Abstract:
An ophthalmic drug delivery device having a first end and a second end, an injection port, a reservoir, and a sleeve is disclosed. The injection port is for sealingly engaging a needle of a syringe, which is for providing a fluid comprising a pharmaceutically active agent. The reservoir is disposed within the device, is fluidly coupled to the injection port, and has an opening for communicating the fluid to an outer surface of a sclera of an eye. The sleeve is for engaging the device proximate overlapping portions of the first end and the second end for forming a generally ring-shaped three-dimensional geometry upon implantation of the device on the outer surface of the sclera. The device is useful for the treatment of a disease of the posterior segment of the eye.

Description:
This application is a continuation of PCT/US02/23048 filed Jul. 22, 2002 entitled “Ophthalmic Drug Delivery Device,” which claims priority from U.S. Provisional Application No. 60/307,284 filed Jul. 23, 2001. This application is related to U.S. Pat. Nos. 6,413,540 and 6,416,777, both of which are incorporated herein in their entirety by this reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention generally pertains to biocompatible implants for delivery of pharmaceutically active agents to the eye. More particularly, but not by way of limitation, the present invention pertains to biocompatible implants for delivery of pharmaceutically active agents to the posterior segment of the eye. 
     DESCRIPTION OF THE RELATED ART 
     Several diseases and conditions of the posterior segment of the eye threaten vision. Age related macular degeneration (ARMD), choroidal neovascularization (CNV), retinopathies (e.g., diabetic retinopathy, vitreoretinopathy), retinitis (e.g., cytomegalovirus (CMV) retinitis), uveitis, macular edema, glaucoma, and neuropathies are several examples. 
     Age related macular degeneration (ARMD) is the leading cause of blindness in the elderly. ARMD attacks the center of vision and blurs it, making reading, driving, and other detailed tasks difficult or impossible. About 200,000 new cases of ARMD occur each year in the United States alone. Current estimates reveal that approximately forty percent of the population over age 75, and approximately twenty percent of the population over age 60, suffer from some degree of macular degeneration. “Wet” ARMD is the type of ARMD that most often causes blindness. In wet ARMD, newly formed choroidal blood vessels (choroidal neovascularization (CNV)) leak fluid and cause progressive damage to the retina. 
     In the particular case of CNV in ARMD, three main methods of treatment are currently being developed, (a) photocoagulation, (b) the use of angiogenesis inhibitors, and (c) photodynamic therapy. Photocoagulation is the most common treatment modality for CNV. However, photocoagulation can be harmful to the retina and is impractical when the CNV is near the fovea. Furthermore, over time, photocoagulation often results in recurrent CNV. Oral or parenteral (non-ocular) administration of anti-angiogenic compounds is also being tested as a systemic treatment for ARMD. However, due to drug-specific metabolic restrictions, systemic administration usually provides sub-therapeutic drug levels to the eye. Therefore, to achieve effective intraocular drug concentrations, either an unacceptably high dose or repetitive conventional doses are required. Periocular injections of these compounds often result in the drug being quickly washed out and depleted from the eye, via periocular vasculature and soft tissue, into the general circulation. Repetitive sub-Tenon&#39;s capsule injections of these compounds carry the potential risk of penetrating the globe and the severe, often blinding, complications of retinal detachment and endophthalmitis. In addition, it is difficult to perform such injections in a reproduceable manner, and each injection may result in a different distribution of drug along the scleral surface. Furthermore, many attempts to inject drug below the Tenon&#39;s capsule actually result in injections into the Tenon&#39;s capsule itself or the surrounding tissue, which is not desirable. Repetitive intraocular injections may also result in retinal detachment and endophthalmitis. Photodynamic therapy is a new technology for which the long-term efficacy is still largely unknown. 
     In order to prevent complications related to the above-described treatments and to provide better ocular treatment, researchers have suggested various implants aimed at delivery of anti-angiogenic compounds to the eye. U.S. Pat. No. 5,824,072 to Wong discloses a non-biodegradable polymeric implant with a pharmaceutically active agent disposed therein. The pharmaceutically active agent diffuses through the polymer body of the implant into the target tissue. The pharmaceutically active agent may include drugs for the treatment of macular degeneration and diabetic retinopathy. The implant is placed substantially within the tear fluid upon the outer surface of the eye over an avascular region, and may be anchored in the conjunctiva or sclera; episclerally or intrasclerally over an avascular region; substantially within the suprachoroidial space over an avascular region such as the pars plana or a surgically induced avascular region; or in direct communication with the vitreous. 
     U.S. Pat. No. 5,476,511 to Gwon et al. discloses a polymer implant for placement under the conjunctiva of the eye. The implant may be used to deliver neovascular inhibitors for the treatment of ARMD and drugs for the treatment of retinopathies, and retinitis. The pharmaceutically active agent diffuses through the polymer body of the implant. 
     U.S. Pat. No. 5,773,019 to Ashton et al. discloses a non-bioerodable polymer implant for delivery of certain drugs including angiostatic steroids and drugs such as cyclosporine for the treatment of uveitis. Once again, the pharmaceutically active agent diffuses through the polymer body of the implant. 
     All of the above-described implants require careful design and manufacture to permit controlled diffusion of the pharmaceutically active agent through a polymer body or polymer membrane to the desired site of therapy. Drug release from these devices depends on the porosity and diffusion characteristics of the matrix or membrane, respectively. These parameters must be tailored for each drug moiety to be used with these devices. Consequently, these requirements generally increase the complexity and cost of such implants. 
     U.S. Pat. No. 5,824,073 to Peyman discloses an indentor for positioning in the eye. The indentor has a raised portion that is used to indent or apply pressure to the sclera over the macular area of the eye. This patent discloses that such pressure decreases choroidal congestion and blood flow through the subretinal neovascular membrane, which, in turn, decreases bleeding and subretinal fluid accumulation. 
     U.S. Pat. Nos. 5,725,493 and 5,830,173 both disclose non-bioerodable implants that have a drug containing reservoir located outside the globe of the eye and a drug delivery tube running from the reservoir and into the vitreous cavity at the pars plana. 
     Despite the above-described ophthalmic implants, a need still exists for a surgically implantable ophthalmic drug delivery device capable of safe, effective, rate-controlled, delivery of a wide variety of pharmaceutically active agents. The surgical procedure for implanting such a device should be safe, simple, quick, and capable of being performed in an outpatient setting. Ideally, such a device should be easy and economical to manufacture. Furthermore, because of its versatility and capability to deliver a wide variety of pharmaceutically active agents, such an implant should be capable of use in ophthalmic clinical studies to deliver various agents that create a specific physical condition in a patient. Ideally, such an ophthalmic drug delivery device would be capable of localized delivery of pharmaceutically active agents to a specific portion of the retina, as well as pan-retinal delivery of pharmaceutically active agents. 
     SUMMARY OF THE INVENTION 
     One aspect of the present invention is an ophthalmic drug delivery device having a first end and a second end, an injection port, a reservoir, and a sleeve. The injection port is for sealingly engaging a needle of a syringe, which is for providing a fluid comprising a pharmaceutically active agent. The reservoir is disposed within the device, is fluidly coupled to the injection port, and has an opening for communicating the fluid to an outer surface of a sclera of an eye. The sleeve is for engaging the device proximate overlapping portions of the first end and the second end for forming a generally ring-shaped three-dimensional geometry upon implantation of the device on the outer surface of the sclera. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       For a more complete understanding of the present invention, and for further objects and advantages thereof, reference is made to the following description taken in conjunction with the accompanying drawings in which: 
         FIG. 1  is a side sectional view schematically illustrating the human eye; 
         FIG. 2  is a partially dissected, three dimensional schematic representation of the human eye; 
         FIG. 3  is a perspective view of an ophthalmic drug delivery device according to a preferred embodiment of the present invention; and 
         FIG. 4  is a perspective view of the ophthalmic drug delivery device of  FIG. 3  showing a preferred method of operation. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The preferred embodiments of the present invention and their advantages are best understood by referring to  FIGS. 1–4  of the drawings, like numerals being used for like and corresponding parts of the various drawings. 
       FIGS. 1–4  schematically illustrate an ophthalmic drug delivery device  10  according to a preferred embodiment of the present invention. Device  10  may be used in any case where delivery of a pharmaceutically active agent to the eye is required. Device  10  is particularly useful for delivery of active agents to the posterior segment of the eye. A preferred use for device  10  is the delivery of pharmaceutically active agents to the retina for treating ARMD, choroidial neovascularization (CNV), retinopathies, retinitis, uveitis, macular edema, and glaucoma. 
     Referring to  FIGS. 1–2 , a human eye  52  is schematically illustrated. Eye  52  has a cornea  54 , a lens  56 , a sclera  58 , a choroid  60 , a retina  62 , and an optic nerve  64 . An anterior segment  66  of eye  52  generally includes the portions of eye  52  anterior of a line  67 . A posterior segment  68  of eye  52  generally includes the portions of eye  52  posterior of line  67 . Retina  62  is physically attached to choroid  60  in a circumferential manner proximate pars plana  70 . Retina  62  has a macula  72  located slightly lateral to its optic disk  19 . As is well known in the ophthalmic art, macula  72  is comprised primarily of retinal cones and is the region of maximum visual acuity in retina  62 . A Tenon&#39;s capsule or Tenon&#39;s membrane  74  is disposed on sclera  58 . A conjunctiva  76  covers a short area of the globe of eye  52  posterior to limbus  77  (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of upper eyelid  78  and lower eyelid  79 , respectively. Conjunctiva  76  is disposed on top of Tenon&#39;s capsule  74 . Eye  52  also has an equator  21 . As shown in  FIG. 2 , superior rectus muscle  80 , inferior rectus muscle  82 , lateral rectus muscle,  84 , and medial rectus muscle  86  are attached to sclera  58 . 
     As is shown in  FIGS. 1 and 2 , and as is described in greater detail hereinbelow, device  10  is preferably disposed directly on the outer surface of sclera  58 , below Tenon&#39;s capsule  74  for treatment of most posterior segment diseases or conditions. Device  10  is most preferably disposed directly on the outer surface of sclera  58 , below Tenon&#39;s capsule  74 , proximate equator  21 . 
       FIGS. 3 and 4  schematically illustrate device  10  in greater detail. Device  10  preferably includes a body  12  having a generally ring-shaped three-dimensional geometry in its assembled state shown in  FIGS. 3 and 4 . In its unassembled stated, body  12  preferably has a generally rectangular three-dimensional geometry. A sleeve  26  encircles overlapping ends  28  and  30  of body  12  to maintain the ring-shaped three-dimensional geometry. 
     Body  12  has a scleral surface  14 , an orbital surface  16 , an anterior side  18 , and a posterior side  20 . Body  12  also has a reservoir  22  located in its interior. Reservoir  22  preferably runs the entire length of body  80 , and preferably has a plurality of openings  25  to posterior side  20 . Although not shown in  FIGS. 3–4 , reservoir  22  may also have one or more openings to scleral surface  14 , anterior side  18 , or orbital surface  16  of body  12 . As shown in  FIGS. 3–4 , openings  25  have a generally rectangular cross-section, but any cross-section can be used for these openings. 
     Body  12  preferably further has an injection port  24 . At least a portion of injection port  24  is preferably made of a fluid impervious material that can be penetrated by a needle and that reseals itself upon removal of the needle. A preferred material is silicone rubber. In addition, injection port  24  is preferably colored or marked by raised protuberances. Injection port  24  preferably extends from anterior side  18  of body  12 . Reservoir  22  extends into injection port  24 . 
     The remainder of body  12  preferably comprises a biocompatible, non-bioerodable material. Body  12  more preferably comprises a biocompatible, non-bioerodable polymeric composition. Said polymeric composition may be a homopolymer, a copolymer, straight, branched, cross-linked, or a blend. Examples of polymers suitable for use in said polymeric composition include silicone, polyvinyl alcohol, ethylene vinyl acetate, polylactic acid, nylon, polypropylene, polycarbonate, cellulose, cellulose acetate, polyglycolic acid, polylactic-glycolic acid, cellulose esters, polyethersulfone, acrylics, their derivatives, and combinations thereof. Examples of suitable soft acrylics are more fully disclosed in U.S. Pat. No. 5,403,901, which is incorporated herein in its entirety by reference. Said polymeric composition most preferably comprises silicone. Of course, said polymeric composition may also comprise other conventional materials that affect its physical properties, including, but not limited to, porosity, tortuosity, permeability, rigidity, hardness, and smoothness. Exemplary materials affecting certain ones of these physical properties include conventional plasticizers, fillers, and lubricants. Said polymeric composition may comprise other conventional materials that affect its chemical properties, including, but not limited to, toxicity and hydrophobicity. 
     As shown in  FIG. 4 , a conventional syringe  100  and needle  102  may be used to impart a fluid  104  (indicated by arrows) containing a pharmaceutically active agent or agents into reservoir  22  via injection port  24 . Fluid  104  may comprise a solution, a suspension, an emulsion, an ointment, a gel forming solution, a gel, a bioerodable polymer, a non-bioerodable polymer, microparticles, or combinations thereof. Most preferably, fluid  104  is a suspension with or without microparticles formed from bioerodable polymers. Fluid  104  includes one or more ophthalmically acceptable pharmaceutically active agents, and may also include conventional non-active incipients. Examples of pharmaceutically active agents suitable for fluid  104  are anti-infectives, including, without limitation, antibiotics, antivirals, and antifungals; antiallergenic agents and mast cell stabilizers; steroidal and non-steroidal anti-inflammatory agents; cyclooxygenase inhibitors, including, without limitation, Cox I and Cox II inhibitors; combinations of anti-infective and anti-inflammatory agents; decongestants; anti-glaucoma agents, including, without limitation, adrenergics, β-adrenergic blocking agents, α-adrenergic agonists, parasypathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and prostaglandins; combinations of anti-glaucoma agents; antioxidants; nutritional supplements; drugs for the treatment of cystoid macular edema including, without limitation, non-steroidal anti-inflammatory agents; drugs for the treatment of ARMD, including, without limitation, angiogenesis inhibitors and nutritional supplements; drugs for the treatment of herpetic infections and CMV ocular infections; drugs for the treatment of proliferative vitreoretinopathy including, without limitation, antimetabolites and fibrinolytics; wound modulating agents, including, without limitation, growth factors; antimetabolites; neuroprotective drugs, including, without limitation, eliprodil; and angiostatic steroids for the treatment of diseases or conditions of posterior segment  26 , including, without limitation, ARMD, CNV, retinopathies, retinitis, uveitis, macular edema, and glaucoma. Such angiostatic steroids are more fully disclosed in U.S. Pat. Nos. 5,679,666 and 5,770,592. Preferred ones of such angiostatic steroids include 4,9(11)-Pregnadien-17α,21-diol-3,20-dione and 4,9(11)-Pregnadien-17α,21-diol-3,20-dione-21-acetate. These preferred angiostatic steroids are preferably formulated as a suspension. A preferred non-steroidal anti-inflammatory for the treatment of cystoid macular edema is nepafenac. The conventional non-active excipients may include, but are not limited to, ingredients to enhance the stability, solubility, penetrability, or other properties of fluid  104 . In particular, hydrolytic enzymes such as proteases, esterases, hyaluronidases, and collegenases may be utilized to enhance the penetration of the pharmaceutically active agents through natural and newly formed connective tissue that may encapsulate device  10  after implantation. Body  12  is preferably impermeable to fluid  104 . 
     Device  10  may be made by conventional polymer processing methods, including, but not limited to, injection molding, extrusion molding, transfer molding, and compression molding. Preferably, device  10  is formed using conventional injection molding techniques. 
     Device  10  is preferably surgically placed directly on the outer surface of sclera  58  below Tenon&#39;s capsule  74  using a simple surgical technique that is capable of being performed in an outpatient setting. The surgeon first performs a 360 degree peritomy about 3 mm posterior to limbs  77  of eye  52 . The surgeon then performs a blunt dissection to separate Tenon&#39;s capsule  74  from sclera  58  up to a point slightly posterior of equator  21 . As shown best in  FIG. 2 , the surgeon then positions device  10  on the outer surface of sclera  58  below superior rectus muscle  80 , medial rectus muscle  86 , inferior rectus muscle  82 , and lateral rectus muscle  84  generally near equator  21 . Injection port  24  is preferably located in the infra-temporal quadrant of eye  52  between inferior rectus muscle  82  and lateral rectus muscle  84 . The surgeon tightens device  10  around sclera  58  and fixes overlapping ends  28  and  30  of body  12  with sleeve  26 . The surgeon then moves Tenon&#39;s capsule  74  back to its original position and sutures it in place. After closing, the surgeon places antibiotic ointment on the surgical wound. 
     Once device  10  is located in the desired position, the surgeon uses syringe  100  and needle  102  to inject fluid  104  into reservoir  22 . The surgeon preferably moves lower eyelid  79  downward and instructs the patient to look upward so as to expose injection port  24 . Injection port  24  may be easily visualized beneath the Tenon&#39;s capsule and any connective tissue encapsulating device  10  due to its color or raised protuberances. The surgeon sticks needle  102  into injection port  24 , injects fluid  104  into reservoir  22 , and removes needle  102  from the port  24 . Port  24  reseals automatically upon removal of the needle. Fluid  104  is disposed throughout reservoir  22 , and is in communication with sclera  58  via openings  25 , or any other openings from reservoir  22 . 
     It is believed that device  10  can be used to deliver a pharmaceutically effective amount of a pharmaceutically active agent through sclera  58  and choroid  60  into retina  62  for many years, depending on the particular physicochemical properties of the particular fluid  104  and its pharmaceutically active agent employed. Important physicochemical properties include hydrophobicity, solubility, dissolution rate, diffusion coefficient, and tissue affinity. In addition, it is believed that device  10  may be used to deliver both a localized distribution of drug primarily proximate macula  72 , or to deliver drug to substantially the entire retina, depending upon the particular fluid  104  and its pharmaceutically active agents and incipients. After reservoir  22  no longer contains any fluid  104 , a surgeon may refill reservoir  22  as described hereinabove. Although not shown in  FIGS. 1–4 , posterior side  20  of body  12  may also include a sharp surface or edge. During refilling of reservoir  22 , the surgeon may move device  10  slightly posteriorly so that such sharp surface or edge pierces any connective tissue that may encapsulate device  10  after implantation. Piercing this connective tissue facilitates proper distribution of fluid  104  via openings  25 . In addition, unlike repetitive sub-Tenon&#39;s capsule injections of drug formulations, device  10  minimizes the risk of penetrating the globe of the eye, always results in fluid  212  being distributed below the Tenon&#39;s capsule  74  on the outer surface of sclera  58 , and results in a reproduceable distribution of fluid  212  on a desired portion of the outer surface of the sclera  58 . 
     From the above, it may be appreciated that the present invention provides improved devices and methods for safe, effective, rate-controlled delivery of a variety of pharmaceutically active agents to the eye. The devices of the present invention are especially useful for localized and/or pan-retinal delivery of pharmaceutically active agents to the posterior segment of the eye to combat diseases such as ARMD, CNV, retinopathies, retinitis, uveitis, macular edema, and glaucoma. The surgical procedure for implanting the devices is safe, simple, quick, and capable of being performed in an outpatient setting. The devices are easy and economical to manufacture. Furthermore, because of their capability to deliver a wide variety of pharmaceutically active agents, such devices are useful in clinical studies to deliver various agents that create a specific physical condition in a patient or animal subject. 
     It is believed that the operation and construction of the present invention will be apparent from the foregoing description. While the apparatus and methods shown or described above have been characterized as being preferred, various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined in the following claims.