Subretinal space. sloped transition segment). Without being bound by theory, The core may comprise a biocompatible matrix of a hydro it is believed that feathering the distal and proximal ends of gel or other biocompatible matrix material that stabilizes the the device may enhance the uniformity, processing repro position of the bioactive agent. The jacket may be manu ducibility, and ease of implantation. factured from various polymers and polymer blends includ ing, for example, polyacrylates (including acrylic copoly 0.155 The cross-sectional shape of the core may be any mers), polyvinylidenes, polyvinyl chloride copolymers, desired shape, but is typically circular. The diameter of the polyurethanes, polystyrenes, polyamides, cellulose acetates, core (or maximum cross-sectional dimension, if not circular) cellulose nitrates, polysulfones (including polyether Sul is typically less than about 200 um, in Some embodiments fones), polyphosphaZenes, polyacrylonitriles, poly(acryloni ranging from about 10 um to about 200 um. The size, geometry and materials used in forming the core may be trile/covinyl chloride), as well as derivatives, copolymers, selected to provide desired characteristics to the device. For and mixtures thereof. example, the material forming the core and the diameter (or 0152. In some embodiments, the subretinal sustained maximum cross-sectional dimension) of the core may be delivery device comprises a polymer matrix containing one selected to provide the desired rigidity and flexibility to the or more bioactive agents. Referring to FIG. 6, an embodi device. For example, a thin (i.e., Small diameter) core ment of a sustained delivery device 50 is shown. Sustained material may be used if a less rigid device is desired. Thin delivery device 50 comprises polymer matrix 52 which is core materials also allow for thicker coating layers, thereby embedded with one or more bioactive agents 54. Sustained maximizing the Volume of bioactive agent(s) that may be US 2006/01 10428 A1 May 25, 2006
contained in the device. The core material may also be stainless steel, cobalt-chromium alloys, and biodegradable selected to facilitate the ability of the polymer layer to magnesium alloys. It is to be understood that the core adhere as a coating. For example, the Surface of the core material is not limited to the examples provided herein and material may be primed, roughened, or chemically modified can be any conventional material used in implant devices. In to facilitate adhesion of the polymer layer to the core Some embodiments, the core comprises titanium-nickel material. wire. In one embodiment, the core is titanium-nickel wire 0156. In some embodiments, the subretinal sustained having a diameter of about 80 um (or the Smallest commer delivery device (with or without the core material) may cially available diameter), in order to maximize the volume further include a layer of material that modifies the bioactive of bioactive agent in the device. agent release rate characteristics. For example, a thin layer 0.161 Subretinal sustained release delivery devices may of polycaprolactone can be coated on the device. Such a be prepared by the steps of: (a) dissolving one or more polycaprolactone layer can also provide a degradation rate polymers in a solvent to form a complex fluid; (b) adding controlling barrier, protection of the bioactive agent from one or more bioactive agents to the complex fluid to produce environmental degradation prior to implantation, or even a homogeneous solution of the one or more bioactive agents delay the time point of release of the drug. and/or a solution with a dispersed phase of one or more 0157. In some embodiments, the outer diameter (or maxi bioactive agents; (c) optionally drying the complex fluid to mum cross-sectional dimension) of the Sustained release a solid form; (d) optionally heating the solid form to a delivery device is no greater than about 1000 um in order to temperature just below the melting point of the polymer(s): minimize retinal detachments and hemorrhaging. In other and (e) forming the device out of the solution of (b) or the embodiments, the outer diameter (or maximum cross-sec solid form of (c). tional dimension) of the device is 900 um or less, in other 0162. In some embodiments, the method comprises a low embodiments 800 um or less, in other embodiments 700 um temperature process (e.g., from about 20° C. to about 100° or less, in other embodiments 600 um or less, in other C., more preferably from about 50° C. to about 90° C.). In embodiments 500 um or less, in other embodiments 400 um one embodiment, the method comprises a process that or less, in other embodiments 300 um or less, in other involves homogenously mixing the polymer and one or embodiments 200 um or less, in other embodiments 100 um more bioactive agents in solvent, drying, and melt-extru or less, in other embodiments 100 um or less. Typically, the Sion-drawing the prepared solid-form into the device shape. diameter (or maximum cross-sectional dimension) ranges More specifically, the method comprises: dissolving one or from about 200 um to about 500 um. more polymers in a suitable solvent Solution to produce a 0158. In some embodiments, the length of the sustained complex fluid; adding one or more bioactive agents to the release delivery device is about 5.0 mm or less, in other complex fluid to produce a homogeneous solution of one or embodiments about 4.5 mm or less, in other embodiments more bioactive agents and/or a solution with a dispersed about 4.0 mm or less, in other embodiments about 3.5 mm phase of one or more bioactive agents; drying the solution to or less. In a specific embodiment, the device is about 3.0 mm a solid form; heating the solid form to a temperature below or less in length as such lengths have been found to provide the melting point of the polymer (e.g., about 1° C. to about the additional benefit of coming to a resting point in the eye 5° C. below the melting point); forming the device out of that does not cross multiple tissue layers. However, it is this semi Solid; and shaping the filament into the desired possible to provide devices longer than about 3.0 mm that shape by drawing it into a lengthy filament and mechanically can be inserted with special care so as to minimize multiple sectioning it into a fixed length. Bending the device can add tissue layer crossing. In other embodiments, the length of the curvature. In other embodiments the complex fluid is not device is 2.9 mm or less, in other embodiments about 2.8 dried to a solid form. In these embodiments, heating may not mm or less, in other embodiments about 2.7 mm or less, in be required during the forming step because of the presence other embodiments about 2.6 mm or less, in other embodi of the solvent in the complex fluid. ments about 2.5 mm or less, in other embodiments about 2.4 0.163 The steps of forming the subretinal sustained mm or less, in other embodiments about 2.3 mm or less, in release delivery device and shaping the filament into the other embodiments about 2.2 mm or less, in other embodi desired shape can be accomplished by a variety of conven ments about 2.1 mm or less, in other embodiments about 2.0 tional methods for forming and shaping a device out of a mm or less. In some embodiments, the length of the device solid. For example, the solid form may be processed by ranges from about 2.0 to about 3.0 mm. melt-extrusion-drawing (applying tensile force) to form the 0159. As the device becomes smaller in diameter (or solid into the desired shape and thickness. The length can be maximum cross-sectional dimension) or in length, the inser modified by cutting the device with any conventional cutting tion and handling of the device may become more difficult tool. The distal and/or proximal ends of the device can be and the amount of bioactive agent contained in the device shaped by cutting, Sanding, and other methods for forming will typically be reduced. Such factors may be taken into tapered, rounded, beveled and other desired end shapes. account when determining the diameter and/or length of the 0.164 Referring to FIG. 20 a schematic depiction of an device. embodiment of a Sustained release delivery device prepara 0160 The core may be a polymer matrix material as tion process 400 is shown. As depicted in the figure, the described herein or may be a non-polymer based material. device may be fabricated by: solubilizing polycaprolactone Representative examples of non-polymer based materials 401 in a solvent 403 at a temperature below boiling under include titanium-nickel alloy wire (e.g., Nitinol wire, com still or continuous stirring conditions; adding one or more mercially available from Nitinol Devices and Components, bioactive agents 405 to the solution in a ratio that preferably Freemont Calif.), titanium alloys, nickel-cobalt base alloys, ranges from 1:99 to 70:30 (weight bioactive agent:weight US 2006/01 10428 A1 May 25, 2006 polymer) (step 402); allowing the solvent 403 to evaporate 0169. In an embodiment, the ultrasonic spray head is under still or stirring conditions after the solution becomes moved back and forth over the rotating core in a grid-like translucent or dispersed (step 404); transferring the solid pattern. By way of example, an exemplary grid-like pattern form of the loaded polymer 407 to an extrusion device 409 140 is shown in FIG. 11. The grid-like pattern starts at point (step 406); heating the extrusion device 409 to about 50° C. 143 and ends at point 145. The grid-like pattern has a series to about 90° C., depending on the molecular weight of the of transverse Sweeps 142 and longitudinal movements 144. polycaprolactone (M=3,000 to 120,000), such that the Depending upon the length of the longitudinal movements polymer temperature approaches the melt temperature (but 144, any number of transverse Sweeps can be used to cover does not exceed it); drawing the solid-form of the loaded the length of a given coating layer. In embodiments of the polymer 407 to its desired geometry once the extrusion device reaches the desired sub melt temperature (step 408): invention, the grid-like pattern 140 includes between 3 and and shaping the resulting device 411 to the desired implan 100 transverse sweeps 142. In embodiments of the inven tation length (l) and shape after the temperature of the tion, the grid-like pattern 140 includes between 3 and 100 drawn implant falls (step 410). longitudinal movements 144. The desired length of the longitudinal movements will depend upon a number of 0165. In embodiments where the device includes a core, factors including the diameter of the spray pattern and the the device may be fabricated by applying a coating compo relative spray density of various parts of the spray pattern. sition comprising one or more polymers and one or more bioactive agents over at least a portion of the outer Surface 0170 Referring now to FIG. 12, grid-like pattern 140 is of the core. The coating composition can be applied to the Superimposed over an exemplary core material 146 having outer Surface of the core using any Suitable method. For distal end 147 and proximal end 149 to illustrate how core example, the coating composition may be applied by dip material 146 would be coated with reference to the grid-like ping, spraying, and other known methods for applying pattern 140. coating compositions to Substrates. The Suitability of the coating composition for use on a particular material can be 0171 In some embodiments, the ultrasonic coating head evaluated by those skilled in the art. follows the grid-pattern multiple times (that is, multiple passes) in order to deposit a coating layer onto a core. On 0166 In some embodiments, the coating composition is each pass, an amount of the coating layer is deposited. Thus, applied to the core utilizing a precision coating system the precise number of passes made by the ultrasonic coating wherein the coating material is atomized ultrasonically (an ultrasonic coating system). Exemplary ultrasonic coating head can be varied depending upon the total coating thick systems and methods are described in U.S. Published Appli ness desired. In some embodiments, the mass of the coating cation 2004/0062875 (Chappa et al.) and in U.S. application layer comprises between about 10 ug and about 1000 ug dry Ser. No. 11/102,465, filed Apr. 8, 2005, and entitled “Medi weight. In other embodiments, the mass of the coating layer cal Devices and Methods for Producing Same.” comprises between about 50 ug to about 300 ug dry weight. 0167. In some embodiments, a core (e.g., a TiNi wire) to 0.172. In some embodiments, the same longitudinal start be coated is mounted in a pin Vise, or other device that is ing position is used with respect to the core for each pass of capable of rotating the core about its longitudinal axis. The the ultrasonic coating head. For example, for each pass, the pin vice is rotated and an ultrasonic spray head is passed ultrasonic coating head would start at the same longitudinal back and forth relative to the rotating core. Ultrasonic point and follow the same pattern. In other embodiments, the coating systems can produce a spray stream that narrows longitudinal starting position of the ultrasonic coating head down as it moves away from the coating head. Referring may change with each additional pass. Referring to FIG. 13, now to FIG. 9, spray stream 120 narrows as it travels away the first transverse Sweep of the first pass may start at point from the coating head 122 before passing through a focal 150. Then, the first transverse sweep of the second pass may point 124 (or point of smallest spray stream diameter) before start at an offset position 152 that is offset at a distance 151 starting to expand. In an embodiment, the focal point has a from starting point 150. Similarly, the first transverse sweep cross-sectional diameter of about 0.5 mm to about 1.0 mm. of the third pass and fourth pass begin at points 154 and 156, In contrast, other types of spray systems frequently produce respectively. This technique of moving the starting position a spray stream that continuously expands in diameter as the in the direction of arrow 158 can be used to extend the stream leaves the spray head. For example, referring now to distance over which the coating builds up to its full thickness FIG. 10, the spray stream 130 continues to get wider as it thereby controlling the slope of the transition segment of the travels away from the coating head 132. coating layer. By way of example, the offset distance between successive passes could be 0.5 mm. This would 0168 Ultrasonic coating systems may be used to coat a generally result in a longer transition segment with a lower core with a large degree of accuracy, particularly where the slope in comparison with a coating layer that was applied core to be coated is positioned at or near the focal point of with an offset between successive passes of less than 0.5 the spray stream. This is because the spray stream has a mm, for example 0.2 mm. The slope of the transition relatively small cross-sectional area at or near the focal point segment may be desirably low (e.g., less than about 1.0) because the spray stream has a relatively small amount of when the device will undergo stresses (for example, fric spray droplets that are outside of the focal point. As the spray tional stresses) that may result in delamination or failure of stream has a relatively small cross-sectional area, the posi the coating. The slope of the transition segment may be tion of the spray stream with respect to the core must be desirably high (e.g., greater than about 1.0) where it is moved if a broader area of the core is to be coated with a desired to maximize the amount of the coating layer on the coating layer. Either the core or the spray head may be device. The proximal and distal transition segments of the moved in order to coat a broader area. coating layer may have slopes that are the same or different. US 2006/01 10428 A1 May 25, 2006
For example, in some embodiments, the distal transition 0177. The bioactive agent to be administered may be segment has a slope that is less than the proximal transition concentrated to minimize the volume to be administered Segment. subretinally or into the subretinal space. After the liquid and the bioactive agent is administered or instilled subretinally, 0173. In some embodiments, the coating comprises at the surrounding tissues absorb the liquid and the bioactive least two layers, wherein each layer comprises the same agent resides Subretinally (e.g., as a Solid) and diffuses or composition, or a different composition. In one Such otherwise is absorbed by the surrounding tissues of the eye embodiment, a first layer having either bioactive agent over time. In this way, the methods of the invention provide alone, or bioactive agent together with one or more of the a localized subretinal deposit of the bioactive agent within biodegradable polymers is applied, after which one or more the eye. In addition, the action of the deposit or depot of the additional layers are applied, each with or without one or bioactive agent also is localized at the retina and the choroid. more bioactive agents. These different layers, in turn, can cooperate in the resultant composite coating to provide an 0.178 The bioactive agent may include a pharmaceuti overall release profile having certain desired characteristics, cally acceptable carrier or excipient and/or one or more and is particularly preferred for use with bioactive agents accessory molecules which may be Suitable for diagnostic or having high molecular weight. According to the invention, therapeutic use in vitro or in vivo. The term “pharmaceuti the composition of individual layers of the coating can cally acceptable carrier as used herein encompasses any of include any one or more of the following: one or more the standard pharmaceutical carriers, such as a phosphate bioactive agents, and/or a biodegradable polymer, as buffered saline solution, water, and emulsions, such as an desired. oil/water or water/oil emulsion, and various types of wetting agents. The bioactive agent may also include Stabilizers and 0174 Preferably, the coating composition is applied to preservatives. For examples of carriers, stabilizers and adju the core of the device in one or more applications. The vants, see Martin Remington's Pharm. Sci., 15th Ed. (Mack method of applying the coating composition to the body Publ. Co., Easton (1975)). member is typically governed by Such factors as the geom etry of the device and other process considerations. The 0.179 For subretinal instillation of one or more bioactive coated composition can be subsequently dried by evapora agent(s), the following procedure may be used. With refer tion of the solvent. The drying process can be performed at ence to FIG. 14, the step of instilling the bioactive agent(s) any Suitable temperature, (for example, room temperature or (Step 200) includes forming a limited or localized retinal elevated temperature), and optionally with the assistance of detachment (e.g., a bleb detachment) using any of a number of devices and/or techniques known to those skilled in the art WaCl. (Step 202), thereby defining or forming a subretinal space 0175. In some embodiments, the coating composition is and instilling (i.e., injecting or implanting) bioactive applied to the core under conditions of controlled relative agent(s) into the Subretinal space formed by the retinal humidity. As used herein, “relative humidity” is the ratio of detachment (Step 204). The limited or local subretinal the water vapor pressure (or water vapor content) to the detachment is created in Such a fashion that the detachment saturation vapor pressure (or the maximum vapor content) at itself generally does not have an appreciable or noticeable a given temperature of the air. The Saturation vapor pressure long-term effect on the vision of the patient. In more in the air varies with air temperature: the higher the tem particular embodiments, the bioactive agent is instilled perature, the more water vapor it can hold. When saturated, Subretinally or in a Subretinal space that is proximal to a the relative humidity in the air is 100% relative humidity. given site or locus of particular tissues of the eye that require According to Some embodiments of the invention, the coat Such treatment or are an appropriate pathway for effective ing composition can be applied to the core under conditions delivery of the bioactive agent to tissues requiring treatment of increased or decreased relative humidity as compared to or prevention of the disease or disorder. In this way, the ambient humidity. action of the bioactive agent is localized at the choroid and 0176). According to the invention, humidity can be con the retina and also minimizes the drug action at other tissue. trolled in any suitable manner, including at the time of 0180 Methods of the invention bypass the mechanisms preparing and/or applying the coating composition to the or barriers that may limit the effective delivery of bioactive body member. For example, when humidity is controlled at agents when injected only directly into the vitreous, thereby the time of preparing the coating composition, the water permitting more Sustained therapy to the target tissue. Locat content of the coating composition can be adjusted, before ing the bioactive agent Subretinally also minimizes the loss and/or after the coating composition is applied to the body or removal of the bioactive agent from the eye such as member. When humidity is controlled at the time of apply expiration of the bioactive agent via the anterior segment of ing the coating composition, the coating composition can be the eye after being initially located or injected in the applied to the body member in a confined chamber or area vitreous. Subretinal locating of the bioactive agent mini adapted to provide a relative humidity that differs from mizes the need for follow up injections, as typically needed ambient humidity. Generally, it has been found that applying with injections into the vitreous in order to maintain an coating compositions under conditions of increased humid adequate therapeutic concentration within the vitreous as ity will typically accelerate release of the bioactive agent, well as minimizing the risks attendant with Such injections while applying coating compositions under conditions of to the vitreous. Further, because the bioactive agent is decreasing humidity levels will tend to decelerate release of delivered directly to the subretinal space, it follows that the bioactive agent. As contemplated in the invention, even higher concentrations of the bioactive agent is delivered to ambient humidity can be considered “controlled humidity the choroidal vessels and retinal pigment epithelial cells as if it has been correlated with and determined to provide a compared to intravitreal injection and intraocular implants corresponding controlled release of the bioactive agent. that introduce drugs into the vitreous humor. US 2006/01 10428 A1 May 25, 2006
0181. Now referring to FIG. 15, there is shown a flow capable of providing a source of light therein for the diagram of an eye treatment methodology according to one Surgeon. Accordingly, the Surgeon would determine the embodiment of the invention, which methodology includes positioning of the operable end of the instrument by viewing inserting a delivery device or delivery instrument into the the interior of the eye using the lens assembly and being eye to be treated (Step 302). The instrument being inserted illuminated by the light transmitting apparatus. can be any of a number of instruments known to those 0186. After localizing the operable end of the instrument skilled in the art that can be used to form a retinal detach to the target site, for example the surface of the retina ment. More particularly, the instrument is configured and proximal the target site, the Surgeon forms the limited retinal arranged so as to be capable of forming a limited or localized detachment (Step 306). In an illustrative exemplary embodi retinal detachment and to minimize the area of the retinal ment, the Surgeon forms the limited retinal detachment by detachment Such that there is no long-term apparent loss in injecting a fluid, such as liquid orgas, from the instruments visual acuity. operable end. More specifically, the fluid is injected from the 0182. In some embodiments, the step of inserting (Step instrument's operable end in Such a manner that the injected 302) includes inserting a portion of the delivery instrument fluid is disposed between the retina and the choroid thereby or device, such as the exemplary delivery device illustrated causing the retina to detach therefrom. In more specific in U.S. Patent Application No. 2004/0133155 (Varner et al.), embodiments, the instrument's operable end is positioned into the eye in a minimally invasive manner. This method such that the stream of fluid flowing from the operable end ology also yields a technique that can be implemented in an of the instrument is directed towards the targeted site of the outpatient clinic setting. According to this embodiment, a retina and the stream of fluid pierces the retina and flows delivery instrument or device is provided, a portion of which beneath the retina. is configured and arranged Such that when the instrument is 0187. Referring to FIG.16, the sharp distal end 18 of the inserted into the eye, the opening formed in the Sclera to piercing member 12' is localized to a desired location on the receive the instrument is Small enough so as to not require surface of the conjunctiva or the sclera 104" of the eye 100'. Sutures to seal or close the opening in the Sclera. In other A pressure or force is applied to the device 10' such that the words, the opening is Small enough that the wound or sharp distal end 18 of the piercing member 12 penetrates opening is self-sealing, thereby preventing the aqueous the sclera 104 of the eye 100" or both the conjunctiva and humor from leaking out of the eye. sclera of the eye and the distal end is within the vitreous 0183 In addition, the step of inserting further includes humor 102 of the eye 100'. This also thus creates a con inserting the insertable portion of the delivery instrument or tinuous passageway (not shown) between the device 10' and device transconjunctivally so the operable end thereof is the vitreous humor 102 of the eye 100' providing a pathway within the vitreous. In this regard, transconjunctival shall be for the Surgeon to gains access to the vitreous humor. understood to mean that the instrument's operable end is 0188 The piercing member 12" also has a length such that inserted through both the conjunctiva and through the Sclera once its proximal end 16' is in contact with a portion of the into the vitreous. More particularly, inserting the insertable outer periphery of the sclera or the conjunctiva of the eye, portion that forms an opening in the Sclera and the conjunc the distal end 18 of the piercing member is within the tiva that is Small enough so as to not require Sutures or the vitreous humor 102 of the eye 100'. Once inserted the like to seal or close the opening in the Sclera. In conventional piercing member 12" can be angled by gently tilting or Surgical techniques for the posterior segment of the eye, the manipulating any portion of the device that lies outside of conjunctiva is routinely dissected to expose the Sclera, the eye 100'. In this way, the device 10" can be localized to whereas according to the methodology of this embodiment, multiple target sites within the eye without necessitating the conjunctiva need not be dissected nor pulled back. multiple, separate insertions of the device into the eye. 0184 Consequently, when the instrument is removed 0189 Once a passageway into the eye 100' is thus cre from the eye (step 310), the surgeon does not have to seal or ated, the cannula 44' and attached tubing 32", is advanced close the opening in the Sclera with Sutures to prevent into and through the device 10' and localized to a treatment/ leaking of the aqueous humor because as indicated above target site. As illustrated in FIG. 17, the target site is the Such an opening or wound in the Sclera is self-sealing. In retina 110' of the eye 100'. The cannula 44' is guided through addition, with the transconjunctical approach, the Surgeon the device 10' until a distal portion 46 of the cannula does not have to deal with reattaching the dissected con emerges from the guiding member 12", and into the vitreous junctiva. Thus, further simplifying the Surgical procedure as humor 102 and the cannula is further advanced within the well as reducing if not eliminating the Suturing required eye 100' until the distal portion 46 of the cannula enters the under the Surgical procedure. retina 110'. 0185. After the insertable portion of the instrument is 0190. An operator of the device 10' is able to determine inserted into the eye, the operable end thereof is localized to that the distal portion 46' of the cannula 44' has entered, but the targeted site (Step 304) including the tissues that are not traveled completely through, the retina 48' by virtue of being targeted for treatment. As is known to those skilled in techniques generally known in the art. For example, once an the art, Surgical personnel typically mount a lens assembly operator estimates that the distal portion 46' of the cannula (not shown) onto the cornea of the eye in accordance with is approaching the retina, S/he can inject an agent through known and accepted practices and techniques. This lens the cannula 44'. In order to simplify this estimation, the assembly is provided so that the Surgeon can view the cannula 44' can include one or more markings that serve as interior of the eye as well as any instruments inserted visual and/or tactile indicators of the relative position of the therein. In addition, a light-transmitting apparatus as is cannula with respect to the retina. If, following this injec known in the art also is inserted into the vitreous so as to be tion, the formation of a retinal detachment is observed, the US 2006/01 10428 A1 May 25, 2006
operator can safely deduce that the distal portion 46' of the lar illustrative embodiment of the invention, the opening or cannula 44' has entered, and still remains within, the retina through aperture is formed by a small gauge needle that is 110' and can halt the distal advancement of the cannula. disposed within the vitreous and manipulated by the Surgeon So as to pierce the tissues of the retina. For example, a 0191 Referring now to FIG. 15, after forming the local Surgeon can use micro-forceps as is known to those skilled ized or limited retinal detachment (e.g., a bleb detachment), in the art that the Surgeon would use to grip and manipulate the bioactive agent is instilled (i.e., injected or implanted) in the needle. the subretinal spaced defined by the limited retinal detach ment (Step 308). In the case, where the bioactive agent is in 0.195 As previously described, the inserted instrument is a liquid form or formulation, the instrument forming the localized to the targeted site (Step 354) that includes the retinal detachment can be used to inject the bioactive agent tissues that are being targeted for treatment. As is known to into the retinal detachment. Alternatively, a fluid including those skilled in the art, Surgical personnel typically mount a the bioactive agent can be used to form the retinal detach lens assembly (not shown) onto the cornea of the eye in ment and thereby simultaneously form the detachment and accordance with known and accepted practices and tech inject the bioactive agent. Thus, the forming of the detach niques. This lens assembly is provided so that the Surgeon ment (Step 308) and the injection of the bioactive agent (step can view the interior of the eye as well as any instruments 310) are performed essentially simultaneously, thereby fur inserted therein. In addition, a light-transmitting apparatus ther simplifying the procedure or process. as is known in the art also is inserted into the vitreous so as to be capable of providing a source of light therein for the 0.192 Referring now to FIG. 18, in the case where the Surgeon. Accordingly, the Surgeon would determine the bioactive agent is in a solid or implantable form or formu positioning of the operable end of the instrument by viewing lation, the operable end 902 of the instrument may be further the interior of the eye using the lens assembly and being configured and arranged so to include a cannula 904 or illuminated by the light transmitting apparatus. lumen. The bioactive agent in its implantable form 910 such as a capsule, rod or sheet is disposed in the cannula or lumen 0196. After localizing the operable end of the instrument prior to it being deployed there from subretinally. Thus, after to the tissues of the retina proximal the target site, the forming the limited retinal detachment, the Surgeon or Surgeon manipulates the instrument to penetrate or pierce medical personnel manipulates the instrument so that the the tissues of the retina as herein described (Step 356). As bioactive agent in its implanted form 910 is dispensed from indicated hereinabove, this action preferably creates or the end of the cannula 904 in the instruments operable end forms an opening or through aperture in the retina of small 902 into the subretinal space formed by the limited retinal diameter that provides access the area or region between the detachment. Alternatively, the Surgeon or medical personnel retina and the choroids. Preferably the opening or through can manipulate the implantable form of the bioactive agent aperture created or formed by Such action generally does not So as to insert the bioactive agent at the same time as forming have an appreciable or noticeable long-term effect on the the retinal detachment. Such dispensing can be accom vision of the person. plished by mechanical action on the implantable form of the drug (e.g., a rod acting on the capsule form of the drug) or 0.197 After forming the opening or aperture (Step 356), by fluid or hydraulic action on the implantable form. the Surgeon then manipulates the form the bioactive agent is in so that the form of the bioactive agent is passed through 0193 After completing such injection or implanting, the the opening in the tissues of the retina and slide between the instrument is removed from the eye (Step 310). Prior to tissues of the choroid and the retina. In more particular sealing or closing the opening formed in the eye, one or embodiments, the bioactive agent is provided in the form of more bioactive agent(s) may be injected into the vitreous a sustained release device or other delivery device and the humor using a small gauge needle and Syringe (Step 312). Sustained release device or delivery device is manipulated Such bioactive agent(s) may be the same as the bioactive by the Surgeon so as it passes through the opening or agents instilled subretinally or may be different than such aperture in the tissues of the retina and so it is slide bioactive agent(s). Following this, in the case where an subretinally between the tissues of the retina and the chor incision was made in the Sclera to insert the instrument, oids (Step 358). After completion of the instilling of the sutures would be used to close the incision. In addition, if the bioactive agent(s), the Surgeon removes the Surgical instru particular technique also involved dissection of the conjunc ments from the vitreous (Step 360). Optionally, the surgeon tiva, the conjunctiva would be re-attached to the eye. As may inject one or more bioactive agents into the vitreous indicated herein, if the technique used to form the opening humor using a small gauge needle and Syringe (Step 362). yields an opening in the Sclera Small enough so as to be self Such bioactive agent(s) may be the same as or different from sealing, Suturing may not be required and for the transcon the bioactive agent(s) instilled subretinally. As indicated junctival technique, re-attachment of the conjunctiva should herein, the process of inserting the instruments into the not be required. vitreous and removal preferably are accomplished using techniques whereby an opening(s) formed in the Sclera for 0194 Referring now to FIG. 19, there is shown a flow admission of the instruments into the vitreous is self-sealing. diagram of an eye treatment methodology according to yet In addition, the technique used for inserting the instruments another embodiment of the invention, which methodology into the vitreous also is more particularly a transconjunctival includes inserting a device or instrument into the eye to be technique whereby the instruments are inserted through both treated (Step 352). The instrument being inserted can be any of the conjunctiva and the Sclera. of a number of instruments known to those skilled in the art that can be used to pierce the tissues of the retina and form 0.198. In further embodiments, the bioactive agent is an opening or aperture therein so as to provide access to the inserted or implanted through the retinal tissues semi-per area or region between the retina and choroids. In a particu manently or temporarily. Thus, in Such further embodiments US 2006/01 10428 A1 May 25, 2006
the methodology further includes inserting a withdrawal Intravitreous Injections. The Journal of Retinal and Vitreous instrument (e.g., micro-forceps) into the vitreous following Diseases, Vol. 24, No. 5 (2004). completion of the treatment phase and localizing the oper 0201 The methodologies of the invention are contem able end of the withdrawal instrument proximal the target plated as being practiced alone, or in combination with other site, more particularly proximal the tissues containing the therapies or treatments. For example, where laser treatment device. Thereafter, the surgeon manipulates the withdrawal of an eye is indicated, the method of the invention can be instrument so as to withdraw the bioactive agent, for practiced before and/or after the laser treatment. example, withdrawing the bioactive agent delivery device from the subretinal region. The bioactive agent is withdrawn Bioactive Agents: from the vitreous along with any instruments. In yet further 0202 As used herein, “bioactive agent” refers to an agent particular embodiments, the methodology of the invention that affects physiology of biological tissue. Bioactive agents contemplates insertion of another depot of bioactive agent, useful according to the invention include virtually any for example insertion of another delivery device with a fresh Substance that possesses desirable therapeutic and/or pro charge of bioactive agent, into the Subretinal region follow phylactic characteristics for application to the implantation ing Such withdrawal of the used device or bioactive agent. site. Method C Intravitreal Delivery: 0203) While reference may be made to a “bioactive agent, it will be understood that the invention can provide 0199. In some embodiments, the method of the invention any number of bioactive agents to a treatment site. Thus, includes instilling one or more bioactive agents into the reference to the singular form of “bioactive agent” is vitreous humor of the eye. The intravitreal delivery will intended to encompass the plural form as well. typically be performed after implantation of the intraocular sustained release delivery device (see, Method A) and/or 0204 Exemplary bioactive agents include, but are not after instillation of the bioactive agent(s) subretinally (see, limited to, thrombin inhibitors; antithrombogenic agents; Method B). Typically, the intravitreal delivery will be thrombolytic agents (such as plasminogen activator, or TPA: accomplished by direct intravitreal injection of the one or and streptokinase); fibrinolytic agents; vasospasm inhibi more bioactive agents, for example, using a 27 to 30-gauge tors; calcium channel blockers; vasodilators; antihyperten needle (or smaller) having a length of about 0.5 to about 0.62 sive agents; clotting cascade factors (for example, protein inches. Alternatively, the intravitreal delivery may be S); anti-coagulant compounds (for example, heparin and accomplished using transscleral iontophoresis as discussed, nadroparin, or low molecular weight heparin); antimicrobial for example, in Ashim K. Midra; Ophthalmic Drug Delivery agents, such as antibiotics (such as tetracycline, chlortetra System; 2" Edition (2004) at Chapter 12 (Marvin E. Myles cycline, bacitracin, neomycin, polymyxin, gramicidin, ceph et al., Ocular Inotophoresis). Iontophoresis is the direct alexin, oxytetracycline, chloramphenicol, rifampicin, cipro transport of ionized Substances through tissue by application floxacin, tobramycin, gentamycin, erythromycin, penicillin, of an external electric current. Bioactive agents having one Sulfonamides, sulfadiazine, Sulfacetamide, Sulfamethizole, or more pKa values either below pH 6 or above pK8 may be Sulfisoxazole, nitrofuraZone, Sodium propionate, minocy Suitable for iontophoresis because these bioactive agents cline, doxycycline, Vancomycin, kanamycin, cephalosporins will be in their ionized form at the physiological pH of the Such as cephalothin, cephapirin, cefazolin, cephalexin, ceph eye. The salt form of the bioactive agent may also be ardine, cefadroxil, cefamandole, cefoxitin, cefaclor, preferred. The bioactive agent is driven into the ocular tissue cefuroxime, cefonicid, ceforanide, cefitaxime, moxalactam, with an electrode carrying the same charge ionized form as cetizoxime, ceftriaxone, cefoperaZone), geldanamycin and the bioactive agent. In transscleral iontophoresis the elec analogues, antifungals (such as amphotericin B and micona trical current is applied through the pars plana. Specifically, Zole), and antivirals (such as idoxuridine trifluorothymidine, for transscleral iontophoresis the bioactive agent is con acyclovir, gancyclovir, interferon, C.-methyl-P-adamantane tained in a tube within an eyecup held to the conjunctiva by methylamine, hydroxy-ethoxymethyl-guanine, adamantan Suction. The tube is placed over the pars plana to avoid amine, 5-iodo-deoxyuridine, trifluorothymidine, interferon, current damage to the retina. Devices for iontophoresis are adenine arabinoside); inhibitors of Surface glycoprotein commercially available from a number of sources, for receptors; antiplatelet agents (for example, ticlopidine); anti example, Iomed, Inc. (Salt Lake City, Utah): Life-Tech, Inc. mitotics; microtubule inhibitors; anti-secretory agents; active inhibitors; remodeling inhibitors; antisense nucle (Stafford, Tex.): General Medical Co. (Los Angeles, Calif.); otides (such as morpholino phosphorodiamidate oligomer); and Fischer Co., Inc. (Glendale Calif.). anti-metabolites; antiproliferatives (including antiangiogen 0200. The one or more bioactive agents instilled into the esis agents, taxol. Sirolimus (rapamycin), analogues of rapa vitreous humor may be the same as the one or more mycin (“rapalogs'), tacrolimus, ABT-578 from Abbott, bioactive agents in the intraocular device (Method A) or everolimus, paclitaxel, taxane, Vinorelbine); anticancer che instilled subretinally (Method B), or the bioactive agent(s) motherapeutic agents; anti-inflammatories (such as hydro may be different. The bioactive agent(s) are typically cortisone, hydrocortisone acetate, dexamethasone 21-phos injected as liquids. The Volume will depend, for example, on phate, fluocinolone, medrysone, methylprednisolone, the method of treatment, the type of bioactive agent(s) being prednisolone 21-phosphate, prednisolone acetate, fluo injected, the concentration of the bioactive agent(s), disease romethalone, betamethasone, triamcinolone, triamcinolone state, location of disease and affected tissue. Typically the acetonide); non-steroidal anti-inflammatories (such as Sali volume of the injection will be up to about 500 uL, more cylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, typically from about 50 uL to 500 uL. Additional details piroXicam); antiallergenics (such as Sodium chromoglycate, regarding intravitreal injections can be found, for example, antazoline, methapyriline, chlorpheniramine, cetrizine, in Lloyd P. Aiello, MD et al., Evolving Guidelines For pyrilamine, prophenpyridamine); anti-proliferative agents US 2006/01 10428 A1 May 25, 2006 20
(such as 1.3-cis retinoic acid); decongestants (such as phe agents include aspirin (salicylic acid), indomethacin, sodium nylephrine, naphazoline, tetrahydrazoline); miotics and anti indomethacin trihydrate, Salicylamide, naproxen, colchi cholinesterase (such as pilocarpine, Salicylate, carbachol, cine, fenoprofen, Sulindac, diflunisal, diclofenac, indoprofen acetylcholine chloride, physostigmine, eserine, diisopropyl and sodium salicylamide. Local anesthetics are substances fluorophosphate, phospholine iodine, demecarium bro that have an anesthetic effect in a localized region. Examples mide); mydriatics (such as atropine, cyclopentolate, homa of Such anesthetics include procaine, lidocaine, tetracaine tropine, Scopolamine, tropicamide, eucatropine, and dibucaine. hydroxyamphetamine); sympathomimetics (such as epi nephrine); antineoplastics (such as carmustine, cisplatin, 0208. Other bioactive agents include abamectin, abun fluorouracil); immunological drugs (such as vaccines and diazole, acaprazine, acabrose, acebrochol, aceburic acid, immune stimulants); hormonal agents (such as estrogens, acebutolol, acecainide, acecarbromal, aceclidine, ace estradiol, progesterol, progesterone, insulin, calcitonin, par clofenac, acedapsone, acediasulfone, acedoben, acefluranol, athyroid hormone, peptide and vasopressin hypothalamus acefurtiamine, acefylline clofibrol, acefylline piperazine, releasing factor); beta adrenergic blockers (such as timolol aceglatone, aceglutamide, aceglutamide aluminium, acem maleate, levobunolol HCl, betaxolol HCl); immunosuppres etacin, acenocoumarol, aceperone, acepromazine, sive agents, growth hormone antagonists, growth factors aceprometazine, acequinoline, acesulfame, acetaminophen, (such as epidermal growth factor, fibroblast growth factor, acetaminosalol, acetanilide, acetarSone, acetergamine, ace platelet derived growth factor, transforming growth factor tiamine, acetiromate, acetohexamide, acetohydroxamic beta, Somatotropin, fibronectin, insulin-like growth factor acid, acetomeroctol, acetophenazine, acetorphine, acetosul (IGF)); carbonic anhydrase inhibitors (such as dichlorophe fone, acet: OZate, acetryptine, acetylcolchinol, acetylcys namide, acetazolamide, methazolamide); inhibitors of teine, acetyldigitoxin, acetylleucine, acetylsalicyclic acid, angiogenesis (such as angiostatin, anecortave acetate, acevaltrate, acexamic acid, acifran, acipimoX, acitemate, thrombospondin, anti-VEGF antibody such as anti-VEGF acitretin, acivicin, aclantate, aclarubicin, aclatonium napa fragment—ranibizumab (Lucentis)): dopamine agonists; disilate, acodazole, aconiazide, aconitine, acoxatrine, acri radiotherapeutic agents; peptides; proteins; enzymes; dorex, acrihellin, acrisorcin, acrivastine, acrocinide, acro nucleic acids and nucleic acid fragments; extracellular nine, actinoquinol, actodigin, adafenoxate, adamexine, matrix components; ACE inhibitors; free radical Scavengers; ademetionine, adenosine phosphate, adibendan, adicillin, chelators; antioxidants; anti-polymerases; photodynamic adimolol, adinazolam, adiphenine, aditeren, aditoprim, therapy agents; gene therapy agents; and other therapeutic adrafinil, adrenalone, afloqualone, afurolol, aganodine, agents such as prostaglandins, antiprostaglandins, prostag ajmaline, aklomide, alacepril, alafosfalin, alanine mustard, landin precursors, and the like. alanosine, alaproclate, alazanine triclofenate, albendazole, albendazole oxide, albuterol, albutoin, alclofenac, alcometa 0205 Another group of useful bioactive agents are anti Sone dipropionate, alcloxa, alcuronium chloride, aldioxa, septics. Examples of antiseptics include silver Sulfadiazine, aldosterone, alepride, aletamine, alexidine, alfacalcidol. chlorhexidine, glutaraldehyde, peracetic acid, sodium alfadex, alfadolone, alfaprostol, alfaxalone, alfentanil, alfu hypochlorite, phenols, phenolic compounds, iodophor com Zosin, algestone acetonide, algestone acetophenide, aliben pounds, quaternary ammonium compounds, and chlorine dol, aliconazole, aliifedrine, alliflurane, alimadol, alinidine, compounds. alipamide, alitame, alizapride, allantoin, alletorphine, allo 0206. Another group of useful bioactive agents are barbital, alloclamide, allocupreide, allomethadione, allopu enzyme inhibitors. Examples of enzyme inhibitors include rinol, allylestrenol, allyl isothicyanate, allylprodine, allylth chrophonium chloride, N-methylphysostigmine, neostig iourea, almadrate Sulfate, almasilate, almecillin, almestrone, mine bromide, physostigmine Sulfate, tacrine HCL, tacrine, alminoprofen, almitrine, almoxatone, alonacic, alonimid, 1-hydroxymaleate, iodotubercidin, p-bromotetramisole, aloxi statin, aloZafone, alpertine, alphacetylmethadol, alpha 10-(C.-diethylaminopropionyl)-phenothiazine hydrochlo meprodine, alphamethadol, alphaprodine, alpha-Vinylaziri ride, calmidazoliurn chloride, hemicholinium-3,3,5-dinitro dinoethyl acetate, alpidem, alpiropride, alprazolam, alpre catechol, diacylglycerol kinase inhibitor 1, diacylglycerol nolol, alprostadil, alrestatin, altanserin, altapizone, kinase inhibitor II, 3-phenylpropargylamine, N-monom alteconazole, althiazide, altrenogest, altretamine, aluminium ethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydra acetate, aluminium clofibrate, aluminium Subacetate, alver zine HCl, hydralazine HCl, clorgyline HCl, deprenyl HCl, ine, amadinone acetate, amafolone, amanozine, amantadine, L(-)deprenyl HCl, iproniazid phosphate, 6-MeO-tetrahy amantanium bromide, amantocillin, ambasilide, ambazone, dro-9H-pyrido-indole, nialamide, pargyline HCl, quinacrine ambenonium chloride, ambenoxan, ambroXol, ambruticin, HCl, semicarbazide HCl, tranylcypromine HCl, N,N-diethy ambucaine, ambucetamide, ambuphylline, ambuside, ambu laminoethyl-2,2-diphenylvalerate hydrochloride, 3-isobutyl tonium bromide, amcinafal, amcinafide, amcinonide, amdi 1-methylxanthine, papaverine HCl, indomethacin, 2-cy nocillin, amdinocillin pivoxil, amebucort, amedalin, amet clooctyl-2-hydroxyethylamine hydrochloride, 2,3-dichloro antrone, ameZepine, amezinium metilsulfate, amfenac, C.-methylbenzylamine (DCMB), 8,9-dichloro-2,3,4,5- amfepentorex, amfetaminil, amflutizole, amfonelic acid, tetrahydro-1H-2-benzazepine hydrochloride, amicarbalide, amicibone, amicloral, amicycline, amidantel, p-aminoglutethimide, p-aminoglutethimide tartrate, R(+) amidapsone, amidephrine, amiflamine, amifloverine, ami p-aminoglutethimide tartrate, S(-)-iodotyrosine, alpha-me floxacin, amifostine, amikacin, amikhelline, amiloride, ami nacrine, amindocate, amineptine, aminobenzoic acid, ami thyltyrosine, L(-)alpha methyltyrosine, D.L(-)cetazola nocaproic acid, aminoethyl nitrate, aminoglutethimide, mide, dichlorophenamide, 6-hydroxy-2-benzothiazole aminohippuric acid, aminometradine, aminopentamide, Sulfonamide, and allopurinol. aminophylline, aminopromazine, aminopterin, aminopyrine, 0207 Another group of useful bioactive agents are anti aminoquinol, aminoquinuride, a minorex, aminosalicyclic pyretics and antiinflammatory agents. Examples of Such acid, aminothiadiazole, aminothiazole, amiodarone, amiper US 2006/01 10428 A1 May 25, 2006 one, amipheaZole, amipizone, amiprilose, amiquinsin, ami tate, benzopyrronium bromide, benzoquinium chloride, ben Sometradine, amisulpride, amiterol, amithioZone, amitraz, Zotript, benzoxiduine, benzoxonium chloride, benzoyl per amitriptyline, amitriptylinoxide, amiXetrine, amlexanox, oxide, benzoylpas, benzphetamine, benzpiperylon, amlodipine, amobarbital, amodiaquine, amogastrin, amol benZpyrinium bromide, benzquercin, benzquinamide, benz anone, amonofide, amoproxan, amopyroquin, amorolfine, thiazide, benztropine, benzydamine, benzylpenicillin, ben amocanate, amoSulalol, amotriphene, amoxapine, amox Zylsulfamide, beperidium iodide, bephenium naphtoate, ecaine, amoxicillin, amoxydramine camsilate, amperozide, amphecloral, amphenidone, amphetamine, amphotalide, bepiastine, bepridil, beraprost, berberine sulfate, bermastine, ampicillin, ampiroXicam, amprolium, ampyrimine, ampy bermoprofen, berythromycin, besulpamide, beslunide, beta Zine, amduinate, amrinone, amsacrine, amygdalin, amylene, carotene, betacetylmethadol, betahistine, betaine, betame amylmetacresol, amyl nitrite, anagestone acetate, prodine, betamethadol, betamethasone acetate, betametha anagrelide, anaxirone, anazocine, anazolene, ancarolol. Sone acibutate, betamethasone benzoate, betamethasone ancitabine, androstanediol, androstanol propionate, andros dipropionate, betamethasone phosphate, betamethasone val tenetrione, androstenonol propionate, anethole, anguidine, erate, betamicin, betaprodine, betazole, bethanechol chlo anidoxime, anilamate, anilleridine, aniline, anilopam, ride, bethanidine, betiatide, betoxycaine, bevantolol, bevo anipamil, aniracetam, anirolac, anisacril, anisindione, nium metilsulfate, bezafibrate, bezitramide, bialamicol, anisopirol, anisoylbromacrylic acid, anitraZafen, anpirtoline, bibenzonium bromide, bibrocathol, bici fadine, biclodil, ansoxetine, antafenite, antazonite, anthelmycin, anthi biclofibrate, biclotymol, bicozamycin, bidimazium iodine, olimine, anthralin, anthramycin, antienite, antimony potas bietamiverine, bietaserpine, bifemelane, bifepramide, biflu sium tartrate, antimony thioglycollate, antipyrine, antrafe ranol, bifonazole, binedaline, binfloxacin, binfibrate, bioal nine, apalcillin, apaZone, apicycline, apomorphine, lethrin, bioresmethrin, biotin, bipenamol, biperiden, biphe apovincamine, apraclonidine, apramycin, aprindine, namine, biriperone, bisacodyl, bisantrene, bis(aziridinyl) aprobarbital, aprofene, aptazapine, aptocaine, arabinosylm butanediol, bisbendazole, bisbentiamine, bisfenaZone, bis ercaptopurine, aranotin, arbaprostil, arbekacin, arclofenin, fentidine, bismuth betanaphthol, bismuth-triglycollamate, arfendazam, arginine, arginine glutamat, arildone, arnolol. bismuth subgallate, bismuth subsalicylate, bisorbin, biso aronixil, arotinolol, arpinocid, arpromidine, arsanilic acid, prolol, bisorcic, bioxatin acetate, bispyrithione magSulfex, arsthinol, artemisinin, articaine, asaley, ascorbic acid, ascor bithionol, bithionoloxide, bitipazone, bitoterol, bitoscantate, byl palmitate, asocainol, aspartame, aspartic acid, asperlin, bleomycin, bluenSomycin, bofumustine, bolandiol dipropi aspoxicillin, astemizole, atameStane, atenolol, atipamezole, onate, bolasterone, bolazine, boldenone undecylenate, bole atiprosin, atolide, atracurium besilate, atromepine, atropine nol, bolmantalate, bometolol, bopindolol, bomaprine, oxide, auranofin, aurothoiglucose, aurothioglycanide, avila bomaprolol, bomelone, botiacrine, boxidine, bralobarbital, mycin-A, pyridine, axamozide, azabon, aZabuperone, aza braZergoline, brefonalol, bremazocine, brequinar, bretylium citodine, azaclorzine, azaconazole, azacosterol, azacyclonol, tosylate, brindoxime, brivundine, brobactam, broclepride, aZaftozine, azaguanidine, azaloxan, azamethonium bromide, brocresine, brocrinat, brodimoprim, brofaromine, brofezil, aZamulin, azanator, azanidazole, azaperone; azapicyl, aza brofoxine, brolaconazole, brolamfetamine, bromacrylide, procin, azaquinzole, azaribine, azarole, azaserine, aza bromadoline, bromamid, bromazepam, bromchlorenone, spirium chloride, azastene, azastrptonigrin, azatodine, aza bromebric acid, bromerguride, brometenamine, bromfenac, bromhexine, bromindione, bromisovalum, bromociclen, thioprine, azauridine, azelastine, azepexole, azepindole, bromocriptine, bromodiphenhydramine, bromofenofos, bro aZetepa, azidamfenicol, azidocillin, azimexon, azintamide, mopride, bromoxandide, bromperidol, bromperidol aZipramine, azithromycin, azlocillin, azolimine, azosemide, decanoate, brompheniramine, bronopol, broparestrol, brop aZotomycin, aztreonam, and azumolene. eramole, bropirimine, broquinaldol, broSotamide, broSuxim 0209 Also, bacampicillin, baclofen, bacmecillinam, bal ide, brotianide, brotizolam, brovanexine, brovincamine, Salazide, bamaluzole, bambuterol, bamethan, bamifylline, broxaldine, broXaterol, broxitalamic acid, broXuridine, broX bamipine, bamidazole, baduiloprim, barbexaclone, barbital, ycuinoline, bruceantin, brucine, bucainide, bucetin, buciclo barucainide, batilol, bazinaprine, becanthone, beclamide, vir, bucillamine, bucindolol, bucladesine, buclizine, beclobrate, beclomethasone dipropionate, beclotiamine, buclosamide, bucloxic acid, bucolome, bucricaine, bucro befiperide, befunolol, befuraline, bekanamycin, belarizine, marone, bucrylate, bucumolol, budesonide, budipine, beloxamide, bemarinone, bemegride, bemetizide, bemitra budotitane, budralazine, bufenadrine, bufeniode, bufetolol, dine, benactyzine, benafentrine, benanserin, benapry Zine, bufexamac, bufezolac, buflomedil, bufogenin, buformin, benaxibine, benazepril, bencianol, bencisteine, bencloni bufrolin, bufuralol, bumadizone, bumecaine, bumepidil, dine, bencyclane, bendamustine, bendaZac, bendaZol, ben bumetanide, bumetrizole, bunaftine, bunamidine, bunami derizine, bendroflumethiazide, benethamide penicillin, ben odyl, bunaprolast, bunaZosin, bunitrolol, bunolol, buparva exate, benflorex, benfosformin, benfotiamine, benfurodil quone, bupicomide, bupivacaine, bupranolol, buprenor hemisuccinate, benhepaZone, benidipine, benmoxin, beno phine, bupropion, buquineran, buquinolate, buquiterine, lizime, benorilate, benorterone, benoxafos, benoxaprofen, buramate, burodiline, buspirone, busulfan, butabarbital, benoximate, benperidol, benproperine, benrixate, bensalan, butacaine, butacetin, butaclamol, butadiaZamide, butafos benserazide, benSuldazic acid, bentazepam, bentemazole, fan, butalamine, butalbital, butamben, butamirate, butami bentiamine, bentipimine, bentiromide, benurestat, benzalde sole, butamoxane, butanediol cyclic Sulfite, butanilicaine, hyde, benzalkonium chloride, benZaprinoxide, benzarone, butanixin, butanserin, butantrone, butaperazine, butaprost, benzbromarone, benzestrol, benzethidine, benzethonium butaverine, butedronate, buterizine, butetamate, chloride, benzetimide, benzilonium bromide, benzindopy butethamine, buthiazide, butibufen, butidrine, butikacin, rine, benziodarone, benzmalecene, benZnidazole, benzobar butilfenin, butinazocine, butinoline, butirosin, butixirate, bital, benzocaine, benzoclidine, benzoctamide, benzodepa, butobendine, butoconazole, butoprolol, butoctamide, buto benzododecinium chloride, benzoic acid, benzoin, benzona filolol, butonate, butopamine, butopiprine, butoprozine, US 2006/01 10428 A1 May 25, 2006 22 butopyrammonium iodide, butorphanol, butoxamine, rphenoxamine, chlorphentermine, chlorproethazine, chlor butoxylate, butriptyline, butropium bromide, butylated proguanil, chlorpromazine, chlorpropamide, chlorprothix hydroxyanisole, butylated hydroxytoluene, butylparaben, ene, chlorquinaldol, chlortetracycline, chlorthalidone, butynamine, and buZepide metiodide. chlorthenoxazine, chlorZoaxaZone, chloecalciferol, cholic 0210 Also, cabastine, cabergoline, cadralazine, cafami acid, choline chloride, choline glycerophosphate, chro nol, cafedrine, caffeine, calcifediol, calcitrol, calcium cit mocarb, chromonar, ciadox, ciamexon, cianergoline, ciani rate, calcium dobesilate, calcium glubionate, calcium glu dol, cianopramine, ciapilome, cicaprost, cicarperone, ciclac ceptate, calcium gluconate, calcium glycerophosphate, tate, ciclafrine, ciclaZindol, cicletanine, ciclomenol, calcium hypophosphite, calcium lactate, calcium lactobion ciclonicate, ciclonium bromide, ciclopiroX, ciclopramine, ate, calcium levulinate, calcium mandelate, calcium pan cicloprofen, cicloprolol, ciclosidomine, ciclotizolam, ciclo tothenate, calcium phosphate dibasic, calcium phophate tropium bromide, cicloxilic acid, cicloxolone, cicortonide, tribasic, calcium saccharate, calcium Stearate, calusterone, cicrotic acid, cidoxepin, cifenline, cifostodine, ciglitaZone, camazepam, cambendazole, camiverine, camoStast, cam ciheptolane, ciladopa, cilastatine, cilaZapril, cilaZaprilat, photamide, camptothecin, camylofin, canbisol, cannabinol, cilobamine, cillofungin, cilostamide, cilostaZol, ciltoprazine, canrenoic acid, canrenone, cantharidine, capobenic acid, cimaterol, cimemoxin, cimepanol, cimetidine, cimetropium capreomycin, caproxamine, capsaicine, captamine, captodi bromide, cimoxatone, cinchonine, cinchophen, cinecromen, ame, captopril, capuride, caracemide, caramiphen, cara cinepaXadil, cinepazet, cinepazic acid, cinepazide, cinfe Zolol, carbadox, carbaldrate, carbamazepine, carbamide per nine, cinfenoac, cinflumide, cingestol, cinitapride, cinmeta oxide, carbantel lauryl Sulfate, carbaril, carbarSone, cin, cinnamaverine, cinnamedrine, cinnarizine, cinnarizine carbaspirin calcium, carbazeran, carbazochrome, carbazach clofibrate, cinnofuradione, cincotramide, cinodine, cino rome Salicylate, carbazachrome Sulfonate, carbazocine, car lazepam, cinoquidox, cinoaxin, cinoxate, cinoXolone, cino beniciltin, carbenicillin indanyl, carbencillin phenyl, car oXopazide, cinperene, cinprazole, cinpropazide, cinromide, benoXolone, carbenzide, carbestrol, carbetapentane, cintaZone, cintriamide, cinperone, ciprafamide, ciprafaZone, carbidopa, carbimazole, carbinoxamine, carbiphene, car ciprefadol, ciprocinonide, ciprofibrate, cipropride, ciprocqua bocloral, carbocysteine, carbofenotion, carbol-fuschin, car Zone, ciprostene, ciramadol, cirazoline, cisapride, ciscona bomycin, carboplatin, carboprost, carboprost methyl, carbo Zole, cismadinone, cistinexine, citalopram, citatepine, cit quone, carbromal, carbubarb, carburazepam, carbutamide, enamide, citenaZone, citicoline, citiolone, clamidoxic acid, carbuterol, carcainium chloride, carebastine, carfentanil, clamoxyquin, clanfenur, clanobutin, clantifen, clarithromy carfimate, carisoprodol, carmantadine, cannetizide, carmo cin, clavulanic acid, clazolam, clazolimine, claZuril, clebo fur, camidazole, carnitine, carocainide, caroverine, caroX pride, clefamide, clemastine, clemeprol, clemizole, clen aZone, carperidine, caperone, carphenazine, carpindolol. buterol, clenpirin, cletoquine, clibucaine, clidafidine, carpiramine, carprofen, carpronium chloride, carsalam, car clidanac, clidinum bromide, climaZolam, climbazole, climi taZolate, carteolol, carubicin, carumonam, carvedilol. qualine, clindamycin, clindamycin palmitate, clindamycin carzenide, carzolamide, cathine, cathinone, cefaloniurm, phosphate, clinofibrate, clinolamide, cliquinol, clioxanide, cefaloram, cefamandole naftate, cefaparole, cefatrizine, clipoxamine, cliprofen, clobazam, clobenoside, cloben cefazaflur, cefazedone, cefazolin, cefbuperaZone, cefcanel, Zepam, clobenzorex, clobenztropine, clobetasol propionate, cefcanel daloxate, cefedrolor, cefempidone, cefepime, cefe clobetasone butyrate, clobutinol, clobuZarit, clocanfamide, tamet, cefetrizole, cefvitril, cefixime, cefinenoxime, cefine clocapramine, clociguanil, clocinizine, clocortolone acetate, pidium chloride, cefimetazole, cefiminox, cefodizime, clocortolone pivalate, clocoumarol, clodacaine, cefonizid, cefotaxime, cefotetan, cefotiam, cefoxazole, cef clodanolene, clodazon, clodoxopone, clodronic acid, clofa pimizole, ce?piramide, cefpirome, cefpodoxime, cefpo Zimine, clofenamic acid, clofenamide, clofenciclan, clofen doXime proxetil, cefauinome, cefrotil, cefroxadine, cefsulo etamine, clofenoxyde, clofenvinfos, clofeverine, clofexam din, cefsumide, ceftazidime, cefteram, cefiezole, ceftiofur, ide, clofeZone, clofibrate, clofibric acid, clofibride, clofilium ceftiolene, ceftioxide, ceftizoxime, cefuracetime, phosphate, cloflucarban, clofoctol, cloforex, clofurac, cloge cefuraxime axetil, cefurzonam, celiprolol, cephacetrile, stone acetate, cloguanamil, clomacran, clomegestone cephaloglycin, cephaloridine, cephradine, cetaben, ceta acetate, clometacin, clometherone, clomethiazole, clometo molol, cethexonium chloride, cetiedil, cetirizine, cetocy cillin, clomifenoxide, clominorex, clomiphene, clomi cline, cetohexazine, cetophenicol, cetotiamine, cetoxime, pramine, clomocycline, clomoxir, clonazepam, clonazoline, cetraxate, chaulmosulfone, chendiol, chiniofon, chlophedi clonidine, clonitaZene, clonitrate, clonixeril, clonixin, clo anol, chloracy Zine, chloral betaine, chloral hydrate, chloral pamide, clopenthixol, cloperastine, cloperidone, clopi ose, chlorambucil, chloramine, chloramphenicol palmitate, dogrel, clopidol, clopimozide, clopipazan, clopirac, clo chloramphenicol Succinate, chlorazanil, chlorbenzoxamine, ponone, cloprednol, cloprostenol, cloprothiazole, chlorbetamide, chlorcyclizine, chlordantoin, chlordiazep cloquinate, cloquinozine, cloracetadol, cloranolol, cloraZe oxide, chlordimorine, chlorhexadol, chlorhexidine, chlo pate, clorethate, clorexolone, cloricromen, cloridarol, clo rhexidine phosphanilate, chlorindanol, chlorisondamine rindanic acid, clorindione, clormecaine, cloroperone, clo chloride, chlormadinone acetate, chlormerodrin, chlormeza rophene, cloroqualone, clorotepine, clorprenaline, clorSulon, none, chlormidazole, chloronaphazine, chloroaZodin, chlo clortermine, closantel, closiramine, clostebol, clothiapine, robutanol, chlorocresol, chlorodihydroxyandrostenone, clothixamide, clotiazepam, cloticaSone propionate, clotioX chloroethyl mesylate, 5-chloro-3'-fluoro-2'3-dideoxyuri one, clotrimazole, clovoxamine, cloxacepride, cloxacillin, dine, chloroguanide, chlorophenothane, chloroprednisone cloxacillin benZathine, cloxazolam, cloxestradiol, cloxi acetate, chloroprocaine, chloropyramine, chloroquine, chlo mate, cloXotestosterone, cloxypendyl, cloxyquin, clozapine, roserpidine, chlorothen, chlorothiazide, chlorotriansene, cobamide, cocaine, cocarboxylase, codeine, codoxime, cofi chloroxine, chloroxylenol, chlorozotocin, chlorphenesin, satin, cogaZocine, colchicine, colestolone, colfenamate, col chlorphenesin carbamate, chlorphenoctium amsonate, chlo forsin, colterol, conessine, conorphone, copper gluconate, US 2006/01 10428 A1 May 25, 2006
cormethasone acetate, corticosterone, cortisone acetate, cor bine, dicarfen, dichlorallyl lawsone, dichlorisone acetate, tisuZol, cortivaZol, cortodoxone, cotamine chloride, coti dichlormezanone, dichlorofluorimethane, dichlorom, ethotr nine, cotriptyline, coumaphos, coumazoline, coumermycin, exate, dichlorophen, dichlorophenarsine, dichlorotetrafluo coumetarol, creatinolfosfate, crisinatol, croconazole, cro roethane, dichloroxylenol, dichlorphenamide, dichlorvos, makalim, cromitrile, cromolyn, cropropamide, crospovi diciferron, dicirenone, diclaZuril, diclofensine, diclofurime, done, crotamiton, crotetamide, crotoniazide, crufomate, cuprimyxin, cuproxoline, cyacetacide, cyamemazine, diclometide, diclonixin, dicloxacillin, dicobalt edetate, cyanocobalamine, cyclacillin, cyclandelate, cyclarbamate, dicolinium iodide, dicresulene, dicumarol, dicyclomine, cyclazocine, cyclazodone, cyclexanone, cyclindole, cyc didemnin, dideoxycytidine, didrovaltrate, dieldrin, dienes liramine, cyclizine, cyclobarbital, cyclobendazole, trol, dienogest, diethadione, diethazine, diethylpropion, cyclobenzaprine, cyclobutoic acid, cyclobutyrol, cyclofenil. diethylstilbestrol, diethylstilbestrol diphosphate, diethylstil cycloguanil, cloheximide, cycloleucine, cyclomenol, bestrol dipropionate, diethylthiambutene, diethyltoluamide, cyclomethicone, cyclomethycaine, cyclopentamine, cyclo dietifen, difebarbamate, difemerine, difemetorex, difenami penthiazide, cyclopenazine, cyclophosphamide, cyclopreg Zole, difencloxazine, difenoximide, difenoxin, difetarSone, nol, cyclopyrronium bromide, cycloserine, cyclosporine, difeterol, diflorasone diacetate, difloxacin, difluanine, diflu cyclothiazide, cyclovalone, cycotiamine, cycrimine, cyhep cortolone, diflurcortolone pivalate, diflumidone, diflunisal, tamide, cyheptropine, cynarine, cypenamine, cypothrin, difluprednate, diftalone, digalloyl trioleate, digitoxin, cyprazepam, cyprenophine, cyprodenate, cyproheptadine, digoxin, dihexyverine, dihydralazine, dihydroazacytidine, cyprolidol, cyproduinate, cyproterone acetate, cyproximide, dihydroergotamine, dihydrolenperone, dihydrostreptomy cystine, and cytarabine. cin, dihydrotachysterol, dihydroxyfluoroprogestrone, diiso promine, diisopropanolamine, dilaZep, dilevalol, dilimefone, 0211 Also, dacarbazine, dacemazine, dacisteine, dacino mycin, dacuronium bromide, dagapamil, dalbraminol, diloxanide, diltiazem, dimabefylline, dimecamine, dime daledalin, daltroban, dametralast, damotepine, danazol. colonium iodide, dimecrotic acid, dimefadane, dimefline, danitracen, danosteine, danthron, dantrolene, dapiprazole, dimelazine, dimemorfan, dimenhydrinate, dimenoxadol, dapsone, daptomycin, darenzepine, darodipine, datelliptium dimeheptanol, dimepranol, dimepregnen, dimeproZan, chloride, dunorubicin, daZadrol, dazepinil, dazidamine, dimercaprol, dimeSna, dimesone, dimetacrine, dimetamfe daZmegrel, dazolicine, dazopride, dazoquinast, dacoxiben, tamine, dimethadione, dimethaminostyrylquinoline, dimet deanol aceglumate, deanol acetaminobenzoate, deazauri hazan, dimethindene, dimethiodal, dimethisoquin, dimethis dine, deboxamet, debrisoquin, decamethonium bromide, terOne, dimetholizine, dimethoxanate, decimemide, decitropine, declaben, declenperone, declox dimethylhydroxytestosterone, dimethylnorandrostadienone, izine, decominol, decoquinate, deditonium bromide, defer dimethylnortestosterone, dimethylstilbestrol, dimethyl, dim oxamine, deflazacort, defosfamide, dehydroacetic acid, ethylthiambutene, dimethyltubocurarinium chloride, dehydroemetine, dehydro-7-methyltestosterone, delanter dimetipirium bromide, dimetofrine, dimetridazole, dimina one, delapril, delergotrile, delfantrine, delmadinone acetate, Zene, dimoxamine, dimoxaprost, dimoxyline, dimpylate, delmetacin, delmopinol, delorazepam, deloxone, delproste dinaline, dinaZafone, diniprofylline, dinitolmide, dinoprost, nate, dembrexine, demeclocycline, demecolcine, demecy dinoprostone, dinsed, dioSmin, dioxadillol, dioxadrol, diox cline, demegestone, demelverine, demexiptiline, democona amate, dioxaphetyl butyrate, dioxethedrin, dioxifedrine, Zole, demoxepam, denaverine, denbufylline, denipride, dioxybenzone, dipenine bromide, diperodon, diphemanil denopamine, denpidazone, denZimol, deoxyspergualin, methylsulfate, diphenadione, diphenan, diphenhydramine, depramine, deprodone, deprostil, deptropine, derpanicate, diphendiol, diphenoxylate, diphenylpraline, diphoxazide, desacetylcolchicine tartrate, desaspidin, desiclovir, descino dipipanone, dipipoverine, dipliverin, diprafenone, diprenor lone acetonide, deserpidine, desipramine, deslanoside, des phine, diprobutine, diprofene, diprogulic acid, diproleando methylcolchicine, desmethylmisonidazole, desmethylmora mycin, diprocqualone, diproteverine, diprotriozate, diproxa mide, desocriptine, desogestrel, desomorphine, desonide, dol, dipyridamole, dipyrithione, dipyrocetyl, dipyrone, desoximetasone, desoxycorticosterone acetate, desoxycorti dirithromycin, disobutamide, disofenin, disogluside, disopy costerone pivalate, desoxypyridoxine, detajmium bitartrate, ramide, disoxaril, distigmine bromide, disulergine, disulfa detanosal, deterenol, detomidine, detorubicin, detrothronine, mide, disulfiram, disuprazole, ditazole, ditercalinium chlo devapamil, dexamethasone, dexamethasone acefurate, dex ride, dithiazanine iodide, ditiocarb, ditiomustine, amethasone acetate, dexamethasone dipropionate, dexami ditolamide, ditophal, divabuterol, dixanthogen, dizatrifone, sole, dexbrompheniramine, dexchlorpheniramine, dex dizocilpine, dobupride, dobutamine, docarpamine, docona clamol, dexetimide, dexetoZoline, dexfenfluramine, Zole, docusate, doliracetam, domazoline, domiodol, domi deximafen, dexindoprofen, dexivacaine, dexlofexidine, phen bromide, domipizone, domoprednate, domoxin, dom dexmedetomidine, deXOXadrol, dexpanthenol, dexpropra peridone, don, donetidine, dopamantine, dopamine, nolol, dex.proxibutene, dexecoverine, dextilidine, dextroam dopexamine, dopropidil, doqualast, dorastine, doreptide, phetamine, dextrofemine, dextromethorphan, dextromora dosergoside, dotarizine, dotefonium bromide, dothiepin, mide, dextrorphan, dextrothyroxine, dezaguanine, dezocine, doxacurium chloride, doxaminol, doxapram, doxaprost, diacerein, diacetamate, diacetolol, diacetylmorphine, diam doxazosin, doxefazepam, doxenitoin, doxepin, doxibetasol, fenetide, diaminomethylphenazinium chloride, diamocaine, doxifluridine, doxofylline, doxorubicin, doxpicomine, doxy diampromide, diamthazole, dianhydrogalactitol, diapamide, lamine, dramedilol, draquinolol, deaZidox, dribendazole, diarbarone, diathymosulfone, diatrizoic acid, diaveridine, drindene, drobuline, drocinonide, droclidinium bromide, diazepam, diaziquone, diazoacetylglycine hydrazide, diaz drocode, drofenine, droloxifene, drometrizole, dromo ouracil, diaZoxide, dibekacin, dibemethine, dibenamine, stanolone, dromostanolone propionate, dronabinol, dropem dibenzepin, dibrompropamidine, dibromsalan, dibrospidium pine, droperidol, droprenilamine, dropropizine, drotaverine, chloride, dibucaine, dibuprol, dibupyrone, dibusadol, dicar drotebanol, droxacin, droXicainide, droxicam, droxidopa, US 2006/01 10428 A1 May 25, 2006 24 droxypropine, dulofibrate, duloZafone, duometacin, duoper euprocin, evandamine, Evans blue, exalamide, exametazine, one, dupracetam, durapatite, dyclonine, dydrogesterone, exaprolol, exepanol, exifone, and exiproben. dymanthine, and dyphylline. 0213 Also, fallintolol, fallipamil, famiraprinium chloride, 0212. Also, ebastine, ebrotidine, ebselen, ecastolol, echi famotidine, famotine, famiprofaZone, fanetizole, fantridone, nomycin, echothiophate iodide, ecipramidil, eclanamine, fazadinium bromide, fazaribine, febantel, febarbamate, eclaZolast, econazole, ectylurea, edelfosine, edetic acid, februpol, febuverine, feclemine, feclobuzone, fedrilate, fel edetol, edifolone, edogestrone, edoxudine, edrophonicum bamate, felbinac, felipyrine, felodipine, femoxetine, fen chloride, efaroxan, efetozole, eflomithine, efloxate, efroto abutene, fenacetinol, fenaclon, fenadiazole, fenaptic acid, mycin, elantrine, elanzepine, elderfield's pyrimidine mus femalamide, fenalcomine, fenamifuril, penamole, fenaper tard, elfazepam, elagic acid, elliptinium acetate, elmustine, one, fenbendazole, fenbencillin, fenbufen, fenbutrazate, fen elnadipine, eltenac, eltoprazine, elucaine, elziverine, camfamine, fencibutirol, fenclexonium metilsulfate, fen embramine, embutramide, emepronium bromide, emetine, clofenac, fenclonine, fenclorac, fenlozic acid, fendiline, emiglitate, emilium tosylate, emopanil, emorfaZone, emyl fendosal, feneritrol, fenestrel, fenethazine, fenethylline, fen camate, enalapril, enalaprilat, enbucrilate, encainide; etradil, fenflumizole, fenfluramine, fenfluthrin, fengabine, enciprazine, enclomiphene, encyprate, endomide, endrala fenharmane, fenimide, feniodium chloride, fenipentol, Zine, endrysone, enefexine, enestebol, enfenamic acid, fenirofibrate, fenisorex, fenmetozole, fenmetramide, enflurane, eniclobrate, enilconazole, eniloSpirone, eniso fenobam, fenocinol, fenoctimine, fenofibrate, fenoldopam, prost, enocitabine, enolicam, enoxacin, enoXamast, enoxi fenoprofen, fenoterol, fenoverine, fenoxazoline, fenoxedil, mone, enoXolone, eniprazole, eniproline, emprazepine, fenozolone, fenpentadiol, femperate, fenipalone, fenipra enprofylline, enpromate, enprostil, enrofloxacin, entSufon mide, feniprane, fempiverinium bromide, fenprinast, fenpro Sodium, enviomycin, enviradene, epalretat, epanolol. porex, fenprostalene, fenduizone, fenretinide, fenspiride, eperisone, ephedrine, epicainide, epicillin, epicriptine, epi fentanyl, fentiazac, fenticlor, fenticonazole, fentonium bro estriol, epimestrol, epinastine, epinephryl borate, epipropi mide, fenyripol, fepentolic acid, fepitrizol, fepradinol, fepra dine, epirizole, epiroprim, epirubicin, epithiazide, epi Zone, fepromide, feprosidnine, ferriclate calcium, ferrotre tiostanol, epoprostenol, epostane, eprazinone, eprovafen, nine, ferrous fumarate, ferrous gluconate, fetoxylate, eproxindine, eproZinol, epsiprantel, eptaloprost, eptazocine, fexicaine, fexinidazole, fezatione, fezolamine, fiacitabine, equilin, erdosteine, ergocalciferol, ergoloid mesylates, fibracillin, filenadol, filipin, fifexide, flamenol, flavamine, ergonovine, ergosterol, ergotamine, ericolol, erizepine, flavodic acid, flavodil, flavoneactic acid, flavoxate, flaza erocainide, erythrityl tetranitrate, erythromycin acistrate, lone, flecainide, flerobuterol, fleroxacin, flesinoxan, fles erythromycin ethylsuccinate, erythromycin propionate, tolol, fletazepam, floctafenine, flomoxe?, flopropione, flo erythrosine, esaprazole, esculamine, eseridine, esflurbipro rantyrone, flordipine, floredil, florfenicol, florifenine, fen, esmolol, esorubicin, esproquin, estazolam, estradiol floSequinan, flotrenizine, floverine, floxacillin, floxacrine, benzoate, estradiol cypionate, estradiol dipropionate, estra floXuridine, fluacizine, fluialamide, fluianisone, fluazacort, diol enanthate, estradiol undecylate, estradiol Valerate, estra flubanilate, flubendazole, flubepride, flucabril, flucetorex, mustine, estramustine phosphate, estrapronicate, estraZinol, flucindole, fluciprazine, flucloronide, fluconazole, flucrylate, estriol, estrofurate, estrone, estrone hydrogen Sulfate, flucytosine, fludalanine, fludarabine phosphate, fludazonium estropipate, esuprone, etabenzarone, etacepride, etafedrine, chloride, fludiazepam, fludorex, fludoxopone, fludrocorti etafenone, etamestrol, etamiline, etamiphyllin, etamocy sone acetate, flufenamic acid, flufenisal, flufosal, flufylline, cline, etanidazole, etanterol, etaqualone, etasuline, fluindarol, fluindione, flumazenil, flumecinol, flumedroX etazepine, etazolate, etebenecid, eterobarb, etersalate, one-17-acetate, flumequine, flumeridone, flumethasone, flu ethacridine, ethacrynic acid, ethambutol, ethamivan, etham methasone pivalate, flumethiazide, flumetramide, flumexa Sylate, ethanolamine oleate, ethaverine, ethchlorVynol, dol, flumeZapine, fluminorex, flumizole, flumoxonide, ethenZamide, ethazide, ethidium chloride, ethinamate, ethi flunamine, flunarizine, flunidazole, flunisolide, flunisolide nyl estradiol, ethiofos, ethionamide, ethsterone, ethohep acetate, flunitrazepan, flunixin, flunoprost, flunoxaprofen, tazine, ethomoxane, ethonam, ethopropazine, ethoSuximide, fluocinolone acetonide, fluocinonide, flourcortin butyrate, ethotoin, ethoxazene, ethoxazorutoside, ethoXZolamide, fluocortolone, fluocortolone caproate, fluorescein, fluo ethyybenztropine, ethyl biscoumacetate, ethyl carfluZepate, resone, fluoroadenosine, 3-fluoroandrostanol, fluorodopane, ethyl cartrizoate, ethyl dibunate, ethyl dirazepate, ethylene fluorohydroxyandrosterone, fluorometholone acetate, fluo diamine, ethylestrenol, ethylhydrocupreine, ethyl loflaze rosalan, 6-fluorotestosterone propionate, 9-fluoroXotes pate, ethylmethylthiambutene, ethylmorphine, 9-ethyl-6- tenololactone, 9-fluoroXotestololacetone, fluotracen, flucX mercaptopurine, ethyl nitrite, ethylnorepinephrine, etine, fluoxymesterone, fluparoxan, flupentixol, ethylparaben, ethylphenacemide, ethylstibamine, ethyner fluperamide, fluperlapine, fluperolone acetate, fluphenazine, one, ethynodiol diacetate, ethypicone, etibendazole, eticlo fluphenazine enanthate, flupimazine, flupirtine, flupranone, pride, eticyclidine, etidocaine, etidronic acid, etifelmine, fluprazine, fluprednidene, fluprednisolone, fluprednisolone etifenin, etifoxine, etilamfetamine, etilefrine, etilefrine piv Valerate, fluprofen, fluprofylline, fluproduaZone, flupros alate, etintidine, etiochlanolone, etipirium iodide, etiproston, tenol, flucuaZone, fluradoline, flurandrenoline, flurantel, flu etiracetam, etiroXate, etisazole, etisomicin, etisulergine, eti razepam, flurbiprofen, fluretofen, flurithromycin, flurocitab Zolam, etocarlide, etocrylene, etodolac, etodroXZine, etofa ine, flurofamide, flurogestone acetate, flurothyl, fluroxene, mide, etofenamate, etofemproX, etofibrate, etoformin, eto flusoxolol, fluspiperone, fluspirilene, flutamide, flutazolam, furadine, etofylline, etoglucid, etolorex, etolotifen, flutemazepam, flutiazin, fluticaSone propionate, flutizenol, etoloxamine, etomidate, etomidoline, etomoxir, etonitaZene, flutonidine, flutoprazepam, flutroline, flutropium bromide, etoperidone, etoposide, etoprindole, etoprine, etorphine, eto fluvoxamine, fluZinamide, fluZoperine, folescutol, folic acid, salamide, etoxadrol, etoxeridine, etoZolin, etrabamine, fomidacillin, fominoben, fomocaine, fonazine, fopiirtoline, etretinate, etryptamine, etymemazine, eucalyptol, eugenol, forfenimex, formebolone, formetorex, formintrazole, for US 2006/01 10428 A1 May 25, 2006
mocortal, formoterol, fosarilate, fosazepam, foscarnet, fos ponate, hydrocortisone butyrate, hydrocortisone cypionate, colic acid, foSenazide, fosfocreatine, fosfomycin, foSfonet, hydrocortisone-phosphate, hydrocortisone Succinate, hydro fosfosal, fosinapril, foSmenic acid, fosmidomycin, forpirate, cortisone Valerate, hydroflumethiazide, hydromadinone, fostedil, fostriecin, fotemustine, fotreamine, frabuprofen, hydromorphinol, hydromorphone, hydroquinone, hydroxin frentizole, fronepidil, froxiprost, ftaxilide, ftivazide, dasate, hydroxindasol, hydroxyoxocobalamin, hydroxychlo forafur, formetazine, florpropazine, fubrogonium iodide, roquine, hydroxydimethandrostadienone, hydroxydione fuchsin, fumagillin, fumoXcillin, fuprazole, furacrinic acid, Succinate, hydroxymethylandrostanone, 10-hydroxynore furafylline, furalazine, furaltadone, furaprofen, furazabol, histerone, hydroxypethidine, hydroxyphenamate, hydroxyp furazolidone, furazolium chloride, furbucillin, furcloprofen, rocaine, hydroxyprogeserone, hydroxyprogesterone furegrelate, furethidine, furfenorex, furidarone, furmethoxa caproate, hydroxypyridine tartrate, hydroxyStilbamidine, done, furobufen, furodazole, furofenac, furomazine, furo 7-hydroxytestololacetone, hydroxytestosterone propionate, semide, furostilbestrol, fursalan, fursultiamine, furterene, hydroxytetracaine, hydroxytoluic acid, hydroxyurea, furtrethonium iodide, fusidic acid, and fuzlocillin. hydroxy Zine, hymecromone, hyoscyamine, and hypericin. 0214. Also, gabapentin, gabexate, gaboxadol, galan 0216. Also, ibacitabine, ibafloxacin, ibazocine, ibopam tamine, gallamine triethodide, gallopamil, galosemide, gal ine, ibrotamide, ibudilast, ibufenac, ibuprofen piconol, ibu tifenin, gampexine, gamolenic acid, ganglefene, gapicom proxam, ibuterol, ibuverine, icazepam, icosipiramide, icoti ine, gapromidine, gefarnate, gemazocine, gemcadiol. dine, idarubicin, idaverine, idazoxan, idebenone, idenast, gemeprost, gemfibrozil, gentian violet, gepefrine, gepirone, idralfidine, idrocilamide, idropranolol, ifenprodil, ifosfa geroquinol, gestaclone, gestadienol, gestodene, gestonorone mide, ifoxetine, ilmofosine, iloprost, imafen, imanixil, ima caproate, gestrinone, giparmen, gitaloxin, gitoformate, Zodan, imcarbofos, imexon, imiclopazine, imidazole salicy glafenine, glaziovine, gliamilide, glibomuride, glibutimine, late, imidazopyrazole, imidecyl iodine, imidocarb, glicaramide, glicetanile, geroquinol, gestaclone, gestadi imidoline, imidurea, imiloxan, iminophendimide, imi enol, gestodene, gestonorone caproate, gestrinone, gipar penem, imipramine, imipraminoxide, imirestat, imolamine, men, gitaloxin, gitoformate, glafenine, glaziovine, gliamil imoXiterol, impacarzine, impromidine, improsulfan, imurac ide, glibornuride, glibutimine, glicaramide, glicetanile, etam, inaperisone, indacrinone, indalpine, indanazoline, gliclazide, glicondamide, glidaZamide, gliflumide, glime indanidine, indanorex, indapamide, indatraline, indacainide, piride, glipentide, glipizide, gliquidone, glisamuride, glisin indeloxazine, indenolol, indicine-N-oxide, indigotindisul damide, glisolamide, glisoxepide, gloxazone, gloXimonam, fonic acid, indobufen, indocate, indocyanine green, indola glucametacin, glucosamine, glucosulfamide, glucosulfone, pril, indolidan, indopanolol, indopine, indoprofen, glucurolactone, glucuronamide, glunicate, glutamic acid, indoramin, indorenate, indoxole, indriline, inicarone, inoco glutaral, glutarimide, glutaurine, glutethimide, glyburide, terone, inosine, inosine dialdehyde, inositol niacinate, inp glybuthiazol, glybuzole, glyceryl monostearate, glycidyl roquone, intrazole, intriptyline, iobenzamic acid, iobutic methacrylate, glycine, glyclopyramide, glybiarsol, glycopy acid, iocarmic acid, iocetamic acid, iodamide, iodecimol, rrolate, glycyclamide, glyhexamide, glymidine, glyocta iodetryl, iodipamide, iodixanol, iodoalphionic acid, iodol. mide, glypinamide, glyprothiazol, glySobuzole, gold thi iodophthalein, iodoquinol, iodothiouracil, iodoxamic acid, omalate, gold sodium thiosulfate, granisetron, griseofilvin, ioglicic acid, ioglucol, ioglucomide, ioglunide, ioglycamic guabenXan, guacetisal, guaifecainol, guaiactamine, guaiap acid, iogulamide, iohexol, iodlidonic acid, iolixanic acid, ate, guaietolin, guaifenesin, guaimeSal, guaisteine, guaith iomeglamic acid, iomeprol, iomorinic acid, iopamidol. yline, guamecycline, guanabenZ, guanacline, guanadrel, iopanoic acid, iopentol, iophendylate, iophenoxic acid, guanaZodine, guanazole, guanclofine, guancydine, guanethi ioprocemic acid, iopromide, iopronic acid, iopydol, iopy dine, guanfacine, guanisoquin, guanoclor, guanoctine, gua done, iosarcol, iosefamic acid, ioseric acid, iosimide, ioSu noXabenz, guanoxan, and guanoxyfen. lamide, ioSumetic acid, iotasul, iotetric acid, iothalamic acid, 0215. Also, hadacidin, halazepam, halazone, halcinonide, iotranic acid, iotrizoic acid, iotrolan, iotroXic acid, ioversol, halethazole, halocortolone, halofantrine, halofenate, ioxabrolic acid, ioxaglic acid, ioxitalamic acid, ioxotrizoic halofluginone, halometaSone, halonamine, halopemide, acid, ioZomic acid, ipexidine, ipodic acid, ipragratine, ipra halopenium chloride, haloperidol, haloperidol decanoate, midil, ipratropium bromide, iprazochrome, ipriflavone, haloperidone acetate, haloprogesterone, haloprogin, hal iprindole, iprocinodine, iproclozide, iprocrolol, iprofenin, othane, haloxazolam, haloxon, halquinols, hedaquinium iproheptine, iproniazid, iproidazole, iproplatin, iprotiazem, chloride, hepronicate, heptabarbital, heptaminol, heptaver iproxamine, iprozilamine, ipsalazide, ipsapirone, iquin ine, heptolamide, hepzidine, hetacillin, hetaflur, heteronium damine, irindalone, irloxacin, irolapride, irsogladine, isam bromide, hexachlorophene, hexacyclonate, hexacyprone, faZone, isamoltan, isamoxole, isaxonine, isbogrel, isepami hexadiline, hexadimethrine bromide, hexafluorenium bro cin, isoaminile, isobromindione, isobucaine, isobutamben, mide, hexamethonium bromide, hexamidine, hexapradol, isocarboxazid, isoconazole, isocromil, isoetharine, isof hexaprofen, hexapropymate, hexasonium iodide, hexacarba eZolac, isoflupredone acetate, isoflurane, isoflurophate, iso choline bromide, hexedine, hexestrol, hexetidine, hexobar leucine, isomazole, isomerol, isometamidium, isometha bital, hexobendine, hexocyclium methylsulfate, hexoprena done, isometheptene, isomylamine, isoniazid, isonixin, line, hexopyrronium bromide, hexylcaine, hexylene glycol, isopraZone, isoprednidene, isoprofen, isoprofamide iodide, hexylresorcinol, histamine, histapyrrodine, homarylamine, isopropicillin, isopropyl myristate, isopropyl palmitate, iso homatropine methylbromide, homidium bromide, homo proterenol, isosorbide, isosorbide dinitrate, isosorbide chlorcyclizine, homofenazine, homoharringtonine, mononitrate, isospalglumic acid, isosulfan blue, isosulpride, homopipramol, homosalate, homotestosterone propionate, isothipendyl, isotic, isotiquimide, isotretinoin, isoxaprolol. homprenorphine, hopantenic acid, hoquizil, hycanthone, isoxepac, isoxicam, isoxSuprine, isradipine, itanoxone, itazi hydracarbazine, hydrargaphen, hydrobentizide, hydrochlor grel, itraconazole, itrocainide, ivermectin bib, and ivoqual thiazide, hydrocodone, hydrocortamate, hydrocortisone ace 1C. US 2006/01 10428 A1 May 25, 2006 26
0217. Also, josamycin. mefenorex, mefeserpine, mefexamide, mefloquine, mefru 0218. Also, kainic acid, kalafungin, kebuZone, keracya side, megalomicin, megestrol acetate, meglitinide, megucy nin, ketamine, ketanserin, ketazocine, ketazolam, kethoxal, cline, meglumine, meglutol, meladrazine, melarsonyl, ketipramine, ketobemidone, ketocaine, ketocainol, keto melarsoprol, melengestrol acetate, meletimide, melinamide, conazole, ketoprofen, ketorfanol, ketorolac, ketotifen, melitracen, melizame, meloxicam, melperone, melphalan, ketotrexate, khellin, khelloSide, and kitasamycin. memantine, memotine, menabitan, menadiol, menadiol diphosphate, menadiol disulfate, menadione, menadione 0219. Also, labetalol, lacidipine, lactalfate, lactose, lactu Sodium bisulfite, menatetrenone, menbutone; menfegol, lose, lamotrigine, lamtidine, lanatoside, lapachol, lapinone, menglytate, menitrazepam, menoctone, menogaril, menthol, lapyrium chloride, lasalocid, laudexium methyl sulfate, lau meobentine, meparfynol, mepazine, mepenZolate bromide, ralkonium chloride, laureth, laurixamine, laurocapram, lau meperidine, mephenesin, mephenoxalone, mephentermine, roguadine, laurolinium acetate, lauryl isoquinolinium, lefe tamine, leflunomide, leiopyrrole, lemidosul, lenampicillin, mephenylon, mephobarbital, mepindolol, mepiprazole, leniquinsin, lemperone, leptacline, lergotrile, letimide, leto mepiroXol, mepitioStane, mepivacaine, mepixanox, mepra Steine, leucine, leucinocaine, leucocianidol, leucovorin, midil, meprednisone, meprobamate, meproscillarin, levacecamine, levallorphan, levamfetamine, levamisole, meproxitol, meprylcaine, meptazinol, medulidox, meduinol, levdropropizine, levisoprenaline, levlofexidine, levocabas meduitazine, meralein, meralluride, merbarone, merbromin, tine, levocarnitine, levodopa, levofacetoperane, levofenflu mercaptamine, mercaptomerin, mercaptopurine, mercudera ramine, levofluraltadone, levoglutamide, levomenol, mide, mercufenol chloride, mercumatilin, mercurobutol, levomethadone, levomethadyl acetate, levomethorphan, mergocriptine, merophan, mersalyl, mesabolone, levometiomeprazine, levomopranol, levomoramide, levo mesalamine, meseclaZone, mesna, mesocarb, meso-hex nantradol, levonordeprin, levonorgestrel, levophenacyl mor estrol, mesoridazine, mesipirenone, mestanolone, mester phan, levopropoxyphene, levopropylcillin, levopropyl olone, mestranol, meSudipine, meSulergine, mesulfamide, hexedrine, levoprotiline, levorin, levorphanol, meSulfen, meSuprine; metabromsalan, metacetamol, meta levothyroxine, levoxadrol, lexofenac, libecillide, libenza clazepam, metaglycodol, metahexamide, metamelfalan, pril, lidamidine, lidocaine, lidofenin, lidoflazine, lifibrate, metamfaZone, metamfepramone, metampicillin, metanixin, lilopristone, limaprost, lincomycin, lindane, linsidomine, metapramine, metaproterenol, metaraminol, metaterol, iothyronine, liroldine, lisinopril, lisuride, lithium carbonate, metaxalone, metaZamide, metazide, metazocine, metbufen, lithium citrate, litracen, lividomycin, lixazinone, lobeline, meteneprost, metergoline, metergotamine, metescufylline, lobendazole, lobenzarit, lobuprofen, locicortone, lodax metesculetol, metethoheptazine, metformin, methacholine aprine, lodacezarlodinixil, lodiperone, lodoxamide, lodoxa chloride, methacycline, methadone, methadyl acetate, meth mide ethyl, lofemizole, lofendazam, lofentanil, lofepramine, allenestril, methallibure, methalthiazide, methamphetamine, lofexidine, loflucarban, lombazole, lomefloxacin, lometra methandriol, methandrostenolone, methaniazide, meth line, lomevactone, lomifylline, lomofingin, lomustine, lona antheline bromide, methaphenilene, methaqualone, methar palene, lonaprofen, lonazolac, lonidamine, loperamide, lop bital, methastyridone, methdilazine, methenamine, meth eramide oxide, lopirazepam, loprazolam, loprodiol. enolone acetate, methenolone enanthate, metheptazine, lorajmine, lorapride, loratadine, lorazepam, lorbamate, methestrol, methetoin, methicillin, methimazole, methiodal lorcainide, lorcinadol, lorglumide, lormetazepam, lorta Sodium, methioguanine, methiomeprazine, methionine, methisaZone, methitural, methixene, methocarbamol. lamine, lorZafone, losindole, losulazine, lotifazole, lotrifen, methohexital, methopholine, methoserpidine, methotrexate, lotucaine, lovastatin, loxanast, loxapine, loxiglumide, loXo methotrimeprazine, methoxamine, methoXSalen, methoxy profen, loXtidine, lozilurea, lucanthone, lucartamide, luci flurane, methoxyphedrine, methoxyphenamine, methox mycin, lufuradom, lupitidine, luprostiol, luxabendazole, ypromazine, methScopolamine bromide, methSuximide, lyapolate Sodium, lycetamine, lydimycin, lymecycline, methyllothiazide, N-methyladrealone hcl. methyl alcohol, lynestrenol, lysergide, and lysine. methylatropine nitrate, methylbenactyzium bromide, meth 0220 Also, mabuterol, maduramicin, mafenide, mafo ylbenzethonium, methylchromone, methyldesorphine, prazine, mafosfamide, magnesium citrate, magnesium glu methyldihydromorphine, methyldopa, methyldopate, meth conate, magnesium salicylate, malathion, malethamer, malic ylene blue, methylphedrine, methylergonovine, methylfor acid, malotilate, manidipine, manganese gluconate, manni mamide, methyl nicotinate, 2-methyl-19-nortestosterone, tol, mannitol hexanitrate, mannomustine, mannosulfan, 2-methyl-11-oxoprogestrone, methyl palmoxirate, meth manoZodil, maprotiline, maridomycin, mariptiline, maroX ylparaben, methylphendiate, methylprednisolone aceponate, epin, maytansine, maZaticol, mazindol, maZipredone, meba methylprednisolone acetate, methylprednisolone hemisucci nazine, mebendazole, mebenoside, mebeverine, mebeZo nate, methylprednisolone phosphate, methylprednisolone nium iodide, mebhydrolin, mebiquine, mebolazine, Suleptanate, methyl salicylate, methylstreptonigrin, 4-meth mebrofenin, mebutamate, mebutizide, mecamylamine, yltestosterone, 7-methyltestosterone, 17-methyltestosterone, mecarbinate, mecetronium ethylsulfate, mechlorethamine, 7-methyltesosterone propionate, methylthionosine, 16-me meciadanol, mecinarone, meclizine, meclocycline, meclo thylthioprogestone, methylthiouracil, methynodiol diac cycline Sulfosalicylate, meclofenamic acid, meclofenoxate, etate, methyprylon, methysergide, metiamide, metiapine, meclonazepam, mecloqualone, mecloralurea, meclorisone metiazinic acid, metibride, meticrane, metildigoxin, metin dibutyrate, mecloxamine, mecobalamin, mecrylate, mecys dizate, metioprim, metioxate, metipirox, metipranolol, meti teine, medazepam, medazomide, medetomidine, mediba prenaline, metitepine, metizoline, metkephamid, metochal Zine, medifoxamine, medorinone, medorubicin, medroge cone, metocinium iodide, metoclopramide, metocurine stone, medronic acid, medroxalol, medroxyprogestrone, iodide; metofenazate, metogest, metolaZone, metomidate, medroxyprogestrone acetate, medrylamine, mefeclorazine, metopimazine, metopon, metoprine, metoprolol, meto mefenamic acid, mefenidil, mefenidramium metilsulfate, quizine, metoserpate, metostilenol, metoxepin, metrafaZo US 2006/01 10428 A1 May 25, 2006 27 line, metralindole, metrazifone, metrenperone, metribolone, eZone, nifuralide, nifuratel, nifuratrone, nifurdazil, nifuret metrifonate, metrifudil, metrizamide, metrizoic acid, met haZone, nifurfoline, nifurimide, nifurizone, nifurmazole, ronidazole, meturedepa, metyrapone, metyridine, mety nifurmerone, nifuroquine, nifuroxazide, nifuroxime, nifurpi rosine, mevastatin, mexafylline, mexazolam, mexenone, pone, nifurpirinol, niftirprazine, nifurcquinazole, nifursemi mexiletine, mexiprostil, mexoprofen, mexrenoate, meza Zone, nifursol, nifurthiazole, nifurtimox, nifurtoinol, nifur copride, meZepine, mezilamine, meZlocillin, mianserin, vidine, nifurzide, niguldipine, nihydraZone, nikethamide, mibolerone, micinicate, micronomicin, midaflur, midagli nileprost, nilprazole, niludipine, nilutamide, nilvadipine, Zole, midalcipran, midamaline, midazogrel, midazolam, nimaZone, nimeSulide, nimetazepam, nimidane, nimodipine, midecamycin, midodrine, mifentidine, mifepristone, mifo nimorazole, nimustine, niometacin, niperotidine, nipradillol, bate, miglitol, mikamycin, millacemide, milemperone, mili niprofaZone, niridazole, nisbuterol, nisobamate, nisoldipine, pertine, miloxacin, milrinone, milverine, mimbane, nisoxetine, nisterime acetate, nitarSone, nitazoxanide, nithia minaprine, minaxolone, mindolilol, mindoperone, minepen mide, nitracrine, nitrafudam, nitralamine, nitramisole, tate, minocromil, minoxidil, mioflazine, mipimazole, mirin nitraquaZone, nitrazepam, nitrefazole, nitrendipine, nitricho camycin, miristalkonium chloride, miroprofen, mirosami line, nitrochlofene, nitrocycline, nitrodan, nitrofurantoin, cin, misonidazole, misoprostol, mitindomide, mitobronitol, nitroglycerin, nitromersol, nitromide, nitromifene, nitros mitoclomine, mitoguaZone, mitolactol, mitomycin, mitona canate, nitrosulfathiazole, nitroXinil, nitroxoline, nivaZol. fide, mitopodozide, mitoquidone, mitotane, mitotenamine, nivimeldone, nixylic acid, nizatidine, niZofenone, noberas mitoxantrone, mitoZolomide, mivacurium chloride, mixi tine, nocloprost, nocodazole, nofecainide, nogalamycin, dine, misoprostol, mitindomide, mitobronitol, mitoclomine, nolinium bromide, nomegestrol, nomelidine, nomifensine, mitoguaZone, mitolactol, mitomycin, mitonafide, mito nonabine, nonaperone, nonapyrimine, nonoxynol-4, nonox podozide, mitoquidone, mitotane, mitotenamine, mitox ynol-9, noracymethadol, norbolethone, norbudrine, nor antrone, mitozolomide, mivacurium chloride, mixidine, clostebol, norcodeine, nordazepam, nordefrin, nordinone, mizoribine, mobecarb, mobenzoxamine, mocimycin, norepinephrine, norethandrolone, norethindrone, norethin mociprazine, moclobemide, moctamide, modafinil, moda drone acetate, norethynodrel, noreximide, norfenefrine, nor line, mofebutaZone, mofloverine, mofoXime, molfamate, floxacin, norfloxacin Succinil, norflurane, norgesterone, molinaZone, molindone, molracetam, molsidomine, norgestimate, norgestomet, norgestrel, norgestrienone, nor mometasone furoate, monalaZone disodium, monensin, letimol, norlevorphanol, normethadone, normethandrone, monobenzone, monoethanolamine, monometacrine, mono normorphine, norpipanone, nortestosterone propionate, phosphothiamine, monothioglycerol, monoxerutin, montire nortetrazepam, nortriptyline, norvinisterone, noSantine, nos lin, moperone, mopidamol, mopidralazine, moprolol. capine, nosiheptide, novobiocin, noxiptiline, noxytiolin, moduizone, morantel, moraZone, morclofone, morforex, nuclomedone, nuclotixine, nufenoXole. nuvenZepine, moricizine, morinamide, morniflumate, morocromen, nylestriol, nylidrin, and nystatin. moroxydine, morpheridine, morphine, morSuximide, mot apiZone, motrazepam, motretinide, moveltipril, moxadolen, 0222 Also, obidoxime, ocilitide, ocrylate, octabenzone, moxaprindine, moxastine, moXaverine, moxazocine, moX octacaine, octafonium chloride, octamoxin, octamylamine, estrol, moxicoumone, moxipraquine, moxisylyte, moXnida octanoic acid, octapinol, octastine, octaverine, octaZamide, Zole, moXonidine, mupirocin, murabutide, murocainide, octenidine, octenidine saccharin, octicizer, octimibate, octo muZolimine, mycophenolic acid, my fadol, myralact, myro rylene, octodrine, octopamine, octotiamine, octoxynol-9, phine, and myrtecaine. octriptyline, octrizole, ofloxacin, oftormine, oftasceine, olaflur, olaquindox, oleanomycin, oletimol, oleyl alcohol, 0221) Also, nabazenil, nabilone, nabitan, naboctate, olivomycin a, olmidine, olpimedone, olSalazine, oltipraz. nabumetone, nadide, nadolol, nadoxolol, naepaine, nafamo olvanil, omeprazole, omidoline, omoconazole, omonasteine, stat, nafazatrom, nafcaproic acid, nafcillin, nafenodone, onapristone, ondansetron, ontianil, opiniazide, opipramol. nafenopin, nafetolol, nafimidone, nafiverine, naflocort, nafo oraZamide, orbutopril, orconazole, orestrate, onnetoprim, mine, nafoxadol, nafoxidine, nafronyl, naftalofos, nafta ornidazole, ornipressin, ornithine, ornoprostil, orotic acid, Zone, naftifine, naftopidil, naftoxate, naftypramide, nalbu orotirelin, orpanoxin, orphenadrine, ortetamine, osalmid, phine, nalidixic acid, nalmefene, nalmexone, nalorphine, osmadizone, otilonium bromide, otimerate Sodium, ouabain, maltrexone, naminterol, namoxyrate, nanaprocin, nan oXabolone cipionate, oXabrexine, oxaceprol, oxacillin, oxa drolone cyclotate, nandrolone decanoate, nandrolone phen dimedine, oxafloZane, oxaflumazine, oxagrelate, Oxalinast, propionate, nanofin, nantradol, napactadine, napamezole, oxaliplatin, OXamarin, Oxametacin, oxamisole, oxam naphthonone, naprodoxime, naproxen, naproxol, naranol, niquine, Oxanamide, Oxandrolone, oxantel, Oxapadol, narasin, natamycin, naxagolide, naxaprostene, nealbarbital, oxapium iodide, oxapropanium iodide, oxaprotiline, nebidrazine, nebivolol, nebracetam, nedocromil, nefaZ oxaprozin, oxarbazole, Oxatomide, oxazafone, oxazepam, odone, neflumozide, nefopam, neleZaprine, neoarsphe oxazidione, oxazolam, oxazorone, oXcarbazepine, oxdrala namine, neocinchophen, nequinate, neraminol, nerbacadol, Zine, Oxeladin, oxendolone, oxepinac, oxetacillin, oxet nesapidil, nesosteine, netilmicin, netobimin, neutramycin, hazaine, oxetorone, Oxfendazole, Oxfenicine, oxibendazole, nexeridine, niacin, niacinamide, nialamide, niaprazine, oxibetaine, oxiconazole, oxidopamine, oxidronic acid, nibroxane, nicafenine, nicainoprol, nicametate, nicarbazin, oxifentorex, oxifungin, oxilorphan, oximonam, OXindanac, nicarpidine, nicergoline, niceritrol, niceverine, niclofolan, oxiniacic acid, oxiperomide, oxiracetam, oxiramide, oxiso niclosamide, nicoboxil, nicoclonate, nicocodine, nicocor pred. Oxisuran, oxitefonium bromide, oxitriptan, oxitrip tonide, nicodicodine, nicofibrate, nicofuranose, nicofurate, tyline, oxitropium bromide, oxmetidine, Oxodipine, oxoge nicogrelate, nicomol, nicomorphine, nicopholine, nic stone phenpropionate, oxolamine, oxolinic acid, orandil, nicothiaZone, nicotinyl alcohol, nicoXamat, nic oXomemazine, oXonazine, oxophenarsine, Oxoprostol, tiazem, nictindole, nodroxy Zone, nifedipine, nifenalol, oXpheneridine, oXprenoate potassium, oXprenolol, Oxtriph nifenaZone, niflumic acid, nifluridide, nifuradene, nifurald ylline, oxybenzone, oxybutynin, oxychlorosene, oxycin US 2006/01 10428 A1 May 25, 2006 28 chophen, oxyclozanide, oxycodone, oxydipentonium chlo picolamine, piconol, picoperine, picoprazole, picotamide, ride, oxyfedrine, oxymesterone, Oxymetazoline, picotrin diolamine, picumast, pidolic acid, pifamine, oxymetholone, oxymorphone, oxypendyl, oxypertine, pilfenate, pifexole, piflutixole, pilfoxime, piketoprofen, oxyphenbutaZone, oxyphenonium bromide, oxypurinol, pildralazine, pimoclone, pimethylline, pimelautde, pimeta oxypyrronium bromide, oxyquinoline, Oxyridazine, oxyso cin, pimethixene, pimetine, pimetremide, piminodine, nium iodide, oxytiocin, oZagrel, and oZolinone. pimobendan, pimondiazole, pimozide, pinacidil, pinadoline, 0223) Also, pacrinolol, pactamycin, padimate, pafenolol. pinafide, pinaverium bromide, pinazepam, pincainide, pin palatrigine, paldimycin, palmidrol, palmoxiric acid, pam dolol, pinolcaine, pinoxepin, pioglitaZone, pipacycline, abrom, pamaquine, pamatolol, pamidronic acid, pancuro pipamazine, pipaperone, pipazethate, pipebuZone, pipecuro nium bromide, panidazole, panomifene, patenicate, pan nium bromide, pipemidic acid, pipenZolate bromide, thenol, pantothenic acid, panuramine, papaverine, pipequaline, piperacetazine, piperacillin, piperamide, pip papaveroline, parachlorophenol, paraflutizide, paraldehyde, erazine, piperazinedione, piperidolate, piperilate, piper paramethadione, paramethasone acetate, paranyline, parap ocaine, piperoxan, piperylone, pipobroman, pipoctanone, enzolate bromide, parapropamol, pararosaniline, pararosa pipofezine, piposulfan, pipotiazine palmiate, pipoxizine, niline embonate, paraxaZone, parbendazole, parconazole, pipoxolan, pipradimadol, pipradol, pipramadol, pipratecol, pareptide, parethoxycaine, pargeverine, pargolol, pargyline, piprinhydrinate, piprocurarium iodide, piprofurol, piproZo paridocaine, parodilol, paromomycin, paroxetine, paroX lin, piquindone, piquizil, piracetam, pirandamine, pirarubi ypropione, parsalmide, partricin, parvaquone, pasiniazid, cin, piraxelate, piraZmonam, piraZolac, pirbenicillin, pir paulomycin, paxamate, paZelliptine, paZOxide, pcnu, pecilo buterol, pirdonium bromide, pirenoXine, piremperone, cin, pecocycline, pefloxacin, pelanserin, pelretin, pelrinone, pirenzepine, pirepolol, piretanide, pirfenidone, piribedil, pemedolac, pemerid, pemoline, pempidine, penamecillin, piridicillin, piridocaine, piridoxilate, piridironic acid, pirifi penbutolol, pendecamaine, penfluridol, penflutizide, pengi brate, pirindazole, pirinixic acid, pirinixil, piriprost, piriqua toxin, penicillamine, procaine, penicillin, penimepicycline, lone, pirisudanol, piritramide, piritrexim, pirlimycin, pirlin penimocycline, penirolol, penmesterol, penoctonium bro dole, pirmagrel, pirmenol, pimabine, piroctone, pirogliride, mide, penprostene, pentabamate, pentacynium chloride, piroheptine, pirolate, pirolaZamide, piromidic acid, piroX pentaerythritol tetranitrate, pentafluranol, pentagastrin, pent antrone HCL, piroxicam cinnamate, piroxicillin, piroxi agestrone, pentalamide, pentamethonium bromide, pentam mone, pirozadil, pirprofen, pirquinozol, pirralkonium bro ethylmelamine, pentamidine, pentamoxane, pentamustine, mide, pirtenidine, pitenodil, pitofenone, pituxate, pentapiperide, pentapiperium methylsulfate, pentaquine, pivampicillin, pivenfrine, pivopril, pivoxazepam, pizotyline, pentazocine, pentetate calcium trisodium, pentetic acid, plafibride, plaunotol, pleuromulin, plicamycin, podilfen, penthienate bromide, penthrichloral, pentiapine maleate, podophylloxoxin, poldine methylsulfate, polidocanol, poly pentifylline, pentigetide, pentisomicin, pentisomide, pentizi thiazide, ponalrestat, ponfibrate, porfiromycin, poskine, done, pentobarbital, pentolinium tartrate, pentomone, pen potassium guaiacolsulfonate, potassium nitrazepate, potas topril, pentorex, pentosan polysulfate sodium, pentostatin, sium Sodium tartrate, potassium Sorbate, potassium thiocy pentoxifylline, pentrinitrol, pentylenetrazole, peplomycin, anate, practolol, prajmalium, pralidoxime chloride, prami pepstatin, peraclopone, peradoxime, perafensine, peralo pexole, pramiracetam, pramiverine, pramoxime, prampine, pride, peraquinsin, perastine, peratizole, perbufylline, per pranolium chloride, pranoprofen, pranosal, prasterone, prav fluamine, perflunafene, pergolide, perhexilene, periciazine, astatin, praxadine, praZepam, praZepine, praZiquantel, praZi perimetazine, perindopril, perindoprilat, perisoxal, perlap tone, prazocillin, prazosin, preclamol, prednazate, predna ine, permethrin, perphenazine, persilic acid, petrichloral, Zoline, prednicarbate, prednimustine, prednisolamate, pexantel, phanquone, phenacaine, phenacemide, phenacetin, prednisolone, prednisolone hemisuccinate, prednisolone phenact tropinium chloride, phenadoxone, phenaglycodol. Steaglate, prednisolone tebutate, prednisone, prednival, phenamaZoline, phenampromide, phenarsone Sulfoxylate, prednylidene, prefenamate, pregnenolone, pregnenolone phenazocine, phenaZopyridine, phencarbamide, phencyclid Succinate, premazepam, prenalterol, prenisteine, prenover ine, phendimetrazine, phenelZine, pheneridine, phenesterin, ine, prenoXdiazine, prenylamine, pretamazium iodide, pre penethicillin, phenformin, phenglutarimide, phenicarbazide, tiadil, pribecaine, pridefine, prideperone, pridinol, prifelone, phenindamine, phenindione, pheniprazine, pheniraminie, pri?inium bromide, prifuroline, prilocaine, primaperone, pri phenisonone, phenmetrazine, phenobarbital, phenobutiodil, maquine, primidolol, primidone, primycin, prinomide, pris phenolphtalein, phenolsulfonphthalein, phenomorphan, tinamycin, prizidilol, proadifen, probarbital, probenecid, phenoperidine, phenothiazine, phenothrin, phenoxyben probicromil, probucol, procainamide, procaine, procarba Zamine, phenoxypropazine, phenprobamate, phenprocou Zine, procaterol, prochlorperazine, procinolol, procinonide, mon, phenpromethamine, phensuXimide, phentermine, proclonol, procodazole, procyclidine, procymate, prodeco phentolamine, phenylalanine, phenyl aminosalicylate, phe nium bromide, prodilidine, prodipine, prodolic acid, profa nylbutaZone, phenylethyl alcohol, phenylmercuric acetate, dol, profexalone, proflavine, proflazepam, progabide, pro phenylmercuric borate, phenylmercuric chloride, phenylm glumetacin, proglumide, proheptazine, proligestone, ercuric nitrate, phenylmethylbarbituric acid, phenylpro proline, prolintane, prolonium iodide, promazine, promege panolamine, phenylthildne, phenyltoloxamine, phenyrami stone, promestriene, promethazine, promolate, promox dol, phenyloin, phethafbital, pholcodine, pholedrine, olane, pronetalol, propacetamol, propafenone, propamidine, phosphoramide mustard, phoxim, phthalofyne, phthalysul propanidid, propanocaine, propantheline bromide, propara facetamide, phthalylsulfamethizole, phthalylsulfathiazole, caine, propatyl nitrate, propazolamide, propendiazole, pro phytic acid, phytonadiol diphosphate, phytonadione, pibe pentofylline, propenZolate, properidine, propetamide, pro carb, pibenzimol, pibecarb, pibenZimol, piberaline, picafi petandrol, propicillin, propikacin, propinetidine, brate, picartamide, picenadol, picilorex, piclonidine, piclo propiolactone, propiomazine, propipocaine, propiram, pro pastine, picloxydine, picobenzide, picodralazine, pisergide, propiverine, propizepine, propofol, propoxate, US 2006/01 10428 A1 May 25, 2006 29 propoxycaine, propoxyphene, propranolol, propyl docetri vamycin, Saperconazole, sarcolysin, Sarmazenil, Sarmoxicil Zoate, propylene glycol, propylene glycol monostearate, lin, Sarpicillin, Saterinone, satranidazole, Savoxepin, Scarlet propyl gallate, propylhexedrine, propyliodone, propylpara red, scopafungin, seclaZone, secnidazole, secobarbital, sec ben, propylthiouracil, propyperone, propyphenaZone, pro overine, securinine, sedecamycin, Seganserin, seglitide, sel pyromazine bromide, produaZone, produinolate, prorenoate egiline, selenium sulfide, selprazine, sematilide, Semustine, potassium, proroXan, proscillaridin, prospidium chloride, sepazonium chloride, Seperidol, sequifenadine, serfibrate, prostalene, proSulpride, prosultiamine, proterguride, pro theobromine, prothipendyl, prothixene, protiofate, protiona Sergolexole, serine, sermetacin, serotonin, Sertaconazole, mide, protirelin, protizinic acid, protokylol, protoveratine, Sertraline, setastine, setaZindol, Setiptiline, Setoperone, Sevit protriptyline, proxazole, proxibarbal, proxibutene, proxicro ropium mesilate, sevoflurane, Sevopramide, siagoside, mil, proxifeZone, proXorphan, proxyphylline, prozapine, Sibutramine, siccanin, silandrone, silibinin, silicristin, silidi pseudoephedrine, psilocybine, pumiteba, puromycin, anin, silver Sulfadiazine, simetride, Simfibrate, simtraZene, pyrabrom, pyran copolymer, pyrantel, pyrathiazine, pyrazi simvastatin, sineflungin, Sintropium bromide, Sisomicin, namide, pyrazofurin, pyricarbate, pyridarone, pyridofylline, Sitalidone, sitofibrate, sitogluside, sodium benzoate, sodium pyridostigmine bromide, pyridoxine, pyrimethamine, dibunate, sodium ethasulfate, sodium formaldehyde Sul pyrimitate, pyrinoline, pyrithione Zinc, pyrithyldione, pyriti foxylate, sodium gentisate, Sodium gualenate, sodium dium bromide, pyritinol, pyronine, pyrophenindane, pyrov nitrite, sodium nitroprusside, Sodium oxybate, Sodium phe alerone, pyroxamine, pyrrobutamine, pyrrocaine, pyrro nylacetate, sodium picofosfate, sodium picosulfate, sodium liphene, pyrrolnitrin, pyrvinium chloride, and pytamine. Stibocaptate, Sodium Stibogluconate, Sodium tetradecyl Sul fate, sodium thiosulfate, Sofalcone, Solasulfone, Solpecainol, 0224. Also, quadazocine, quadrosilan, quatacaine, Solypertine. Somantadine, Sopitazine, Sopromidine, Soqui quaZepam, quaZinone, quaZodine, quaZolast, quifenadine, nolol, Sorbic acid, Sorbinicate, Sorbinil, Sorbitan monolau quillifoline, quinacainol, quinacillin, quinacrine, quinaldine rate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan blue, quinapril, quinaprilat, quinaZosin, quinbolone, quin monostearate, Sorbitan trioleate, Sorbitan tristearate, Sorbi carbate, quindecamine, quindonium bromide, quindoxin, tol, Sorndipine, Sotalol, Soterenol, spaglumic acid, sparfosic quinestradol, quinestrol, quinethaZone, quinetolate, quineza acid, sparsomycin, Sparteine, spectinomycin, spiclamine, mide, quinfamide, quingestanol acetate, quingestrone, quin spiclomazine, spiperone, spiradoline, spiramide, spiramy dine, quinine, quinocide, quinpirole, quinterenol, quintiofos, cin, spirapril, spiraprilat, spirendolol, spirgetine, spirilene, quinuclium bromide, quinupramine, quipazine, and quisul spirofylline, spirogermanium, Spiromustine, Spironolactone, tazine. Spiroplatin, Spirorenone, Spirotriazine, spiroXasone, SpiroX 0225. Also, racefemine, racemethionine, racemethor atrine, SpiroXepin, Spizofurone, stallimycin, stanolone, stan phan, racemetirosine, raclopride, ractopamine, rafoxanide, Zolol, Stearic acid, Stearyl alcohol, Stearylsulfamide, Stefli ralitoline, raloxifene, ramciclane, ramefenaZone, ramipril, mycin, Stenbolone acetate, stepronin, Stercuronium iodide, ramiprilat, ramixotidine, ramnodignin, ranimustine, ranimy Stevaladil, Stibamine glucoside, Stibophen, stilbamidine, stil cin, ranitidine, ranolazine, rapamycin, rathyronine, razin bazium iodide, stilonium iodide, Stirimazole, Stiripentol, odil, raZobazam, razoxane, reboxetine, recainam, stirocainide, Stirifos, Streptomycin, streptonicoZid, streptoni reclazepam, relomycin, remoxipride, renanolone, rentiapril, grin, streptovarycin, Streptozocin, strinoline, Strychnine, repirinast, repromicin, reproterol, recimetol, rescinnamine, styramate, Subathizone, Subendazole. Succimer, Succinyl reserpine, resorantel, resorcinol, resorcinol monoacetate, choline chloride, Succinylsulfathiazole. Succisulfone, retelliptine, retinol, revenast, ribavirin, riboflavin, riboflavin Suclofenide, Sucralfate. Sucrose octaacetate, Sudexanox, 5'-phosphate, riboprine, ribostamycin, ridazolol, ridiflone, Sudoxicam, Sufentanil, Sufosfamide, Sufotidine, Sulazepam, rifabutin, rifamide, rifampin, rifamycin, rifapentine, rifaxi Sulbactam, Sulbactam pivoxil, Sulbenicillin, Sulbenox, Sul min, rilapine, rilmazafone, rillmenidine, rilopiroX, riloZ bentine, Sulbutiamine, Sulclamide, Sulconazole, Sulfabenz, arone, rimantadine, rimazolium metilsulfate, rimcazole, Sulfabenzamide, Sulfacarbamide, Sulfacecole, Sulfachlorpy rimexolone, rimiterol, rimoprogin, riodipine, rioprostil, ridazine, Sulfachrysoidine, Sulfaclomide, Sulfaclorazole, Sul ripazepam, risocaine, risperidone, ristianol, ristocetin, faclozine, Sulfacytine, Sulfadicramide, Sulfadimethoxine, ritanserin, ritiometan, ritodrine, ritropirronium bromide, Sulfadoxine, Sulfaethidole, Sulfaguandide, Sulfaguanole, Sul ritrosulfan, robenidine, rocastine, rociverine, rodocaine, falene, Sulfaloxic acid, SulfamaZone, Sulfamerazine, Sul rodorubicin, rofelodine, roflurante, rokitamycin, roletamide, fameter, Sulfamethazine, Sulfamethoxazole, Sulfamethoxy rolgamidine, rolicyclidine, rolicyprine, rolipram, rollitetra pyridazine, Sulfamethoxypyridazine acetyl, cycline, rolodine, rolziracetam, romifenone, romifidine, Sulfametomidine, Sulfametrole, Sulfamonomethoxine, Sulfa ronactolol, ronidazole, ronifibrate, ronipamil, ronnel, ropi moXole, Sulfanil amide, Sulfanitran, Sulfaperin, Sul toin, ropivacaine, ropizine, roquinimex, rosaprostol, rosa faphenazole, Sulfaproxyline, Sulfapyridine, Sulfaquinoxa line, Sulfarsphenamine, SulfaSalazine, Sulfasomizole, ramicin, rosaramicin butyrate, rosaramicin propionate, SulfaSuccinamide, Sulfasymazine, Sulfathiazole, Sulfathio rosoxacin, rosterolone, rotamicillin, rotoxamine, rotraxate, urea, Sulfatolamide, Sulfatroxazole, Sulfatrozole, Sulfazamet, roXarsone, roXatidine acetate, roXibolone, roXindole, Sulfinalol, Sulfinpyrazone, Sulfiram, Sulfisomidine, Sulfisox roXithromycin, roXolonium metilsulfate, roXoperone, azole, sulfobromophthalein, sulfonethylmethane, sulfon rufloxacin, rutamycin, rutin, and ruvaZone. methane, Sulfonterol, Sulforidazine, Sulfoxone sodium, Suli 0226. Also, sabeluzole, saccharin, salacetamide, Salafi crinat, Sulindac, Sulisatin, Sulisobenzone, Sulmarin, brate, salantel, salaZodine, SalazoSSulfadimedine, Salazosul Sulmazole, Sulmepride, Sulinidazole, Sulocarbilate, Sulocti famide, Salazosulfathiazole, Salethamide, Salfluverine, Sali dil, Sulosemide, Sulotroban, Suloxifen, Sulpiride, Sulprosal, cin, Salicyl alcohol, Salicylamide, Salicylanilide, Salicylic Sulprostone, Sultamicillin, Sulthiame, Sultopride, Sultosilic acid, Salinazid, salinomycin, salmefanol, salmeterol, Salm acid, Sultroponium, Sulverapride, Sumacetamol, Sumatriptan, isteine, salprotoside, Salsalate, salverine, Sancycline, Sangi Sumetizide, Sunagrel, Suncillin, Supidimide, Suproclone, US 2006/01 10428 A1 May 25, 2006 30
Suprofen, Suramin, Suricainide, Suriclone, Suxemerid, SuX nolol, tiprinast, tipropidil, tiprostanide, tiprotimod, tiquina ethonium chloride, SuXibuZone, Symclosene, Symetime, Syn mide, tiquizium bromide, tiratricol, tiropramide, tisocro ephrine, and Syrisingopine. mide, tisopurine, tisoquone, tivandizole, tixadil, tixanox, tiXocortol pivalate, tiZabrin, tianidine, tizolemide, tizoprolic 0227. Also, taclamine, taglutimide, talampicillin, talas acid, tobuterol, tocainide, tocamphyl, tocofenoxate, tocofi tine, talbutal, taleranol, talinolol, talipexole, talisomycin, brate, tocophersolan, todralazine, tofenacin, tofetridine, talmetacin, talmetoprim, talniflumate, talopram, talosalate, tofisoline, tofisopam, tolamolol, tolaZamide, tolaZoline, tol taloXimine, talSupram, taltrimide, tameridone, tameticillin, boxane, tolbutamide, tolciclate, toldimfos, tolfamide, tolfe tametraline, tamitinol, tamoxipen, tampramine, tandamine, namic acid, tolgabide, tolimidone, tolindate, toliodium chlo taprostene, tartaric acid, tasuldine, taurocholic acid, tauro ride, toliprolol, tolmesoxide, tolmetin, tolnaftate, lidine, tauromustine, tauroselcholic acid, taurultam, tazad tolnapersine, tolnidamine, toloconium metilsulfate, toloni olene, tazanolast, tazaburate, tazeprofen, tazifylline, dine, tolonium chloride, toloxatone, toloxychlorinol, tolpa taZiprinone, tazolol, tebatizole, tebuquine, teclothiazide, dol, tolpentamide, tolperisone, toliprazole, tolpronine, tol teclozan, tedisamil, tefazoline, tefenperate, tefludazine, propamine, tolpyrramide, tolduinzole, tolrestat, toltraZuril, teflurane, teflutiXol, tegafur, telenZepine, temafloxacin, tolufazepam, tolycaine, tomelukast, tomoglumide, tomoxet temarotene, temazepam, temefos, temelastine, temocillin, ine, tomoxiprole, tonazocine, topiramate, toprilidine, tona temodox, temozolomide, temurtide, tenamfetamine, tenilap Zocine, topiramate, toprilidine, topterone, toguizine, ine, teniloxazine, tenilsetam, teniposide, tenocyclidine, torasemide, toebafylline, toremifene, tosifen, toSufloxacin, tenonitroZole, tenoxicam, tenylidone, teopranitol, teoprolol. to Sulur, toyocamycin, toyomycin, traboxepine, tracazolate, tepirindole, tepoxalin, teraZosin, terbinafine, terbucromil. tralonide, tramadol, tramazoline, trandolapril, tranexamic terbufibrol, terbuficin, terbuprol, terbutaline, terciprazine, acid, tranilast, transcainide, trantelinium bromide, tranyl terconazole, terfenadine, terfluranol, terguride, terizidone, cypromine, trapencaine, trapidil, traXanox, trazilitine, tra ternidazole, terodiline, terofenamate, teroxalene, teroxirone, Zium esilate, traZodone, traZolopride, trebenzomine, trec terpin hydrate, tertatolol, tesicam, tesimide, testolactone, adrine, treloxinate, trenbolone acetate, trengestone, testosterone, testosterone cypionate, testosterone enanthate, trenizine, troSulfan, trepibutone, trepipam, trepirium iodide, testosterone ketolaurate, testosterone phenylacetate, test treptilamine, trequensin, trestolone acetate, trethinium tosi osterone propionate, tetrabarbital, tetrabenazine, tetracaine, late, trethocanoic acid, tretinoin, tretoquinol, triacetin, tri tetrachloroethylene, tetradonium bromide, tetraethylammo afungin, triamcinolone acetonide-phosphate, triamcinolone nium chloride, tetramethrin, tetramisole, tetrandrine, tetran benetonide, triamcinolone diacetate, triamcinolone fure toin, tetrazepam, tetriprofen, tetronasin 5930, tetroquinone, tonide, triamcinolone hexacetonide, triampyZine, triam tetroxoprim, tetrydamine, texacromil, thalicarpine, thalido terene, triaZinate, triaziquone, triazolam, tribendilol. mide, thebacon, thebaine, thenalidine, thenium closylate, tribenoside, tribromoethanol, tribromsalan, tribuzone, triac thenyldiamine, theobromine, theodrenaline, theofibrate, etamide, trichlormethiazide, trichlormethine, trichloroacetic theophylline, thiabendazole, thiacetarsamide, thialbarbital, acid, trichloroethylene, tricribine phosphate, triclabenda thiambutosine, thiamine, thiamiprine, thiamphenicol, thia Zole, triclacetamol, triclazate, triclobisonicum chloride, tri mylal, thiazesim, thiazinamium chloride, thiazolsulfone, thi clocarban, triclodaZol, triclofenol, piperazine, triclofos, tri ethyperazine, thihexinol methylbromide, thimerfonate, clofylline, triclonide, triclosan, tricyclamol chloride, thimerosal, thiocarbanidin, thiocarzolamide, thiocolchio tridihexethyl chloride, trientine, triethylenemelamine, trieth side, thiofuradene, thioguanine, thioguanine alpha-deoxyri ylenephosphoramide, trifenagrel, trifeZolac, triflocin, tri boside, thioguanine beta-deoxyriboside, thioguanosine, flubazam, triflumidate, trifluomeprazine, trifluoperazine, tri thiohexamide, thioinosine, thiopental, thiopropazate, thio fluperidol, triflupromazine, trifluridine, triflusal, trigevolol, properazine, thioridazine, thiosalan, thiotepa, thiotetrabar trihexyphenidyl, triletide, trilostane, trimazosin, trimebu bital, thiothixene, thiouracil, thiphenamil, thiphencillin, tine, trimecaine, trimedoxime bromide, trimeperidine, tri thiram, thonzonium bromide, thonzylamine, thoZalinone, meprazine, trimetazidine, trimethadione, trimethamide, tri threonine, thymidine, thymol, thymol iodide, thymopentin, methaphan camsylate, trimethidinium methosulfate, thyromedan, thyropropic acid, tiacrilast, tiadenol, tiafibrate, trimethobenzamide, trimethoprim, trimetozine, trimetrexate, tiamenidine, tiametonium iodide, tiamulin, tianafac, tianep trimexiline, trimipramine, trimoprostil, trimoxamine, triox tine, tiapamil, tiapirinol, tiapride, tiaprofenic acid, tiaprost, ifene, trioXSalen, tripamide, triparanol, tripelennamine, tri tiaramide, tiaZoflurin, tiaZuril, tibalosin, tibenalast Sodium, potassium dicitratobismuthate, triprolidine, tritioZine, trito tibenzate, tibeZonium iodide, tibolone, tibric acid, tibrofan, qualine, trityl cysteine, trixolane, trizoxime, trocimine, tic-mustard, ticabesone propionate, ticarbodine, ticarcillin, troclosene potassium, trofosfamide, troleandomycin, trolni ticarcillin cresyl, ticlatone, ticrynafen, tidiacic, tiemoium trate, tromantadine, tromethamine, tropabazate, tropanserin, iodide, tienocarbine, tienopramine, tienoXolol, tifemoxone, tropapride, tropatepine, tropenZiline bromide, tropigline, tiflamizole, tiflorex, tifluadom, tiflucarbine, tiformin, tifurac, tropiprine, tropodifene, trospectomycin, trospium chloride, tigemonam, tigestol, tigloidine, tilbroquinol, tiletamine, tili troXerutin, troXipide, troXolamide, troxonium tosilate, troxy dine, tiliquinol, tilisolol, tilmicosin, tilomisole, tillorone, pyrrolium tosilate, troxypyrrolium tosilate, truXicurium tilozepine, tilsuprost, timefurone, timegadine, timelotem, iodide, truXipicurium iodide, tryparsamide, tryptophan, tryp timepidium bromide, timiperone, timobesone acetate, tophane mustard, tuaminoheptane, tubercidine, tubocurarine timofibrate, timonacic, timoprazole, tinabinol, tinazoline, chloride, tubulozole, tuclazepam, tulobutrol, tuvatidine, tinidazole, tinisulpride, tinofedrine, tinoridine, tiocarlide, tybamate, tylocrebin, tylosin, tyramine, tyropanic acid, and tioclomarol, tioconazole, tioctilate, tiodaZosin, tiodonium tyrosine. chloride, tiomergine, tiomesterone, tioperidone, tiopinac, tiopronin, tiopropamine, tioSpirone, tiotidine, tioxacin, 0228. Also, ubenimex, ubidecarenone, ubisindine, ufe tioXamast, tioxaprofen, tioxidazole, tioXolone, tipentosin, namate, ufiprazole, uldazepam, ulobetasol, undecoylium tipepidine, tipetropium bromide, tipindole, tipredane, tipre chloride, undecyclenic acid, uracil mustard, urapidil, urea, US 2006/01 10428 A1 May 25, 2006 uredepa, uredofos, urefibrate, urethane, uridine, urSodeoxy 75% by weight or less, preferably about 50% by weight or cholic acid, and urSucholic acid. less. The amount of bioactive agent in the polymeric mate 0229. Also, Vadocaine, Valconazole, Valdetamide, val rial can be in the range of about 1 lug to about 10 mg, or dipromide, Valine, Valnoctamide, valofane, Valperinol, Val about 100 ug to about 1000 ug, or about 100 g to about 500 proate pivoxil, Valproic acid, valpromide, Valtrate, Vanco l2. mycin HC1, Vaneprim, Vanillin, Vanitolide, 0237. In some aspects, the concentration of bioactive Vanyldisulfamide, Vapiprost, vecuronium bromide, Velna agent can also be selected to provide a desired elution rate crine maleate, Venlafaxine, Veradoline, Veralipride, Vera from the device. As discussed herein, some aspects of the pamil, Verazide, Verilopam, Verofylline, Vesnarinone, invention provide methods including steps of selecting one vetrabutine, Vidarabine, Vidarabine phophate, vigabatrin, or more bioactive agents to administer to a patient, deter viloxazine, Viminol, vinbarbital, vinblastine, vinburnine, mining a treatment course for a particular patient, and Vincamine, Vincanol, Vincantril, Vincofos, Vinconate, Vinc formulating the polymeric material to achieve the treatment ristine, vindrbumol. Vindesine, Vindepidine, Vinformide, COUS. Vinglycinate, Vinpocetine, Vinpoline, Vinrosidine, Vintiamol. vintriptol, vinylbital, vinylether, Vinzolidine, viomycin, 0238. In some aspects, the concentration of bioactive Viprostol, vidualine, Viduidil, Virginiamycin factors, agent can be selected to provide a desired tissue concentra ViroXime, Visnadine, Visnafylline, Vitamine, and volazocine. tion of bioactive agent at the treatment site. Given the site-specific nature of the inventive devices, methods and 0230. Also, warfarin. systems, it will be apparent that the tissue concentration of 0231. Also, Xamoterol, Xanoxic acid, Xanthinol niacinate, bioactive agent will be greater at the treatment site than at Xanthiol, Xantifibrate, Xantocillin, Xenalipin, Xenazoic acid, areas within the patient outside the treatment site. As dis Xenbucin, Xenipentone, Xenthiorate, Xenygloxal, Xeny cussed herein, this provides several benefits to the patient, hexenic acid, Xeny tropium bromide, Xibenolol, Xibomol. such as reduced risk of toxic levels of the bioactive agent Xilobam, Ximoprofen, Xinidamine, Xinomiline, Xipamide, within the body, reduced risk of adverse affects caused by Xipranolol. Xorphanol. Xylamidine, Xylazine, Xylocoumarol, bioactive agent outside the treatment site, and the like. The Xylometazoline, and Xyloxemine. location of the bioactive agent on or within the device and on or within the polymer can also affect tissue concentration 0232 Also, yohimbic acid. of bioactive agent (for example, when substantially the 0233 Also, Zabicipril, Zacopride, Zafiuleptine, Zaltidine, entire device body includes bioactive agent, or selected Zapizolam, Zaprinast, Zardaverine, Zenazocine mesylate, portion(s) of the device body include bioactive agent). Zepastine, Zeranol, Zetidoline, Zidapamide, Zidometacin, Moreover, inclusion of optional coating layers that contain Zidovudine, Zilantel, Zimeldine, Zimidoben, Zinc acetate, bioactive agent can also impact tissue concentration of Zinc phenolsulfonate, Zinc undecylenate, Zindotrine, Zindox bioactive agent. ifene, Zinoconazole, Zinterol, ZinviroXime, Zipeprol, 0239). The particular bioactive agent, or combination of Zocainone, Zofenopril, Zoficonazole, Zolamine, Zolazepam, bioactive agents, can be selected depending upon one or Zolenzepine, Zollertine, Zolimidine, Zoliprofen, Zoloperone, more of the following factors: the application of the device Zolpidem, Zomebazam, Zomepirac, Zometapine, Zonisamide, (for example, Subretinal implant, intraocular implant, Zopiclone, Zorubicin, Zotepine, Zoxazolamine, Zuclomi intraocular injection, and the like), the amount of the device phene, Zuclophenthixol, and Zylofuramine. composed of the polymer material, the condition to be 0234. The bioactive agent can be present as a liquid, a treated, the treatment method, the anticipated duration of finely divided solid, or any other appropriate physical form. treatment, characteristics of the implantation site, the num Typically, but optionally, the biodegradable composition ber and type of bioactive agents to be utilized, and the like. will include one or more additives, such as diluents, carriers, 0240 The amount of the bioactive agent that is to be excipients, stabilizers, or the like. delivered to the treatment site may be determined by one of 0235. The particular bioactive agent, or combination of ordinary skill in the art and will vary depending on the bioactive agents, can be selected depending upon one or condition to be treated and the particular treatment method. more of the following factors: the application of the device In addition, the amount also will depend upon the particular (for example, Subretinal implant or intraocular implant), the formulation of the bioactive agent. Further, the amount of amount of the device composed of the polymeric material the bioactive agent to be delivered also takes into account (for example, percentage of the device fabricated of degrad the period of time expected for administration and/or treat able material, inclusion of a biodegradable material as a ment and/or the frequency or periodicity of Such adminis coating on a surface of the body member, as well as the tration and/or treatment. amount of Surface provided with the coating), the condition to be treated, the anticipated duration of treatment, charac 0241. In some embodiments, an intraocular or subretinal teristics of the implantation site, the number and type of Sustained release delivery device has a bioactive agent elution rate of at least 0.0001 ug per day, in other embodi bioactive agents to be utilized, and the like. ments at least 0.001 ug per day, in other embodiments at 0236. The concentration of the bioactive agent in the least 0.01 g per day, in other embodiments at least 0.1 ug polymeric material can be provided in the range of about per day, in other embodiments at least 1 lug per day, in other 0.01% to about 75% by weight, or about 0.01% to about embodiments at least 10 ug per day. In some embodiments, 50% by weight, based on the weight of the final polymeric an intraocular device has an elution rate of at least 0.01 ug material. Preferably, the bioactive active agent is present in per day, in other embodiments at least 0.1 ug per day, in the polymeric material in an amount in the range of about other embodiments at least 1 ug per day, in other embodi US 2006/01 10428 A1 May 25, 2006 32 ments at least 10 ug per day, in other embodiments at least include bioactive agent). Moreover, inclusion of optional 100 ug per day, and in other embodiments at least 1000 ug coating layers that contain bioactive agent can also impact per day. tissue concentration of bioactive agent. 0242. The elution rate can vary and can be customized as 0247. In some embodiments, the invention provides for desired for each type of eye condition treated, the nature of the treatment of disorders or diseases of the choroid and the the ocular tissue being treated (for example, Subretinal retina. As such, the bioactive agents may be instilled directly versus intraocular), the treatment method, the selected bio in the choroid, the retina or Subretinal space, so as to deliver active agent(s), the potency of bioactive agent(s), the size of the bioactive agent precisely to the portion of the tissue the bioactive agent(s), and the severity of the condition being treated. In some embodiments, the invention provides being treated. In some aspects, the elution rate can be for the treatment of disorders or diseases via intraocular customized depending upon any physiological barriers that routs, for example, using devices that are inserted and may exist between the implant site and the tissue to be implanted in the vitreous of the eye. Such localized delivery treated. In general, it is desired to maximize the total to various targeted portions of the eye is efficient and bioactive agent(s) loading while maintaining mechanical delivers the bioactive agent substantially only to the portion integrity of the device. of the eye being treated and does not deliver any significant 0243 The sustained release delivery devices can be amount of bioactive agent to healthy tissues. As used herein, implanted to release or deliver bioactive agent(s), more the terminology delivery substantially only to the portion of particularly a therapeutic dosage of the bioactive agent(s), the eye being treated is understood to mean that at least 5%, for a sustained period of time, that is for example for about more preferably at least 10%, more preferably at least 20%, 1 month to about 20 years, such as from about 6 months to more preferably at least 30%, more preferably at least 40%, about 5 years and more specifically from about 3 months to more preferably at least 50%, more preferably at least 60%, 2 years. In some embodiments the Sustained release device more preferably at least 70%, more preferably fit least 75%, releases the bioactive agent(s) by pseudo Zero order release more preferably at least 80% more preferably at least 85%, kinetics. more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, 0244. The devices can be utilized to deliver any desired more preferably at least 94%, more preferably at least 95%, bioactive agent or combination of bioactive agents to the more preferably at least 96%, more preferably at least 97%, eye, Such as the bioactive agents described herein. The more preferably at least 98%, more preferably at least 99%, amount of bioactive agent(s) delivered over time is prefer more preferably all of the bioactive agent delivered by the ably within the therapeutic level, and below the toxic level. device is delivered to the treatment site. As used herein, the For example, a preferred target dosage for intraocular deliv terminology "does not deliver any significant amount of ery of triamcinolone acetonide for use in treating diseases or bioactive agent to healthy tissues” is understood to mean disorders of the eye is preferably in the range of about 0.5 that less than 95%, more preferably less than 90%, more ug/day to about 10 ug per day. Preferably, the treatment preferably less than 80%, more preferably less than 70%, course is greater than 6 months, more preferably greater than more preferably less than 60%, more preferably less than one year. Thus, in preferred embodiments, the bioactive 50%, more preferably less than 40%, more preferably less agent is released from the coated composition in a thera than 30%, more preferably less than 20%, more preferably peutically effective amount for a period of 6 months or more, less than 15%, more preferably less than 10%, more pref or 9 months or more, or 12 months or more, or 36 months erably less than 5%, more preferably less than 4%, more or more, when implanted in a patient. preferably less than 3%, more preferably less than 2%, more 0245. In some aspects, the concentration of bioactive preferably less than 1% of the total bioactive agent delivered agent(s) can also be selected to provide a desired elution rate by the device. from the device. As discussed herein, some aspects of the 0248. This is in contrast to systemic, topical, and oral invention provide methods including steps of selecting one delivery mechanisms that may have been used to treat or more bioactive agents to administer to a patient, deter diseases and disorders of the eye, as such mechanisms mining a treatment course for a particular patient, and require the administration of significantly larger dosages of formulating the polymeric material to achieve the treatment bioactive agents systemically, topically, or orally so as to COUS. deliver a therapeutically effective amount of bioactive agent 0246. In some aspects, the concentration of bioactive to the treatment site. agent can be selected to provide a desired tissue concentra Polymers tion of bioactive agent at the treatment site. Given the site-specific nature of the devices and methods, it will be 0249 Polymers useful in the sustained release delivery apparent that the tissue concentration of bioactive agent will devices (e.g., as cores and/or as coating layers) are biocom be greater at the treatment site than at areas within the patible and may be biodegradable or biostable (i.e., non patient outside the treatment site. As discussed herein, this biodegradable). Representative biostable polymers include provides several benefits to the patient, such as reduced risk polyurethanes, silicones, polyesters, polyolefins (e.g., poly of toxic levels of the bioactive agent within the body, ethylene or polypropylene), polyisobutylene, acrylic poly reduced risk of adverse affects caused by bioactive agent mers, vinyl halide polymers, polyvinyl ethers, polyvinyl outside the treatment site, and the like. The location of the methyl ether, polyvinylidene halides, polyacrylonitrile, bioactive agent on or within the device and on or within the polyvinyl ketones, polyvinyl aromatics, polyvinyl esters polymer can also affect tissue concentration of bioactive (e.g., poly(alkyl(meth)acrylates) Such as poly(methyl agent (for example, when Substantially the entire device )methacrylate) or poly((butyl)methacrylate)), polyvinyl includes bioactive agent, or selected portion(s) of the device amides, polyamides, polycaprolactam, polycarbonates, US 2006/01 10428 A1 May 25, 2006 polyoxymethylenes, polyimides, polyethers, polyurethanes, 0255 The coating layer formed from the coating com rayon, rayon-triacetate, cellulose acetate, cellulose butyrate, position is biocompatible. In addition, the layer is preferably cellophane, cellulose nitrate, cellulose propionate, cellulose useful under a broad spectrum of both absolute concentra ethers, carboxymethyl cellulose and copolymers (e.g., poly tions and relative concentrations of the polymers. In the ethylene vinyl acetate) and blends of the above polymers. context of the previous sentence, the physical characteristics 0250 Representative examples of biodegradable poly of the coating layer (such as tenacity, durability, flexibility mers include poly(L-lactic acid), polycaprolactone, poly and expandability) will typically be suitable over a broad (lactide-co-glycolide), poly(hydroxybutyrate), poly(hy range of polymer concentrations. Furthermore, the ability to droxybutyrate-co Valerate), polydioxanone, polyorthoesters, control the release rates of a variety of bioactive agents can polyanhydrides, poly(glycolic acid), poly(D.L. lactic acid), preferably be manipulated by varying the absolute and/or poly(glycolic acid-co-trimethylene carbonate), poly(phos relative concentrations of the polymers and/or the bioactive phate esters), polyphosphoester urethanes, poly(amino agent(s). acids), cyanoacrylates, poly(trimethylene carbonates), poly 0256 In one embodiment, the polymer matrix comprises carbonates, poly(iminocarbonates), polyesters, copoly a hydrogel. Representative examples of hydrogels include (ether-esters), polyalkylene oxalates, polyphosphaZenes and the dextran-based hydrogels described in WO 02/17884 copolymers and blends of the above polymers. Biodegrad (Hennink et al.). able materials such as fibrin, fibrinogen, cellulose, dextrans, 0257. In one embodiment, the polymeric material com polysaccharides, starch collagen, chromic gut, and hyalu prises a composition as described in U.S. Pat. No. 6,214,901 ronic acid could also be used. (Chudzik et al.) and U.S. Publication No. 2002/0188037 A1 0251 Selection of the polymers may depend, for (Chudzik et al.) (each commonly assigned to the assignee of example, on the desired properties of the sustained delivery the present invention). As described therein, the composition device including the desired bioactive agent that is to be comprises a plurality of polymers, including at least two delivered by the device and the rate and duration of desired polymer components, for example, primary and secondary bioactive agent release. polymer components. As used herein “primary and 'sec 0252) In some embodiments, the biocompatible polymer ondary are used solely for designation of the polymer is made up, in whole or in part, of repeating caprolactone components are not intended to reflect the relative amounts monomer units (e.g., poly(caprolactone) or co-polymers of polymer components in the composition. The polymer thereof). It has been found that polycaprolactone is well components are adapted to be mixed to provide a mixture tolerated by the retinal tissue and can elute bioactive agents that exhibits an optimal combination of physical character without eliciting unacceptable inflammatory response or istics (such as adherence, durability, flexibility) and bioac complications. For example, polycaprolactone can elute tive release characteristics as compared to the polymers steroid for a period of at least 4 weeks without eliciting when used alone or in admixture with other polymers unacceptable inflammatory response or complications. previously known. For example the polymeric material can Thus, in one embodiment, the device is formed using a include an adherent polymer and a polymer having drug biodegradable polycaprolactone polymer matrix. In another release characteristics. embodiment, the device includes corticosteroid triamcino 0258. In some aspects the adherent polymer preferably lone acetonide in a biodegradable polycaprolactone polymer includes poly(alkyl(meth)acrylates) and poly(aromatic matrix. Such embodiments may optionally include a core. (meth)acrylates), where “(meth) will be understood by 0253) In some embodiments the polymer comprises a first those skilled in the art to include such molecules in either the polymer and a second polymer. Suitable first polymers and acrylic and/or methacrylic form (corresponding to the acry second polymers can be prepared using conventional lates and/or methacrylates, respectively). organic synthesis procedures and/or are commercially avail 0259 Examples of suitable poly(alkyl (meth)acrylates) able from a variety of sources. Preferably, such polymers are include those with alkyl chain lengths from 2 to 8 carbons, either provided in a form suitable for in vivo use or are inclusive, and with molecular weights from 50 kilodaltons to purified for such use to a desired extent (for example, by 900 kilodaltons. In one preferred embodiment the polymeric removing impurities) by conventional methods available to material includes a poly(alkyl (meth)acrylate) with a those skilled in the art. molecular weight of from about 100 kilodaltons to about 1000 kilodaltons, preferably from about 150 kilodaltons to 0254 For application to a core, a coating composition about 500 kilodaltons, most preferably from about 200 can be prepared to include a solvent, a first polymer and kilodaltons to about 400 kilodaltons. An example of a second polymer dissolved in the solvent, and one or more particularly preferred polymer is poly (n-butyl methacry bioactive agents dispersed in the polymer/solvent. The Sol late). Examples of other preferred polymers are poly(n-butyl vent is preferably one in which the polymers form a true methacrylate-co-methyl methacrylate, with a monomer ratio solution. The bioactive agent(s) can either be soluble in the of 3:1, poly(n-butyl methacrylate-co-isobutyl methacrylate, Solvent or may form a dispersion in the solvent. In some with a monomer ratio of 1:1 and poly(t-butyl methacrylate). embodiments, the solvent is tetrahydrofuran (THF). Other Such polymers are available commercially (e.g., from Solvents may also be used, for example, alcohols (such as Sigma-Aldrich, Milwaukee, Wis.) with molecular weights methanol, butanol, propanol, isopropanol, and the like), ranging from about 150 kilodaltons to about 350 kilodaltons, alkanes (such as halogenated or unhalogenated alkanes Such and with varying inherent viscosities, solubilities and forms as hexane and cyclohexane), amides (such as dimethylfor (e.g., as slabs, granules, beads, crystals or powder). mamide), ethers (such as dioxolane), ketones (such as meth ylketone), aromatic compounds (such as toluene and 0260 Examples of suitable poly(aromatic (meth)acry Xylene), acetonitrile, and esters (such as ethyl acetate). lates) include poly(aryl (meth)acrylates), poly(aralkyl US 2006/01 10428 A1 May 25, 2006 34
(meth)acrylates), poly(alkaryl (meth)acrylates), poly(ary 0265 Other useful mixtures of polymers that can be loxyalkyl (meth)acrylates), and poly (alkoxyaryl (meth included in the coating composition are described in com )acrylates). monly assigned U.S. Provisional Application Ser. No. 60/559,821, filed Apr. 6, 2004, and entitled “Coating Com 0261) Examples of suitable poly(aryl (meth)acrylates) positions For Bioactive Agents’. These blends include a first include poly(9-anthracenyl methacrylate), poly(chlorophe polymer and a second polymer. The first polymer can be nyl acrylate), poly(methacryloxy-2-hydroxybenzophenone), selected from the group consisting of (i) poly(alkylene-co poly(methacryloxybenzotriazole), poly(naphthyl acrylate), alkyl(meth)acrylates, (ii) ethylene copolymers with other poly(naphthylmethacrylate), poly-4-nitrophenylacrylate, alkylenes, (iii) polybutenes, (iv) diolefin derived non-aro poly(pentachloro(bromo, fluoro) acrylate) and methacrylate, matic polymers and copolymers, (v) aromatic group-con poly(phenyl acrylate) and poly(phenyl methacrylate). taining copolymers, and (vi) epichlorohydrin-containing Examples of suitable poly(aralkyl (meth)acrylates) include polymers. A second polymer can be selected from the group poly(benzyl acrylate), poly(benzyl methacrylate), poly(2- consisting of poly(alkyl (meth)acrylates) and poly(aromat phenethyl acrylate), poly(2-phenethyl methacrylate) and ic(meth)acrylates). poly(1-pyrenylmethyl methacrylate). Examples of suitable poly(alkaryl(meth)acrylates include poly(4-sec-butylphenyl 0266 Other useful mixtures of polymers that can be methacrylate), poly(3-ethylphenyl acrylate), and poly(2-me included in the coating are described in U.S. Publication No. thyl-1-naphthyl methacrylate). Examples of suitable pol 2004/0047911. This publication describes polymer blends y(aryloxyalkyl (meth)acrylates) include poly(phenoxyethyl that include poly(ethylene-co-methacrylate) and a polymer acrylate), poly(phenoxyethyl methacrylate), and poly(poly selected from the group consisting of a poly(vinyl alkylate), ethylene glycol phenyl ether acrylate) and poly(polyethyl a poly(vinyl alkyl ether), a poly(Vinyl acetal), a poly(alkyl ene glycol phenyl ether methacrylate) with varying polyeth and/or aryl methacrylate) or a poly(alkyl and/or aryl acry ylene glycol molecular weights. Examples of Suitable late); not including pEVA. poly(alkoxyaryl(meth)acrylates) include poly(4-methoX 0267 The polymeric material can also be a styrene yphenyl methacrylate), poly(2-ethoxyphenyl acrylate) and copolymer, such as poly(styrene-isobutylene-styrene); the poly(2-methoxynaphthyl acrylate). preparation of medical devices having such coatings that 0262 Acrylate or methacrylate monomers or polymers include poly(styrene-isobutylene-styrene) is described in, and/or their parentalcohols are commercially available from for example, U.S. Pat. No. 6,669,980. Sigma-Aldrich (Milwaukee, Wis.) or from Polysciences, 0268. The invention will now be described with reference Inc. (Warrington, Pa.). to the following non-limiting examples. 0263. One of the other polymer components in the mix ture provides an optimal combination of similar properties, EXAMPLE 1. and particularly when used in admixture with the primary Materials Used: polymer component. Examples of Suitable secondary poly mers are available commercially and include poly(ethylene Polycaprolactone (Average Mw 80,000, O(CH2)CO— co-vinyl acetate) having vinyl acetate concentrations in the Melt index 125° C./0.3 MPa, Sigma Aldrich Biochemi range of about 1% to about 50%, in the form of beads, cals, St. Louis, Mo.) pellets, granules, and the like. Triamcinolone acetonide (Purity 99%, M. 434.5, 0264. In some embodiments, the composition comprises CHFO, Sigma Aldrich Biochemicals, St. Louis, Mo.) at least one poly(alkyl)(meth)acrylate, as a primary, adherent Prednisolone (Purity 99%, CHOs, M, 360.5, Sigma polymeric component, and poly(ethylene-co-vinyl acetate) Aldrich Biochemicals, St. Louis, Mo.) as a secondary polymeric component. Preferably, the poly Chloroform (purity 99.8%, CHCl, A.C.S. spectroscopic mer mixture includes mixtures of poly(butylmethacrylate) grade, Sigma Aldrich Chemicals) (PBMA) and poly(ethylene-co-vinyl acetate) (pVA). This mixture of polymers has proven useful with absolute poly Ether (purity 99%, M, 74.12. (CH)O A.C.S. reagent, mer concentrations (total combined concentrations of both Sigma Aldrich Chemicals) polymers in the composition) in the range of about 0.25 to Balanced salt solution (Sterile, preservative free, Akorn, about 70% (by weight). It has furthermore proven effective Inc., Somerset, N.J.) with individual polymer concentrations in the coating solu tion in the range of about 0.05 to about 70% (by weight). In Bovine serum albumin (Molecular biology grade, Sigma one preferred embodiment, the polymer mixture includes Aldrich Biochemicals, St. Louis, Mo.) poly (n-butylmethacrylate) (PBMA) with a molecular Abbreviations: weight in the range of about 100 kD to 900 kD and a pBVA copolymer with a vinyl acetate content in the range of about 0269 PCL: polycaprolactone biodegradable filament 24 to 36% (by weight). In another preferred embodiment, the polymer mixture includes poly (n-butylmethacrylate) 0270 TA: triamcinolone (PBMA) with a molecular weight in the range of about 200 0271 PCL/TA: biodegradable triamcinolone loaded kD to 400 kD and a pVA copolymer with a vinyl acetate polycaprolactone filaments content in the range of about 30 to 34% (by weight). Filament Preparation: According to these embodiments, the concentration of the bioactive agent or agents dissolved or Suspended in the 0272. The filaments used in the example were prepared as coating mixture can be in the range of about 0.01 to 90%, by follows. PCL was solubilized in chloroform at 35° C. weight, based on the weight of the final coating composition. overnight under continuous stirring conditions. Triamcino US 2006/01 10428 A1 May 25, 2006
lone acetonide (TA) was then added to the solution in a 0279. Using intraocular microscopic forceps (Bausch & polymer/drug weight ratio (w/w) of 70:30, 60:40 or 50:50. Lomb, USA), the filaments were inserted in the subretinal Once the Solution became homogeneous, it was poured onto space through a small self-sealing retinotomy. The beveled an evaporating tray and left in a fume hood for 72 hours to tip of the implant allowed easy insertion through the retina. solidify. The white solid-form sheath of the TA loaded PCL The filament was left in position and the forceps was was rolled into a tight column and packed into a 10 mL. withdrawn from the eye. No laser retinopexy was applied to syringe. The syringe was heated to 80°C. in a water bath to seal the retinal breaks. The infusion line was removed and ensure even heat distribution and to prevent high localized the Sclerotomies and conjunctival openings were closed temperatures that could damage the drug or polymer. using Vycril 7-0 (Ethicon, USA). During week 4, all rabbits Although the polymer was not fully in the melt state, the underwent fundus examination and were then sacrified temperature was sufficiently high to initiate the transition of under anesthesia using an intracardiac injection of pento this semi-crystalline closed packed macromolecular poly barbital sodium (Anpro Pharmaceuticals, Oyster Bay, N.Y.). mer to a sufficiently viscous state to be extruded. Addition ally, it was noted that drug crystals within the polymeracted Elution, Drug Extraction and Histology: as a “flow enhancing plasticizer when comparing the In Vitro Elution process to a PCL only filament extrusion. 0280 For in vitro drug elution characterization, drug 0273. Once the syringe reached 80° C. it was rapidly loaded PCL filaments were prepared according to Table 1. removed from the water bath and 1 cm of material was extruded from it. The extruded material was subsequently TABLE 1. drawn to a filament by imparting a tensile force. For the 70:30, 60:40 or 50:50 w/w formulations, ~150 um fila In vitro Sample parameters ment diameters were achieved by a drawing length of Formulation Diameter Length approximately 20, 15 and 10 cm, respectively, while -300 Sample PCLTA (Lm) (mm) um filament diameters were achieved by a drawing length of 1 70:30 210 30 approximately 15, 10 and 5 cm, respectively. The formula 2 70:30 210 30 tion with the highest drug load (50:50 w/w) broke more 3 70:30 250 30 frequently during the drawing process. The drawn filament 4 70:30 250 30 cooled rapidly and could be subsequently cut under a 5 70:30 360 30 6 60:40 150 30 microscope to the desired implantation length. 7 60:40 150 30 8 60:40 32O 30 0274 Filaments without drug were also prepared by 9 60:40 32O 30 directly inserting the PCL pellets into the Syringe, heating 10 50:50 150 30 them to 80° C. and then extruding and drawing in a similar 11 50:50 150 30 manner to that previously described. 12 50:50 32O 30 13 50:50 32O 30 0275 Six pigmented rabbits underwent fluorescein angiography, fundus photography, and optical coherence tomography (Zeiss Model 3000, Germany) at baseline and 4 0281. Each filament was placed in a 15 mL capped tube weeks after implantation. The rabbits were subdivided into containing 10 mL of a 1% bovine serum albumin (BSA)/ the following groups: balance salt solution (BSS). Tubes were incubated at 37° C. in a shaking water bath (100 rpm). At each time increment 0276 Group 1: 2 rabbits with PCL only filaments (PCL, of 2, 4, 8, 24, 72, 168,336, 504 and 672 hours, the filaments Rabbits 1 and 2): were removed from the BSS/BSA solution and placed into 0277 Group 2: 4 rabbits with PCL/TA 60:40 (w/w) a new 10 ml BSS/BSA Solution. filaments (Rabbits 3-6). 0282. After the final time period, the filaments were 0278 Both groups underwent standard pars plana vitrec removed from the BSS/BSA solution and placed in tubes tomy, and insertion of the drug delivery device into the containing 2 mL of ether for complete extraction of the subretinal space. Briefly, animals were anesthetized with an remaining TA. Ether (2 mL) and a 50 uL of internal standard intramuscular injection of 0.3 mL of ketaminehydrochloride (prednisolone 2 mg/ml) were added to the remaining BSS/ (100 mg/mL.; Fort Dodge Lab., Iowa) and 0.1 mL of BSA solutions. Each solution was vortexed for 2 min and xylazine hydrochloride (100 mg/mL; Miles Inc, USA) per then centrifuged for 3 min at 10,000 rpm to separate the kilogram of body weight. Pupils were dilated with 1 drop ether and BSS/BSA phases. The top layer ether phase was each of 2.5% phenylephrine and 1% tropicamide. A 3-mm removed using a glass syringe and added to a 2 mL capped peritomy was made at the Superotemporal and Superonasal microtube for solvent evaporation in fume hood. Following quadrant of the right eye. Sclerotomies were created with a complete evaporation, 1 mL of 60% methanol was added to 20-gauge microvitreoretinal blade 1 to 2 mm posterior to the the microtube and vortexed. The solution was then trans limbus in the Superotemporal and Superonasal quadrants. An ferred to a 1 mL glass shell high performance liquid chro infusion line was inserted and Sutured through the Supero matography (HPLC) vial for analysis. nasal sclerotomy and a vitreous cutter (Bausch & Lomb, USA) was inserted through the Superotemporal Sclerotomy. In Vivo Elution The vitreous cutter and infusion line were used to perform 0283 Two rabbits (PCL/TA 60:40 filaments) were used a 2-port core vitrectomy. The illumination provided by the for analysis of in vivo drug elution. Rabbits were anesthe operating microscope (Zeiss, Germany) was sufficient for tized prior to the collection of aqueous (-0.3 mL) and blood the operation. into lithium heparin tube (2 mL). Rabbits were then eutha US 2006/01 10428 A1 May 25, 2006 36 nized and the eyes enucleated. The implanted device and the implant. No abnormalities were reported from increasing Surrounding tissues (Sclera, choroid, retina, lens, and vitre the filament diameter. An increase in the filament diameter ous) were dissected and separated into 2 mL micro tubes. merely resulted in a slightly more demanding Surgical pro Individual tissue was weighed and then homogenized in 0.5 cedure and a larger area of cellular disruption. mL BSS by sonication (1-2 pulse/sec at 50% power). Once completed, samples were enriched with 50 uL internal 0288 The in vitro elution rates for the different polymer standard (prednisolone 2 mg/ml) and Vortexed. TA was drug ratios and geometries into a BSS/BSA (1%) solution extracted from the tissue sample by adding ether (0.5 mL), are shown in FIGS. 24-26. In general, the elution rates vortexing and centrifuging at 10,000 rpm for 10 min. The showed an early burst phase followed by a late first order top ether layer was removed and placed in a new 2 mL phase. Without being bound by a particular theory, it is microtube for evaporation and substitution of the solvent for believed that the initial early rapid-release phase is attributed methanol as previously described in the in vivo study. to the absorption of drug crystals in the Surface to Subsurface region of the filament into the medium, preceding diffusion 0284. A Millennium high performance liquid chromato from the polymer core. This initial burst may be particularly graph (Waters Corp., USA) equipped with a 515 pump. 2996 useful if it is desired to rapidly achieve local therapeutic photodiode array detector and 717-plus autosampler injector dosage. For each of the different polymer-drug ratios, was used in this study to process the in vitro and in vivo increasing the filament diameter or drug:polymer ratio samples. The Millennium software provided with the high resulted in an increase in the amount of drug eluted. Without performance liquid chromatograph (HPLC) was used for being bound by theory, it is believed that this change results integration of chromatographic peaks. The Solvents were from the increased drug content and/or eluting Surface area. linked to an in-line degasser. The samples were injected into For the larger (-300 um) filaments, increasing the ratio of reverse phase HPLC system consisting of stationary phase drug in the formulation from PCL/TA 70:30 to 50:50 also of Nova-Pak C18 column (3.9x150 mm) and Nova-Pack increased the drug elution rate, while a drug dumping effect guard column (Waters Corp., USA); and an isocratic mobile occurs if both the drug ratio is high (PCL/TA 50:50) and the phase of 60% methanol. The peaks of TA and prednisolone filament diameter is small, as shown in FIG. 26. In this latter were eluted at a flow rate of 1 mL/min with detection at 245 case, total drug release had occurred during the initial burst, nm. Parallel 50 uL of prednisolone was chromatogramed and the rate of TA absorption by the subretinal tissue was under the same HPLC condition to determine the extraction most likely a limiting factor. The near Superimposition of all efficiency of TA. Further, the co-chromatography technique the elution profiles during the first few hours of each study was adopted to validate the identification of both com also indicated that it was the rate of TA absorption that was pounds. The calculation of TA concentration was based on the limiting step during the first stage of elution. Polyca the area peaks and percentage recovery of prednisolone. The prolactone is hydrophobic and impermeable to enzyme HPLC condition separated the peaks of triamcinolone and diffusion; therefore swelling, bulk diffusion, or degradation prednisolone with good resolution. The retention time of is unlikely in a bodily environment. Without intending to be prednisolone was 3.46 minutes while that of triamcinolone bound by a particular theory, the TA elution profile that was 5.2 minutes. occurs after the initial surface to subsurface event is believed to be the result of a microporous drug boundary layer being Histology formed and moving deeper toward the core as the TA 0285) The eyes of the four remaining rabbits (2 rabbits crystals are progressively absorbed by the body. As a result, with PCL only filaments; 2 rabbits with PCL/TA 60:40 the lower the drug loading, the Smaller the polymer porosity filaments) were enucleated and fixed in 4% paraformalde formed during drug absorption and the lower the rate of TA hyde for 24 hours and then Bouin’s fixative for a further 24 elution. hours. The specimens were then embedded in paraffin, 0289 Illustrative images (optical and histology staining) sectioned, and hematoxylin and eosin (H & E) stained under of implanted filaments are shown in FIGS. 27 through 29. standard histology laboratory conditions. The size of the retinotomy shown in the optical images is Results approximately 500 um. However, smaller sized retinotomies are possible with the use of custom implantation tools. 0286 Clinical examination using slit-lamp and indirect ophthalmoscopy at 1, 2, 3 and 4 weeks showed that there 0290 Compared with the initial implant, the explanted was no detectable accumulation of Subretinal fluid, exudates, filaments at four weeks post Surgery had a somewhat more hemorrhage or fibrosis Surrounding the device at any of the fibrous polymer microstructure, as shown in FIG. 30, than follow up points. Fundus photography showed that the the initial implant. In some studies, only a flaky fibrous/ filament maintained its position without signs of inflamma porous polymer microstructure remained once the entire tion or migration, as shown in FIG. 21 for a representative drug was extracted from the device during the in vitro rabbit. Fluorescein angiography demonstrated the absence elution studies. The molecular number selected for this of vascular leakage, pooling, retinal pigmented epithelium polymer was at the high end (M. 80,000) of the commer (RPE) abnormalities, or fibrosis at any of the follow-up cially available range. PCL degrades by a reduction in M, points for a representative rabbit, as shown in FIG. 22. so a longer degradation time is expected with this high M. Optical coherence tomography revealed the Successful There was no indication that polymer degradation had begun placement of the implant in the subretinal space of all the during the follow-up period. rabbit eyes, as shown in FIG. 23. 0291. Histology revealed that the implants, whether drug 0287. The topographical effect of using different filament loaded or not, were encapsulated by one or two cell layers diameters (150 um vs. 320 um) can also be seen in FIG. 23 that did not appear fibrotic in nature, as shown in FIGS. 28 by the comparative increase in retinal thickness at the site of and 29. The nerve fiber layer (ganglion axles) above the US 2006/01 10428 A1 May 25, 2006 37 filament appeared intact, while the Support cells immedi EXAMPLE 2 ately over the filament location are clearly absent in the PCL only implant and somewhat disrupted and thinned in the Materials Used and Abbreviations: TA/PCL implanted eye. The Bruch's membrane appeared Core: intact but there was evidence of thinning and disruption of NIT: 80 um etched Nitinol wire, commercially available the outer nuclear and RPE layers adjacent to the filament. from Nitinol Devices and Components (Freemont Calif.). Due to the lack of inflammatory response, PCL demon strated excellent compatibility with this tissue region and the Bioactive Agent: bulk of the observed cellular changes were attributed to the RAP: Rapamycin, commercially available from LC Labo mechanical damage during the implantation. Other factors ratories, Woburn Mass. Such as the impact of interfering with the nutritional Source Polymers: of these outer cellular layers may also play a role in these pEVA: polyethylene vinyl acetate copolymer (33% wt. vinyl cellular changes. acetate and 67% wt. polyethylene), commercially available 0292. It has been found that PCL degrades by random from Aldrich Chemical Co. hydrolytic chain scission in subdermally implanted rabbits. pBMA: poly(n-butyl methacrylate), commercially available The degradation initially manifests by a progressive reduc from Aldrich Chemical Co. tion in molecular weight as the chain Scission reactions Solvent: propagate. However, it has also been shown that the physical weight of PCL does not change until the molecular weight CHCl: chloroform solvent, commercially available from has fallen to 5000 that is, there is no weight loss during the Burdick & Jackson. first phase of the degradation (Pitt C G. Polye caprolactone Implant Preparation: and its copolymers. In Chassin M Langer R, editors, Bio degradable polymers as drug delivery systems, New York: Coating Solution Preparation: Dekker, 1990. p. 71-119). Thus, phagocytosis and metabo 0296. A coating solution was prepared by first adding lism of small PCL fragments will not begin until the final 25.0 parts pEVA and 25.0 parts pEBMA to an aliquot of phase of the degradation process. Further, PCL has shown CHCl, solvent. In order to dissolve the pEVA, the compo excellent biocompatibility during the one-month follow up nents were heated to 30° to 40°C. for approximately 1 hour. period. After the pEVA and pBMA had dissolved in the CHCl, the resulting polymer/solvent Solution was allowed to cool to 0293. The PCL/TA drug delivery system showed less room temperature. Then, 50 parts of RAP was added to the disruption to the RPE layer and less tissue layer thinning in polymer/solvent solution and the RAP was stirred into the polymer/solvent solution at room temperature for approxi the adjacent regions of the implant than the PCL only mately 30 minutes to form a coating solution. The resulting filament, as shown in FIGS. 28 and 29. However, it is coating solution was filtered using a 10 um polypropylene difficult to conclude whether this could be attributed to the filter (Gelman Sciences pall membrane Part No. 61756). The anti-inflammatory effect of the steroid or was simply due to final coating solution contained about 40 mg/ml of Solids variability in Surgical procedure and positioning. The region (i.e., pEVA, pBMA, and RAP). of retinal cell layers disruption where the implant resides extends for approximately 300 um in width and 2000 um in Coating Procedure: length. It has been found that the nerve fiber layer remains 0297 NIT wire was cut into lengths of approximately 1 intact over the implant, but is disrupted at the site of the cm each using a Scissors. The wire lengths were cleaned with retinotomy. Thus, only a very focal region of vision loss is a wipe (Alpha Wipe from Tex Wipe) that had been damp expected and one that is certainly less invasive than laser ened with isopropyl alcohol. Each wire length was then photocoagulation therapy. weighed to +/-0.003 ug using a microbalance (Type UMX2, from Metler-Toledo). 0294 HPLC confirmed the presence of TA four weeks 0298 The coating solution was sprayed onto the NIT after the implant in the posterior tissue samples (FIG. 31). wire using ultrasonic coater equipment that consisted of an TA was not detected in the anterior structures or the blood. ultrasonic spray head (Sono-Tek, Milton, N.Y.) and syringe HPLC peaks for TA are marked on the graphs shown in FIG. pump system for the coating Solution. A cylindrical pin Vise 31. The additional peaks present indicate the internal stan was used to hold the end of the NIT wire. The NIT wire was dard prednisolone. held perpendicular to the spray head at the focal point of the spray (i.e., about 2-3 mm from the spray head) and was 0295 Based upon this initial investigation, it has been rotated at about 200 rpm. The spray head was moved demonstrated that PCL has at least a one month elution longitudinally over the NIT wire to apply the coating com capability with TA. Drug levels in the tissue were shown to position. A grid-like pattern as shown in FIGS. 11-12 was be localized to the posterior eye segment. Histology showed used for the coating with 0.1 mm longitudinal movements no indication of inflammatory response from the presence of 144. The coating was dried by evaporation of the solvent at PCL. Minor mechanical damage from the insert was room temperature (approximately 20° C. to 22°C.) over observed and is believed to be the leading cause of changes night. The resulting coating was about 3.0 mm in total in the cellular layers and structures PCL encapsulation was length, comprising a center portion of about 2.0 mm in also evident and is expected for implanted materials. length having a uniform thickness of about 300 um, and two US 2006/01 10428 A1 May 25, 2006
segments of about 0.5 mm in length with transitional thick tamicin (0.2 mL of 40 mg/mL Solution, American Pharma ness on each side of the center portion. After drying, the ceutical Partners, Schaumberg, Ill.) was performed. coated NIT wire was weighed to +/-0.003 ug using a microbalance (Type UMX2, from Metler-Toledo). The Monitoring and Evaluation: implant coating weight was calculated by Subtracting the 0305 Indirect ophthalmoscopic examination, fundus weight of the uncoated wire from the final weight of the photography, fluorescein angiography, and optical coher coated wire. The total amount of RAP in each implant was ence tomography were performed on the right eye of each calculated by multiplying the coating weight by 0.50, which rabbit at 1, 2, and 4 weeks post-operatively. After the week represents the weight percent of RAP in the coating. The 4 studies were completed, the rabbits were euthanized with total amount of RAP in the polymer coating of the filament an intracardiac injection of sodium pentobarbital (Anpro ranged from 26 to 89 ug (see, Table 2). Pharmaceuticals, Arcadia, Calif.). The right eye of each 0299 Prior to implanting in rabbits, the implants were rabbit was enucleated and placed in 4% paraformaldehyde for 24 hours. The eyes were then transferred to Dulbecco's trimmed to a length of between about 2.3 to 3.04 mm (see, phosphate buffered saline for storage at 4°C. until further Table 2). dissection, at which time they were sectioned down to a 2 Implantation: cmx2 cm block of the retina-choroid-sclera complex at the 0300 Experimental protocols were approved by the Insti posterior pole. This was embedded in paraffin, sectioned, tutional Animal Care and Use Committee of the University and stained with hematoxylin and eosin using standard of Southern California. Experiments were conducted in techniques. accordance with the ARVO Statement for the Use of Ani Implantation Results: mals in Ophthalmic and Visual Research. 0306 Filaments were implanted into the subretinal space 0301 Six Dutch pigmented rabbits were given general in three rabbits and into the sub-RPE space in one rabbit. anesthesia by an intramuscular injection of 1-1.5 mL of a 4:1 (see, Table 2) In four eyes (RS1-RS4), no bleb of subretinal mixture of ketamine hydrochloride (100 mg/mL.; Fort Dodge fluid was raised prior to implantation of the filament. In Labs. Fort Dodge, Iowa) and xylazine hydrochloride (100 these cases, there was one Subretinal implantation (RS1), mg/mL, Miles, Inc., Shawnee Mission, Kans.). one sub-RPE implantation (RS3), and two unsuccessful 0302) In all rabbits, surgery was performed on the right attempts at implantation. In two cases (RS5 and RS6), a bleb eye only. Pupillary dilation was achieved with topical 1% of subretinal fluid was raised before filament placement. In tropicamide and 2.5% phenylephrine. After limited conjunc both of these instances, the filament was inserted into the tival peritomy in the Superior quadrant, stab incisions were subretinal space without difficulty. made approximately 1 mm posterior to the limbus using a 0307 The presence or absence of the vitreous body over 20-gauge microvitreoretinal blade. In three rabbits (RS1, the area of implantation was found to be a factor determining RS3 and RS4) no vitrectomy was performed. A vitreoretinal the ease of the procedure. In one of the cases in which no microforceps was used to grasp the end of a filament, and it vitrectomy was performed (RS1), the surgeon was able to was introduced into the posterior chamber through the insert the filament into the subretinal space, and the filament sclerotomy. The tip of the filament was used to puncture the remained in place upon removal of the forceps. However, retina several millimeters inferior to the disc and the vas two rabbits (RS2 and RS4), both of which did not undergo cular arcades. The forceps were then used to slide the vitrectomy prior to filament implantation, were sacrificed at filament into the Subretinal space through this retinotomy. the time of surgery because of the creation of multiple 0303) In three rabbits (RS3, RS5, and RS6), a vitrectomy retinotomies during attempted implantation. In these two was performed prior to filament insertion. In these eyes, one cases, the vitreous body prevented Successful implantation Sclerotomy was created Superiorly and another Superona by adhering to the filament and causing it to egress from the Sally. An infusion cannula was inserted through the Supero Subretinal space when the implantation forceps were with nasal Sclerotomy and Sutured into place. A vitreous cutter drawn. By contrast, when a vitrectomy had been performed (Bausch and Lomb Surgical, St. Louis, Mo.) was introduced prior to implantation (RS3, RS5, and RS6), it was possible through the Superior Sclerotomy. After completion of a core to release the filament and withdraw the forceps without vitrectomy, the vitrector was removed from the eye. In two disturbing the position of the device. of the rabbits having a vitrectomy (RS5 and RS6), a Tolerance of Filament Implants in the Rabbit Eye: 25-gauge needle was used to puncture the retina several millimeters inferior to the disc and the vascular arcades and 0308 All scheduled follow-up exams were completed raise a small subretinal bleb by injecting approximately 0.1 over a one-month time period for three of the four rabbits mL of balanced salt solution into the subretinal space. With that received implants (RS1, RS3, and RS5). In one rabbit the microforceps, the filament was then inserted through the (RS6), posterior synechiae developed between weeks 1 and retinotomy into the Subretinal space in this location. In one 2, so adequate pupillary dilation could not be achieved on of the rabbits (RS3) no subretinal bleb was raised; rather, the the follow-up exams at weeks 2 and 4. Consequently, filament was inserted directly beneath the retina after vit fluorescein angiography (FA) and optical coherence tomog rectomy in the manner described above. raphy (OCT) studies could not be performed at these visits. No retinal detachment occurred in any of the four eyes that 0304. In all rabbits, after the filament had been inserted, received implants. the instruments were removed from the eye, and the scle rotomies were closed with 7-0 Vicryl sutures (Johnson and 0309. In three rabbits (RS1, RS3, and RS5), no signs of Johnson, Piscataway, N.J.). The conjunctiva was left to close inflammation or toxicity were detected on follow-up exami by secondary intention. Subconjunctival injection of gen nation. In addition, the filaments did not migrate from their US 2006/01 10428 A1 May 25, 2006 39 initial implantation sites. In RS1, in which no bleb of by one skilled in the art without departing from the true subretinal fluid was raised prior to device insertion, at week scope and spirit of the invention which is indicated by the 1 small amounts of residual subretinal hemorrhage from the following claims. All patents, patent documents, and publi procedure were still present adjacent to the filament, causing cations cited herein are hereby incorporated by reference as blockage on fluorescein angiography (FIG. 32). This if individually incorporated. resolved with time, so that less blockage from subretinal hemorrhage was noted at week 2 (FIG. 33) and none by What is claimed is: week 4 (FIG. 34). The angiogram otherwise showed only 1. A method for instilling one or more bioactive agents blockage by the device. OCT also confirmed the subretinal into ocular tissue within an eye of a patient for the treatment location of the device (FIG. 34). There was no evidence of atrophy or damage to adjacent retina or RPE. In RS5, in of an ocular condition, the method comprising concurrently which a bleb of subretinal fluid was raised to assist with using at least two of the bioactive agent delivery methods correct subretinal device placement, there was no subretinal (A)-(C): hemorrhage noted at any time point. Fluorescein angiogra (A) implanting a Sustained release delivery device com phy showed a linear hypofluorescent spot inferior to the prising one or more bioactive agents in a posterior device that was the site of instrument touch during Surgery. region of the eye so that it delivers the one or more In addition, mild hypopigmentation could be seen around bioactive agents into a vitreous humor; the device, corresponding to the area in which the Subretinal bleb had been raised. This circular area appeared mildly (B) instilling one or more bioactive agents Subretinally: hyperfluorescent on angiography (FIG. 35). There was no and indication of other damage to adjacent tissue by the implant. (C) instilling one or more bioactive agents into the 0310. In RS6, exams at weeks 1 and 2 showed that the vitreous humor. filament remained stable at the site of implantation, and the 2. The method of claim 1, wherein method (A) is used adjacent tissue appeared normal. Mild anterior chamber concurrently with method (B). inflammation and posterior Synechiae developed by week 2. 3. The method of claim 2, wherein the one or more so pupillary dilation was impaired, making photography bioactive agents delivered by the sustained release delivery difficult. Indirect ophthalmoscopy showed no evidence of device of method (A) are the same as the one or more posterior chamber inflammation. bioactive agents instilled subretinally in method (B). 4. The method of claim 2, wherein the one or more 0311. In RS3, in which the device was implanted beneath bioactive agents delivered by the sustained release delivery the RPE, the filament also remained in a stable position and device of method (A) are different than the one or more did not cause any visible abnormalities of adjacent areas. bioactive agents instilled subretinally in method (B). The implant could not be directly visualized on examination, 5. The method of claim 1, wherein method (A) is used but angiography showed blockage by it, and OCT appeared concurrently with method (C) to corroborate its location (FIG. 36). 6. The method of claim 5, wherein the one or more Histology Results: bioactive agents delivered by the sustained release delivery device of method (A) are the same as the one or more 0312. In eyes in which the filament was implanted sub bioactive agents instilled into the vitreous humor of the eye retinally, sections of the posterior pole at the implantation in method (C). site showed loss of photoreceptors overlying the device. 7. The method of claim 5, wherein the one or more Adjacent structures appeared normal. A histology photo of bioactive agents delivered by the sustained release delivery RS1 is shown in FIG. 37. device of method (A) are different than the one or more bioactive agents instilled into the vitreous humor of the eye TABLE 2 in method (C). Filament Characteristics and Implantation Results 8. The method of claim 1, wherein method (B) is used concurrently with method (C). Filament Total Rabbit Length RAP Content 9. The method of claim 8, wherein the one or more No. Vitrectomy Bleb (mm) (ug) Outcome bioactive agents instilled subretinally in method (B) are the same as the one or more bioactive agents instilled into the RS1 No No 2.3 28 Subretinal Implantation vitreous humor of the eye in method (C). RS2 No No 3.04 61.5 Sacrificed 10. The method of claim 8, wherein the one or more RS3 Yes No 2.54 88.5 Sub-RPE bioactive agents instilled subretinally in method (B) are Implantation different than the one or more bioactive agents instilled into RS4 No No 2.88. 28 Sacrificed RSS Yes Yes 2.7 26 Subretinal the vitreous humor of the eye in method (C). Implantation 11. The method of claim 1, wherein method (A) is used RS6 Yes Yes 2.46 89 Subretinal concurrently with both method (B) and method (C). Implantation 12. The method of claim 1, wherein method (B) comprises injecting or implanting one or more bioactive agents Sub retinally. 0313 Other embodiments of this invention will be appar 13. The method of claim 1, wherein method (B) com ent to those skilled in the art upon consideration of this prises: specification or from practice of the invention disclosed herein. Various omissions, modifications, and changes to the (a) forming a localized retinal detachment to define a principles and embodiments described herein may be made Subretinal space; and US 2006/01 10428 A1 May 25, 2006 40
(b) instilling one or more bioactive agents in the Subreti 29. The method of claim 14, wherein the sustained release nal space formed by localized retinal detachment. delivery device has a bioactive agent elution rate of at least 14. The method of claim 12 wherein the one or more 0.0001 ug per day. bioactive agents are provided in a Sustained release delivery 30. The method of claim 1, wherein the one or more device that is configured for implantation in the subretinal bioactive agents are selected from antiproliferative agents, Space. anti-inflammatory agents, anti-angiogenic agents, antibiot 15. The method of claim 14, wherein the sustained release ics, neurotrophic factors, or combinations thereof. delivery device is tapered at a proximal end, a distal end, or 31. The method of claim 1, wherein the sustained release both the proximal and distal ends. delivery device of (A) comprises: 16. The method of claim 14, wherein the sustained release delivery device is a solid in the form of a capsule, pellet, rod, a nonlinear body member having a direction of extension, sheet, or film. a longitudinal axis along the direction of extension, and 17. The method of claim 14, wherein the sustained release a proximal end and a distal end, delivery device is in the form of a flexible rod, thin film, wherein at least a portion of the body member deviates foldable disc, biodegradable polymer with the bioactive from the direction of extension, agent embedded within, bioactive agent-eluting polymer and wherein the body member includes the one or more coating over a rigid scaffold, compressed pellet of one or bioactive agents, and a polymer matrix. more bioactive agents, or one or more bioactive agents 32. The method of claim 31, wherein the body member is encapsulated in a semi-permeable membrane. coil-shaped. 18. The method of claim 14, wherein the sustained release 33. The method of claim 31, wherein a cap is positioned delivery device is in the form of a biocompatible polymer at the proximal end of the body member. capsule comprising (a) a core comprising one or more 34. The method of claim 31, wherein the body member bioactive agents; and (b) a jacket Surrounding the core includes a lumen. comprising a membrane that is biocompatible and that 35. The method of claim 31, wherein the device is permits diffusion of the one or more bioactive agents. removable from the eye. 19. The method of claim 14, wherein the sustained release 36. The method of claim 31, wherein the polymer matrix delivery device comprises a core having an outer Surface; comprises a first polymer and a second polymer wherein the and a coating layer of a polymer matrix and a least one first polymer is a poly(alkyl(meth)acrylate) or a poly(aro bioactive agent applied over at least a portion of the outer matic(meth)acrylate) and wherein the second polymer is surface of the core. poly(ethylene-co-vinyl acetate). 20. The method of claim 19, wherein the coating layer is 37. The method of claim 36, wherein the first polymer provided on a portion of the outer surface of the core. comprises a poly(aromatic (meth)acrylate) selected from the 21. The method of claim 19, wherein the coating layer is group consisting of poly(aryl (meth)acrylate), poly(aralky provided on an intermediate portion of the core. l(meth)acrylate), poly(alkaryl(meth)acrylate), poly(aryloxy 22. The method of claim 19, wherein the coating includes alkyl (meth)acrylate), and poly (alkoxyaryl(meth)acrylate). proximal a transition segment, a distal transition segment, or 38. The method of claim 36, wherein the first polymer both a proximal and a distal transition segment. comprises a poly(alkyl(meth)acrylate) selected from the 23. The medical device according to claim 19, wherein the group consisting of poly (n-butyl methacrylate), poly(n- core is selected from titanium alloys, nickel-cobalt base butyl methacrylate-co-methyl methacrylate), poly(n-butyl alloys, stainless steel, cobalt-chromium alloys, and biode methacrylate-co-isobutyl methacrylate), and poly(t-butyl gradable magnesium alloys. methacrylate). 24. The method of claim 19, wherein the polymer matrix 39. The method of claim 36, wherein the first polymer is comprises a first polymer and a second polymer wherein the poly(butylmethacrylate) and the second polymer is poly(eth first polymer is a poly(alkyl(meth)acrylates) or a poly(aro ylene-co-vinyl acetate). matic(meth)acrylates) and wherein the second polymer is 40. The method of claim 1, wherein method (C) comprises poly(ethylene-co-vinyl acetate). injecting on or more bioactive agents into the vitreous 25. The method of claim 24, wherein the first polymer humor. comprises a poly(aromatic (meth)acrylates) selected from 41. The method of claim 1, wherein method (C) comprises the group consisting of poly(aryl (meth)acrylates), pol delivering on or more bioactive agents into the vitreous y(aralkyl(meth)acrylates), poly(alkaryl(meth)acrylates), humor using iontophoresis. poly(aryloxyalkyl (meth)acrylates), and poly (alkoxyaryl 42. The method of claim 41, wherein the iontophoresis is (meth)acrylates). transscleral iontophoresis. 26. The method of claim 24, wherein the first polymer 43. The method of claim 1, wherein the one or more comprises a poly(alkyl(meth)acrylates) selected from the bioactive agents are selected from antiproliferative agents, group consisting of poly (n-butyl methacrylate), poly(n- anti-inflammatory agents, inhibitors of angiogenesis, anti butyl methacrylate-co-methyl methacrylate), poly(n-butyl biotics, hormonal agents, neurotropic factors, or combina methacrylate-co-isobutyl methacrylate), and poly(t-butyl tions thereof. methacrylate). 44. The method of claim 43, wherein the antiproliferative 27. The method of claim 24, wherein the first polymer is agents are selected from taxol. Sirolimus (rapamycin), ana poly(butylmethacrylate) and the second polymer is poly(eth logues of rapamycin, tacrolimus, ABT-578, everolimus, ylene-co-vinyl acetate). paclitaxel, taxane, and vinorelbine. 28. The method of claim 14, wherein the sustained release 45. The method of claim 43, wherein the anti-inflamma delivery device has a total diameter of no greater than about tory agents are selected from hydrocortisone, hydrocortisone 1000 um and a length of no greater than about 6 mm. acetate, dexamethasone 21-phosphate, fluocinolone, US 2006/01 10428 A1 May 25, 2006
medrysone, methylprednisolone, prednisolone 21-phos 48. A method for instilling one or more bioactive agents phate, prednisolone acetate, fluoromethalone, betametha into ocular tissue within an eye of a patient for the treatment Sone, triamcinolone, and triamcinolone acetonide. of an ocular condition, the method comprising: (A) implant 46. The method of claim 43, wherein the inhibitors of ing a Sustained release delivery device comprising one or angiogensis are selected from angiostatin, anecortave acetate, thrombospondin, anti-VEGF antibody, and anti more bioactive agents in a posterior region of the eye so that VEGF fragment. it delivers the one or more bioactive agents into a vitreous 47. The method of claim 43, wherein the hormonal agent humor; and (B) instilling one or more bioactive agents is selected from estrogen, estradiol, progesterol, progester subretinally. one, insulin, calcitonin, parathyroid hormone, peptide, and vasopressin hypothalamus releasing factor.