HK1166599A - Lacrimal implants and related methods - Google Patents

Description

Lacrimal implants and related methods

Cross reference to related applications

The present patent application claims a drug from U.S. provisional patent application No.61/154,693 entitled "lacrimal implants and related methods" filed on 23/2/2009; U.S. provisional patent application No.61/209,036 entitled "lacrimal implants and related methods" filed 3,2, 2009; U.S. provisional patent application No.61/209,630 entitled "lacrimal implant and related methods" filed 3, 9, 2009; U.S. provisional patent application No.61/271,862 entitled "lacrimal implants and related methods" filed on 27/7/2009; and U.S. provisional patent application No.61/252,057 entitled "lacrimal implant and associated method" filed on 10/15/2009, the entirety of which is pending and is incorporated by reference herein in its entirety.

This patent application is related to U.S. patent application No.12/231,989 entitled "lacrimal implant and related method" filed on 5.9.2008, the latter of which is pending.

Technical Field

This patent document relates generally to ophthalmic instruments, and more particularly, to ocular implants. More particularly, but not by way of limitation, this patent document relates to lacrimal implants; methods of making such implants; and methods of using such implants to treat an eye, respiratory, inner ear, or other disease or disorder (e.g., a lung or immune disorder).

Background

Dry eye, including keratoconjunctivitis sicca, is a common ocular condition that may require treatment. Dry eye has been experienced by a broad statistical population and is common in the elderly. Various current treatments target physiological conditions affecting dry eye, including increases in normal tear fluid, enhanced production of tear film components, and methods of increasing tear residence time, such as blocking tear flow from the eye into the lacrimal canaliculus and through the lacrimal canaliculus.

Many of the current tear flow retardation techniques have a number of disadvantages, including being irreversible in nature. For example, some tear flow retardation techniques involve closing the canalicular canal by suturing the associated pore (puntal) opening closed, or by using electrical or laser cautery to close the pore opening. While such procedures may provide the desired result of blocking tear flow to treat dry eye, they are not reversible without reconstructive surgery.

In addition to the symptomatic relief of dry eye, patients and physicians in the field of treatment of diseases or disorders of the eye, respiratory and inner ear are faced with various challenges, including the delivery of appropriate drugs or other therapeutic agents to the eye, nasal cavity or inner ear. For example, in ocular therapy, many current ocular drug delivery systems require repeated manual administration and are often inefficient due to lack of patient compliance or inadequate drug concentration to reach the eye. For example, when an eye drop is injected into the eye, it tends to spill over the conjunctival sac (i.e., the bag between the eye and the eyelid), causing a large portion of the eye drop to be lost by spilling over the lid margin and over the cheek. Shortly after application, a large portion of the eye drops remaining on the surface of the eye ball may be washed away into and through the lacrimal canaliculus, whereby the drug concentration is diluted before the drug is able to treat the eye absorptively. In addition, topical medications often have a peak ocular effect at about two hours after application, after which additional applications of the medication should be scheduled, but often not, to maintain the desired therapeutic effect of the medication.

In a field other than ocular therapy, control of respiratory-related (e.g., allergy) and inner ear diseases or disorders often requires repetitive artificial digestion or other ingestion of drugs (e.g., drugs or other therapeutic agents) and can be inefficient due to lack of patient compliance or non-localized drug delivery.

Disclosure of Invention

The present inventors have recognized various promising techniques for increasing tear residence time on the eye, and delivery of drugs or other therapeutic agents to the eye, nasal cavity, inner ear, or other body systems. These techniques may include implanting a removable, and selectively released drug lacrimal implant through the lacrimal punctum and into the associated canaliculus. It is believed that patient comfort and implant retention in the ocular anatomy can be met by designing lacrimal implants that take advantage of the features of the nasolacrimal drainage system (e.g., by mimicking the shape of the lacrimal canaliculus). In this manner, the present lacrimal implants may overcome some of the following disadvantages associated with current dry eye relief: such as drug administration which is irreversible in nature, and which is based on manual instillation or digestion, such as poor patient compliance, waste, untimely administration, or non-localized delivery.

Yet further, the present inventors have recognized that lacrimal implants may benefit from one or more of the following capabilities: the ability to be easily implanted and removed without significant biasing of the lacrimal punctum or associated canaliculus; the ability to be reliably retained in the lacrimal canaliculus upon implantation, optionally without being pre-sized for a particular lacrimal punctum or canalicular diameter; the ability to permit tear fluid, drugs or other agents to flow into the nasolacrimal system; and the ability to permit sustained, localized release of one or more drugs or other therapeutic agents at desired therapeutic levels over an extended period of time when made and used as a drug delivery system.

In view of these insights, lacrimal implants for treating diseases or disorders are disclosed. More specifically, lacrimal implants are disclosed; methods of making such implants; and methods of using such implants to treat ocular, respiratory, inner ear, lung, or immune diseases or disorders. Clinical trials evaluating the safety, tolerability, comfort, ease of handling, insertion and removal, retention, effectiveness, and dosage of the various lacrimal implants disclosed in this patent document indicate that lacrimal implants, such as those shown in fig. 12, 13, and 43A-43C, are effective and well tolerated by clinical trial patients. In addition, it has been found that the retention of certain lacrimal implants (such as the lacrimal implant shown in fig. 13) is about 60% or more at 8 weeks and about 47% or more at 12 weeks, and it has been found that the retention of other lacrimal implants (such as those of the types shown in fig. 12 and 43A-C) is about 75% or more after 8 weeks.

To better illustrate the subject matter described herein, a non-limiting list of illustrative aspects and embodiments is provided herein:

1. a lacrimal implant insertable into a lacrimal canaliculus, comprising: an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion; the proximal end of the first portion defines a longitudinal proximal axis and includes retention protrusions that project laterally non-equidistantly around a perimeter of the proximal end; the distal end of the second portion defines a longitudinal distal axis; and the implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant against at least a portion of the lacrimal canaliculus at or more distal to the canalicular bend.

2. The lacrimal implant of aspect 1, wherein a proximal end of the retention projection of the first portion projects laterally outward at unequal lateral distances around a circumference thereof and tapers down to an outer diameter of the distal end of the first portion.

3. The lacrimal implant of aspect 2, comprising a graspable projection extending at least partially from the proximal end of the first portion, the graspable projection configured to sit against or near the lacrimal punctum when the implant is implanted; and wherein the proximal end of the retention protrusion of the first portion comprises a perimeter having a value about equal to a perimeter of the graspable protrusion.

4. The lacrimal implant of any of aspects 2 or 3, wherein a proximal end of the retention projection of the first portion protrudes outward in opposite directions on the first and second opposing sides without protruding outward from an outer diameter on the third and fourth opposing sides.

5. The lacrimal implant according to any of aspects 1-4, further comprising one or more therapeutic agents.

6. The lacrimal implant of aspect 5, wherein the one or more therapeutic agents are disposed in a drug insert at least partially positioned in the first portion, the drug insert configured to deliver sustained release of the one or more therapeutic agents.

7. A kit comprising a lacrimal implant according to any of aspects 1-6, and instructions for using the lacrimal implant to treat an eye disorder.

8. A lacrimal implant insertable into a lacrimal canaliculus, comprising: an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion; the proximal end of the first portion defines a longitudinal proximal axis; the distal end of the second portion defines a longitudinal distal axis and includes a retention projection projecting laterally about a periphery of the distal end, the retention projection including an outward lateral step at one of a proximal end location of the retention projection or a distal end location of the retention projection; and the implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant against at least a portion of the lacrimal canaliculus at or more distal to the canalicular bend.

9. The lacrimal implant of aspect 8, wherein the lateral step extends laterally outward in a direction perpendicular to a direction in which the second portion extends, the lateral step being greater than or equal to about 0.14 mm.

10. The lacrimal implant of any of aspects 8 or 9, wherein the transverse step is positioned at a proximal end of the retention projection and tapers to an outer diameter of the second portion at a distal end of the retention projection.

11. The lacrimal implant according to aspect 10, wherein the distal end of the retention projection includes an integral dilator to facilitate implantation of the implant into the lacrimal canaliculus.

12. The lacrimal implant according to any of aspects 8-11, further comprising one or more therapeutic agents.

13. The lacrimal implant of aspect 12, wherein the one or more therapeutic agents are disposed in a drug insert at least partially positioned in the first portion, the drug insert configured to deliver sustained release of the one or more therapeutic agents.

14. The lacrimal implant of aspect 13, wherein the drug insert includes at least about 44 micrograms of the one or more therapeutic agents.

15. The lacrimal implant of aspect 13, wherein the drug insert comprises at least about 81 micrograms of the one or more therapeutic agents.

16. A kit comprising a lacrimal implant according to any of aspects 8-15, and instructions for using the lacrimal implant to treat an eye disorder.

17. A lacrimal implant for insertion into a lacrimal canaliculus, comprising: an implant extending non-linearly from a proximal end portion to a distal end portion with an intermediate portion therebetween, the proximal end portion being positionable in a vertical section of a lacrimal canaliculus, the distal end portion being positionable in a horizontal section of the lacrimal canaliculus; the intermediate portion extends partially in a first direction toward the proximal end portion and partially in a second direction toward the distal end portion, so as to be implanted in a lacrimal canaliculus; and wherein the intermediate portion includes a recess storing an expandable material configured to partially expand in a third direction toward the ampulla of the lacrimal canaliculus when the implant is implanted, the third direction being generally opposite the second direction.

18. The lacrimal implant of aspect 17, wherein the expandable material comprises a hydrogel.

19. The lacrimal implant according to any of aspects 17 or 18, wherein, when the implant body is implanted, the expandable material expands laterally relative to the second direction, the lateral expansion urging one or more surrounding portions of the implant body outward against a wall of the lacrimal canaliculus.

20. The lacrimal implant according to any of aspects 17-19, wherein at least one of the proximal end portion and the distal end portion includes at least one intermediately-disposed retention projection having a larger cross-sectional dimension than an adjacent implant body portion.

21. The lacrimal implant according to any of aspects 17-20, further comprising one or more therapeutic agents.

22. The lacrimal implant of aspect 21, wherein the one or more therapeutic agents are disposed in a drug insert positioned at least partially in the proximal end portion, the drug insert including at least one exposed surface configured to deliver sustained release of the one or more therapeutic agents.

23. A kit comprising a lacrimal implant according to any of aspects 17-22, and instructions for using the lacrimal implant to treat an eye disorder.

24. A lacrimal implant insertable into a lacrimal canaliculus, comprising: an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion; the proximal end of the first portion defines a longitudinal proximal axis and includes a retention projection projecting laterally about a periphery of the proximal end; the distal end of the second portion defines a longitudinal distal axis; the retention projection includes an outward transverse step at a proximal end thereof and tapers directly to the second portion; and the implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant against at least a portion of the lacrimal canaliculus at or more distal to the canalicular curvature.

25. The lacrimal implant of aspect 24, wherein a length of the retention projection is about 0.96mm or greater.

26. The lacrimal implant according to any of aspects 24 or 25, wherein the distal end of the retention projection includes an integral dilator to facilitate implantation of the implant into the lacrimal canaliculus.

27. The lacrimal implant according to any of aspects 24-26, further comprising one or more therapeutic agents.

28. The lacrimal implant of aspect 27, wherein the one or more therapeutic agents are disposed in a drug insert at least partially positioned in the first portion, the drug insert configured to deliver sustained release of the one or more therapeutic agents.

29. The lacrimal implant of aspect 28, wherein the drug insert is positioned in a first cavity of the first portion, the first cavity having a diameter of at least about 0.56 mm.

30. The lacrimal implant of any of aspects 28 or 29, wherein the drug insert comprises at least about 81 micrograms of the one or more therapeutic agents.

31. A kit comprising a lacrimal implant according to any of aspects 24-28, and instructions for using the lacrimal implant to treat an eye disorder.

32. A lacrimal implant insertable into a lacrimal canaliculus, comprising: an implant extending non-linearly from a proximal end portion to a distal end portion, and having a middle portion, the proximal end portion being positionable in a vertical segment of a lacrimal canaliculus, the distal end portion being positionable in a horizontal segment of the lacrimal canaliculus; the intermediate portion extends in part in a first direction toward the proximal end portion and in part in a generally tapering manner in a second direction toward the distal end portion such that when implanted in the lacrimal canaliculus, the implant is directionally laterally biased against at least a portion of the lacrimal canaliculus that is at or more distal of the canalicular bend; the extension in the second direction has a longitudinal length that is less than four times a longitudinal length of the extension in the first direction; and wherein, when the implant is implanted, the intermediate portion extends partially in a third direction towards the ampulla of the lacrimal canaliculus, the third direction being generally opposite the second direction, the extension in the third direction comprising a flattened lenticular shape.

33. The lacrimal implant of aspect 32, comprising a graspable projection extending at least partially from the proximal end portion, the graspable projection comprising an ovoid shape.

34. The lacrimal implant of any of aspects 32 or 33, wherein the flat pod-like shape includes a length between about 0.4 and 0.5 millimeters, and a thickness of about 0.5 to 0.6 millimeters.

35. The lacrimal implant according to any of aspects 32-34, further comprising a therapeutic agent.

36. The lacrimal implant according to aspect 35, comprising at least one drug insert, distinct from the implant, disposed in the cavity of the proximal end portion, the drug insert comprising a polymer matrix comprising the therapeutic agent.

37. The lacrimal implant of any of aspects 35 or 36, wherein the therapeutic agent is integrated into one or more portions of the implant body.

38. A kit comprising a lacrimal implant according to any of aspects 32-37, and instructions for using the lacrimal implant to treat an eye disorder.

39. A lacrimal implant insertable into a lacrimal canaliculus, comprising: an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion, the proximal end of the first portion defining a longitudinal proximal axis and the distal end of the second portion defining a longitudinal distal axis; the implant is configured such that, when implanted in a lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant against at least a portion of the lacrimal canaliculus located at or more distal to a canalicular bend; and a graspable projection extending at least partially from the proximal end of the first portion, the graspable projection including an inwardly extending retention lip that overhangs a cavity within the first portion.

40. The lacrimal implant according to aspect 39, further comprising at least one drug insert, distinct from the implant body, disposed in the cavity of the first portion, the drug insert including a therapeutic agent.

41. The lacrimal implant of aspect 40, wherein the inwardly extending retention lip, when fully seated in the cavity, suspends a proximal surface of the drug insert, thereby fixing a position of the insert.

42. The lacrimal implant according to aspect 41, wherein the hanging does not significantly affect a release rate of a drug stored in the drug insert.

43. A method of making a lacrimal implant insertable into a lacrimal canaliculus, the method comprising: forming an implant extending from a proximal end of the first body portion to a distal end of the second body portion, the forming including forming a cavity in the first body portion, extending the second body portion to a longitudinal length that is less than four times a longitudinal length of the first body portion, and configuring the proximal end and the distal end to define, when implanted in a lacrimal canaliculus, a longitudinal proximal axis and a longitudinal distal axis, respectively, the longitudinal proximal axis and the longitudinal distal axis intersecting at an angle, thereby configuring the implant to be directionally laterally offset with respect to at least a portion of the lacrimal canaliculus located at or more distal of a canaliculus bend; and disposing a drug insert in the cavity of the first body portion, the drug insert distinct from the implant, the disposing including positioning an exposed surface of the drug insert over the proximal end of the first body portion.

44. A lacrimal implant for insertion into a lacrimal canaliculus, comprising: an implant extending from a proximal end portion to a distal end portion with an intermediate portion therebetween, the proximal end portion being positionable in a vertical segment of a lacrimal canaliculus, the distal end portion being positionable in a horizontal segment of the lacrimal canaliculus; the intermediate portion extends partially in a first direction toward the proximal end portion and partially in a second direction toward the distal end portion such that when implanted in a lacrimal canaliculus, the implant is directionally laterally offset with respect to at least a portion of the lacrimal canaliculus at or more distal of a canalicular curvature; and a retention projection disposed at or near the distal end portion.

45. The lacrimal implant of aspect 44, wherein the second direction extension includes a generally concave shape relative to the first direction extension; and wherein the radius of the generally concave shape is less than the radius of the tubular bend.

46. A lacrimal implant for insertion into a lacrimal canaliculus, comprising: an implant comprising at least one cavity; a drug insert, distinct from the implant, disposed in the at least one cavity; the drug insert includes a polymer matrix and a therapeutic agent; and wherein the implant includes a therapeutic agent integral with the one or more body portions.

47. The lacrimal implant according to aspect 46, further comprising a sheath surrounding one or more surfaces of the drug insert.

48. The lacrimal implant according to any of aspects 46 or 47, further comprising a coating applied to one or more portions of the surface of the external implant.

49. The lacrimal implant according to aspect 48, wherein a first coating thickness is applied to the first implant body surface portion and a second coating thickness is applied to the second implant body surface portion, the second coating thickness being different than the first coating thickness.

50. The lacrimal implant of any of aspects 48 or 49, wherein the coating comprises at least one of xylene, ceramic, or silver.

51. The lacrimal implant according to any of aspects 46-50, wherein the drug insert includes a first supply of the therapeutic agent and the implant includes a second supply of the therapeutic agent.

These and other embodiments, advantages, and aspects of the lacrimal implants and methods will be set forth in part in the detailed description that follows. This exemplary embodiments section is intended to provide an overview of the subject matter of the present patent application. It is not intended to provide an exclusive or exhaustive explanation of the present implant. The detailed description section is intended to provide additional information regarding the present patent document.

Drawings

In the drawings, like numerals may be used to describe like elements throughout the several views. Like reference numerals having different letter suffixes may be used to represent different instances of like elements. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

Fig. 1-2 show illustrative views of anatomical structures associated with an eye, some of which provide a suitable environment in which a lacrimal implant may be used.

Fig. 3A shows an isometric view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated lacrimal canaliculus anatomy, the lacrimal implant including an angled intersection between first and second implants.

Fig. 3B shows a cross-sectional view of an illustrative lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 3B-3B, and expansion of the implant-receiving anatomical structure.

Fig. 4 illustrates a side view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including an integral dilator.

Fig. 5 shows a schematic view of an exemplary lacrimal implant retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including at least one drug or other therapeutic agent.

Fig. 6A shows an isometric view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a portion positionable within a lacrimal canaliculus ampulla.

Fig. 6B shows a cross-sectional view of an illustrative lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 6B-6B.

Fig. 7A shows an isometric view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including an annular graspable projection.

Fig. 7B shows a cross-sectional view of an illustrative lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 7B-7B.

Fig. 8A shows an isometric view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a portion positionable within a lacrimal canaliculus ampulla and including a depression to facilitate insertion.

Fig. 8B shows a cross-sectional view of an illustrative lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 8B-8B.

Fig. 9 illustrates a side view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a depression for ease of insertion.

Fig. 10A shows an isometric view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a portion positionable within a lacrimal canaliculus ampulla.

Fig. 10B shows a cross-sectional view of an illustrative lacrimal implant taken along a line parallel to a longitudinal axis of the implant, such as along line 10B-10B.

Fig. 11-17 show side or isometric views of various examples of lacrimal implants configured to be retained within a lacrimal punctum and associated canalicular anatomy, each lacrimal implant including at least one intermediately disposed retention projection.

Fig. 18-19 illustrate exemplary lacrimal implants configured to be retained within lacrimal canaliculus and associated canalicular anatomy, each lacrimal implant including a non-linear second implant body portion.

Fig. 20 illustrates an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including one or more material incisions that allow for deflection of the second body portion.

Fig. 21A-22B show side views of an illustrative lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, each lacrimal implant including one or more laterally extendable arms.

Fig. 23A-23B show a side view of an illustrative lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including an expandable retention element disposed about one or more portions of an implant body.

Fig. 24 shows a schematic view of an illustrative lacrimal implant retained within a lacrimal punctum and associated canalicular anatomy.

Fig. 25A-25B show isometric views of exemplary lacrimal implants configured to be retained within a lacrimal punctum and associated canalicular anatomy, each lacrimal implant including an implant body portion having a generally concave shape.

Fig. 26 illustrates an isometric view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including an implant body portion having a generally convex shape.

Fig. 27 shows a side view of an illustrative lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including an implant body portion having a wave shape.

Fig. 28 shows a side view of an illustrative lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including at least one intermediately disposed projection.

Fig. 29-32 show side views of various lacrimal implant examples configured to be retained within a lacrimal punctum and associated canalicular anatomy, each lacrimal implant including a fluid-expandable retention element.

Fig. 33 shows a side view of an illustrative lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including an expandable retention element.

Fig. 34A-34B show schematic views of exemplary lacrimal implants retained within a lacrimal punctum and associated canalicular anatomy, each lacrimal implant including a directional graspable projection.

Fig. 35-38 show isometric views of proximal end portions of various lacrimal implants, each including a graspable projection or void.

Fig. 39A-39B show isometric views of exemplary drug inserts and removal-facilitating wires.

Fig. 40 shows an illustrative method of making a lacrimal implant configured to be retained within a lacrimal punctum, and related canalicular anatomy.

Fig. 41 illustrates a side view of an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including at least one intermediately disposed projection.

Fig. 42A-42D illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including at least one intermediately disposed projection, such as having a retention mechanism on a distal second section, which may include an abrupt step.

Fig. 43A-43C illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including at least one intermediately disposed projection, such as having a retention mechanism on a proximal segment that may taper to a distal segment.

Fig. 44A-44C illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a notch extending from a proximal end of a distal segment.

Fig. 45A-45C illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a notch extending from a proximal end of a distal segment and including a swellable material therein.

Fig. 46-47 show illustrative experimental results of a lacrimal implant including a recess including a swellable material therein.

Fig. 48A-48E illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a substantial projection disposable within a lacrimal canaliculus concha ventral.

Fig. 49A-49F illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a retaining lip configured to assist in securing a dissimilar drug insert within an implant cavity.

Fig. 50A-50B illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including a raised drug insert.

Fig. 51-52 illustrate an exemplary lacrimal implant configured to be retained within lacrimal canaliculus and associated canalicular anatomy, the lacrimal implant including a retention element at or near a distal end.

Fig. 53A-53D illustrate an exemplary lacrimal implant configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant including one or both of a distinct drug insert or a drug integral with the implant body.

Detailed Description

In this patent document, lacrimal implants and related methods are described that provide secure, wedgable retention within the lacrimal fossa and associated canaliculus of the eye. The lacrimal implant may include an implant body configured for insertion at least partially through the lacrimal punctum and into an associated canaliculus. The implant may include first and second portions, and may extend from a proximal end of the first portion defining a longitudinal proximal axis to a distal end of the second portion defining a longitudinal distal axis. The implant may be configured such that there is an angular intersection of, for example, at least 45 degrees between the proximal axis and the distal axis when implanted using the full body dilator. In this manner, at least a portion of the implant can be offset relative to at least a portion of the lacrimal canaliculus that is located at or more distal to the canalicular bend, thereby maintaining the implantation site of the lacrimal implant using anatomical structures.

In various examples, the lacrimal implant may further include a distinct drug insert or an integrated drug or other agent disposed in at least one of the first portion or the second portion of the implant that provides for sustained release of the drug or other therapeutic agent to one or more systems of the eye, nasal cavity, or inner ear system.

Fig. 1-2 show illustrative views of anatomical structures associated with an eye 100. Certain of the anatomical structures shown may be suitable for treatment using the various lacrimal implants and methods discussed herein. The eye 100 is a spherical structure comprising a wall with three layers: an outer sclera 102, an intermediate choroid layer 104, and an inner retina 106. Sclera 102 comprises a tough fiber outer coating that protects the inner layers. It is mostly white except for the clear area at the front, commonly referred to as the cornea 108, which allows light to enter the eye 100.

The choroid layer 104, which is located within the sclera 102, contains a plurality of blood vessels and changes to a colored iris 110 at the anterior portion of the eye 100. The lenticular lens 112 is located directly behind the pupil. The eye chamber 114 behind the lens 112 is filled with vitreous, a gel-like substance. Anterior and posterior chamber 116 are located between cornea 108 and iris 110, respectively, and are filled with aqueous humor. At the back of the eye 100 is a light detecting retina 106.

The cornea 108 is an optically transparent tissue that transmits an image to the back of the eye 100. It includes avascular tissue to which nutrients and oxygen are supplied via bathing with tears and aqueous humor and from blood vessels embedded in the junction between the cornea 108 and sclera 102. The cornea 108 includes a pathway for drugs to penetrate into the eye 100.

Turning to fig. 2, other anatomical structures associated with the eye 100 are shown, including the lacrimal drainage system, which includes a drainage system 230, a distribution system, and a drainage system. The secretion system 230 includes: secretory glands, which are stimulated by blinking and temperature changes caused by tear evaporation; and reflex secretory glands, which have an efferent parasympathetic supply and secrete tears in response to physical or emotional stimuli. The dispensing system includes an eyelid 202 and a tear meniscus around the eyelid margin of an open eye that distributes tears on the surface of the eye by blinking, thus reducing the occurrence of dry areas.

The drainage portion of the lacrimal drainage system includes, in order of flow drainage, the lacrimal canaliculus, the lacrimal sac 204, and the lacrimal duct 206. From the tear duct 206, tears and other flowable materials drain into the channels of the nasolacrimal system. The lacrimal canaliculus includes an upper (superior) lacrimal canaliculus 208 and a lower (inferior) lacrimal canaliculus 210, the upper and lower lacrimal canaliculus 208 and 210 terminating in an upper 212 lacrimal canaliculus and a lower lacrimal canaliculus 214, respectively. The upper lacrimal punctum 212 and the lower lacrimal punctum 214 are slightly elevated at the medial end of the lid margin at the junction 216 of the ciliary and lacrimal gland portions near the conjunctival sac 218. The upper and lower lacrimal canaliculus 212, 214 are generally circular or slightly oval shaped openings surrounded by a ring of connective tissue. Each of the lacrimal canaliculus 212, 214 is bent more horizontally at the canalicular bend 250 to lead into the vertical portions 220, 222 of the respective canaliculus of the lacrimal canaliculus 212, 214 before joining with each other at the entrance of the lacrimal sac 204. The tubules 208, 210 are generally tubular in shape and lined with a stratified squamous epithelium surrounded by elastic tissue that allows the tubules 208, 210 to expand. As shown, there is a canalicular ampulla 252 near the outer edge of each canalicular bend 250.

Fig. 3A shows an exemplary lacrimal implant 300 that can be inserted through the lacrimal canaliculus 212, 214 and into the associated lacrimal canaliculus 208, 210 (fig. 2) of the exemplary lacrimal implant 300. Insertion of the lacrimal implant 300 through the lacrimal canaliculus 212, 214 and into the associated lacrimal canaliculus 208, 210 may allow one or more of the following functions to be performed: cause a blockage or obstruction to the flow of tears therethrough (e.g., to treat dry eye); or the sustained delivery of drugs or other therapeutic agents to the eye (e.g., to treat infection, inflammation, glaucoma, or other ocular diseases or disorders), nasal cavity (e.g., to treat sinus disorders or allergies), or inner ear system (e.g., to treat dizziness or migraine).

As shown in this example, the lacrimal implant 300 can include an implant 302-the implant 302 includes a first portion 304 and a second portion 306, and can extend from a proximal end 308 of the first portion 304 to a distal end 310 of the second portion 306. In various examples, the proximal end 308 can define a longitudinal proximal axis 312 and the distal end 310 can define a longitudinal distal axis 314. The implant 300 can be configured such that, when implanted within the lacrimal punctum and associated canaliculus, there is an angled intersection 316 of at least 45 degrees between the proximal axis 312 and the distal axis 314 to bias at least a portion of the implant 302 relative to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2) located at or more distally of the canalicular curvature 250 (fig. 2). In some examples, the implant 302 can be configured with the angled intersection 316 between about 45 degrees and about 135 degrees. In this example, the implant 302 is configured such that the angular intersection 316 is about 90 degrees (i.e., the intersection 316 between the proximal axis 312 and the distal axis 314 is about perpendicular). In various examples, the distal end 326 of the first portion 304 can be integral with the second portion 306 at or near the proximal end 328 of the second portion 306.

In some examples, the implant 302 can include obliquely arranged cylindrical structures including one or both of a first cavity 318 or a second cavity 320, the first cavity 318 being disposed near the proximal end 308 and the second cavity 320 being disposed near the distal end 310. In this example, a first cavity 318 extends inwardly from the proximal end 308 of the first portion 304 and a second cavity 320 extends inwardly from the distal end 310 of the second portion 306. Optionally, one or more portions of the implant 302 may include an oval cross-sectional shape for anatomical fit purposes.

A first drug-releasing or other agent-releasing insert (e.g., a drug core) 322 may be disposed in first cavity 318 to provide sustained release of the drug or other therapeutic agent to the eye; while a second drug-releasing or other agent-releasing insert (e.g., drug core) 324 may alternatively or in conjunction be disposed in the second cavity 320 to provide sustained release of the drug or other therapeutic agent to, for example, the nasal cavity or inner ear system. The implant spacer 330 can be positioned between the first cavity 318 and the second cavity 320 and can be used to inhibit or prevent communication of material (e.g., an agent) between the first drug insert 322 and the second drug insert 324. In various examples, the first drug-releasing or other agent-releasing insert 322 or the second drug-releasing or other agent-releasing insert 324 may include at least 21 micrograms, at least 42 micrograms, at least 44 micrograms, at least 81 micrograms, or at least 95 micrograms of drug (e.g., latanoprost), as discussed further in the following patent applications: commonly owned U.S. patent application No.12/463,279 to butiner et al, entitled "sustained release delivery of active agents for the treatment of glaucoma and ocular hypertension," filed 5/8 of 2009; and co-owned U.S. patent application No.61/277,000 to Utkhede, entitled "improved drug core for sustained ocular release of therapeutic agents," filed on 9/18 of 2009, both of which are incorporated by reference in their entirety, including a description of their drug or other agent concentrations.

In some instances, the implant 302 is substantially solid in nature, i.e., it does not include one or more cavities or other cavities for receiving drug-releasing or other agent-releasing inserts. Rather, the implant 302 may be configured to receive one or more drugs or other agents that are integral throughout one or more body portions. In this manner, the entire implant 302, or portions thereof, may function as a drug-release or other agent-release insert, and agent release may be directed using an impermeable or substantially impermeable cover (e.g., a xylene cover) that surrounds portions of the implant 302. In other examples, a permeable cover material may be used to allow release of the drug or other agent.

In some examples, drug or other therapeutic agent release may occur at least partially through the exposed, unsheathed surfaces of the drug inserts 322, 324. By controlling the geometry of the exposed surface, a predetermined drug or agent release rate can be achieved. For example, the exposed surface can be constructed with a particular geometry or other technique suitable for controlling the release rate of a drug or other therapeutic agent onto the eye 100, such as acutely or chronically between outpatient visits. Further description of the effective release rate of one or more drugs or other therapeutic agents from drug inserts 322, 324 may be found in commonly owned U.S. patent application No.11/695,545 to DeJuan et al, entitled "nasolachrymal drainage system implant for drug therapy," which is incorporated herein by reference in its entirety, including the description thereof for specific release rates.

In some examples, as shown in fig. 3B, the exposed surfaces of the drug inserts 322, 324 may be flush with or slightly below the proximal end 308 of the first portion 304 or the distal end 310 of the second portion 306, respectively, so that the drug inserts do not protrude out of the implant 302. In some examples, as shown in fig. 4, an exposed surface of the first drug insert 322 can, for example, be positioned over the proximal end 308 such that the first drug insert 322 at least partially protrudes out of the implant 302.

The implant 302 can include a graspable or other protrusion 332, such as one or more protrusions, extending at least partially laterally from or about the proximal end 308 of the first implant portion 304. In some examples, the graspable or other protrusion 332 can include a set of tabs for inserting the lacrimal implant 300 into an implantation site, or for removing the lacrimal implant 300 from the implantation site. The set of fins or other protrusions 332 can be configured without concern for migration because the non-linear configuration of the implant 302 prevents migration of the implant 300 by assuming the size or shape of the canalicular curvature 250 and optionally the canalicular ampulla 252 (fig. 2). In some examples, the graspable or other protrusion 332 may be configured to sit against or near the lacrimal punctum openings 212, 214, such as to stop or prevent the lacrimal implant 300 from passing completely within the lacrimal canaliculus 208, 210, or to provide tactile or visual feedback information to the implantation user, for example, as to whether the implant is sufficiently implanted.

As shown in fig. 34A-34B, and discussed further below, the graspable or other protrusion 332, when implanted, may extend laterally in a direction parallel to the eye 100 or away from the eye 100. It is believed that this may reduce irritation of the eye 100 as compared to the case where a portion of the protrusion extends toward the eye 100. Additionally, the direction of lateral extension of the protrusion 332 from the proximal end 308 may be substantially the same as the direction of lateral extension of the second implant body portion 306 relative to the distal end 326 of the first implant body portion 304, as shown, for example, in fig. 3A-3B. This may also avoid the protrusion extending towards the eye and may facilitate the insertion orientation for the care giver. The first drug insert 322 may extend partially over the area of the protrusion 332, such as to provide sustained release of the first drug or other therapeutic agent onto the eye.

In various examples, the implant 302 may be molded using an elastomeric material, such as silicone, polyurethane, or other urethane-based polymers or copolymers; NuSil (e.g., NuSil4840 with 2% 6-4800); or acrylic of a non-biodegradable, partially biodegradable, or biodegradable nature (i.e., erodible within the body), allows the implant 302 to be configured such that, when implanted in the lacrimal canaliculus 208, 210, there is an angular intersection 316 between the proximal axis 312 and the distal axis 314 to be formed. For example, it is believed that silicone is soft enough to be comfortable for the patient and hard enough to facilitate insertion by the care giver. In various examples, a biocompatible colorant (e.g., a green colorant) can be mixed with the elastomeric material of the implant 302 to allow the patient and their caregiver to more easily see the implant and confirm that it remains in the implanted position. In some examples, a biocompatible coloring agent may be mixed with the material of drug insert 322 for implant feedback or to indicate the type, size, agent, or other characteristic of the implant.

In some examples, the biodegradable elastomeric material may include a crosslinked polymer, such as poly (vinyl alcohol). In some examples, the implant 302 may include a silicone/polyurethane copolymer. Other copolymers that may be used to form the implant 302 include, but are not limited to, silicone/urethane, silicone/poly (ethylene glycol) (PEG), and silicone/hydroxyethyl 2 methacrylate (HEMA). Urethane-based polymer and copolymer materials allow for a variety of treatment methods, and are well-associated with each other, as discussed in commonly owned U.S. patent application No.12/231,986, filed on 5.9.2008, attorney docket No.2755.045US1, entitled "drug core for sustained release of therapeutic agents," which is incorporated herein by reference in its entirety.

Fig. 3B shows an illustrative cross-sectional view of lacrimal implant 300 taken along a line parallel to a longitudinal axis of the implant, such as along line 3B-3B of fig. 3A. As shown in fig. 3B, the lacrimal implant 300 can include an implant 302-the implant 302 includes a first portion 304 and a second portion 306, and can extend from a proximal end 308 of the first portion 304 to a distal end 310 of the second portion 306. In various examples, the proximal end 308 can define a longitudinal proximal axis 312 and the distal end 310 can define a longitudinal distal axis 314. The implant 300 can be configured such that, when implanted, there is an angled intersection 316 of at least 45 degrees between the proximal axis 312 and the distal axis 314 to bias at least a portion of the implant 302 relative to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2) that is located at or more distally of the canalicular curvature 250 (fig. 2). In this example, the implant 300 is configured such that the angular cross 316 is approximately about 90 degrees.

In various examples, the distal end 326 of the first portion 304 can be integral with the second portion 306 at or near the proximal end 328 of the second portion 306. In some examples, the second portion 306 may include a length having a value of less than four times the length of the first portion 304. In one example, the second portion 306 may comprise a length of less than about 10 millimeters and have a configuration similar to that shown in fig. 3B. In another example, the second portion 306 may include a length of less than about 2 millimeters and have a configuration similar to that shown in fig. 24.

In various examples, the second portion 306 can include an integral dilator 350 to dilate anatomical tissue 352, such as one or both of the lacrimal canaliculus 212, 214 (fig. 2) or associated canaliculus 208, 210, to a sufficient diameter when the lacrimal implant 300 is being implanted. In this manner, lacrimal implant 300 can be implanted in various sizes of ocular anatomy without the need for pre-dilation with a separate dilation tool. The dilator 350 can be formed so as not to traumatize the inner lining of the lacrimal canaliculus 212, 214 and the canaliculus 208, 210. In some examples, a lubricious coating may be used to further aid in insertion of lacrimal implant 300 into anatomical tissue 352, the lubricious coating being disposed on or impregnated into an outer surface of implant body 302. In one example, the lubricious coating may include a silicone lubricant.

The dilator 350 can generally taper from a location near the proximal end 328 of the second portion 306 to the distal end 310 of the second portion 306, such as from a diameter of about 0.6 millimeters to a diameter of about 0.2 millimeters. In some examples, the slope of the outer surface of dilator 350, as measured from a position near proximal end 328 of second portion 306 to distal end 310 of second portion 306, can be between about 1 degree and about 10 degrees (e.g., 2 degrees, 3 degrees, 4 degrees, or 5 degrees) relative to longitudinal distal axis 314. In some examples, the slope of dilator 350 may be less than 45 degrees relative to the longitudinal distal axis 314. Among other factors, the determination of the desired slope of the dilator 350 for a given implantation scenario may be made by balancing the strength of the implant 302 desired for implantation with the desire to have a soft, flexible, and compliant implant when implanted (e.g., to accommodate the lacrimal canaliculus anatomy). In some examples, dilator tip 354 can have a diameter between about 0.2 millimeters and about 0.5 millimeters.

In some examples, the proximal end 328 of the second implant body portion 306 can include a retaining element 356, the retaining element 356 configured to be biased against at least a portion of the canalicular ampulla 252 (fig. 2) when implanted. In this example, the retaining element 356 projects proximally from the intersection between the first implant body portion 304 and the second implant body portion 306, such as in a direction opposite the extension of the dilator 350. When presented and implanted in the ampulla 252, the retention element 356 may help secure the seated position of the graspable or other projection 332 relative to the lacrimal punctum openings 212, 214.

In some examples, the implant 302 includes a first cavity 318, the first cavity 318 being disposed near the proximal end 308. In this example, the first cavity 318 extends inward about 2 millimeters or less from the proximal end 308 and houses a first drug-releasing or other agent-releasing drug insert 322 to provide sustained drug or other agent release to the eye. In some examples, drug insert 322 may include a plurality of therapeutic agent inclusions 360, and these therapeutic agent inclusions 360 may be distributed in matrix 362. In some examples, inclusion 360 may include a concentrated (e.g., crystalline) form of the therapeutic agent. In some examples, the matrix 362 may include a silicone matrix or the like, and the distribution of inclusions 360 within the matrix may be generally homogeneous or heterogeneous. In some examples, reagent inclusion 360 may include oil droplets, such as oil droplets of Latanoprost oil. In other examples, reagent inclusion 360 may include solid particles, such as Bimatoprost particles in crystalline form. In some examples, drug insert 322 comprises a urethane-based (e.g., polyurethane) polymer or copolymer that includes therapeutic agent inclusions that can be delivered into the eye or surrounding tissue. The inclusions can have a variety of sizes and shapes. For example, the inclusions may include particles having a size on the order of about 1 micron to about 100 microns. Further discussion of drug-releasing or other agent-releasing drug inserts may be found in commonly owned U.S. patent application No.12/231,986 to utkhide et al, filed 9/5 of 2008, entitled "drug core for sustained release of a therapeutic agent," attorney docket No.2755.045US1, which is incorporated herein by reference in its entirety.

In various examples, drug insert 322 can include a sheath 366, the sheath 366 being disposed over at least a portion of the insert to define at least one insert exposed surface 368. Exposed surface 368 may be located, for example, at or near proximal end 308 of implant 302, thereby allowing direct contact with tears or tear film fluid and release of drugs or other therapeutic agents from drug insert 322 over a sustained period of time when lacrimal implant 300 is inserted through lacrimal canaliculus 212, 214 and into associated canaliculus 208, 210.

Fig. 4 shows an illustrative side view of another integral dilator 450 for the second portion 406 of the implant 402 of the lacrimal implant 400. In this example, the dilator 450 tapers sharply near the distal end 410 of the second portion 406. As shown, the implant first portion 404 can include a first cavity 418, the first cavity 418 being disposed near the proximal end 408. In this example, a first cavity 418 extends inwardly from proximal end 408 and houses a first drug-releasing or other agent-releasing drug insert 422 to provide sustained release of a drug or other therapeutic agent to, for example, the eye. In some examples, the drug or other therapeutic agent may be released to the eye through the exposed, uncovered sheath surface 468 of the drug insert 422. In this example, the exposed surface 468 of the drug insert 422 is positioned over the proximal end 408 such that the drug insert 422 at least partially protrudes out of the implant 402.

In various examples, the outer surface 482 of the implant 402 can be formed, or surface treated, to be generally smooth to inhibit bacteria from attaching to and hatching on the lacrimal implant 400. The generally smooth outer surface 482 may also prevent damage to the lining of the anatomical tissue intended to be received during implantation, such as damage to the lacrimal canaliculus 212, 214 (fig. 2) or associated canaliculus 208, 210 (fig. 2). As further discussed in commonly owned U.S. patent application No.12/283,002 to Rapacki et al, filed 9/5.2008, attorney docket No.2755.036US1, entitled "surface treatment of implants and related methods," the outer surface 482 of implant 402 may be surface treated to be generally smooth via a polishing process, which is incorporated herein by reference in its entirety. The polishing process may include: during the period of time that the implant 402 is in the enlarged, expanded state, the implant 402 is impinged with a polishing medium. This may smooth one or more surfaces or edges of the implant 402. In various examples, the polishing medium may comprise at least some granules having a diameter greater than about 3 millimeters.

In various examples, an antimicrobial coating 484 can be disposed on or impregnated into at least a portion of the outer surface 482 to further prevent bacterial growth on the implant 402. In some examples, antimicrobial coating 484 can include an agent selected from the group consisting of: 2-bromo-2-nitropropane-1, 3-diol; 5-bromo-5-nitro-1, 3-dioxane; 7-ethylbicyclic oxazolidine; benzalkonium chloride; benzethonium chloride; benzoic acid; benzyl alcohol; boric acid; bronopol; cetyl pyridinium chloride; chlorhexidine; chloroacetamide; chlorobutanol; chloromethyl isothiazolinone and methylisothiazoline; sulfamonomethoxine (dimethoxane); a dimethyloxazolidine; a dimethylol pyrazole; chloroxylenol; dehydroacetic acid; diazolidinyl urea (diazolidinyl urea); dichlorobenzyl alcohol; DMDM hydantoin; ethanol; formaldehyde; glutaraldehyde; hexachlorophene; a hexetidine; hexamethylenetetramine (hexamethylenetetramine); imidazolidinyl urea; iodopropylcarbamate butyl carbamate; isotiazolinones; methammonia chloride; methyl dibromoglutaronitrile; MDM hydantoin; minocycline; o-phenylphenol; p-chloro-m-cresol; benzoates (butyl paraben; ethyl paraben; methyl paraben); phenyl ethyl alcohol; phenoxyethanol; piroctane ketoamine; polyaminopropyl biguanide; polymethoxybicyclo oxazole; 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; trichloro; triclocarban; undecylenic acid; zinc phenol sulfonate; and zinc pyrithione. In some examples, antimicrobial coating 484 can include 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 lodate), silver nitrate, silver sulfadiazine, silver palmitate, or a mixture or mixtures thereof. In some examples, antimicrobial coating 484 can include at least one of an antibiotic or antiseptic. For example, the antimicrobial coating 484 can include a temporary anesthetic duration, on average between a few hours and a day. In other examples, antimicrobial coating 484 can include a drug or other therapeutic agent, such as a pill, that is used to treat the underlying disease for immediate effect.

Fig. 5 shows an illustrative schematic view of a lacrimal implant (such as lacrimal implant 300 shown in fig. 3) implanted in lower lacrimal punctum 214 and associated canaliculus 210. In some examples, lacrimal implant 300 may be implanted in upper lacrimal punctum 212 and canaliculus 208. As discussed further above, lacrimal implant 300 may include an implant body 302, the implant body 302 including a first portion 304 and a second portion 306. In various examples, the implant 302 can be configured such that, when implanted, at least a portion of the implant 302 is biased relative to at least a portion of the lacrimal canaliculus 210 to securely maintain the implant position of the implant 300, the at least a portion of the lacrimal canaliculus 210 being located at or more distal of the canalicular bend 250. As shown, the first portion 304 can be configured to be inserted through the lacrimal punctum 214 and into the associated canaliculus 210 and to be positioned between the lacrimal punctum opening and the lacrimal canaliculus ampulla 252; and the second portion 306 can be configured to be inserted through the lacrimal punctum 214 and into the canaliculus 210 and to be positioned between the ampulla 252 and the lacrimal sac 204. In some examples, a retaining element 356 protruding from a proximal end of the second portion 306 can be configured to bias into and rest on at least a portion of the ampulla 252 when implanted. In various examples, first portion 304 and second portion 306 can be configured to bend, stretch, or fold as desired to maintain a proper anatomic implant fit without unduly stretching the ocular anatomy.

In some examples, a hydrogel or other fluid-swellable material may be disposed (e.g., coated) on an exterior surface portion of the implant 302 in order to further secure the implant 300 within the lacrimal punctum 214 and lacrimal canaliculus 210, or to make the size of the implant 302 adjustable. The fluid-swellable material is effective to partially swell an outer surface diameter of the implant 302 when implanted. In some examples, the outer surface of the implant 302 can include longitudinal channels or grooves or a coating of a wicking material to allow fluid flow around the implant 302. Using one or a combination of these techniques, the lacrimal implant 300 can be configured to completely occlude or partially occlude them when implanted in the lacrimal canaliculus 208, 210. For example, the use of longitudinal channels or grooves in one or both of the first portion 304 or the second portion 306 of the implant 302 can allow for reduced volume or tear drainage to occur, potentially facilitating release of the drug or other therapeutic agent from the drug insert.

Forceps or another insertion tool may be used to implant the lacrimal implant 300 through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210. In some instances, the insertion tool discussed in U.S. patent application No.12/231,984, which is commonly owned by De Juan et al, attorney docket No.2755.018US1, entitled "insertion and extraction tool for lacrimal implant," filed 9/5 of 2008, which is incorporated herein by reference in its entirety, may be used to implant lacrimal implant 300. In various instances, the second portion 306 of the implant 302 can be advanced to the depth of the lacrimal canaliculus 208, 210 by manipulation of an insertion tool until a graspable or other projection 332 (if present) can be seated against the lacrimal opening 212, 214.

In various examples, after the lacrimal punctum size has been measured and an appropriately sized implant 300 (e.g., small, medium, or large) is selected, the lacrimal punctums 212, 214 can be selectively expanded (e.g., via an integral dilator of the implant) prior to or during insertion. Implant 300 can be grasped at second portion 306 with forceps or another insertion tool and introduced vertically into lacrimal punctum 212, 214. The implant 300 can then be rotated so that it advances into the horizontal portion of the canaliculus 208, 210 until the heel-like retention element 356. Forceps or another insertion tool may also be used to grasp the portion of the retaining element 356 of the implant 300 to rotate it into the lachrymal cavity 212, 214 so that the graspable or other cap-like projection 332 may sit on the lachrymal cavity.

When it is desired to remove the lacrimal implant 300, the protrusion 332 may be grasped with, for example, forceps, and withdrawn from the lacrimal opening 212, 214 by a gentle pulling motion. Optionally, one or two drops of anesthetic may be administered prior to removal of the implant 300. Care may be taken not to grasp the outermost edge of the protrusion 332, as this may tear or separate the protrusion 332.

In some examples, the implant 302 can include one or both of a first cavity 318 or a second cavity 320, the first cavity 318 disposed near the proximal end 308, the second cavity 320 disposed near the distal end 310. In this example, a first cavity 318 extends inwardly from the proximal end 308 of the first portion 304 and a second cavity 320 extends inwardly from the distal end 310 of the second portion 306. A first drug-releasing or other agent-releasing insert 322 may be disposed in first cavity 318 to provide sustained drug or other therapeutic agent release to the eye (e.g., to treat infection, inflammation, glaucoma, or other ocular disease or disorder); while a second drug-releasing or other agent-releasing insert 324 may alternatively or collectively be disposed in the second cavity 320 to provide sustained drug or other therapeutic agent release, for example, to the nasal cavity (e.g., to treat sinus disorders or allergies) or to the inner ear system (e.g., to treat dizziness or migraine).

Fig. 6A-6B illustrate an example of another lacrimal implant 600, the lacrimal implant 600 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 600 can include implant 602-implant 602 includes first portion 604 and second portion 606, and can extend from a proximal end 608 of first portion 604 to a distal end 610 of second portion 606. The proximal end 608 may define a longitudinal proximal axis 612 and the distal end 610 may define a longitudinal distal axis 614. The implant 600 can be configured such that, when implanted, there is an approximately 90 degree angular intersection between the proximal axis 612 and the distal axis 614 to bias at least a portion of the implant relative to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2) that is located at or more distal of the canalicular curvature 250 (fig. 2).

In this example, the proximal end 628 of the second implant portion 606 can include a retaining element 656, the retaining element 656 configured to be biased against at least a portion of the canalicular ampulla 252 (fig. 2) when implanted. In this example, the implant 602 includes a first cavity 618, the first cavity 618 being configured to receive a first drug-releasing or other agent-releasing drug insert, disposed near the proximal end 608 of the first implant portion 604. Also in this example, the implant 602 can include a graspable or other protrusion 632, such as a set of tabs having a combined length of, for example, about 1 millimeter, extending laterally from the proximal end 308.

Fig. 6B shows an illustrative cross-sectional view of lacrimal implant 600 taken along a line parallel to a longitudinal axis of the implant, such as along line 6B-6B of fig. 6A. As shown in fig. 6B, the distal end 626 of the first portion 604 can be integral with the second portion 606 at or near the proximal end 628 of the second portion 606. In various examples, the second portion 606 can include a longitudinal length, as measured from the proximal axis 612 to the proximal end 610, having a value that is less than four times the longitudinal length of the first portion 604, as measured from the proximal end 608 to the distal axis 614. In some examples, the first portion may include a longitudinal length of about 1.54 millimeters and the second portion may include a longitudinal length of between about 4.5 millimeters and about 5.42 millimeters.

In various examples, the second portion 606 can include an integral dilator 650 to dilate anatomical tissue, such as one or both of the lacrimal canaliculus 212, 214 (fig. 2) or associated canaliculus 208, 210, to a sufficient diameter when the lacrimal implant 600 is being implanted. In some examples, the second portion 606 tapers from a diameter of the proximal end of between about 0.50 millimeters to about 0.75 millimeters to a diameter of the dilator tip 654 of about 0.36 millimeters.

Fig. 7A-7B illustrate an example of another lacrimal implant 700 that the lacrimal implant 700 can be inserted through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 700 can include implant 702-implant 702 includes first portion 704 and second portion 706, and can extend from a proximal end 708 of first portion 704 to a distal end 710 of second portion 706. The proximal end 708 may define a longitudinal proximal axis 712, and the distal end 710 may define a longitudinal distal axis 714. The implant 700 can be configured such that, when implanted, there is an approximately 90 degree angular intersection between the proximal axis 712 and the distal axis 714 to bias at least a portion of the implant with respect to at least a portion of the canaliculus 208, 210 (fig. 2), the at least a portion of the canaliculus 208, 210 being located at or more distally of the canaliculus bend 250 (fig. 2). As shown in the example of fig. 7A, there may be a smooth transition between the first portion 704 and the second portion 706.

In this example, the implant 702 includes a first cavity 718, the first cavity 718 configured to receive a first drug-releasing or other agent-releasing drug insert, disposed near the proximal end 708 of the first implant portion 704. Also in this example, the implant 702 can include a graspable or other protrusion 732, such as an annular protrusion extending laterally from the proximal end 708 and completely around it. In some examples, the graspable or other protrusion 732 comprises a partial trim protrusion having a trim width of about 0.75 millimeters and extending around the proximal end 708 by different amounts.

Fig. 7B shows an illustrative cross-sectional view of lacrimal implant 700 taken along a line parallel to a longitudinal axis of the implant, such as along line 7B-7B of fig. 7A. As shown in fig. 7B, the distal end 726 of the first portion 704 may be integral with the second portion 706 at or near the proximal end 728 of the second portion 706. In various examples, the second portion 706 can include a longitudinal length, as measured from the proximal axis 712 to the proximal end 710, having a value that is less than four times the longitudinal length of the first portion 704, as measured from the proximal end 708 to the distal axis 714. In some examples, the first portion may include a longitudinal length of about 1.5 millimeters and the second portion may include a longitudinal length of about 5 millimeters.

In various examples, the second portion 706 can include an integral dilator 750 to dilate anatomical tissue, such as one or both of the lacrimal canaliculus 212, 214 (fig. 2) or the associated canaliculus 208, 210, to a sufficient diameter when the lacrimal implant 700 is being implanted. In some examples, the second portion 706 tapers from a diameter of the proximal end of about 0.46 millimeters to a diameter of the dilator tip 754 of about 0.36 millimeters.

Fig. 8A-8B illustrate an example of another lacrimal implant 800, the lacrimal implant 800 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 800 can include an implant 802-implant 802 includes a first portion 804 and a second portion 806, and can extend from a proximal end 808 of first portion 804 to a distal end 810 of second portion 806. The proximal end 808 may define a longitudinal proximal axis 812, and the distal end 810 may define a longitudinal distal axis 814. The implant 800 can be configured such that, when implanted, there is an approximately 90 degree angular intersection between the proximal axis 812 and the distal axis 814 so as to bias at least a portion of the implant with respect to at least a portion of the canaliculus 208, 210 (fig. 2) that is located at or more distal of the canalicular bend 250 (fig. 2).

In this example, the proximal end 828 of the second implant portion 806 may include a retaining element 856 configured to be biased against at least a portion of the canalicular ampulla 252 (fig. 2) when implanted. Retaining element 856 can include a depression 875 to facilitate insertion or other grasping means to aid in one or both of implant insertion or removal. In this example, the implant 802 includes a first cavity 818 configured to receive a first drug-releasing or other agent-releasing drug insert, disposed near the proximal end 808 of the first implant portion 804. Also in this example, the implant 802 may include a graspable or other protrusion 832, such as an annular protrusion extending laterally from and completely around the proximal end 808. In some examples, the graspable or other protrusion 832 includes a partial trim protrusion that extends a different amount around the proximal end 808.

Fig. 8B shows an illustrative cross-sectional view of the lacrimal implant 800 taken along a line parallel to a longitudinal axis of the implant, such as along line 8B-8B of fig. 8A. As shown in fig. 8B, the distal end 826 of the first portion 804 may be integral with the second portion 806 at or near the proximal end 828 of the second portion 806. In various examples, the second portion 806 may include a longitudinal length, as measured from the proximal axis 812 to the proximal end 810, having a value of less than four times the longitudinal length of the first portion 804, as measured from the proximal end 808 to the distal axis 814. In some examples, the first portion may include a longitudinal length of between about 1.725 millimeters and about 1.77 millimeters, and the second portion may include a longitudinal length of between about 4.77 millimeters and about 5 millimeters.

In various examples, the second portion 806 can include an integral dilator 850 to dilate anatomical tissue, such as one or both of the lacrimal canaliculus 212, 214 (fig. 2) or associated canaliculus 208, 210, to a sufficient diameter when the lacrimal implant 800 is being implanted. In some examples, the second portion 806 tapers from a diameter of the proximal end 828 of about 0.46 millimeters to a diameter of the dilator tip 854 of about 0.36 millimeters.

Fig. 9 shows an example of another lacrimal implant 900, the lacrimal implant 900 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, the lacrimal implant 900 can include an implant 902-the implant 902 includes a first portion 904 and a second portion 906, and can extend from a proximal end 908 of the first portion 904 to a distal end 910 of the second portion 906. The proximal end 908 may define a longitudinal proximal axis 912, and the distal end 910 may define a longitudinal distal axis 914. The implant 900 can be configured such that, when implanted, there is an approximately 90 degree angular intersection between the proximal axis 912 and the distal axis 914 to bias at least a portion of the implant with respect to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2), the at least a portion of the lacrimal canaliculus 208, 210 being located at or more distal of the canalicular curvature 250 (fig. 2).

As shown, there may be a smooth transition between the first portion 904 and the second portion 906. In this example, the smooth transition may include a depression 975 or other grasping device to facilitate insertion to aid in one or both of implant insertion or removal. Also in this example, the implant 902 may include a graspable or other protrusion 932, such as an annular protrusion extending laterally from the proximal end 908 and completely around it. In some examples, the graspable or other protrusion 932 includes a partial finishing protrusion that extends around the proximal end 908 by different amounts.

Fig. 10A-10B illustrate an example of another lacrimal implant 1000, the lacrimal implant 1000 being insertable through a lacrimal punctum 212, 214 and into an associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 1000 can include an implant 1002-implant 1002 includes a first portion 1004 and a second portion 1006, and can extend from a proximal end 1008 of first portion 1004 to a distal end 1010 of second portion 1006. The proximal end 1008 may define a longitudinal proximal axis 1012, and the distal end 1010 may define a longitudinal distal axis 1014. The implant 1000 can be configured such that, when implanted, there is an approximately 90 degree angular intersection between the proximal axis 1012 and the distal axis 1014 to bias at least a portion of the implant with respect to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2), the at least a portion of the lacrimal canaliculus 208, 210 being located at or more distal of the canalicular curvature 250 (fig. 2).

In this example, the proximal end 1028 of the second implant portion 1006 may include a retention element 1056, the retention element 1056 configured to be biased against at least a portion of the lacrimal canaliculus ampulla 252 (fig. 2) when implanted. The retaining element 1056 may include a recess 1075 or other grasping means to facilitate insertion to aid in one or both of implant insertion or removal. In this example, the implant 1002 includes a first cavity 1018, the first cavity 1018 configured to receive a first drug-releasing or other agent-releasing drug insert, disposed proximate the proximal end 1008 of the first implant body portion 1004. Also in this example, the implant 1002 may include a graspable or other protrusion 1032, such as an annular protrusion having a diameter of about 1.3 millimeters, extending laterally from and completely around the proximal end 1008. In some examples, the graspable or other projections 1032 include partial trim projections that extend different amounts around the proximal end 1008.

Fig. 10B shows an illustrative cross-sectional view of lacrimal implant 1000 taken along a line parallel to a longitudinal axis of the implant, such as along line 10B-10B of fig. 10A. As shown in fig. 10B, the distal end 1026 of the first portion 1004 can be integral with the second portion 1006 at or near the proximal end 1028 of the second portion 1006. In various examples, the second portion 1006 can include a longitudinal length, as measured from the proximal axis 1012 to the proximal end 1010, having a value that is less than four times the longitudinal length of the first portion 1004, as measured from the proximal end 1008 to the distal axis 1014. In some examples, the first portion may include a longitudinal length of about 1.5 millimeters and the second portion may include a longitudinal length of about 5 millimeters.

In various examples, the second portion 1006 can include an integral dilator 1050 to dilate anatomical tissue, such as one or both of the lacrimal canaliculus 212, 214 (fig. 2) or associated canaliculus 208, 210, to a sufficient diameter when the lacrimal implant 1000 is being implanted. In some examples, the second portion 1006 tapers from a diameter of the proximal end 1028 of about 0.46 millimeters to a diameter of the dilator tip 1054 of about 0.36 millimeters.

Fig. 11-17 show examples of other lacrimal implants 1100, 1200, 1300, 1400, 1500, 1600, 1700, these lacrimal implants 1100, 1200, 1300, 1400, 1500, 1600, 1700 being insertable through the lacrimal punctum 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, each lacrimal implant 1100, 1200, 1300, 1400, 1500, 1600, 1700 can include an implant 1102, 1202, 1302, 1402, 1502, 1602, 1702-the implant 1102, 1202, 1302, 1402, 1502, 1602, 1702 including a first portion 1104, 1204, 1304, 1404, 1504, 1604, 1704, and a second portion 1106, 1206, 1306, 1406, 1506, 1606, 1706, and can extend from a proximal end 1108, 1208, 1308, 1408, 1508, 1608, 1708 of the first portion 1104, 1204, 1304, 1404, 1504, 1604, 1704 to a distal end 1110, 1210, 1310, 1410, 1510, 1610, 1710 of the second portion 1106, 1206, 1306, 1406, 1506, 1606, 1706. Each implant 1102, 1202, 1302, 1402, 1502, 1602, 1702 can include at least one intermediately disposed retention protrusion 1192, 1292, 1392, 1492, 1592, 1692, 1792 to potentially further fix the implantation location of the lacrimal implant. The intermediately arranged retention protrusions 1192, 1292, 1392, 1492, 1592, 1692, 1792 can be positioned on one or both of the first implant body portion 1104, 1204, 1304, 1404, 1504, 1604, 1704 or the second implant body portion 1106, 1206, 1306, 1406, 1506, 1606, 1706 and can take the form of annular, semi-annular, cylindrical or cylindrical protrusions. The intermediately disposed retention protrusions 1192, 1292, 1392, 1492, 1592, 1692, 1792 can include a larger cross-sectional dimension than the adjacent implant body portion and can deform a portion of the small tube wall slightly to provide additional fixation to hold the implant in place during use (see, e.g., fig. 5).

It is believed that occlusion of the lower lacrimal canaliculus 210, for example by a lacrimal implant, can cause a back pressure to build within the canaliculus 210, thereby pushing the implant from the implantation site. It is believed that such backpressure may occur, for example, during blinking (where tears are being drawn from the front surface of the eye along the drainage system) or sneezing (where pressure is being emitted from the pulmonary system). Accordingly, one or more of the additional retention features, now represented in the form of at least one intermediately disposed retention projection 1192, 1292, 1392, 1492, 1592, 1692, 1792, may serve to prevent implant migration and further fix the location of the implanted lacrimal implant. These additional retention features may be designed to prevent migration in the proximal direction while not increasing the difficulty of implanting the implant to a considerable extent.

Current clinical trials were conducted to evaluate the safety, tolerability, comfort, ease of handling and insertion/removal, retention, efficacy, and dosage of the various lacrimal implants disclosed in this patent document. Preliminary reports indicate that lacrimal implants, such as those shown in fig. 12, 13, and 43A-43C, are effective and well tolerated by patients participating in the trial. For example, based on preliminary data measured after 4 weeks of post-placement tracking for a lacrimal implant of the type shown in fig. 13, when adverse events were noted, the overall adverse event ranged from only 1.7% to 11.7%. The most common adverse events were ocular itching (common to initial implant wear, and also typically part of the adaptation process), lacrimation, and eye irritation (11.7%, 6.7%, and 5.0%, respectively). Other adverse events reported less frequently than the above include fever, ocular discomfort, superficial punctate keratitis. No conjunctival or ocular hyperemia was observed after 4 weeks of follow-up. Comfort and tear records were reported for 4 weeks of implants that included 44 microgram latenoprost drug inserts as follows: comfort was rated as 'no feel' or 'mild feel' in 88% of patients, and tear was rated as 'no' in 76% of patients. Physician operative assessment of lacrimal implants of the type shown in fig. 12, 13, and 43A-43C indicates that the implant is easy to insert and remove. Physicians rated lacrimal implants of the type shown in fig. 12 and 43A-43C as easy to insert (80%) and easy to remove (100%).

In one example, as generally shown in fig. 12, the proximal end 1208 may provide a protrusion such as a cap having an outer diameter of about 1.2 millimeters and a cap thickness in a longitudinal direction of the first portion 1204 of between about 0.13 millimeters and about 0.19 millimeters. In this example, the cap portion of the proximal end 1208 can be spaced apart from the retention protrusion 1292 of the first portion 1204, such as by a shaft portion that can have an outer diameter of about 0.56 millimeters, and a longitudinal shaft length of about 0.6 millimeters. In this example, the retention protrusion 1292 of the first portion 1204 can have a proximal outer diameter of about 0.9 millimeters, which can taper to a distal outer diameter (e.g., where the first and second portions 1204, 1206 meet) that is less than or equal to the outer diameter of the shaft portion. Better retention may be achieved with a more sharply tapered retention protrusion 1292 of the first portion 1204, which retention protrusion 1292 may instead have a proximal outer diameter of about 1.1 millimeters in another example. In yet another example, the proximal end 1208 can instead provide a cap having an outer diameter of about 1.4 millimeters, and the proximal outer diameter of the retention protrusion 1292 of the first portion 1204 can instead be about 1.4 millimeters.

Similar dimensions and dimensional changes may be applied to other examples described herein, including the examples generally shown in fig. 11-17. For example, as generally shown in fig. 13, the retention protrusion 1392 of the first portion 1304 may protrude outward from a starting diameter of about 0.56 millimeters to about 0.70 millimeters. The first cavity in the first portion 1304 may have a diameter of about 0.42 millimeters (approximately 0.0165 inches), and a depth of about 1.22 millimeters (approximately 0.048 inches). Such a first cavity dimension may result in a first portion wall thickness surrounding the cavity of at least about 0.07 millimeters. In some examples, a drug insert having approximately 44 micrograms (μ g) of latanoprost (assuming approximately 33% drug loading) is inserted and secured within the first cavity. Optionally, more or less drug or other agent may be inserted within the first cavity by respectively increasing or decreasing the size (e.g., diameter or depth) of the cavity, and the drug insert that may be placed therein. By way of example, as shown and described in connection with fig. 43A-43C, the first cavity may have a diameter of about 0.56 millimeters (approximately 0.022 inches) and a depth of 1.22 millimeters (approximately 0.048 inches). Such a first cavity size may receive a drug insert having a latenoporst of about 81 μ g (assuming approximately 33% drug loading).

Fig. 18-19 show examples of other lacrimal implants 1800, 1900 that can be inserted through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In these examples, each lacrimal implant 1800, 1900 may include an implant 1802, 1902-these implants 1802, 1902 include a first portion 1804, 1904 and a second portion 1806, 1906, and may extend from a proximal end 1808, 1908 of the first portion 1804, 1904 to a distal end 1810, 1910 of the second portion 1806, 1906. As shown, intermediate portion 1896, 1996 of each implant 1802, 1902 can be angled relative to first implant portion 1804, 1904 or second implant portion 1806, 1906 to potentially further fix the implantation position of the lacrimal implant.

It is believed that the inclination of the intermediate portions 1896, 1996 can help capture the anatomy of the lacrimal canaliculus 212, 214 and canaliculus 208, 210 to hold the lacrimal implants 1800, 1900 in the implanted position, such as via directional forces applied via inclination relative to the lacrimal canaliculus. Such directional force may be designed to continuously apply feedback, or to force other protrusions 1832, 1932 flush with the lacrimal canaliculus 212, 214.

Fig. 20 shows an example of another lacrimal implant 2000, the lacrimal implant 2000 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 2000 can include implant 2002-the implant 2002 includes a first portion 2004 and a second portion 2006, and can extend from a proximal end 2008 of first portion 2004 to a distal end 2010 of second portion 2006. The proximal end 2008 can define a longitudinal proximal axis 2012, and the distal end 2010 can define a longitudinal distal axis 2014. The implant 2000 can be configured such that, when implanted, there is an approximately 90 degree angular intersection between the proximal axis 2012 and the distal axis 2014 to bias at least a portion of the implant relative to at least a portion of the canaliculus 208, 210 (fig. 2) that is at or more distal to the canalicular bend 250 (fig. 2). In various examples, the distal end 2026 of the first portion 2004 can be integral with the second portion 2006 at or near the proximal end 2028 of the second portion 2006.

In this example, one or more material cuts 2080 are made in the outer surface of the implant 2002. As a result, the angled intersection between the proximal axis 2012 and the distal axis 2014 can be more linearly aligned during implantation, as shown in phantom, to facilitate insertion through the lacrimal punctums 212, 214 and into the associated canaliculus 208, 210.

Fig. 21A-21B and 22A-22B illustrate examples of side views of other lacrimal implants 2100, 2200 that can be inserted through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In these examples, each lacrimal implant 2100, 2200 may include an implant body 2102, 2202-these implant bodies 2102, 2202 include a first portion 2104, 2204 and a second portion 2106, 2206, and may extend from a proximal end 2108, 2208 of the first portion 2104, 2204 to a distal end 2110, 2210 of the second portion 2106, 2206. Each second portion 2106, 2206 may include one or more arm members 2170, 2270 that are movable between a first configuration in which the one or more arm members 2170, 2270 are adjacent to the implant and a second configuration in which the one or more arm members 2170, 2270 extend laterally from the sides of the implant. In the first configuration, the one or more arm members 2170, 2270 facilitate insertion of the lacrimal implant through the lacrimal punctum 212, 214 and into the associated canaliculus 208, 210 by providing a narrow profile. In the second configuration, the one or more arm members 2170, 2270 extend laterally to fill at least one of the lacrimal canaliculus ampulla 252 (fig. 2) or the canaliculus 208, 210 when implanted. Optionally, the one or more arm members 2170, 2270 can include a fluid swellable material, such as a hydrogel, to further secure the implanted lacrimal implant within the lacrimal ampulla 252 or canaliculus 208, 210 when hydrated.

In some examples, one or more arm members 2170, 2270 can be incorporated into a mold that is also used to form the implant body 2102, 2202. The one or more arm members 2170, 2270 can be attached to the existing implant body 2102, 2202 by molding or gluing. Different thicknesses and shapes for one or more of the arm members 2170, 2270 may be employed for different stiffness and securing/removal characteristics. In addition to hydrogels, the one or more arm members 2170, 2270 may be made of other materials, such as those used in the field of haptics on intraocular lenses and the like.

Fig. 23A-23B show illustrative side views of another lacrimal implant 2300, the lacrimal implant 2300 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 2300 may include an implant body 2302-the implant body 2302 comprising a first portion 2304 and a second portion 2306, and may extend from a proximal end 2308 of the first portion 2304 to a distal end 2310 of the second portion 2306. Second portion 2306 can be at least partially surrounded by an expandable retention element (e.g., an inflatable balloon) 2372, which expandable retention element 2372 is configured to bias second portion 2306 away from the lacrimal canaliculus wall when expanded.

In some examples, the expandable retention element 2372 contains or can be inflated by an agent that is delivered to the eye or tissue of the nasolacrimal system. In some examples, 2372 of the expandable retention element may employ one or more balloons that are separate from any drug inserts or other agent retention structures. One or more balloons may optionally be similar to those used on balloon catheters, with inflation lumens or the like optionally included in the implant insertion tool to allow controlled inflation of the balloon. In such an example, lacrimal implant 2300 may be inserted with the balloon deflated, as shown in fig. 23A. Once the lacrimal implant 2300 is in place, the balloon can be inflated to secure the implant position of the implant, as shown in fig. 23B.

The balloon may also be deflatable to facilitate removal of lacrimal implant 2300. The balloon may optionally conform partially or substantially to variations in the size and shape of the tubules 208, 210. Alternative examples of balloons may be inflated by the expansion of a material disposed within the balloon, such as a hydrogel that expands by absorbing moisture through perforations or openings in the balloon. The one or more balloons may be annular structures disposed about the supporting implant, or may be disposed eccentrically about the axis of the implant. As shown in fig. 23B, the balloon may be disposed distally enough to reside within or adjacent to the horizontal portion of the tear drainage tube, within or adjacent to the lacrimal sac of the tear drainage system, or the like. Alternative examples may include one or more balloons closer to the proximal side.

Fig. 24 shows an illustrative schematic view of another lacrimal implant 2400, which lacrimal implant 2400 is implanted through the lower lacrimal punctum 212 and into the associated canaliculus 210. Lacrimal implant 2400 may include an implant 2402, where implant 2402 includes a first portion 2404 and a second portion 2406. In various examples, the implant 2402 can be configured such that, when implanted, at least a portion of the implant 2402 is offset relative to at least a portion of the lacrimal canaliculus 210 located at or more distal to the canalicular bend 250 to reliably maintain the implant position of the implant 2400. In this example, second portion 2406 includes a longitudinal length that is less than about 2 millimeters, such as a dimension that is greater than a diameter of first portion 2404, but less than 2 millimeters. Also in this example, the implant body 2402 can include graspable or other protrusions 2432, such as extending laterally at least partially around the proximal end of the first implant body portion 2404.

Fig. 25A-25B illustrate an example of another lacrimal implant 2500 that can be inserted through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In these examples, the lacrimal implant 2500 can include an implant 2502-the implant 2502 includes a first portion 2504 and a second portion 2506, and can extend from a proximal end 2508 of the first portion 2504 to a distal end 2510 of the second portion 2506. The implant may comprise an overall shape that may generally match the anatomical features of the tubules 208, 210 to provide, for example, patient comfort and secure retention. Proximal end 2508 may define a longitudinal proximal axis 2512, and distal end 2510 may define a longitudinal distal axis 2514. The implant 2502 can be configured such that, when implanted, there is a 45-90 degree angular intersection between the proximal axis 2512 and the distal axis 2514, e.g., to bias at least a portion of the implant 2502 relative to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2) located at or more distal of the canalicular bend 250 (fig. 2).

In the example of fig. 25A-25B, the implant 2502 includes both a first cavity 2518, with the first cavity 2518 disposed near the proximal end 2508, and a second cavity 2520 disposed near the distal end 2510. A first cavity 2518 extends inwardly from a proximal end 2508 of the first portion 2504 and a second cavity 2520 extends inwardly from a distal end 2510 of the second portion 2506. A first drug-releasing or other agent-releasing drug insert may be disposed in first cavity 2518 to provide sustained drug or other therapeutic agent release to the eye; while a second drug-releasing or other agent-releasing drug insert may be disposed in second cavity 2520 to provide for sustained release of the drug or other therapeutic agent, for example, to the nasal cavity or inner ear system. In some examples, first cavity 2518 can extend inwardly from proximal end 2508 of first portion 2504 to a location near distal end 2510 of second portion 2506, as shown in fig. 26, and be filled with a first drug-releasing or other agent-releasing drug insert. In some examples, second cavity 2520 extends inwardly from distal end 2510 of second portion 2506 to a location near proximal end 2508 of first portion 2504 and is filled with a second drug-releasing or other agent-releasing drug insert.

In some examples, second portion 2506 includes a one-piece dilator 2550 to dilate anatomical tissue, such as one or both of lacrimal canaliculus 212, 214 or canaliculus 208, 210, to a sufficient diameter while lacrimal implant 2500 is being implanted. In this manner, lacrimal implant 2500 can be implanted in various sizes of ocular anatomy without the need for pre-dilation by means of a separate dilation tool. In these examples, unitary dilator 2550 includes a generally concave shape relative to first portion 2504. In some examples, the concave shape includes a radius that is less than the radius of the tubule bend 250. In some examples, the concave shape includes a radius that is substantially the same as the radius of the tubule bend 250. As shown in the example of fig. 25B, there may be a smooth transition between the first portion 2504 and the second portion 2506.

In some examples, the proximal end 2528 of the second implant portion 2506 can include a retaining element 2556, the retaining element 2556 configured to be biased against at least a portion of the canalicular ampulla 252 (fig. 2) when implanted. In the example of fig. 25A, a retaining element 2556 projects proximally from the intersection between the first and second implant body portions 2504, 2506.

Fig. 26 illustrates an example of another lacrimal implant 2600, the lacrimal implant 2600 being insertable through a lacrimal punctum 212, 214 and into an associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 2600 includes an implant 2602-the implant 2602 includes a first portion 2604 and a second portion 2606, and extends from a proximal end 2608 of the first portion 2604 to a distal end 2610 of the second portion 2606. The proximal end 2608 can define a longitudinal proximal axis 2612, and the distal end 2610 can define a longitudinal distal axis 2614. The implant 2600 can be configured such that, when implanted, there is a 90-135 degree angular intersection between the proximal axis 2612 and the distal axis 2614 so as to bias at least a portion of the implant 2602 relative to at least a portion of the lacrimal canaliculus 208, 210, the at least a portion of the lacrimal canaliculus 208, 210 being located at or more distal of the canaliculus bend 250 (fig. 2).

In some examples, the implant 2602 can include a first cavity 2618, the first cavity 2618 being disposed near the proximal end 2608. In this example, the first cavity 2618 extends inwardly from the proximal end 2608 of the first portion 2604 to a position near the distal end 2610 of the second portion 2606. A first drug-releasing or other agent-releasing drug insert having a volume, for example, between about 0.2 cubic centimeters and about 0.25 cubic centimeters may be disposed in the first cavity 2618 to provide sustained drug or other therapeutic agent release to the eye.

In some examples, the second portion 2606 includes an integral dilator 2650 to dilate anatomical tissue, such as one or both of the lacrimal canaliculus 212, 214 or the canaliculus 208, 210, to a sufficient diameter while the lacrimal implant 2600 is being implanted. In this manner, lacrimal implant 2600 can be implanted into various sizes of ocular anatomy without the need for pre-dilation by means of a separate dilation tool. In this example, the unitary dilator 2650 includes a generally convex shape relative to the first portion 2604. In some examples, the convex shape includes a radius that is less than the radius of the tubule bend 250. In some examples, the convex shape includes a radius that is substantially the same as the radius of the tubule bend 250.

In some examples, the proximal end 2628 of the second implant portion 2606 can include a retention element 2656, the retention element 2656 configured to be biased against at least a portion of the canalicular ampulla 252 (fig. 2) when implanted. In this example, the retention element 2656 projects proximally from the intersection between the first and second implant body portions 2604, 2606. In some examples, as shown for example in fig. 29-30, the proximal end 2628 of the second implant portion 2606 can include a retaining element 2656, the retaining element 2656 including a hydrogel retaining element configured to expand into the ampulla 252 when the implant 2602 is implanted.

Fig. 27 shows an example of another lacrimal implant 2700, the lacrimal implant 2700 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 2700 includes implant 2702, where implant 2702 includes first and second portions that are linear relative to each other prior to implantation. The implant 2702 extends from the proximal end 2708 of the first portion to the distal end 2710 of the second portion. The proximal end 2708 can define a longitudinal proximal axis 2712 and the distal end 2710 can define a longitudinal distal axis 2714. The implant 2702 can be configured such that, when implanted, there is a 45-135 degree angular intersection between the proximal axis 2712 and the distal axis 2714, e.g., to offset at least a portion of the implant 2702 relative to at least a portion of the canaliculus 208, 210 (fig. 2) that is located at or more distal of the canaliculus bend 250 (fig. 2). In this example, the second portion of the implant 2702 includes at least one undulation 2790 to facilitate biasing of the implant 2702 relative to portions of the lacrimal canaliculus 208, 210.

Fig. 28 shows an illustrative side view of another lacrimal implant 2800, the lacrimal implant 2800 being insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 2800 includes an implant body 2802, where implant body 2802 includes first and second portions that are linear relative to each other prior to implantation. The implant 2802 extends from a proximal end 2808 of the first portion to a distal end 2810 of the second portion. The proximal end 2808 can define a longitudinal proximal axis 2812, and the distal end 2810 can define a longitudinal distal axis 2814. The implant 2802 can be configured such that, when implanted, there is an angular intersection of 45-135 degrees between the proximal axis 2812 and the distal axis 2814 to bias at least a portion of the implant 2802 relative to at least a portion of the lacrimal canaliculus 208, 210 (fig. 2) that is located at or more distal of the canalicular bend 250 (fig. 2). In this example, the second portion of the implant 2802 includes at least one intermediately disposed retention projection 2892, such as an annular rib projection. The retention protrusions 2892 comprise a larger cross-sectional dimension than the adjacent implant body portions and can facilitate fixation of the implant position of the implant 2802, while the adjacent thinner implant body portions can facilitate biasing of the implant 2802 relative to portions of the lacrimal canaliculus 208, 210.

Fig. 29-32 show examples of side views of other lacrimal implants 2900, 3000, 3100, 3200, which lacrimal implants 2900, 3000, 3100, 3200 can be inserted through the lacrimal punctum 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In these examples, each lacrimal implant 2900, 3000, 3100, 3200 may include an implant 2902, 3002, 3102, 3202 — these implants 2902, 3002, 3102, 3202 include a first portion 2904, 3004, 3104, 3204 and a second portion 2906, 3006, 3106, 3206, and may extend from a proximal end 2908, 3008, 3108, 3208 of the first portion 2904, 3004, 3104, 3204 to a distal end 2910, 3010, 3110, 3210 of the second portion 2906, 3006, 3106, 3206. The proximal ends 2908, 3008, 3108, 3208 may define longitudinal proximal axes 2912, 3012, 3112, 3212.

The second portions 2906, 3006, 3106, 3206 may include fluid-expandable retention elements 2994, 3094, 3194, 3294, which fluid-expandable retention elements 2994, 3094, 3194, 3294 are configured to expand laterally relative to the proximal axis 2912, 3012, 3112, 3212 when the implant 2902, 3002, 3102, 3202 is implanted. In various examples, the fluid-inflatable retention elements 2994, 3094, 3194, 3294 may be formed such that one or both of the direction or amount of inflation is controllable. For example, the fluid-expandable retention elements 2994, 3094, 3194, 3294 may expand more in one plane than in another to securely anchor the lacrimal implant. In some examples, the fluid-expandable retention element 2994, 3094, 3194, 3294 includes a portion configured to expand laterally relative to the proximal axis 2912, 3012, 3112, 3212 in a direction away from the lacrimal canaliculus ampulla 252 (fig. 2) when the implant is implanted. In some examples, as shown in fig. 29-30, the fluid-expandable retention element 2994, 3094, 3194, 3294 includes a portion configured to expand laterally relative to the proximal axis 2912, 3012, 3112, 3212 in a direction toward the lacrimal canaliculus ampulla 252 (fig. 2) when the implant is implanted.

In some examples, the fluid-expandable retention elements 2994, 3094, 3194, 3294 may comprise a hydrogel that can be inserted through the lacrimal punctum 212, 214 and into the associated canaliculus 208, 210 in a fine profile. After insertion, the hydrogel or other fluid-expandable retention element may be hydrated and expanded to a rough configuration. While the hydrogel or other expandable retention element is expanded, a projection such as at least one intermediately disposed retention projection 2992, 3092, 3192, 3292 may be used to maintain the implantation position to the lacrimal implant.

Fig. 33 shows a schematic side view of another lacrimal implant 3300, which lacrimal implant 3300 is insertable through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 3300 includes implant body 3302-the implant body 3302 includes a first section 3304 and a second section 3306, and may extend from a proximal end 3308 of first section 3304 to a distal end 3310 of second section 3306. As shown, the second section 3306 can include an expandable retention element 3393, the expandable retention element 3393 including at least one of a coil, a braid, a stent, a mesh tube, a suture, a thermoset polymer, a thermoplastic, a heat activated material, or a shape memory material. Expandable retaining element 3393 may be configured to expand laterally relative to a proximal axis 3312 defined by first portion 3304 when the implant is implanted. A projection, such as at least one intermediately disposed retention projection 3392, can be used to potentially further secure the implantation location of the lacrimal implant.

Figures 34A-34B illustrate an example of a schematic view of another lacrimal implant 3400 and an implantation environment. In various examples, the implant 3402 can include graspable or other protrusions 3432, such as one or more protrusions extending at least partially laterally from or around the proximal end 3408 of the first implant portion. In some examples, as shown in fig. 34B, protrusion 3432 can include a set of tabs for inserting lacrimal implant 3400 into an implant site, or for removing an implant from the site. The set of fins can be configured without concern for migration, and the non-linear configuration of the implant 3402 when implanted can prevent migration by exhibiting the size or shape of the canalicular curvature 250 and optionally the canalicular ampulla 252.

In the example of fig. 34A-34B, one or more protrusions 3432, when implanted, extend laterally in a direction parallel to or away from their eye 100. In this manner, protrusions 3432 can still function as a graspable or feedback feature, but can limit patient discomfort when lacrimal implant 3400 is implanted. In addition, the protrusions 3432, by extending away from the eye 100, are not buried in tissue and can be easily identified by the patient or the physician. This can allow a quick determination of whether lacrimal implant 3400 is remaining in its place without having to dig and search through the soft tissue surrounding eye 100. In some cases, for a simple pull of the lower eyelid, the protrusion 3432 pointing in a direction away from the eye 100 may be exposed. In the example of fig. 34B, the at least one protrusion 3432 extends laterally from the proximal end 3408 in substantially the same direction as the lateral extension of the second implant body portion relative to the distal end of the first implant body portion.

Fig. 35-38 show examples of isometric views of various graspable tabs or other grasping devices 3532, 3632, 3732, 3832 extending from the proximal end of lacrimal implants 3500, 3600, 3700, 3800. The graspable or other protrusions 3532, 3632, 3732, 3832 can be used for a variety of functions, including providing a structure that a user can grasp during implant insertion and removal, inhibiting or preventing the lacrimal implant from passing entirely within the lacrimal punctum 212, 214 and associated canaliculus 208, 210 (fig. 2), or to provide tactile or visual feedback information to the user, for example, as to whether the implant is fully implanted.

In some examples, as shown in fig. 35, graspable projection 3532 may include two or more expandable arm members sized to rest on the exterior of the lacrimal punctum. The arm component can be attached to the implant 3502, for example, via molding, gluing, or welding. The expandable arm member is expandable to limit penetration of the lacrimal implant 3500 through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210. Although two arm members are shown, some embodiments include more than two arm members, such as four arm members. The expandable arm component may exhibit an expanded profile separation distance 3505, the expanded profile separation distance 3505 corresponding to twice the diameter of the implant, such that the proximal end of the proximal expandable arm component remains on the exterior of the lacrimal punctum. The expandable arm member is expandable from a narrow profile configuration to an expanded profile configuration in a variety of ways, and may include at least one of a coil, braid, suture, thermoset polymer, thermoplastic, heat activated material, nitinol, shape memory material, polymer, polypropylene, polyester, nylon, natural fiber, stainless steel, polymethylmethacrylate, or polyimide. In some examples, the expandable arm member can be manually expanded, such as by a physician, after the lacrimal implant has been positioned in the canalicular cavity 208, 210.

In some examples, as shown in fig. 36, graspable projection 3632 may comprise a loop of wire that is embedded in a proximal end of lacrimal implant 3600 to allow the implant to be removed with proximal tension to the loop, e.g., with forceps. In some examples, the wire loop assumes a shape similar to a purse pull handle, which extends in a loop from the lacrimal implant, thereby facilitating removal of the lacrimal implant. The wire may include at least one of a heat activated material, a nickel titanium alloy, a shape memory material, a polymer, polypropylene, polyester, nylon, natural fibers, stainless steel, polymethyl methacrylate, or polyimide. In certain embodiments, the wire may include an absorbable thermoplastic polymer, such as at least one of polylactic acid (PLA), polyglycolic acid (PGA), or polyglycolic acid (PLGA). The distal end of the wire may be embedded in, molded or otherwise attached to the implant 3602 in order to secure the wire to the lacrimal implant.

In some examples, as shown in fig. 37, the graspable tab 3732 may include at least one axially extending tab coupled to an implant 3702, the implant 3702 configured to bias the outermost portions of the lacrimal canaliculus 208, 210. The interaction between the axially extending projection and the tubule prevents over-insertion of the associated lacrimal implant 3700 due to natural contraction against outward biasing of the tubule.

In some instances, as shown in fig. 38, a longitudinal groove, channel, or other indentation 3832 in implant body 3802 can be used in place of the graspable projection to allow insertion or removal of lacrimal implant 3800. The groove, channel, or other recess 3832 can extend axially along only a portion of the implant a distance sufficient to facilitate extraction of the associated lacrimal implant. In further examples, for removal of the implant from the lacrimal punctum, the lacrimal implant may include a wire molded into the implant and extending proximally.

Fig. 39A-39B show an example of an isometric view of a drug insert 322 and a removal facilitation wire 3999. In some examples, as shown in fig. 39A, a wire 3999 may extend from the drug insert 322 for removal purposes and be molded therein. In particular, the wire 3999 may include sutures, thermoset polymers, or shape memory alloys. In some examples, as shown in fig. 39B, the wire 3999 extends along the drug insert 322 adjacent to the implant 3902 and is bonded to the distal end of the insert for removal purposes. The wire may be bonded to the distal end of the drug core insert with an adhesive, such as cyanoacrylate, acrylic, epoxy, polyurethane, or hot melt adhesive.

Fig. 40 is a block diagram illustrating an exemplary method 4000 of manufacturing a lacrimal implant configured to be at least partially insertable through a lacrimal punctum and into an associated canaliculus. At 4002, an implant is formed that extends from a proximal end of the first body portion to a distal end of the second body portion. In various examples, the proximal end is formed to define a longitudinal proximal axis and the distal end is formed to define a longitudinal distal axis. The implant can be formed so that, when implanted, the proximal axis and the distal axis intersect at an angle of at least 45 degrees to bias at least a portion of the implant relative to at least a portion of the lacrimal canaliculus at or more distal to the canalicular curvature. Optionally, the forming of the implant may include integrating one or more particles of a drug or other therapeutic agent into the body. The implant may then be selectively coated with a permeable or impermeable material to direct the agent release to the patient's body tissue(s) as desired.

In some examples, implants of various sizes are formed to fit various patient anatomies. To determine the patient's tear-chamber size, one or two drops of topical ophthalmic anesthetic may be applied to the eye while the patient closes his/her eyelid in the tilted position for a brief period of time (e.g., approximately 60 seconds). Later, the lachrymal gauge can be used to measure the diameter of one or both of the upper or lower lachrymal canals. The lachrymal gauge can be pushed into the lachrymal chamber until a slight resistance is felt on the gauge, at which point the measurement corresponding to the gauge scale can be read and recorded.

In some examples, the second body portion is formed to include a dilator that generally tapers from a location near a proximal end of the second body portion to a distal end of the second body portion. In some examples, the dilator is formed by tilting an outer surface of the second portion of the implant between about 1 degree and about 10 degrees relative to the longitudinal distal axis. In some examples, the outer surface of the second implant body portion is sloped to a dilator tip between about 0.2 millimeters and about 0.5 millimeters.

In some examples, the implant is formed to include a graspable or other protrusion extending laterally from the proximal end of the first body portion. In some examples, the protrusion is formed to be generally aligned with a transverse extension direction of the second body portion relative to the first body portion. In some examples, the protrusion is formed such that, when implanted, it extends laterally from the proximal end of the first body portion in a direction parallel to or away from the eye.

At 4004, a drug insert may be disposed in at least one of the first body portion and the second body portion. In various examples, the drug insert is positioned such that the exposed drug insert surface is seated adjacent at least one of the proximal end or the distal end so as to provide sustained release of the drug or other therapeutic agent to, for example, the eye, nasal cavity, or inner ear. In some examples, the first drug insert is disposed in the first body portion and the second drug insert is disposed in the second body portion. In various examples, one or more drug inserts include a drug core that includes a drug or other therapeutic agent.

At 4006, an outer surface portion of the implant or the implant coating may be coated with at least one of a fluid-swellable material, a lubricious coating, or an antimicrobial coating. In various examples, the outer surface portion of the implant is polished using a polishing process.

Other examples are:

fig. 41 illustrates an example in which a lacrimal implant, such as the example of fig. 12, can be modified such that retention mechanisms 1292 of first portion 1204 need not project laterally about its periphery equidistantly. Instead, in the example shown in fig. 41, the proximal ends of the retention mechanisms 4192 of the first portion 1204 can project laterally outward at unequal lateral distances around its circumference, and the retention mechanisms 4192 of the first portion 1204 can taper to the outer diameter of the first portion 1204 at the distal end of the retention mechanisms 4192. In one example, the proximal end of the retention mechanism 4192 may include a circumference that is numerically equal to the circumference of the cap 1208 or other protrusion at the proximal end of the first portion 1204.

In one example, the proximal end of the retention mechanism 4192 of the first portion 1204 may protrude outwardly contralaterally, such as in opposite directions on opposing first and second sides of the retention mechanism 4192 of the first portion 1204, but not outwardly from the shaft portion outer dimension on opposing third and fourth sides of the retention mechanism (where the third and fourth sides define a second lateral direction that is generally orthogonal to the first lateral direction defined by the first and second sides). In this manner, the opposing protruding portions of the retaining mechanism 4192 of the first portion 1204 may define an end-to-end transverse distance in the first transverse direction that may be substantially equal to a protruding outer diameter of the proximal end of the retaining mechanism 1292 of the first portion 1204, as shown and described with respect to fig. 12.

Various other options for the implant are possible. Smooth corners may optionally be provided, such as to reduce tissue irritation or damage. Sharp corners may optionally be provided, such as to enhance retention. However, in a perpendicular second lateral direction, there may be no protrusion beyond the outer axial diameter of the retention mechanism 4192 of the first portion 1204. In one example, the first lateral direction of the opposing protruding portion of the retention mechanism 4192 of the first portion 1204 is also generally orthogonal to the direction in which the second portion 1206 extends from the first portion 1204, which may provide better retention. However, in another example, the first lateral direction of the opposing protruding portion of the retention mechanism 4192 of the first portion 1204 may be substantially parallel to the direction in which the second portion 1206 extends from the first portion 1204. In other examples, the first lateral direction of the opposing protruding portion of the retention mechanism 4192 of the first portion 1204 may be at other angles (e.g., between 0 and 90 degrees) relative to the direction in which the second portion 1206 extends from the first portion 1204.

Fig. 42A-42D illustrate an example in which a lacrimal implant, such as those shown in the examples in fig. 12 and 41, may be modified such that the retention mechanism 1292 of the second portion 1206 does not necessarily gradually protrude outward from the transverse outer dimensional profile of the second portion 1206. More specifically, fig. 42A shows a side view of an exemplary lacrimal implant, fig. 42B shows a cross-sectional view taken along section line a-a shown in fig. 42A, fig. 42C shows a top view of the lacrimal implant, and fig. 42D shows an end view of the lacrimal implant, as viewed from a proximal end of the second portion 1206.

In the example of 42A-42D, the second portion 1206 can include a retention mechanism 4292, the retention mechanism 4292 having a relatively abrupt change in profile, such as an outward transverse step, at one of the proximal end portion 4201 of the retention mechanism 4292 or the distal end portion 4202 of the retention mechanism 4292. For example, retaining mechanism 4292 may include an abrupt step at its proximal end portion 4201, such as an at least partially circumferentially protruding outer diameter (e.g., about 0.76 millimeters, about 0.86 millimeters, or about 0.89 millimeters) from the outer diameter of second portion 1206 (e.g., about 0.46 millimeters to about 0.62 millimeters) to proximal end portion 4201 of retaining mechanism 4292. Smooth corners may optionally be provided, such as to reduce tissue irritation or damage. Sharp corners may optionally be provided, such as to enhance retention. In this example, the outer diameter of the retention mechanism 4292 can taper (e.g., about 0.46 millimeters to about 0.62 millimeters) toward the outer diameter of the second portion 1206 as the distal end portion 4202 of the retention mechanism 4292 is approached.

The example of fig. 42A-42D can include a tapered retention mechanism 4192 of the first portion 1204 that extends laterally outward in a direction perpendicular to a direction in which the second portion 1206 extends outward from the first portion 1204, but does not extend laterally outward in a direction parallel to the direction in which the second portion 1206 extends outward from the first portion 1204, and providing a shaft portion that defines a tapered, at least partially circumferential neck portion 4203 between a proximal cap 1208 of the first portion 1204 and the retention mechanism 4192 of the first portion 1204, as explained above with respect to fig. 41. A tapered, at least partially circumferential neck portion 4204 may also be provided at the junction between the first and second portions 1204, 1206 for retention purposes. It is believed that the lacrimal canaliculus tissue can compress into and around the neck portion 4204, thereby helping to secure the implantation site of the lacrimal implant.

Fig. 43A-43C illustrate an example in which lacrimal implants such as those shown in the examples in fig. 12, 41, and 42A-42D may be modified such that the retention mechanisms 1292, 4192 of the first portion 1204 need not include a neck portion at the junction between the first portion 1204 and the second portion 1206. More specifically, fig. 43A shows a side view of an exemplary lacrimal implant, fig. 43B shows a bottom view of the lacrimal implant, and fig. 43C shows a cross-sectional view of the lacrimal implant taken along section line a-a shown in fig. 43B.

In the example of fig. 43A-43C, the proximal end 1208 can provide a protrusion, such as a cap, having an outer diameter of about 1.1 millimeters and a cap thickness of about 0.13 millimeters in a longitudinal direction of the first portion 1204. In this example, the cap portion of the proximal end 1208 can be separated from the retention projection 4392 of the first portion 1204, such as by a shaft portion, which can have an outer diameter of about 0.56 millimeters, and a longitudinal shaft length of about 0.66 millimeters. In this example, the retention projection 4392 of the first portion 1204 may have a proximal outer diameter of about 1.1 millimeters, which may taper directly to the second portion 1206 over about 0.96 millimeters, such that no neck portion is provided at the junction 4305 between the first and second portions 1204, 1206. By eliminating the neck portion, as shown in fig. 42A-42D, the length of the retention projection 4392 can be made effectively longer, allowing for a thicker proximal outer diameter-such as a diameter greater than about 1.1 millimeters, and/or expansion and easier insertability via a gradual taper angle increase. In some examples, the proximal outer perimeter may optionally include sharp corners, such as to enhance retention.

Other size options for the illustrative insert of fig. 43A-43C may be as follows. The proximal end 1208 may provide a protrusion, such as a cap, having an outer diameter of about 1.4 millimeters. The retention projection 4392 of the first portion 1204 can have a proximal outer diameter of about 1.3 millimeters. The neck portion between proximal cap 1208 and retaining projection 4392 can have a diameter of about 0.7 millimeters, and the first cavity within first portion 1304 can have a diameter of about 0.56 millimeters. The thickness of the retaining projection 4392 at the interface 4305 between the first and second portions 1204, 1206, as measured perpendicular to the outer converging face of the projection 4392, may be, for example, 0.043 millimeters, 0.086 millimeters, or 0.175 millimeters, depending on the depth of the first cavity, and the configuration and position of the projection 4392 relative to the first portion 1204.

In some examples, the retention mechanisms 1292, 4192, 4392 of the first portion 1204 or the retention mechanisms 1292, 4292 of the second portion 1206 may be selectively implanted into a self-expanding hydrogel coating on the plug body, wherein the self-expanding coating expands to form a shape generally similar to those shown in fig. 41, 42A-42D, and 43A-43C.

Fig. 44A-44C and 45A-45C illustrate examples in which lacrimal implants, such as those shown in the examples in fig. 12, 41, 42A-42D, and 43A-43C, can be modified such that the comparatively deep notch 4405 or the comparatively shallow notch 4505 can extend from a proximal end of the second portion 1206, such as into the second portion 1206. Fig. 44A and 45A show examples of end views of the lacrimal implant, as viewed from the distal and proximal ends, respectively, of second portion 1206; FIGS. 44B and 45B illustrate examples of cross-sectional views of the lacrimal implant taken along section line A-A shown in FIGS. 44A and 45A, respectively; and fig. 44C and 45C show examples of top views of lacrimal implants.

In one example, the notches 4405, 4505 can be used to function during implantation, such as by allowing insertion of an instrument into the notches 4405, 4505. In one example, the notches 4405, 4505 can include therein an expandable material 4407, such as a hydrogel (e.g., "TG-500" or "TG-2000" manufactured by lubrizol corporation of Cleveland, Ohio), the expandable material 4407 being expandable when implanted and exposed to bodily fluids. In one example, the notches 4405, 4505 can serve two purposes, allowing insertion of the instrument during implantation, and also allowing expansion of the hydrogel when implanted, such as to aid in retention. The depth of the notches 4405, 4505 relative to the proximal end of the second portion 1206 may be appropriate to allow at least some expansion of the expandable material 4407, if it is present. In some examples, the depth of the recess is twice the longitudinal length of the expandable material 4407. In some examples, the depth of the recess is slightly greater than the longitudinal length of the expandable material 4407.

The expandable material 4407 can be configured and positioned within the notches 4405, 4505, e.g., to expand in various directions (e.g., laterally and/or circumferentially in a balloon-like manner) when implanted, e.g., to push one or more portions of the implant 1202 outward and against the wall of the lacrimal canaliculus. The lacrimal implant may be more securely retained within the lacrimal punctum by engagement between the outwardly pushed portion of the implant 1202 and the wall of the lacrimal canaliculus. Optionally, the position of the expandable material 4407 within the recesses 4405, 4505 of the second portion 1206 can be adjusted as desired, such as to achieve desired retention characteristics. In some examples, the swellable material 4407 is positioned within the recess 4405, 4505 such that, upon swelling, a portion of the swellable material 4407 protrudes outward relative to the recess 4405, 4505. In other examples, the swellable material 4407 is positioned within the notches 4405, 4505 such that, upon swelling, the swellable material 4407 is substantially retained within the notches and does not protrude significantly outward relative to the notches 4405, 4505.

In various examples, the implant 1202 may include an elastomeric material, such as silicone, polyurethane, or other urethane-based material, or acrylic of a non-biodegradable, partially biodegradable, or biodegradable nature (i.e., erodible within the body), such as to allow at least partial outward deformation of the implant 1202 as the expandable material 4407 absorbs or otherwise retains fluid. In some examples, different portions of the implant 1202 may be made of different materials. For example, the first portion 1204 may include a stiffer, less expandable material, while the second portion 1206 may include a more resilient material. The second portion 1206 may also include a fluid permeable material, such as to facilitate or allow better fluid penetration into the swellable material 4407. Optionally, the wall thickness around the second portion 1206 of the swellable material 4407 can be made thinner to facilitate outward deformation when the swellable material 4407 absorbs or otherwise retains fluid.

As shown in the example of fig. 44B and 45B, the expandable material 4407 may have a non-expanded, "dry" state, which may facilitate insertion through the lacrimal punctum and into the lacrimal canaliculus. Once placed in the tubule, the swellable material 4407 may absorb or otherwise retain the tubule or other bodily fluid, such as through the aperture of the notch 4405, 4505, or through the fluid permeable material of the second portion 1206, or a lumen therein, the second portion 1206 surrounding the material 4407. In some examples, the swellable material 4407 can include a non-biodegradable material. In some examples, the expandable material 4407 may include a biodegradable material. Other options for the expandable material 4407 may also be used. For example, the expandable material 4407 may be molded as a single piece with the implant 1202, or may be separately formed and later coupled, or otherwise disposed within the implant 1202.

The desired expansion characteristics of the expandable material 4407 can be achieved, such as by appropriate material construction and processing. In some examples, an expandable material such as a hydrogel is extruded at a high draw down ratio, such as to create a size (e.g., a diameter of about 0.3 millimeters) configured to fit within the recess 4405, 4505. It has been found that extrudates formed at high draw ratios can have a radial expansion greater than the longitudinal expansion. In some instances, the expandable material 4407 is molded at a temperature and pressure found to produce desirable expansion characteristics (e.g., radial expansion greater than longitudinal expansion). For example, in some instances, the expandable material 4407 is configured and positioned to expand laterally out of the notches 4405, 4505 when implanted, such as into the ampulla, to assist in retention of the lacrimal implant in the lacrimal punctum. It has been found that the lateral expansion of the expandable material 4407 can continuously push the cap 1208 or other protrusion at the proximal end of the first portion 1204 flush with the lacrimal punctum. In one example, the swellable material 4407 may allow for a swelling capacity of up to about one time its "dry" volume, up to about ten times its "dry" volume, or up to about 20 times its "dry" volume.

It has been found that expansion of the expandable material 4407 within the notches 4405, 4505, when implanted, can help lock the angled intersection 4450 between the implant first portion 1204 and the implant second portion 1206 to help retain the lacrimal implant within the lacrimal punctum. It is believed that as the swellable material 4407 swells in different directions within the notches 4405, 4505, portions of the implant 1202 are pushed outward, becoming less and less elastic as these body portions become larger and larger.

As shown in fig. 44B and 45B, a lacrimal implant, such as between a first cavity or recess 4418 and a second recess 4405, 4505, can include a septum 4430, the first cavity or recess 4418 configured to receive a drug-releasing or other agent-releasing insert (e.g., drug core). The septum 4430 may serve to block or prevent the expandable material 4407 from expanding into the drug insert-receiving notch 4418. However, in one example, the septum 4430 may comprise a lumen or porous portion that allows the drug or other therapeutic agent(s) to travel from the insert and into and through the swellable material 4407 to the surrounding tubule tissue, thereby providing systemic drug or other agent release.

Fig. 48A-48E illustrate an exemplary lacrimal implant 4800, the lacrimal implant 4800 comprising: a secure retention element 4856, which when implanted, may be disposed within the lacrimal canaliculus ampulla; an oval graspable or other protrusion 4832; and lacking a medial protrusion on either first implant portion 4804 or second implant portion 4806. More specifically, fig. 48A represents an isometric view of an exemplary lacrimal implant, fig. 48B represents a side view of the lacrimal implant, fig. 48C represents a cross-sectional view taken along section line a-a in fig. 48B, fig. 48D represents a top view of the lacrimal implant, and fig. 48E represents an end view of the lacrimal implant, as viewed from the proximal end of second portion 4806.

In the example of fig. 48A-48D, the implant 4802 includes oval-shaped graspable or other protrusions 4832, which oval-shaped graspable or other protrusions 4832 can be configured to sit against or near the lacrimal canaliculus opening 212, 214 (fig. 2) when the implant 4800 is fully inserted within the lacrimal canaliculus 208, 210. Protrusions 4832 can prevent or prevent complete passage of the implant 4800 within the lacrimal canaliculus, or provide tactile or visual feedback to the implant care practitioner. In some examples, the oval shape may include a width of about 1.36 millimeters, a length of about 1.92 millimeters, and a thickness of about 0.30 millimeters.

The proximal end 4828 of the second implant body portion 4806 can include a secure retention element 4856, the secure retention element 4856 configured to be biased against at least a portion of the lacrimal canaliculus ampulla 252 when the lacrimal implant is implanted. The retention element 4856 projects proximally from the intersection between the first and second implant body portions 4804, 4806 in a direction opposite the extension of the longitudinal dilator 4850 of the second body portion. In some examples, the retaining element 4856 can project proximally by about 0.44 millimeters and have a height or thickness of about 0.53 millimeters. In this example, the retaining element 4856 comprises a hull shape and may include a depression 4875 graspable by an insertion tool to facilitate insertion. When implanted in the ampulla 252, the retention element 4856 can help secure the seated position of the graspable or other protrusion 4832 relative to the lacrimal punctum openings 212, 214.

In various examples, the second portion 4806 can include a length having a value of less than four times the length of the first portion 4804. In one example, the second portion 4806 can comprise a length of less than about 10 millimeters and have a configuration including a longitudinal dilator 4850 and a constant diameter portion 4890. In some examples, the implant 4802 includes a first cavity 4818, the first cavity 4818 disposed adjacent to the proximal end 4808. In this example, the first cavity 4818 extends inward from the proximal end 4808 about 1.22 millimeters and contains a first drug-releasing or other agent-releasing drug insert having an outer diameter of about 0.56 millimeters.

Fig. 49A-49F illustrate an example in which a lacrimal implant 4900, such as the implant example of fig. 12, may be modified such that a graspable or other projection 4932 includes a retaining lip 4990. The retaining lip 4990 may be configured to secure a seated position of a drug-releasing or other agent-releasing drug insert that is placed in the implant cavity 4918. More specifically, fig. 49A represents an isometric view of an exemplary lacrimal implant, fig. 49B represents a side view of the lacrimal implant, fig. 49C represents a cross-sectional view taken along section line a-a in fig. 49B, fig. 49D represents a top view of the lacrimal implant, fig. 49E represents an end view of the lacrimal implant, as viewed from a proximal end of the second portion 4906, and fig. 49F represents an enlarged view of section B-B shown in fig. 49C.

In various instances, the retaining lip 4990 may be configured to secure the position of a drug insert placed in the implant cavity 4918 without significantly affecting the release rate of the drug or other agent stored in the insert. In some examples, the retaining lip 4990 extends inward about 0.05 millimeters (+0.02 millimeters) from the surface of the implant cavity 4918. In some examples, the retaining lip 4990 includes a thickness of about 0.05 millimeters (+0.02 millimeters). Other options for a drug insert secured within the implant cavity 4918 may include one or more of the following: a tighter interference fit between the outer surface of the drug insert and the surface of the cavity, or an overlapping design (e.g., snap fit, etc.) between the drug insert and the cavity at the medial or distal portion of the insert.

The exposed, outward facing surface of the drug insert fully seated in the implant cavity 4918 may be slightly lower than the proximal end 4908 of the first portion 4904 or the distal end 4910 of the second portion 4906 due to the presence of the retaining lip 4990; however, this recessed arrangement does not form, and does not intentionally form any type of void that is used to control the release rate of the drug or other agent from the insert.

Fig. 50A and 50B illustrate an example in which a lacrimal implant 5000 (in addition to a notch and expandable material) such as the implant example of fig. 44A-44C can be modified such that a proximal surface of a drug insert 5022 is positioned over a proximal end 5008 of the implant before being fully implanted within a patient. More specifically, fig. 50A shows a side view of an exemplary lacrimal implant, and fig. 50B shows a cross-sectional view taken along section line a-a shown in fig. 50A.

In some examples, the proximal surface of the drug insert 5022 can be positioned about 0.25 millimeters (+0.05 millimeters) above the proximal end 5008 of the implant. The distal end surface of the drug insert 5022 can be positioned a similar amount above the base of the implant cavity 5018, which implant cavity 5018 is configured to receive the insert. In this manner, the exposed portion of the drug insert 5022 can be used to facilitate insertion of the lacrimal implant 5000 through the lacrimal punctum and into the associated canaliculus. Then, after implantation, the drug insert 5022 can be pushed completely or almost completely into the cavity 5018. When the drug insert 5022 is pushed into the cavity 5018, the insert diameter is selectively slightly larger than the cavity diameter, which can cause a biasing of the external implant surface against a portion of the lacrimal canaliculus, providing further implant fixation.

Fig. 51 and 52 are similar to fig. 25A and 25B, showing another example of a lacrimal implant 5100 that can be inserted through the lacrimal canaliculus 212, 214 and into the associated canaliculus 208, 210 (fig. 2). In this example, lacrimal implant 5100 may include an implant 5102-the implant 5102 includes a first portion 5104 and a second portion 5106, and may extend from a proximal end 5108 of the first portion 5104 to a distal end 5110 of the second portion 5106. The implant may include a shape that generally matches the anatomical features of the lacrimal canaliculus 208, 210, thereby providing patient comfort and reliable retention. In some examples, the concave shape between the first portion 5104 and the second portion 5106 includes a radius that is substantially the same as the radius of the small tube bend 250 (fig. 2).

In some examples, the retention element 5192 can be disposed at or near the distal end 5110 of the second implant portion 5106. In this manner, implant 5100 can utilize a stiffer lacrimal region and a smaller, deeper diameter region of the tubule to help secure the implant location. In addition, tear flow from the eye and around the implant can generate a force against the proximal surface of the distally disposed retention element 5192 to help secure the implant location. The retention element 5192 can be passive or active (e.g., using a hydrogel or other expandable material). In some examples, second implant portion 5106 includes a length of between about 6 and 12 millimeters, such as about 10 millimeters.

Fig. 52 shows an illustrative schematic view of a lacrimal implant 5100 implanted in the lower lacrimal punctum 214 and associated canaliculus 210. In some examples, lacrimal implant 5100 can be implanted in upper lacrimal punctum 212 and canaliculus 208. As shown, the first portion 5104 can be configured to be inserted and inserted through the lacrimal punctum 214 into the associated canaliculus 210 and to be disposed between the lacrimal punctum opening and the lacrimal canaliculus ampulla 252, while the second portion 5106 can be configured to be inserted and inserted through the lacrimal punctum 214 into the canaliculus 210 and to be disposed between the ampulla 252 and the lacrimal sac 204.

Similar dimensions and dimensional changes as shown and described with respect to FIGS. 41, 42A-42D, 43A-43C, 44A-44D, 45A-45D, 48A-48E, 49A-49F, and 50-52 may be applied to other examples described throughout this patent document.

Fig. 53A-53D illustrate an example (not shown in full outline) of an additional lacrimal implant 5300, the lacrimal implant 5300 configured to be retained within a lacrimal punctum and associated canalicular anatomy, the lacrimal implant 5300 including one or both of a dissimilar drug insert 5322 or a drug integral with one or more portions of the implant 5302. The drug or other therapeutic agent stored in the distinct drug insert 5322 or integrated with the implant 5302 is released on a sustained release basis at a desired rate into one or more of the eye, nasal cavity, or inner ear system. Where a larger amount of drug or other agent is desired, it is possible that implant 5302, due to its larger volume, may be used as a storage mechanism, with or without drug insert 5322.

In some examples, as shown in fig. 53A, 53B, and 53C, a first amount of an agent is stored in drug insert 5322 and a second amount of the agent is stored in implant 5302. It is believed that such an arrangement may ensure maximum agent retention capacity, as drug loading may adversely affect the cure or strength of the implant material. Accordingly, the drug loading in the implant 5302 can be limited. Alternatively, drug insert 5322 may not include sheath 5366 (which sheath 5366 covers one or more portions of insert 5322), and as a result, drug or agent diffusion between implant 5302 and insert 5322 is possible.

In some instances, as shown in fig. 53D, the implant 5302 is substantially solid in nature, i.e., it does not include one or more cavities or other cavities for receiving a distinct drug-releasing or other agent insert. Rather, the implant 5302 can be configured to receive one or more drugs or other agents that are integral throughout one or more body portions. In this manner, the entire implant 5302, or portions thereof, may function as a drug-release or other agent-release insert, and preformed openings in a permeable or substantially impermeable cover (e.g., a xylene cover) surrounding portions of the implant 5302 may be used to direct agent release. In other examples, a permeable cover material may be employed to allow release of the drug or other agent.

The coating material 5396 may be applied to one or more portions of the surface of the external implant in different thicknesses depending on the desired release rate and direction. In some examples, as shown in fig. 53A, the coating material 5396 is applied to a substantial portion of the surface of the implant body, except for the surface of the graspable or other protrusion 5332 at the proximal end 5308. In some examples, as shown in figure 53B, the coating material 5396 is applied to a substantial portion of the surface of the implant, but does not cover the exposed surface of the drug insert 5322. In some examples, as shown in fig. 53C and 53D, a coating material 5396 having a first thickness (e.g., about 5-6 μm) is applied to a majority of the implant surface, and a coating material 5398 having a second thickness (e.g., about 1 μm) is applied to the proximal surface 5308 of the implant 5302 and/or the drug insert 5322.

It is believed that some preferred coating materials are xylene, ceramic and silver, all of which can exhibit good flexibility. In some instances, a xylene coating material is used and may advantageously be vapor deposited on the implant at relatively low temperatures.

Examples of the experiments

In order that the present lacrimal implants of fig. 44A-44C and 45A-45C may be more fully understood, the following examples are given by way of illustration and not by way of limitation.

Experimental example 1:

fig. 46 shows a lacrimal implant including a notch extending from a proximal end of an implant second portion. In the recess, a swellable hydrogel material is arranged. To allow fluid to be received by the hydrogel material, the aperture of the recess is left open.

The hydrogel material and a portion of the surrounding implant at 30 minutes of hydration are indicated at 4602. The hydrogel material and a portion of the surrounding implant at 120 minutes of hydration are indicated at 4604. The hydrogel material and a portion of the surrounding implant at 240 minutes of hydration are indicated at 4606. The hydrogel material and a portion of the surrounding implant at 1440 minutes of hydration are indicated at 4608. As shown, expansion of the hydrogel material causes the surrounding portions of the implant, and particularly the second portion of the implant, to expand outwardly, e.g., to the size and shape of the small vessel wall, to reliably maintain the desired position of the implant. In addition, expansion of the hydrogel material locks the angled intersection between the first portion of the implant and the second portion of the implant by pressing against a spacer that separates a first cavity or recess that holds a drug-releasing or other agent insert (e.g., a drug core) and a second recess that holds the hydrogel material.

Experimental example 2:

fig. 47 illustrates a lacrimal implant including a notch extending from a proximal end of an implant second portion. In the recess, a swellable hydrogel material is arranged. To allow fluid to be received by the hydrogel material, the aperture of the recess is left open.

In this example, the hydrogel material is configured and positioned to expand laterally out of the notch and into the ampulla 4770 to aid in retention of the lacrimal implant within the lacrimal punctum when implanted. As shown, lateral expansion of the hydrogel material pushes a cap or other protrusion at the proximal end of the first portion flush with the teardrop-shaped surface 4772.

Examples of sheaths:

in various ways, the sheath may comprise suitable shapes and materials to control migration of a drug or other therapeutic agent from a dissimilar drug insert or implant that includes an integrated drug or other agent. In some examples, the sheath is configured to conform to the anatomy of the implant, such as the anatomy of the lacrimal punctum or associated canaliculus. In some examples, the sheath at least partially covers or surrounds the drug insert and may be suitably mated with the outer surface of the matrix/agent mixture. In other examples, the sheath covers or encloses portions of the implant that include one or more integrated reagents. The sheath may be made of a material that is substantially impermeable to the drug or other therapeutic agent, such that the mobility of the drug or agent is primarily controlled by the exposed surface area of the drug insert or implant that is not covered by the sheath. In various examples, the agent may migrate through the sheath about one tenth, or less, of the agent's migration through the exposed surface of the drug insert.

Suitable sheath materials may include polyimide, polyethylene terephthalate (PET), or xylene, among others. The sheath can have a thickness of about 0.00025 inches to about 0.0015 inches, which is defined as from a sheath surface adjacent to the outer surface of the matrix/reagent mixture to an opposing sheath surface remote from the outer surface. The overall diameter of the sheath, which extends across the drug insert, may range from about 0.2 mm to 1.2 mm. The drug insert may be formed by dip coating the matrix in the sheath. In some examples, the sheath may comprise a tube into which the matrix/reagent mixture may be introduced. The sheath may also be dip coated around the substrate/agent mixture, for example around a preformed substrate/agent core or implant.

The sheath may be provided with one or more additional functions, such as facilitating clinical use of the lacrimal implants discussed herein. For example, the sheath may receive a drug insert while the implant remains implanted in the patient, or after its removal, which is replaceable in situ. In some examples, the sheath can be provided with one or more external protrusions that apply a force to the sheath during extrusion, which causes the matrix/reagent mixture to be ejected from the sheath. An alternative drug insert may then be positioned in the sheath.

Examples of therapeutic agents:

therapeutic agents (or simply "agents") may include, inter alia, drugs made from one or any combination of anti-glaucoma agents (e.g., adrenergic receptor agonists, adrenergic receptor antagonists (beta-blockers), carbonic anhydrase inhibitors (CAI, systemic and topical), parasympathomimetics, prostaglandins, and hypotensives, and combinations thereof), antibacterial agents (e.g., antibiotics, antivirals, antineoplastics, antifungals, etc.), corticosteroids or other anti-inflammatory agents (e.g., NSAIDs or other analgesic and pain management compounds), decongestants (e.g., vasoconstrictors), agents to prevent altered factors of allergic agents (e.g., antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators), or their equivalents, derivatives, or analogs, Mast cell stabilizers, cycloplegics, mydriatic agents, and the like.

Exemplary useful agents include, but are not limited to, thrombin inhibitors; an antithrombotic agent; a thrombolytic agent; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; hypotensor; antibacterial agents, such as antibiotics (e.g., tetracycline, bacitracin, chlortetracycline, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfanilamide, sulfadiazine, sulfacetamide, sulfamethoxazole, sulfisoxazole, nitrofurazone, sodium propionate), antifungal agents (e.g., amphotericin B and miconazole), and antiviral agents (e.g., herpanin, acyclovir, ganciclovir, interferon); inhibitors of surface glycoprotein receptors; antiplatelet agents; an anti-mitotic agent; a microtubule inhibitor; an antisecretory agent; an activity inhibitor; a remodeling inhibitor; a reverse-forking nucleotide; an antimetabolite; antiproliferative drugs (including anti-angiogenic agents); anti-cancer chemotherapeutic agents; anti-inflammatory agents (e.g., hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisone 21-phosphate, prednisone acetate, fluorometholone, betamethasone, triamcinolone acetonide); non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., salicylic acid, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naxopren, piroxicam, and nabumetone). Examples of such anti-inflammatory steroids contemplated for use with the present lacrimal implants include triamcinolone acetonide (common name) and corticosteroids including, for example, triamcinolone acetonide, dexamethasone, fluocinolone, cortisone, prednisolone, flumetholone, and derivatives thereof); antiallergic drugs (such as Sodium chromoglycate, antazoline, methamphetamine, chlorpheniramine, cetrizine, trimethoprim, 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, salicylic acid, carbamoylcholine, acetylcholine chloride, physostigmine, irine, diisopropylfluoride, diethoxyphosphorylthiocholine iodide, decamethylenediamine bromide); antineoplastic agents (e.g., carmustine, cisplatin, fluorouracil 3; immunological drugs (e.g., vaccines and immunostimulants), hormonal agents (e.g., estrogen, estradiol, progestin, progesterone, insulin, calcitonin, parathyroid hormone, polypeptide, and vasopressin hypothalamic releasing factor), immunosuppressive agents, growth hormone receptor 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, anti-VEGF antibodies), dopamine receptor agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrices, members, ACE inhibitors, radical scavengers, chelating agents, antioxidants, anti-polymerases, photodynamic therapeutic agents, gene therapeutic agents, and other therapeutic agents, such as prostaglandins, anti-prostaglandins, prostaglandin precursors, including anti-glaucoma drugs including beta-receptor blockers, such as timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogs, such as equine prost, travoprost, latanoprost, and the like; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, acetomethazole, dichlorobenzensulfonamide, acetazolamide; and neuroprotective agents such as lubezole, nimodipine and related compounds; and parasympathomimetics such as carbamoylcholine, pilocarpine, physostigmine, and the like.

Additional agents that may be used with the present lacrimal implants include, but are not limited to, drugs that have been approved under 505 of the U.S. Federal food, drug, and cosmetic Act or under the public health services Act, some of which may be found at the U.S. Food and Drug Administration (FDA) website http:// www.accessdata.fda.gov/scripts/cder/drugsatfda/index. The present lacrimal implants may also be used with drugs listed in Orange Book, either in hypotenuse or in electronic form, which may be found at the FDA Orange Book website (http:// www.fda.gov/cder/ob /)) having or recording the same date, an earlier date, or a later date as the filing date of the present patent document. For example, such drugs may include, among others, dorzolamide, olopatadine, travoprost, bimatoprost, cyclosporine, brimonidine, moxifloxacin, tobramycin, brinzolamide, acyclovir timolol maleate, ketorolac tromethamine, prednisolone acetate, sodium hyaluronate, nepafenac, bromfenac, diclofenac, flurbiprofen, suprofnac, binoxan, patanol, dexamethasone/tobramycin compositions, moxifloxacin, or acyclovir.

Examples of diseases or disorders that may be treated with the above listed agents include, but are not limited to: glaucoma, and glaucoma; pre-and post-operative eye treatment; dry eye syndrome; anti-ocular allergy; resisting infection; post-operative inflammation or pain; respiratory-related diseases, such as allergies; inner ear diseases such as dizziness or migraine; or other systemic diseases such as hypertension, cholesterol management, pulmonary diseases or immune diseases. In some examples, the therapeutic agent may include a lubricant, a surfactant, such as a lubricant for treating dry eye. In other examples, the therapeutic agent may include an absorbent agent capable of absorbing tears from the eye.

Examples of drug inserts:

the drug insert may include one or more drugs or other therapeutic agents, and in some instances, one or more matrix materials to provide sustained release of the drugs or other agents. Similarly, where a greater amount of agent is desired, a majority of the implant may include one or more integrated drugs or other agents and a matrix material configured to provide for release of the agent.

One or more drugs or other therapeutic agents may migrate from the exposed surface of the drug insert to the target tissue based at least in part on the solubility of the drug or agent in the matrix. The rate of migration of the drug or agent from the exposed surface may also be related to the concentration of the drug or agent dissolved in the matrix. In some instances, the concentration of the dissolved drug or agent in the drug insert may be controlled to provide a desired release rate of the drug or agent. Additionally or in combination, the rate of migration of the drug or agent from the exposed surface may be related to one or more properties of the matrix in which the drug or agent is dissolved, such as the nature of silicone matrix formation. In some examples, the drug or agent included in the drug insert may include a liquid, a solid gel, a solid crystalline, a solid amorphous, a solid particulate, or a dissolved form. In one such example, liquid latanoprost droplets or solid bimatoprost particles are dispersed in a silicone matrix.

The drug insert may comprise one or more biocompatible materials capable of providing sustained release of one or more drugs or agents. Although the drug insert is discussed above primarily with respect to an example including a matrix comprising a substantially non-biodegradable silicone matrix having drug or agent soluble inclusions located therein, the drug insert may include other structures, such as a biodegradable matrix, a porous drug insert, a liquid drug insert, or a solid drug insert, that provide for sustained release of the drug or agent. The matrix comprising the drug or agent may be formed from a biodegradable or non-biodegradable polymer. In some examples, the non-biodegradable drug insert may include silicone, acrylates, polyethylene, polyurethane, hydrogel, polyester (e.g., dacron. rtm from e.i. dupont de Nemours and Company, Wilmington, Del), polypropylene, Polytetrafluoroethylene (PTFE), expanded PTFE (eptfe), Polyetheretherketone (PEEK), nylon, extruded collagen, polymeric foam, silicone rubber, polyethylene terephthalate, ultra high molecular weight polyethylene, polycarbonate polyurethane, polyimide, stainless steel, nickel titanium alloys (e.g., Nitinol), titanium, stainless steel, cobalt chromium alloys (e.g., elgiloy. rtm from Elgin Specialty Metals, Elgin, Ill; conhrome.rtm from Carpenter Metals p.wyoming, Pa). In some examples, the biodegradable drug insert can include one or more biodegradable polymers such as proteins, hydrogels, polyglycolic acid (PGA), polylactic acid (PLA), poly (L-lactic acid) (PLLA), poly (L-hydroxy acid) (PLGA), polyglycolide, poly-L-lactic acid, poly-D-lactic acid, poly (amino acids), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified celluloses, collagens, polyorthoesters, polyhydroxybutyrates, anhydrides, polyphosphoesters, poly (alpha-hydroxy acids), and combinations thereof. In some examples, the drug insert may include a hydrogel polymer.

End notes:

lacrimal implants and related methods are heavily discussed that provide reliable retention in the lacrimal canaliculus and canaliculus of the eye. The lacrimal implant may include an implant body configured to be inserted at least partially through the lacrimal punctum and into the canaliculus. The implant may include first and second portions, and may extend from a proximal end of the first portion defining a longitudinal proximal axis to a distal end of the second portion defining a longitudinal distal axis. The implant can be configured such that there is at least a 45 degree angular intersection between the proximal axis and the distal axis when implanted using the one-piece dilator. In this manner, at least a portion of the implant body can be biased relative to at least a portion of the lacrimal canaliculus located at or more distal to the canalicular curvature, thereby maintaining the implantation site of the lacrimal implant using anatomical structures. In various examples, the lacrimal implant may further include a drug insert disposed in at least one of the first portion or the second portion of the implant to provide sustained release of a drug or other therapeutic agent to, for example, the eye, nasal cavity, or inner ear system. The drug insert may include distinct drug cores disposed within the implant cavity, or may include a mixture of drug or other agent particles throughout one or more implant portions, or both.

Advantageously, in some instances, the present lacrimal implants may successfully block tear flow, or provide for the sustained delivery of a drug or other therapeutic agent to the eye, nasal cavity, or inner ear during different time periods, such as from days to months to years. In addition, by selectively including first and second implant cavities or drug-releasing implant portions, a dual drug or other agent release profile is possible. For example, two separate drugs may be released from two different implant sites. In addition, the canalicular curvature, which maintains the configuration of the present implant, reduces overstretching of the lacrimal canaliculus and canaliculus, and accidental detachment of the implant. It is believed that the present lacrimal implants may, but need not, be implanted, provide a mechanism (one-size-fis-all region) of size matching the overall situation, as an expandable coating or other expandable retention material may be applied to or within the implant body, such as to fit within and against hollow tissue structures of different sizes. The expandable nature of the present lacrimal implants may allow for easier implantation, as some of the various retention features of the implant may be activated after implantation.

The present lacrimal implants may also be better retained within the lacrimal canaliculus and canaliculus of a patient due to, for example, a cap-like projection at the proximal end of the first implant portion, a heel-like retention projection at the distal end of the second implant portion, or a combination of one or more intermediate or distally disposed projections on the first or second implant portions. As discussed further above, the cap-like protrusion may prevent the implant from migrating entirely under the lacrimal punctum and into the lacrimal canaliculus. The medial, distal and heel-like protrusions may help hold the implant in place until the care giver chooses to remove it.

The foregoing detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings illustrate specific embodiments by way of example in which the invention may be practiced. These embodiments are also referred to herein as "examples". All publications, patents, and other patent documents mentioned in this document are incorporated by reference herein in their entirety as if individually incorporated by reference. In the event of inconsistent usages between this document and those documents so included by reference, the usage in including reference documents should be considered supplementary to the usage in this document; for irreconcilable contradictions, the use in this document plays a dominant role.

In this document, the terms "a" or "an," as is common in patent documents, are used to include one or more than one, independent of any other instances or uses of "at least one" or "one or more. In this document, the term "or" is used to refer to a non-exclusive or, thus, "a or B" includes "a but not B," "B but not a," 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 nearly equal to the amount indicated.

In this document, the term "proximal" refers to a location that is relatively close to the cornea of the eye, and the term "distal" refers to a location that is relatively far from the cornea and is inserted deeper into the lacrimal canaliculus.

In this document, the term "hydrogel" is used to refer to an absorbent or other retaining material (such as an absorbent material), such as, for example, a superabsorbent polymer, a hydrocolloid, a water-absorbing hydrophilic polymer. Examples of hydrogels for use with the present lacrimal implants include, inter alia, aliphatic Thermoplastic Polyurethanes (TPUs), such as hydrophilic, aliphatic, and polyether-based thermoplastic polyurethanes. Suitable thermoplastic polyurethanes include those available under the trade name Tecophilic from Lubrizol corporation of Cleveland, Ohio. In some applications, hydrogels commercially available under the trade names "Tecophilic TG-500" (or simply "TG-500") and "Tecophilic TG-2000" (or simply "TG-2000") may be utilized. The term "hydrogel" may refer to superabsorbent polymer particles in a "dry" state (e.g., when the hydrogel is not swollen and contains little or no water weight). The term "hydrogel" may also be used to refer to superabsorbent polymer particles in a hydrated or swollen state, and more specifically, hydrogels that have absorbed at least their weight of water (e.g., hundreds of times their weight of water) (e.g., TG-500, which absorbs about 500 times its weight of water; and TG-2000, which absorbs about 2000 times its weight of water). As the hydrogel material absorbs liquid, it may increase in size (e.g., swell) and its shape may change to bias or cause the surrounding material to bias against at least a portion of the lacrimal ampulla or lacrimal canaliculus wall.

In the appended claims, the terms "including" and "in which" are used as the plain-english equivalents of the respective terms "comprising" and "in which". Furthermore, in the following claims, the terms "comprising" and "including" are intended to be open-ended, that is, a system, component, apparatus, article, or process that includes an element other than those following such a term is considered to be within the scope of the claims. Furthermore, in the following claims, the terms "first," "second," and "third," etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.

The above detailed description is intended to be illustrative, and not restrictive. For example, the above examples (or one or more features thereof) may be used in combination with each other. By way of example, one or more dimensions from the various implant embodiments shown or described may be grouped together to form an implant capable of providing a desired drug concentration. Other embodiments may be used, as will occur to those skilled in the art upon reviewing the above description. Also, in the foregoing detailed description, various features may be grouped together for the purpose of streamlining the disclosure. This should not be interpreted as intending that an unprotected 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.e.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 is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

Claims (51)

1. A lacrimal implant insertable into a lacrimal canaliculus, comprising:

an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion;

the proximal end of the first portion defines a longitudinal proximal axis and includes retention protrusions that project laterally non-equidistantly about a perimeter of the proximal end;

the distal end of the second portion defines a longitudinal distal axis; and is

The implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant, located at or more distal to a canalicular bend, relative to at least a portion of the lacrimal canaliculus.

2. The lacrimal implant of claim 1, wherein a proximal end of the retention projection of the first portion projects laterally outward at unequal lateral distances around a circumference thereof and tapers down to an outer diameter of a distal end of the first portion.

3. The lacrimal implant of claim 2, comprising a graspable projection extending at least partially from the proximal end of the first portion, the graspable projection configured to sit against or near a lacrimal punctum when the implant is implanted; and is

Wherein the proximal end of the retention protrusion of the first portion comprises a perimeter having a value about equal to a perimeter of the graspable protrusion.

4. The lacrimal implant of claim 2, wherein the proximal end of the retention projection of the first portion protrudes outward in opposite directions on opposite first and second sides without protruding outward from an outer diameter on opposite third and fourth sides.

5. The lacrimal implant of claim 1, further comprising one or more therapeutic agents.

6. The lacrimal implant of claim 5, wherein the one or more therapeutic agents are disposed in a drug insert at least partially positioned in the first portion, the drug insert configured to deliver sustained release of the one or more therapeutic agents.

7. A kit comprising the lacrimal implant of claim 1, and instructions for using the lacrimal implant to treat an eye disorder.

8. A lacrimal implant insertable into a lacrimal canaliculus, comprising:

an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion;

the proximal end of the first portion defines a longitudinal proximal axis;

the distal end of the second portion defines a longitudinal distal axis and includes a retention projection projecting laterally about a periphery thereof, the retention projection including an outward lateral step at one of a proximal end location of the retention projection or a distal end location of the retention projection; and is

The implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant, located at or more distal to a canalicular bend, relative to at least a portion of the lacrimal canaliculus.

9. The lacrimal implant of claim 8, wherein the lateral step extends laterally outward in a direction perpendicular to a direction in which the second portion extends, the lateral step being greater than or equal to about 0.14 mm.

10. The lacrimal implant of claim 8, wherein the lateral step is positioned at the proximal end of the retention projection and tapers to an outer diameter of the second portion at the distal end of the retention projection.

11. The lacrimal implant of claim 10, wherein the distal end of the retention projection includes an integral dilator to facilitate implantation of the implant into the lacrimal canaliculus.

12. The lacrimal implant of claim 8, further comprising one or more therapeutic agents.

13. The lacrimal implant of claim 12, wherein the one or more therapeutic agents are disposed in a drug insert at least partially positioned in the first portion, the drug insert configured to deliver sustained release of the one or more therapeutic agents.

14. The lacrimal implant of claim 13, wherein the drug insert comprises at least about 44 micrograms of the one or more therapeutic agents.

15. The lacrimal implant of claim 13, wherein the drug insert comprises at least about 81 micrograms of the one or more therapeutic agents.

16. A kit comprising the lacrimal implant of claim 8, and instructions for using the lacrimal implant to treat an eye disorder.

17. A lacrimal implant for insertion into a lacrimal canaliculus, comprising:

an implant extending non-linearly from a proximal end portion to a distal end portion with an intermediate portion therebetween, the proximal end portion being positionable in a vertical section of a lacrimal canaliculus, the distal end portion being positionable in a horizontal section of the lacrimal canaliculus;

the intermediate portion extends partially toward the proximal end portion in a first direction and partially toward the distal end portion in a second direction, so as to be implanted in the lacrimal canaliculus; and is

Wherein the intermediate portion includes a recess storing an expandable material configured to partially expand in a third direction generally opposite the second direction toward the ampulla of the lacrimal canaliculus when the implant is implanted.

18. The lacrimal implant of claim 17, wherein the expandable material comprises a hydrogel.

19. The lacrimal implant of claim 17, wherein, when the implant body is implanted, the expandable material expands laterally relative to the second direction, the lateral expansion urging one or more surrounding portions of the implant body outward against a wall of the lacrimal canaliculus.

20. The lacrimal implant of claim 17, wherein at least one of the proximal end portion and the distal end portion includes at least one intermediately-disposed retention projection having a larger cross-sectional dimension than an adjacent implant body portion.

21. The lacrimal implant of claim 17, further comprising one or more therapeutic agents.

22. The lacrimal implant of claim 21, wherein the one or more therapeutic agents are disposed in a drug insert positioned at least partially in the proximal end portion, the drug insert including at least one exposed surface configured to deliver sustained release of the one or more therapeutic agents.

23. A kit comprising the lacrimal implant of claim 17, and instructions for using the lacrimal implant to treat an eye disorder.

24. A lacrimal implant insertable into a lacrimal canaliculus, comprising:

an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion;

the proximal end of the first portion defines a longitudinal proximal axis and includes a retention projection projecting laterally about a periphery thereof;

the distal end of the second portion defines a longitudinal distal axis;

the retention projection includes an outward transverse step at a proximal end thereof and tapers directly to the second portion; and

the implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant, located at or more distal to a canalicular bend, relative to at least a portion of the lacrimal canaliculus.

25. The lacrimal implant of claim 24, wherein a length of the retention projection is about 0.96mm or greater.

26. The lacrimal implant of claim 24, wherein a distal end of the retention projection includes an integral dilator to facilitate implantation of the implant into the lacrimal canaliculus.

27. The lacrimal implant of claim 24, further comprising one or more therapeutic agents.

28. The lacrimal implant of claim 24, wherein the one or more therapeutic agents are disposed in a drug insert at least partially positioned in the first portion, the drug insert configured to deliver sustained release of the one or more therapeutic agents.

29. The lacrimal implant of claim 28, wherein the drug insert is positioned in a first cavity of the first portion, the first cavity having a diameter of at least about 0.56 mm.

30. The lacrimal implant of claim 29, wherein the drug insert comprises at least about 81 micrograms of the one or more therapeutic agents.

31. A kit comprising the lacrimal implant of claim 24, and instructions for using the lacrimal implant to treat an eye disorder.

32. A lacrimal implant insertable into a lacrimal canaliculus, comprising:

an implant extending non-linearly from a proximal end portion to a distal end portion, and having a middle portion, the proximal end portion being positionable in a vertical section of the lacrimal canaliculus, the distal end portion being positionable in a horizontal section of the lacrimal canaliculus;

the intermediate portion extending partially toward the proximal end portion in a first direction and partially toward the distal end portion in a generally tapering manner in a second direction such that when implanted in the lacrimal canaliculus, the implant is directionally laterally biased against at least a portion of the lacrimal canaliculus located at or more distal of a canalicular curvature; the extension in the second direction has a longitudinal length less than four times a longitudinal length of the extension in the first direction; and is

Wherein, when the implant is implanted, the intermediate portion extends partially toward the ampulla of the lacrimal canaliculus in a third direction that is generally opposite the second direction, the extension in the third direction comprising a flattened lenticular shape.

33. The lacrimal implant of claim 32, comprising a graspable projection extending at least partially from the proximal end portion, the graspable projection comprising an ovoid shape.

34. The lacrimal implant of claim 32, wherein the flattened pod-like shape includes a length between approximately 0.4 to 0.5 millimeters, and a thickness of approximately 0.5 to 0.6 millimeters.

35. The lacrimal implant of claim 32, further comprising a therapeutic agent.

36. The lacrimal implant of claim 35, comprising at least one drug insert, distinct from the implant body, disposed in the cavity of the proximal end portion, the drug insert comprising a polymer matrix including the therapeutic agent.

37. The lacrimal implant of claim 35, wherein the therapeutic agent is integrated into one or more portions of the implant body.

38. A kit comprising the lacrimal implant of any of claims 32-37, and instructions for using the lacrimal implant to treat an eye disorder.

39. A lacrimal implant insertable into a lacrimal canaliculus, comprising:

an implant comprising a first portion and a second portion, the implant extending from a proximal end of the first portion to a distal end of the second portion, the proximal end of the first portion defining a longitudinal proximal axis and the distal end of the second portion defining a longitudinal distal axis;

the implant is configured such that, when implanted in the lacrimal canaliculus, there is an angular intersection between the proximal axis and the distal axis so as to bias at least a portion of the implant, located at or more distal to a canalicular bend, relative to at least a portion of the lacrimal canaliculus; and

a graspable projection extending at least partially from the proximal end of the first portion, the graspable projection including an inwardly extending retaining lip that overhangs a cavity within the first portion.

40. The lacrimal implant of claim 39, further comprising at least one drug insert, distinct from the implant, disposed in the cavity of the first portion, the drug insert including a therapeutic agent.

41. The lacrimal implant of claim 40, wherein the inwardly extending retention lip, when fully seated in the cavity, suspends a proximal surface of the drug insert, thereby fixing a position of the insert.

42. The lacrimal implant of claim 41, wherein the suspension does not significantly affect a release rate of a drug stored in the drug insert.

43. A method of making a lacrimal implant insertable into a lacrimal canaliculus, the method comprising:

forming an implant extending from a proximal end of the first body portion to a distal end of the second body portion, the forming comprising

A cavity is formed in the first body portion,

extending the second body portion to a longitudinal length that is less than four times a longitudinal length of the first body portion,

configuring the proximal end and the distal end to define, respectively, a longitudinal proximal axis and a longitudinal distal axis that intersect at an angle when implanted in the lacrimal canaliculus, thereby configuring the implant to be directionally laterally offset with respect to at least a portion of the lacrimal canaliculus located at or more distal of a canalicular curvature; and

disposing a drug insert in the cavity of the first body portion, the drug insert being distinct from the implant, the disposing including positioning an exposed surface of the drug insert over the proximal end of the first body portion.

44. A lacrimal implant for insertion into a lacrimal canaliculus, comprising:

an implant extending from a proximal end portion positionable in a vertical section of the lacrimal canaliculus to a distal end portion positionable in a horizontal section of the lacrimal canaliculus and having an intermediate portion therebetween;

the intermediate portion extends in a first direction partially toward the proximal end portion and in a second direction partially toward the distal end portion such that when implanted in the lacrimal canaliculus, the implant is directionally laterally offset with respect to at least a portion of the lacrimal canaliculus at or more distal of a canalicular bend; and

a retention projection disposed at or near the distal end portion.

45. The lacrimal implant of claim 44, wherein the second direction extension includes a generally concave shape relative to the first direction extension; and wherein the radius of the generally concave shape is less than the radius of the tubular bend.

46. A lacrimal implant for insertion into a lacrimal canaliculus, comprising:

an implant comprising at least one cavity;

a drug insert, distinct from the implant, disposed in the at least one cavity; the drug insert includes a polymer matrix and a therapeutic agent; and is

Wherein the implant includes a therapeutic agent integral with one or more body portions.

47. The lacrimal implant of claim 46, further comprising a sheath surrounding one or more surfaces of the drug insert.

48. The lacrimal implant of claim 46, further comprising a coating applied to one or more portions of a surface of the external implant.

49. The lacrimal implant of claim 48, wherein a first coating thickness is applied to a first implant body surface portion and a second coating thickness is applied to a second implant body surface portion, the second coating thickness being different than the first coating thickness.

50. The lacrimal implant of claim 48, wherein the coating comprises at least one of xylene, ceramic, or silver.

51. The lacrimal implant of claim 46, wherein the drug insert includes a first supply of a therapeutic agent and the implant body includes a second supply of a therapeutic agent.