Source: https://patents.google.com/patent/EP1221919B1/en
Timestamp: 2019-06-17 17:13:09
Document Index: 446419836

Matched Legal Cases: ['art 15', 'art 18', 'art 15', 'art 18', 'art 15', 'art 18', 'art 18', 'art 18', 'art 18', 'art 18', 'art 18', 'art 18', 'art 15', 'art 17', 'art 18', 'art 17', 'art 18', 'art 17', 'art 17', 'art 18', 'art 18', 'art 15', 'art 18', 'art 15', 'art 18', 'art 15', 'art 18', 'art 15', 'art 18']

EP1221919B1 - Ophthalmic drug delivery device - Google Patents
EP1221919B1
EP1221919B1 EP20000972099 EP00972099A EP1221919B1 EP 1221919 B1 EP1221919 B1 EP 1221919B1 EP 20000972099 EP20000972099 EP 20000972099 EP 00972099 A EP00972099 A EP 00972099A EP 1221919 B1 EP1221919 B1 EP 1221919B1
EP20000972099
EP1221919A1 (en
2000-09-19 Priority to US664790 priority
2002-07-17 Publication of EP1221919A1 publication Critical patent/EP1221919A1/en
2005-02-23 Publication of EP1221919B1 publication Critical patent/EP1221919B1/en
In order to prevent complications related to the above-described treatments and to provide better ocular treatment, researchers have suggested various implants aimed at localizing delivery of anti-angiogenic compounds to the eye. U.S. Patent 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. Patent 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.
Document US-A-5 725 493 discloses a drug delivery device for a human eye comprising a body having a concave shaped surface for placement on the sclera of the eye and an inner reservoir containing a pharmaceutically active agent.
Therefore, a need exists in the biocompatible implant field for a surgically . implantable ophthalmic drug delivery device capable of safe. effective, rate-controlled, localized 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. Such an ophthalmic drug delivery device is especially needed for localized delivery of pharmaceutically active agents to the posterior segment of the eye to combat ARMD, CNV, retinopathies, retinitis, uveitis, macular edema, glaucoma, and neuropathies.
The present invention is directed to a drug delivery device for a human eye as detailed in claim 1. Preferred embodiments are provided in the dependent claims. The human eye has a sclera, an inferior oblique muscle, and a macula. The device of the present invention includes a pharmaceutically active agent, and a geometry that facilitates the implantation of the device on an outer surface of the sclera, beneath the inferior oblique muscle, and with the pharmaceutically active agent disposed above the macula. Because of its unique geometry, the device is especially useful for localized delivery of pharmaceutically active agents to the posterior segment of the eye to combat ARMD, CNV, retinopathies, retinitis, uveitis, macular edema, glaucoma, and neuropathies.
FIG. 3 illustrates a left human eye 90 within its orbit 112. As can be seen from FIG. 3, inferior oblique muscle 107 runs under lateral rectus muscle 105. The insertion line 107a of inferior oblique muscle 107 into sclera 100 is located just above the superior border of lateral rectus muscle 105. Of course, the position of the inferior oblique muscle in a right human eye 90 is a mirror image to its position on left human eye 90 of FIG. 3. Cornea 92, conjunctiva 94, superior rectus muscle 103, inferior rectus muscle 104, superior oblique muscle 106, and limbus 115 are also shown in FIG. 3.
FIG. 4 similarly shows a left human eye 90 within its orbit 112. However, a portion of lateral rectus muscle 105 is not shown in FIG. 4 to allow visibility of the portion of sclera 100 and optic nerve 96 usually hidden by the muscle. In FIG. 4, an insertion line 107b of inferior oblique muscle 107 into sclera 100 is lower than insertion line 107a of FIG. 3, indicating the representative physiological variability of the insertion line of the inferior oblique muscle in the human eye.
The posterior view of human eye 90 is schematically illustrated in FIG. 6. FIG. 6 shows the locations of the superior rectus muscle 103, the lateral rectus muscle 105, the inferior rectus muscle 104, the medial rectus muscle 108, the superior oblique muscle 106, the inferior oblique muscle 107 and its insertion line 107a, the optic nerve 96, the cilliary vessels 109, the sclera 100, the scleral area 110 above macula 98, the long cilliary arteries 111, and the vortex veins 114.
Device 50 generally includes a body 21 having a convex, dome-shaped, orbital surface 12 and a concave, dome-shaped, scleral surface 14. Scleral surface 14 is designed with a radius of curvature that facilitates direct contact with sclera 100. Most preferably, scleral surface 14 is designed with a radius of curvature equal to the radius of curvature 91 of an average human eye 90. (See FIG. 1) Orbital surface 12 is preferably designed with a radius of curvature that facilitates implantation under Tenon's capsule 101. When viewed from the top, body 21 preferably has a generally "F-shaped" geometry with a longitudinal part 15, a transversal part 18, and a knee 32 therebetween. Longitudinal part 15 and transversal part 18 are joined at knee 32 to form an angle of about ninety degrees. Longitudinal part 15 has a proximal end 25, a rounded edge 24, a stopper 36, and a notch 42. As is described in more detail hereinbelow, notch 42 is designed to accommodate the origin of inferior oblique muscle 107. Stopper 36 defines the lower portion of notch 42 and is preferably slightly elevated from the remainder of the generally convex orbital surface 12. As is described in greater detail hereinbelow, stopper 36 is designed to prevent excessive advancement of device 50 toward optic nerve 96 through contact on the anterior border of inferior oblique muscle 107. Transversal part 18 has a distal end 58, a rounded edge 28, and a well or cavity 20 having an opening 64 to scleral surface 14. Well 20 and opening 64 preferably have a generally oval shape. As is explained in more detail hereinbelow, transversal part 18 allows cavity 20 to be placed more directly over the area of sclera 100 overlying macula 98.
An inner core 81, which is shown in FIG. 10, is disposed in well 20. As shown in FIG. 10, inner core 81 is preferably a tablet comprising one or more pharmaceutically active agents. Tablet 81 preferably has a generally oval body 46 with a concave, dome-shaped, scleral surface 85 and a convex, dome-shaped, orbital surface 86. Body 46 also preferably has a peripheral bevel 87 disposed thereon. Alternatively, as shown in FIG. 11, the inner core may comprise mating, half-oval tablets 82a and 82b. Tablet 82a preferably has a body 47 identical to one half of body 46 of tablet 81. Tablet 82b preferably has a body 48 equal to the opposite half of body 46 of tablet 81. Still further in the alternative, inner core 81, or inner cores 82a and 82b, may comprise a conventional hydrogel, gel, paste, or other semi-solid dosage form having one or more pharmaceutically active agents disposed therein.
Although not shown in FIGS. 9 through 11, inner core 81 may alternatively comprise a suspension, solution, powder, or combination thereof containing one or more pharmaceutically active agents.
Body 21 preferably comprises a biocompatible, non-bioerodable material. Body 21 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. Patent No. 5,403,901. 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, hydrophobicity, and body 21 - inner core 81 interaction. Body 21 is preferably impermeable to the pharmaceutically active agent of inner core 81. When body 21 is made from a generally elastic polymeric composition, the shape of well 20 may be made slightly smaller than the shape of inner core 81. This frictional fit secures inner core 81 within well 20. In this embodiment, body 21 may be formed with or without retaining member 62, and inner core 81 may be formed with or without bevel 87, if desired.
Inner core 81 may comprise any ophthalmically acceptable pharmaceutically active agents suitable for localized delivery. Examples of pharmaceutically active agents suitable for inner core 81 are anti-infectives, including, without limitation, antibiotics, antivirals, and antifungals; antiallergenics 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; 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 the posterior segment of the eye, including, without limitation, ARMD, CNV, retinopathies, retinitis, uveitis, macular edema, and glaucoma. Such angiostatic steroids are more fully disclosed in U.S. Patent 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. A preferred non-steroidal anti-inflammatory for the treatment of cystoid macular edema is nepafenac. Inner core 81 may also comprise conventional non-active excipients to enhance the stability, solubility, penetrability, or other properties of the active agent or the drug core.
Device 50 may be made by conventional polymer processing methods, including, but not limited to, injection molding, extrusion molding, transfer molding, and compression molding. Preferably, device 50 is formed using conventional injection molding techniques. Inner core 81 is disposed in well 20 after the formation of body 21 of device 50. Retaining member 62 is preferably resilient enough to allow bevel 87 of inner core 81 to be inserted through opening 64 and then to return to its original position.
Device 50 is preferably surgically placed directly on the outer surface of sclera 100 below Tenon's capsule 101 with well 20 and inner core 81 directly over the area of sclera 100 above macula 98 using the following preferred technique that is capable of being performed in an outpatient setting. The surgeon first performs an 8 mm peritomy in one of the quadrants of eye 90. Preferably, the surgeon performs the peritomy in the infra-temporal quadrant, about 3 mm posterior to limbus 115 of eye 90. Once this incision is made, the surgeon performs a blunt dissection to separate Tenon's capsule 101 from sclera 100. Using scissors and blunt dissection, an antero-posterior tunnel is formed along the outer surface of sclera 100 and below inferior oblique muscle 107, preferably following the inferior border of lateral rectus muscle 105. The inferior oblique muscle 107 is then engaged with a Jamison muscle hook. The tip of the hook is then advanced just posterior to the inferior oblique muscle to form a portion of the tunnel that will accommodate transversal part 18 of device 50. Once the tunnel is formed, the surgeon uses Nuggett forceps to hold transversal part 18 of device 50 with scleral surface 14 facing sclera 100 and distal end 58 of transversal part 18 away from the surgeon. The surgeon then introduces device 50, distal end 58 first, into the tunnel at the level of the peritomy. Once in the tunnel, the surgeon advances device 50 along the tunnel toward inferior oblique muscle 107 until stopper 36 contacts the anterior border of muscle 107. At the level of the visualized inferior oblique muscle 107, the surgeon rotates device 50 underneath muscle 107 so that transversal portion 18 of device 50 enters the portion of the tunnel just posterior to inferior oblique muscle 107. When the surgeon feels that knee 32 cannot advance any further, the surgeon slightly moves device 50 in an antero-posterior direction to allow for the accommodation of inferior oblique muscle 107 within notch 42 between transversal part 18 and stopper 36. Due to the notch 42 and the location of well 20 near distal end 58 of transversal part 18, inner core 81 is positioned directly over the portion of sclera 100 above macula 98. Proximal end 25 of longitudinal part 15 may then be sutured to sclera 100. The surgeon then closes the peritomy by suturing Tenon's capsule 101 and conjunctiva 94 to sclera 100. After closing, the surgeon places a strip of antibiotic ointment on the surgical wound. All sutures are preferably 7-0 Vicryl sutures. For the treatment of ARMD and CNV, the pharmaceutically active agent of inner core 81 is preferably one of the angiostatic steroids disclosed in U.S. Patent Nos. 5,679,666 and 5,770,592.
It is believed that device 50 can be used to deliver a pharmaceutically effective amount of a pharmaceutically active agent to retina 97 for many years, depending on the particular physicochemical properties of the pharmaceutically active agent employed. Important physicochemical properties include hydrophobicity, solubility, dissolution rate, diffusion coefficient, partitioning coefficient, and tissue affinity. After inner core 20 no longer contains active agent, the surgeon may easily remove device 50. In addition, the "pre-formed" tunnel facilitates the replacement of an old device 50 with a new device 50.
Device 65 generally includes a body 29 having a convex, dome-shaped, orbital surface 12 and a concave, dome-shaped, scleral surface 14 (not shown). Scleral surface 14 is designed with a radius of curvature that facilitates direct contact with sclera 100. Most preferably, scleral surface 14 is designed with a radius of curvature equal to the radius of curvature 91 of an average human eye 90. Orbital surface 12 is preferably designed with a radius of curvature that facilitates implantation under Tenon's capsule 101. When viewed from the top, body 21 preferably has a generally "C-shaped" geometry with a longitudinal part 17, a transversal part 18, and a knee 32 therebetween. Longitudinal part 17 and transversal part 18 are preferably joined at knee 32 to form an angle of about ninety degrees. Longitudinal part 17 has a proximal end 25 and a rounded edge 24. A stopper 37 forms the "lower" part of the C-shaped geometry and is preferably slightly elevated from the remainder of the generally convex orbital surface 12. A notch 42 is located in longitudinal part 17 and is defined by transversal part 18 and stopper 37. Similar to notch 42 of device 50 of FIGS. 7 and 9, notch 42 of device 65 is designed to accommodate the origin of inferior oblique muscle 107. Similar to stopper 36 of device 50, stopper 37 is designed to prevent excessive advancement of device 65 toward optic nerve 96 through contact on the anterior border of inferior oblique muscle 107. Transversal part 18 has a distal end 58, a rounded edge 28, and a well or cavity 20 having an opening 64 (not shown) to scleral surface 14 (not shown) for holding an inner core similar to those described above in connection with FIGS. 10 and 11. Well 20 and opening 64 preferably have a generally oval shape.
Device 52 generally includes a body 39 having a convex, dome-shaped, orbital surface 12 and a concave, dome-shaped scleral surface 14 (not shown). Scleral surface 14 is designed with a radius of curvature that facilitates direct contact with sclera 100. Most preferably, scleral surface 14 is designed with a radius of curvature equal to the radius of curvature 91 of an average human eye 90. Orbital surface 12 is preferably designed with a radius of curvature that facilitates implantation under Tenon's capsule 101. When viewed from the top, body 39 preferably has a generally "L-shaped" geometry with a longitudinal part 15, a transversal part 18, and a knee 32 therebetween. Longitudinal part 15 and transversal part 18 are preferably joined at knee 32 to form an angle of about ninety degrees. Similar to notch 42 of device 50 of FIGS. 7 and 9, longitudinal part 15 and transversal part 18 of device 52 form a region 43 designed to accommodate the origin of inferior oblique muscle 107. Longitudinal part 15 has a proximal end 25 and a rounded edge 24. Transversal part 18 has a distal end 58, a rounded edge 28, and a well or cavity 20 having an opening 64 (not shown) to scleral surface 14 for holding an inner core similar to those described above in connection with FIGS. 10 and 11. Well 20 and opening 64 preferably have a generally oval shape.
The present invention is illustrated herein by example, and various modifications may be made by a person of ordinary skill in the art. For example, although the present invention is described hereinabove with reference to an ophthalmic drug delivery device having a generally "F-shaped", "C-shaped", or "L-shaped" geometry when viewed from the top, other geometries may be used, especially if they facilitate the placement of the device under the inferior oblique muscle and the location of pharmaceutically active agent over the macula when the device is implanted on the outer surface of the sclera and below the Tenon's capsule of the human eye.
A drug delivery device (30,40,50,52,54,60,65,67,70,75,80) for a human eye (90), said eye having sclera (100), an inferior oblique muscle (107), and a macula (98), said device comprising:
a body (21, 29, 39) having:
a convex dome shaped orbital surface (12) and a concave dome shaped scleral surface (14), the body having a longitudinal part (15,17), a transversal part (18) and a knee (32) therebetween, the longitudinal part and the transversal part being joined at the knee to form an angle of about 90 degrees, the longitudinal part having a notch (42) or region (43) for accommodating the origin of the inferior oblique muscle , the transversal part having a well (20) having an opening (64) to the scleral surface (14); and
an inner core (81) comprising a pharmaceutically active agent, the inner core (81) being insertable through said opening (64) to be disposed in said well (20);
wherein the geometry of the device allows an implantation of said device on an outer surface of said sclera, beneath said inferior oblique muscle (107), and with said pharmaceutically active agent disposed above said macula.
The drug delivery device of claim 1, wherein said body (21, 29, 39) comprises a biocompatible, non-bioerodable material.
The drug delivery device of claim 1, wherein said body (21, 29, 39) comprises a polymeric composition.
The drug delivery device of claim 3, wherein said polymeric composition comprises one or more polymers selected from the group consisting of silicone, polyvinyl alcohol, ethylene vinyl acetate, polylactic acid, nylon, polypropylene, polycarbonate, cellulose, cellulose acetate, polyglycolic acid, polylactic glycolic acid, cellulose esters, polyethersulfone, and acrylics.
The drug delivery device of claim 3, wherein said polymeric composition comprises silicone.
The drug delivery device of claim 1, wherein said body (21, 29, 39) is impermeable to said pharmaceutically active agent.
The drug delivery device of claim 1, wherein said inner core (81) is a tablet.
The drug delivery device of claim 1, wherein said inner core (81) comprises a semi-solid form, and said pharmaceutically active agent is disposed within said semi-solid form.
The drug delivery device of claim 1, wherein the geometry of the device allows implantation of said device below a Tenon's capsule of the human eye.
The drug delivery device of claim 1, wherein said pharmaceutically active agent is nepafenac.
The drug delivery device of claim 1, wherein said pharmaceutically active agent comprises a compound selected from the group consisting of 4,9(11)-Pregnadien-17a,21-diol-3,20-dione and 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate.
The drug delivery device of claim 1, wherein said pharmaceutically active agent comprises eliprodil.
The drug delivery device of claim 1, further comprising a retaining member (62) extending from said body (21, 29, 39) proximate said opening (64).
The drug delivery device of claim 1, wherein said notch (42) or a region (43) comprises a ramp (45).
EP20000972099 1999-10-21 2000-10-12 Ophthalmic drug delivery device Expired - Fee Related EP1221919B1 (en)
US664790 2000-09-19
EP1221919A1 EP1221919A1 (en) 2002-07-17
EP1221919B1 true EP1221919B1 (en) 2005-02-23
EP20000972099 Expired - Fee Related EP1221919B1 (en) 1999-10-21 2000-10-12 Ophthalmic drug delivery device
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