HK1158490B - Composite lacrimal insert and related methods - Google Patents

Description

Composite lacrimal implants and related methods

Priority declaration

This application claims priority to U.S. provisional patent application serial No. 61/049,337 entitled "LACRIMALIMPLANTS AND RELATED METHODS" filed on 30.4.2008.

Technical Field

This patent document relates generally to ophthalmic devices, and in particular to ocular implants. More particularly, but not by way of limitation, this patent document relates to lacrimal implants (lacrimalimplants), methods of making such implants, and methods of using such implants to treat ocular, respiratory, or other diseases or disorders.

Background

In the field of treatment of ocular and respiratory diseases or disorders, patients and physicians face a number of challenges, including the delivery of appropriate drugs to the eye or nasal passages and the treatment of dry eye (dry eye). In ocular therapy, for example, many current ophthalmic drug delivery systems require repeated manual administration and are often ineffective due to patient lack of compliance or inadequate drug concentration to reach the eye. Many current tear flow retardation techniques also have disadvantages, including being irreversible in nature.

To treat eye infections, inflammation of the eye, glaucoma, and other eye diseases or conditions, drugs often need to be applied to the eye. Traditional drug delivery methods are by applying topical drops to the surface of the eye. Topical eye drops, while effective, are less effective. As one example, when eye drops are dropped into the eye, the eye drops often overfill the conjunctival sac (i.e., the pocket between the eyeball and the eyelid), causing a large portion of the eye drops to be lost due to overflow of the eyelid margin and overflow onto the cheek. In addition, a large portion of the eye drops remaining on the surface of the eye can be washed away into and through the lacrimal canaliculus, thereby diluting the concentration of the drug before the eye drops can treat the eye. Furthermore, topically applied drugs often have the highest ocular effect approximately two hours after application, after which the drug should be reapplied to maintain the desired drug therapeutic benefit, but this is not usually the case.

With the difficulty of compound eye treatment, patients often do not use their eye drops according to the prescription. The poor compliance may be due to, for example, the initial stinging or burning sensation caused by eye drops and experienced by the patient. It is difficult for a person to drip eye drops into their own eyes, in part because of the normal reflex of protecting the eyes. Thus, one or more droplets may miss the eye. Elderly patients may have additional drip problems due to arthritis, instability and impaired vision. It also has difficulties for pediatric and psychiatric populations.

Dry eye has been treated by blocking tear flow from the eye into or through the lacrimal canaliculus. This has included sealing the canalicular duct by suturing a punctal opening latch (punctopen cut) or by sealing the punctal opening using electrical or laser cauterization. While these procedures may provide the desired result of blocking tear flow to treat dry eye, unfortunately, these procedures are irreversible without reconstructive surgery.

In areas other than ocular therapy, control of respiratory-related (e.g., allergic) diseases or conditions often requires repeated manual digestion or other inhalation of the drug, which may be ineffective due to patient lack of compliance or non-topical administration.

Illustrative aspects, examples and embodiments of the invention

The present inventors have recognized that one promising approach to delivering drugs to the ocular or nasal tract system, among others, may be, for example, placing a removable drug-releasing lacrimal implant into the punctum. It is believed that by achieving sustained release of one or more drugs, the lacrimal implants of the present disclosure may overcome some of the disadvantages associated with current administration (i.e., manual instillation or digestion), such as poor patient compliance, waste, untimely administration, or non-topical administration. One promising successful approach to block tear flow from the eye is to place a removable, but retainable lacrimal implant into the punctum. The inventors have further recognized that the lacrimal implants may benefit from, among other things, one or more of the following: the ability to be easily implanted and removed by controlled biasing (biasing) of the punctum or lacrimal canaliculus, the ability to be safely and comfortably retained in the punctum after implantation, and the ability to achieve sustained, localized, long-term release of one or more drugs at desired therapeutic levels when produced and used as a drug delivery system.

Lacrimal implants for treating diseases or disorders are disclosed. Methods of making these implants and methods of using these implants to treat ocular or respiratory diseases or disorders are also disclosed.

In example 1, a lacrimal implant includes an implant body including first and second portions, the implant body sized and shaped for at least partial insertion into a lacrimal canaliculus, the first portion comprising a first biocompatible polymer configured to swell less than 100 wt% when contacted with an aqueous medium, the second portion comprising a second biocompatible polymer configured to swell greater than 100 wt% when contacted with an aqueous medium; wherein the first and second biocompatible polymers are bonded (adhere) at a joint (junction) between the first portion and the second portion.

In example 2, the lacrimal implant of example 1 is optionally configured, the first biocompatible polymer comprising a urethane-based material.

In example 3, the lacrimal implant of at least one of examples 1 or 2 is optionally configured, wherein the first biocompatible polymer comprises a polyurethane (polyurethane) polymer or copolymer.

In example 4, the lacrimal implant of at least one of examples 1-3 is optionally configured, the second biocompatible polymer comprising a urethane-based material.

In example 5, the lacrimal implant of at least one of examples 1-4 is optionally configured, the second biocompatible polymer comprising a hydrogel-forming polyurethane polymer or copolymer.

In example 6, the lacrimal implant of at least one of examples 1-5 is optionally configured, the second biocompatible polymer comprising a hydrogel-forming polyurethane polymer or copolymer, and wherein the polymer or copolymer can swell by about 100 wt% to about 200 wt% when contacted with an aqueous medium.

In example 7, the lacrimal implant of at least one of examples 1-6 is optionally configured such that the second biocompatible polymer comprises a polyurethane hydrogel capable of expanding 500-2000 wt% upon exposure to an aqueous medium.

In example 8, the lacrimal implant of at least one of examples 1-7 is optionally configured, the first polymer, the second polymer, or both, comprising a polyurethane-silicone copolymer, a polyurethane-carbonate copolymer, an aliphatic polyurethane, an aromatic polyurethane, or any combination thereof.

In example 9, the lacrimal implant of at least one of examples 1-8, optionally comprising an external coating or sheath (sheath) configured to expand and thereby swell when the second polymer contacts an aqueous medium.

In example 10, the lacrimal implant of at least one of examples 1-9 is optionally configured, with the second portion disposed as a coating on a first portion of an outer surface of the first portion, and wherein a second portion of the outer surface of the first portion is disposed adjacent the proximal end and is uncoated.

In example 11, the lacrimal implant of at least one of examples 1-10 is optionally configured, with the joint including an intermediate component comprising a third biocompatible polymer configured to adhere the first biocompatible polymer and the second biocompatible polymer, and configured to swell to a greater degree than the first polymer but to a lesser degree than the second polymer upon contact with an aqueous medium.

In example 12, the lacrimal implant of example 11 is optionally configured, the third polymer comprising a polyurethane polymer or copolymer, a polyurethane-silicone copolymer, a polyurethane-carbonate copolymer, an aliphatic polyurethane, an aromatic polyurethane, or any combination thereof.

In example 13, the lacrimal implant of example 12 is optionally configured, the third polymer is configured to absorb about 50% to about 200% of the water.

In example 14, the lacrimal implant of at least one of examples 11-13 is optionally configured such that the bond strength between the first biocompatible polymer and the third biocompatible polymer, or the bond strength between the second biocompatible polymer and the third biocompatible polymer, or both, is greater than the bond strength between the first and second biocompatible polymers.

In example 15, the lacrimal implant of at least one of examples 1-14 is optionally configured, with the first portion including a base member extending from a proximal end to a terminal portion, the proximal end configured to rest (sit) at or near the punctum when implanted and having a first diameter, the terminal portion configured to be inserted through the punctum into the lacrimal canaliculus when implanted and having a second diameter less than the first diameter.

In example 16, the lacrimal implant of example 15 is optionally configured, with the base component shaped to provide sufficient surface area for adhesion (adhesion) of the first biocompatible polymer to the second biocompatible polymer, such that the first portion and the second portion are not under tension in the lacrimal canaliculus when the implant body is withdrawn, and the second portion separates at the joint if it has expanded upon contact with an aqueous medium.

In example 17, the lacrimal implant of example 16 is optionally configured, wherein a surface of the first portion is chemically modified or treated with ionizing radiation or electron beam radiation to couple with the second portion to resist separation under tension.

In example 18, the lacrimal implant of at least one of examples 15-17 is optionally configured, wherein the base member includes one or more arm members extending from an outer surface thereof.

In example 19, the lacrimal implant of example 18 is optionally configured such that at least one of the one or more arm members extends laterally with respect to a longitudinal axis of the base member.

In example 20, the lacrimal implant of at least one of examples 18 or 19 is optionally configured with the one or more arm members having a cross-dimension greater than an adjacent portion of the base member.

In example 21, the lacrimal implant of at least one of examples 15-20 is optionally configured, wherein the base member comprises one or more voids sized to receive a portion of the second portion after coupling (coupling).

In example 22, the lacrimal implant of at least one of examples 15-21 is optionally configured, the second portion comprising an expandable retention member at least partially coupled to the base member, the expandable retention member configured to expand upon absorption of an aqueous medium upon insertion into the lacrimal canaliculus.

In example 23, the lacrimal implant of example 22 is optionally configured, with the expandable retention member substantially enclosing the base member.

In example 24, the lacrimal implant of at least one of examples 22 or 23 is optionally configured, wherein the expandable retention member comprises a gel configured to at least partially conform to a size and shape of a lacrimal canaliculus.

In example 25, the lacrimal implant of at least one of examples 22-24 is optionally configured, wherein the base member comprises a longitudinal axis, and wherein the expandable retention member comprises at least one longitudinal expansion axis extending laterally relative to the base member longitudinal axis.

In example 26, the lacrimal implant of at least one of examples 22-25 is optionally configured, with the expandable retention member configured to extend at least partially toward a horizontal section of the lacrimal canaliculus.

In example 27, the lacrimal implant of at least one of examples 22-26 is optionally configured, wherein the expandable retention member is configured to extend at least partially toward a lacrimal canaliculus (ampulla).

In example 28, the lacrimal implant of at least one of examples 1-27, optionally comprising a first donor of a first active agent contained in the first portion, the first donor configured to provide release of the first active agent to the eye.

In example 29, the lacrimal implant of example 28 is optionally configured, wherein the first portion comprises a lumen extending inward from a proximal end of the first portion, the lumen containing the first donor to provide for release of the first active agent to the eye.

In example 30, the lacrimal implant of at least one of examples 28 or 29 is optionally configured, the first donor comprising a solid matrix comprising a mixture of silicone and a first active agent.

In example 31, the lacrimal implant of at least one of examples 28-30 is optionally configured with the first donor dispersed within a first polymer.

In example 32, the lacrimal implant of at least one of examples 28-31 is optionally configured, with the first donor including at least one exposed surface near a proximal end of the first portion to provide for release of the first active agent to the eye.

In example 33, the lacrimal implant of example 32 is optionally configured, with the at least one exposed surface positioned over the proximal end of the first portion, such that the first donor extends at least partially outside of the implant body.

In example 34, the lacrimal implant of at least one of examples 28-33, optionally comprising a second donor of a second active agent contained in the second portion, the second donor configured to provide release of the second active agent to one or both of a lacrimal canaliculus wall or a nasolacrimal system upon contact with an aqueous medium.

In example 35, the lacrimal implant of at least one of examples 28-34 is optionally configured, wherein the first or second active agent comprises an anti-glaucoma drug, an antimicrobial agent, a corticosteroid or other anti-inflammatory drug, a decongestant, an agent that prevents or modifies an allergic response, a mast cell stabilizer, a cycloplegic drug, a mydriatic drug, or a combination thereof.

In example 36, the lacrimal implant of example 35 is optionally configured, wherein the anti-glaucoma agent comprises an adrenergic agonist, an adrenergic antagonist, a systemic or local carbonic anhydrase inhibitor, a prostaglandin, or a hypotensive lipid (hypotensive lipid), or a combination thereof.

In example 37, the lacrimal implant of example 36 is optionally configured, the prostaglandin comprising bimatoprost, travoprost, or latanoprost, or a combination thereof.

In example 38, the lacrimal implant of example 35 is optionally configured, the antimicrobial agent comprising an antibiotic, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfa drugs, sulfadiazine, sulfacetamide, sulfamethizole, sulfadiazineOxazole, nitrofurazone, sodium propionate, an antifungal, amphotericin B, miconazole, an antiviral, idoxuridine trifluorothymidine, acyclovir, propoxyguanosine, or an interferon, or combinations thereof.

In example 39, the lacrimal implant of example 36 is optionally configured, wherein the corticosteroid or other anti-inflammatory agent comprises cyclosporine, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide, cortisone, flumethasone (flumetholone), a non-steroidal anti-inflammatory agent, salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naproxen (naxopren), piroxicam, nabumetone, ketorolac, bromfenac, nepafenac, or suprofen, or a combination thereof.

In example 40, the lacrimal implant of example 36 is optionally configured, wherein the decongestant comprises a vasoconstrictor, phenylephrine, naphazoline, or tetrahydrozoline, or a combination thereof.

In example 41, the lacrimal implant of example 36 is optionally configured, wherein the agent that prevents or modifies an allergic response comprises an antihistamine, a cytokine inhibitor, a leukotriene inhibitor, an IgE inhibitor, an immunomodulator, a cyclosporin, or a combination thereof.

In example 42, the lacrimal implant of at least one of examples 1-41 is optionally configured, with the middle section of the first portion including a coupling void and a coupling arm sized and shaped to lock within the coupling void.

In example 43, the lacrimal implant of at least one of examples 1-42 is optionally configured, wherein the implant body is non-biodegradable when implanted in a human subject.

In example 44, the lacrimal implant of at least one of examples 1-42, optionally comprising a lateral projection affixed (affix) to a proximal end of the first portion, the lateral projection sized and shaped to rest outside the punctum when a distal end of the first portion is disposed within the lacrimal canaliculus.

In example 45, the lacrimal implant of at least one of examples 1-44 is optionally configured such that the physical shape of the implant body comprises a substantially cylindrical or conical region.

In example 46, a kit comprises the lacrimal implant of at least one of examples 1-45, and instructions for using the lacrimal implant to treat an ocular disease.

In example 47, a method of forming the lacrimal implant of at least one of examples 1-45 includes using a melt (melt) of the polyurethane polymer or copolymer.

In example 48, a method of forming the lacrimal implant of at least one of examples 1-45 includes injection molding the first portion, the second portion, or both using a melt of a first polymer, a melt of a second polymer, or a melt of both polymers, respectively.

In example 49, a method of forming the lacrimal implant of at least one of examples 1-45 includes injection molding the first portion, the second portion, or both using a melt of a first polymer, a melt of a second polymer, or a melt of two polymers, respectively, with an intermediate component disposed as a melt between the first portion and the second portion.

In example 50, the lacrimal implant includes: a unitary implant (unitary implant) body sized to fit at least partially through the punctum and at least partially within the canaliculus, the implant body extending from a proximal portion to a distal portion, the proximal portion including a lumen, the distal portion including a base member having a diameter that is less than a diameter of the proximal portion; a drug donor included in the cavity, the drug donor configured to provide release of a first active agent to an eye; and an expandable retention member at least partially coupled to the base member, the expandable retention member comprising a dehydrated material that is hydratable with an aqueous medium to expand from a first diameter to a second diameter greater than the first diameter.

In example 51, the lacrimal implant of example 50 is optionally configured, with the expandable retention member completely encapsulating the base member.

In example 52, the lacrimal implant of at least one of examples 50 or 51 is optionally configured, the implant body comprising a urethane-based material.

In example 53, the lacrimal implant of at least one of examples 50-52 optionally includes a second active agent contained in an expandable retention member configured to provide release of the second active agent upon contact with an aqueous medium.

In example 54, the lacrimal implant of at least one of examples 50-53 is optionally configured such that the base member includes one or more arm members projecting laterally from an outer surface thereof.

In example 55, the lacrimal implant of at least one of examples 50-54 is optionally configured, wherein the expandable retention member comprises a urethane-based hydrogel material.

In example 56, the lacrimal implant of at least one of examples 50-55 is optionally configured, wherein the second diameter of the expandable retention member is configured to be at least about 5 times greater than the first diameter of the expandable retention member.

In example 57, the lacrimal implant of at least one of examples 50-56 is optionally configured such that a length of the base member is at least about 1/3 of an overall length of the implant body.

In example 58, the lacrimal implant of at least one of examples 50-57 is optionally configured such that a length of the base member is at least about 1/2 of an overall length of the implant body.

In example 59, a kit comprises the lacrimal implant of any of examples 50-58, and instructions for using the lacrimal implant to treat an ocular disease.

In embodiment 60, a method comprises: forming an implant body comprising first and second portions, sized for at least partial insertion into a lacrimal canaliculus, comprising forming the first portion with a first biocompatible polymer configured to swell less than 100 wt% when contacted with an aqueous medium, and forming the second portion with a second biocompatible polymer configured to swell greater than 100 wt% when contacted with an aqueous medium; and coupling the first and second biocompatible polymers at a joint between the first portion and the second portion.

In example 61, the method of example 60 optionally comprises: an intermediate member is disposed between the first and second portions, the member comprising a third biocompatible polymer, the third biocompatible polymer configured to adhere the first biocompatible polymer on a first surface and adhere the second biocompatible polymer on a second surface.

In example 62, the method of at least one of examples 60 or 61 is optionally configured such that forming the first portion comprises forming a base member extending from a proximal end configured to rest at or near the punctum when implanted to a distal end portion configured to be inserted through the punctum into the lacrimal canaliculus when implanted comprises forming one or more arm members extending from an outer surface of the base member.

In example 63, the method of example 62 optionally configured, wherein adhering the first and second biocompatible polymers comprises at least partially coupling an expandable retention member to the base member such that an outer surface of the expandable retention member can absorb aqueous media upon insertion into the lacrimal canaliculus.

In example 64, the method of example 63 optionally configured wherein at least partially coupling the expandable retention member to the base member comprises completely surrounding the base member with the expandable retention member.

In example 65, the method of at least one of examples 60-64 optionally includes providing a first donor of the first active agent in the first portion, the first donor configured to provide release of the first active agent to the eye.

In example 66, the method of at least one of examples 60-65 is optionally configured such that forming the first and second portions from a polymer comprises forming a unitary implant body from a urethane-based material.

In example 67, the method of at least one of examples 63-66 optionally includes disposing an intermediate member between the outer surface of the base member and the inner surface of the expandable retention member, the intermediate member configured to absorb a greater amount of fluid than the polymer of the second portion, but less fluid than the swellable polymer of the expandable retention member.

In example 68, the method of at least one of examples 60-67 is optionally configured such that forming the implant body comprises forming a cavity extending inwardly from the proximal end of the first portion, comprising configuring the cavity to include a drug donor, and placing at least one exposed surface of the drug donor near the proximal end.

In example 69, the method of example 68 optionally configured wherein positioning the at least one exposed surface of the drug donor adjacent the proximal end comprises positioning the at least one exposed surface over the proximal end such that the first donor extends at least partially outside of the implant body.

In example 70, the method of at least one of examples 63-69 is optionally configured such that forming the second portion to include a base member includes forming one or more arm members extending laterally from an outer surface of the base member to increase a surface area for coupling the expandable retention member.

In example 71, the method of at least one of examples 63-70 is optionally configured such that coupling the expandable retention member includes molding a urethane-based hydrogel over the base member.

In example 72, the method of at least one of examples 63-71 is optionally configured such that coupling the expandable retention member comprises dip coating the base member with a urethane-based hydrogel.

In example 73, the method of at least one of examples 63-72 is optionally configured such that coupling the expandable retention member comprises disposing a hydrogel sleeve (sleeve) on an outer surface of the base member.

In example 74, a method of treating a subject having an ocular disorder includes inserting a lacrimal implant into at least one lacrimal canaliculus, the lacrimal implant including an implant body including first and second portions, the implant body sized and shaped for at least partial insertion into a lacrimal canaliculus, the first portion comprising a first biocompatible polymer configured to swell less than 100 wt% when contacted with an aqueous medium, the second portion comprising a second biocompatible polymer configured to swell greater than 100 wt% when contacted with an aqueous medium; wherein the first and second biocompatible polymers are bonded at a joint between the first portion and the second portion.

In example 75, the method of example 74 optionally configured such that inserting the lacrimal implant includes partially inserting the implant body through the punctum until a removable protrusion extending proximally from the proximal end of the first portion is located outside and adjacent to the punctum.

In example 76, the method of at least one of examples 74 or 75 is optionally configured such that inserting the lacrimal implant comprises placing an active agent donor contained in the first portion near an eye of the subject.

In example 77, the method of example 76 is optionally configured such that the active agent is used to treat at least one of glaucoma or seasonal allergy.

In example 78, the method of at least one of examples 76 or 77 is optionally configured such that the period of time to release the active agent comprises at least 1 week, at least 1 month, or at least 3 months.

In example 79, the method of at least one of examples 74-78 optionally includes removing the inserted implant body from the punctum.

In example 80, the method of example 79 optionally comprises, after the interval, replacing the lacrimal implant that has been removed with a second lacrimal implant comprising an active agent donor.

In example 81, the method of example 80 optionally is configured to repeatedly replace the lacrimal implant until the subject no longer requires treatment.

In example 82, a method of treating a disorder (malcondition) in a patient having medically indicated administration of a drug for treatment of the disorder, or peripheral tissue, or both, comprising inserting the lacrimal implant of any of claims 1-45, or the lacrimal implant formed by the method of any of claims 47-49, into a lacrimal canaliculus (punctal canal) of the patient in need of treatment, wherein the implant comprises the drug dispersed therein, placing the implant in contact with an aqueous medium and the implant undergoing expansion to fix the implant within the lacrimal canaliculus, and releasing the drug from the implant into the eye or the peripheral tissue, or both, over a period of time.

In example 83, a method of treating a disorder with medically indicated administration of a drug to treat the disorder, or surrounding tissue, or both, in a patient having the disorder comprises inserting the lacrimal implant of any of claims 1-45, or the lacrimal implant formed by the method of any of claims 47-49, into a lacrimal canaliculus of the patient in need of treatment, wherein the implant comprises a drug-releasing insert having the drug dispersed therein, placing the implant in contact with an aqueous medium and the implant undergoing expansion to secure the implant within the lacrimal canaliculus, and releasing the drug from the drug-releasing insert into the eye or surrounding tissue, or both, over a period of time.

In example 84, a method of treating a disorder treated by administering a drug to the eye or surrounding tissue, or both, of a patient having the disorder medically indicated for the administration of the drug, comprising inserting the lacrimal implant of any of claims 1-45, or the lacrimal implant formed by the method of any of claims 47-49, into a lacrimal canaliculus of the patient in need of treatment, wherein the first portion comprises the active agent dispersed therein, placing a second polymer in contact with an aqueous medium and the second polymer undergoing swelling to fix the implant within the lacrimal canaliculus, and releasing the active agent from the first polymer into the eye or surrounding tissue, or both, over a period of time.

In example 85, a method of treating a disorder with medically indicated administration of a drug to the eye or surrounding tissue or both of a patient having the disorder, the method comprising inserting the lacrimal implant of any of claims 1-45, or the lacrimal implant formed by the method of any of claims 47-49, into a lacrimal canaliculus of a patient in need of treatment, wherein the first portion comprises a drug-releasing insert having an active substance dispersed therein, placing a second polymer in contact with an aqueous medium and the second polymer undergoing swelling to fix the implant within the lacrimal canaliculus, and releasing the active agent from the drug-releasing insert into the eye or surrounding tissue or both over a period of time.

In embodiment 86, the method of at least one of embodiments 82-85 is optionally configured such that the period of time is from about 1 week to about 6 months.

In example 87, the method of at least one of examples 82-86 is optionally configured such that the drug comprises an anti-glaucoma drug, an antimicrobial agent, a corticosteroid or other anti-inflammatory agent, a decongestant, an agent that prevents or modifies an allergic response, a mast cell stabilizer, a cycloplegic drug, a mydriatic drug, or a combination thereof.

In example 88, the method of example 87 is optionally configured such that the anti-glaucoma agent comprises an adrenergic agonist, an adrenergic antagonist, a systemic or local carbonic anhydrase inhibitor, a prostaglandin, or a blood pressure lowering lipid, or a combination thereof.

In embodiment 89, the method of embodiment 88 is optionally configured such that the prostaglandin comprises bimatoprost, travoprost, or latanoprost, or a combination thereof.

In example 90, the method of at least one of examples 82-89 is optionally configured such that the medicament is suitable for treating ocular hypertension in a human having open angle glaucoma or ocular hypertension.

In example 91, theThe method of example 87 optionally configured, the antimicrobial agent comprises an antibiotic, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisomethyimideOxazole, nitrofurazone, sodium propionate, an antifungal, amphotericin B, miconazole, an antiviral, idoxuridine trifluorothymidine, acyclovir, propoxyguanosine, or an interferon, or combinations thereof.

In example 92, the method of example 87 is optionally configured such that the corticosteroid or other anti-inflammatory agent comprises cyclosporine, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide, cortisone, paramethasone, a nonsteroidal anti-inflammatory agent, salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naproxen, piroxicam, nabumetone, ketorolac, bromfenac, nepafenac, or suprofen, or a combination thereof.

In example 93, the method of example 87 is optionally configured such that the decongestant comprises a vasoconstrictor, phenylephrine, naphazoline, or tetrahydrozoline, or a combination thereof.

In example 94, the method of example 87 is optionally configured such that the agent that prevents or modifies an allergic response comprises an antihistamine, a cytokine inhibitor, a leukotriene inhibitor, an IgE inhibitor, an immunomodulator, cyclosporine, or a combination thereof.

These and other embodiments, advantages, and features of the lacrimal implants and methods of the present disclosure will be set forth in part in the detailed description that follows. This summary is intended to provide an overview of the subject matter of the present patent application. And are not intended to provide an exhaustive or exhaustive description of the subject matter. The detailed description is included herein to provide further information regarding the present patent application.

Drawings

In the drawings, like reference numerals may be used to describe similar components throughout the several views. Like reference numerals having different letter suffixes may be used to designate different embodiments of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed herein.

Fig. 1-2 illustrate an embodiment of a schematic view of anatomical tissue structures associated with an eye that provide a suitable environment in which the lacrimal implants of the present disclosure may be used;

fig. 3 illustrates one embodiment of the lacrimal implant of the present invention, showing a "two-piece" implant design.

Fig. 4A illustrates an embodiment of an isometric view of a lacrimal implant of the present invention configured to remain within the punctum and canalicular anatomy.

Fig. 4B illustrates one embodiment of a cross-sectional view of the lacrimal implant of the present invention taken along a line parallel to the longitudinal axis of the implant, such as along line 4B-4B of fig. 4A.

Fig. 4C illustrates another embodiment of a cross-sectional view of the lacrimal implant of the present invention taken along a line parallel to the longitudinal axis of the implant.

Fig. 5 illustrates one embodiment of an assembly of the lacrimal implant of the present invention configured to remain within the punctum and canalicular anatomy.

Fig. 6 illustrates one embodiment of a schematic representation of the lacrimal implant of the present invention, as retained within the punctum and canaliculus anatomy.

Fig. 7A-7G illustrate embodiments of cross-sectional views of other lacrimal implants of the present invention, each configured to remain within the punctum and canalicular anatomy.

Fig. 8 illustrates one embodiment of a method of producing a lacrimal implant of the present invention configured to remain within the punctum and canalicular anatomy.

Fig. 9-12 illustrate and illustrate example experimental results of a lacrimal implant of the present invention configured to remain within the punctum and canalicular anatomy.

Detailed Description

In this patent document, biocompatible lacrimal implants and related methods are described that provide safe, biased retention within the punctum. The lacrimal implant may include an implant body configured to pass at least partially through the punctum and into an associated lacrimal canaliculus. The implant body may include first and second portions, wherein the first portion is formed of a polymer and has a first diameter and the second portion is also formed of a polymer and includes a base member having a second diameter. In various embodiments, the second diameter of the base member is less than the first diameter of the first body portion. An expandable retention member is at least partially coupled to the base member and configured to expand upon insertion into the punctum by absorbing tear fluid. In this manner, at least a portion of the expandable retention member can be biased against at least a portion of the lacrimal canaliculus wall to maintain an implantation position of the lacrimal implant. In one embodiment, the lacrimal implant includes a punctal plug (punctal plug). In various embodiments, the lacrimal implant can additionally include a drug or other agent supply included in at least one of the first portion or the expandable retention member to provide for sustained release of a therapeutic agent to, for example, one or both of the eye or nasal passage

And (4) placing.

The lacrimal implants of the present disclosure may be safely retained in or near the eye, for example, for one or more of the following purposes: successfully block tear flow from the eye, or provide for the sustained delivery of drugs or other therapeutic agents to the eye, nasal passages, or other parts of the nasolacrimal system. Configuring the lacrimal implant to include an expandable retention member at least partially coupled to the second, smaller diameter portion of the implant body may inhibit inadvertent detachment of the lacrimal implant from the implanted punctum and canaliculus location, and may serve to at least partially block fluid flow through the lacrimal canaliculus. In addition, by configuring the expandable retention member to be coupled at least partially over the second, smaller diameter portion of the implant body, adequate adhesion between the expandable retention member (or optionally, the intermediate expandable member) and the implant body is possible through a relatively large surface coupling area.

Fig. 1-2 illustrate an embodiment of a schematic view of an anatomical structure associated with an eye 100. The anatomical structures shown are suitable for treatment using the lacrimal implants and methods discussed herein. The eye 100 is a spherical structure comprising a wall with 3 layers: an outer sclera 102, a middle choroid layer 104, and an inner retina 106. The sclera 102 comprises a hard, fibrous coating that protects the inner layer. Most of the light is white except for the front transmissive region, which is the cornea 108, which allows light to enter the eye 100.

The choroid layer 104 is located on the inner side of the sclera 102, contains many blood vessels, and is modified to form a chromatically-deposited iris 110 in the anterior portion of the eye 100. The lenticular lens 112 is located behind and immediately adjacent to the pupil. The chamber 114 is behind the lens 112 and is filled with a vitreous humor, i.e., a gel-like substance. The anterior and posterior chambers 116 are located between the cornea 108 and the iris 110, respectively, and are filled with aqueous humor. Behind the eye 100 is the retina 106, which perceives light.

The cornea 108 is a light-transmitting tissue that transmits an image to the back of the eye 100. It comprises vascular tissue that is supplied with nutrients and oxygen by immersion in tear fluid and aqueous humor, as well as from blood vessels that connect the junction between the cornea 108 and the sclera 102. The cornea 108 includes a channel for the drug to permeate into the eye 100.

Other anatomical structures associated with the eye 100 include the lacrimal drainage system, which includes the secretory system 230, the distribution system, and the drainage system. The secretory system contains secretions that are stimulated by blinking and temperature changes due to tear evaporation and reflex, and secretions with efferent parasympathetic nerves supply and secrete tears in response to physical or emotional stimuli. The dispensing system includes an eyelid 202 and a tear meniscus (tear meniscus) around the eyelid margin of an open eye that distributes tear fluid over the surface of the eye by blinking, thereby reducing the formation of dry areas.

In order of drainage flow, the drainage portion of the lacrimal drainage system includes the punctum, canaliculus, lacrimal sac 204, and lacrimal duct 206. From the lacrimal duct 206, tears and other flowable materials drain into the passages of the nasal system. The lacrimal canaliculus includes an upper lacrimal canaliculus 208 and a lower lacrimal canaliculus 210 that terminate at superior 212 and inferior 214 puncta, respectively, near the eye 100. The upper 212 and lower 214 puncta bulge slightly at the junction 216 of the ciliary and lacrimal portions near the conjunctival sac 218 at the inner extremity of the eyelid margin. The upper 212 and lower 214 puncta are generally circular or slightly oval openings surrounded by a ring of connective tissue. The puncta 212, 214 each communicate (lead into) with their respective vertical portions 220, 222 of the lacrimal canaliculus, and then turn more horizontally at the canalicular curvature 250 to connect to each other at the entrance to the lacrimal sac 204. The canaliculi 208, 210 are generally tubular in shape and lined internally with stratified squamous epithelium surrounded by elastic tissue, which allows them to be distended or biased. As evidenced, the lacrimal canaliculus 252 is present near the outer edge of the lacrimal canaliculus curvature 250. In accordance with features of the inventive subject matter, a lacrimal implant may be inserted through any of the puncta and into its communicating lacrimal canaliculus.

Fig. 3 illustrates one embodiment of a lacrimal implant 300 that may be inserted into puncta 212, 214 (fig. 2). Insertion of the lacrimal implant 300 into the puncta 212, 214 can accomplish one or more of the following: inhibit or block tear flow through the lacrimal canaliculi 208, 210 (fig. 2) (e.g., to treat dry eye), or to deliver a therapeutic agent continuously to the eye (e.g., to treat infection, inflammation, glaucoma, or other ocular diseases or disorders) or nasal passages (e.g., to treat sinuses or allergic disorders). In certain embodiments, the period of time for delivery of the agent comprises at least 1 week, at least 1 month, or at least 3 months. In certain embodiments, lacrimal implant 300 has a width of about 0.3 millimeters to about 1.5 millimeters. In certain embodiments, lacrimal implant 300 has a length of about 1.5 millimeters to about 6 millimeters, such as about 2 millimeters to about 3 millimeters.

In one embodiment, lacrimal implant 300 includes a polyurethane polymer or copolymer. Typically, lacrimal implants are formed from silicone polymers that are very hydrophobic, and in addition, are often formed by polymerization of silicone precursors in the presence of a catalyst. However, polyurethane polymers and copolymers can be thermoplastic and therefore can be melted and cast into the desired form. The drug may be dispersed within the polyurethane melt, either in molten form as such or as a dispersion of solid material. The polyurethane polymers and copolymers can also be dissolved in different organic solvents (e.g. dichloromethane or tetrahydrofuran) and then cast into the desired form by removing the solvent, for example by evaporation. Alternatively, the drug may be dispersed or dissolved in an organic solvent with the polyurethane, so that after removal of the solvent, the drug-containing polyurethane is obtained in the desired form.

In fig. 3, lacrimal implant 300 is shown as a "two-piece" implant design. In this embodiment, an expandable retention member 314, such as a swellable material that can be bonded or coupled to a portion of lacrimal implant 300 such that it at least partially encapsulates a portion of lacrimal implant 300, forms a joint with first portion 304 of the body of lacrimal implant 300. First portion 304 of the body of lacrimal implant 300 can be formed from a first polymer that is biocompatible and swells less than 100 wt% when contacted with an aqueous medium, such as a biocompatible polyurethane polymer or copolymer. For example, the first polymer may comprise a polyurethane-silicone copolymer. An example isIs suitable forBiocompatible, non-biodegradable copolymers for medical use. Other similar materials may also be used, provided they are biocompatible and do not substantially swell or slightly swell when contacted with an aqueous medium. For example, hydrophilic polyurethanes that do not substantially swell upon contact with aqueous media may be used to increase the surface wettability (wettability) of the non-hydrogel component of lacrimal implant 300. The expandable retention member 314 may be formed from a second polymer that is biocompatible and swells greater than 100% by weight when contacted with an aqueous medium to form a hydrogel, such as a biocompatible hydrogel-forming polyurethane polymer or copolymer. For example, a hydrogel-forming material TG-500 or TG-2000 may be used, which is capable of swelling up to 500-2000 wt% upon exposure to an aqueous medium.

In this two-half design, the expandable retention member 314 is not wrapped. The joint between the first portion 304 of the implant body and the expandable retention member 314 includes an intermediate member 350, which optionally comprises a third polymer having a moderate degree of expansion in an aqueous medium, and which is strong enough to hold the implant intact under a degree of tension, such as when the implant is removed from the lacrimal canaliculus. The third polymer may be a biocompatible polyurethane polymer or copolymer suitable for bonding the first and second polymers. It may be a polymer that swells moderately after exposure to an aqueous medium.

Fig. 4A illustrates a first portion 304 of a lacrimal implant body of other embodiments of lacrimal implants 300 insertable into punctums 212, 214 (fig. 2). In various embodiments, the lacrimal implant 300 includes an implant body 402 including first 304 and second 406 portions, the implant body 402 sized and shaped to be at least partially inserted into the punctum 212, 214. The first portion 304 is formed of a polymer and has a first diameter 408. The second portion 406 is also formed of a polymer and includes a base member 412 (e.g., a mandrel or spine-like member) having a second diameter 410 that is less than the first diameter 408. In one embodiment, the first 304 and second 406 portions are fully coupled and comprise a single implant body 402. In one embodiment, as shown in fig. 7E-7G, the first 304 and second 406 portions are separate components that may be coupled to each other by, for example, engagement between a coupling void and a coupling arm.

An expandable retention member 314, such as a swellable material, may be bonded or coupled to the base member 412 such that it at least partially encapsulates a portion of the base member 412. In one embodiment, the expandable retention member substantially encloses the base member 412. As the expandable retention member 314 absorbs or otherwise retains tears or other fluids, such as after insertion into the punctum 212, 214, it increases in size and can change shape, thereby forcing itself against and lightly biasing the wall of the associated lacrimal canaliculus 208, 210. It is believed that the expandable retention member 314 provides retention comfort to the subject and may enhance lacrimal implant 300 retention by controlled biasing of the lacrimal canaliculus 208, 210 walls.

Placing the expandable retention member 314 over a portion of the implant body 402 allows the retention member 314 to be freely exposed to tear fluid in situ, thereby achieving a wide range of potential expansion rates. In addition, base member 412 provides sufficient coupling surface area to which expandable retention member 314 may be bonded, for example, such that material of expandable retention member 314 does not remain in puncta 212, 214 after removal of lacrimal implant 300 from a subject. As shown in this embodiment, the expandable retention member 314 may include an unexpanded, "dried or dehydrated" state that facilitates insertion through the punctum 212, 214 and into the associated lacrimal canaliculus 208, 210. Once placed in the lacrimal canaliculus 208, 210, the expandable retention member 314 can absorb or otherwise retain tears to form an expanded structure.

In certain embodiments, the implant body 402 can include a cylinder-like structure including a cavity 416 disposed near a proximal end 418 of the first portion 304. In this embodiment, the lumen 416 extends inwardly from the proximal end 418 and includes a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye 100. Drug or other agent release may occur at least in part through the exposed surface of the drug donor 420. In one embodiment, as shown, for example, in fig. 4B, the exposed surface of the drug supply 420 can be positioned above the proximal end 418 such that the drug supply 420 extends at least partially outside of the implant body 402. In some embodiments, the exposed surface of the drug donor 420 can be flush with the proximal end 418 or slightly below such that the drug donor 420 does not extend outside of the implant body 402.

In certain embodiments, a predetermined drug or agent release rate may be achieved by controlling the geometry or drug concentration gradient near the exposed surface. For example, the exposed surface may be constructed with a particular geometry or other technique suitable for controlling the rate of release of a drug or other agent onto the eye 100 in situations such as between outpatient visits on an acute basis (acute basis), or on a chronic basis (chronic basis). Additional discussion regarding the effective release rate of one or more DRUGs or other agents from the DRUG donor 420, including a description of achieving a particular range of release rates, can be found in commonly owned U.S. patent application No. 11/695,545 to DeJuan et al, entitled "nasolacrar image rapid SYSTEM IMPLANTS FOR DRUG THERAPY," which is incorporated herein by reference in its entirety.

The implant body 402 can include an integral feedback or other protrusion 422, such as a protrusion that extends laterally at least partially from or about the proximal end 418 of the implant body first portion 304. In one embodiment, the projection 422 includes a partially-pitched head portion that extends 360 degrees from the implant body outer surface about the proximal end 418. In one embodiment, the protrusion 422 includes an integral head portion that extends 360 degrees from the implant body outer surface about the proximal end 418. In one embodiment, the projections 422 include a cross-sectional shape that resembles a flat disc (i.e., relatively flat top and bottom surfaces). In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site. In one embodiment, the protrusion 422 includes a portion having a diameter of about 0.5-2.0mm to prevent the lacrimal implant 300 from falling into the lacrimal canaliculus 208, 210.

Fig. 4B illustrates one embodiment of a cross-sectional view of lacrimal implant 300 taken along a line parallel to the longitudinal axis of the implant, such as along line 4B-4B of fig. 4A. As shown in fig. 4B, the lacrimal implant 300 includes an implant body 402 including a first 304 and a second 406 portion, the implant body 402 sized and shaped to be at least partially inserted into the punctum 212, 214 (fig. 2). The first portion 304 is formed of a polymer and has a first diameter 408. The second portion 406 is also formed of a polymer and includes a base member 412 (e.g., a mandrel or spine-like member) having a second diameter 410 that is less than the first diameter 408. In one embodiment, the base member 412 is at least about 1/3 of the overall length of the implant body 402. In one embodiment, the base member 412 is at least about 1/2 of the overall length of the implant body 402. In the illustrated embodiment, the implant body 402 also includes an integral feedback or other protrusion 422, such as a protrusion that extends laterally at least partially from or around the proximal end 418 of the implant body first portion 304.

In various embodiments, the implant body 402 may be molded (mold) or otherwise formed from an elastomeric material, such as silicone, polyurethane, or other urethane-based material, or combinations thereof. In one embodiment, one or both of the first 304 and second 406 portions comprise a urethane-based material. In one embodiment, one or both of the first 304 and second 406 portions comprise a silicone-based material, e.g.OrIn one embodimentOne or both of the first 304 and second 406 portions comprise a copolymer material, such as polyurethane/silicone, urethane/carbonate, silicone/polyethylene glycol (PEG), or silicone/2-hydroxyethyl methacrylate (HEMA). In various embodiments, implant body 402 is configured to be non-absorbable in situ, and is strong enough to address issues of cutting strength (e.g., during insertion and removal of lacrimal implant 300) and dimensional stability.

An expandable retention member 314, such as a swellable material, may be bonded or otherwise coupled to the base member 412 such that it at least partially encapsulates a portion of the base member 412. As the expandable retention member absorbs or otherwise retains tear fluid, such as after insertion into the punctum 212, 214, its size increases and its shape may change, forcing itself against and lightly biasing the wall of the associated lacrimal canaliculus 208, 210. In various embodiments, the expandable retention member 314 may be molded or otherwise formed from an expandable material. In one embodiment, the expandable retention member 314 comprises a polyurethane hydrogel, such as TG-TG- Or other urethane-based hydrogels. In one embodiment, expandable retention member 314 comprises a thermoset polymer, which may be configured to be anisotropically (anisotropically) expanded. In one embodiment, the expandable retention member 314 comprises a gel that does not maintain its shape after expansion, but rather conforms to the shape of the lacrimal canaliculus wall or other peripheral structures.

In certain embodiments, lacrimal implant 300 includes a base member 412 and an expandable retention member 314, the base member 412 including a polyurethane or other urethane-based material, and the expandable retention member 314 including a biocompatible polyurethane or other urethane-based expandable material. In one embodiment, the polyurethane hydrogel is coupled directly to an outer surface of the base member 412, such as a plasma treated outer surface. As further discussed in commonly owned U.S. patent application 12/231,986 entitled "DRUG CORES FOR SUSTAINED RELEASE OF THERAPEUTIC AGENTS" by Utkhede et al, which is incorporated herein by reference in its entirety and which claims partial priority to U.S. patent application No. 61/049,317, urethane-based polymer and copolymer materials allow FOR a variety OF processing methods and are well-coupled to each other.

In some embodiments, lacrimal implant 300 includes an intermediate member 350 that is positioned between a portion of implant body 402 (e.g., base member 412) and a portion of expandable retention member 314. The intermediate member 350 may comprise a material configured to absorb a greater amount of tear fluid than the polymer of the base member 412, but less tear fluid than the expandable polymer of the expandable retention member 314 when implanted. Intermediate member 350 can provide the integrity of lacrimal implant 300, for example, between the substantially non-swelling polymer of implant body 402 and the swelling polymer of expandable retention member 314. For example, when the polymer of the expandable retention member 314 swells upon exposure to moisture, the expandable polymer may swell away from the underlying unexpanded polymer of the base member 412 without the intermediate member 350. In one embodiment, the intermediate member 350 includesAnd impregnated or otherwise coated on the outer surface of the base member 412. In one embodiment, the intermediate member 350 comprises a polyurethane configured to absorb about 10% to about 500% water, for exampleCarbamic acid esters orSolution grade carbamate.

In certain embodiments, the implant body 402 may include a cavity 416 disposed near a proximal end 418 of the first portion 304. In one embodiment, the first lumen 416 extends inward from the proximal end 418 about 2 millimeters or less and contains a drug donor 420 that releases a first drug or releases another pharmaceutical agent to provide a sustained release of the drug or other pharmaceutical agent to the eye 100 (fig. 2). In various embodiments, the drug supply 420 stores a medicament and slowly dispenses the medicament to the eye 100 as the medicament is leached by, for example, tear fluid. In one embodiment, the drug donor 420 includes a plurality of therapeutic agent inclusions 452, which may be distributed in a matrix 454. In one embodiment, inclusion 452 comprises a therapeutic agent in a concentrated form (e.g., a crystalline pharmaceutical form). In one embodiment, the substrate 454 comprises a silicone substrate or the like, and the distribution of inclusions 452 within the substrate is uniform or non-uniform. In one embodiment, the medicament inclusion 452 comprises oil droplets, such as latanoprost oil. In another embodiment, the pharmaceutical inclusion 452 comprises solid particles, such as particles of bimatoprost in crystalline form. The inclusions can have many sizes and shapes. For example, the inclusions may include particles having a size on the order of about 1 micron to about 100 microns.

In the illustrated embodiment, the drug supply 420 includes a sheath (sheath body)456 disposed over at least a portion thereof, such as to define at least one exposed surface 458 of the drug supply. In one embodiment, the sheath 456 comprises polyimide. Exposed surface 458 may be located at or near proximal end 418 of implant body 402, for example, to contact tear fluid or tear film fluid as lacrimal implant 300 is inserted into punctum 212, 214, and release therapeutic agent at one or more therapeutic levels for a sustained period of time. Further discussion of the construction and production of the DRUG donor 420 can be found in commonly owned U.S. patent application No. 11/695,537 entitled "DRUG DELIVERY METHODS, sturcuurs, and andscomposotions FOR nasolacrima SYSTEM," which is incorporated herein by reference in its entirety.

In certain embodiments, the expandable retention member may include a drug donor 460 that releases a second drug or releases another agent to provide a sustained release of the drug or other agent to one or both of the walls of the lacrimal canaliculus 208, 210 or the nasolacrimal system. The drug supply 460 may be configured to store a medicament and slowly dispense the medicament upon contact with tears within the lacrimal canaliculus 208, 210. In one embodiment, the agent contained in the expandable retention member may comprise a drug, a therapeutic agent, or an antimicrobial agent (e.g., silver).

Fig. 4C illustrates one embodiment of a cross-sectional view of lacrimal implant 300 taken along a line parallel to the longitudinal axis of the implant. As shown in fig. 4B, some lacrimal implants 300 of the present invention are configured to include: feedback or other projections 422 at or near the proximal end 418 for inhibiting or preventing the lacrimal implant 300 from fully entering the lacrimal canaliculus cavity, and other structures configured for full insertion below the punctal openings 212, 214. As shown in fig. 4C, lacrimal implant 300 includes implant body 402 without feedback or other protrusions 322 (fig. 3A) at or near proximal end 418 of implant body first portion 304. Thus, in certain embodiments, lacrimal implant 300 may be fully inserted into the lacrimal canaliculus lumen.

Fig. 5 illustrates one embodiment of the assembly of lacrimal implant 300 of the present invention. As discussed, lacrimal implant 300 may include a unitary implant body 402 sized to pass at least partially through punctum 212, 214 (fig. 2) and to be placed within lacrimal canaliculus 208, 210 (fig. 2). The implant body 402 may extend from a proximal end portion 502 to a distal end portion 504. In the illustrated embodiment, the proximal portion 502 includes a lumen 416 and the tip portion 504 includes a base member 412 having a diameter 410 that is smaller than the diameter of the proximal portion 502. In one embodiment, a drug core 420 may be contained within the cavity 416 and configured to provide release of the agent to the eye. In various embodiments, the expandable retention member 314 may be at least partially coupled to the base member 412 and comprise a "dry or dehydrated" material that can be hydrated by tears or other fluids to expand from a first diameter to a second diameter that is larger than the first diameter.

The base member 412 may be coupled to the expandable retention member 314 in a variety of ways. In one embodiment, as shown in fig. 5, a pre-formed expandable (e.g., hydrogel) sleeve 506 may be slipped over an outer surface 508 of the base member 412. In one embodiment, the expandable retention member 314 may be impregnated or otherwise coated on the base member 412. In one embodiment, the first polymer-based (e.g., urethane-based) base member 412 and the first polymer-based (e.g., urethane-based) expandable retention member 314 may be injection molded simultaneously (e.g., by bi-injection molding) to form the lacrimal implant 300 in a minimum number of steps. In one embodiment, a multiple injection molding process may be used, which includes sequentially injecting separate materials into different locations in a mold. In one embodiment, an insert over-molding process may be used, i.e., the base member 412 is first molded and then placed in a second mold and overmolded with the polymer of the expandable retention member 314. In various embodiments, the expandable retention member 314 can extend along any desired length portion of the implant body 402.

In some embodiments, one or both of the distal body portion 504 or the distal end 510 of the expandable retention member 314 can include a taper 512 to self-expand (self-dillate) anatomical tissue such that one or both of the punctum 212, 214 (fig. 2) or the associated canaliculus 208, 210 has a diameter sufficient to implant the lacrimal implant 300. In this manner, lacrimal implant 300 may be implanted in eye anatomies of different sizes, without the need for pre-expansion by a separate expansion tool. A cone 512 may be formed that is atraumatic to the lining of the punctum 212, 214 or lacrimal canaliculus 208, 210.

As shown, taper 512 may generally narrow from a portion near the middle portion of expandable sleeve 506 to distal end 510 of sleeve 506, such as from a diameter of about 0.5 millimeters to a diameter of about 0.1 millimeters or less. The desired taper 512 for a given implant location may be determined, among other factors, by balancing implant properties such as the balance between the strength of the implant body 402 required for implant insertion and the desire to have a soft, resilient, and post-implant conforming (e.g., conforming) implant body (e.g., conforming to the lacrimal canaliculus anatomy). In certain embodiments, a lubricious coating disposed or impregnated in either the outer surface of the implant body 402 or the outer surface of the expandable retention member 314 may be used to further assist in the insertion of the lacrimal implant 300 into anatomical tissue. In one embodiment, the lubricious coating may include a silicone lubricant. In one embodiment, to safely incorporate a thin coating of lubricious material (e.g., hydrogel), the outer surface of the implant body 402 or expandable retention member 314 may be treated with plasma or radiation.

In various embodiments, the outer surface of one or both of the implant body 402 or the expandable retention member 314 can be formed or otherwise treated to be generally smooth to inhibit bacterial binding and latency to the lacrimal implant 300. The generally smooth outer surface may also prevent damage to the lining of the receiving anatomy, such as puncta 212, 214 (fig. 2) or associated canaliculi 208, 210 (fig. 2), during implantation. As further discussed in U.S. patent application serial No. 12/283,002, commonly owned by Rapacki et al, entitled "SURFACETIED IMPLANTABLE ARTICLES AND RELATED METHODS," which is incorporated herein by reference in its entirety and which claims priority to U.S. patent application No. 61/057,246, the outer surface of the implant body 402 may be modified, for example, by a polishing operation in which methylene chloride or other suitable media is used in conjunction with an eversion process.

In certain embodiments, an antimicrobial coating may be disposed or impregnated on at least a portion of the outer surface of one or both of the implant body 402 or the expandable retention member 314 to further prevent bacterial growth on the implant body. In one embodiment, the antimicrobial coating may comprise an agent selected from the group consisting of: 2-bromo-2-nitropropane-1, 3-diol, 5-bromo-5-nitro-1, 3-diAlkane, 7-ethylbicycloOxazolidines, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, cetylpyridinium chloride, chlorhexidine digluconate, chloroacetamide, chlorobutanol, chloromethylisothiazolinone and methylisothiazoline, acetyldimethyldiguanideAlkane, dimethylOxazolidines, dimethylhydroxymethylpyrazoles, chloroxylenols, dehydroacetic acid, urea aldehydes, dichlorobenzyl alcohols, DMDM hydantoin, ethanol, formaldehyde, glutaraldehyde, hexachlorophene, hexetidine, hexamethylenetetramine (hexamethylenetetramine), imidazolidinyl urea, iodopropynyl butylcarbamate, isothiazolinone, hexamethylenetetramine chloride (methammonium chloride), methyldobromopentadienyl, MDM hydantoin, minocycline, o-phenylphenol, p-chlorocresol, parabens (butyl paraben, ethyl paraben, methyl paraben), phenylethyl alcohol, phenoxyethanol, piroctone olamine (piroctone olamine), polyaminopropyl bisguanide, polymethoxydicyclic acidOxazolidines, polyformaldehyde, polyquaternium-42, potassium benzoate, potassium sorbate, propionic acid, quaternium-15, rifampin, salicylic acid, selenium disulfide, sodium borate, sodium iodate, sodium hydroxymethylglycinate, sodium propionate, sodium pyrithione, sorbic acid, thimerosal, triclosan, triclocarban, undecylenic acid, zinc phenolsulfonate, and zinc pyrithione. In one embodiment, the antimicrobial coating may comprise a material selected from the group consisting of: silver lactate, silver phosphate, silver citrate, silver acetate, silver benzoate, silver chloride, silver iodide, silver iodate, silver nitrate, silver sulfadiazine, silver palmitate, or a mixture of one or more thereof. In one embodiment, the antimicrobial coating may be included in an antibiotic or antisepticAt least one of (1). For example, the antimicrobial coating may include a short-term anesthetic agent that lasts an average of several hours to several days. In other embodiments, the antimicrobial coating may include a drug for treating an underlying disease, such as an immediate bolus.

Fig. 6 illustrates one embodiment of a schematic view of a lacrimal implant 300 implanted in the lower punctum 214 and associated lacrimal canaliculus 210. In some embodiments, lacrimal implant 300 may be implanted in superior punctum 212 and associated lacrimal canaliculus 208. In this embodiment, the lacrimal implant 300 includes an implant body 402 including a first 304 and a second 406 portion, the implant body 402 sized and shaped to be at least partially inserted into the punctum 214. The first portion 304 is formed of a polymer and has a first diameter 408 (fig. 4B). The second portion 406 is also formed of a polymer and includes a base member 412 (e.g., a mandrel or spine-like member) having a second diameter 410 (fig. 4B) that is less than the first diameter 408. An expandable retention member 314, such as a swellable material, may be bonded or otherwise coupled to the base member 412 such that it at least partially encapsulates a portion of the base member 412. In certain embodiments, the outer surface of one or both of the implant body 402 or the expandable retention member 314 may include grooves or coatings of wicking material, for example, to allow fluid to flow around the implant body 402.

As shown, the first portion 304 of the implant body 402 can be configured to rest on the punctal opening 214 at the proximal end 418 and reside within the associated lacrimal canaliculus 210 at the distal end 602. In this embodiment, integral feedback or other protrusions 422 extending around proximal end 418 inhibit or prevent lacrimal implant 300 from completely entering lacrimal canaliculus cavity 210.

As further shown, the second portion 406, which includes the base member 412 at least partially enclosed by the expandable retention member 314, can be configured to rest and retain the lacrimal implant 300 within the associated lacrimal canaliculus 210. As the expandable retention member absorbs or otherwise retains tears or other fluids, for example, after insertion into punctum 214, its size increases radially or longitudinally and its shape may change, forcing itself against and lightly biasing against the wall of the associated lacrimal canaliculus 210, while still providing comfort to the subject. In one embodiment, the longitudinal expansion direction of the expandable retention member 314 extends laterally relative to the longitudinal axis 606 of the implant body 402. In one embodiment, the portion 608 of the expandable retention member 314 is configured to extend at least partially toward a horizontal cut plane of the lacrimal canaliculus 210. In one embodiment, the portion 610 of the expandable retention member 314 is configured to extend at least partially toward the pouch 252 of the lacrimal canaliculus 210. In one embodiment, the expandable material of the expandable retention member 314 may comprise a hydrogel that, in a fully hydrated state, contains a water content of about 500% to about 2000% (by weight), and, in a "dried or dehydrated" state, contains a water content of less than about 10%, such as about 1%. In certain embodiments, the expandable retention member 314 is configured to allow an expansion capacity of up to about 1 times its "dried or dehydrated" volume, up to about 5 times its "dried or dehydrated" volume, or up to about 10 times its "dried or dehydrated" volume.

Forceps or other insertion tool may be used to insert lacrimal implant 300 into puncta 212, 214 and associated canaliculus 208, 210. In various embodiments, the second portion 406 of the implant body 402 can be advanced into the depth of the canaliculus 208, 210 by manipulating the insertion tool until the feedback or other projection 422 (if present) rests against the punctal opening 212, 214. When it is desired to remove lacrimal implant 300, protrusion 432 can be easily grasped, for example, with forceps, and withdrawn from punctal openings 212, 214. It is believed that in some instances, the insertion and removal methods associated with lacrimal implant 300 of the present disclosure may be performed simply by an average ophthalmologist in his/her office in a short period of time, without the need for special skills or expensive equipment. In some cases, after the first lacrimal implant has been removed, a second lacrimal implant containing an agent donor is inserted into the subject until he/she no longer requires treatment.

In certain embodiments, the implant body 402 may include a cavity 416 disposed near a proximal end 418 of the first portion 304. In this embodiment, a first lumen 418 extends inwardly from the proximal end 418 and includes a drug donor 420 that releases a first drug or releases another pharmaceutical agent. Lacrimal implant 300 may be oriented with expandable retention member 314 in alignment for placement in lacrimal canaliculus 208, 210, while drug supply 420 and proximal end 418 are substantially aligned with the exterior of punctal openings 212, 214 to provide sustained release of drugs or other agents to eye 100 (e.g., to treat infection, inflammation, glaucoma, or other ocular diseases or disorders). Drug or other agent release may occur at least in part through the exposed surface of the drug donor 420. In this embodiment, the exposed surface of the drug donor 420 can be located above the proximal end 418 such that the drug donor 420 extends at least partially outside the implant body 402.

In certain embodiments, the expandable retention member may include a drug donor 460 that releases a second drug or releases another agent to provide a sustained release of the drug or other agent to one or both of the walls of the lacrimal canaliculus 208, 210 or the nasolacrimal system. The drug supply 460 may be configured to store a medicament and slowly dispense the medicament upon contact with tears within the lacrimal canaliculus 208, 210. In one embodiment, the agent contained in the expandable retention member may comprise a drug, a therapeutic agent, or an antimicrobial agent (e.g., silver).

Fig. 7A-7G illustrate an embodiment of a lacrimal implant 300 insertable into puncta 212, 214 (fig. 2). Insertion of the lacrimal implant 300 into the puncta 212, 214 can accomplish one or more of the following: inhibit or block tear flow through the lacrimal canaliculi 208, 210 (fig. 2) (e.g., to treat dry eye), or to deliver a therapeutic agent continuously to the eye (e.g., to treat infection, inflammation, glaucoma, or other ocular diseases or disorders) or nasal passages (e.g., to treat sinuses or allergic disorders).

In various embodiments, the lacrimal implant 300 includes an implant body 402 including first 304 and second 406 portions, the implant body 402 sized and shaped to be at least partially inserted into the punctum 212, 214. The first portion 304 is formed of a polymer and has a first diameter 408 (fig. 4B). The second portion 406 is also formed of a polymer and includes a base member 412 (e.g., a mandrel or spine-like member) having a second diameter 410 (fig. 4B) that is less than the first diameter 408. In some embodiments, such as shown in fig. 7A-7D, the first 304 and second 406 portions are fully coupled and comprise a single implant body 402. In some embodiments, such as those shown in fig. 7E-7G, the first 304 and second 406 portions are separate components that can be coupled to one another by, for example, engagement between a coupling void and a coupling arm. In various embodiments, the base member 412 may include one or more arm members 702 extending from an outer surface 508 thereof.

An expandable retention member 314, such as a swellable material, may be bonded or otherwise coupled to the base member 412 such that it at least partially encapsulates a portion of the base member 412. In one embodiment, the expandable retention member substantially encloses the base member 412. One or more arm members 702 may increase the surface area for bonding or other coupling between one or more of expandable retention member 314, intermediate member 350 (fig. 4B), and base member 412. The expandable retention member 314, for example, upon application, may provide clearance between one or more of the arm members 702. As the expandable retention member 314 absorbs or otherwise retains tears or other fluids, such as after insertion into the punctum 212, 214, it increases in size and can change shape, thereby forcing itself against and lightly biasing the wall of the associated lacrimal canaliculus 208, 210.

In the embodiment of fig. 7A, lacrimal implant 300 includes a single implant body 402 that extends from first portion 304 to second portion 406. The first portion 304 may include a lumen 416 disposed near a proximal end 418 of the first portion 304. The cavity 416 may include a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. The implant body 402 may additionally include integral feedback or other protrusions 422 that laterally extend at least partially from or around the proximal end 318. In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site.

As shown, the second portion 406 can include a base member 412 (e.g., a mandrel or spine-like member) having a diameter 410 (fig. 4B) that is smaller than the diameter 408 (fig. 4B) of the first portion 304. In this embodiment, the base member 412 includes an arm member 702 in the form of one or more ribs (rib) 704. Each rib 704 may include a curved or non-curved protrusion extending from an outer surface of the base member 412, e.g., laterally with respect to a longitudinal axis of the base member 412. In this embodiment, 3 pairs of ribs 704 extend from the base member 412; however, more or less than 3 pairs of ribs 704 may be used without departing from the scope of the inventive subject matter. Ribs 704 may provide strength to lacrimal implant 300 by increasing the surface area of one or both of expandable retention member 314 or intermediate member 350 (fig. 4B) coupled to base member 412.

In the embodiment of fig. 7B, lacrimal implant 300 includes a single implant body 402 that extends from first portion 304 to second portion 406. The first portion 304 may include a lumen 416 disposed near a proximal end 418 of the first portion 304. The cavity 416 may include a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. The implant body 402 may additionally include an integral feedback or other protrusion 422 that laterally extends at least partially from or around the proximal end 418. In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal canaliculus lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site.

As shown, the second portion 406 can include a base member 412 (e.g., a mandrel or spine-like member) having a diameter 410 (fig. 4B) that is smaller than the diameter 408 (fig. 4B) of the first portion 304. In this embodiment, the base member 412 includes one or more arm members 702 in the form of discs 706. Each disk 706 may include a relatively flat top or bottom surface and may include a larger cross-sectional dimension than the base member adjacent portion 412. One or more discs 706 may be spaced along the longitudinal axis of the base member 412 and extend from the outer surface of the base member 412. In one embodiment, 3 disks 706 extend from the base member 412; however, more or less than 3 disks 706, such as 1 disk 706, may be used without departing from the scope of the inventive subject matter. Disc 706 may provide strength to lacrimal implant 300 by increasing the surface area of one or both of expandable retention member 314 or intermediate member 350 coupled to base member 412.

In the embodiment of fig. 7C, lacrimal implant 300 includes a single implant body 402 that extends from first portion 304 to second portion 406. The first portion 304 may include a lumen 416 disposed near a proximal end 418 of the first portion 304. The cavity 416 may include a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. The implant body 402 may additionally include an integral feedback or other protrusion 422 that laterally extends at least partially from or around the proximal end 418. In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site.

As shown, the second portion 406 can include a base member 412 (e.g., a mandrel or spine-like member) having a diameter 410 (fig. 4B) that is smaller than the diameter 408 (fig. 4B) of the first portion 304. In this embodiment, the base member 412 includes an arm member 702 in the form of one or more spikes (spikes) 708. Each of the spikes 708 can extend radially from the outer surface of the base member 412 at any position around the circumference of the base member 412. In one embodiment, 6 or more spikes 708 extend from the base member 412; however, more or less than 6 spikes 708 may be used without departing from the scope of the inventive subject matter. Spikes 708 can provide strength to lacrimal implant 300 by increasing the surface area of one or both of expandable retention member 314 or intermediate member 350 (fig. 4B) coupled to base member 412.

In the embodiment of fig. 7D, lacrimal implant 300 includes a single implant body 402 that extends from first portion 304 to second portion 406. The first portion 304 may include a lumen 416 disposed near a proximal end 418 of the first portion 304. The cavity 416 may include a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. The implant body 402 may additionally include an integral feedback or other protrusion 422 that laterally extends at least partially from or around the proximal end 418. In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site.

As shown, the second portion 406 can include a base member 412 (e.g., a mandrel or spine-like member) having a diameter 410 (fig. 4B) that is smaller than the diameter 408 (fig. 4B) of the first portion 304. In this embodiment, the base member 412 includes one or more arm members 702 having a curved shape, such as a fishhook-like shape 710. Each fishhook-like projection 710 may extend radially from the outer surface of the base member 412 at any position around the circumference of the base member 412. In one embodiment, at least one of the fishhook-like projections comprises a barb or other rearwardly-directed protuberance. In this embodiment, 3 pairs of fishhook-like projections 710 extend from the base member 412; however, more or less than 3 pairs of fishhook-like projections 710 may be used without departing from the scope of the inventive subject matter. A fishhook-like projection 710 or other curved shaped projection can provide strength to lacrimal implant 300 by increasing the surface area of one or both of expandable retention member 314 or intermediate member 350 (fig. 4B) coupled to base member 412.

In the embodiment of fig. 7E and 7G, lacrimal implant 300 includes an implant body 402 that includes first 304 and second 406 separable portions that can be coupled to one another, for example, by engagement between coupling voids 712 and coupling arms 714. In one embodiment, the polymer, e.g., silicone-based material, forming the first portion 304 is different from the polymer, e.g., polyester, silk, polycarbonate, urethane-based material, or other material, forming the second portion 406, which has a melting temperature higher than the temperature at which the polymer of the first portion 304 solidifies or has a greater stiffness. The first portion 304 may include a lumen 416 disposed near a proximal end 418 of the first portion 304. The cavity 416 may include a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. The implant body 402 may additionally include an integral feedback or other protrusion 422 that laterally extends at least partially from or around the proximal end 418. In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site.

As shown, the second portion 406 can include a base member 412 (e.g., a mandrel or spine-like member) that includes a variety of shapes and that has a diameter 410 (fig. 4B) that is smaller than the diameter 408 of the first portion 304. In these embodiments, the base member 412 includes one or more arm members 702 extending from an outer surface of the base member 412, such as laterally with respect to a longitudinal axis of the base member 412. in the embodiment of FIG. 7E, the longitudinal axis of the base member 412 is coincident with the longitudinal axis of the first portion 304. in the embodiment of FIG. 7G, the longitudinal axis of the base member 412 is at an angle 718 with respect to the axis of the first portion 304. In one embodiment, the angle 718 between the longitudinal axis of the base member 412 and the longitudinal axis of the first portion 304 is formed at or after the implant body 402 is implanted in the lacrimal canaliculus 208, 210. One or more arm members 702 can provide strength to lacrimal implant 300 by increasing the surface area of one or both of expandable retention member 314 or intermediate member 350 (fig. 4B) coupled to base member 412.

In the embodiment of fig. 7F, lacrimal implant 300 includes an implant body 402 that includes first 304 and second 406 separable portions that can be coupled to one another, for example, by engagement between coupling void 712 and coupling arm 714. In one embodiment, the polymer, e.g., silicone-based material, forming the first portion 304 is different from the polymer, e.g., polyester, silk, polycarbonate, urethane-based material, or other material, forming the second portion 406, which has a melting temperature higher than the temperature at which the polymer of the first portion 304 solidifies or has a greater stiffness. The first portion 304 may include a lumen 416 disposed near a proximal end 418 of the first portion 304. The cavity 416 may include a drug donor 420 that releases the first drug or releases the other agent to provide a sustained release of the drug or other agent to the eye. The implant body 402 may additionally include an integral feedback or other protrusion 422 that laterally extends at least partially from or around the proximal end 418. In various embodiments, the projection 422 can be configured to rest on or near the punctal openings 212, 214 when the second portion 406 of the implant body 402 is positioned within the associated lacrimal lumen 208, 210, for example, to inhibit or prevent the lacrimal implant 300 from fully entering the lacrimal canaliculus lumen, or to provide tactile or visual feedback information to the implantation user (e.g., regarding whether the implant is fully implanted), or to remove the lacrimal implant 300 from the implantation site.

As shown, the second portion 406 can include a base member 412 (e.g., a mandrel or spine-like member) having a diameter 410 (fig. 4B) that is smaller than the diameter 408 (fig. 4B) of the first portion 304. In these embodiments, the base member 412 includes one or more arm members 702 that extend from an outer surface of the base member 412, such as in a balloon-like shape, from a joint between the coupling void 712 and the coupling arms 714. In one embodiment, one or more arm members 702 include one or more voids 616 sized to receive a portion of expandable retention member 314 or intermediate member 350. One or more arm members 702 can provide strength to lacrimal implant 300 by increasing the surface area of one or both of expandable retention member 314 or intermediate member 350 (fig. 4B) coupled to base member 412.

Fig. 8 is a block diagram illustrating one embodiment of a method 800 of producing a lacrimal implant configured to be at least partially insertable into a punctum. At 802, an implant body is formed that includes first and second portions. Forming the first portion may include melting, molding, or otherwise processing the polymer into a shape having a first diameter. Forming the second portion may include melting, molding, or otherwise processing the polymer into the shape of a base member having a second diameter that is smaller than the first diameter. In one embodiment, forming the first portion, the second portion, or both may include injection molding using a melt of the first polymer, the second polymer, or both polymers, respectively. Polyurethane polymers and copolymers are suitable for melt processing, thus avoiding the additional complexity of solvent casting techniques, the cost of handling the necessary solvent, and the possibility of residual solvent in the polymeric material of the implant. In one embodiment, forming the implant body further comprises forming a cavity extending inwardly from the proximal end of the first portion. In one embodiment, forming the implant body further comprises forming one or more arm members extending laterally from an outer surface of the base member. In certain embodiments, the implant body is formed from a urethane-based material, such as polyurethane. In certain embodiments, the implant body is formed from a silicone material. Optionally, one or more portions of the outer surface of the base component are plasma treated to facilitate coupling with the cover assembly.

At 804, an intermediate component is optionally disposed on an outer surface of the base component. In various embodiments, the intermediate component includes a third polymer configured to absorb a greater amount of fluid (e.g., tears) than the polymer of the implant body. In one embodiment, the third polymer may be incorporated into the lacrimal implant as a melt. In one embodiment, the intermediate component may be applied to the base component using an injection molding process, or it may be applied using a solvent-dip coating process. For example, a dip coating process may be used to apply a thin layer of the intermediate component to the outer surface of the base component.

At 806, an expandable retention member is coupled at least partially over the base member, and optionally with the intermediate member. In one embodiment, the expandable retention member is coupled on the base member such that the base member is fully or substantially enclosed. In various embodiments, the expandable retention member comprises a polymer configured to absorb a greater amount of fluid than the implant body and the intermediate member. In one embodiment, the expandable retention member comprises a urethane-based material, such as a urethane-based hydrogel, and is molded over the base member, which may also comprise a urethane-based material. In one embodiment, the expandable retention member is formed using an injection molding process. For example, the urethane-based base member and the urethane-based expandable retention member may be melted and injected into the mold through 2 separate mold holes (ports), such as in a multiple injection molding process. In another embodiment, the base member or expandable retention member may be molded individually and then the other components injected into the remainder of the mold, such as in an insert overmolding process. In one embodiment, the expandable retention member is dip coated onto the outer surface of the base member. In one embodiment, the device is expandableThe tension retention member includes a hydrogel sleeve (e.g., hydrogel tube) configured to slip over the outer surface of the base member and use, for example, a urethane-based adhesive such as1-MP was coupled.

At 808, a drug donor is disposed within the cavity of the first body portion. In various embodiments, the drug donor stores a medicament and slowly dispenses the medicament to the eye as the medicament is leached by, for example, tear fluid. Drug or other agent release may occur at least in part through the exposed surface of the drug donor. In one embodiment, the exposed surface of the drug donor can be located above the proximal end such that the drug donor extends at least partially outside the implant body. In some embodiments, the exposed surface of the drug donor can be flush with the proximal end or slightly below so that the drug donor does not extend outside the implant body.

Lacrimal implants may also be prepared by methods including: insert overmolding (insert over molding), wherein the implant body may be molded of one material, and after completion, may be placed in a second mold where the next material is injected around the part; multi-component molding, in which multiple materials are simultaneously injected into a mold through the same injection nozzle or separate nozzles; multiple injection molding, in which separate materials are sequentially injected into different locations of a mold; and extruding the hydrogel sleeve and then bonding it (by adhesive or melt bonding) to the molded implant body.

Sheath embodiment:

in a different manner, the sheath around and optionally contained in the drug donor may contain suitable shapes and materials to control migration of one or more agents from the donor. In certain embodiments, the sheath is configured to fit the implant anatomy, such as the anatomy of the punctum or lacrimal canaliculus. As discussed, in certain embodiments, the sheath houses the drug donor and may be suitably abutted against the outer surface of the matrix/agent mixture. The sheath may be formed of a material that is substantially impermeable to the agent, such that the rate of migration of the agent is largely controlled by the exposed surface area of the drug donor that is not covered by the sheath. In many embodiments, the migration of the agent through the sheath can be about 1/10, or less, of the migration of the agent through the exposed surface of the drug donor. Suitable sheath materials may include, among others, polyimide, polyethylene terephthalate (PET). The sheath can have a thickness of about 0.00025 inches to about 0.0015 inches as defined from a sheath surface adjacent an outer surface of the matrix/agent mixture to an opposing sheath surface distal from the outer surface. The overall diameter of the sheath extending across the drug donor is in the range of about 0.2 mm to about 1.2 mm. The drug donor may be formed by dip coating the matrix in the sheath. In certain embodiments, the sheath may comprise a tube into which the matrix/agent mixture is introduced. The sheath may also be dip coated around the matrix/agent mixture, for example around a preformed matrix/agent core.

The sheath can be provided with one or more additional features to facilitate clinical use of the lacrimal implants discussed herein. For example, the sheath may receive a drug donor that may be replaced in situ while the implant body remains implanted in the patient, or after it is removed. In some embodiments, the sheath may be provided with one or more external protrusions that, when squeezed, apply a force to the sheath, which causes the matrix/agent mixture to be ejected from the sheath. A replacement drug donor can then be placed into the sheath.

Therapeutic agent examples:

therapeutic agents (or simply "agents") may include, among other things, drugs formed from one or any combination of the following or their equivalents, derivatives or analogs, including: anti-glaucoma drugs (e.g., adrenergic agonists, adrenergic antagonists (beta-blockers), carbonic anhydrase inhibitors (CAIs, both systemic and local), parasympathomimetics, prostaglandins, and hypotensive lipids) and combinations thereof); antimicrobial agents (e.g., antibiotics, antiviral agents, antiparasitic agents, antifungal agents, etc.); corticosteroids or other anti-inflammatory agents (e.g., NSAIDs or other analgesics and pain treatment compounds); decongestants (e.g., vasoconstrictors); agents that prevent or modify allergic responses (e.g., antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators); mast cell stabilizers; a cycloplegic agent; mydriatic or the like.

Example agents that may be utilized include, but are not limited to: a thrombin inhibitor; an antithrombotic agent; dissolving the blood suppository; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; an antihypertensive agent; antimicrobial agents, such as antibiotics (e.g., tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, terramycin, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazoleAzole, nitrofurazone, sodium propionate), antifungal agents (e.g., amphotericin B and miconazole) and antiviral agents (e.g., idoxuridine trifluorothymidine, acyclovir, ganciclovir, interferon); inhibitors of surface glycoprotein receptors; anti-platelet agents; an anti-mitotic agent; a microtubule inhibitor; an antisecretory agent; an activity inhibitor; remodeling inhibitors (remodelling inhibitors); an antisense nucleotide; antimetabolites (anti-metabolites); antiproliferative agents (including anti-angiogenic agents); an anti-cancer chemotherapeutic agent; anti-inflammatory agents (e.g., hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, betamethasone, triamcinolone acetonide); nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naproxen, piroxicam, and nabumetinMetione). Examples of such anti-inflammatory steroids contemplated for use in the lacrimal implants of the present invention include triamcinolone acetonide (common name) and corticosteroids that include, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, p-flumethasone, and derivatives thereof; antiallergic drugs (e.g. sodium cromoglycate, antazoline, metapyriline, chlorpheniramine, cetirizine, pyrilamine, pheniramine); antiproliferative agents (e.g., 1, 3-cis retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, mitomycin C, and cisplatin); decongestants (e.g., phenylephrine, naphazoline, tetrahydrozoline); miotics and anticholinesterases (e.g., pilocarpine, salicylate, carbachol, acetylcholine chloride, physostigmine, irinotecan, diisopropyl fluorophosphate, iodoecoxite, dimeglumine); antineoplastic agents (e.g., carmustine, cisplatin, fluorouracil 3; immunopharmaceuticals (e.g., vaccines and immunostimulants), hormonal agents (e.g., estrogen, -estradiol, progestational agents, progesterone, insulin, calcitonin, parathyroid hormone, peptides, and vasopressin hypothalamic releasing factor), immunosuppressive agents, growth hormone antagonists, growth factors (e.g., epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, growth hormone, fibronectin), angiogenesis inhibitors (e.g., angiostatin, anecortave acetate, thrombin sensitive protein, anti-VEGF antibodies), dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrices, components, ACE inhibitors, free radical scavengers, chelators, anti-oxidants, anti-polymerase (anti-myelomerase), photodynamic therapeutics, gene therapeutics, and other therapeutics such as prostaglandins, retinoids, growth hormone antagonists, growth factors, anti-prostaglandins, prostaglandin precursors, including anti-glaucoma drugs including beta-blockers such as timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogs such as bimatoprost, travoprost, latanoprost, and the like; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorfenamide, danus; neuroprotective agents such as lubeluzole, nimodipine and related compoundsA compound; and parasympathomimetics such as pilocarpine, carbachol, physostigmine, and the like.

Other agents that may be used with the lacrimal implants of the present invention include, but are not limited to, drugs that have been approved under United States dental Food, Drug, and Cosmetic Act, Section 505 or under Public Health Service Act, some of which may be at the United States Food and Drug Administration (FDA) websitehttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/indexIs found in (1). The lacrimal implants of the present invention may also be used with drugs listed in Orange Book (Orange Book) paper or electronic form, which may be at the FDA Orange Book website (FDA Orange Book websitehttp://www.fda.gov/cder/ob/) And which has or records data of the same, earlier, or later date as the filing date of this patent document. For example, these drugs may include, among others, dorzolamide, olopatadine, travoprost, bimatoprost, cyclosporin, brimonidine, moxifloxacin, tobramycin, brinzolamide, acyclovir, timolol maleate, ketorolac tromethamine, prednisolone acetate, sodium hyaluronate, nepafenac, bromfenac, diclofenac, flurbiprofen, suprofen (suprofnac), binoxan, patarol, dexamethasone/tobramycin combinations, moxifloxacin, or acyclovir.

Examples of diseases or conditions that may be treated with the agents listed above include, but are not limited to, glaucoma, pre-and post-operative eye treatment, dry eye, anti-ocular allergy, anti-infection, post-operative inflammation or pain, or respiratory related conditions such as allergy. In certain embodiments, the therapeutic agent may include a lubricant or surfactant, such as a lubricant for treating dry eye. In other embodiments, the therapeutic agent may include an absorbent agent capable of absorbing tear fluid from the eye.

Drug donor examples:

the drug donor may comprise one or more pharmaceutical agents and, in certain embodiments, one or more matrix materials to provide sustained release of the pharmaceutical agents. One or more agents can migrate from the exposed surface of the drug donor to a target tissue (e.g., ciliary muscle of the eye), based at least in part on the solubility of the agent in the matrix. The rate of migration of the agent from the exposed surface may also be correlated to the concentration of the agent dissolved in the matrix. In certain embodiments, the concentration of the pharmaceutical agent dissolved in the drug donor can be controlled to provide a desired release rate of the pharmaceutical agent. Additionally or in combination, the rate of migration of the agent from the exposed surface may be correlated to one or more properties of the matrix in which the agent is dissolved, such as the properties of a silicone matrix component (formulation). In certain embodiments, the pharmaceutical agent contained in the drug donor may comprise a fluid, a solid gel, a solid crystalline, a solid amorphous, a solid particulate, or a dissolved form. In one such embodiment, liquid latanoprost droplets or solid bimatoprost particles are dispersed in a silicone matrix.

The drug donor may comprise one or more biocompatible materials capable of providing sustained release of the one or more pharmaceutical agents. Although the drug donor is discussed above primarily with respect to embodiments comprising a substantially non-biodegradable silicone matrix with drug inclusions located therein that are soluble, the drug donor may comprise other structures that provide sustained release of the drug, such as a biodegradable matrix, a porous drug donor, a fluid drug donor, or a solid drug donor. The matrix comprising the pharmaceutical agent may be formed from biodegradable or non-biodegradable polymers. In certain embodiments, the non-biodegradable drug donor may include silicone, acrylate, polyethylene, polyurethane, hydrogel, polyester (e.g., dacron. rtm. available from e.i. du Pont de Nemours and Company of wilmington, delaware), polypropylene, Polytetrafluoroethylene (PTFE), expanded PTFE (eptfe), Polyetheretherketone (PEEK), nylon, extruded collagen, polymeric foam, silicone rubber, polyethylene terephthalate, ultra high molecular weight polyethylene, polycarbonate polyurethane (polycarbonate urethane), polyurethane, polyimide, stainless steel, nickel-titanium alloys (e.g., nitinol)Memalloys), titanium, stainless steel, cobalt-chromium alloys (e.g., elgiloy. rtm. available from Elgin Specialty Metals of elm, illinois; CONICHROME.RTM., available from Carpenter Metals, Wyoission, Pa.). In certain embodiments, the biodegradable drug donor can comprise one or more biodegradable polymers, such as proteins, hydrogels, polyglycolic acid (PGA), polylactic acid (PLA), poly (L-lactic acid) (PLLA), poly (L-glycolic acid) (PLGA), polyglycolide (polyglycolide), poly-L-lactide, poly-D-lactide, poly (amino acids), polydi (di) lactideAlkanones (polydioxanones), polycaprolactones, polygluconates, polylactic acid-polyethylene oxide copolymers, modified celluloses, collagens, polyorthoesters, polyhydroxybutyrates, polyanhydrides, polyphosphoesters, poly (alpha-hydroxy acids), and combinations thereof. In certain embodiments, the drug donor may comprise a hydrogel polymer.

Experimental examples

In order that the lacrimal implants of the present invention may be more fully understood, the following examples are given as illustrations.

Experimental example 1

Fig. 9 illustrates a lacrimal implant 300 including an implant body including a base member and an expandable retention member at least partially coupled to the base member. In this embodiment, the implant body comprises a polyurethane/silicone copolymer and the expandable retention assembly comprises a polyurethane hydrogel sleeve.

Lacrimal implant 300 was tested as follows: by soaking in saline solution and measuring the change in diameter and length of the expandable retention member. At 902, the implant body and expandable retention member are shown at t 0 minutes. At 904, the implant body and expandable retention member are shown at t 5 minutes. At 906, the implant body and expandable retention member are shown at t 10 minutes. At 908, the implant body and expandable retention member are shown at t 30 minutes. At 910, the implant body and expandable retention member are shown at t 60 minutes. Table 912 shows that the expandable retention assembly increased in size to 1.23 mm (dimensional change was 2.24 times the original size) in 60 minutes and further increased to 1.31 mm (dimensional change was 2.38 times the original size) in 24 hours.

Experimental example 2

Fig. 10 illustrates a lacrimal implant 300 including an implant body including a base member and an expandable retention member at least partially coupled to the base member. In this embodiment, the implant body comprises a polyurethane/silicone copolymer and the expandable retention assembly comprises a polyurethane hydrogel sleeve.

Lacrimal implant 300 was tested as follows: by soaking in saline solution and measuring the change in diameter and length of the expandable retention member. At 1002, the implant body and expandable retention member are shown at t 0 minutes. At 1004, the implant body and expandable retention member are shown at t 5 minutes. At 1006, the implant body and expandable retention member are shown at t 10 minutes. At 1008, the implant body and expandable retention member are shown at t 30 minutes. At 1010, the implant body and expandable retention member are shown at t 60 minutes. Table 1012 shows that the expandable retention assembly increased in size to 1.17 mm in 60 minutes (dimensional change was 2.02 times the original size) and further increased to 1.24 mm in 24 hours (dimensional change was 2.14 times the original size).

Experimental example 3

Fig. 11 illustrates 2 lacrimal implants 300, each including an implant body having a first portion and a second portion. In this embodiment, the first portion of the implant body comprises a silicone-urethane copolymer and the second portion of the implant body comprises a urethane hydrogel (TG-)。

Lacrimal implant 300 was tested as follows: by soaking in a saline solution and measuring the change in diameter of the second body portion. At 1102, an implant body including first and second portions is shown at t-0 minutes. At 1104, an implant body including first and second portions at t-2 minutes is shown. At 1106, the implant body including the first and second portions is shown at t-5 minutes. At 1108, the implant body including the first and second portions is shown at t-10 minutes. Table 1110 shows, among other things, that the second portion of the implant body increased in size from 0.44 mm to 0.76 mm in only 2 minutes (72% dimensional change).

Experimental example 4

Fig. 12 illustrates 2 lacrimal implants 300, each including an implant body having a first portion and a second portion. In this embodiment, the first portion of the implant body comprises a silicone-urethane copolymer and the second portion of the implant body comprises a urethane hydrogel (TG-)。

Lacrimal implant 300 was tested as follows: by soaking in a saline solution and measuring the change in diameter of the second body portion. At 1202, an implant body including first and second portions at t-0 minutes is shown. At 1204, a first inclusion at t-2 minutes is shown

And a second portion of the implant body. At 1206, the implant body including the first and second portions is shown at t-5 minutes. At 1208, the implant body including the first and second portions is shown at t-10 minutes. At 1210, an implant body including first and second portions at t-30 minutes is shown. Table 1212 shows, among other things, that the second portion of the implant body increased in size from 0.47 millimeters to 0.92 millimeters (95% dimensional change) in only 2 minutes.

End annotation

Lacrimal implants and related methods that provide, among other things, safe retention within the punctum and canaliculus of an eye are discussed herein. The implant body can include first and second portions, wherein the first portion is formed of a polymer and has a first diameter and the second portion is also formed of a polymer and includes a base member having a second diameter. In various embodiments, the second diameter of the base member is less than the first diameter of the first body portion. An expandable retention member is at least partially coupled to the base member and configured to expand upon insertion into the punctum by absorbing tear fluid. In this manner, at least a portion of the expandable retention member can bias against at least a portion of the lacrimal canaliculus wall to maintain an implantation position of the lacrimal implant. In various embodiments, the lacrimal implant may additionally include a drug or other agent supply included in at least one of the first portion or the expandable retention member, e.g., to provide sustained release of the therapeutic agent to, e.g., one or both of the eye or nasal passage.

The lacrimal implants of the present disclosure may be safely retained in or near the eye, for example, for one or more of the following purposes: successfully block tear flow from the eye, or provide for the sustained delivery of drugs or other therapeutic agents to the eye, nasal passages, or other parts of the nasolacrimal system. Configuring the lacrimal implant to include an expandable retention member at least partially coupled to the second, smaller diameter portion of the implant body may inhibit inadvertent detachment of the lacrimal implant from the implanted punctum and canaliculus location, and may serve to at least partially block fluid flow through the lacrimal canaliculus. For example, the amount of expansion of the expandable retention assembly can be controlled to seat the lacrimal implant, but prevent over-expansion, which may tend to push the implant out of the implanted position. In addition, by configuring the expandable retention member to be coupled at least partially over the second, smaller diameter portion of the implant body, adequate adhesion between the expandable retention member (or optionally, the intermediate expandable member) and the implant body is possible through a relatively large surface coupling area.

The foregoing detailed description includes references to the accompanying drawings, which form a part hereof. Which show by way of illustration specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples". All publications, patents, and patent documents mentioned in this document and not claiming priority thereto are incorporated by reference in their entirety into this specification, as if individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated references should be considered supplementary to the usage in this document; for inconsistent inconsistencies, this document controls.

In this document, the terms "a" or "an," as used generally in patent documents, are used to include one or more than one, regardless of any other circumstance or usage of "at least one" or "one or more. In this document, the term "or" is used to refer to nonexclusive, such that "a or B" includes "a is, but B is not," "B is, but a is not," and "a and B," unless otherwise indicated. In this document, the term "about" is used to refer to an amount that is about, near, nearly, or in the vicinity of an amount equal to the recited amount.

In this document, the term "proximal" refers to a location relatively closer to the hand of the practitioner implanting the lacrimal implant in the patient, and the term "distal" refers to a location relatively further from the hand of the practitioner (particularly during implantation of the implant in the patient).

In this document, the term "hydrogel" is used to refer to absorbent materials or other retention materials (e.g., absorbent materials), such as superabsorbent polymers, hydrocolloids, and hydrophilic polymers that absorb water. In certain embodiments, the term "hydrogel" refers to superabsorbent polymer particles in the "dried or dehydrated" state, more specifically, particles ranging from no water to containing water in an amount less than the weight of the particles (e.g., less than about 5% by weight). In certain embodiments, the term "hydrogel" also refers to a superabsorbent polymer in its "dry or dehydrated" state (when the hydrogel is not swellable), and also refers to its hydrated or swollen state, more specifically, hydrogels that have absorbed at least their weight of water, e.g., several times their weight of water. As the hydrogel material absorbs fluid, its size may increase and its shape may change to bias against at least a portion of, for example, the lacrimal canaliculus or the lacrimal canaliculus wall.

In this document, the term "agent" is used to refer to an active agent suitable for use in medical treatment, such as a pharmaceutical compound or drug.

In this document, the term "active agent" refers to a molecular entity that acts on a living organism.

In this document, the term "polymer" refers to an organic macromolecule containing one or more repeating units, as is well known in the art. "copolymer" refers to a polymer comprising at least two types of repeating units. The copolymer may be a block copolymer in which segments containing a plurality of the same type of repeating unit are combined with segments containing a plurality of the second type of repeating unit.

In this document, the term "hydrophilic polymer" refers to a polymer that can be wetted by water, i.e. does not have a surface that repels water. Hydrophilic polymers can absorb water to a small extent, for example about 0-100% by weight, but do not swell as much volumetrically as hydrogel-forming polymers.

In this document, the term "polyurethane" refers to a variety of polymers or copolymers containing repeating units covalently bonded by urethane (i.e., urethane linkages-N-c (O) -O-, where the N and O atoms are attached to an organic radial). The organic radical may be aliphatic, aromatic or mixed; other functional groups may be contained. Each radical (radial) is interrupted by 2 (or more) carbamate groups, except for the radical at the end of the molecular chainCliques are connected to other roots. The polyurethane polymer contains only groups of urethane-type linking repeat units. Polyurethane copolymers, such as polyurethane-silicone copolymers or polyurethane-carbonate copolymers, contain urethane and other types of groups linking repeat units, i.e., silicone and carbonate type groups, respectively. Examples include the Elast-Eon of AorTech^TMOf (a polyurethane-silicone copolymer), LubrizolOf (an aliphatic flexible polyurethane), LubrizolOf (a thermoplastic polyurethane) and Lubrizol(a polyurethane/polycarbonate copolymer).

The polyurethane-silicone copolymer contains polyurethane chain segments and silicone chain segments, as is well known in the art. An example of a polyurethane-silicone copolymer isIt is a product of Polymer Technologies inc. of berkeley, california, described by the manufacturer as a family of aliphatic, thermoplastic, silicone polyether urethane copolymers. These polymers are formed by incorporating silicone into the polymer backbone along with polyether soft segments and using Surface-modifying end Groups^TM(SME) to terminate the polymer chain. The polyurethane-carbonate copolymer contains urethane segments and carbonate (-O-C (O) O-) segments. An example of a polyurethane-carbonate copolymer is Carbothane(Lubrizol)。

"TG-500" and "TG-2000" are polyurethane hydrogel-forming polymers produced by the Thermedics Polymer Products division of Lubrizol advanced Materials, Inc., Wilmington, Mass. They are described by the manufacturer as aliphatic, polyether-based, thermoplastic, hydrogel-forming polyurethanes. Such hydrogel-forming polymers can absorb greater than 100 wt%, e.g., up to 500-2000 wt% of water, with resultant physical size expansion.

In the appended claims, the terms "including" and "in which" are used as the plain-english equivalents of the respective terms "comprising" and "wherein". Furthermore, in the following claims, the terms "comprises" and "comprising" are open-ended, i.e., a system, assembly, device, article, or process that comprises elements other than those listed after such term in a claim is still considered to be within the scope of the claims. Furthermore, in the following claims, the terms "first," "second," and "third," etc. are used merely for labels, and are not intended to impose numerical requirements on their objects.

The above description is intended to be illustrative, and not restrictive. For example, the above-described embodiments (or one or more features thereof) may be used in combination with each other. For example, other embodiments may be used by those of ordinary skill in the art upon reading the above description. Moreover, in the foregoing detailed description, various features may be grouped together to simplify the present disclosure. This should not be interpreted as implying that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus the following claims are hereby incorporated into the detailed description, with each claim standing on its own as a separate embodiment. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

The abstract is provided to comply with 37c.f.r. § 1.72(b), to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

Claims (33)

1. A lacrimal implant, comprising:

an implant body configured to be inserted at least partially through a punctum into an associated lacrimal canaliculus, wherein the implant body is formed from a polyurethane polymer or silicone, the implant body comprising:

a first portion, wherein the first portion is formed from a polymer and comprises a first diameter and a drug donor proximal to the first portion;

a second portion formed of a polymer and comprising a base member having a second diameter, wherein the second diameter is smaller than the first diameter; and

an expandable retention member at least partially coupled to the base member, and configured to expand upon insertion into the punctum by absorption of tear fluid, wherein the expandable retention member is a hydrogel-forming polyurethane polymer.

2. The lacrimal implant of claim 1, wherein the implant body is formed from a polyurethane copolymer.

3. The lacrimal implant of claim 1, wherein the expandable retention member is a hydrogel-forming polyurethane copolymer.

4. The lacrimal implant of claim 1, wherein the drug donor comprises a solid matrix comprising a mixture of silicone and an active agent.

5. The lacrimal implant of claim 4, wherein the active agent is latanoprost or bimatoprost.

6. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of a thrombin inhibitor; an antithrombotic agent; dissolving the blood suppository; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; an antihypertensive agent; an antimicrobial agent; inhibitors of surface glycoprotein receptors; anti-platelet agents; an anti-mitotic agent; a microtubule inhibitor; an antimetabolite; an anti-cancer chemotherapeutic agent; an anti-inflammatory agent; anti-allergic agents; an antiproliferative agent; a decongestant; miotics and anticholinesterase agents; an immunological agent; a vaccine; a growth hormone antagonist; a growth factor; an angiogenesis inhibitor; a dopamine agonist; a radiotherapeutic agent; an extracellular matrix component; a free radical scavenger; an antioxidant; (ii) resistance to polymerase; a photodynamic therapeutic agent; a gene therapy agent; prostaglandins; anti-prostaglandins; a prostaglandin precursor; anti-glaucoma agents; a beta-blocker; a prostaglandin analog; carbonic anhydrase inhibitors; a neuroprotective agent; and parasympathomimetics.

7. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of an immunostimulant; an immunosuppressant; an ACE inhibitor.

8. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, furacilin, sodium propionate, amphotericin B, miconazole, and antiviral agents.

9. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of sulfadiazine, sulfacetamide, sulfamethizole, and sulfadiazineAnd (3) azole.

10. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of idoxuridine trifluorothymidine, acyclovir, gancyclovir, and interferon.

11. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, triamcinolone acetonide; salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, naproxen, piroxicam, nabumetone, dexamethasone, cortisone, prednisolone and p-flumethasone.

12. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of cromolyn sodium, antazoline, metapirine, chlorpheniramine, cetirizine, pyrilamine, and pheniramine.

13. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of 1, 3-cis retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, mitomycin C, and cisplatin.

14. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of phenylephrine, naphazoline, and tetrahydrozoline.

15. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of pilocarpine, a salicylate, carbachol, acetylcholine chloride, physostigmine, irin, diisopropyl fluorophosphate, iodicopherol, and dimeglumine.

16. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of carmustine and fluorouracil.

17. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of an estrogen, a progestational agent, and a peptide.

18. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of angiostatin, anecortave acetate, and an anti-VEGF antibody.

19. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of acetazolamide, dorzolamide, brinzolamide, methazolamide, and diclofenamide.

20. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of Danish.

21. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of lubeluzole and nimodipine.

22. The lacrimal implant of claim 4, wherein the active agent is selected from carbachol and physostigmine.

23. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of a peptide, a protein, and an enzyme.

24. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of a hormonal agent and an anti-tumor agent.

25. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of non-steroidal anti-inflammatory drugs.

26. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of antifungal agents.

27. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of estradiol, progesterone, insulin, calcitonin, parathyroid hormone, and vasopressin hypothalamic releasing factor.

28. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of epidermal growth factor; fibroblast growth factor; platelet-derived growth factors; transforming growth factor beta; a growth hormone; fibronectin.

29. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of timolol; betaxolol; levobunolol; atenolol.

30. The lacrimal implant of claim 4, wherein the active agent is selected from the group consisting of bimatoprosts; travoprost; latanoprost.

31. The lacrimal implant of claim 1, wherein the implant further comprises a projection extending laterally around the proximal end of the first implant body portion, wherein the projection is configured to rest on or near the punctal opening when the second portion of the implant body is positioned within the associated lacrimal canaliculus.

32. The lacrimal implant of claim 31, wherein the second portion of the implant body is for inhibiting or preventing the lacrimal implant from completely entering a lacrimal canaliculus cavity.

33. The lacrimal implant of claims 31 or 32, wherein the projection is a full head portion extending 360 degrees from the outer surface of the implant body about the proximal end.