Ophthalmic drug delivery device

(12) PATENT DESCRIPTION (19) PL (11) 196539 (21) Application number: 355970 ^{(13) B1} (22) Date of notification: 12/10/2000 ^{(51) Int.Cl.}

A61F 9/00 (2006.01) (86) Date and number of the international application:

12.10.2000, PCT / US00 / 28187 (87) International application publication date and number:

April 26, 2001, WO01 / 28474 PCT Gazette No. 17/01 (54)

Device for dispensing drugs into the human eye (30) Priority:

1999-10-21, US, 60 / 160,673

09/19/2000, US, 09 / 664,790 (43) Application announced:

31.05.2004 BUP 11/04 (73) Authorized by the patent:

ALCON INC., Hunenberg, CH (72) Inventor (s):

Yoseph Yaacobi, Fort Worth, US (45) The grant of the patent was announced:

(74)

31.01.2008 WUP 01/08

Proxy:

Sierpińska Urszula, PATPOL Sp. z o. o

(57) 1. A device for dispensing medicaments into the human eye, the eye having a sclera, an inferior oblique muscle and a macula, characterized in that it comprises a housing (21, 29, 39) having a convex dome-shaped orbital surface (12) and a concave dome-shaped scleral surface. (14) and having a longitudinal portion (15, 17) and a transverse portion (18) with a knee (32) therebetween, the longitudinal portion (15, 17) and the transverse portion (18) being joined at the knee (32) to form angle of about 90 °, and further the longitudinal portion (15, 17) has a tooth (42) or region (43) for receiving the edge of the inferior oblique muscle (107), the transverse portion (18) having a recess (20) having an opening (64) leading to the sclera surface (14) and an inner core (81) disposed within said recess (20) containing a pharmaceutically active agent, the inner core (81) being inserted into the recess (20) through an opening (64), and the geometry of the device allows it to be implanted on the outer surface of the sclera (100), below the inferior oblique muscle (107), with the pharmaceutically active center positioned above the macula (98).

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PL 196 539 B1

Description of the invention

The subject of the invention is a device for the delivery of drugs to the human eye, constituting an implant for the topical application of pharmaceutically active agents to the eye.

It has long been known that diseases of the posterior segment of the eye endanger eyesight. Age-related macular degeneration (ARMD), choroidal vascularization (CNY), retinopathy (for example diabetic retinopathy, vitreous retinopathy), retinitis (for example caused by cytomegalovirus (CMV)), uveitis, macular edema , glaucoma and neuropathy are just a few examples.

Age-related macular degeneration (ARMD) is the leading cause of blindness in old age. ARMD attacks the center of the field of vision and blurs it, making reading, driving, and other activities that require detailed vision impossible. About 200,000 new cases of ARMD are revealed annually in the United States alone. This approximation applies to approximately forty percent of the population over the age of 75, approximately twenty percent of those over the age of 60 suffer from some degree of macular degeneration. "Wet" ARMD is the type of ARMD that most commonly causes blindness. In wet ARMD, newly formed choroidal blood vessels (choroidal vascularization (CNY)) leak fluid and cause progressive damage to the retina.

There are three main treatments for ARMD in the individual case of CNY: (a) photocoagulation, (b) the use of inhibitors to inhibit vascular formation, and (c) photodynamic therapy. Photocoagulation is the most commonly used method. However, photocoagulation can be detrimental to the retina and is impractical when CNY is located near the fovea. In addition, CNY recurs frequently after some time of use of photocoagulation. Oral or parenteral (non-ophthalmic) use of anti-angiogenesis agents is also being tested as a general treatment for ARMD. However, due to the particular limitations of drug metabolism, systemic administration usually results in too little dose being delivered to the eye. Therefore, in order to achieve adequate drug concentration in the eye, unacceptable high doses of drugs or frequent repetition of the doses used are required. Periocular injections of these agents often result in the drug draining from the eye through the periocular blood vessels and soft tissue into the systemic circulation. Repeated periocular injections can cause serious complications and even blindness from detachment of the retina and inflammation of the eye interior. Photodynamic therapy is a new technology whose long-term effects are still unknown.

To prevent complications of the treatments described above and to provide better ophthalmic treatment, ongoing studies have identified the use of various implants for the topical ocular application of vasoconstrictors. U.S. Patent No. 5,824,072 discloses a non-degradable polymer implant with an active pharmaceutical agent deposited thereon. The active pharmaceutical agent diffuses through the polymeric housing of the implant into the target tissue. The active pharmaceutical agent can include drugs for the treatment of macular degeneration or diabetic retinopathy. The implant is placed inside the lacrimal fluid on the outer surface of the eye in the non-vascularized part and can be attached to the conjunctiva or sclera; outside the sclera or inside the sclera over the non-vascularized portion; inside the supravascular space above the non-vascularized portion, such as in a smooth portion or a surgically separated non-vascularized portion; or in direct contact with the vitreous.

U.S. Patent No. 5,476,511 discloses a polymeric implant placed under the conjunctiva of the eye. The implant can be used to deliver anti-vascular agents for the treatment of ARMD and agents for the treatment of retinopathy and retinitis. The active pharmaceutical agent diffuses through the polymer housing of the implant.

U.S. Patent No. 5,773,019 discloses a non-degradable polymer implant for the delivery of certain drugs containing anti-angiogenesis steroids and drugs for the treatment of uveitis, such as cyclosporine. In this case also the active pharmaceutical agent diffuses through the polymer housing of the implant.

All the implants described above need to be carefully shaped and manufactured to control the diffusion of the active pharmaceutical agent through the polymer housing (i.e. matrix) or polymer membrane (i.e. reservoir) to the desired treatment site. The release of the drug from these devices depends on the porosity and diffusion properties of the matrix or, respectively

PL 196 539 B1 membrane. These parameters must be appropriately selected for each specific drug molecule to be used. Consequently, these requirements increase the complexity and cost of such implants.

U.S. Patent No. 5,824,073 to Peyman describes an eye indenter. The indenter has a raised portion that is used to indent or press against the sclera over the macular area of ​​the eye. This patent describes how this pressure reduces choroidal congestion and blood flow through subretinal new blood vessels, which in turn reduces bleeding and subretinal fluid build-up.

From U.S. Patent Nos. 5,743,274, US 5,725,493 and DE 4,022,553, various devices are known, which constitute a contact lens with suitable material properties, containing a cavity of precisely configured dimensions, which houses specific volumes of a solution, suspension or ointments and from which the active or indicator substances are released in a spatially uniform and time-controlled manner onto the area of ​​the corneal surface located opposite the recess.

From application description PL 355 263 there is known an ophthalmic drug delivery device which comprises a housing having an inner surface for placement adjacent to a target eye tissue and a recess having an opening leading to that inner surface. Placed in the cavity is an inner core containing a pharmaceutically active substance.

In the field of biocompatible implants for the surgical implantation of ophthalmic drug delivery devices, there is a need for safe, effective, topical application of a wide variety of dose controlled pharmaceutically active agents. The surgical procedure for implanting such a device should be safe, simple, quick, and manageable on an incoming patient. Ideally, such devices should be easy and economical to produce. Moreover, due to its versatility and the ability to use a wide variety of pharmaceutically active agents, such an implant would be applicable in clinical trials of the eye to deliver pharmaceutically active agents to produce a particular specific physical condition in a patient. Such an ophthalmic drug delivery device is particularly needed for the topical application of pharmaceutical active agents to the end segment of the eye in the control of ARMD, CNY, retinopathy, retinitis, uveitis, macular edema, glaucoma and neuropathy.

The device for delivering medicaments to the human eye, the eye having a sclera, an inferior oblique muscle and a macula, according to the invention is characterized in that it comprises a housing having a domed domed orbital surface and a concave dome-shaped sclera surface and having a longitudinal portion and a transverse portion. with the knee between them, the longitudinal part and the transverse part connected at the knee making an angle of approximately 90 °, and the longitudinal portion further comprises a tooth or region for receiving the inferior edge of the oblique muscle, the transverse portion having a recess having an opening leading to the scleral surface and an inner core disposed in the recess containing a pharmaceutically active agent, the inner core being inserted into the recess by the hole, and the geometry of the device allows it to be implanted on the outer surface of the sclera, below the inferior oblique muscle, with a pharmaceutically active agent located above the spot.

The housing contains biocompatible, non-biodegradable material.

The housing contains a polymer composition.

The polymer 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 acrylic compounds.

The polymer composition includes silicone.

The housing is impermeable to the pharmaceutically active agent.

The inner core is a tablet.

The inner core is semi-solid and the pharmaceutically active agent is contained within this semi-solid form.

The geometry of the device allows it to be implanted below Tenon's capsule in the human eye.

The pharmaceutically active agent is nepafenac.

The pharmaceutically active agent comprises a compound selected from the group consisting of 4.9 (11) -Pregnadiene-17a, 21-diol-3,20-dione and 4.9 (11) -Pregnadiene-17a, 21-diol-3,20-dione. -21-acetate.

PL 196 539 B1

The pharmaceutically active agent comprises eliprodil.

A retainer protrudes from the housing near the opening.

The clove or area contains a slope.

The subject of the invention is illustrated in an embodiment in which Fig. 1 shows a side view of a diagram of a human eye with an ophthalmic drug delivery device according to the invention implanted in the posterior segment of the eye, Fig. 2 is a detailed sectional view of the eye of Fig. 1, along line 2-2, Fig. 3 is a three-dimensional schematic view of the location of the human eye, Fig. 4 - the eye of Fig. 3 after partial removal of the lateral rectus muscle, Fig. 5 - schematic front view of the human eye, fig. 6 - schematic rear view of the human eye, fig. 7 - perspective view of an ophthalmic drug delivery device to the right human eye in a first preferred embodiment of the invention, fig. 8 - perspective view of the delivery device The ophthalmic drugs of Figures 7 and 9 having a slope to match the inferior oblique muscle. Figure 9 is a perspective view of the ophthalmic drug delivery device of Figure 9. 7, sclera side, Figure 10 is a perspective view of an oval core or tablet for use with ophthalmic drug delivery devices of the invention, Figure 11 is a perspective view of two mating semi-oval drug cores or tablets for use with ophthalmic drug delivery devices 12 is a perspective view of the drug delivery device of Figs. 7 and 9 to the left human eye, Fig. 12. 13 - perspective view of the ophthalmic drug delivery device of Figures 12 and 14 having a slope to match the inferior oblique muscle; Figure 14 - perspective view, from the sclera side, of the ophthalmic drug delivery device of Figures 7 and 9 to the left human eye Fig. 15 is a perspective view of the ophthalmic drug delivery device of Figs. 7 and 9 with reference to a conical longitudinal portion of the device. 16 - perspective view of a truncated version of the ocular drug delivery device of Figs. 7 and 9, Fig. 17 - perspective view of the ophthalmic drug delivery device of Fig. 16 having a slope to fit the inferior oblique muscle, Fig. 18 - perspective view of the delivery device Fig. 19 is a perspective view of the ophthalmic drug delivery device of Fig. 19 in a second preferred embodiment of the present invention. Fig. 18 having a slope to match the inferior oblique muscle, Fig. 20 is a perspective view of the ophthalmic drug delivery device for the right human eye in a third preferred embodiment of the present invention, and Fig. 21 is a perspective view of the ophthalmic drug delivery device of Fig. 20. having a slope to match the inferior oblique muscle.

Figures 1 to 6 show the various parts of the human eye that are necessary for understanding the essence of the device according to the invention. Fig. 1 shows schematically a human eye 90. The eye 90 has a cornea 92, a lens 93, a vitreous 95, a sclera 100, a choroid 99, a retina 97, and an optic nerve 96. The eye is divided into a posterior segment 89 and an anterior segment 88. Anterior segment 88. an eye 90 includes a portion of an eye 90 from the toothed limb 11 anteriorly. The posterior segment 89 of the eye 90 includes an eye portion 90 from the toothed limb 11 posteriorly. Retina 97 is physically connected to the choroid 99 in a peripheral manner, close to the smooth portion 13, in front of the optic disc 19. Retina 97 has a spot 98 located slightly to the side of the optic disc 19. It is well known in the field of ophthalmology that macula 98 consists of mainly from retinal suppositories 97 and is the area of ​​greatest visual acuity in the retina 97. Tenon's capsule 101 sits on the sclera 100. The conjunctiva 94 covers a short area of ​​the globe 90 posteriorly from the limbus 115 (conjunctival bulb) and curls up (upper tip) or down (lower tip) to cover the inner surfaces of the upper eyelid, respectively 78 and lower eyelid 79. The conjunctiva 94 covers the top of Tenon's bag 101.

As shown in Figures 1 and 2, and as will be described in detail below, the device 50 of the invention is placed directly on the outer surface of the sclera 100, beneath Tenon's capsule 101 to treat most diseases or conditions of the anterior segment 88. In addition to treating ARMD and CNY. in humans, device 50 is placed directly on the outer surface of the sclera 100 below Tenon's capsule 101, and the core of device 50 is positioned close to spot 98.

Figure 3 shows the left human eye seated inside the orbit 112. As can be seen, the inferior oblique muscle 107 extends under the rectus 105. The line 107a for inserting the oblique posterior muscle 107 into the sclera 100 is just above the upper limit of the lateral rectus 105. Of course in this the oblique lower muscle 107 position in the right human eye 90 is a mirror image of the position in the left human eye of Fig. 3. Cornea 92 is also shown in Fig. 3.

The conjunctiva 94, the upper rectus 103, the lower rectus 104, the upper oblique muscle 106, and the limbus 115.

Figure 4 similarly shows the left human eye 90 inside the orbit 112, although a portion of the lateral rectus muscle 105 is not shown to show those portions of the sclera 100 and optic nerve 96 that are typically hidden behind this muscle. The line 107b of insertion of the inferior oblique muscle 107 into the sclera 100 is below line 107a of Figure 3 to mark the physiological variation of the line of insertion of the posterior oblique muscle in the human eye.

Figure 5 shows the human eye 90 from the front with its four straight muscles: upper rectus 103, median rectus 108, lower rectus 104 and lateral rectus 105. Fig. 5 also shows the relative position of the limbus represented by the circumferential line 115 and straight muscle insertion lines, represented by the perimeter line 113.

Figure 6 shows the human eye 90 from the rear, illustrating the distribution of the upper rectus muscle 103, lateral rectus muscle 105, lower rectus muscle 104, middle rectus muscle 108, upper oblique muscle 106, lower oblique muscle 107 and its insertion line 107a, optic nerve 96. ciliary vessels 109, sclera 100, sclera surface 110 above the macula 98, ciliary processes 111, and vortex veins 114.

Figures 7 and 9 schematically show an ophthalmic drug delivery device 50 for the right human eye in a first embodiment of the invention. Device 50 can be used in any case where local delivery of a pharmaceutically active agent to the eye is desired. Device 50 is particularly suitable for delivering a pharmaceutically active agent to the posterior segment of the eye. A preferred use for device 50 is to deliver a pharmaceutically active agent to the retina proximal to the macula for the treatment of ARMD, choroidal vascularization (CNY), retinopathy, retinitis, uveitis, macular edema, glaucoma, and neuropathy.

Device 50 comprises a housing 21 having a convex, dome-shaped orbital surface 12 and a concave, dome-shaped sclera surface 14. The scleral surface 14 has a radius of curvature that conforms to direct contact with the sclera 100. Preferably, the sclera surface 14 is made with a radius of curvature equal to the radius of curvature 91 of the average human eye 90 (see Fig. 1). The orbital surface 12 is constructed with a radius of curvature that allows implantation below Tenon's capsule 101. Viewed from above, housing 21 is generally F-shaped with a longitudinal portion 15, a transverse portion 18, and a knee 32 therebetween. Longitudinal portion 15 and transverse portion 18 connect by knee 32 at an angle of approximately 90 °. The longitudinal portion 15 has a proximal end 25, a rounded edge 24, a stop 36, and a tooth 42. As will be described in more detail below, tooth 42 is adapted to be positioned at the beginning of the inferior oblique muscle 107. The stop 36 forms the bottom of the tooth 42 and should be slightly elevated relative to the rest of the convex orbital surface 12. As will be described in more detail below, the stop 36 is shaped to prevent the device 50 from being over-slipped towards the optic nerve 96 by contacting the anterior border of the inferior oblique muscle 107. The transverse portion 18 has a distal end 58, a rounded end 28 and recess 20 having an opening 64 facing the sclera 14. The recess 20 and opening 64 should be oval in shape. As will be described in more detail below, the transverse portion 18 allows the recess 20 to be positioned more precisely in the region of the sclera 100 that is above the spot 98.

Inner core 81, as shown in Fig. 10, should be seated in recess 20. As shown in Fig. 10, inner core 81 should be a tablet containing one or more pharmaceutically active agents. The tablet should have an oval shell 46 with a recessed dome-shaped scleral surface 85 and a convex dome-shaped orbital surface 86. The coating 46 should also have an undercut 87. Alternatively, as shown in FIG. 11, inner core 81 may include corresponding semicircular tablets 82a and 82b. Tablet 82a should have a coating 47 identical to half of the shell 46 of core 81, and tablet 82b should have a coating 48 identical to that of opposite half of shell 46 of core 81. In a further alternative, inner core 81 or tablets 82a and 82b may contain a conventional hydrogel, gel , a paste, or other semi-solid dispenser containing one or more pharmaceutically active agents.

As shown in Fig. 9, the retention member 62 should be close to the opening 64. The retention member 62 prevents the core 81 from falling out of the recess 20. When e6

If the inner core 81 is a tablet, the retention member 62 should be a continuous rim or edge around the periphery of the opening 64 made to match the undercut 87 of the core 81. Alternatively, the retention member 62 may include one or more members protruding from the housing. 21 inside hole 64.

Although not shown in Figures 9 to 11, inner core 81 may alternatively comprise a suspension, solution, powder, or other combination thereof that includes one or more pharmaceutically active agents. In this embodiment, scleral surface 14 does not have an opening 64, and a suspension, solution, powder, or other combination thereof diffuses through the relatively thin widening of the scleral surface 14 or some other membrane beneath the inner core 81. Further, alternatively, device 50 may not have a cavity 20 or inner core 81, and the pharmaceutically active agent (s) in the form of a suspension, solution, powder, or other combination thereof may be dispersed over the entire length of housing 21 of device 50. In this embodiment, the pharmaceutically active agent diffuses through the entire housing 21 into the target tissue.

The geometric shape and dimensions of device 50 increase communication between the pharmaceutically active agent from the inner core 81 and the tissue underlying the scleral surface 14. The sclera surface 14 should make physical contact with the outer surface of the sclera 100. Alternatively, the scleral surface 14 may be close to the scleral surface 100. For example, device 50 may be positioned in the periocular tissues just above the sclera surface 100 or intra-lamellar inside the cornea 100.

Housing 21 should consist of a biocompatible, bio-degradable material. Housing 21 should consist of a biocompatible, bio-degradable polymer composition. They can be homogeneous polymers, copolymers, straight, branched, cross-linked or mixtures thereof. Examples of polymers suitable for use in said composition are: silicone, polyvinyl alcohol, ethylene vinyl acetate, polylactic acid, nylon, polypropylene, polycarbonate, cellulose, cellulose acetate, polyglycolic acid, polylactic glycolic acid, cellulose esters, polyethersulfone, acrylic compounds, their derivatives and mixtures. Examples of suitable soft acrylic compounds are described in U.S. Patent No. 5,403,901. The said polymer compositions should contain silicone. Of course, said polymer compositions may contain other materials used that affect their physical properties, including porosity, labyrinthine, permeability, stiffness, hardness, and smoothness. Exemplary materials that affect any of these properties include plasticizers, fillers, and coating agents. Said polymer compositions may also contain other materials affecting their chemical properties, such as toxicity, hydrophobicity and reaction with inner core 81. Housing 21 should be impermeable to pharmaceutically active agents from the inner core 81. If housing 21 is made of a flexible polymer composition, the size of the recess 20 may be slightly smaller than that of the inner core 81. This frictional connection secures the inner core 81 within the cavity 20. In this embodiment, the housing 21 can be made with or without a retention member 62 as desired, and the core 81 with or without an undercut 87.

Inner core 81 can contain any pharmaceutically acceptable active agents suitable for topical application. Examples of pharmaceutically active agents suitable for the inner core 81 are anti-infective drugs, including antibiotics, antiviral and antifungal drugs, antiallergic drugs and drugs that stabilize the cell skeleton, steroidal and non-steroidal anti-inflammatory drugs, cyclooxygenase inhibitors including Cox I and Cox II inhibitors, combinations anti-infective and anti-inflammatory drugs; anti-glaucoma agents, including adrenergics, β-adrenergic blockers, α-adrenergic agonists, parasympathomimetics, cholinesterase inhibitors, carbonic anhydride and prostaglandin inhibitors, combinations of anti-glaucoma agents, antioxidants, nutritional supplements and drugs for cystic macular edema non-steroidal anti-inflammatory drugs, anti-ARMD drugs including angiogenesis inhibitors and nutritional supplements drugs against herpesviral infections and ophthalmic CMV infections, drugs against vitreous hyperplastic retinopathy including antimetabolites and fibrinolytics, healing agents including growth factors, antimetabolites, neuroprotectors including eliprodil, angiostatic steroids for the treatment of posterior disease or conditions segment of the eye including ARMD, CNY, retinopathies, retinitis, uveitis, macular edema, and glaucoma. Angiostatic steroids are described in U.S. Patent Nos. 5,679,666 and 5,770,592. Preferred angiostatic steroids include

PL 196 539 B1

4.9 (11) -Pregnadiene-17a, 21-diol-3,20-dione or 4,9 (11) -Pregnadiene-17a, 21-diol-3,20-dione-21-acetate. Nepafenac is the preferred steroidal anti-inflammatory drug for the treatment of cystic macular edema. Inner core 81 may also contain inactive ingredients to improve the stability, solubility, permeability and other properties of the active agents of the drug core.

If the inner core 81 is a tablet, it may further contain the usual ingredients necessary for tablet production, such as, for example, fillers or coating agents. Such tablets can be produced by conventional tablet production methods. The pharmaceutically active agent should be evenly distributed over the entire surface of the tablet. In addition to conventional tablets, the inner core 81 may contain a special tablet that is biodegradable to a controlled extent, releasing the pharmaceutically active agent. For example, such biodegradability may take the form of hydrolysis or enzymatic cleavage. If the inner core 81 is a hydrogel or a gel, such a gel can degrade to a controlled extent, releasing the pharmaceutically active agent. Alternatively, such a gel may be biodegradable but may allow diffusion of the pharmaceutically active agent.

The apparatus 50 can be made using common polymer production methods, including injection molding, extrusion molding, stamping, and compression molding. Device 50 is preferably made using conventional injection techniques. The inner core 81 should be placed in the recess 20 after the housing 21 of the device 50 has been formed. The retainer 62 should be resilient enough to allow the undercut 87 of the inner core 81 to slide into the opening 64 and then return to its proper position.

The device 50 should be surgically positioned directly on the outer surface of the sclera 100 below Tenon's capsule 101 with the recess 20 and inner core 81 directly above the sclera surface 100 and above the macula 98 using a technique that allows an outpatient procedure to be performed. The surgeon first makes an 8 mm incision of the conjunctiva around the cornea in one of the quarters of the eye 90. The surgeon should make this incision in the craniometric quadrant about 3mm behind the limbus 115 of the eye 90. When the incision is made, the surgeon proceeds to a blunt dissection to separate Tenon's capsule 101 from the sclera 100. Using scissors and a blunt dissection, an anteroposterior tunnel is created along the outer surface. sclera surface 100 and below the inferior oblique muscle 107, preferably along the inferior border of the lateral rectus muscle 105. The inferior oblique muscle 107 engages the Jamison muscle hook. The top of the hook slides just behind the inferior oblique muscle to form part of a tunnel into which the transverse portion 18 of the device 50 will be placed. Once the tunnel has been formed, the surgeon uses a nugget to hold the transverse portion 18 of the device 50 with the sclera surface 14 facing the sclera 100 and beyond. end 58 of the transverse portion 18 away from the surgeon. The surgeon then inserts device 50 first through distal end 58 into the tunnel at the level of the incision. Once the device 50 is in the tunnel, the surgeon advances it toward the inferior oblique muscle 107 until the stop 36 contacts the anterior border of the inferior oblique muscle 107. At the level where the lower oblique muscle 107 is visible, the surgeon rotates the device 50 underneath the muscle so that the transverse portion 18 of the device 50 is within the tunnel portion of the back of the lower oblique muscle 107. When the surgeon senses that the knee 32 cannot be further away. inserted, then gently moves device 50 back and forth, allowing the lower oblique muscle 107 to contact the tooth 42 between the transverse portion 18 and the stop 36. Due to the tooth 42, the recess 20 near the distal end 58 of the transverse portion 18 is positioned such that the inner core 81 is positioned exactly above the sclera surface 100 above the spot 98. The proximal end 25 of the longitudinal portion 15 can then be sutured to the sclera 100. The surgeon then closes the incision. by suturing the Tenon's capsule 101 and conjunctiva 94 to the sclera 100. After closure, the surgeon applies an antibiotic ointment patch to the surgical wound. All sutures should be sutured 7-0 Vicryl.

For the treatment of ARMD and CNY, the pharmaceutically active inner core 81 agent should be one of the angiostatic steroids described in U.S. Patent Nos. 5,679,666 and 5,770,592.

The geometric shape of the housing 21 of the device 50 is concave on the side of the sclera 14. The shape and location of the transverse portion 18, the recess 20, the opening 64, the inner core 81 and the retention member 62, and the shape and position of the tooth 42 and stop 36 are responsible for the correct pharmaceutical application. effective amount of pharmaceutically active agent from inner core 81 through sclera 100, choroid 99 to retina 97, and in particular 8

The lack of a polymeric coating or membrane between the inner core 81 and the sclera 100 also improves and simplifies the application of the active agent to the retina 97.

The device 50 of the invention can be used to deliver a pharmaceutically effective amount of a pharmaceutically active agent to the retina 97 for many years, depending on the particular physicochemical properties of the pharmaceutically active agent used. Important physicochemical properties include hydrophobicity, solubility, degree of dissolution, diffusivity coefficient, partition coefficient and tissue similarity, among others. When the inner core 81 no longer contains active agent, the surgeon can easily remove the device 50, and the previously made tunnel allows the used device 50 to be replaced with a new one.

Figure 8 shows an ophthalmic drug delivery device 60 that is slightly modified from device 50. As shown in Figure 8, device 60 has a geometric shape similar to that of device 50 in Figures 7 and 9 except for the orbital surface 12. of the housing 21, a slope 45 is added, located near the notch 42. A slope 45 is an inclined surface extending from the sclera surface 14 on one side to the orbital surface 12 on the other side.

Alternatively, a slope 45 may extend from the edge 24 of the longitudinal portion 15 on one side to the orbital surface 12 on the other side. The slope 45 allows the inferior oblique muscle to position within the tooth 42 between the transverse portion 18 and the stop 36 when the device 60 is implanted in the eye 90, as described above for the device 50. The device 60 can be made using the same techniques as in device case 50.

Figures 12 and 14 schematically show an ophthalmic drug application device 70 to the left human eye. The geometric shape of device 70 is a mirror image of the geometric shape of the right human eye device 50 described with reference to Figures 7 and 9. The use of device 70 is identical to device 50, and device 70 may be made using the same techniques as device 50.

Figure 13 shows an ophthalmic drug delivery device 75 to the left human eye that is a slight modification of device 70. The geometric shape and use of device 75 in Figure 13 is similar to the geometric shape and method of use of device 60 in Figure 8 except, that device 75 is a mirror image of device 60.

Figure 15 shows an ophthalmic drug delivery device 30 to the left human eye that is a slight modification of device 50. The geometric shape of the device 30 of Figure 13 is similar to that of the device 50 of Figures 7 and 9, except that the longitudinal portion 15 is has a decreasing thickness from location 33 to distal end 25 when viewed from edge 24. This section of longitudinal portion 15 is at the rear of the eye 90 and may be visible to the environment, therefore the reduced thickness of the device 30 may be more comfortable or cosmetically acceptable to the patient. The application of the device 30 of Fig. 15 is the same as that of the device 50, and the device 30 can be made by the same techniques as the device 50.

Figure 16 shows the ophthalmic drug application device 40 that is a slight modification of the device 50. The geometric shape of the device 40 of Figure 16 is similar to the geometric shape of the device 50 of Figures 7 and 9, except that the longitudinal portion 15 of the device 40 is shortened relative to device 50. Similar to device 30, shortening of longitudinal portion 15 makes device 40 more comfortable and cosmetically acceptable to the patient. The application of the device 40 of Fig. 16 is the same as the application of the device 50, and the device 40 may be made by the same techniques as the device 50.

Figure 17 shows the ophthalmic drug delivery device 80, which is slightly modified from device 40. As shown in Figure 17, device 80 has a geometric shape similar to that of device 40 in Figure 16, except for the orbital surface 12. of the housing 21, a slope 45 is added, located near the notch 42. A slope 45 is an inclined surface extending from the sclera surface 14 on one side to the orbital surface 12 on the other side. Alternatively, a slope 45 may extend from the edge 24 of the longitudinal portion 15 on the one hand, to the orbital surface 12 on the other hand. The slope 45 allows the inferior oblique muscle to position within the tooth 42 between the transverse portion 18 and the stop 36 when the device 80 is implanted in the eye 90, as described above for the device 50. The device 80 can be made using the same techniques as in device case 50.

PL 196 539 B1

Figure 18 schematically shows devices 65 for delivering ophthalmic drugs to the right human eye in a second embodiment of the invention. Device 65 can be used in all cases where topical application of a pharmaceutically active agent to the eye is required. Device 65 is especially useful for topically applying active agents to the posterior segment of the eye.

A preferred application of device 65 is the application of active agents to the retina near the macula for the treatment of ARMD, choroidal vascularization (CNY), retinopathy, retinitis, uveitis, macular edema, glaucoma, and neuropathy.

Device 65 is comprised of a housing 29 having a convex dome-shaped orbital surface 12 and a concave, dome-shaped scleral surface 14 (not shown). The sclera surface 14 has a radius of curvature that is suited to direct contact with the sclera 100. Preferably, the sclera surface 14 is constructed with a radius of curvature that equals the radius of curvature 91 of the average human eye 90. The orbital surface 12 is constructed with a radius of curvature that allows implantation below Tenon's capsule 101. Viewed from above, the housing 29 is generally C-shaped with a longitudinal portion 17, a transverse portion 18, and a knee 32 therebetween. Longitudinal portion 17 and transverse portion 18 connect at knee 32 at an angle of approximately 90 °. The longitudinal portion 17 has a proximal end 25 having a rounded edge 24. The stop 36 forms the lower part of the letter C and is slightly raised relative to the rest of the convex orbital surface 12. A tooth 42 is located on the longitudinal portion 17 and is formed by the transverse portion 18 and the stop 37. Like the stop 36 of the device 50 of Fig. 7 and 9, tooth 42 of device 65 is adapted to be positioned at the origin of the inferior oblique muscle 107. Like the stop 26 of the device 50, the stop 37 is configured to prevent the device 65 from being over-slipped towards the optic nerve 96 by contacting the anterior border of the inferior oblique muscle 107.

The transverse portion 18 has a distal end 58, a rounded end 28, and a recess 20 having an opening 64 (not shown) facing the sclera 14 (not shown) to retain an inner core similar to that described with reference to Figures 10 and 11. The recess 20 and opening 64 should be oval in shape.

The use of the device 65 is the same as the use of the device 50. The device 65 may be made by the same techniques as the device 50.

Figure 19 shows an ophthalmic drug delivery device 67 which is slightly modified from device 65. As shown in Figure 19, device 67 has a geometric shape similar to that of device 65 of Figure 18, except for the orbital surface 12. of the case 29, a slope 45 is added, located near the notch 42. A slope 45 is an inclined surface extending from the sclera surface 14 on one side to the orbital surface 12 on the other side. Alternatively, a slope 45 may extend from the edge 24 of the longitudinal portion 17 on one side to the orbital surface 12 on the other side. The slope 45 allows the inferior oblique muscle to position within the tooth 42 between the transverse portion 18 and the stop 37 when the device 67 is implanted in the eye 90, as described above for the device 50. The device 67 can be made using the same techniques as in device case 50.

Figure 20 schematically shows the device 52 for delivering ophthalmic drugs to the right human eye in a third embodiment of the invention. The device 52 can be used in all cases where topical application of a pharmaceutically active agent to the eye is necessary. Device 52 is especially useful for topically applying active agents to the posterior segment of the eye.

A preferred application of device 52 is the application of active agents to the retina near the macula for the treatment of ARMD, choroidal vascularization (CNY), retinopathy, retinitis, uveitis, macular edema, glaucoma, and neuropathy.

Device 52 comprises a housing 39 having a convex dome-shaped orbital surface 12 and a concave, dome-shaped scleral surface 14 (not shown). The sclera surface 14 has a radius of curvature that conforms to direct contact with the sclera 100. Preferably, the sclera surface 14 is constructed with a radius of curvature that equals the radius of curvature 91 of an average human eye 90. The orbital surface 12 is made with a radius of curvature that allows the implant 10

Not below Tenon's bag 101. Viewed from above, housing 39 is generally L-shaped with a longitudinal portion 15, a transverse portion 18, and a knee 32 therebetween. Longitudinal portion 15 and transverse portion 18 connect by knee 32 at an angle of approximately 90 °. Like the stop 42 of the device 50 of Figures 7 and 9, the longitudinal portion 15 and the transverse portion 18 of the device 52 define an area 43 adapted to be located at the edge of the inferior oblique muscle 107.

Transverse portion 18 has a distal end 58, a rounded end 28, and a recess 20 having an opening 64 (not shown) facing the sclera 14 for retaining an inner core similar to that described with reference to Figs. 10 and 11. Recess 20 and aperture 64 should be oval in shape.

The use of the device 52 is the same as the use of the device 50 described above. Device 52 may be manufactured by the same techniques as device 50.

Figure 21 shows the ophthalmic drug delivery device 54, which is slightly modified from device 52. As shown in Figure 21, device 54 has a geometric shape similar to that of device 52 in Figure 20, except for the orbital surface 12. of the housing 29, a ramp 45 was added, located near the area of ​​43. A slope 45 is an inclined surface extending from the sclera surface 14 on one side to the orbital surface 12 on the other side. Alternatively, a slope 45 may extend from the edge 24 of the longitudinal portion 15 on one side to the orbital surface 32 on the other side. The slope 45 allows the inferior oblique muscle 107 to be positioned within area 43 when device 54 is implanted in eye 90, as described above in relation to device 50. Device 54 can be made using the same techniques as device 50.

It can be seen from the above description that the device according to the invention provides the safe, effective, topical administration to the eye of a controlled dose of various pharmaceutically active agents, and in particular to the posterior segment of the eye for the purpose of combating ARMD, CNY, retinopathy, retinitis, membrane inflammation. vascular eyeball, macular edema, glaucoma and neuropathy. The surgical procedure for implanting these devices is safe, simple, quick, and manageable for the out-patient. Such devices are easy and economical to manufacture. In addition, because of the possibility of topical application of various pharmaceutically active agents to the eye, these devices are helpful in clinical trials that enable the discovery of various ophthalmic agents, since they enable a specific condition to be created in a patient.

The subject matter of the invention has been illustrated by way of example only, and many different modifications may be made to those skilled in the art. For example, although the subject matter of the invention has been described with reference to an F, C, or L-shaped ophthalmic drug delivery device in top view, devices with other shapes may equally well be used, especially if they ensure that the device is positioned underneath the bottom. oblique muscle and placing the pharmaceutically active agent above the macula when the device is implanted in the human eye on the outer surface of the sclera below Tenon's capsule.