Anterior segment drug delivery

Information

  • Patent Grant
  • 10004636
  • Patent Number
    10,004,636
  • Date Filed
    Friday, August 5, 2016
    8 years ago
  • Date Issued
    Tuesday, June 26, 2018
    6 years ago
Abstract
A therapeutic system comprises an ocular insert placed on a region outside an optical zone of an eye. The ocular insert comprises two structures: a first skeletal structure and a second cushioning structure. The first structure functions as a skeletal frame which maintains positioning of the implant along the anterior portion of the eye and provides support to the second, cushioning structure. This first structure maintains the attachment of the therapeutic system to the anterior portion of the eye for at least thirty days. In some embodiments the first structure remains a constant size and shape, e.g. a ring shape, a ring with haptics, or a curvilinear ring that is confined to and restrainingly engages the inferior and superior conjunctival fornices so as to retain the implant within the tear fluid and/or against the tissues of the eye.
Description
BACKGROUND OF THE INVENTION

1. Field of the Invention


The invention relates to structures, systems, and methods for treatment of an eye. Exemplary embodiments provide ocular inserts used for drug delivery, along with methods for using ocular inserts positioned on or near the anterior segment of the eye. The exemplary inserts may be worn along the front surface of the eye outside the optical zone, and can deliver one or more drugs at a safe, therapeutically-effective level for at least thirty days.


2. Background of the Invention


A variety of ophthalmic and non-ophthalmic conditions necessitate administration of various drugs to the eye. Eye drops and gels can be effective drug delivery vehicles, but can also have significant disadvantages. Specifically, eye drops mix with fluid in the tear film, but may have a residence time of only 2-5 minutes in the tear film. As little as 5% of the drug may be absorbed locally; some or all of the rest being carried from the lacrimal sac into the lacrimal duct and eventually absorbed into the bloodstream. The absorption into the bloodstream can have at least two adverse effects: first, most of the drug is wasted and, second, the presence of the drug in the bloodstream may have harmful side effects on the rest of the body. Gels may adhere more effectively to the eye, but can also blur the patient's vision for prolonged time periods. Both eye drops and gels need to be reapplied frequently for some therapies. Thus, a need remains for an improved drug delivery method to the eye that is neither cleared out of its targeted location, nor needs frequent reapplication.


In light of the disadvantages of eye drops, it is understandable that a variety of alternatives have been proposed. Among the known alternatives to drops include treatments in which structures containing or impregnated with drugs have been placed under the eyelid.


Such solid ocular dosage forms appear to present significant potential advantages over drop-administered drug treatments of the eyes. In particular, eye drug delivery implants might help overcome low patient compliance, the difficult application and frequent misapplication of traditional eye drops and other dosage forms, and limited effective drug absorption presented by eye drops, while potentially facilitating the advantageous application of advances in polymer chemistry and introduction of the concepts of sustained/controlled drug release from other known drug-delivery systems.


Despite the tremendous potential advantages of drug delivery implants, drug application to the front of the eyes remains dominated by eye drops. Factors that may have contributed to the limited acceptance of prior ocular inserts include their lack of comfort, their propensity for displacement or movement around the eye, their excessive incidents of inadvertent expulsion during sleep or rubbing of eyes, their interference with vision, and/or the difficulty in placing and removing the known drug delivery implants.


In light of the above, new drug delivery devices, systems, and methods would be beneficial, particularly for delivering therapeutic compounds to the anterior segment of the eye. It would be particularly advantageous to provide improved ocular inserts so as to gain both physician and user acceptance, with such inserts ideally being easy to insert and remove, providing patient comfort, being non-toxic and not interfering with vision or oxygen penetration, allowing for reproducible release kinetics, and/or being easy to manufacture at a reasonable price.


BRIEF SUMMARY OF THE INVENTION

The present invention provides therapeutic systems and methods of delivery of at least one drug. Exemplary embodiment delivers one or more drugs from an ocular insert to an anterior portion of an eye, with the insert.


In a first aspect, embodiments of the present invention provide a therapeutic system. The therapeutic system comprises an ocular insert. The ocular insert is placed on a region outside an optical zone of an eye. The ocular insert comprises two structures: a first skeletal structure and a second cushioning structure.


The first structure functions as a skeletal frame which maintains positioning of the implant along the anterior portion of the eye and provides support to the second, cushioning structure. This first structure maintains the attachment of the therapeutic system to the anterior portion of the eye for at least thirty days. In some embodiments the first structure remains a constant size and shape, e.g. a ring shape, a ring with haptics, or a curvilinear ring that is confined to and restrainingly engages the inferior and superior conjunctival fornices so as to retain the implant within the tear fluid and/or against the tissues of the eye.


In many embodiments, the first structure stretches or changes shape so as to maximize its attachment to the anterior structure of the eye. The drug may be dispersed in or on the first structure, on or in the second structure, or both.


In exemplary embodiments of the invention, the therapeutic system is designed for easy insertion and removal by the patient.





BRIEF DESCRIPTION OF THE DRAWINGS


FIGS. 1-1 and 1-2 show an anatomical tissue structure of an eye 2 suitable for treatment with ocular inserts;



FIG. 2-1 shows an exemplary embodiment of a therapeutic system comprising an ocular insert, that may also include an insertion device, a configuration altering material that dissolves (or swells, weakens, tightens, or effects some other activation mechanism) to reconfigure the implant from an insertion configuration to a deployed configuration, or the like;



FIGS. 2-2 and 2-3 show a top view and cross-sectional view of the therapeutic system shown in FIG. 2-1;



FIG. 2-4 shows an embodiment of the therapeutic system where the ring comprises two radially outwardly and/or anteriorly extending protrusions or bumps on opposed portions of its surface;



FIG. 2-5 shows an alternative embodiment of the ring-shaped therapeutic device system. In this embodiment, a crescent or banana-shaped reservoir is attached to the inferior portion of the ocular insert;



FIGS. 3-1 to 3-3 show another embodiment of the therapeutic system including a ring-shaped structure with a diameter of at least 8 mm, sized to fit outside the optical zone of the cornea, and also having two or more haptics;



FIGS. 4-1 to 4-2 show an alternate embodiment of the therapeutic system in which two or more concentric ring-shaped structures are held together by four or more haptics;



FIG. 4-3 shows an embodiment that employs an eccentric design such that the one or more ring portions or arc segments are present in the inferior area of the ring to target delivery to the area of the eye where tears may more readily pool, as in the cul-de-sac;



FIGS. 5-1 through 5-3 show a serpentine embodiment of therapeutic system which shows an expandable ocular insert;



FIGS. 6-1 and 6-2 show another embodiment where the second cushioning structure comprises two hydrogel scleral contact lenses attached to each other, so as to sandwich the first rigid structure between them;



FIGS. 7-1 shows a close-up of an exemplary ocular insert of the therapeutic device system in which the second structure is disposed throughout the circumferential length of the first structure;



FIG. 7-2 shows a cross-section of a therapeutic device system comprising a second structure with a tapered outer and/or inner edge;



FIG. 7-3 shows a cross-section of a therapeutic device system comprising a second structure with a beveled edge;



FIG. 7-4 shows a cross-section of a therapeutic device system comprising a second structure with a rounded edge;



FIG. 8-1 shows a therapeutic device system with a second structure that may have an anterior and/or posterior surface that can be shaped as well to the radius of curvature of the eye;



FIG. 9-1 shows the second, cushioning structure disposed over discrete portions of the length of the first supporting structure;



FIGS. 10-1 and 10-2 show an embodiment where the coating is partially dispersed around the second structure to allow for preferential expansion of the second structure in certain areas;



FIG. 11-1 shows a ring-shaped ocular insert in which separated and/or opposed portions are approximate or pinched in toward the center to form a non-planar taco shape;



FIG. 11-2 shows the ring-shaped ocular insert upon insertion on the surface of the eye, before a dissolvable material has allowed for a slow release back into a ring-shape;



FIGS. 11-3 and 11-4 show an embodiment where the annular shape includes a serpenting shape or series of bends such that radially outer portions or protrusions are interspersed with radially inner portions;



FIGS. 11-5 and 11-6 show an alternative embodiment 88 where a three-leaf clover shape is produced;



FIG. 11-7 shows a fully expanded ocular insert positioned on the surface of the eye;



FIGS. 12-1 and 12-2 show two alternatives of a modified grasping tool, with a notch or groove on the end to facilitate grasping the device;



FIGS. 12-3 to 12-6 show different embodiments for jaws of the grasping tool modified to have a specific shape on the notch to help fold the device into a shape that matches that of the eye and a method of using it;



FIGS. 13-1 to 13-4 show an alternative manner of releasing the ring from the grasping tool;



FIGS. 14-1 to 14-5 show an alternative syringe-shaped insertion device, along with a method for, inserting the ring-shaped ocular insert;



FIGS. 15-1 to 15-3 show another alternative ocular insert insertion device that resembles a classical bike horn;



FIGS. 16-1 to 16-6 show an alternative insertion device comprising a soft flexible cone that supports the ring-shaped device along its outer rim and a method of using it to place an ocular insert on the sclera of the eye; and



FIGS. 17-1 to 17-2 show an alternative insertion device comprising a flexible curved band.





DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS


FIGS. 1-1 and 1-2 show an anatomical tissue structure of an eye 2 suitable for treatment with ocular inserts. The eye 2 includes a cornea 4, an iris 6, and a white-colored sclera 8. A substantially transparent conjunctival layer 10 covers the sclera 8. Posterior to the cornea 4 lies a crystalline lens 12. A retina 14 that responds to light is located in the posterior portion of the eye. A fovea 16 is a part of the retina that provides sharp focused vision. The cornea 4 and lens 12 refract light to form an image on the fovea 16 and retina 14.



FIG. 1-2 shows the lacrimal system 18 which is responsible for producing and draining the tear fluid. The lacrimal system consists of two general areas: first, the lacrimal gland 20, which secretes the tears, and its excretory ducts 22, which transport the fluid to the surface of the eye and, second, the lacrimal canaliculi 24, the lacrimal sac 26, and the nasolacrimal duct 28, which bring the tear fluid is conveyed into the nose cavity.



FIG. 2-1 shows an exemplary embodiment of a therapeutic system 30. The therapeutic system 30 comprises an ocular insert 31, and may also include an insertion device, a configuration altering material that dissolves (or swells, weakens, tightens, or effects some other activation mechanism) to reconfigure the implant from an insertion configuration to a deployed configuration, or the like. In alternative embodiments, activation of the insertion device (or some other tool) may also reconfigure the insert from the insertion configuration to the deployed configuration, or may simply releasably hold the insert in a manner so as to assist insertion. In still further embodiments, the ocular insert may not undergo significant changes in shape or other properties before, during, or after deployment. Regardless, the ocular insert is eventually positioned on a region outside an optical zone of an eye. The ocular insert comprises two structures: a first structure 32 and a second structure 34. FIG. 2-1 shows the exemplary therapeutic system 30 placed outside the optical zone of the eye.


First Structure


The first structure functions as a skeleton which largely holds the implant in place relative to the structures of the eye, thereby attaches the implant to the eye, and thus provides support for the cushioning structure relative to the anterior portion of the eye. This first or skeletal structure preferably maintains the attachment of the therapeutic system to the anterior portion of the eye for at least thirty days. Should it become medically desirable or should a patient so desire, the therapeutic system may be removed sooner than the thirty days; however, from a physical standpoint, it is capable of maintaining the ocular insert of the anterior surface of the eye for at least thirty days. In some embodiments, the first structure may continue to help maintain the overall implant in the eye for sixty days or more, for ninety days or more, or even for 180 days or more, ideally with safe and effective delivery of therapeutic agents continuing throughout such implant periods. Alternative treatment devices and methods may benefit from shorter implant periods, optionally for periods of one or more days, at least a plurality of days, a week or more, two weeks or more, or the like.


Due to its role as skeleton for the insert 31 of therapeutic system 30, the first structure may determine the overall shape of the ocular insert. The first structure typically comprises a thin metal wire, a hard plastic such as nylon, PMMA, polycarbonate, polyethylene terepthalate, and/or another polymer, polypropylene or other synthetic suture material capable of providing the structural support to maintain the therapeutic system attached to the eye. The first structure may also comprise a coated plastic or metal such that the coating contains the therapeutic medication or provides easier attachment of the second, cushioning element to the skeletal member. The first structure may have a surface treatment such as plasma etching or the like to enable the second structure to be suitably attached to the skeletal member.



FIG. 2-1 shows a basic embodiment of the first structure. Here the first structure 32 is annular or ring-shaped and, has a diameter of at least 8 mm, and is sized to fit outside the optical zone of the cornea so as not to interfere with patient vision. The annulus of first structure 32 will preferably comprise a complete ring or torroid, but may have some gap along its circumference. The arc angle of the annulus in such embodiments will be over 180°. FIGS. 2-2 and 2-3 show a top view and cross-sectional view of the therapeutic system shown in FIG. 2-1. The therapeutic system shown in FIGS. 2-1 to 2-3 can be sized much larger so that the edges of the structure will lie within the cul-de-sac of the eye. In the case where the therapeutic system is intended to be located within the cul-de-sac of the eye, the therapeutic system will desirably be produced in at least two sizes to accommodate varying sizes of eyes (e.g. pediatric versus adult, and optionally different adult eye sizes). Alternative shapes of the first structure may include those of the inserts shown and described in U.S. Pat. No. 3,995,635, the disclosure of which is incorporated herein by reference.



FIG. 2-4 shows an embodiment 36 of the therapeutic system 30 where the ring comprises two radially outwardly and/or anteriorly extending protrusions or bumps 42 on opposed portions of its surface. When the eye blinks, the lids “trap” the two bumps between the lids and push the ocular implant (which otherwise can freely glide on the surface of the eye) back into its therapeutically effective position outside the optical zone of the cornea.



FIG. 2-5 shows an alternative embodiment 40 of the ring-shaped therapeutic device system 30. In this embodiment, a crescent or banana-shaped reservoir 42 is attached to the inferior portion of the ocular insert.



FIGS. 3-1 to 3-3 show another embodiment 44 of the therapeutic system 30 again including a ring-shaped structure with a diameter of at least 8 mm, sized to fit outside the optical zone of the cornea, and also having two or more haptics 46, each radiating from the ring-shaped structure across to the cul-de-sac of the eye, thus providing an additional support point for the therapeutic system. FIG. 3-1 shows the ring-shaped therapeutic system with haptics placed on the anterior structure of the eye. FIGS. 3-2 and 3-3 show a top- and a cross-sectional view, respectively, of ocular insert 44.



FIGS. 4-1 to 4-2 show an alternate embodiment 48 of the therapeutic system 30 in which two or more concentric ring-shaped structures 52 are held together by four or more haptics 50. The inner ring-shaped structure has a diameter of at least 8 mm and is sized to fit outside the optical zone of the cornea. The next (and subsequent) outer ring-shaped structures have progressively larger diameters, the outermost ring-shaped structure optionally having a diameter of at least 12 mm and being sized to fit on the sclera, fornix or cul-de-sac of the eye. FIG. 4-1 shows the embodiment 48 of the therapeutic system placed on the eye. FIG. 4-2 shows the embodiment 48 of the therapeutic system before insertion on the eye. The embodiment 48 has the advantage of providing a larger surface area for drug delivery, due to the presence of the two or more rings and four or more haptics. Additional insert shapes having enhanced surface areas may be seen in U.S. Pat. No. 4,540,417, the disclosure of which is incorporated by reference. FIG. 4-3 shows a related embodiment 49 that employs an eccentric design such that the one or more ring portions or arc segments 54 are present in the inferior area of the ring to target delivery to the area of the eye where tears may more readily pool, as in the cul-de-sac. This eccentric design may also stabilize the device in a more fixed position and be less likely to rotate out of position or move into the optical zone of the eye. In addition, targeting delivery to the cul-de-sac may enable more effective delivery of some medications to the nasolacrimal system in addition to the ocular surface, such as in the case of nasal allergy medications.


In the embodiments described above, the first structure typically remains of a constant size and shape, e.g. a ring-shape, or a ring with haptics that anchor/attach to the sclera, fornix or cul-de-sac of the eye.


In other embodiments, the first structure can expand or change shape so as to enhance its attachment to the anterior structure of the eye. FIGS. 5-1 through 5-3 show a serpentine embodiment 56 of therapeutic system 30 which shows an expandable ocular insert. FIG. 5-1 shows the embodiment 56 inserted on the surface of the eye; FIG. 5-2 shows the embodiment 56 before insertion, and FIG. 5-3 shows the embodiment in its expanded state. A variety of alternative serpentine configurations may be developed or modified so as to take advantage of the cushioning and/or configuration-changing techniques described herein, including those of U.S. Pat. No. 4,540,417, the disclosure of which is incorporated herein by reference.


With respect to the already described embodiments, the skeletal member can be shaped to conform to the radius of curvature of the eye.


The first structure can expand as it absorbs fluid from the tear fluid in the eye or can stretch through a spring action mechanism. Examples of materials that can swell upon insertion in the eye include PVPE, PVA and polyurethane gels. Examples of materials that may stretch through spring action include platinum alloys, titanium alloys, all stainless steel alloys & tempers, various clad metals and insulated wires. The first structure may comprise a shape-memory material, such as nitinol, which will allow it to change to a desired shape using thermal, magnetic or electromagnetic activation, from a martensitic to an austenitic state. Other examples of shape memory materials include shape memory polyurethanes, crosslinked trans-polyoctylene rubber, polynorbornene polymers, nitinol, polyethylene, PMMA, polyurethane, cross-linked polyethylene, cross-linked polyisoprene, polycycloocetene, polycaprolactone, copolymers of (oligo)caprolactone, PLLA, PL/DLA copolymers, PLLA PGA copolymers, and other shape memory materials well-known to those of ordinary skill in the art.


Additional Configurations of the First Structure



FIGS. 6-1 and 6-2 show another embodiment 58 where the second cushioning structure comprises two hydrogel scleral contact lenses 60 attached to each other, so as to sandwich the first rigid structure between them. FIG. 6-1 shows the embodiment 58 placed on the surface of the eye; FIG. 6-2 shows the embodiment 58 before placement. In embodiment 58, the first structure 62 functions as a skeleton for the ocular insert and serves as a drug delivery material. As tear fluid penetrates the hydrogel lenses, it comes into contact with the first structure and causes the drug to elute into the tear fluid. Another embodiment (not shown) comprises an exoskeletal first structure comprising a drug delivery material attached to the anterior side of a contact lens. Another embodiment (also not shown) comprises a first structure comprising a drug delivery material placed on an eye and covered by a regular, non-drug delivery contact lens to provide a comfortable lid movement.


Second Structure



FIGS. 7-1 shows a close-up of an exemplary ocular insert 31 of the therapeutic device system 30 in which the second structure 34 is disposed throughout the circumferential length of the first structure 32. The second structure 34 provides cushioning to facilitate extended implantation or wearing of the device, optionally inhibiting irritation to the eye sufficiently to encourage a patient to wear the therapeutic system for at least thirty days. The cushioning effect may be achieved at least in part by the material used in the second structure, as well as by the shape of the surfaces and/or edges of the second structure. In some embodiments, the second structure may comprise a coating.


Desirably the material of the second structure is soft, biocompatible, and non-irritant. Examples of such material comprise polymers such as hydrogel or silicone.


Regardless of its overall shape and configuration, edges of the second structure are often shaped so as to inhibit friction between them and the inside portion of the eyelid. FIG. 7-2 shows a cross-section of a therapeutic device system comprising a second structure 34 with a tapered outer and/or inner edge 64. FIG. 7-3 shows a cross-section of a therapeutic device system comprising a second structure 34 with a beveled edge 66. FIG. 7-4 shows a cross-section of a therapeutic device system comprising a second structure 34 with a rounded edge 68. FIG. 8-1 shows a therapeutic device system 30 with a second structure 34 that may have an anterior and/or posterior surface 70 that can be shaped as well to the radius of curvature of the eye 70.


In some embodiments 72 the second, cushioning structure 74 is disposed only over certain discrete portions along the length of the first structure, desirably at locations where sharper edges or bends may provoke irritation to the eye. FIG. 9-1 shows the second, cushioning structure 74 disposed over discrete portions of the length of the first supporting structure 32.


The second structure may also comprise a coating, partially disposed on the second structure, which prevents the expansion of the otherwise expandable, desirably hydratable, second structure. FIGS. 10-1 and 10-2 show an embodiment 76 where the coating 78 is partially dispersed around the second structure to allow for preferential expansion of the second structure in certain areas. FIG. 10-1 shows an embodiment where the coating is partially dispersed around the second structure 80, with the first structure 32 in an unhydrated state. FIG. 10-2 shows the embodiment of the second structure 80 of FIG. 10-1 in a hydrated, thus expanded, state 76′.


In one embodiment, the first and second structure may comprise similar compositions or materials having differing durometers and/or other characteristics, particularly where the material can be processed so as to exhibit the desired properties for both the first and second structures.


Drug Delivery Matrix


The drug used in the therapeutic system will often be placed on, embedded, encapsulated or otherwise incorporated into a delivery matrix. The delivery matrix may be included in or on either the first skeletal structure or the second cushioning structure, or both. The delivery matrix, in turn, comprises either a biodegradable or a non-biodegradable material. The delivery matrix may include, although it is not limited to, a polymer. Examples of biodegradable polymers include protein, hydrogel, polyglycolic acid (PGA), polylactic acid (PLA), poly(L-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(alpha-hydroxy acid), and combinations thereof. Non-biodegradable polymers may comprise silicone, acrylates, polyethylenes, polyurethane, polyurethane, hydrogel, polyester (e.g., DACRON® from E. I. Du Pont de Nemours and Company, Wilmington, Del.), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether ether ketone (PEEK), nylon, extruded collagen, polymer foam, silicone rubber, polyethylene terephthalate, ultra high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimides, stainless steel, nickel-titanium alloy (e.g., Nitinol), titanium, stainless steel, cobalt-chrome alloy (e.g., ELGILOY® from Elgin Specialty Metals, Elgin, Ill.; CONICHROME® from Carpenter Metals Corp., Wyomissing, Pa.).


To prevent a potential allergic reaction to the ocular insert in a patient, the ocular insert, desirably will comprise a hypoallergenic, material. Desirably, either or both the first and/or second structure may comprise materials such as hydrogels, polyethylene glycol (PEG), or polyethylene oxide (PEO) that prevent adhesion of proteins and thus minimize the chance of developing an allergic reaction. Alternatively, the drug delivery matrix of the ocular insert may comprise an anti-allergenic and/or antihistaminic compound to prevent an allergic reaction to the ocular insert. In certain embodiments, the delivery matrix may also include other materials known in the art.


Therapeutic System Drugs


A variety of drugs may be delivered to the eye using the therapeutic system. Desirably these drugs will include drugs needed for long-term treatment to the eye. Examples of conditions that require long-term treatment include: dry eye, glaucoma, allergies, infections, bacterial, viral and other infections, chronic inflammatory conditions such as acne rosacea keratitis, cyclitis, and blepharitis, selected retinal conditions such as diabetic retinopathy, age related macular degeneration and other retinal conditions, post-surgery, amblyopia, etc.


Some drug families used in the treatment of the above-mentioned conditions comprise: steroids, anti-inflammatories, antibiotics, glaucoma treatment compounds, antihistamines, dry eye medication, neuroprotectives, retinoids, antineovasculars, antioxidants, and biologics.


Examples of steroids include glucocorticoids, aprogestins, amineralocorticoids, or corticosteroids. Exemplary corticosteroids include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, triamcinolone, fluoromethalone, dexamethasone, medrysone, betamethasone, loteprednol, fluocinolone, flumethasone, rimexolone or mometasone. Other examples of steroids include androgens, such as testosterone, methyltestosterone, or danazol.


Examples of anti-inflamatories include NSAIDs such as piroxicam, aspirin, salsalate (Amigesic), diflunisal (Dolobid), ibuprofen (Motrin), ketoprofen (Orudis), nabumetone (Relafen), piroxicam (Feldene), naproxen (Aleve, Naprosyn), diclofenac (Voltaren), indomethacin (Indocin), sulindac (Clinoril), tolmetin (Tolectin), etodolac (Lodine), ketorolac (Toradol), oxaprozin (Daypro), and celecoxib (Celebrex).


Examples of antibiotics include amoxicillin, penicillin, sulfa drugs, erythromycin, streptomycin, tetracycline, clarithromycin, terconazole, azithromycin, bacitracin, ciprofloxacin, evofloxacin, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, aminoglycosides, tobramycin, gentamicin, as well as polymyxin B combinations including polymyxin B/trimethoprim, polymyxin B/bacitracin, polymyxin B/neomycin/gramicidin.


Glaucoma treatment medications include beta-blockers, such as timolol, betaxolol, levobetaxolol, and carteolol; miotics, such as pilocarpine; carbonic anhydrase inhibitors, such as brinzolamide and dorzolamide; prostaglandins, such as travoprost, bimatoprost, and latanoprost; seretonergics; muscarinics; dopaminergic agonists; and adrenergic agonists, such as apraclonidine and brimonidine, and prostaglandins or prostaglandin analogs such as latanoprost, bimatoprost, or travoprost.


Antihistamines and mast cell stabilizers include Olopatadine and epinastine, the acute care anti-allergenic products ketorolac tromethamine, ketotifen fumarate, loteprednol, epinastine HCl, emedastine difumarate, azelastine hydrochloride, Olopatadine hydrochloride, ketotifen fumarate; while the chronic care anti-allergenic products include pemirolast potassium, nedocromil sodium, lodoxamide tromethamine, cromolyn sodium.


Antineovasculars include biologics, Ranibizumab (Lucentis) and Bevacizumab (Avastin). Amblyopia medicine includes anesthetics and cycloplegics such as atropine. Dry eye medication includes cyclosporine.


Control of the Drug Elution Process


Drug elution can be controlled either through concentration of the drug present, or by embedding into or combining the drug with various other compounds. The drug's particular solubility characteristic, whether hydrophobic or hydrophilic, will determine the means of controlling the rate of elution for that particular drug. In some embodiments where the drug is hydrophobic, the drug may be finely ground up and dispersed into the second cushioning structure comprising silicone or a polymer such as hydrogel that is highly hydrophilic. Hydrophilic drugs can either be immobilized in a first structure, e.g. a plastic, or a second structure such as a hydrogel. The specific choice of polymers used for immobilizing depends on the drug and its characteristics, the rate of elution desired, and the wall thickness of the coating that contains the drug which may also alter the rate of elution. For instance, if the drug is embedded in a first polymer, then the wall thickness of the second polymer may at least in part control the rate at which the drug passes through. Conversely, the wall thickness of the coating may be used to control drug release if the drug is embedded into the skeletal element.


Other considerations may include choice of substrate material for the skeleton and whether the drug can be incorporated into the skeleton, then cast into the specific skeletal shape, and then coated with a hydrogel or other polymer.


In the case of hydrophobic drugs, surfactants comprising bile salts (e.g. deoxycholate, taurodeoxycholate, and glycocholate) or calcium chelators, such as ethylenediaminetetraacetic acid (EDTA), may be added to increase their solubility.


Conversely, to decrease the rate of elution, the drug particles may be coated, a less soluble salt form of the drug may be produced, or a rate-limiting coating, polymer, or other material may be incorporated in and/or on the delivery matrix such that the distance the drug travels to exit the device or the resistance of the material to passage of the drug restricts flow of the drug from the device.


Other variables include whether or not the polymer absorbs enough aqueous/tear fluid to force the drug out of the matrix, such as a sponge-like or naturally porous material or a material with artificially created pores or other materials that saturate such that an osmotic pumping effect occurs.


The surface area and geometric configuration of the therapeutic system can also be used to control the elution rate of the drug. The geometric configuration of the therapeutic device can be thus designed to maximize, or minimize, the flow of tear fluid over the therapeutic system, according to the specific need. For example, an increased surface area will increase the contact area between the drug and the tear fluid. The device could also be constructed such that it has more delivery area/surface area in the lower or upper fornix depending on if a targeted delivery is desired. Conversely, to decrease the elution rate of the drug, the contact area between the eye and the drug particles should be decreased.


Therapeutic System Coatings


In some embodiments, the second structure also comprises a coating to further soothe the patient's eye. The coating may comprise a lubricious material, e.g., Hydak® hyaluronan-based coating from Biocoat. The advantages of Hydak include that it is lubricious when wet, biocompatible, highly hydrophilic, may be applied using thin, flexible coatings, and it is a carrier for bioactive substances. Other coatings could also include either hydrophilic or drug delivery coatings from SurModics (hydrophilic or drug delivery) and Hydromer.


To ease the insertion process, some embodiments will be coated so that the ocular inserts will have a firm texture during insertion. Once such ocular inserts are in place, the coating will dissolve to allow the ocular insert to become more comfortable for every-day use.


Insertion and Removal of the Therapeutic System


The therapeutic system may first be placed onto the eye by a physician and then, once a desired drug-delivery time period is complete, subsequently be removed from the anterior surface of the eye by the same or a different physician. The physician may optionally then teach the patient how to insert and then take out the ocular implant by him- or herself.


A challenge to insertion and removal of the device comes from maintaining the fine balance between rigidity and flexibility. A device that is too flexible will be very difficult to insert; while a device that is too rigid will be uncomfortable to wear for extended periods of time.


One way of maintaining the fine balance between rigidity and flexibility is by folding or pinching the device into various shapes. The folds in the device create a structure that maintains its shape more effectively during insertion and thus is more “pushable” than a ring structure that deforms easier.


One alternative for maintaining the folds in the device for purposes of insertion is to tether the folds with a dissolvable material until the device is placed in the eye. The dissolvable material allows for a slow release of the shape back into a ring.



FIG. 11-1 shows a ring-shaped ocular insert 31 in which separated and/or opposed portions are approximate or pinched in toward the center to form a non-planar taco shape 82. The pinched ring-shaped device can be positioned such that one end can be slipped under the lower or upper lid, then the other end can be positioned under the other lid. FIG. 11-2 shows said ocular insert 31 upon insertion on the surface of the eye, before a dissolvable material has allowed for a slow release back into a ring-shape; FIG. 11-7 shows said device on the surface of the eye, in its fully expanded state 94.



FIG. 11-3 shows one embodiment 84 where the annular shape includes a serpenting shape or series of bends such that radially outer portions or protrusions are interspersed with radially inner portions. This embodiment has four protrusions and a clover leaf shape is produced such that each of the four protrusions 86 would facilitate placement into the upper and lower lids as well as the nasal and temporal aspects of the eye. The inner portions of this shape could also be held together (or near each other) with a dissolvable material, but it may not be necessary since a good initial position could be achieved. FIG. 11-4 shows said embodiment 84 upon insertion on the surface of the eye; FIG. 11-7 shows said device on the surface of the eye, in its fully expanded state 94.



FIG. 11-5 shows an alternative embodiment 88 where a three-leaf clover shape 90 is produced. In this case the top protrusion 92 would first be inserted behind the top eyelid and then the bottom two protrusions would be inserted behind the bottom eyelid. As in the previous embodiment, this shape could also be held in place with a dissolvable material, but it may not be necessary since a good initial position could be achieved. FIG. 11-6 shows said device upon insertion on the surface of the eye; FIG. 11-7 shows said device on the surface of the eye, in its fully expanded state 94.


Insertion of the device can also be facilitated by use of delivery instruments. FIGS. 12-1 and 12-2 show two alternatives of a modified grasping tool 150 and 160, with a notch or groove 170 on the end to facilitate grasping the device. Desirably, the jaws have an antramatic distal surface with, for example, a top layer comprising silicone or Teflon so that if they come in contact with the surface of the eye, they will not scratch it. In FIG. 12-2, an embodiment of a delivery instrument that can accommodate two or more jaws is shown, there are preferably three or four jaws 162 (the drawing shows two jaws for simplicity) that create the three or four leaf clover shape when the device 160 is clamped onto the ring. The three or four jaws 162 come together simultaneously via an outer tube that forces the tines of the jaws to compress from their more relaxed outward position.



FIGS. 12-3 to 12-5 show different embodiments for jaws 162 of the grasping tool modified to have a specific shape on the notch to help fold the device into a shape that matches that of the eye. FIG. 12-3 shows jaws with a groove 172 that runs horizontally across the jaws. FIG. 12-4 shows jaws with a groove 175 that is curved so as to bend the ring into a shape that conforms more easily to the shape of the eye.



FIG. 12-5 shows an alternative antramatic embodiment of a jaw with a curved groove 176. In this embodiment the jaw consists of three adjacent slabs with a horizontal groove. As shown in FIG. 12-5, to grab the ring-shaped ocular insert 31, the middle slab 178 is raised slightly, to allow the formation of a curved groove for the ring material. As shown in FIG. 12-6, to release the ocular insert 31, once the protruding fold of the ring has touched the surface of the eye, the middle slab is pushed down so that all the slabs are flush with each other and the groove running on the side of the three slabs is now horizontal; the ring will now be easily released from the grasping tool.



FIGS. 13-1 to 13-4 show an alternative manner of releasing the ring from the grasping tool. FIG. 13-1 shows a modified grasping tool 160 comprising four jaws 162, each jaw comprising a groove 170 positioned at the anterior end of each jaw and facing the center of the grasping tool. FIG. 13-2 shows a modified grasping tool 160 that has grasped an ocular insert 31 in the grooves 170, tightened the jaws 162 on the insert, creating four protrusions to ease insertion of the ocular insert behind a patient's eye lids. Once the protruding folds of the ring-shaped device have been placed on the eye, the arms with the jaws each turn 180° so that the groove is not located along the external circumference of the gasping tool; the folded ring can now slide out easily, as it is no longer maintained in the groove. FIG. 13-3 shows the modified grasping tool 160 where each jaw has turned approximately 180° so that each groove 170 now faces away from the center of the grasping tool. The 180° turn of the grooves has resulted in a release of the ocular insert 31. FIG. 13-4 shows the ocular insert 131 released from the modified grasping tool 160.



FIGS. 14-1 to 14-5 show an alternative device, along with a method for, inserting the ring-shaped device. FIG. 14-1 shows a syringe-shaped device 180 comprising a barrel 182 with a flat tip 184 through which ocular insert 31 can be pushed, and a plunger 186. To insert the ring-shaped device in the syringe, the plunger of the syringe is taken out, the ring-shaped device is folded flat and inserted into the body of the syringe and the plunger is placed back into the syringe. FIG. 14-2 shows a syringe-shaped device 180 where and ocular insert 31 has been folded flat and inserted into the barrel 182. The plunger 186 has been inserted into the barrel, with the barrel comprising a lumen and the open tip comprising a port through which insert 31 can be pushed. To insert the ring-shaped device into the eye, the plunger pushed into the body of the syringe so as to allow the ring-shaped device to slowly squeeze through the flat tip of the syringe. FIG. 14-3 shows the loop of the ocular insert 31 substantially extruded from the tip 184 of the syringe-shaped device 180 and ready for placement on the sclera of the eye. FIG. 14-4 shows the loop of the ocular insert 31 partially placed on the sclera of the eye; the rest of the ocular insert will be pushed through the tip 184 of the syringe-shaped device 180 and released onto the eye. FIG. 14-5 shows the ocular insert 31 placed on the sclera of the eye.



FIGS. 15-1 to 15-3 show another alternative ocular insert insertion device that resembles a classical bike horn. FIG. 15-1 shows a bike horn-shaped insertion device 180 comprising two parts: a trumpet 182 and a squeeze bulb 184. FIG. 15-2 shows a close-up of the trumpet 182. The trumpet comprises a soft material 182 with channels 188 that connect the squeeze bulb to the outer rim of the insertion device. The outer rim of the trumpet comprises a groove 186 which is sized to fit a ring-shaped device. FIG. 15-3 shows a cross-section of the bike-horn shaped insertion device comprising a trumpet and a squeeze bulb. The squeeze bulb comprises a vacuum source and a reservoir for liquid 190, desirably saline. The squeeze bulb is attached to the trumpet.


To pick up a ring-shaped device for insertion on the surface of the eye, the squeeze bulb is squeezed, thereby creating a vacuum seal which picks up and holds the ring-shaped device in the groove of the outer rim of the trumpet. To place the ring-shaped device on the anterior surface of the eye, the trumpet is gently inserted under both eyelids of an eye and the squeeze bulb is gently squeezed, causing the liquid from the squeezed bulb's reservoir to flow through the channels of the trumpet, breaking the vacuum seal between the ring-shaped device and the outer rim of the trumpet. The trumpet is then gently pulled out from underneath the eyelids.



FIGS. 16-1 to 16-6 show an alternative insertion device 192. FIG. 16-1 shows an alternative insertion device 192 comprising a soft flexible cone 194 that supports the ring-shaped device along its outer rim 196 and a method of using it to place an ocular insert on the sclera 8 of the eye 2. FIG. 16-2 shows a close-up view of the outer rim of the delivery device 196. The outer rim comprises a groove 198 designed to fit the ring-shaped ocular insert 31. FIG. 16-3 shows a front view of the insertion device 192 comprising a soft flexible cone. The soft flexible cone comprises two slits 198, to allow the diameter of the cone to be modifiable. FIGS. 16-4 to 16-6 show a method for using the insertion device 192 to insert the ocular insert 31. FIG. 16-4 shows the insertion device 192 loaded with the ring-shaped ocular insert 31 being gently tucked under the top 202 and bottom eyelid 204. FIG. 16-5 shows the soft flexible cone 194 being pinched or pulled, so as to lower the circumference of the cone and release the ring-shaped ocular insert 31 from the outer rim 196 of the cone. FIG. 16-6 shows the ring-shaped ocular insert 31 left in the eye, while the cone 194 is pulled away from under the eyelids.



FIGS. 17-1 to 17-2 show an alternative insertion device. FIG. 17-1 shows the insertion device 206 comprising a flexible curved band 208. As shown in FIG. 17-2, the curved band comprises a curved groove that can support ocular insert 31, while the ocular insert is gently slid behind at least one of the eyelids.


Example 1: Calculation of a Drug's Therapeutically Effective Dosage for an Ocular Insert—Olopatadine

The drug Olopatadine, for treatment of allergic conditions, will demonstrate a method that can be used in calculating a drug's therapeutically effective plant-delivered dosage based on a drop-administered treatment regimen for that drug. The calculation method involves the following steps: 1.) determining the number of drops desired per application; 2.) multiplying the number of drops by 30 uL (the volume of one drop); 3.) determining the amount of solid drug per uL; 4.) multiplying the results from step 2 by the result from step 3, to find out the amount of solid drug to be applied to the eye on a daily basis; 5.) multiplying the result in step 4 by the number of days of therapy desired for the particular drug; and 6) multiplying by the efficiency of drug delivery. This final amount will preferably be dispersed from an ocular insert.


Olopatadine is an ophthalmic antihistamine (H 1-receptor) and mast cell stabilizer. The usual adult dosage for Olopatadine may be, for example, one drop in each affected eye twice a day, when using the 0.1% solution and one drop per day in each affected eye, when using the 0.2% solution.


Estimating use of the 0.1% Olopatadine solution, 1 mL of the drug corresponds to 1 mg of the drug. One drop is 30 uL, which corresponds to 0.03 mL of the solution and 30 ug of Olopatadine. Since the 0.1% solution is applied twice a day, the daily dosage of Olopatadine is 60 ug. Due to the inefficiency of eye drops in drug delivery 90-95% of the Olopatadine applied to the eye is washed out. This leaves only 3-6 ug of Olopatadine in the eye. 3-6 ug per day for 30 days amounts to about 90-180 ug of Olopatadine that may be delivered to one eye within a period of one month.


Example 2: Drug Delivery Procedure & Elution Rate Control for a Hydrophilic Drug—Olopatadine Hydrochloride

Olopatadine HCl (OH) for ophthalmic applications can be formulated as a 0.2% (2 mg/mL) solution. A single 50 uL drop containing 100 ug of OH may be instilled in the eye once a day for 2 weeks. Estimating 5% availability, this gives a 5 ug/day dose delivered to the cornea, for a total of 70 ug over the course of the 2 week treatment. At least 70 ug in dry form could be loaded into the implant and released into the tear film by partitioning the drug reservoir with a membrane (e.g. HEMA, PVA, PVP, GMA, dialysis tubing of cellulose, etc) or embedding the drug within the implant. The release rate could be controlled by altering the surface area exposed to the tear film to tailor the desired 5 ug/day (0.21 ug/hour), by altering a drug release controlling membrane, or the like. It is again assumed in this calculation that 100% of the targeted dose gets to its target location without being washed out with tear film, and more accurate calculations can be performed using wash-out data.


For both examples, the outside of the implant could be coated for either example with a bolus of the drug for immediate dosing while the hydration process, and thus flux of drug across the membrane or through the reservoir can take place. These coatings could be in solid drug form with a readily dissolvable layer (e.g. starch, sugar) to maintain placement of the solid drug upon the exterior of the implant.


Example 3: Drug Delivery Procedure & Elution Rate Control for a Hydrophobic Drug—Prednisolone Acetate

Generally, a 1% Prednisolone acetate suspension (10 mg/mL) is given 2 drops (total of approximately 100 uL volume) 4 times daily for a week. Working with the estimate that 5% of a dose is actually available for absorption into the cornea, this amounts to 20 ug/day of Prednisolone acetate. A week's available dose is then 140 ug. The solubility of Prednisolone acetate in aqueous solutions is approximately 240 ug/mL. At least 140 ug of solid Prednisolone acetate could be loaded into the implant, allowing the Prednisolone acetate to dissolve into the tear layer at a rate of about 0.83 ug/hour. The rate could be controlled by the porosity of the implant as well as the surface area exposed to the tear film.


For these simplified calculations, it has been assumed that 100% of the dose hits the target (the cornea) and is absorbed completely and not lost by tear layer flow away from the cornea. Adjustments can be made based on test data, modeling, or the like.


While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of skill in the art will recognize that a variety of modifications, adaptations, and changes may be employed. Hence, the scope of the present invention should be limited solely by the appended claims.

Claims
  • 1. An ocular insert for use in an eye, the eye having upper and lower lids extendable along an anterior eye surface with an optical zone therebetween, the insert comprising: a first structure comprising an annulus formed of a non-biodegradable suture having a length disposable along the anterior surface of the eye of a patient sized to fit outside the optical zone of the cornea;a second structure completely surrounding the suture such that at least a portion of the length of the suture threads through an interior of the second structure, the second structure cushioning engagement between the insert and the eye so as to inhibit irritation of the eye when the first structure helps maintain the insert in contact with the eye for a plurality of days; andat least one drug disposed on or embedded into the second structure so as to release a safe and therapeutically effective quantity of the drug to the eye for each of the plurality of days.
  • 2. The ocular insert of claim 1, wherein the at least one drug is further disposed on or in the first structure.
  • 3. The ocular insert of claim 1, wherein the at least one drug is releasable from the second structure for at least 30 days.
  • 4. The ocular insert of claim 1, wherein the at least one drug is hydrophilic, and wherein the second structure is a hydrophilic polymer.
  • 5. The ocular insert of claim 1, wherein the at least one drug is hydrophobic, and wherein the insert comprises surfactants to increase the drug solubility.
  • 6. The ocular insert of claim 1, wherein the at least one drug is hydrophobic, and wherein the insert comprises an elution rate decrease material, the elution rate decrease material comprising a coating over the second structure or a component of a delivery matrix forming the second structure.
  • 7. The ocular insert of claim 1, wherein the first structure further comprises two radial protrusions extending radially outwardly from the annulus so as to engage the lids and position the insert around the optical zone when the eye blinks.
  • 8. The ocular insert of claim 1, wherein the first structure further comprises a local thickening along at least one portion of the annulus.
  • 9. The ocular insert of claim 1, wherein the first structure further comprises a plurality of haptics extending radially from the annulus.
  • 10. The ocular insert of claim 1, wherein the first structure further comprises at least one arc radially offset from the annulus, and a plurality of radial members extending between the at least one arc and annulus.
  • 11. The ocular insert of claim 1, wherein the annulus of the first structure comprises a serpentine annulus having radially inward portions interspersed with radially outward portions.
  • 12. The ocular insert of claim 1, wherein the annulus of the first structure has inner and outer edges, at least one of the edges being atraumatically shaped to avoid sharp-edge irritation of the eye.
  • 13. The ocular insert of claim 1, wherein the annulus of the first structure has a non-planar eye-engagement surface.
  • 14. The ocular insert of claim 1, wherein the second structure swells when hydrated, and the insert further comprises a separated series of swell-inhibiting bands disposed over the first and second structures.
  • 15. The ocular insert of claim 1, wherein the at least one drug comprises one or more members selected from the group consisting of: a steroid selected from the group consisting of at least one of glucocorticoids, aprogestins, amineralocorticoids, corticosteroids, cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, triamcinolone, fluoromethalone, dexamethasone, medrysone, betamethasone, loteprednol, fluocinolone, flumethasone, rimexolone mometasone, androgens, testosterone, methyltestosterone, and danazol;a non-steroidal anti-inflammatory (NSAID) selected from the group consisting of at least one of piroxicam, aspirin, salsalate, diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac, oxaprozin, and celecoxib;an antibiotic selected from the group consisting of at least one of amoxicillin, penicillin, sulfa drugs, erythromycin, streptomycin, tetracycline, clarithromycin, terconazole, azithromycin, bacitracin, ciprofloxacin, evofloxacin, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, aminoglycosides, tobramycin, gentamicin, and polymyxin B combinations, wherein the polymyxin B combinations are selected from the group consisting of polymyxin B/trimethoprim, polymyxin B/bacitracin, and polymyxin B/neomycin/gramicidin;a glaucoma treatment medication selected from the group consisting of at least one of beta-blockers, mitotics, carbonic anhydrase inhibitors, prostaglandins, prostaglandin analogs, seretonergics, muscarinics, dopaminergic agonists, and adrenergic agonists,wherein the beta-blockers are selected from the group consisting of timolol, betaxolol, levobetaxolol, and carteolol,wherein the mitotics are selected from the group consisting of pilocarpine,wherein the carbonic anhydrase inhibitors are selected from the group consisting of brinzolamide, and dorzolamide,wherein the prostaglandin analogs are selected from the group consisting of travoprost, bimatoprost, and latanoprost, andwherein the adrenergic agonists are selected from the group consisting of apraclonidine, and brimonidine;an antihistamine and mast cell stabilizer selected from the group consisting of at least one of ketorolac tromethamine, ketotifen fumarate, loteprednol, epinastine HCl, emedastine difumarate, azelastine hydrochloride, olopatadine hydrochloride;a chronic care anti-allergenic product selected from the group consisting of at least one of pemirolast potassium, nedocromil sodium, lodoxamide tromethamine, and cromolyn sodium; anda dry eye medication selected from the group consisting of cyclosporine; andan anesthetic.
  • 16. The ocular insert of claim 1, wherein the second structure has a cross-sectional shape that is rounded or beveled.
  • 17. The ocular insert of claim 1, wherein the first structure is a polypropylene suture or a nylon suture.
  • 18. The ocular insert of claim 17, wherein the second structure is a silicone matrix.
  • 19. The ocular insert of claim 18, wherein the second structure comprises a plurality of cushioning structures, each cushioning structure completely surrounding a discrete portion of the length of the suture.
CROSS REFERENCE TO RELATED APPLICATION

This application is a Continuation of patent application Ser. No. 13/151,001, filed Jun. 1, 2011, issuing on Aug. 23, 2016, as U.S. Pat. No. 9,421,126, entitled “Anterior Segment Drug Delivery”, which is a Continuation of PCT/US2010/037268 filed Jun. 3, 2010, entitled “Anterior Segment Drug Delivery”, which claims the benefit of U.S. Provisional Application No. 61/183,839 filed Jun. 3, 2009, entitled “Anterior Segment Drug Delivery”, the contents of which are hereby fully incorporated by reference.

US Referenced Citations (254)
Number Name Date Kind
3113076 Jacobs Dec 1963 A
3312215 Silber et al. Apr 1967 A
3416530 Ness Dec 1968 A
3545439 Kalamazoo et al. Dec 1970 A
3566874 Shepherd et al. Mar 1971 A
3618604 Ness Nov 1971 A
3626940 Zaffaroni Dec 1971 A
3710796 Neefe Jan 1973 A
3760805 Higuchi Sep 1973 A
3811444 Heller et al. May 1974 A
3826258 Abraham Jul 1974 A
3828777 Ness Aug 1974 A
3845201 Haddad et al. Oct 1974 A
3867519 Michaels Feb 1975 A
3903880 Higuchi et al. Sep 1975 A
3916899 Theeuwes et al. Nov 1975 A
3920805 Roseman Nov 1975 A
3926188 Baker et al. Dec 1975 A
3960150 Hussain et al. Jun 1976 A
3961628 Arnold Jun 1976 A
3962414 Michaels Jun 1976 A
3963025 Whitaker et al. Jun 1976 A
3991760 Drobish et al. Nov 1976 A
3993073 Zaffaroni Nov 1976 A
3995633 Gougeon Dec 1976 A
3995634 Drobish Dec 1976 A
3995635 Higuchi et al. Dec 1976 A
4008719 Theeuwes et al. Feb 1977 A
4012496 Schopflin et al. Mar 1977 A
4014334 Theeuwes et al. Mar 1977 A
4014335 Arnold Mar 1977 A
4016251 Higuchi et al. Apr 1977 A
4052505 Higuchi et al. Oct 1977 A
4057619 Higuchi et al. Nov 1977 A
4067961 Laughlin Jan 1978 A
4093709 Choi et al. Jun 1978 A
4131648 Choi et al. Dec 1978 A
4155991 Schopflin et al. May 1979 A
4157864 Koller et al. Jun 1979 A
4160452 Theeuwes Jul 1979 A
4164560 Folkman et al. Aug 1979 A
4177256 Michaels et al. Dec 1979 A
4179497 Cohen et al. Dec 1979 A
4190642 Gale et al. Feb 1980 A
4201210 Hughes et al. May 1980 A
4215691 Wong Aug 1980 A
4249531 Heller et al. Feb 1981 A
4281654 Shell et al. Aug 1981 A
4285987 Ayer et al. Aug 1981 A
4292965 Nash et al. Oct 1981 A
4303637 Shell et al. Dec 1981 A
4304765 Shell et al. Dec 1981 A
4322323 Capozza Mar 1982 A
4343787 Katz Aug 1982 A
4432964 Shell et al. Feb 1984 A
4439198 Brightman, II et al. Mar 1984 A
4469671 Zimmerman et al. Sep 1984 A
4484922 Rosenwald Nov 1984 A
4524776 Withers et al. Jun 1985 A
4540417 Poler Sep 1985 A
4652099 Lichtman Mar 1987 A
4678466 Rosenwald Jul 1987 A
4822616 Zimmermann et al. Apr 1989 A
4888074 Pocknell Dec 1989 A
4961931 Wong Oct 1990 A
4973304 Graham et al. Nov 1990 A
5071657 Oloff et al. Dec 1991 A
5098443 Parel et al. Mar 1992 A
5137728 Bawa Aug 1992 A
5147647 Darougar Sep 1992 A
5178635 Gwon et al. Jan 1993 A
5205611 Stephens Apr 1993 A
5248700 Lance Sep 1993 A
5300114 Gwon et al. Apr 1994 A
5314419 Pelling May 1994 A
5322691 Darougar et al. Jun 1994 A
5370607 Memmen Dec 1994 A
5378475 Smith et al. Jan 1995 A
5395618 Darougar et al. Mar 1995 A
5443505 Wong et al. Aug 1995 A
5472436 Fremstad Dec 1995 A
5474780 Chang Dec 1995 A
5476511 Gwon et al. Dec 1995 A
5496811 Aviv et al. Mar 1996 A
5605696 Eury et al. Feb 1997 A
5618274 Rosenthal Apr 1997 A
5694947 Lehtinen et al. Dec 1997 A
5773019 Ashton et al. Jun 1998 A
5773021 Gurtler et al. Jun 1998 A
5788977 Aguadisch et al. Aug 1998 A
5824086 Silvestrini Oct 1998 A
5851547 Fujioka et al. Dec 1998 A
5855906 McClay Jan 1999 A
5902598 Chen et al. May 1999 A
5972372 Saleh et al. Oct 1999 A
5989579 Darougar et al. Nov 1999 A
6001386 Ashton et al. Dec 1999 A
6015213 Nakada et al. Jan 2000 A
6096076 Silvestrini Aug 2000 A
6109537 Heath Aug 2000 A
6120460 Abreu Sep 2000 A
6146366 Schachar Nov 2000 A
6149685 Sigoloff Nov 2000 A
6217896 Benjamin Apr 2001 B1
6264971 Darougar et al. Jul 2001 B1
6361780 Ley et al. Mar 2002 B1
6375642 Grieshaber et al. Apr 2002 B1
6375972 Guo et al. Apr 2002 B1
6394094 McKenna et al. May 2002 B1
6485735 Steen et al. Nov 2002 B1
6547714 Dailey Apr 2003 B1
6634576 Verhoff et al. Oct 2003 B2
6669950 Yaacobi Dec 2003 B2
6719750 Varner et al. Apr 2004 B2
6746686 Hughes et al. Jun 2004 B2
6841574 Mo et al. Jan 2005 B2
6939569 Green et al. Sep 2005 B1
6964781 Brubaker Nov 2005 B2
6966927 Silverstrini Nov 2005 B1
6986900 Yaacobi Jan 2006 B2
6991808 Brubaker et al. Jan 2006 B2
7094226 Yaacobi Aug 2006 B2
7195774 Carvalho et al. Mar 2007 B2
7488343 O'Brien et al. Feb 2009 B2
7544371 Kunzler et al. Jun 2009 B2
7762662 Eno Jul 2010 B1
7785578 Miller et al. Aug 2010 B2
7799336 Hughes Sep 2010 B2
7833545 Ron et al. Nov 2010 B2
7862552 McIntyre et al. Jan 2011 B2
7910126 Ahmed et al. Mar 2011 B2
7985208 Christensen Jul 2011 B2
7998497 de Juan, Jr. et al. Aug 2011 B2
8021680 Anderson et al. Sep 2011 B2
8715712 de Juan, Jr. May 2014 B2
8939948 de Juan, Jr. Jan 2015 B2
9421126 Alster Aug 2016 B2
20020026176 Varner et al. Feb 2002 A1
20020047058 Verhoff et al. Apr 2002 A1
20020115985 Larson et al. Aug 2002 A1
20030088307 Shulze et al. May 2003 A1
20030176854 Rodstrom Sep 2003 A1
20040042073 Pynson Mar 2004 A1
20040115234 Gewirtz Jun 2004 A1
20040121014 Guo et al. Jun 2004 A1
20040133155 Varner et al. Jul 2004 A1
20040170685 Carpenter et al. Sep 2004 A1
20040220660 Shanley et al. Nov 2004 A1
20040241243 Lin et al. Dec 2004 A1
20040249364 Kaploun Dec 2004 A1
20040265355 Shalaby Dec 2004 A1
20050019371 Anderson et al. Jan 2005 A1
20050042292 Muldoon et al. Feb 2005 A1
20050048099 Shiah et al. Mar 2005 A1
20050053639 Shalaby Mar 2005 A1
20050060021 O'Brien et al. Mar 2005 A1
20050125059 Pinchuk et al. Jun 2005 A1
20050163844 Ashton Jul 2005 A1
20050196424 Chappa Sep 2005 A1
20050197651 Chen et al. Sep 2005 A1
20050228473 Brown Oct 2005 A1
20050228482 Herzog et al. Oct 2005 A1
20050244461 Nivaggioli et al. Nov 2005 A1
20050244464 Hughes Nov 2005 A1
20050276841 Davis et al. Dec 2005 A1
20050288197 Horn Dec 2005 A1
20060024350 Varner et al. Feb 2006 A1
20060034891 Lawin et al. Feb 2006 A1
20060140867 Helfer et al. Jun 2006 A1
20060185678 Bronnenkant et al. Aug 2006 A1
20060212115 Maldonado Bas Sep 2006 A1
20060216328 Kis et al. Sep 2006 A1
20060235513 Price Oct 2006 A1
20060246112 Snyder et al. Nov 2006 A1
20060264912 McIntyre et al. Nov 2006 A1
20060292222 Jonasse Dec 2006 A1
20070112318 Leahy et al. May 2007 A1
20070134305 Zilberman Jun 2007 A1
20070196433 Ron et al. Aug 2007 A1
20070202150 Dave Aug 2007 A1
20070212387 Patravale et al. Sep 2007 A1
20070243230 de Juan et al. Oct 2007 A1
20070269487 de Juan et al. Nov 2007 A1
20080090911 Frank et al. Apr 2008 A1
20080097591 Savage et al. Apr 2008 A1
20080103584 Su et al. May 2008 A1
20080145406 Asgharian et al. Jun 2008 A1
20080181930 Rodstrom et al. Jul 2008 A1
20080243095 Kaiser et al. Oct 2008 A1
20090005864 Eggleston Jan 2009 A1
20090012836 Weissbach et al. Jan 2009 A1
20090081278 De Graaff et al. Mar 2009 A1
20090082863 Schieber et al. Mar 2009 A1
20090092654 de Juan, Jr. et al. Apr 2009 A1
20090104243 Utkhede et al. Apr 2009 A1
20090104248 Rapacki et al. Apr 2009 A1
20090110756 McCray, Jr. et al. Apr 2009 A1
20090143752 Higuchi et al. Jun 2009 A1
20090148485 Whitehead Jun 2009 A1
20090155326 Mack et al. Jun 2009 A1
20090155338 Conway et al. Jun 2009 A1
20090162417 Eells Jun 2009 A1
20090163596 Gutman et al. Jun 2009 A1
20090196903 Kliman Aug 2009 A1
20090220573 Kaufman Sep 2009 A1
20090234005 Ishida et al. Sep 2009 A1
20090252807 Jenkins et al. Oct 2009 A1
20090280158 Butuner Nov 2009 A1
20090287300 Dave et al. Nov 2009 A1
20090291120 Tuominen et al. Nov 2009 A1
20090312724 Pipkin et al. Dec 2009 A1
20090318549 Butuner Dec 2009 A1
20100040671 Ahmed et al. Feb 2010 A1
20100055139 Lee Mar 2010 A1
20100069857 Christensen Mar 2010 A1
20100074942 Ratner et al. Mar 2010 A1
20100114309 de Juan, Jr. et al. May 2010 A1
20100124565 Spada et al. May 2010 A1
20100140114 Pruitt et al. Jun 2010 A1
20100166841 Roth et al. Jul 2010 A1
20100178316 Chauhan et al. Jul 2010 A1
20100209477 Butuner et al. Aug 2010 A1
20100209478 Sawhney et al. Aug 2010 A1
20100226962 Rodstrom et al. Sep 2010 A1
20100233241 Leahy et al. Sep 2010 A1
20100266664 Asgharian et al. Oct 2010 A1
20100278898 Hughes et al. Nov 2010 A1
20100331796 Leahy et al. Dec 2010 A1
20110009958 Wardle et al. Jan 2011 A1
20110105986 Bronstein et al. May 2011 A1
20110184358 Weiner et al. Jul 2011 A1
20110195123 Shemi Aug 2011 A1
20110268783 Shalaby et al. Nov 2011 A1
20110280909 Moazed Nov 2011 A1
20110282328 Ambati et al. Nov 2011 A1
20120022473 Shikamura et al. Jan 2012 A1
20120089072 Cunningham, Jr. Apr 2012 A1
20120109054 Thompson et al. May 2012 A1
20120136322 Alster et al. May 2012 A1
20120168422 Boyd et al. Jul 2012 A1
20120177716 Ho et al. Jul 2012 A1
20120187594 Utkhede et al. Jul 2012 A1
20120215184 Lim Aug 2012 A1
20120245505 Robinson et al. Sep 2012 A1
20120253459 Reich et al. Oct 2012 A1
20120269893 Lee Oct 2012 A1
20130090612 de Juan, Jr. et al. Apr 2013 A1
20130142858 Kopczynski et al. Jun 2013 A1
20130144128 de Juan, Jr. et al. Jun 2013 A1
20130177615 Lee Jul 2013 A1
20130209538 Venkatraman et al. Aug 2013 A1
20130261569 Weiner et al. Oct 2013 A1
20140121612 Rubin et al. May 2014 A1
20150133878 de Juan, Jr. et al. May 2015 A1
Foreign Referenced Citations (32)
Number Date Country
1630494 Jun 2005 CN
100339058 Sep 2007 CN
201012180 Jan 2008 CN
102026599 Apr 2011 CN
1473003 Nov 2004 EP
1372944 Nov 1974 GB
1529143 Oct 1978 GB
S48-036993 May 1973 JP
S5560452 May 1980 JP
S629561 Feb 1987 JP
H07067910 Mar 1995 JP
2007167358 Jul 2007 JP
2008523917 Jul 2008 JP
2010513555 Apr 2010 JP
2010538696 Dec 2010 JP
2011520805 Jul 2011 JP
2012512904 Jun 2012 JP
2012528695 Nov 2012 JP
2357709 Jun 2009 RU
2414199 Mar 2011 RU
WO-92014450 Sep 1992 WO
WO-9501764 Jan 1995 WO
WO-9711655 Apr 1997 WO
WO-9743984 Nov 1997 WO
WO-2002076426 Oct 2002 WO
WO-02096868 Dec 2002 WO
WO-2005020907 Mar 2005 WO
WO-2006066103 Jun 2006 WO
WO-2007083293 Jul 2007 WO
WO-2009035562 Mar 2009 WO
WO-2009140345 Nov 2009 WO
WO-2010141729 Dec 2010 WO
Non-Patent Literature Citations (10)
Entry
U.S. Appl. No. 14/063,571, filed Oct. 25, 2013, US 2014-0121612.
U.S. Appl. No. 14/775,989, filed Sep. 14, 2015, US 2016-0022695.
International Search Report and Written Opinion of PCT Application Nol PCT/US2010/037268 dated Jul. 21, 2010, 8 pages.
International Search Report and Written Opinion of PCT Application No. PCT/US2012/055532. dated Feb. 26, 2013.
Kawakita et al.,“Measurement of fornix depth and area: a novel method of determining the severity of fornix shortening”, Eye (2009) 23, 1115-1119.
Zeus Technical Newsletter. “Strength and Stiffness of Plastics”. (Obtained from http://www.zeusinc.com/UserFiles/zeusinc/Documents/technical_newsletters/Zeus_StrengthStiffnessPlastics.pdf on Oct. 18, 2013).
Kumari A. et al. “Ocular inserts—Advancement in therapy of eye diseases.” J. Adv. Pharm. Technol. Res. Jun.-Sep. 2010, 1(3): 291-296. Web. Downloaded from Internet Jan. 4, 2018.
U.S. Appl. No. 14/600,505, filed Jan. 20, 2015, US 2015-0133878.
U.S. Appl. No. 15/027,573, filed Apr. 6, 2016, US 2016-0243291.
U.S. Appl. No. 15/096,329, filed Apr. 12, 2016, US 2016-0296532.
Related Publications (1)
Number Date Country
20170056242 A1 Mar 2017 US
Provisional Applications (1)
Number Date Country
61183839 Jun 2009 US
Continuations (2)
Number Date Country
Parent 13151001 Jun 2011 US
Child 15230275 US
Parent PCT/US2010/037268 Jun 2010 US
Child 13151001 US