Ocular device and drug delivery system, as well as case thereof

Abstract

To provide an ocular device for placement under an eyelid.SOLUTION: The ocular device includes a plate with a back surface having at least one protrusion, where the at least one protrusion has a convex contact surface to contact the sclera of the eye and to provide an offset space. The plate can be connected to an elongated support member. The ocular device can deliver, to an eye of a user, a material including, e.g., a pharmaceutically active agent. A case for holding and dispensing an ocular device includes a well configured to retain fluid, a stabilizer, and a lid. The lid is connected to the well and rotatable between a position covering the well and a position with the well uncovered. The lid can have a port for adding fluid to the well, and a receiver, which can hold an ocular device, can project from the lid.SELECTED DRAWING: Figure 7H

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 925,695, filed October 24, 2019, the entire teachings of which are incorporated herein by reference. [Background technology]

[0002] Devices for the delivery of medications into the eye have a long history for a number of purposes. An early example is a pair of eyeglasses equipped with a medication chamber that is worn over the eye to apply and deliver medication into the eye over a set period of time. This example demonstrates a clinical device for treating ocular physiology by direct contact.

[0003] Over time, the art has progressed to include devices and / or materials loaded with therapeutic agents that are intended to be independently placed within the anatomical space of the eye. Examples include constructs and drug delivery systems that can provide a uniform drug delivery rate to the eye, as well as purpose-designed geometries that are intended to be placed and retained in some fashion within the anatomical space of the eye. This historical shift toward direct clinical application of therapy has given rise to multiple treatment modalities.

[0004] The evolution of ophthalmic devices has progressed over time to include smaller and more complex devices. Many of these devices require the device to be placed within the eye space in a specific orientation. For example, a contact lens should be placed on the eye with one surface of the lens facing the eye and the other surface not. Typically, a user identifies the surface of the contact lens to apply to the eye. For ophthalmic devices designed for placement in a specific orientation, it would be advantageous for the case to simply and clearly indicate to the user the preferred orientation for the ophthalmic device. Current cases for ophthalmic devices (e.g., contact lenses) identify the left and right ocular devices to the user.

[0005] Users may be unable to determine the correct orientation of ophthalmic devices, which are smaller and more complex than contact lenses. Ophthalmic devices that are not placed on the cornea of ​​the eye present challenges for correct placement and orientation. Without correct placement and orientation, these devices may function improperly or suboptimally. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 9,937,073 [Patent Document 2] U.S. Patent No. 3,302,646 [Patent Document 3] U.S. Patent No. 3,416,530 [Patent Document 4] U.S. Patent No. 4,309,996 [Patent Document 5] U.S. Patent No. 6,071,266 [Patent Document 6] U.S. Patent No. 6,331,313 [Patent Document 7] U.S. Patent No. 7,211,272 [Patent Document 8] U.S. Patent No. 8,167,855 [Patent Document 9] U.S. Patent No. 8,287,504 [Patent Document 10] U.S. Patent No. 8,574,659 [Patent Document 11] U.S. Patent No. 8,679,078 [Patent Document 12] U.S. Patent No. 8,939,948 [Patent Document 13] U.S. Patent No. 9,005,649 [Patent Document 14] U.S. Patent No. 9,421,126 [Patent Document 15] U.S. Patent No. 9,549,846 [Patent Document 16] U.S. Patent No. 9,750,636 [Patent Document 17] U.S. Patent No. 9,814,671 [Patent Document 18] U.S. Patent No. 9,849,085 [Patent Document 19] U.S. Patent No. 9,931,306 [Non-patent literature]

[0007] [Non-Patent Document 1] Bekerman, I; Gottlieb, P; & Vaiman, M; (2014)“Variations in Eyeball Diameters of the Healthy Adults”, Journal of Ophthalmology, vol. 2014, Article ID 503645, 5 pages, 2014 [Non-patent document 2] Robinson DA; (1964) “The Mechanics of Human Saccadic Eye Movement” J. Physiol

[1964] 174 PP 245-264 [Non-patent document 3] Castelhano, M; & Henderson, J (2008) “Stable Individual Differences Across Images in Human Saccadic Eye Movements” Canadian Journal of Experimental Psychology: 2008 Vol. 62 No.1 PP 1-14 [Non-patent document 4] Schneider, C., et al., Journal of Controlled Release 262(2017), 284-295 [Non-patent document 5] Schneider, C., et al., Journal of Controlled Release 278(2018), 156-158 [Non-patent document 6] SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19 Summary of the Invention [Problem to be solved by the invention]

[0008] Ophthalmic devices can be useful for placement within the eye. Contact lenses are ophthalmic devices that are placed on the surface of the eyeball. The ophthalmic device can be placed under the eyelid. The eyelid can be the upper or lower eyelid. People with dry eye may have a reduced ability to form a tear meniscus, may have reduced tear volume, and tear fluid may decrease with age. A comfortable, adaptive, hydrophilic (water-attracting) ophthalmic device placed under the eyelid can be beneficial, for example, because it can collect tear fluid and, in doing so, increase the amount and residence time of tear fluid. The ophthalmic device can include features configured to retain tear fluid and may be able to retain a significant volume of tear fluid, which is desirable, for example, in the elderly population and in users with dry eye (who experience difficulty achieving sufficient ocular lubrication). An ophthalmic device for placement under the eyelid can be used, for example, to deliver a therapeutic agent to the eye. It would be advantageous to have an ophthalmic device placed under the eyelid that can accommodate patient-to-patient variability in ocular anatomy and ocular kinematic movement, including variability that may result from factors such as age, health, and genetic or ancestral factors. [Means for solving the problem]

[0009] An ophthalmic device for placement under an eyelid includes a plate having a posterior surface with at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate, wherein insertion of the device into the eye further offsets the eyelid relative to the sclera.

[0010] The plate may be connected to an elongate support member of flexible material having a first end and a second end. The plate may be connected proximate to the first end of the elongate support member. The ophthalmic device may further include a plate connected proximate to the second end of the elongate support member.

[0011] A flexible connector may connect the at least one plate to the elongate support member. The connection between the flexible connector and the elongate support member may be configured to be positioned adjacent the canthus of the eye when the ophthalmic device is under the eyelid. The contact surface may form a boundary around the offset space.

[0012] At least one protrusion may be a complete ring. At least one protrusion may be a toroid.

[0013] The posterior surface of the plate can have at least three protrusions, the at least three protrusions having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate. The contact surface of the at least one protrusion on the posterior surface can be a convex contact surface.

[0014] Each plate includes an anterior surface on the other side of the plate from the posterior surface. The anterior surface can have at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the anterior surface of the plate. The contact surface of the at least one protrusion on the anterior surface can be a convex contact surface.

[0015] The periphery of at least one plate of the ophthalmic device may be curved.

[0016] At least one plate of the ophthalmic device may extend laterally from the elongate support member.

[0017] The length of the elongated support member of the ophthalmic device can be between about 3 millimeters and about 24 millimeters. The length of the elongated support member of the ophthalmic device can be between about 3 millimeters and about 8 millimeters. The length of the elongated support member of the ophthalmic device can be between about 4 millimeters and about 10 millimeters. The length of the elongated support member of the ophthalmic device can be between about 6 millimeters and about 16 millimeters.

[0018] The elongated support member, the plate connected proximate to the first end of the elongated support member, and the plate connected proximate to the second end of the elongated support member are substantially coplanar and flexibly interconnected, and can be configured to conform to irregular surfaces.

[0019] The at least one plate may be connected to the elongated support member of the ophthalmic device between the first end and the second end of the elongated support member, and the at least one plate is substantially flush with the elongated support member.

[0020] The ophthalmic device may include at least three plates.

[0021] Each plate of the ophthalmic device may be connected to the elongate support member by a flexible connector.

[0022] At least two plates of the ophthalmic device may be connected to the elongated support member by curved flexible connectors, and at least two additional plates of the ophthalmic device may be connected to the elongated support member by substantially straight flexible connectors.

[0023] The thickness from anterior to posterior of at least one of the plates of the ophthalmic device may decrease with distance from a central area of ​​the ophthalmic device.

[0024] The plates of the ophthalmic device may be connected to the same side of the elongate support member.

[0025] The ophthalmic device may include an elongate support member that is curved.The ophthalmic device may include an elongate support member that has a smoothly curved outer surface.

[0026] The ophthalmic device may include at least one plate that is substantially circular.

[0027] The ophthalmic device may include at least one plate having a posterior surface, wherein the widest portion of the posterior surface of the at least one plate is between about 2 millimeters and about 7 millimeters.

[0028] The ophthalmic device may have a substantially circular plate. The substantially circular plate may have a diameter ranging from about 2 millimeters to about 7 millimeters.

[0029] The ophthalmic device may have an elongate support member with an arch portion and an outer sweep portion, each sweep portion extending from the arch portion. The arch portion of the elongate support member may have a radius of curvature between about 0.0 millimeters and about 6.0 millimeters. The arch portion of the elongate support member may be an arcuate arch positioned in a central area of ​​the ophthalmic device between the ends of the elongate support member.

[0030] The ophthalmic device may have a substance to be delivered to the eye. The substance to be delivered to the eye may be in at least one plate of the ophthalmic device. The at least one plate of the ophthalmic device may provide at least one pocket for holding the substance to be delivered to the eye. The pocket in the plate may be cylindrical. The substance to be delivered to the eye may be in the pocket in the plate. The plate may have an opening to the pocket, and the pocket may be configured to receive the substance to be delivered to the eye through the opening.

[0031] An insert containing a substance to be delivered to the eye may be placed in a pocket in the plate of the ophthalmic device.

[0032] The ophthalmic device may have a retention element for retaining the insert in the pocket. The retention element may be, for example, a sealing membrane coupled to the ophthalmic device, to the insert, or to the ophthalmic device and the insert. The sealing membrane serving as the retention element may include an aperture. A lip at the opening of the pocket may serve as the retention element. The opening to the pocket may be substantially polygonal in shape. The opening to the pocket may be substantially hexagonal in shape.

[0033] An orifice may be present in the plate of the ophthalmic device, the ophthalmic device being configured to dispense a substance from an insert in the plate through the orifice to the eye. The orifice may be different from the opening, providing a bidirectional drug delivery system.

[0034] At least a portion of the ophthalmic device may be formed from a polymeric material.

[0035] An ophthalmic device for placement under the eyelid includes an elongated support member made of a flexible material and at least one plate connected to the elongated support member. The plate has a posterior surface with at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate. The contact surface can be convex. The elongated support member and the plate can be substantially coplanar. The at least one plate can be connected to the elongated support member proximate an end of the elongated support member. The ophthalmic device can include at least two plates connected to the elongated support member proximate an end of the elongated support member, the elongated support member and the plate being substantially coplanar. The ophthalmic device can include at least three plates connected to the elongated support member.

[0036] An ophthalmic device for placement under an eyelid to deliver a material to the eye includes an elongated support member and a plate connected proximate each end of the elongated support member, the plate being substantially coplanar with the elongated support member, each plate including a posterior surface having at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate. The contact surface may be convex. The ophthalmic device may further include a pharmaceutically active agent. The pharmaceutically active agent may be disposed in at least one of the plates.

[0037] Ophthalmic devices for placement under the eyelid are capable of delivering materials, such as pharmaceutically active agents, to the eye by forming at least a portion of the ophthalmic device from a pharmaceutically active agent blended with other materials.

[0038] The ophthalmic device can include at least one plate having pockets capable of receiving a pharmaceutically active agent. The pharmaceutically active agent can be in the pockets of the plate of the ophthalmic device. A removable insert containing the pharmaceutically active agent can be in at least one of the pockets. The plate can further include a retention element for retaining the insert in the pocket.

[0039] An ophthalmic device for placement under the eyelid of an eye includes a sclera-contacting surface with at least three points configured to contact the sclera of the eye, and a remote surface configured to be maintained remote from the sclera of the eye by the at least three contact points, the remote surface and the at least three contact points providing an offset space configured to hold tear fluid. The ophthalmic device can further include a pharmaceutically active agent for delivery to the eye. The ophthalmic device can be placed under the eyelid, and the pharmaceutically active agent can be delivered to the eye by the tear fluid.

[0040] An ophthalmic device for placement under the eyelid of the eye may have a contact surface for contacting the sclera that is less than about 20% of the surface area of ​​the remote surface. The ophthalmic device may be flexible and conformable to the sclera-contacting surface.

[0041] A method for delivering a pharmaceutically active agent to an eye includes providing an ophthalmic device having an elongated support member and plates connected proximate each end of the elongated support member, the plates being substantially flush with the elongated support member, at least one plate having a posterior surface with at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and providing an offset space between the sclera and the posterior surface of the plate; adding a pharmaceutically active agent to at least one of the plates; and placing the ophthalmic device under an eyelid of the eye. The contact surface may be convex. Adding a pharmaceutically active agent to at least one of the plates of the ophthalmic device may include disposing the pharmaceutically active agent in at least one pocket in at least one of the plates. Disposing the pharmaceutically active agent in at least one pocket may include inserting an insert into the at least one pocket, the insert containing the pharmaceutically active agent.

[0042] The ophthalmic device may be placed under the eyelid with the posterior surface of the at least one plate facing the sclera of the eye. The ophthalmic device may be placed under the eyelid with the anterior surface of the at least one plate facing the sclera of the eye. The ophthalmic device may be placed under the eyelid with the elongated support member facing the fornix. The ophthalmic device may be placed under the eyelid with the at least one plate facing the fornix.

[0043] The insert or method for use with an ophthalmic device can comprise, consist essentially of, or consist of a composition comprising a pharmaceutically active agent and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can comprise a water-soluble polymer. The pharmaceutically acceptable carrier can comprise a water-insoluble polymer. The pharmaceutically acceptable carrier can form a matrix, and the pharmaceutically active agent can be dispersed within the matrix.

[0044] The composition comprises one or more pharmaceutically active agents; about 20% to about 80% by weight of a water-insoluble polymer; and about 20% to about 80% by weight of a water-soluble polymer. The composition can comprise about 25% to about 70% by weight of the water-insoluble polymer. The composition can comprise about 40% to about 75% by weight of the water-soluble polymer. The water-insoluble polymer of the composition can be ethylene vinyl acetate (EVA). The weight percentage of vinyl acetate in the EVA can be 25% or more. The water-soluble polymer of the composition can be polyethylene oxide (PEO). The molecular weight of the PEO can be about 100,000 to about 300,000. The water-insoluble polymer of the composition can have a melting temperature of about 99°C or less. The water-soluble polymer of the composition can have a melting temperature of about 99°C or less. The composition can have about 0.5% to about 50% by weight of the pharmaceutically active agent. Each of the one or more pharmaceutically active agents can have a melting temperature greater than about 99°C and can be water soluble. The one or more pharmaceutically active agents can be in the form of particles. The one or more pharmaceutically active agents can include ciprofloxacin, dexamethasone, olopatadine, pilocarpine, hyaluronic acid, or hydroxypropyl cellulose, or a pharmaceutically acceptable salt thereof.

[0045] The composition can be formulated for ocular administration. The composition can be in the form of a semi-erodible polymer matrix. The composition can be formulated to provide controlled release of one or more pharmaceutically active agents.

[0046] The disclosed method of making the composition includes hot-melt blending one or more pharmaceutically active agents, a water-insoluble polymer, and a water-soluble polymer to form a hot-melt blend, and cooling the hot-melt blend to produce the composition. The hot-melt blending step can be performed at a temperature less than about 99° C. The hot-melt blending step can be performed at a temperature below the melting temperature of the one or more pharmaceutically active agents.

[0047] A case for holding and administering an ophthalmic device includes a well configured to hold a fluid, the well having an open top; a stabilizer connected to the well; a lid connected to the well, the lid being rotatable between a position covering the open top of the well and a position in which the well is uncovered; the lid having a port that is fluidly connected to the interior of the well when the lid covers the open top of the well; and a receiver protruding from the lid, the receiver configured to receive and hold the ophthalmic device in proximity to the port, the receiver being within the well when the well is covered by the lid.

[0048] The receiver of the case may form a channel that is open on at least one side of the receiver. The channel may be open on two sides of the receiver, and the channel may be configured to allow the ophthalmic device to be administered from either of the two sides of the receiver and may maintain the orientation of the administered ophthalmic device. The channel may be shorter than the ophthalmic device. The receiver may include a restraining element configured to hold the ophthalmic device in a particular orientation. The restraining element may be a ridge.

[0049] The lid may be removably secured to the well when the lid is in a position covering the open top of the well, and the lid may be configured to extend past the well when the lid is in a position covering the open top of the well.

[0050] The case can include a latch for removably securing the lid in position covering the open top of the well. The latch can be a latch post and key.

[0051] The lid may be connected to the well by a hinge formed from a flexible material.

[0052] The stabilizer may form a ring surrounding the well.

[0053] The well, stabilizer, lid, and receiver can be of unitary construction.

[0054] The port may be configured to allow fluid to enter the well when the lid is in position covering the open top of the well, and the port is of sufficient length to allow escape of gas from the well and entry of fluid into the well.

[0055] The case may include a removable peel strip that seals the port.

[0056] The case may be constructed from a high melt flow polypropylene material.

[0057] The case may have an ophthalmic device therein.

[0058] The case may include features for orienting the ophthalmic device. The features for orienting the device may be tactile and visual features.

[0059] The case can be for holding and dispensing an ophthalmic device (including the ophthalmic devices disclosed herein).

[0060] The receiver of the case may further include a restraining element, which may be a ridge.

[0061] A case for holding and administering an ophthalmic device includes a well configured to hold a fluid, the well having an open top, a stabilizer connected to the well, a lid connected to the well, the lid being rotatable between a position covering the open top of the well and a position in which the well is uncovered, and a receiver protruding from the lid, the receiver configured to receive and hold the ophthalmic device, the receiver being within the well when the well is covered by the lid.

[0062] The case may include a port. The port may be on the lid and may be in fluid communication with the interior of the well when the lid is in a position covering the open top of the well. The ophthalmic device held by the receiver may be proximate to the port.

[0063] The port may be configured to allow liquid to enter the well through the port and flow across the ophthalmic device when the lid is in position covering the open top of the well.

[0064] A kit may be provided that includes the ophthalmic device, a case, and a material for administration to the user's eye. The material may be a medicine, a pharmaceutical, a drug, or a combination. The kit may include a solution for wetting the ophthalmic device.

[0065] A method of inserting an ophthalmic device held in a case by a receiver into a user's eye, the ophthalmic device having a surface for contacting the sclera of the eye, the method comprising the steps of positioning the case on a substantially flat surface in front of a user with the surface of the ophthalmic device that will contact the sclera oriented toward the user, rotating a lid covering an open top of a well in the case to remove the receiver from the well, revealing the ophthalmic device held by the receiver, removing the ophthalmic device from the receiver while maintaining the orientation of the ophthalmic device, and inserting the ophthalmic device into the user's eye under the eyelid.

[0066] The method may further comprise the step of sterilizing the ophthalmic device sealed in the well with the lid in position covering the open top of the well.

[0067] The method can further include adding a material to the well to be administered to the user's eye. The material can be added through a port.

[0068] Materials can be added directly to the interior space of the well through the open top of the well.

[0069] The method can include removing a peel strip from the lid, where removal of the peel strip can leave the port unsealed.

[0070] Prior to rotation of the lid, the lid can cover the open top of the well and the port can be in fluid communication with the interior space of the well.

[0071] The step of removing the ophthalmic device from the case is accomplished by the pulling hand, either the right or left, which can grasp the protruding portion of the ophthalmic device from the right or left side of the receiver, and the pushing hand can be used to direct the protruding portion of the ophthalmic device toward the pulling hand when removing the ophthalmic device.

[0072] The foregoing will become apparent from a more particular description of exemplary embodiments, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed on illustrating the embodiments. The drawing descriptions identifying "front," "back," "top," and "bottom" views provide a frame of reference and are not intended as limitations on the orientation of use of what appears in the drawings. [Brief explanation of the drawings]

[0073] [Figure 1] Isometric view of a three-dimensional (3D) model of an eyeball with normal focus (emmetropia), identifying the sagittal (transverse) plane, the transverse (horizontal) plane, and the optical axis as spatial references, and showing degrees of freedom. [Figure 2A] FIG. 1 is an isometric view of a model of an eyeball showing the surface and sagittal plane of an emmetropic eye. [Figure 2B] FIG. 2B is a transverse (horizontal) cross-section of the eyeball illustrating axial length and transverse width measurements for an emmetropic eye corresponding to FIG. 2A. [Figure 2C]FIG. 1 is a cross-sectional view of the eyeball depicting the clinical assessment and observed anatomical measurements of axial length and transverse width as further summarized in Table 1. [Figure 2D] FIG. 1 is a cross-sectional view of the eyeball depicting the clinical assessment and observed anatomical measurements of axial length and transverse width as further summarized in Table 1. [Figure 2E] FIG. 1 is a cross-sectional view of the eyeball depicting the clinical assessment and observed anatomical measurements of axial length and transverse width as further summarized in Table 1. [Figure 2F] FIG. 1 is a cross-sectional view of the eyeball depicting the clinical assessment and observed anatomical measurements of axial length and transverse width as further summarized in Table 1. [Figure 3A] FIG. 1 is an isometric view of a representative eyeball and eyelid without specific parameters. [Figure 3B] FIG. 3B is a side view of the eyeball and eyelid of FIG. 3A. [Figure 4A] FIG. 1 is a front view of the emmetropic eye of Table 1 with the eyelids representing a typical 20-30 year old person, shown as a cross section in the transverse plane. [Figure 4B] FIG. 4B is a cross-sectional view of the eyeball and eyelid of FIG. 4A showing the average upper eyelid depth (“UFD”) and the average lower eyelid depth (“LFD”). [Figure 4C] FIG. 1 is a front view of the eyeball and eyelids representing an individual with a smaller palpebral fissure width ("PFW"), which is the average canthal width measurement of the eyes more likely to be observed in a given population, shown as a cross-section in a transverse plane. [Figure 4D] FIG. 4D is a cross-sectional view of the eyeball and eyelid of FIG. 4C showing the minimum UFD and LFD. [Figure 4E] FIG. 1 is a frontal view of the eyeball and eyelid representing an individual with PFW, the mean canthal width measurement of larger eyes more likely to be observed in certain populations, shown in cross section in a transverse plane. [Figure 4F]FIG. 4C is a cross-sectional view of the eyeball and eyelid of FIG. 4E showing maximum UFD and LFD. [Figure 5A] 1 is an isometric view of an example ophthalmic device. [Figure 5B] FIG. 5B is a bottom view of the ophthalmic device of FIG. 5A. [Figure 5C] FIG. 5B is a front view of the ophthalmic device of FIG. 5A. [Figure 5D] 5B is an isometric view of the ophthalmic device of FIG. 5A illustrating multiple degrees of freedom of adaptability of the ophthalmic device of FIG. 5A. [Figure 6A] 1 is an isometric view of an example elongate support member for an ophthalmic device. [Figure 6B] 1 is an isometric view of an example elongate support member for an ophthalmic device. [Figure 6C] 6C is an isometric view of the elongated support member of FIG. 6B, including vertical, horizontal, and torsional axes and associated arrows indicating rotational degrees of freedom. The axes are provided for reference and are not part of the device. [Figure 6D] FIG. 10 is a front view of an elongated support member with a plate connected to the elongated support member, showing the flexible connector. [Figure 6E] 6D, including vertical, horizontal, and torsional axes and associated arrows indicating rotational degrees of freedom. The axes are provided for reference and are not part of the device. [Figure 6F] FIG. 10 is a front view of an elongated support member with a plate connected to the elongated support member, showing the flexible connector. [Figure 6G] 6F, including vertical, horizontal, and torsional axes and associated arrows indicating rotational degrees of freedom. The axes are provided for reference and are not part of the device. [Figure 7A] FIG. 1 is a front view of a portion of the eye with the lower eyelid partially cut away to reveal the ophthalmic device installed and seated in the eye. [Figure 7B]FIG. 7B is an isometric view of the eye and ophthalmic device of FIG. 7A showing the force vectors of the eyelid positioning and holding the device. [Figure 7C] FIG. 7B is a side view of the eye and ophthalmic device of FIG. 7A with force vectors showing the forces holding the device under the eyelid. [Figure 7D] 7B is an isometric view of a portion of the eye with the lower eyelid partially cut away to reveal the ophthalmic device of FIG. 7A installed and seated within the eye. [Figure 7E] FIG. 7E is a side view of the eye and ophthalmic device shown in FIG. 7D. [Figure 7F] FIG. 7B is a rear view of the device of FIG. 7A. [Figure 7G] 7B is a top view of the ophthalmic device shown in FIG. 7A in cross section above a horizontal plane. [Figure 7H] FIG. 7B is an exploded cross-sectional view of a plate of the device of FIG. 7A in contact with the sclera of an eyeball cutout. [Figure 8A] 1 is a flowchart illustrating an example of a manufacturing process for a clinical use device according to an exemplary embodiment. [Figure 8B] 1 is a diagram illustrating performance attribute contributions of an ophthalmic device and an insert. [Figure 9A1] FIG. 1 is a front view of an ophthalmic device with the plate cut in a horizontal plane to reveal the pocket. [Figure 9A2] FIG. 9A2 is a front view of the device of FIG. 9A1 with the insert aligned for insertion into the pocket in the plate. [Figure 9B] FIG. 9A is a front view of the device of FIG. 9A2 with the insert inserted into the plate. [Figure 10A] A front view of an ophthalmic device with the plate cut on a horizontal plane to reveal the pockets in the plate, and different inserts aligned to be inserted into each pocket of the plate. [Figure 10B]FIG. 10B is a front view of the ophthalmic device of FIG. 10A with the insert inserted into the plate. [Figure 11A] FIG. 1 is a front view of an ophthalmic drug delivery system illustrating its component elements. [Figure 11B] FIG. 11B is a bottom view of the system of FIG. 11A. [Figure 12A] FIG. 1 is a front view of an ocular drug delivery system with the plate cut on a horizontal plane to reveal pockets in the plate. [Figure 12B] 12B is a rear view of the ocular drug delivery system of FIG. 12A with the plate cut on a horizontal plane to reveal the pockets in the plate. [Figure 13A] FIG. 2 is a front view of an ophthalmic device. [Figure 13B] 13B is a top view of the device of FIG. 13A showing the pockets of the plate and showing the membrane sealing surface. [Figure 13C] FIG. 13C is an illustration of a front view of the device of FIG. 13B with the plate cut open to reveal the inside of the pocket. [Figure 14A] FIG. 2 is a front view of an ophthalmic device. [Figure 14B] 14B is a bottom view of the ophthalmic device of FIG. 14A in cross section on a horizontal plane. [Figure 14C] 14B is a front view of the ophthalmic device of FIG. 14A in cross section on a transverse plane. [Figure 15A] FIG. 2 is a front view of an ophthalmic device. [Figure 15B] FIG. 15B is a bottom view of the ophthalmic device of FIG. 15A. [Figure 15C] 15B is a partial cross-section of the plate of the ophthalmic device of FIG. 15A showing the pocket opening at the rear of the plate. [Figure 16A] FIG. 2 is a front view of an ophthalmic device. [Figure 16B] FIG. 16B is a top view of the ophthalmic device of FIG. 16A rotated 180 degrees. [Figure 17A] FIG. 2 is a front view of an ophthalmic device. [Figure 17B] FIG. 17B is a rear view of the ophthalmic device of FIG. 17A. [Figure 18A] FIG. 2 is a front view of an ophthalmic device. [Figure 18B] FIG. 18B is a top view of the ophthalmic device of FIG. 18A. [Figure 18C] FIG. 18B is a top view of the ophthalmic device of FIG. 18A with the top portion of the plate cut away. [Figure 19A] 1A-1C are front views of an ophthalmic device, with successive views illustrating the device as it is rotated about an elongate support member in 90° rotational increments toward the viewer while maintaining a left-to-right orientation. [Figure 19B] 1A-1C are top views of an ophthalmic device, with successive views illustrating the device as it is rotated about an elongate support member in 90° rotational increments toward the viewer while maintaining a left-to-right orientation. [Figure 19C] 1A-1C are rear views of an ophthalmic device, with successive views illustrating the device as it is rotated about an elongate support member in 90° rotational increments toward the viewer while maintaining a left-to-right orientation. [Figure 19D] FIG. 19B is a cross-sectional view of the device of FIG. 19A taken along line AA. [Figure 19E] FIG. 19B is a cross-sectional view of the device of FIG. 19A taken along line BB. [Figure 19F] FIG. 19B is a cross-sectional view of the device of FIG. 19A taken along line CC. [Figure 19G] FIG. 19B is an isometric view of a portion of the ophthalmic device of FIG. 19A with the plate cut away to show the pockets in the plate. [Figure 19H] FIG. 19B is a cross-sectional view of the device of FIG. 19A taken along line DD. [Figure 19I] 19A-19H are isometric views of examples of inserts (or drug inserts) that may be placed into ophthalmic devices (including the ophthalmic devices of FIGS. 19A-19H). [Figure 20A] FIG. 2 is a front view of an ophthalmic device. [Figure 20B] 20B is a cross-sectional view of the ophthalmic device of FIG. 20A taken along line BB. [Figure 20C] 20B is a cross-sectional view of the ophthalmic device of FIG. 20A taken along line AA. [Figure 20D] FIG. 20B is a simplified front view of the ophthalmic device of FIG. 20A, where the pockets are not visible in the plate. [Figure 20E] FIG. 20D is a front view of an ophthalmic device as shown in FIG. 20D with shading added to show open space 250 within the perimeter of the ophthalmic device. [Figure 20F] FIG. 20F is a view of the open space of FIG. 20F with the ophthalmic device removed. [Figure 20G] FIG. 20B is a view of the open space of FIG. 20F rotated 45 degrees. [Figure 21A] 10A and 10B illustrate examples of plates with protrusions. [Figure 21B] 10A and 10B illustrate examples of plates with protrusions. [Figure 21C] 10A and 10B illustrate examples of plates with protrusions. [Figure 21D] 10A and 10B illustrate examples of plates with protrusions. [Figure 21E] 10A and 10B illustrate examples of plates with protrusions. [Figure 21F] 10A and 10B illustrate examples of plates with protrusions. [Figure 21G] 10A and 10B illustrate examples of plates with protrusions. [Figure 21H] 10A and 10B illustrate examples of plates with protrusions. [Figure 21I] 10A and 10B illustrate examples of plates with protrusions. [Figure 21J] 10A and 10B illustrate examples of plates with protrusions. [Figure 21K] 10A and 10B illustrate examples of plates with protrusions. [Figure 21L] 10A and 10B illustrate examples of plates with protrusions. [Figure 22A] FIG. 2 is a front view of an ophthalmic device. [Figure 22B]FIG. 10 is a diagram illustrating a plate with protrusions. [Figure 22C] FIG. 10 is a diagram illustrating a plate with protrusions. [Figure 22D] FIG. 10 is a diagram illustrating a plate with protrusions. [Figure 22E] FIG. 10 is a diagram illustrating a plate with protrusions. [Figure 23A] FIG. 1 is a front view of an example ophthalmic device. [Figure 23B] FIG. 23B is a rear view of the ophthalmic device of FIG. 23A. [Figure 23C] FIG. 1 is a front view of an example ophthalmic device. [Figure 23D] FIG. 23D is a rear view of the ophthalmic device of FIG. 23C. [Figure 23E] FIG. 1 is a front view of an example ophthalmic device. [Figure 23F] FIG. 23F is a rear view of the ophthalmic device of FIG. 23F. [Figure 23G] FIG. 1 is a front view of an example ophthalmic device. [Figure 23H] FIG. 23H is a rear view of the ophthalmic device of FIG. 23G. [Figure 23I] 23H is a cross-section of the ophthalmic device along AA. [Figure 24A] FIG. 2 is a front view of an ophthalmic device. [Figure 24B] FIG. 24B is a rear view of the ophthalmic device of FIG. 24A. [Figure 24C] 24B is a cross-sectional view of the ophthalmic device of FIG. 24A taken along line AA. [Figure 24D] 24A-24C are isometric views of examples of inserts (or drug inserts) that may be placed into ophthalmic devices (including the ophthalmic devices shown in FIGS. 24A-24C). [Figure 25A] FIG. 1 is a perspective view of the open case. [Figure 25B] 25B is a side cross-sectional view of the open case shown in FIG. 25A. [Figure 25C] FIG. 25B is a perspective view of the case shown in FIG. 25A with the lid in the closed position. [Figure 25D]FIG. 25D is a perspective view of the case shown in FIG. 25C with a peel strip covering the port in the lid. [Figure 26A] FIG. 1 is a perspective view of an open case holding an example ophthalmic device. [Figure 26B] FIG. 1 is a perspective view of a closed case holding an example ophthalmic device (not shown). [Figure 26C] FIG. 1 is a perspective view of an open case holding an example ophthalmic device protruding from the side of the receiver distal to the well. [Figure 26D] FIG. 1 is a perspective view of an open case holding an example ophthalmic device protruding from a receiver adjacent to a well. [Figure 27A] FIG. 1 is a schematic diagram illustrating an example of a kit including a case for holding an ophthalmic device (not shown) and a solution. [Figure 27B] FIG. 1 is a schematic diagram illustrating an example of a kit with a solution applied to an ophthalmic device (not shown) in a case. [Figure 28A] 1 is a graph of cumulative ciprofloxacin FB released versus time, showing the release profiles of the three components in the device inserts from Table 7. [Figure 28B] 1 is a graph of cumulative ciprofloxacin hydrochloride released versus time showing the release profiles of the three components in the device insert from Table 7. [Figure 29A] 1 is a graph of cumulative dexamethasone FB released versus time showing the release profiles of the three components in the device inserts from Table 8. [Figure 29B] 1 is a graph of cumulative dexamethasone phosphate released versus time, showing the release profiles of the three components in the device inserts from Table 8 (Table 9). [Figure 30] 1 is a graph of cumulative olopatadine FB released versus time showing the release profiles of the three components in the device inserts from Table 9. [Figure 31A] 1 is a graph of percentage Polyox 200,000MW released in 12 hours versus percentage of initial Polyox 200,000MW loading, showing the effect of Polyox loading on Polyox release for Polyox 200,000MW. [Figure 31B] 1 is a graph of percentage Polyox 300,000MW released in 12 hours versus percentage of initial Polyox 300,000MW loading, showing the effect of Polyox loading on Polyox release for Polyox 300,000MW. [Figure 31C] 1 is a graph of percentage Polyox 100,000MW released over 12 hours versus percentage of initial Polyox 100,000MW loading, showing the effect of Polyox loading on Polyox release for Polyox 100,000MW. [Figure 31D] 1 is a graph of percentage Polyox released at 12 hours versus percentage of initial Polyox loading, showing the effect of Polyox loading on Polyox release for various insert compositions. [Figure 32] 1 is a graph of the cumulative percentage of ciprofloxacin FB released from the insert versus time, showing the cumulative percentage of ciprofloxacin released from the insert in the device over 7 days. DETAILED DESCRIPTION OF THE INVENTION

[0074] An example of an ophthalmic device will now be described.

[0075] An exemplary ophthalmic device is configured to be placed in the eye. The anterior of the device is the surface of the device that faces the eyelid. The posterior of the device is the surface that faces the sclera of the eye. The device may optionally be configured so that either the anterior or posterior of the device can face the sclera of the eye.

[0076] Clinical details and illustrations of the physical geometry and measurements of the eye and eyelid

[0077] Researchers studying ocular anatomy have described a wide range of variability in anatomical data across human populations.

[0078] Figure 1 is an isometric view of a three-dimensional (3D) "CAD" model of an emmetropic eye with normal focus (emmetropia), identifying the sagittal (transverse) plane, the transverse (horizontal) plane, and the optical axis as spatial references and indicating degrees of freedom. The model includes the eyeball, the outer cornea, and the outer scleral surface. The sclera, or scleral surface, is the white outer layer of the eyeball. The sclera is the eye's opaque, fibrous, tough, protective outer layer (the "white of the eye"), continuous with the cornea at the front of the eyeball and with the sheath covering the optic nerve at the back of the eye. Clinically defined cross-sectional planes (from which clinical imaging measurements are performed across populations) are depicted with the eyeball, along with the optical axis, which defines focal length, and kinematic axial rotation indicators, which define the ocular motor abilities and degrees of freedom of visual gaze movement of the human eyeball. The anatomical model is derived from representative clinical published data. The retina is a thin layer of tissue that lines the eye internally and is located near the optic nerve. The purpose of the retina is to receive light focused by the lens, convert the light into nerve signals, and send these signals to the brain for visual perception.

[0079] The eyeball 090 includes the cornea 101 and sclera 102, which represent the outer surface boundaries of an emmetropic eye. The cornea 101 is an optical visual focusing element comprised of a spherical geometry with a historically classic outer radius measurement of 7.7 mm and a diameter of generally 11.7 mm, which optically defines an optical "focus" axis ("X") 105 that projects an image onto the retina. A sagittal (transverse) plane 103 and a transverse (horizontal) plane 104 are perpendicular to each other and intersect along the optical axis ("X") 105.

[0080] Using the "6DOF" convention to define the local origin, three axes, and centerline cross-sectional planes, the vertical axis ("Z") 106 is perpendicular to the horizontal axis ("Y") 107 and the optical axis ("X") 105. The horizontal axis ("Y") 107 is also perpendicular to the optical axis ("X"). The defined axes 105, 106, and 107 intersect singly at the local origin 100 (the nominal center point for the anatomy of the visual eye). The sagittal plane (vertical meridian) 103 is generated by the vertical axis 106 and the optical axis 105. The transverse plane (horizontal meridian) 104 is generated by the horizontal axis 107 and the optical axis 105. The sagittal plane 103 is perpendicular to the transverse plane 104, which intersects the optical axis 105.

[0081] 1 further illustrates the rotational movement capabilities of the eye 090 as constrained by the eye's fixation and muscle movement anatomy (not shown). Vertical axis rotation arrow 108 describes the visual input effects of left 110 and right 109 eye rotation about the vertical ("Z") axis 106. Horizontal rotation arrow 111 describes the visual input effects of up 112 and down 113 eye rotation about the horizontal ("Y") axis 107. In combination, these gaze rotations define two degrees of rotational freedom of the eye 090 about the origin 100 sufficient to observe any object in the field of view.

[0082] While the optical focus internal structure of the eye has been demonstrated to be relatively consistent, the external width and optical axis length of the eye have been shown to have a wide range of variability, which defines the curvature and surface shape of the non-optical scleral surface and adjacent supporting tissues.

[0083] Figure 2A is an isometric view of an eye 091 including the cornea 101 and sclera 102, which represent the outer surface boundaries of an emmetropic eye. A transverse (horizontal) plane 104, as shown in Figure 1, defines the cross-sectional location of the eye for the remaining figures. The eye shown in Figure 2A represents an emmetropic (normal) eye with the measurements shown in Table 1.

[0084] Figure 2B is a transverse (horizontal) cross-section of the emmetropic eye 091 shown in Figure 2A. The diagram shows the internal optical eye anatomy, including the lens capsule and iris 114, the cornea 101, and the sclera 102. The axial length 116 of the exemplary eye 091 is 23.5 mm, and the transverse (horizontal) width 115 is 24.2 mm, representing average values ​​for an "idealized" clinical eye model.

[0085] FIG. 2C is a transverse (horizontal) cross-section of a myopic (near-sighted) eye 092, with an axial length 116 of 26 mm and a transverse (horizontal) width 115 of 24.2 mm, representing the average values ​​for a myopic clinical eye model.

[0086] FIG. 2D is a transverse (horizontal) cross-section of a hyperopic (farsighted) eye 093, with an axial length 116 of 21 mm and a transverse (horizontal) width 115 of 24.2 mm, representing typical average values ​​for a hyperopic clinical eye model.

[0087] FIG. 2E is an isometric view of the eye 094 at maximum volume, with an axial length 116 of 26 mm and a transverse (horizontal) width 115 of 27 mm.

[0088] FIG. 2F is a transverse (horizontal) cross-section of a minimum volume eyeball 095, with an axial length 116 of 20 mm and a transverse (horizontal) width 115 of 21 mm.

[0089] Measurements are shown in illustrations for comparison and understanding of the range of variability in surface and curve shapes as seen in a transverse (horizontal) plane cross-section meridian (FIG. 2A, 104) (see non-patent document 1, which is incorporated herein by reference in its entirety).

[0090] [Table 1]

[0091] Figures 3A and 3B and 4A through 4F illustrate the clinical and anatomical variability of eyelid size, shape, fornix depth, width, and canthus-to-canthus opening across human populations, based on research in the literature on this topic. The figures follow the "6DOF" nomenclature introduced in Figure 1, apply the nominal emmetropic clinical corneal and scleral measurements used in Figures 2A and 2B, and present the average and variability ranges of eyelid data as described by clinical studies in the literature.

[0092] FIG. 3A is an isometric view of a representative eyeball 125 without specific parameters. The geometric control values ​​are ideal average values ​​of representative clinical data from cited papers. The diagram includes the cornea 101 and sclera 102, the upper eyelid 119, the lower eyelid 118, the conjunctival tissue 117, the two canthi (corners) 120 of the palpebral fissure where the upper and lower eyelids meet, and the palpebral fissure width ("PFW") 122 along the transverse (horizontal) plane 104 between the canthi 120, which defines the geometry of the upper eyelid 119 and the lower eyelid 118.

[0093] As in FIG. 1, the sagittal (transverse) plane 103 and the transverse (horizontal) plane 104 are perpendicular to each other and are positioned on and intersect the optical axis of the cornea 101 .

[0094] 3B is a side view of an eyeball 125 with the eyelid anatomy of FIG. 3A, further illustrating the cornea 101, sclera 102, upper and lower eyelids 119 and 118, conjunctival tissue 117, and one of the two canthi 120. The figure also illustrates the clinical measurement location 121 of the palpebral fissure height (“PFH”), which measures the vertical eyelid gap across the cornea.

[0095] Table 2 summarizes the variability of eyelid width and under-eyelid depth across many populations and cultures. Table 2 presents the mean, minimum, and maximum common clinical measurements for eyelid width from canthus to canthus along the transverse plane, as well as under-eyelid measurements (mean, minimum, and maximum along the transverse plane for both upper eyelid depth UFD and lower eyelid depth LFD), illustrating the range of anatomical variability in human populations. Figures 4A through 4F show an example eyeball (with eyelids) illustrating the data summarized in Table 2.

[0096] 4A is a front view of the emmetropic eye of Table 1 with eyelids 096 representing a person aged 20 to 30, perpendicular to the sagittal plane 103 and transverse plane 104, shown as a cross-section in a transverse plane parallel to the median plane (sagittal section). The eye 096 has a cornea 101, a sclera 102, an upper eyelid 119, a lower eyelid 118, conjunctival tissue 117, two canthi (corners) 120 of the palpebral fissures where the upper and lower eyelids meet, and a PFW 122. The exemplary eye 096 is shown in FIG. 4A and has a PFW of 30 mm, shown as a cross-section in the transverse plane.

[0097] Figure 4B is a cross-sectional view of the eyeball 096 shown in Figure 4A. Figure 4B illustrates that the forniceal depth 123 of the upper eyelid (119) is 16.2 mm, and the forniceal depth 124 of the lower eyelid (118) is 11.5 mm.

[0098] Figure 4C is a front view of eye 097, shown as a cross-section in the transverse plane, having the smallest observed value for PFW, as shown in Table 2. Exemplary eye 097 has a PFW of 27 mm.

[0099] Figure 4D is a cross-sectional view of the eyeball 097 of Figure 4C. Figure 4D illustrates that the fornix depth 123 of the upper eyelid (119) is 13.8 mm, and the fornix depth 124 of the lower eyelid (118) is 9.9 mm.

[0100] Figure 4E is a front view of eyeball 098, representing an eyeball with a maximum observed PFW122, maximum upper eyelid depth (mean) (“UFD”), and maximum lower eyelid depth (mean) (“LFD”) of 37 mm, as provided in Table 2.

[0101] FIG. 4F is a cross-sectional view of the eyeball and eyelid of FIG. 4E.

[0102] [Table 2]

[0103] Clinical details and illustrations of eye and eyelid kinematics and observed forces

[0104] Researchers studying the kinematics of ocular anatomy have described significant rapid and frequent movements of the eyeball and eyelids in the human population. The following description, summary table, and accompanying figures illustrate clinical observations, measurements, and ocular forces as background to aid in understanding the following description. Clinical observations include measurements of saccadic eye movements, saccadic eye movements during fixation, eye blinks, and eyelid tension.

[0105] Saccades

[0106] Saccadic eye movements are rapid, have a nominally constant intensity value, and are millisecond-long in duration, which is a function of angular displacement. Vision requires continuous movement of the ocular anatomy for retinal cell stimulation. Therefore, the eye is typically not completely motionless.

[0107] The extent to which the surface of an eyeball (sclera) of a known radius (half the diameter) moves (known as the surface translation) can be calculated from the angle through which the eye moves. The formula for determining surface translation is the radius of the eye (r) times the angle of movement θ (degrees) times pi (π) divided by 180, or (r × θ × π) / 180. As an example, an eyeball with a diameter of 24 mm would have a radius of 12 mm. If the eyeball moves 5 degrees, the surface translation would be (12 mm × 5 × 3.14) / 180, or 1.05 mm.

[0108] Table 3 below summarizes scleral surface translations based on clinical saccadic eye movement studies of an eyeball with a diameter of 24 mm (radius of 12 mm) for: Gross (macro) angular eye movements in the visual field; and Fixational saccades (micro-angular eye movements) across image types. See Non-Patent Document 2 and Non-Patent Document 3.

[0109] The studies summarized in Table 3 considered macroscopic nonfixational saccadic angular displacements in the range of 5° to 40° for eyeballs with a nominal cross-section thickness of 12 mm outer surface radius 102 with outer surface curvature length displacements as defined by angular saccade values ​​of 5°, 10°, 15°, 20°, 25°, 30°, 35°, and 40°. Calculated values ​​of surface displacement are provided, representing the expected surface displacement for each macroscopic saccadic angle.

[0110] Table 3 further summarizes the results of the gaze-fixation microsaccadic angular displacement study of eyes with nominal cross-sections having a 12 mm outer surface radius at angular saccade values ​​of 1.4°, 2.5°, and 3.3°. The calculated scleral surface translations appear in Table 3 for each fixation type.

[0111] The summary in Table 3 of successive saccadic movements and times pertains to devices placed under the eyelid or in the "conjunctival sac" and therefore subject to this dynamic, rapid-motion environment.

[0112] [Table 3]

[0113] Eye blinking

[0114] Blinking is the movement of the eyelids to wipe the ocular surface. The blinking action closes the palpebral fissure height ("PFH") from 25% to 100% in approximately 0.1 seconds, with extended blink closure lasting a minimum of 1 / 2 second. Eyelid movement (translation of the inner eyelid surface relative to the ocular anatomy) is generally along the vertical ocular meridian. The eyelids typically move from 25% to 100% (at 100%, "PFH" = 0).

[0115] Information on blink rate and blinking behavior is summarized in Table 4.

[0116] [Table 4]

[0117] Eyelid tension

[0118] Eyelid forces are important for the retention of devices intended to be placed under the eyelid, and eyelid forces have been measured in the posteroanterior (PA), nasal, and temporal directions. These forces represent the performance of the lower eyelid anatomy with respect to device retention ability. Relevant factors are summarized in Tables 5 and 6.

[0119] [Table 5]

[0120] [Table 6]

[0121] A system of interactive elements is described that works in concert to provide a user with an adaptive ophthalmic device that remains stable and comfortable when placed under the eyelid. The unique challenges and degree of anatomical variability, movement, and forces in this area of ​​the eye anatomy provide a particular environment for an ophthalmic device to this end.

[0122] The description illustrates aspects of the ophthalmic device, including its adaptive characteristics. Features of the ophthalmic device may be presented separate from the device for added clarity. Features may be integrated into the ophthalmic device.

[0123] Systems are described that include ophthalmic devices that adapt to changes in the ocular anatomy, are comfortable within the ocular space, remain positioned and stable within the ocular anatomy, resist forces from eyeball and eyelid movement, and retain tear fluid.

[0124] The devices are described with respect to the upper and lower eyelids. The devices have adaptive characteristics. The device descriptions are not intended to be restrictive or limiting in any way. In particular, alternative anatomical placement locations may exist for any of the described devices.

[0125] Materials for Ophthalmic Devices

[0126] Advantageously, the composition and properties of the ophthalmic device allow for translation along multiple degrees of freedom.

[0127] Materials that facilitate the transition from a planar "as-manufactured" configuration, or from an intermediate partially transitioned manufactured configuration shape, to a patient-compatible device when placed within the ocular anatomy to fulfill its purpose would be advantageous.

[0128] Ophthalmic devices can be made from materials that provide the device with a adaptable design. A combination of virgin and composite materials that are compatible with the anatomy can be used to make the ophthalmic device, including injection moldable materials.

[0129] Materials that may be used in making ophthalmic devices with adaptive properties may include, but are not limited to, metals, polymers, composites, thermoplastic polymers, thermosetting polymers, thermoplastic elastomers, thermosetting elastomers, metallic compositions, or pure elements (e.g., carbon nanotubes), or combinations thereof, either alone, in combination, or as composites.

[0130] Suitable materials can be, but need not be, hydrophilic. Materials with hydrophilic properties for either under the eyelid, over the cornea, or over the scleral device are well defined and characterized by contact lens material practice and many ophthalmic clinical publications.

[0131] A suitable low-cost, injection-moldable material, which has a proven history of use in anatomic contact drug delivery systems that provide excellent patient comfort within the ocular space, is the ethyl vinyl acetate (EVA) thermoplastic copolymer class. These materials, with hydrophilic properties that are compatible with the ocular anatomy, provide adequate hardness, flexural modulus for translation during application, and tear wetting properties important for compatibility and comfort within the ocular anatomy.

[0132] Surface Finishes for Ophthalmic Devices

[0133] The surface finish of the optical device can include an injection molded surface with an optical quality finish.

[0134] Compositions, materials, and methods known in the art may be used and may be selected to increase patient comfort and device retention, as well as to minimize user sensation.

[0135] Manufacturing method

[0136] The manufacture and validation of ophthalmic devices and transport mechanisms requires process steps that involve process losses that impact costs. The manufacturing process is described in U.S. Patent No. 9,937,073 (de Juan et al.), the entire teachings of which are incorporated herein by reference in their entirety.

[0137] There are many manufacturing methods that can be used to generate the device. One example that can be used is to select an injection molding material that meets material performance attributes and utilize an injection molding process to generate the device, and then apply a mechanical assembly method to place the medication delivery insert into the ophthalmic device.

[0138] The ophthalmic device is not limited to devices made by any particular method. The manufacturing process steps may, for example, follow the flow chart in Figure 8A:

[0139] injection molding ophthalmic devices;

[0140] generating a medication insert to fit into the ophthalmic device pocket;

[0141] Optionally, adding a medicine or other substance; and

[0142] The insert is assembled with an ophthalmic device to create a clinically usable device.

[0143] This example is a scalable, low cost, simple process that provides manufacturing process steps that generally follow those of Figure 8A and provides the performance attributes of the ophthalmic device and insert shown in Figure 8B.

[0144] The ophthalmic device may be formed, in whole or in part, from a pharmaceutically active agent blended with other materials that enable delivery of the pharmaceutically active agent from the ophthalmic device. By way of example, the ophthalmic device may be or may include a plate, which is formed, in whole or in part, from a material that includes the pharmaceutically active agent.

[0145] Ophthalmic devices provided as structural examples

[0146] Ophthalmic devices for placement under the eyelid are described and shown in figures illustrating features that may be included in the ophthalmic device. The description and figures include multiple features connected together (e.g., one or more plates connected to an elongated support member). The features are shown connected for purposes of illustration and not by way of limitation. An ophthalmic device for placement under the eyelid can be a plate that is not connected to other features. Thus, it should be understood that each of the plates illustrated herein can function as an ophthalmic device even without any other features attached to the plate. Alternatively, one or more plates can be connected to a support member or elongated support member. The connection of one or more plates to a support member or elongated support member is not limited to any of the configurations described or shown in the particular figures.

[0147] A normal eye's tear fluid volume is considered to be approximately 7.2 μL. Each eye may have a tear fluid volume that is greater or less than normal. It should be understood that the ophthalmic devices shown in the figures or described herein provide an open space 250 when placed under the eyelid. An eye with an ophthalmic device placed under the eyelid generally has a greater tear fluid volume than the eye would have without the ophthalmic device.

[0148] The increased tear fluid volume can promote enhanced residence time for drug absorption into the ocular anatomical tissues. The drug experiences a longer residence time in contact with the ocular tissues compared to eye drop ophthalmic drug delivery systems. The low solubility barrier of many drugs can be overcome by increasing the drug delivery in concert with the increased tear residence time.

[0149] 5A, 5B, and 5C are isometric, bottom, and front views, respectively, of an example adaptive ophthalmic device 299 for an eye. The ophthalmic device 299 includes an elongated support member 301, plates 511 and 521, and plates 531, 541, and 551, where the plates 511 and 521 are connected proximate their respective ends to the support member and are substantially flush with the support member, and the plates 531, 541, and 551 are connected to the support member between the plates 511 and 521. The ophthalmic device may be placed under the eyelid in a variety of positions and orientations. By way of example (and not limitation), the ophthalmic device may be placed under the eyelid with the elongated support member facing the fornix. As another example (and not limitation), the ophthalmic device may be placed under the eyelid with the plates facing the fornix. Once placed under the eyelid, the ophthalmic device can position itself and rotate about its horizontal axis. Plates 511 and 521 are configured to be positioned adjacent to the canthus of the eye. The plates are configured to accommodate the anatomical structure of the eye. Plates 531, 541, and 551 are substantially flush with the support member and plates 511 and 521. The plates have a posterior surface, which may have at least one protrusion with a convex contact surface. The ophthalmic device may include a substance (e.g., a medication) to be delivered to the eye. The elongated support member 301 extends toward each canthus of the eye when in the eye. The elongated support member 301 may be made of a flexible material. The elongated support member 301 may include an arch 303. The ophthalmic device may have an elongated support member with a variable cross-section along its length (see FIG. 19A ).

[0150] The adaptability of each plate of the ophthalmic device 299, either alone or in concert, advantageously provides an adaptive device that adjusts to changes in the anatomy of the eye.

[0151] FIG. 5A illustrates an exemplary ophthalmic device 299, along with the presence of an open space 250 around the ophthalmic device 299. The open space 250 allows multiple degrees of freedom of movement of the respective plates and other features of the ophthalmic device 299 relative to one another. The ophthalmic device 299 in the eye generates a larger tear fluid volume than the eye without the ophthalmic device. The open space 250 and offset space between the sclera and the posterior surface of the plate help realize the larger tear fluid volume resulting from insertion of the ophthalmic device into the eye. The elongated support member 301 may itself be formed from a flexible material, providing its own degrees of freedom and further providing an adaptive ophthalmic device.

[0152] Plates 511 and 521 may stabilize the ophthalmic device while in the eye.

[0153] In Figures 5A and 5C, the ophthalmic device 299 includes flexible connectors 411, 431, 441, 451, and 421, which connect the plate to the support member.

[0154] Figure 5B illustrates an ophthalmic device with a planar curved surface 300, showing the projected feature shape or height of a plate in an exemplary ophthalmic device 299. The planar curved surface 300 appears in Figure 5B for illustrative purposes only.

[0155] The eyelid has both a decreasing volume capacity and a decreasing fornix-to-lid depth as the eyelid approaches the canthus 120 junction (located at the nasal and temporal positions) (see FIGS. 3A and 3B). To achieve a comfortable design fit and device retention, it is advantageous for the plates 511, 521 to be located closer to the canthus, connected to an elongated support member 301 that is compatible with the fornix, and for the plates to be adapted in shape, size, and contour to reside within the eyelid volume and depth.

[0156] In FIG. 5B, in the exemplary ophthalmic device 299, the planar curved surface 300 for illustrative purposes is best described as follows: starting with plate 511, the plate generally follows the planar curved surface 300 as shown, starting on the left side of FIG. 5B at plate 511, increasing in height across plate 531 to a peak at plate 541 (shown in the center within this device 299), then decreasing in height across plate 551, and returning to a reduced height along plate 521 (shown on the right side of FIG. 5B).

[0157] The radius of curvature of 300 can be adjusted to be steeper (smaller radius) or flatter (larger radius) than that illustrated in Figure 5B, providing more or less volume for plates 531, 541, and 551 and varying the overall device height along the path of curve 300. The plate volume and overall device height determine the offset location of the eyelid relative to the sclera upon insertion, where the eyelid is the surface furthest from the sclera.

[0158] Device 299 (comprising a plate, a flexible connector, and an elongated support member made from a flexible material) provides an ophthalmic device that can be inserted under the eyelid and that can adjust and adapt to changes in the ocular anatomy and structure, either individually or in concert.

[0159] The shape and height of the curve 300 for the ophthalmic device may be adjusted to account for the tension of the user's eyelid and the shape of the user's eyelid, such adjustments can provide the ophthalmic device with a cosmetically acceptable appearance when inserted under the eyelid to achieve successful adoption of the ophthalmic device.

[0160] Plates in ophthalmic devices such as those illustrated in FIGS. 5A-5C can include a front surface from the rear surface to the other side of the plate, and the front surface can optionally have at least one protrusion with a convex contact surface that contacts the sclera of the eye and provides an offset space between the sclera and the front surface of the plate so that the ophthalmic device can be inserted with the front surface facing the sclera (see, e.g., device 591 illustrated in FIGS. 18A-18C). The ophthalmic device can be placed in the eye with either the rear surface or the front surface of the device facing the sclera.

[0161] FIG. 5D is an isometric view of the ophthalmic device of FIG. 5A. To illustrate the adaptability capabilities of the exemplary ophthalmic devices of FIGS. 5A-5C, FIG. 5D shows an ophthalmic device 299 with an added axis of rotation that does not actually exist within the device but is shown in FIG. 5D for illustrative purposes. FIG. 5D provides arrows to illustrate multiple degrees of freedom and illustrates the adaptability of the ophthalmic device 299. In FIG. 5D, the rotational degrees of freedom of the plate are illustrated by "arrows" in the rotational directions associated with the inserted axes of rotation added for each of the plates. Also, the degrees of freedom of the elongated support member are identified within the example.

[0162] The disclosed ophthalmic devices are further described by reference to FIGS. 6A-6G, which show examples of an elongated support member 301 that can be present in an adaptive ophthalmic device and an example of an ophthalmic device. The exemplary elongated support member 301 can have different configurations.

[0163] FIG. 6A illustrates an elongated support member 301 without an arch.

[0164] As illustrated in FIG. 6B, the elongate support member 301 can have a rectangular cross-section 306. The cross-section of the elongate support member 301 can vary along the length of the elongate support member (see, for example, device 800 illustrated in FIGS. 19A-19C). The cross-section can be rounded to provide an atraumatic surface and have an approximate thickness of about 0.2 mm to about 1.5 mm and a height of about 0.45 mm to 2.25 mm. The member 301 can follow a sweep curve 304 across the width of the device and can include an arch 303, which can be located in the general area of ​​the midpoint of the member 301. The arch 303 can be centrally located within the structure 301.

[0165] 6B, the peak of arch 303 is at approximately twice the vertical cross section 306 and is also around the device midpoint. Arch 303 can represent approximately 15% of the overall horizontal width of member 301.

[0166] 6A and 6B, the elongate support member of the ophthalmic device may be fabricated with or without an arch 303. When an arch is present, the underside 302 of the arch 303 may include attachments to aid in manufacturing. Placing the attachments or manufacturing aids on the underside 302 of the arch 303 so that they are separate from and do not interfere with the placement of the ophthalmic device under the eyelid may minimize adverse clinical effects on the performance of the ophthalmic device.

[0167] The manufacturing aid can be a gate for injection molding or injection casting or solution casting by single-step or multi-step methods and with materials including, but not limited to, thermoplastic polymers, thermosetting polymers, in-situ polymerization, drug-polymer composite constructs, and coatings. The manufacturing aid can also be a handling attachment tab for manufacturing processing and / or high-speed automation. Additionally, the manufacturing aid can also be a location feature for subsequent element production processing, lamination, composite assembly, coating, drug insertion, and / or drug infusion by multiple process step methods. The manufacturing aid can also be a removable patient or physician identification marker with or without an embedded electronic scannable identification tag component or a scannable device barcode identifier approved by medical device regulations.

[0168] 6C illustrates the rotational capabilities of an exemplary elongate support member 301 that contribute to the adaptability of the ophthalmic device. A horizontal (vertically projecting) axis 001 and a vertical (perpendicular to the horizontal plane) axis 003 define a local origin 999 of the elongate support member 301. The arch 303 provides a rotational feature, with each sweeping arc 304 having the ability to twist about the rotational feature as defined by the axis 004 and twisting arrow 008 at one end and the axis 006 and twisting arrow 009 at the other end.

[0169] 6D illustrates an ophthalmic device 270 with plates 511, 521 proximately connected to each end of the elongate support member, each of which is configured to be positioned adjacent the canthus of the eye. The plates 511, 521 of the ophthalmic device 270 can adapt to the anatomical structure of the eye. The ophthalmic device 270 is an example of a device that does not include plates other than the plates proximately connected to each end of the elongate support member 301.

[0170] Elongated support member 301 appears in Figure 6D with arch 303 and sweeping arc 304. Flexible connector 411 is connected to the elongated support member at an acute angle 1125, connecting plate 511 to the elongated support member, and similarly, at the other end of the elongated support member, flexible connector 421 is connected to the elongated support member at an acute angle, connecting plate 521 to the elongated support member.

[0171] Generally, the flexible connector is capable of forming an angle with the elongated support member ranging from less than 90 degrees to more than 180 degrees, connecting the elongated support member to the plate, and the surfaces of the elongated support member and the plate are substantially coplanar.

[0172] Figure 6E illustrates an isometric front view of the ophthalmic device 270 shown in Figure 6D with the plates 511, 521 and flexible connectors 411, 421 attached to the elongated support member 301. The vertical, facial, and torsional axes (which are not part of the device and are provided for illustration purposes) and associated rotational arrows indicate the degrees of freedom of movement of the plates relative to the elongated support member, allowing for adaptation to the ocular anatomy.

[0173] 6E, the rotational capabilities of plates 511, 521 and connecting elements 411, 421 are shown relative to elongated support member 301. Point 998 on flexible connector 411 (the element shown on the left) provides a reference point for adaptive movement of connector 411 and plate 511 about cross axis 011, horizontal axis 012, and vertical "torsional" axis 013. Directional arrow 015 indicates movement about axis 011, arrow 016 indicates movement about axis 012, and arrow 017 indicates movement about axis 013, relative to the location and position of plate 511 and flexible connector 411 relative to the sweeping arc 304 location and position. Point 997 on flexible connector 421 (element shown on the right) provides a reference point for adaptive movement of connector 421 and plate 521 in cross axis 021, horizontal axis 022, and vertical "torsional" axis 023. Directional arrow 025 indicates movement about axis 021, arrow 026 indicates movement about axis 022, and arrow 027 indicates movement about axis 023, relative to the location and position of sweeping arc 304 and plate 521 and connector 421.

[0174] 6F illustrates an ophthalmic device 280 with plates 531, 541, 551 that are adaptable to the anatomical structure of the eye and that are linked to the elongated support member 301 by flexible connectors 431, 441, 451. It may be noted that plates 531 and 551 are connected farther from the end of the elongated support member than plates 511 and 521 in FIG. 6E.

[0175] In Figure 6F, the elongate support member 301 is shown with an arch, sweeping arc, and flexible connectors 431, 441, 451 that protrude perpendicular to the curvature of the elongate support member and engage plates 531, 541, 551, respectively. The connector 441 and plate 541 in the ophthalmic device 280 are centrally positioned and attached to the top of the arch of the elongate support member 301. The connector 441 and plate 551 may alternatively be positioned in a non-central location, and the arch may not be present, as shown in Figure 6A. It should be recognized that features shown in any figure (e.g., vertical protrusions on the connectors, etc.) are merely illustrative.

[0176] 6G is an isometric front view illustrating plates 531, 541, 551 and connectors 431, 441, 451 attached to the elongated support member 301 of the ophthalmic device 280. The vertical, facial, and torsional axes and associated rotational arrows define the degrees of freedom of movement of the plates relative to the elongated support member within the device 280 to accommodate the ocular anatomy.

[0177] FIG. 6G provides a further illustration of the rotatability of plates 531 , 541 , 551 and flexible connectors 431 , 441 , 451 relative to elongate support member 301 .

[0178] Ophthalmic device positioned within the ocular anatomy

[0179] An adaptive ophthalmic device with multiple degrees of freedom capability will be further described by illustrating an ophthalmic device within an eye. The description and associated figures are not meant to be limiting. For example, an example ophthalmic device may be shown positioned under the lower eyelid of an emmetropic eye, but the same ophthalmic device could instead be shown under the upper eyelid of an emmetropic eye, or under the upper or lower eyelid of an eye with myopia or hyperopia. As a further example, an example ophthalmic device may be shown in one orientation, and the ophthalmic device could be shown in a different orientation within the eye. Similarly, and as a further example, an ophthalmic device may be shown in a location under the eyelid, but the location under the eyelid where it is shown is not a limitation on where the ophthalmic device may be placed or where it can move under the eyelid.

[0180] When placed within the ocular space, the disclosed optical devices self-adjust to adapt and fit the ocular anatomy. The disclosed ophthalmic devices are able to continue to accommodate and self-correct to conform to possible changing changes in the non-corneal ocular anatomy, which may be present as a result of visual movement and which may come into contact with any element or group of elements of the ophthalmic device in any configuration.

[0181] FIG. 7A is an isometric front view of a portion of an eye 125 illustrating placement of an ocular device 126 under the lower eyelid 118. The lower eyelid is partially cut away in FIG. 7A to reveal the device placed, seated, and oriented with the elongated support member facing the fornix of the eye. Engagement of the ocular device with the inner surface of the eyelid can be adversely affected by changes in the eyelid (e.g., draping, etc.). The drape is the natural conjunctival sac space of the eyelid where portions of the ocular device may reside. The ocular device 126 is adaptable and can engage with eyelids of increased size or drooping or draped eyelids. Typically, the eyelids of population groups over 50 years of age (which are most affected by eye diseases) may have larger conjunctival sacs for ocular device placement. The ophthalmic device shown in Figure 7A has degrees of freedom that allow the device to adjust and adapt to fit within the surrounding ocular surface. A portion of the elongate support member can be seen as a result of the eyelid cutout that spans the width of the ophthalmic device configuration, illustrating an example of placement of the ophthalmic device with the elongate support member oriented toward the fornix of the eye.

[0182] Plates 511, 521 (which are positioned adjacent the canthus 120 of the eye and linked to the elongated support member 301) each rotate to fit both the eyelid 118 and the local scleral surface 102 across the eyelid interaction surface (which is partially cut out). Plates 531, 541, and 551 (which are linked to the elongated support member 301) rotate to fit both the eyelid 118 and the local scleral surface 102 across the eyelid interaction surface (which is cut out). Open space 250 (shown in FIG. 7A within the closed space of the ophthalmic device and bounded by the eyelid and scleral surfaces) provides additional space for retaining tear fluid and helps achieve a larger tear fluid volume.

[0183] The plate functions to direct natural eyelid forces and eyelid tensions through the ophthalmic device in a balanced manner, keeping the device positioned under the eyelid with minimal surface contact area for saccadic surface kinematic influence.

[0184] By way of example, plates 531, 541, and 551, as relative to plates 511 and 521 (which are configured to be positioned adjacent the canthus of the eye), have sufficient mass and height to properly interact with the eyelid along their span, resulting in a device that is comfortable within the eye, causing the device to behave as if it were monolithic and able to accommodate the natural reduction in eyelid tension due to tissue elasticity and distance from the canthus.

[0185] In FIG. 7B, the eye 125 and ophthalmic device 126 (see FIG. 7A) are shown in an isometric view, including the cornea 101, sclera 102, lower eyelid 118, and canthus 120. The lower eyelid 118 is cut away in the middle to reveal the ophthalmic device 126. The elongated support member 301 is shown adapted adjacent to the fornix. An arch 303 rises upward from the fornix along the surface of the sclera 102 to accommodate the optical anatomy in and around the arch 303. Plates 511, 521 adjacent the canthus 120 of the eye have been moved and rotated to fit the eyelid 118 and scleral surface 102. Plates 531, 541, 551 (linked to elongated support member 301) are moved and rotated to fit both eyelid 118 and scleral surface 102 across the surface of the eyelid (cut away in FIG. 7B). Eyelid force direction vector arrow 062 indicates that the sub-lid force is applied downward and centrally relative to plate 521. Also, eyelid force direction vector arrow 061 indicates that the sub-lid force is applied downward and centrally relative to plate 511. The eyelid pressure force (generally directed toward the vertical meridian and fornix) on each plate (511 and 521) adjacent the canthus results in the eyelid's ability to self-center within the central conjunctival sac. FIG. 7B shows that the eyelid force direction vector arrow 061 indicates that the under-eyelid force is applied downward and centrally against the plate 511, towards the fornix and towards the vertical meridian anatomy. The force applied to the ophthalmic device 126 is a result of the volume and eyelid tension of the eyelid spanning section of the eyelid 118 from the canthus to the plate 511, including the conjunctival sac-eyelid "drape" effect of the engagement of the eyelid inner surface 018 with the plate 511, which section is extended and cut towards the vertical meridian (eyelid extension not shown).As seen in FIG. 7B , the eyelid force direction vector arrow 062 indicates that the under-eyelid force is applied downward and centrally against the plate 521, toward the fornix and also toward the vertical meridian anatomy, much like the force applied to the ophthalmic device 126. The applied force is a result of the volume of the eyelid spanning section 118 from the canthus 120 to the plate 521 and eyelid tension, including the eyelid “drape” effect of the engagement of the inner eyelid surface with the plate 521. The eyelid pressure force against the plate closest to the vertical meridian (see FIG. 7C ), caused by the central eyelid drape and generally directed toward the conjunctival fornix, results in a retention force that resists drainage from saccadic eye movements.

[0186] FIG. 7C shows the span of the eyelid across the central portion of the device 126 and the pressure of the eyelid sac tissue below and against the device where the eyelid sac 018 is in contact with the device. The eyelid force direction vector arrow 060 in FIG. 7C indicates that the eyelid applies force downward and centrally against the plate 541 and arch 303 ( FIG. 7B ) as the inner eyelid surface 018 accommodates the plate 541 (and all other plates) within the “conjunctival sac.” The eyelid 118 is illustrated as a cross-section at the central meridian of the central-most plate 541 of the ophthalmic device. In FIG. 7C , the eyeball 125 and ophthalmic device 126 of FIG. 7B are shown in a right-side view, including the cornea 101, sclera 102, lower eyelid 118, and canthus 120. The lower eyelid 118 is cut away in the center to reveal the installed and adapted ophthalmic device 126. The elongated support member 301 is shown nested and adapted under the eyelid and oriented towards the fornix.

[0187] Figure 7D is an isometric view of a portion of an eye with the lower eyelid partially cut away to reveal the ophthalmic device of Figure 7A installed and seated in the eye. In Figure 7D, the ophthalmic device is oriented with the plate facing the fornix of the eye.

[0188] FIG. 7E is a side view of the eye and ophthalmic device shown in FIG. 7D.

[0189] In Figure 7F, the ophthalmic device 126 is shown as viewed from behind the eye. All elements are flexible with the "degrees of freedom" capabilities seen in Figures 7A-7C, and open spaces 250 allow movement of features of the ophthalmic device 126. Attached to the elongated support member are plates 511 and 521 (linked to the elongated support member 301 by flexible connectors 411 and 421) adjacent the canthus of the eye, and plates 531, 541, and 551 linked to the elongated support member 301 by flexible connectors 431, 441, and 451, respectively. In the example in Figure 7F, plate 541 and flexible connector 441 are linked to the elongated support member 301 at an arch 303 in the ophthalmic device 126. The plates 511, 521, 531, 541, and 551 have anatomy-adaptive torus-style protrusions 311, 321, 331, 341, and 351 that protrude from the planar, scleral-adjacent surfaces of the plates 511, 521, 531, 541, and 551, respectively. The elongated support members, flexible connectors, and protrusions provide surfaces for contacting the sclera. The remaining space includes an open space 250, which provides empty space between features of the ophthalmic device 126 for flexibility and freedom of independent and coordinated feature movement. As shown, the lower eyelid placement of the device further provides an opportunity to retain generated tear fluid within the ocular space within the open space 250 for a longer dwell time. Alternatively, the ophthalmic device may be placed under the upper eyelid (not shown). Protrusions 311, 321, 331, 341, 351 protrude from the posterior surface of the plate, illustrating the surface interactions and relationships of protrusions having a torus geometry. The protrusions have contact surfaces and can be of various geometric shapes in addition to torus or ring. The protrusions can be bumps and other shapes with contact surfaces. The contact surfaces of the protrusions can be convex.

[0190] In Figures 7F-7G, the device 126 has plates 521, 551, 541, 531, and 511. Figure 7F shows the posterior surfaces of the plates, which are configured to contact the sclera of the eye. Specifically, the ophthalmic device 126 has plates 521, 551, 541, 531, and 511 with posterior surfaces 322, 352, 342, 332, and 312 (shown in Figure 7G), respectively, the posterior surfaces having at least one protrusion 321, 351, 341, 331, and 311, which has a convex contact surface and contacts the sclera of the eye, providing an offset space between the sclera and the posterior surfaces of the plates. The protrusion may define a perimeter around the offset space. The presence of an offset space between the sclera and the posterior surface of the plate provides additional accommodation to the ocular anatomy and allows for the formation of tear fluid between the sclera and the ocular device. The protrusion in the example of Figure 7F is toroidal, forming a complete ring as one example of a protrusion on the posterior surface of the ocular device.

[0191] Figure 7G is a horizontal cross-section through line 128 of the ophthalmic device 126 shown in Figure 7F. The elongated support member 301 and arch 303 are shown as viewed from the top of the ophthalmic device. Plates 521, 551, 541, 531, and 511 have protrusions 321, 351, 341, 331, and 311 that protrude from posterior surfaces 322, 352, 342, 332, and 312, respectively.

[0192] The ophthalmic device torus features as shown in Figures 7F and 7G provide an atraumatic ophthalmic device with minimal surface contact. In Figure 7G, the posterior surfaces 322, 352, 342, 332, and 312 may be spaced apart from the surface of the sclera by protrusions, allowing tear fluid to collect in the offset space of the ophthalmic device 126, providing an opportunity for increased tear fluid lubrication.

[0193] The interaction between the protrusions on the plate and the eyeball can be described by referring to a ring (which is similar to the protrusion, which is a torus or ring) and a sphere (which is like the eyeball). For simplicity's sake, the ring and sphere are referred to initially as proxies for the protrusions and the eyeball.

[0194] A ring with a set diameter smaller than the diameter of the sphere can seat itself on the sphere regardless of the size of the sphere. The ring will find the correct circular surface on the sphere to seat itself on regardless of the ring's orientation. Also, other geometric surfaces can mate with each other on round surfaces (including, for example, the mating of convex and conical surfaces).

[0195] Applying these geometric principles to ophthalmic devices results in a protrusion (e.g., a ring or torus) that interacts with the eyeball and allows the protrusion to seat itself on the eyeball regardless of the size of the eyeball or the location of the protrusion on the ophthalmic device, providing adaptability to eyeballs of varying sizes.

[0196] The presence of at least one protrusion having a convex contact surface for contacting the sclera of the eye and providing an offset space between the sclera and the posterior surface of the plate reduces the surface area of ​​the plate in direct contact with the eye. That is, the convex contact surface of the protrusion contacts the sclera of the eye, and the surface area of ​​the convex contact surface will generally be smaller than the surface area of ​​the posterior surface of the plate. Application of this geometric principle of surface interaction provides an ophthalmic device with reduced adhesion to adjacent surfaces.

[0197] It would be advantageous to have an ophthalmic device that manages rapid saccadic events and blink surface displacements with reduced impact on ocular anatomy and increased patient comfort, where the ophthalmic device is adaptable, provides offset space, has a reduced contact surface area, allows tear fluid to accumulate within its geometry, provides a wearable device to the user, and the wearable device is highly lubricious, comfortable, and allows the ophthalmic device to adapt to varying ocular anatomy of individuals and populations.

[0198] A device with a protrusion in contact with the globe positioned under the eyelid of an eye with rapid eye movement presents a smooth, blended, atraumatic surface and minimal adhesion to the scleral and eyelid anatomy, minimizing a traumatic device interface during saccadic eye movements. This result can be achieved without suturing the device to the eye. As discussed more fully below, this type of device can be used, for example, to deliver materials to the eye.

[0199] FIG. 7H illustrates an exploded cutaway view of the right cross section of the plate 511 of the ophthalmic device shown in FIG. 7G, which interacts with the sclera 102 of the eye to form an offset space 089 within which tear fluid resides. As shown in FIG. 7H, the design of the exemplary plate 511 allows the dynamically translating scleral surface to be advantageously offset from the plate 511 and contact the tear fluid. The tear fluid provides lubrication, which increases user comfort. The elongated support member, flexible connector, and protrusions contact the sclera while maintaining the offset space 089, retaining tear fluid within the offset space. As shown, the ophthalmic device retains additional tear fluid within the ocular space for a longer dwell time when placed under the eyelid as a result of the ophthalmic device's features and surrounding open space 250 (see FIG. 7F). When the ophthalmic device is inserted under the eyelid of the eye, the pharmaceutically active agent may be delivered to the eye by the tear fluid.

[0200] A 100-millisecond saccade duration for a 40-degree angular shift (providing 8+ mm surface translation (Table 3, FIG. 4A)) is a significant surface translation distance relative to the eyelid. Advantageously, an ocular device residing under the eyelid does not adversely affect the ocular anatomy during these events. The design intent of the disclosed ocular device is to generate a collected tear clot adjacent to the sclera, mitigating or minimizing surface-to-surface contact between the ocular device and the sclera. Natural tear fluid may be retained by the ocular device, or portions thereof (including protrusions), as a result of its geometry. When in place within the eye, the ocular device is able to "float" during saccadic translation as a result of the tear clot being accelerated by the kinematic motion of the surface translation, providing little resistance and reduced contact during these eye movement events. The natural adaptation of the ophthalmic device (including the plate and protrusions from the plate) to variations in the anatomy of the eye allows for the generation and retention of sufficient tear fluid for this purpose.

[0201] In Figure 7H, the scleral surface 102 and plate 511 of Figure 7G are shown in a sagittal cut plane with additional material removed for clarity. The convex torus feature 311 of the plate 511 is shown with the plate 511 fully adapted and in contact with the scleral surface 102 via the convex geometry 311. The boundary of the scleral surface 102, the protrusion 311, and the posterior surface 312 of the plate 511 provides an offset space 089 where tears can form. Scleral movement in any direction will draw tear fluid with it, providing the ability to displace the plate 511 from scleral contact, thus increasing available tear volume and lubrication across the scleral surface contact zone and to the protrusion within the device periphery.

[0202] Drug delivery

[0203] The described ophthalmic devices are capable of adapting to the ocular anatomy. Advantageously, these devices are comfortable within the ocular space, have a reduced impact on the patient's vision, remain stable with respect to placement and retention, and resist dynamic kinematic movements and ocular forces.

[0204] Ophthalmic devices can be fabricated to hold and deliver materials to a user, such as a medicament, a pharmaceutically active agent, or a drug, or a combination of a medicament, a pharmaceutically active agent, or a drug (collectively referred to as a "pharmaceutical active agent" or "drug"). The drug can be within the ophthalmic device itself, within a drug insert, or both. For example, the drug can be within a plate of the ophthalmic device. The drug can also be applied to the device through a port while the device is in a delivery system, for example, as part of an insertion protocol. The drug can be singular or multiple, applied to the device within a plate, across multiple plates, or through a delivery system port. For example, the plate can include a pocket, and the drug can be within the pocket of the plate. Drug delivery can be achieved by transporting the drug to the anatomical structure of the eye via various transport mechanisms. It would be advantageous for the ophthalmic device and delivery mechanism to be comfortable for the user, compatible with the ocular anatomy, and of a composition that will deliver the drug to the ocular anatomy at a defined dosage rate and total dosage over a known period of time. It would be further advantageous from a cost standpoint to avoid process loss of drug.

[0205] Optionally, a drug insert (also referred to as an "insert") may be used with the ophthalmic device, with a material (e.g., a drug, medication, or pharmaceutically active agent) located within the drug insert, which serves as a transport mechanism or as part of a method of drug delivery to the eye. The drug insert may be placed within the ophthalmic device, for example, within a plate of the ophthalmic device. The drug insert may be placed within an insert pocket in the plate of the ophthalmic device.

[0206] As an example, therapeutic medicines or drugs may be delivered to a user's eye by combining the ophthalmic device 299 shown in FIG. 5A with a drug insert to provide the user with an adaptive ophthalmic device for drug delivery.

[0207] FIG. 8A is a flow chart illustrating an example of a manufacturing process for a clinical use device according to an exemplary embodiment.

[0208] 8B is a diagram illustrating the performance attribute contributions of an ophthalmic device and an insert (drug delivery component), as well as a combination of an ophthalmic device and an insert, using a Venn diagram illustrating singular and combined performance attributes. Drugs can be transported from an ophthalmic device or from an ophthalmic device with an insert by tear fluid. Tear fluid is a transport mechanism for delivering medications or drugs to both the eye and mucosal absorptive tissues. Drug transport occurs across and through the ocular anatomical structures in local proximity to the ophthalmic device, and tear fluid can also be used to therapeutically target the ophthalmic anatomical structures.

[0209] Figures 9A1, 9A2, and 9B illustrate an ophthalmic device 598 that can be used to deliver a material, including a drug, to the eye. Figure 9A1 is a front cross-sectional view of the ophthalmic device 598 with a pocket. Figure 9A2 is a front view of the device of Figure 9A1 with an insert aligned to be inserted into the pocket in the plate. Figure 9B is a front view of the device of Figure 9A2 with the insert inserted into the plate.

[0210] It is worth noting that there are no limitations regarding the method of placement of the insert in the ophthalmic device or the method of delivery of the drug from the ophthalmic device (such as, for example, the ophthalmic devices shown in FIGS. 9A1, 9A2, and 9B). For example, the insert may be mechanically placed in the ophthalmic device. By way of example, and not by way of limitation, the insert may be mechanically placed in a pocket in the plate of the ophthalmic device. As a further example, the insert may be generated in situ by polymerization. By way of example, and not by way of limitation, silicone may be polymerized with the drug in the pocket in the plate of the ophthalmic device. Also, there are no limitations regarding the method of delivery of the drug from the ophthalmic device (such as, for example, the devices shown in FIGS. 9A1, 9A2, and 9B). For example, known methods of drug delivery may be used. Drug delivery can be by a controlled-flow membrane that creates a single, multiple, or gradient drug delivery curve, and / or may be driven by a charged, uncharged, or osmotic drug-driven process.

[0211] The design focus of the insert may be to achieve dosage rate-time goals for any therapeutic pharmaceutical agent, biologic, drug, medication, gene interaction agent ("gene therapy"), and / or delivery method.

[0212] The illustrative configurations for the ophthalmic devices and inserts are provided to provide further detail and are not intended as limitations on the ophthalmic devices and inserts, either alone or in combination.

[0213] Figure 9A1 is a front view of an ophthalmic device 598 with the plates cut in a horizontal plane to reveal the pockets. The ophthalmic device 598 includes plates 511, 531, 541, 551, and 521, which include insert pockets 611, 631, 641, 651, and 621. As a frame of reference, Figure 9A1 identifies posterior surfaces 312, 332, 342, 352, and 322. The ophthalmic device 598 is shown curved in Figure 9A1 to illustrate its ability to conform to the surface of the eye.

[0214] Figure 9A2 is a front view of the ophthalmic device 598 of Figure 9A1, with inserts 711, 731, 741, 751, and 721 aligned to be inserted into pockets in the plate. A cross-section of insert 731 appears in Figure 9A2, revealing a chamber empty of material with an orifice or hole to the chamber therein. Insert 721 in Figure 9A2 has a through hole, indicating a tubular or cylindrical style insert design.

[0215] To assemble the ophthalmic device 598 and the insert, the insert 711 is placed and secured in the pocket 611 in the plate 511; the insert 731 is placed and secured in the pocket 631 in the plate 531; the insert 741 is placed and secured in the pocket 641 in the plate 541; the insert 751 is placed and secured in the pocket 651 in the plate 551; and the insert 721 is placed and secured in the pocket 621 in the plate 521.

[0216] The insert shown in Figures 9A2 and 9B is configured to be assembled into the anterior side of the plate of an ophthalmic device.

[0217] FIG. 9B is a front view of the ophthalmic device 598 of FIG. 9A2 with the insert inserted into the pocket in the plate.

[0218] 10A and 10B illustrate an ophthalmic device 589. FIG. 10A is a front view of the ophthalmic device 589 with the plate cut on a horizontal plane to reveal the pockets in the plate. FIG. 10A is a front view showing the ophthalmic device 589 with different inserts aligned to be inserted into the pockets in each of the plates. The inserts in FIG. 10A have sealing membranes. Insert 712 has sealing membrane 713, insert 722 has sealing membrane 723, insert 732 has sealing membrane 733, insert 742 has sealing membrane 743, and insert 752 has sealing membrane 753. By way of example, insert 712 is placed into pocket 612 with sealing membrane 713, and membrane 713 is sealed to the posterior surface 312 of plate 511. Also shown in Figure 9A2 is an insert 721 having an eyelid drug release orifice 70, which provides a bidirectional delivery system when used in combination with the plate 541 (with holes 072) of the ophthalmic device 589 illustrated by Figure 10A. The insert 721 is an example of a cored insert with holes therethrough.

[0219] FIG. 10B is a front view of the ophthalmic device 589 of FIG. 10A with the insert inserted into the plate.

[0220] Therapeutic drugs may be delivered together or in sequence using single or multiple inserts and drug delivery techniques (see insert 741 in FIG. 9A2).

[0221] The insert and sealing membrane may be fabricated using any volumetric shape appropriate to the design and function of the insert and sealing membrane to provide the volume (including, but not limited to, squares, rectangles, triangles, polygons, circles, ellipses, spheres, splined surfaces, thin films, and combinations thereof, as appropriate). Such geometric shapes will then also generate open space for the insert geometry to reside within and be held within.

[0222] The sealing membrane composition and design, which may be applied alone or in combination with the insert, can be any suitable drug delivery material and / or system (e.g., porous materials, foams, grids, slits, orifices, woven fabrics, nonwoven fabrics, permeable films, polymeric films, layers, composites, laminates, metallic constructions, all useful examples of controlled release barriers representing just a few of the many possibilities in terms of polar and non-polar properties, composition and construction).

[0223] The examples illustrate ophthalmic devices for positioning and retaining inserts within the ocular anatomy, providing a comfortable, adaptive ophthalmic drug delivery system (which can contain the insert) and providing therapeutic clinical benefits. The examples illustrate the depth, breadth, and versatility of the disclosed ophthalmic devices across multiple possible drug delivery regimens.

[0224] FIG. 11A illustrates a drug delivery system with a front view of an ophthalmic device 298, and FIG. 11B illustrates a bottom view of the system of FIG. 11A. The ophthalmic device 298 includes an elongated support member 301 having an arch 303, insertable under the eyelid (where it can position itself to accommodate the anatomical structure) and rotatable about its horizontal axis. When the ophthalmic device is in place, the elongated support member 301 extends toward each canthus of the eye, and plates 511 and 521 are connected to each end of the elongated support member 301 by flexible connectors 411 and 421. Between plates 511 and 521, plates 531 and 551 (which accommodate the anatomical structure of the eye) are connected to the elongated support member 301 by flexible connectors 431 and 451. The open space 250 (shown, for example, in FIG. 11B ) provides empty space between features of the ophthalmic device 298, providing unoccupied volume for tear fluid retention within the closed space of the ophthalmic device and for independent and coordinated adaptability of the features of the ophthalmic device. The plates 511, 531, 551, and 521, the flexible connectors 411, 431, 451, and 421, and the elongated support member 301 (with arch 303) individually and coordinately adapt to the anatomical structure of the eye to provide an ophthalmic device under the eyelid that can deliver medicines or drugs to the eye.

[0225] Pockets in plates 511, 531, 551, and 521 allow for the placement and retention of medications or drugs to deliver a desired therapeutic effect.

[0226] FIG. 12A shows an ophthalmic device 597 illustrating an elongated support member 301 with an arch 303 connected to plates 511, 531, 551, and 521, which are cut on a horizontal plane, respectively, to reveal pockets 611, 631, 651, and 621 therein.

[0227] The pocket is configured to retain the insert within the plate of the ophthalmic device, and the drug delivery rate over time is controlled by adjusting the small diameter lip opening into which the insert is pressed, providing a mechanical retention system for the eroding or non-eroding insert.

[0228] Figure 12B illustrates an ophthalmic device 587. In addition to the membrane seal as previously described, the ophthalmic device 587 includes features for securing an insert such that the insert is designed to fit into pockets 622, 652, 632, and 612, and once placed in the pockets is mechanically retained by retention features exemplified by 325, 355, 335, and 315, respectively. As shown, the mechanical retention is achieved by a retention lip. There are no orientation restrictions on the addition of this feature, and it may be included in the ophthalmic device of Figure 12A as well.

[0229] Elongated support member 301 with arch 303 is shown in connection with a cross-sectional view of plates 521, 551, 531, and 511 containing pockets 622, 652, 632, and 612 with rear surfaces 322, 352, 332, and 312, which can be used to additionally facilitate membrane element sealing. Plates 551 and 531 are shown containing large volume pockets 632, 652 and optional planar membrane sealing features 332, 352, respectively.

[0230] Ophthalmic device 587 is capable of holding an insert. Features 315, 325, 335, and 355 may be configured to control the drug delivery rate by controlling the orifice size, while features 612, 622, 632, and 652 present an opportunity for the delivery of a significant volume of drug, which may be sustained for a longer duration depending on the design and composition of the insert itself.

[0231] 13A, 13B, and 13C illustrate an ophthalmic device 596, which is another example of an ophthalmic device.

[0232] As illustrated in Figure 13A, the ophthalmic device 596 is insertable under the eyelid and will accommodate variations in the ocular anatomy. When the ophthalmic device is in place, the elongated support member 301 extends toward each canthus of the eye, and plates 511 and 521 are connected to each end of the elongated support member 301 by flexible connectors 411, 421. Between plates 511 and 521, plates 531, 551 (which will accommodate the ocular anatomy) are connected to the elongated support member 301 by flexible connectors 431 and 451. Plates 511, 531, 551, and 521, flexible connectors 411, 431, 451, and 421, and elongated support member 301 (with arch 303) individually and cooperatively adapt to the anatomical structure of the eye to provide an ophthalmic device under the eyelid that can deliver medicine or drugs to the eye.

[0233] Figure 13B is an illustration of a top view of ophthalmic device 596. In Figure 13B, plate 531 shows pocket 633 and sealing membrane 333. Plate 551 shows pocket 653 and sealing membrane 353.

[0234] FIG. 13C is an illustration of a front view of ophthalmic device 596 with plates 531 and 551 cut open to reveal the inside of pockets 633 and 653. FIG.

[0235] 14A, 14B, and 14C illustrate an ophthalmic device 595, which is another example of an ophthalmic device. The ophthalmic device 595 has a plate with a larger volume pocket.

[0236] 14A is a front view of an ophthalmic device 595. As illustrated in FIG. 14A , the ophthalmic device 595 includes an elongated support member 301 with an arch 303 and plates 5102 and 5202, which are positioned adjacent the canthus of the eye and may be connected to the elongated support member 301 by flexible connectors 4112 and 4212, respectively. The plate 5102 has a pocket 630, and the plate 5202 has a pocket 650. The pockets 630 and 650 are capable of receiving a substance (such as, for example, a drug for delivery to the eye).

[0237] Figure 14B is a horizontal cross-section through line 139 of the ophthalmic device 595 shown in Figure 14A. The figure shows a cross-section of plate 5102 with pocket 630, protrusion 320, and posterior surface 350, and also shows a cross-section of plate 5202 with pocket 650, protrusion 310, and posterior surface 330.

[0238] FIG. 14C is a front view of the ophthalmic device 595 of FIG. 14A in cross section on a transverse plane to reveal pockets 630 and 650.

[0239] 15A, 15B, and 15C illustrate an ophthalmic device 594, which is another example of an ophthalmic device. The ophthalmic device 594 has plates 5103 and 5203.

[0240] The ophthalmic device 594 has a reduced conjunctival sac width and vertical height. As a result, the ophthalmic device 594 is advantageous for users with ocular anatomies that have a smaller conjunctival sac volume (e.g., users with narrow palpebral fissure widths and reduced fornix depths).

[0241] As shown in FIG. 15A , the anterior side of the ophthalmic device 594 includes a segmented torus circumscribing the width of the plates 5103 and 5203 (see FIG. 22B ). The elongated support member 301 extends toward the respective canthus of the eye when in the eye. The flexible connectors 471 and 481 are configured to be positioned more distally toward the canthus when inserted into a user's eye, while the plates 5103 and 5203 (adjacent the canthus) are configured to be more central within the conjunctival sac ocular anatomy. As a result, the flexible connectors 471 and 481 protrude beyond the plates, positioning the plates toward the vertical midline of the eye when the ophthalmic device 594 is in the eye. As a result, the ophthalmic device 594 has a reduced width in the area of ​​the plates for insertion into the conjunctival sac and wider elongated support members.

[0242] Flexible connectors 471 and 481 curve perpendicularly from the elongated support member 301, articulate about local origin pivots 472 and 482, and connect in a spring-loop-like manner to plates 5103 and 5203, respectively. By including spring-like features, the ophthalmic device 594 can adjust to anatomical forces, such that the ophthalmic device maintains a generally controlled and predictable shape outside the eye space. Users are more likely to handle the insertion and removal of a device that presents a predictable shape, providing a feature that has some similarity to a contact lens. Additionally, softer, more flexible, and adaptable material compositions can be used without losing the desired ease of user handling.

[0243] FIG. 15B illustrates a bottom view of the ophthalmic device 594 as shown in FIG. 15A.

[0244] Figure 15C illustrates a partial cross-sectional bottom view of the plate 5103 of the ophthalmic device 594. The plate 5103 appears in Figure 15C with an optional pocket 620 and protrusion 3103, which is torus-like and segmented (see Figure 22B). The pocket 620 opens into the posterior surface 3303 of the plate 5103 and is positioned such that when it is in the eye, the pocket is adjacent to the sclera and is offset from the surface of the sclera by the protrusion 3103.

[0245] 16A and 16B illustrate an ophthalmic device 593. In the ophthalmic device 593, the elongated support member 301 and flexible connector are curved around points 472 and 482 and connect to plates 5114 and 5214, which connect to plates 531 and 551, respectively.

[0246] 16A is a front view of an ophthalmic device 593. In the ophthalmic device 593, there are four plates 5114, 531, 551, and 5214. Plates 531 and 551 have pockets 631 and 651, respectively. Plate 5114 is connected to the elongated support member 301 by a flexible connector 471 and to plate 531 by a plate connector 432. Similarly, plate 5214 is connected to the elongated support member 301 by a flexible connector 481 and to plate 551 by a plate connector 452.

[0247] Flexible connectors 471 and 481 connect to elongated support member 301, curve around points 472 and 482, and connect to plates 5114 and 5214. The flexible connectors are configured to be positioned more distally, toward the canthus, when inserted into a user's eye, while plates 531 and 551 are configured to be more central within the ocular anatomy.

[0248] Alternatively, the connections of plates 551, 5214, 5114, and 531 in FIG. 16A may be realized by supports 452 / 481 / 301 / 471 / 432 that are embedded in the plates or travel through the plates as shown in FIG. 16A.

[0249] Figure 16B is a top view of the ophthalmic device 593 shown in Figure 16A rotated 180 degrees and showing the link between plate 5114 and plate 531 by connector 432, and the link between plate 5214 and plate 551 by connector 452. As shown in Figure 16B, connectors 432 and 452 may be offset from posterior surfaces 3114, 3214, 331, and 351 to reduce constraints on movement of plate connectors 432 and 452 that may be caused by anatomical surfaces of the eye.

[0250] 17A and 17B illustrate an ophthalmic device 592. FIG. 17A illustrates a front view of the ophthalmic device 592, and FIG. 17B illustrates a rear view of the ophthalmic device 592. The ophthalmic device 592 is more compact than the ophthalmic devices 597 and 587 shown in FIGS. 12A and 12B. In the ophthalmic device 592, each plate is connected to the elongated support member 301 without an intervening plate.

[0251] FIG. 17B shows that flexible connectors 471 and 481 also curve around points 472 and 482, forming an outer angle 130. The outer angle 130 is an obtuse angle. Further flexibility in providing a device that is accommodating to a particular user can be achieved by providing the device with an obtuse angle, an acute angle, or a combination of obtuse and acute angles. Additional options are also available in the angle formed at the connection between each plate of the ophthalmic device disclosed herein and the elongate support member in each disclosed ophthalmic device. For example, in FIG. 11A , the angle formed between flexible connector 431 and the elongate support member 301 to the left of the flexible connector is an obtuse angle. In a particular device, the angles at which the plate and flexible connector connect to the elongate support member can be the same or different.

[0252] 18A, 18B, and 18C illustrate an ophthalmic device 591. FIG. 18A is a front view of the ophthalmic device. The ophthalmic device 591 can be oriented with the rear or front of the plate facing the sclera. The protrusions on the plate of the ophthalmic device 591 can engage and accommodate curved surfaces of the sclera and eyelids, regardless of curvature, direction, or size. Flexibility regarding the orientation for placement of the ophthalmic device 591 results in simplified user instructions and user training.

[0253] Figure 18B is a top view of the ophthalmic device 591 of Figure 18A. It can be appreciated from Figures 18A and 18B that each feature of the ophthalmic device 592 is freely translatable horizontally and vertically and can be rotated to fit the anatomy of the eye upon insertion, and each plate and protrusion is freely orientationally adaptable, providing a device that can be inserted in either orientation.

[0254] Figure 18C is a top view of the ophthalmic device 591 of Figure 18A with the top portions of the plates cut away. The device is shown twisted around arch 303, deviating the plates from the midline of the device, with plates 511 and 531 twisted opposite plates 551 and 521, simultaneously illustrating the anterior and posterior sides of the plates. Plates 511, 531, 551, and 521 have protrusions 311, 331, 351, and 321, and "posterior surfaces" 312, 332, 352, and 322. Plates 531 and 551 have pockets 631 and 651, respectively. "Posterior surfaces" appear in quotation marks because 312, 332, 352, and 322 appear on both sides of each plate, emphasizing that the ophthalmic device 591 can be inserted into the eye in either orientation.

[0255] 19A to 19H illustrate an ophthalmic device 800 and illustrate isolated views of features of the ophthalmic device 800. The ophthalmic device 800 has a large volume and can be inserted under the eyelid.

[0256] 19A, 19B, and 19C are front, top, and back views, respectively, of the ophthalmic device 800. The successive views illustrate the device as it is rotated about the support member in 90° rotational increments toward the viewer while maintaining a left-to-right orientation.

[0257] As can be seen in Figures 19A and 19C, the elongated support member 801 is segmented with variable cross sections from a central arch. The design of the ophthalmic device 800 allows for material flow distribution, which may be advantageous for a thermoplastic injection molding manufacturing process. It can be seen from Figures 19A-19C that the ophthalmic device 800 incorporates and accommodates features that are more fully described with reference to other ophthalmic devices illustrated herein. The ophthalmic device 800 allows for predictable adjustment of features and connectivity to accommodate a multitude of polymer compositions, each with its own process and thermal dimensional characteristics.

[0258] The pocket in the plate presents a large volume cylindrical pocket for the drug or drug-containing insert, which is assembled by snap-in mechanical assembly, compatible with well-known tablet manufacturing techniques. An additional sealing membrane, as previously exemplified, may be applied. The insert dimensions provide a pocket with a large volume, advantageously providing a high drug weight to carrier weight ratio.

[0259] 19C, plates 812, 822, 832, 842, 852, and 862 are arranged and generally extend from canthus to canthus. Protrusions 813, 823, 833, 843, 853, and 863 are present on plates 812, 822, 832, 842, 852, and 862, respectively, and have convex contact surfaces for contacting the sclera of the eye, providing an offset space between the sclera and the posterior surfaces of the plates.

[0260] Flexible connectors 810, 820, 830, 840, 850, and 860 connect the plates to elongated support member 801 (FIGS. 19A and 19C). Plates 812, 822, 832, 842, 852, and 862, which are flexibly connected along elongated support member 801, further include features 811, 821, 831, 841, 851, and 861, which are material on the anterior side of the plates that protrude toward and contact the eyelid.

[0261] 19D, 19E, 19F, and 19H are cross-sectional views of the device of FIG. 19A along lines AA, BB, CC, and DD, respectively.

[0262] As illustrated in FIG. 19D, plate 811 includes a posterior surface 812 and a protrusion 813, which has a convex contact surface for contacting the sclera of the eye and provides an offset space between the posterior surface and the sclera.

[0263] FIG. 19E illustrates plate 831 and flexible connector 830, with plate 831 cut open to reveal posterior surface 832 and protrusion 833, with an offset space between the sclera and posterior surface 832 of plate 831.

[0264] Figure 19F illustrates plate 851, which includes pocket 871 and retaining elements 875, 876, and 877 that can hold an insert. Pocket 871 is an example of a pocket that can receive a cylindrically shaped insert, which can have, for example, a radius 875 and a width (not shown) that is pressed by retaining lips 876 to reside and secure within plate 851. The distance between retaining lips 876 provides an orifice to pocket 871 (shown in cross-section in Figures 19F and 19H and in front view in Figure 19A).

[0265] FIG. 19G is an isometric view of a portion of the ophthalmic device 800 of FIG. 19, with the plate cut away to reveal the pocket therein. FIG. 19G illustrates an alternative pocket, demonstrating optional eyelid and optional scleral controllable drug delivery ports. FIG. 19G shows further variations in pocket arrangements within the ophthalmic device 800. Cutaways of the elongate support member 801, plates 811, 831, and plate 851 (with a modified drug insert pocket 871) can be seen in FIG. 19G. Pockets may be designed for drug delivery in more than one direction (e.g., a plate providing bidirectional delivery of medication). For example, the pocket 871 shown in FIG. 19G has the features shown in FIG. 19F with the addition of an orifice 878 through plate 851, providing a secondary delivery pathway for medication directly to the sclera through the orifice 878.

[0266] FIG. 19H shows a plate 861 with a pocket 881 and a transverse width 889. A cylindrical or rod-shaped insert holding a larger volume can be inserted transversely to the plate 861. The cylindrical or rod-shaped insert can be made with a larger volume of drug or other material to be delivered to the eye. The pocket can be of any geometric configuration that secures the insert and exposes at least a portion of the insert's surface to tear fluid. Geometric features of the ophthalmic device can be used, among other things, to retain the insert within the pocket of the ophthalmic device. By way of example and not limitation, the insert can be retained within the pocket of the ophthalmic device 800 by features 876 shown in FIGS. 19F and 19G.

[0267] Figure 191 is an isometric view of an example of a drug insert (or inserts) that may be inserted into an ophthalmic device (including the ophthalmic devices of Figures 19A-19H). The insert in Figure 191 is rod-shaped, which is one example and not a limitation on the shape or size of an insert to be inserted into ophthalmic device 800 or other ophthalmic devices.

[0268] 20A through 20G show examples of pocket orientations for drug inserts, which are shown generally along a transverse (horizontal) plane to illustrate the pocket features. This illustration is not a limiting or restrictive "orientation" of any drug insert pocket. As an alternative, non-exhaustive example, it may be compatible with manufacturing and processing methods for the pocket to be aligned with or perpendicular to the flexible connectors.

[0269] Figure 20A is a front view of an ophthalmic device 1008. In addition to the ophthalmic device features previously described (which may also be seen in Figure 20A), the ophthalmic device 1008 includes support curves 1301 and 1304, which are separated from one another. It should be appreciated that the pockets 1631 and 1651 in the plates 1531 and 1551 may be transverse, as shown, or may be otherwise oriented.

[0270] A horizontal surface 1302 extends inside the arch 1303 and provides an anchor around which other features can exercise their degrees of freedom. The horizontal surface 1302 also provides a mounting location for manufacturing aids. See FIG. 6B and the above discussion of the underside 302 of the arch 303.

[0271] Figure 20B is a cross-sectional view of the ophthalmic device of Figure 20A taken along line BB, and Figure 20C is a cross-sectional view of the ophthalmic device of Figure 20A taken along line AA. The ophthalmic device 1008 has plates 1511, 1531, 1551, and 1521, which are further described, for example, in the discussion of Figure 20C. The protrusions 1311 and 1331 shown in Figure 20B are similar to features further shown and described, for example, in the discussion of Figures 21A through 21L. The pocket 1631 is similar to the pocket further shown and described, for example, in Figures 19A through 19H.

[0272] FIG. 20C shows a cross section of the plate 1531 with the posterior surface 1332 facing right. As can be seen in FIG. 20C, the pocket 1631 in the plate 1531 has an oval peripheral cross section of the surface 1871. The pocket 1631 can securely capture the insert and provide sufficient “side gaps” and “end gaps” for tear fluid access to the surface of the insert within the pocket. The retention lip 1876 shown in FIG. 20C need not be a continuous feature across its span 1889 as shown in FIG. 20B. Rather, the retention lip 1876 can be of one or more “finger-like” geometries (with material relief within and between them) that allow for the passage of tear fluid into the well 1631 and that contact the insert surface 1900 when the insert resides in the ophthalmic device 1008. The insert 1900 is shown in FIG. 20C in dotted lines within the pocket 1631. The insert 1900 fits within the pocket 1631, which has an oval cross section. An exemplary insert length that is compatible with the span 1889 of the pocket 1631 is shown in Figure 20B.

[0273] The pockets in the plates may have tear fluid transport capabilities in two or more different directions, as described above with reference to the orifices or holes 072 on the plate 541 in Figure 10A. Similarly, the plates of the ophthalmic device 1008 shown in Figures 20A, 20B, and 20C may include holes, orifices, or slits to allow medication to exit the pockets in the plates from the scleral side and to provide a tear pathway from the scleral side of the plate into the pockets.

[0274] It should also be appreciated that the plate may include one or more snap-in features that may mechanically retain the insert.

[0275] It should also be understood that the pocket 1631 can be any useful shape capable of capturing and holding an insert.

[0276] FIG. 20D is a simplified front view of the ophthalmic device of FIG. 20A, where the pockets are not visible in the plate.

[0277] FIG. 20E is an ophthalmic device as shown in FIG. 20D, with shading added to show the open space 250 within the periphery of the ophthalmic device, which is bounded by the eyelid.

[0278] Figure 20F is a view of the open space of Figure 20E with the ocular device removed. When the ocular device 1008 is inserted into the eye, tear fluid is allowed to fill the open space 250.

[0279] Figure 20G is a front view (at a 45 degree angle) of the open space 250 of Figure 20F. When in the eye, the eyelids drape over the device and define the open space 250. See, for example, Figures 7A, 7B, and 7C.

[0280] In the ophthalmic device, each plate with a pocket can contain an insert with a different pharmaceutically active agent. For example, two pockets with two different pharmaceutically active agents can be present in a single device. One pocket can have an insert with more than one active agent.

[0281] Human eye compatibility and comfort

[0282] It is advantageous for an ophthalmic device to be compatible with the anatomy of the human eye and for users to find the ophthalmic device comfortable. The following list provides features that can increase the compatibility and comfort of an ophthalmic device. This list is not a limitation on the ophthalmic devices disclosed herein. Positioning under the eyelid. Anchoring the stabilization geometry adjacent to the canthus maintains eyelid position and centration. Minimal contact with the sclera to reduce the effects of saccadic eye movements. Enhanced tear fluid volume retention and tear residence time for user comfort and consistent drug delivery into the ocular anatomy. Optical quality polished surface to expand surface area, enhance tear fluid flow, and reduce the coefficient of friction for eye movements. · Self-adaptability to various scleral and eyelid anatomies and local anatomical variations. · Total flexibility in therapeutic insert size, technique, composition and location. · Minimal ocular footprint configuration compatible with minimal measurements of ocular physiology. · Wide range of anatomical conjunctival sac widths: fitting, configuration, and design capabilities. Eye-friendly hydrophilic carrier construction material composition for patient comfort.

[0283] 21A through 21L illustrate examples of plates and protrusions in various configurations that can be or be used in ophthalmic devices.

[0284] FIG. 21A is a perspective view of an exemplary plate 911 including a rear surface 912 with a toroidal protrusion 913, which in this example forms a complete annulus.

[0285] FIG. 21B is a perspective view of an exemplary plate 921 including a rear surface 922 that includes a protrusion 923, which in this example is an open segment of a torus.

[0286] FIG. 21C is a perspective view of an exemplary plate 931 including a rear surface 932 that includes a single dome-shaped protrusion 933 that is positioned off-center relative to the center of the plate 932. A close-up of the small off-center protrusion 933 is shown in FIG. 21D. FIG. 21C serves to illustrate that the plate 931 can form a dome-shaped curved surface 934 that protrudes in a direction opposite to that of the protrusion 933. As can be seen in FIGS. 21A, 21B, and 21F, plates 911, 921, and 941 similarly form dome-shaped curved surfaces.

[0287] As illustrated by plate 941 in Figure 21E, a plate can include a plurality of protrusions 943. As shown in Figure 21E, the plurality of protrusions 943 can be arranged around a periphery of a rear surface 942. The front surface of plate 941 forms a dome-shaped curved surface 944 on the other side of the plate from the rear surface 942. As further illustrated in Figure 21F, which is a cross-sectional view of plate 941 in Figure 21E, each protrusion 943 has a contact surface.

[0288] FIG. 21G is a perspective view of an exemplary plate 951 that includes a rear surface 952 having a protrusion 953 with a contact surface 955 .

[0289] 21H is a left-side cross-sectional view of plate 951 of FIG. 21G (as viewed along line 128 in FIG. 21G) and a cutaway view of sclera 102, showing contact between contact surface 955 of protrusion 953 and sclera 102. Plate 951 includes an anterior surface 954 on the other side of the plate from posterior surface 952. When plate 951 is placed under the eyelid, contact surface 955 contacts sclera 102 and anterior surface 954 contacts the eyelid (not shown).

[0290] FIG. 21I is a perspective view of an exemplary plate 961 that includes a rear surface 962 having a protrusion 963 with a contact surface 965 .

[0291] 21J is a left-side cross-sectional view of the plate 961 of FIG. 21I (as viewed along line 128 in FIG. 21I) and a cutaway view of the sclera 102, showing the contact between the contact surface 965 of the protrusion 963 and the sclera 102. The plate includes an anterior surface 964 on the other side of the plate from the posterior surface 962. When the plate 961 is placed under the eyelid, the contact surface 965 contacts the sclera 102 and the anterior surface 964 contacts the eyelid (not shown).

[0292] FIG. 21K is a perspective view of an exemplary plate 971, which includes a rear surface 972 having a protrusion 973 with a contact surface 975, which is a combination of a curved surface 975A, a generally planar surface 975B, and a curved surface 975C.

[0293] 21L is a left-side cross-sectional view of plate 971 of FIG. 21K (as viewed along line 128 in FIG. 21K) and a cutaway view of sclera 102. FIG. 21K shows contact between contact surface 975 and sclera 102. It should be appreciated that at any time, any of 975A, 975B, and 975C of contact surface 975 can be in contact with sclera 102.

[0294] 21L further shows, on the other side of the plate from the posterior surface 972, an anterior surface 974 having a protrusion 976 with a contact surface 977, which is a combination of 977A, 977B, and 977C. As shown in FIG. 21L, the protrusion 977 is in contact with the eyelid 118, which has an eyelid drape 018. Although not shown in FIG. 21K or 21L, it should be understood that the plate 971 can be placed under the eyelid 118 with the anterior surface 974 facing the sclera 102, in which case the contact surface 977 of the protrusion 976 would be in contact with the sclera 102. It should also be understood that when the plate 971 is placed under the eyelid 118 with the posterior surface 972 facing the sclera 102, it can rotate or move around so that the anterior surface 974 is directed toward the sclera 102. Thus, the plate 971 with the protrusions 973 and 976 can be placed under the eyelid with the posterior or anterior surface facing the sclera 102. This is the case either when the plate 971 is placed under the eyelid as a standalone ophthalmic device, or when the plate 971 is part of an ophthalmic device with other features (e.g., an elongated support member, etc.), and the ophthalmic device (of which the plate 971 is a part) is placed under the eyelid.

[0295] The illustrations and descriptions of the plates and protrusions are provided by way of example and not by way of limitation.

[0296] 21A-21L illustrate various plate shapes with protrusions arranged as shown. The plate shapes and protrusion arrangements are not limiting, and other shapes and arrangements are contemplated. By way of further example, but not limitation, FIGS. 22A-22E illustrate additional plate shapes and protrusion arrangements.

[0297] FIG. 22A is a front view of an adaptable, non-directional ophthalmic device 1000 without a central "arch" according to another example of an ophthalmic device. The ophthalmic device 1000 includes two interlocking elements 1011 and 1021 connected to an elongated support member 1001. As demonstrated by the ophthalmic device of FIG. 22A, the arch (shown in other ophthalmic devices) need not be present. The ophthalmic device 1000 (which does not have an arch) can be inserted under the eyelid to deliver drugs to the eye. The ophthalmic device shown in FIG. 22A illustrates an angular rotation extension of the elongated support member 1001 to connect to a plate 1021 at an angle 132 greater than 180 degrees, illustrating further flexibility of the ophthalmic devices disclosed herein.

[0298] 22B-22E illustrate examples of sclera-interacting convex features (e.g., protrusions) that may be used with embodiments of the present invention, the protrusions providing a convex contact surface for contacting the sclera of the eye.

[0299] FIG. 22B illustrates the plate 1011 of FIG. 22A, which includes a rear surface 1030 with protrusions 1010 and 1013 having convex contact surfaces formed by two segments of a torus.

[0300] FIG. 22C illustrates an exemplary plate 1021 that includes a rear surface 1030 with protrusions 1013 , 1023 having convex contact surfaces formed by two domes 1023 and torus segment 1013 .

[0301] FIG. 22D illustrates an exemplary plate 1031 that includes a rear surface 1030 with protrusions 1023, 1033, 1043 having convex contact surfaces formed by the combination of dome 1023 and torus swept segments 1033, 1043.

[0302] Figure 22E is a cross-sectional view of plate 1031 of Figure 22D. Dome-shaped protrusion 1023 is shown in cross-section. The anterior surface shown in Figure 22E (which is on the opposite side of the plate from the posterior surface) can follow the planar curve 300 shown in Figure 5B. The eyelid can be draped over the surface of the plate that is shaped to follow the planar curve 300.

[0303] 23A illustrates features of a front view and FIG. 23B illustrates features of a back view of an ophthalmic device 1201 for placement under an eyelid, which are provided to illustrate embodiments of the disclosed ophthalmic device. As shown in FIG. 23A, the ophthalmic device 1201 includes an elongated support member 3015 of flexible material configured to be positioned under an eyelid (not shown) of an eye, and plates 5105, 5205 connected proximate respective ends of the support member 3015 and substantially flush with the support member. As shown in FIG. 23B, each plate 5105, 5205 includes a posterior surface 3125, 3225 having at least one protrusion 3115, 3215 having a convex contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface 3125, 3225 of the plate 5105, 5205.

[0304] 23C is a front view and FIG. 23D is a rear view of an ophthalmic device 1203 for placement under an eyelid, which are provided to illustrate embodiments of the disclosed ophthalmic device. As shown in FIG. 23C, the ophthalmic device 1203 includes an elongated support member 3017 of a flexible material configured to be positioned under an eyelid (not shown) of the eye, and plates 5107, 5207 connected proximate to respective ends of the elongated support member 3017 and substantially flush with the support member. As shown in FIG. 23D, each plate 5107, 5207 includes a posterior surface 3127, 3227, the posterior surface having at least one protrusion 3117, 3217, the at least one protrusion 3117, 3217 having a convex contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface 3127, 3227 of the plate 5107, 5207, the at least one protrusion 3117, 3217 being toroidal.

[0305] 23E is a front view and FIG. 23F is a rear view of an ophthalmic device 1202 for placement under the eyelid, which is provided as a further example of an ophthalmic device. As shown in FIG. 23E, the ophthalmic device 1202 includes an elongated support member 3016 of a flexible material configured to be positioned under the eyelid of the eye and at least one plate 5106 connected to the support member 3016. As shown in FIG. 23F, the plate 5106 includes a posterior surface 3126 having at least one protrusion 3116 having a convex contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface 3126 of the plate 5106.

[0306] FIG. 23G is a front view and FIG. 23H is a rear view of the ophthalmic device 1204. FIG. 23I is a cross-section of FIG. 23H illustrating the plate anterior convex protrusion surface 9348 (also seen in FIG. 23G). The protrusion 9348 is a further example of a convex anterior surface discussed above with respect to the example of FIG. 21F (cross-section of FIG. 21E). As discussed, FIG. 21F provides an illustration of the anterior surface of an example plate comprising a posterior surface 942, a protrusion 943 projecting from the posterior surface 942, and an anterior surface with a convex shape 944. FIG. 23I is a cross-section along AA of the plate 5108 of the ophthalmic device 1204 of FIG. 23H, which is provided to illustrate a further example of the disclosed ophthalmic devices.

[0307] As shown in FIG. 23G , the ophthalmic device 1204 includes an ophthalmic device for placement under the eyelid, the ophthalmic device including an elongated support member 3018 of a flexible material configured to be positioned under the eyelid of the eye, and at least one plate 5108 connected to the support member 3018. As shown in FIG. 23H , the plate 5108 includes a posterior surface 3128 having at least one protrusion 3118, the protrusion 3118 having a convex contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface 3128 of the plate 5108. The protrusion 3118 of the ophthalmic device 1204 is toroidal. As can be seen in FIG. 23G , the protrusion 3118 has a surface 9348 on the anterior side of the plate 5108, which surface 9348 can contact the eyelid when the ophthalmic device 1204 is in the eye.

[0308] 23G and 23I (a cross-sectional view of FIG. 23H), the posterior protrusion toroidal scleral convex contact surface 3118 of FIG. 23H includes an anterior convex protrusion eyelid contact surface 9348 (also seen in FIG. 23G), which is a toroidal protrusion that protrudes toward the anterior side of 1204 where the eyelid resides.

[0309] Plate 5108 is not constrained by the protrusion geometry perimeters of 3118, 9348, and the posterior surface 3128 of plate 5108 does not completely occlude the posterior protrusion geometry features of 3118 and the anterior protrusion geometry features of 9348, resulting in a material-free area (also referred to herein as open space), which is bounded posteriorly and anteriorly by the sclera and eyelid, respectively, and resides within the combined maximum perimeter of plate 5108 and the posteriorly-facing protrusion geometry 3118. The posterior surface 3128 of plate 5108 and the inner eyelid surface proximate the material-free area may be defined as the scleral surface and the surface remote from protrusion 3118, respectively. The resulting tear fluid volume engaging the device is substantial compared to other under-lid devices in the art.

[0310] Surface 3128 is at a different sclera offset height than the eyelid as defined by protrusion 3118. The eyelid is the surface furthest from the sclera.

[0311] Figures 24A, 24B, and 24C illustrate an ophthalmic device 3592. Figure 24A is a front view of the ophthalmic device 3592, Figure 24B is a rear view of the ophthalmic device 3592, and Figure 24C is a cross-sectional view of the ophthalmic device of Figure 24A along line AA.

[0312] To facilitate orientation of the ocular device 3592 in the eye with the posterior or anterior surface of the plate facing the sclera, plates 3511 and 3521 have protrusions 3311 on both the posterior and anterior surfaces, and plates 3531 and 3551 have protrusions 3331 on both the posterior and anterior surfaces.

[0313] As can be seen in Figures 24A and 24C, plates 3531 and 3551 have pockets 3631 and 3651 that are open on both the anterior and posterior surfaces. Ophthalmic device 3592 illustrates the possibility that an ophthalmic device can be made with polygonal (e.g., hexagonal) holes or openings into the pockets of the plates, and the openings can be of different sizes. As can be seen in Figure 24C, the insert can be held in the plate by a retaining lip 3332.

[0314] Figure 24D is an isometric view of an example of a drug insert (or inserts) that may be inserted into an ophthalmic device (including the ophthalmic devices shown in Figures 24A-24C). It should be understood that a round insert 9100 is shown as an example to illustrate that an insert having that shape may be inserted into a hexagonal opening into pocket 3631 or 3651 with a point of contact between the round insert and the hexagonal opening into the pocket. Inserts of any shape may be made and inserted into the pockets of the plates of an ophthalmic device.

[0315] The ophthalmic device may be inserted into the eye by a user. The user may have a mechanism for storing and delivering the device for insertion into the eye. The ophthalmic device may be used with or without such a mechanism, and is not limited to use with such a mechanism.

[0316] case

[0317] Disclosed herein is a case that can be used as a mechanism for storing and delivering an ophthalmic device for insertion into an eye. The case allows a user to remove an ophthalmic device, as delivered by the case, for gripping and ease of insertion into the eye. Described is a case for holding and dispensing (typically by a person's fingers) an ophthalmic device to be inserted and removed for insertion into a user's eye. The person can be the user or another person (e.g., a doctor, other eye care professional, or caregiver). The case presents the ophthalmic device to be grasped by the fingers with the ophthalmic device oriented in the correct three-dimensional orientation relative to the user for placement in the user's eye. The case and its components can have tactile features that allow a visually impaired person to determine or confirm the orientation of the ophthalmic device for placement in the eye, remove the ophthalmic device from the case, and insert the ophthalmic device knowing its orientation.

[0318] The case may provide a port for introducing a fluid to coat the ophthalmic device within the case, and gas (including air) may pass through the port. The fluid may be introduced without manipulating features of the case or the ophthalmic device within the case.

[0319] The case can dispense the ophthalmic device from either of two sides of the case and maintain the orientation of the ophthalmic device. For example, the case can have a receiver with channels that are open on two sides of the receiver, and the channels are configured to allow the ophthalmic device to be dispensed from either of the two sides of the receiver without changing the orientation of the ophthalmic device. As a result, the ophthalmic device can be removed from the device using the fingers of the left or right hand without having to reorient the case or reposition the ophthalmic device when removed from the case.

[0320] The case may be constructed from a thermoplastic material (eg, a polypropylene thermoplastic material).

[0321] FIG. 25A is a perspective view of case 900, with case 900 in an open position. Case 900 includes well 901. Well 901 is configured to hold a fluid therein, which is shown in FIG. 25A as interior space 902. Well 901 is shown in FIG. 25A with an elongated oval shape. It should be appreciated that the well can have a different shape than that shown in FIG. 25A, depending on the shape of the ophthalmic device to be held therein, the needs of the user, and the desired shape of case 900. As shown in FIG. 25A, well 901 has an open top.

[0322] The case may be formed as a single piece of material. The case may be made from a thermoplastic or thermosetting polymer that demonstrates an ASTM D638 ISO 527-1 Tensile Test Method Elongation Percentage (%) at Yield in the range of approximately 6% to 250%. The features of the case may be interconnected. Each feature of the case may serve a different function. By way of example and not limitation, one or more features of the case, or the entire case, may be made from a polypropylene thermoplastic material.

[0323] The case can be manufactured using a relatively low cost injection molding process.

[0324] The well 901 is connected to the stabilizer 904 at a joint 905. The well 901 may be connected perpendicularly to the side of the stabilizer 904 at the joint 905. The connection between the well 901 and the side of the stabilizer 904 at the joint 905 may be realized in many ways and is not limited to the connection shown in Figure 25A. As shown in Figure 25A, the stabilizer 904 forms a ring surrounding the well 901, and the well 901 protrudes into the inside of the ring so that the well 901 is surrounded and protected by the stabilizer 904.

[0325] The stabilizer 904 provides a place to grip the case 900. When dispensing the ophthalmic device, the case may be secured to a substantially flat surface by, for example, placing a hand, a portion of a hand, or a finger on the stabilizer 904. The stabilizer 904 can stabilize the case 900 on a substantially flat surface, for example, by preventing the case from tipping over. The stabilizer 904 can include features that visually, tactilely, or otherwise indicate the orientation of the case relative to the user of the ophthalmic device that will be dispensed from the case. For example, the stabilizer can be labeled with words, Braille, or colors, alone or in combination, to convey the message "Place facing user."

[0326] Case 900 includes a lid 906. The lid 906 is connected to the well 901 and is rotatable between a position covering the open top of the well, such that the case is closed, and a position in which the well is uncovered, such that the case is open. The connection between the lid 906 and the well 901 can be a hinge. The hinge can be a living hinge, in which the material connecting the well 901 and the lid 906 is a single manufactured part that can flex back and forth. It should be understood that the case lid 906 and well 901 can be connected directly or by an intervening material (e.g., including a portion of the stabilizer 904).

[0327] As shown in FIG. 25A , the lid 906 is a planar lid with a top and a bottom. Lids for use in cases for ophthalmic devices can be constructed of any combination of geometric shapes, provided that the lid can cover the top of the well when in a position covering the open top of the well. As shown in FIG. 25A , the lid 906 is generally constructed of two planar rectangles, which are of different dimensions to allow for easier identification and manipulation. The elongated planar rectangle (close to the joint 905) can cover the open top of the well 901. When in a position covering the top of the well (see FIG. 25B ), the planar rectangle distal to the joint 905 extends beyond the well 901, allowing a user to use the remote planar rectangle to remove the lid 906 from the top of the well 901 and rotate the lid about the joint 905.

[0328] The case may further include a fastener for removably securing the lid 906 in a position covering the open top of the well 901. The fastener may be, for example, a latch or a lock. As shown in FIG. 25A , the case includes a latch 907 / 903, which includes a key 907 on the lid and a post 903 on a protrusion extending from the well 903. The key 907 is shown in FIG. 25A as a gap in the lid 906. The key 907 is shaped to allow engagement with the post 903, removably securing the lid 906 in a position covering the open top of the well 901. As shown in FIG. 25A , the post 903 is positioned on the protrusion from the well 901 at the opposite end of the well from the joint 905. The post 903 extends perpendicularly from the protrusion extending from the well 901. The post 903 may be cylindrical. It should be understood that the fastener can be a latch, anchor, or other device that removably secures the lid to the well. Also, the fastener can be a friction fit between the lid and the well, or a friction fit of features on the lid or the well, or both. It should further be understood that the fastener component can be or can be added to any part of the case.

[0329] The case may further include features for holding and dispensing an ocular device. As shown in FIG. 25A , the case has a receiver 908 that protrudes from the lid 906 and is configured to receive and hold an ocular device. The receiver 908 is positioned such that when the lid 906 is in the closed position, the receiver 908 is within the interior space 902 of the well 901, such that any fluid in the well (e.g., fluid transferred through the port 909) contacts the ocular device held within the receiver 908, allowing the ocular device to be submerged in the fluid. The receiver 908 may be adjacent to the port 909, such that when the lid is in the closed position, fluid entering the port 909 flows past the ocular device. There is a channel through the receiver 908 that opens on both sides of the receiver. The channel is configured to hold an ocular device and allow the ocular device to be dispensed from either of the two sides of the receiver without changing the orientation of the ocular device. As a result, the ocular device can be removed from the case using the fingers of a hand to pull the ocular device from the receiver without having to reorient the case or reposition the ocular device when removed from the case. Optionally, the pushing hand can be used to orient the ocular device toward the pulling hand when removing the ocular device with the pulling hand.

[0330] The channel in the receiver 908 can be of any three-dimensional shape capable of receiving an ophthalmic device. One side of the channel is defined by the top surface of the lid 906, and three sides are defined by the receiver. The channel is shown in Figure 25A as being open on two ends.

[0331] Figure 25B is a side view of the case 900 shown in Figure 25A cut longitudinally through the center of the case. The lid 906 is in position to cover the open top of the well, allowing the case to be closed. The ridges 910 (which can be seen in the cut-open receiver in Figure 25B) are restraining elements configured to hold an ophthalmic device. It should be understood that the restraining elements can be ridges or other elements configured to hold an ophthalmic device in a particular orientation or position and to allow for insertion and removal of the ophthalmic device. It should be understood that the receiver 908 can be any geometric shape that allows it to accept, hold, and dispense an ophthalmic device.

[0332] Figure 25C is a perspective view of the case shown in Figure 25A with the lid in the closed position. As shown in Figure 25C, post 903 is engaged with key 907, removably securing lid 906 in the closed position and preventing liquid from entering or exiting interior space 902 except through port 909 during operation of case 900. The latch can be any shape of post and key, provided that friction between post 903 and key 907 removably secures lid 906 in the closed position when lid 906 is in the closed position. The lid and well can include additional features to form a seal between the lid and well.

[0333] The lid 906 is shown in FIG. 25B with a port 909. The port 909 is a gap in the lid 906. When the lid 906 is in the closed position, the port 909 is in fluid communication with the interior space 902 of the well 901, allowing fluids (including liquids (e.g., solutions) and gases (e.g., air)) to enter or exit the interior space 902 of the well 901 through the port 909. By way of example, the port 909 allows a solution to be added to the interior space 902 of the well 901 of the case 900 without having to remove the lid 906 from the well 901 to expose the interior space 902 or any devices held within the case 900. The port 909 can be of sufficient length to allow the escape of gases (e.g., air) from the interior space 902 of the well 901 and the entry of liquids into the interior space 902 of the well 901. Liquids and gases can be exchanged simultaneously through the port 909.

[0334] FIG. 25D is a perspective view of the case shown in FIG. 25C, with a removable peel strip 911 covering the port in the lid. The peel strip seals the port 909 of the well 901. In FIG. 25D, a portion of the peel strip 911 (labeled 912 in FIG. 25D) protrudes away from the lid surface, allowing for removal of the peel strip and revealing the port. The peel strip may be made of a material that provides a biological barrier for sterilization of the chamber. When the lid is in the closed position and the peel strip is in place, a sealed chamber is formed in the well 901 within the interior space 902. It should be understood that any method may be used for sterilization of the sealed chamber, including, but not limited to, gamma radiation, electron beam, steam, autoclave, and ethylene oxide (ETO). When the peel strip is removed and the lid is in the closed position, fluid can be added to the case through the port and the fluid will flow past the ophthalmic device with the ophthalmic device inside.

[0335] The case 900 may include a removable peel strip 911 that covers the port 909. The removable peel strip 909 protects the interior space 902 and the contents of the receiver 908 from contamination and destruction. When a user requires access to the port 909, the removable peel strip 911 may be peeled from the lid 906. The removable peel strip 911 may include a tab 912 that is detached from the lid 906. The tab 912 allows for removal of the peel strip 911 by grasping and removing it. In addition to protecting the interior space 902, the peel strip resists tampering and provides a warning against possible tampering. Other tamper-evident devices and warnings (e.g., breakaway tape, etc.) may be applied to the case.

[0336] The ophthalmic device may be sterilized in a sealed chamber. It should be understood that any method may be used for sterilization of the ophthalmic device in a sealed chamber, including but not limited to gamma radiation, electron beam, steam, autoclave, and ethylene oxide (ETO).

[0337] Figure 26A is a perspective view of the case 1990 with the lid 1906 in an open position, holding an example ophthalmic device (labeled as 2126). It should be understood that the case 1990 is not limited to use with the particular ophthalmic device 2126 shown in Figure 26A. The receiver may include a channel that is open on at least one side of the receiver. As shown in Figure 26A, the channel in the receiver 1908 is open on two sides of the receiver.

[0338] Figure 26B is a perspective view of a closed case holding an example ophthalmic device (not shown), with port 1909 uncovered for introducing fluid past the ophthalmic device and into the well.

[0339] FIG. 26C is a perspective view of an open case holding an example ophthalmic device protruding from the side of the receiver distal to the well.

[0340] FIG. 26D is a perspective view of an open case holding an example ophthalmic device protruding from the receiver adjacent to the well.

[0341] FIG. 26A is a schematic diagram illustrating an exemplary embodiment of a case 1990 in an open position holding an exemplary embodiment of an ophthalmic device 2126, and FIG. 26B is a schematic diagram illustrating an exemplary embodiment of a case 1990 in a closed position holding an exemplary embodiment of an ophthalmic device 2126. The case 1990 is positioned on a substantially flat surface in front of a user with the surface of the ophthalmic device 2126 that will contact the sclera of the eye facing the user. An embodiment of the present invention enables the case 1990 to have the ophthalmic device 2126 held by the receiver 1908 in the interior space 1902 when the lid 1906 is in the closed position covering the well 1901, as shown in FIG. 26B. The post 1903 and key 1907 may be interconnected to secure the lid 1906 in the closed position. The case 1990 may be delivered to a user in the closed position shown in FIG. 26B with the ophthalmic device 2126 protected and held in a desired orientation. When the case 1990 is accepted by the user, the case 1990 is configured to allow the user to orient the ocular device 2126 in a particular orientation and / or position that facilitates proper insertion of the ocular device 2126.

[0342] A user can rotate the lid 1906 from a position covering the open top of the well to the open position shown in FIG. 26A . When the lid 1906 is in the open position, the receiver 1908 delivers the ocular device 2126 for insertion into the eye. It should be appreciated that the ocular device 2126 may require a specific orientation for proper ocular insertion, or a specific orientation may be preferred. The receiver 1908 may be configured to hold and present the ocular device 2126 in a specific orientation. When the case 1903 is placed on a table or other substantially flat surface, the orientation of the ocular device 2126 is determined by the orientation of the case 1990. As a result, controlling the orientation of the case 1990 determines and controls the orientation of the ocular device 2126. The case 1990 may be oriented relative to the user such that the ocular device 2126 is correctly oriented for insertion into the user's eye. With the case correctly oriented relative to the user, the lid 1906 is rotated to the open position to deliver the ocular device 2126, which is removed from the receiver 1908 and inserted into the user's eye, maintaining the orientation of the ocular device relative to the user.

[0343] 26C is a schematic diagram illustrating an exemplary embodiment of the case 1990 in the open position holding an exemplary embodiment of an ophthalmic device 2126 protruding from the receiver 1908 on the side of the receiver distal to the well, and FIG. 26D is a schematic diagram illustrating an exemplary embodiment of the case 1990 in the open position holding an exemplary embodiment of an ophthalmic device 2126 protruding from the receiver 1908 on the side of the receiver proximal to the well. The ophthalmic device 2126 can be removed from the receiver 1908 through either open side of the receiver 1908 as shown in FIGS. 26C and 26D. A user can use a pulling hand to grasp the protruding portion of the ophthalmic device 2126 from either the proximal or distal side. A user can also use a pushing hand to direct the protruding portion of the ophthalmic device 2126 toward the pulling hand. Because the ophthalmic device 2126 can be inserted or removed through either open side of the receiver 1908, the case 1990 can be held at multiple angles and the ophthalmic device can be accessed by either hand of the user. This allows the user to choose a preferred hand and grip when performing the delicate task of manipulating and / or inserting the ophthalmic device 2126.

[0344] The case 1990 may include tactile and visual features that allow the user to identify the orientation of the ophthalmic device 2126 without opening the lid 1906 of the case 1990 to expose the ophthalmic device 2126. The case 1990 may be larger than the ophthalmic device 2126, allowing the orientation to be apparent even when the orientation of the ophthalmic device itself is not apparent. The orientation of the case 1990 may be used to determine the orientation of the ophthalmic device 2126 instead of directly examining the ophthalmic device 2126, reducing the risk of misidentifying the orientation and misplacing the device due to incorrect orientation. The positioning of the case, stabilizer 1904, lid 1906, and / or receiver 1908 may visually, tactilely, or otherwise indicate the proper orientation of the ophthalmic device 2126 to the user.

[0345] As shown in Figures 26C and 26D, delivery of the ophthalmic device 2126 from both sides of the receiver allows removal of the device from either side of the case, with either hand pulling the device from the case. The device can optionally be pushed into the position shown in Figure 26C or 26D using a hand other than the hand used to pull the device.

[0346] FIG. 27A is a schematic diagram illustrating an exemplary embodiment of a kit, which includes a case 1990 for holding an ophthalmic device (not shown) and materials for administration to a user's eye. The kit includes the case 1990, materials for administration to a user's eye, and the ophthalmic device, contained in a bottle 2400. The materials for administration to the eye can be, for example, a wetting solution, a medicine, a drug, or a pharmaceutical. The kit can be combined with a sterilization pouch (not shown), which is configured to hold and protect the case 1990. The sterilization pouch can be comprised of a plastic cover attached to a biological barrier bottom film composition with a seal along all edges of the plastic cover. This peripheral seal can ensure that the case 1990 (and any contents therein) remain within the pouch during delivery and can serve as evidence that the sterility of the case 1990 has been maintained. The pouch seal can be configured to allow a user to tear open at least one edge to expose the case. By way of example, a commercially available Tyvek pouch may be used. The kit may also include a sealed case 1990 (see FIG. 25D) with a biological barrier (e.g., a peel strip) sealing the port, material for administration to the user's eye in a bottle 2400, and the ophthalmic device in the sealed case. The material for administration to the eye may be, for example, a wetting solution, a drug, a medication, or a pharmaceutical, or a combination of these materials.

[0347] FIG. 27B is a schematic diagram illustrating an exemplary embodiment of a kit in which a material is applied to an ophthalmic device in a case. In this particular example, a user pours liquid 2405 through port 1909. During this process, the case 1990 remains in a closed position, the ophthalmic device therein remains covered, and the port is in fluid communication with the inside of the well. The ophthalmic device in the case 1990 is submerged in liquid 2405 because the liquid 2405 flows through port 1909 and fills the well of the case 1990. Air escaping from the well case 1990 can also flow through port 1909. The ophthalmic device in the case 1990 is coated in liquid 2405.

[0348] Terms such as "convex," "torus," and "sphere" are communication tools to describe the attributes and interactions of the disclosed devices and ocular anatomical structures and to inform regarding surface interaction relationships, and are not meant to be limitations on the precise geometric form of the disclosed ophthalmic devices.

[0349] The pockets and drug inserts shown in the figures are meant to illustrate possible features for ease of explanation and are not intended to be limiting in any way.

[0350] It should be understood that the terminology describing geometric shapes and relationships should not be construed as mathematically describing any device or feature with mathematical precision.

[0351] Insert Compositions and Methods of Manufacture

[0352] In particular, any number of inserts can be placed into the ophthalmic devices described herein, provided that they are fabricated with a geometry that allows for placement within the ophthalmic device. Typically, the inserts include one or more pharmaceutically active agents and a pharmaceutically acceptable carrier. Using two or more pharmaceutically active agents can, for example, provide for the release of pharmaceutically active agents that can simultaneously treat two or more ocular conditions.

[0353] Thus, provided herein are compositions (e.g., pharmaceutical (e.g., ophthalmic) compositions or insert compositions) comprising one or more pharmaceutically active agents and a pharmaceutically acceptable carrier (e.g., an ophthalmically compatible carrier). In some embodiments, the pharmaceutically acceptable carrier forms a matrix, and the one or more pharmaceutically active agents are dispersed (e.g., uniformly dispersed) within the matrix. In some embodiments, the matrix comprises one or more polymers (e.g., a blend of two or more polymers, such as a water-soluble polymer and a water-insoluble polymer). Pharmaceutically active agents (e.g., for use within an insert in an ophthalmic device) can be of various compositions, structures, and properties, including, but not limited to, ciprofloxacin, dexamethasone, olopatadine, pilocarpine, hyaluronic acid, and hydroxypropyl cellulose, and pharmaceutically acceptable salts thereof. Pharmaceutically active agents can include agents needed for short-term, long-term, or both short-term and long-term ocular treatment. Examples of ocular conditions that may be beneficially treated using the devices and compositions described herein include dry eye, glaucoma, allergies, infections (e.g., bacterial, viral, and other infections), chronic inflammatory conditions (e.g., rosacea keratitis, cyclitis, and blepharitis), selected retinal conditions (e.g., diabetic retinopathy, age-related macular degeneration, and other retinal conditions), post-surgical, and amblyopia.

[0354] Classes of pharmaceutically active agents useful in treating the above-mentioned conditions include steroids, anti-inflammatory agents, antibiotics, compounds for treating glaucoma, antihistamines, dry eye medications, neuroprotective agents, retinoids, antineovascular agents, antioxidants, antimuscarinic drugs, and biologics. Examples of steroids include glucocorticoids, aprogestins, amineralocorticoids, and corticosteroids. Exemplary corticosteroids include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, triamcinolone, fluorometholone, dexamethasone, medrysone, betamethasone, loteprednol, fluocinolone, flumethasone, rimexolone, and mometasone. Other examples of steroids include androgens (e.g., testosterone, methyltestosterone, or danazol). Examples of anti-inflammatory agents include NSAIDs such as piroxicam, aspirin, salsalate (Amigesic), diflunisal (Dolobid), ibuprofen (Motrin), ketoprofen (Orudis), nabumetone (Relafen), piroxicam (Feldene), naproxen (Aleve, Naprosyn), diclofenac (Voltaren), indomethacin (Indocin), sulindac (Clinoril), tolmetin (Tolectin), etodolac (Lodine), ketorolac (Toradol), oxaprozin (Daypro), and celecoxib (Celebrex). Examples of antibiotics include amoxicillin, penicillin, sulfa drugs, erythromycin, streptomycin, tetracycline, clarithromycin, terconazole, azithromycin, bacitracin, ciprofloxacin, evofloxacin, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, aminoglycosides, tobramycin, and gentamicin, as well as polymyxin B combinations (including polymyxin B / trimethoprim, polymyxin B / bacitracin, and polymyxin B / neomycin / gramicidin).Medicaments for treating glaucoma include beta-blockers such as timolol, betaxolol, levobetaxolol, and carteolol; miotics such as pilocarpine; carbonic anhydrase inhibitors such as brinzolamide and dorzolamide; prostaglandins such as travoprost, bimatoprost, and latanoprost; serotonergic agents; muscarinic agents; dopamine agonists; and adrenergic agonists such as apraclonidine and brimonidine, and prostaglandins or prostaglandin analogs such as latanoprost, bimatoprost, and travoprost. Antihistamines and mast cell stabilizers include olopatadine and epinastine; acute treatment antiallergen products include ketorolac tromethamine fumarate, ketotifen fumarate, loteprednol, epinastine HCl, emedastine fumarate, azelastine hydrochloride, olopatadine hydrochloride, and ketotifen fumarate; while chronic treatment antiallergen products include pemirolast potassium, nedocromil sodium, lodoxamide tromethamine, and cromolyn sodium. Antimuscarinic drugs include atropine, scopolamine, tropicamide, ipratropium bromide, and glycopyrrolate, which are used for myopia control. Anti-vascular agents include the biologics ranibizumab (Lucentis) and bevacizumab (Avastin). Amblyopia medications include anesthetics and cyclomodulators, such as atropine. Treatment of retinitis pigmentosa can be achieved with N-acetylcysteine, N-acetylcysteine ​​amide, and boretigene neparvovec. Dry eye medications include cyclosporine and lifitegrast, and ocular lubricants such as methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, polyethylene oxide, polyethylene glycol, and hyaluronic acid. Any of the foregoing agents can exist in free base form or as their pharmaceutically acceptable salts.

[0355] Other examples of pharmaceutically active agents include nerve growth factors (e.g., human nerve growth factor), platelet-derived growth factors, transforming growth factors, fibroblast growth factors (e.g., human fibroblast growth factor), growth hormones (e.g., human growth hormone), neurotrophin-3 growth factors, brain-derived neurotrophic factors, glial cell line-derived neurotrophic factors, platelet-activating factors (PAFs, e.g., PAF receptor agonists and / or antagonists), tumor angiogenesis factors, albumin, beta-lactoglobulin, bovine serum albumin, gamma-globulin, monoclonal immunoglobulins, and the like. Examples of pharmaceutically active agents include phospholipids, immunoglobulin G, ovalbumin, insulin, monoclonal antibodies (e.g., anti-hCG), alkaline phosphatase, tumor-associated antigens, catalase, ferritin, lactogen and variants thereof, anti-horseradish peroxidase, prolactin and variants thereof, macrophage inflammatory protein 3β, thrombospondin, trypsin, soybean trypsin inhibitor, DNA, high molecular weight reporter plasmids, RNA, heparin, lipopolysaccharide, GRGDSP peptide, and leuprolide, and pharmaceutically acceptable salts thereof. Pharmaceutically active agents (e.g., for use with EVA copolymers) are described in Non-Patent Document 4 and Non-Patent Document 5, the contents of which are incorporated herein by reference.

[0356] In some embodiments, the pharmaceutically active agent comprises an antiallergic and / or antihistamine compound, e.g., to prevent an allergic reaction to the ocular insert composition. In the compositions described herein, the antiallergic and antihistamine compounds are typically used in combination with another pharmaceutically active agent. Thus, in some embodiments, the composition comprises a first pharmaceutically active agent and a second pharmaceutically active agent, wherein the second pharmaceutically active agent is an antiallergic and / or antihistamine compound.

[0357] In some embodiments, the pharmaceutically active agent has a melting temperature greater than about 99° C. In some embodiments, the pharmaceutically active agent is water soluble. In some embodiments, the pharmaceutically active agent has a melting temperature greater than about 99° C. and is water soluble.

[0358] As used herein, "water soluble" means that 10,000 or fewer parts by volume per volume of aqueous medium (typically water, but sometimes a buffer) are required to dissolve one part by volume per volume of solute. Various levels of solubility are illustrated in the table below.

[0359] [Table 7]

[0360] In some embodiments, the pharmaceutically active agent is highly soluble, freely soluble, soluble, sparingly soluble, slightly soluble, or very slightly soluble in an aqueous medium (e.g., water). In some embodiments, the pharmaceutically active agent is highly soluble, freely soluble, or soluble in an aqueous medium (e.g., water).

[0361] In particular, when a pharmaceutically active agent is incorporated into a composition using hot melt blending as described herein, the pharmaceutically active agent will typically be in the form of microparticles and / or nanoparticles. Thus, in some embodiments, the pharmaceutically active agent is in the form of particles (e.g., microparticles, nanoparticles). In some embodiments, the pharmaceutically active agent has a melting temperature greater than about 99°C, is water soluble, and is in the form of particles.

[0362] Typically, the pharmaceutically active agent comprises from about 0.1% to about 99% by weight of the composition, e.g., from about 0.1% to about 75%, from about 0.1% to about 50%, from about 0.5% to about 50%, or from about 1% to about 40%.

[0363] By way of example, and not limitation, inserts that deliver pharmaceutically active agents are described in the following: U.S. Pat. No. 3,302,646 (Behney), U.S. Pat. No. 3,416,530 (Ness), U.S. Pat. No. 4,309,996 (Theeuwes), U.S. Pat. No. 6,071,266 (Kelley), U.S. Pat. No. 6,331,313 (Wong), U.S. Pat. No. 7,211,272 (Renner), U.S. Pat. No. 8,167,855 (Leahy), U.S. Pat. No. 8,287,504 (Leahy), U.S. Pat. No. 8,574,659 (Ashton), U.S. Pat. No. 8,679,078 (Leahy), U.S. Pat. No. 8,939,948 (de No. 9,421,126 (de Juan), U.S. Pat. No. 9,549,846 (Clauson), U.S. Pat. No. 9,750,636 (de Juan), U.S. Pat. No. 9,814,671 (Lee), U.S. Pat. No. 9,849,085 (Ashton), U.S. Pat. No. 9,931,306 (Barman), and U.S. Pat. No. 9,937,073 (de Juan), the teachings of which are incorporated herein by reference in their entireties.

[0364] As used herein, the term "pharmaceutically acceptable" refers to a species that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals without undue toxicity, irritation, allergic response, etc., and for which a reasonable benefit / risk ratio is warranted. For example, a substance is pharmaceutically acceptable if, in the amounts employed in a dosage form according to a dosing schedule, it is suitable for use in contact with animal or human cells, tissues, or organs without undue toxicity, irritation, allergic response, immunogenicity, or other adverse response, and for which a reasonable benefit / risk ratio is warranted.

[0365] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with mammalian tissues without undue toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Non-Patent Document 6 describes pharmaceutically acceptable salts in detail, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts include salts derived from suitable inorganic and organic acids and bases.

[0366] Examples of pharmaceutically acceptable acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, etc.), or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, etc.), or by using other methods used in the art (e.g., ion exchange, etc.). Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethanesulfonate, These include hydroxymaleate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 2-phenoxybenzoate, phenylacetate, 3-phenylpropionate, phosphate, pivalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts, etc. Either mono-, di-, or tri-acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form.

[0367] Salts derived from appropriate bases include those derived from inorganic bases (e.g., alkali metal, alkaline earth metal, and ammonium bases), and those derived from aliphatic, alicyclic, or aromatic organic amines (e.g., methylamine, trimethylamine, and picoline, or N +Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxyls, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0368] In one embodiment, the composition (e.g., a pharmaceutical composition (e.g., an ophthalmic composition, etc.)) comprises one or more pharmaceutically active agents and a water-insoluble polymer (e.g., EVA, according to any of the embodiments described herein). In some embodiments, the composition further comprises a water-soluble polymer (e.g., PEO, according to any of the embodiments described herein). In some embodiments, the water-insoluble polymer has a melting point of less than about 99°C, e.g., according to DSC ASTM D2417. In some embodiments, the water-soluble polymer has a melting point of less than about 99°C, e.g., according to DSC ASTM D2417. In some embodiments, the water-soluble polymer and the water-insoluble polymer, collectively, have a processing melting point of less than about 99°C, e.g., according to DSC ASTM D2417. Typically, in such embodiments, the water-insoluble polymer and the water-soluble polymer (if present) form a matrix, and the one or more pharmaceutically active agents are dispersed (e.g., uniformly dispersed) within the matrix.

[0369] Also provided herein is a matrix (e.g., for delivery of one or more pharmaceutically active agents) comprising a water-insoluble polymer (e.g., EVA, according to any of the embodiments described herein) and a water-soluble polymer (e.g., PEO, according to any of the embodiments described herein).

[0370] Without wishing to be bound by any particular theory, it is believed that the water-insoluble polymers described herein and in the composition matrix act as scaffolds to provide shape and stability to the composition. In addition, it is believed that the water-insoluble polymers can prevent the pharmaceutically active agent in the matrix from escaping from the matrix.

[0371] A non-limiting example of a water-insoluble polymer includes ethylene vinyl acetate (EVA). EVA is a copolymer of ethylene and vinyl acetate and can be represented by the following structural formula, which describes a block copolymer of EVA:

[0372] [ka]

[0373] where n and m represent the weight percent of ethylene and vinyl acetate, respectively, in the copolymer, and the sum of n and m is 100%. Typically, m is 25% or greater (e.g., 28%, 40%). In some embodiments, the EVA has a tensile elongation of 750% or greater, e.g., according to ASTM D638. In some embodiments, the EVA has a melt flow index of 6.0 g / 10 min or greater, e.g., according to ASTM D1238. In some embodiments, the EVA has a melting point of less than about 99°C, e.g., according to DSCAS™ D2417.

[0374] Typically, the weight percentage of the water-insoluble polymer in the composition is from about 5% to about 99%, from about 20% to about 99%, from about 20% to about 75%, from about 25% to about 75%, or from about 20% to about 50%.

[0375] It should be recognized that tear fluid is an aqueous liquid. Water-soluble polymers dissolve (at least partially) in aqueous fluids (e.g., tear fluid). Thus, upon exposure to aqueous fluids, water-soluble polymers present in the compositions described herein are expected to dissolve (at least partially) and thereby erode from the composition. Desirably, including a water-soluble polymer in the compositions described herein enhances the dissolution and erosion of the pharmaceutically active agent in the composition, causing the pharmaceutically active agent to erode faster than would occur if the water-soluble polymer were not present. The rate of delivery of each pharmaceutically active agent is a direct function of the solubility of the individual drug particles. Thus, each drug particle, whether alone or in an insert, will independently disperse each drug at its own rate. When a water-soluble polymer is present, it transports the pharmaceutically active agent dispersed therein. Thus, the rate of drug delivered per unit time can be greater and can be adjusted and / or controlled in manufacturing by adjusting the component relationships.

[0376] Non-limiting examples of water-soluble polymers include polyethylene oxide (Polyox or PEO), also known as polyethylene glycol (PEG). In some embodiments, the PEO has a molecular weight of about 100,000 to about 300,000 (e.g., about 100,000, about 200,000, about 300,000). In some embodiments, the PEO has a viscosity of about 10 CPS to about 20,000 CPS at about a 5 weight percent concentration in water at about 25°C (e.g., C=5% HO at 25°C). In some embodiments, about 96% to about 100% of the PEO is in the form of 20 mesh particles. In some embodiments, the PEO has a melting point less than about 99°C. While not wishing to be bound by any particular theory, it is believed that the presence of polyethylene oxide in the compositions or delivery matrices described herein (e.g., those for ocular administration) can reduce allergic reactions to the compositions in a subject (e.g., a patient). The elution of polyethylene oxide along with the pharmaceutically active agent can prevent protein adhesion, thus minimizing the chance of developing an allergic reaction. Polyethylene oxide can also provide lubrication to the eye.

[0377] Typically, the weight percentage of the water-soluble polymer in the composition (if present) is from about 1% to about 90%, e.g., from about 1% to about 75%, from about 1% to about 50%, from about 2.5% to about 85%, from about 5% to about 80%, from about 25% to about 80%, or from about 40% to about 75%.

[0378] The compositions and matrices described herein can be created by hot-melt blending the components of the composition or matrix to form a hot-melt blend. The hot-melt blend can then be shaped and / or cooled. The resulting shaped composition or matrix is ​​also referred to herein as an insert.

[0379] Accordingly, also provided herein are methods of making a composition (e.g., a pharmaceutical composition (e.g., an ophthalmic composition, etc.)) comprising hot-melt blending one or more pharmaceutically active agents and a pharmaceutically acceptable carrier (e.g., one or more polymers (e.g., two or more polymers; a water-insoluble polymer; a blend of a water-insoluble polymer and a water-soluble polymer, etc.)) to form a hot-melt blend; and cooling the hot-melt blend. In some embodiments, the method further comprises molding the hot-melt blend. In some embodiments, the method comprises hot-melt blending one or more pharmaceutically active agents, a water-insoluble polymer (e.g., EVA, according to any of the embodiments described herein), and a water-soluble polymer (e.g., PEO, according to any of the embodiments described herein) to form a hot-melt blend.

[0380] Also provided herein is a method of making a matrix (e.g., for delivery of one or more pharmaceutically active agents) comprising hot-melt blending a water-insoluble polymer (e.g., EVA, according to any of the embodiments described herein) and a water-soluble polymer (e.g., PEO, according to any of the embodiments described herein) to form a hot-melt blend, and cooling the hot-melt blend. In some embodiments, the method further comprises molding the hot-melt blend.

[0381] It is advantageous for the therapeutic agent to maintain its integrity during manufacturing (including melt processing), e.g., as a microparticle- or nanoparticle-like structure dispersed within the blended polymer matrix. Perhaps this is most useful for delivery of agents that may be minimally soluble in tear fluid and require more residence time for transport across the membrane, and / or where natural tear production retention is indeed minimal. Thus, typically, in the methods described herein, hot-melt blending is performed at a melting temperature sufficiently low that the structure and / or performance of the pharmaceutically active agent are not compromised (e.g., below about 99°C, below the melting temperature of the pharmaceutically active agent). Thus, in some embodiments, the components of the matrix (e.g., the water-insoluble polymer and / or the water-insoluble polymer), individually or collectively, have a processing melting point of about 99°C or less (e.g., below 99°C) and / or below the melting temperature of the pharmaceutically active agent. In some embodiments, hot melt blending is performed at a temperature below about 99° C. (e.g., below 99° C.). In some embodiments, hot melt blending is performed at a temperature below the melting temperature of one or more pharmaceutically active agents (e.g., 25° C., 50° C., 75° C., 100° C., or more below the melting temperature).

[0382] Pharmaceutically active agents typically have a melting point (Mp) above 99° C. For example, ciprofloxacin has a melting point of 318° C. to 320° C., dexamethasone has a melting point of 262° C. to 264° C., and olopatadine has a melting point of 242° C. to 245° C.

[0383] In use, an insert containing one or more pharmaceutically active agents can be placed into the ophthalmic device, and the assembled ophthalmic device can be placed under the eyelid in the eye to deliver one or more pharmaceutically active agents to the eye. As one example, the insert can be shaped as a cylinder or rod. Alternatively, the insert can be in the form of a film or other configuration.

[0384] Without wishing to be bound by any particular theory, the following is a description of the steps believed to occur when a pharmaceutically active agent is delivered to the eye from an ophthalmic device containing a composition or insert described herein. When an insert-loaded device is placed in the eye (e.g., under the bottom eyelid (lower eyelid)), it comes into contact with tear fluid. The tear fluid penetrates the surface of the insert and begins to dissolve the water-soluble polymer, exposing the pharmaceutically active agent to the tear fluid, which also begins to dissolve. The dissolution of the water-soluble polymer also frees up space within the insert (which has been replaced by tear fluid in the matrix), allowing the pharmaceutically active agent particles to be released and transported from the insert and / or device through the ocular membrane surface into the tear retention zone. Thus, the water-soluble polymer and pharmaceutically active agent are slowly released from the ophthalmic device into the eye. The natural tear fluid continues to transport the pharmaceutically active agent particles at increasingly decreasing concentrations, following the primary drug delivery system. The water-insoluble polymer is expected to maintain the geometric shape of the insert, ultimately resulting in a scaffold containing the water-insoluble polymer and retained tear fluid. As the dissolution process continues, the insert may swell, but the scaffold formed by the water-insoluble polymer can provide stability and prevent fracturing. The release of the water-soluble polymer can provide the added benefit of lubricating the eye. In addition, the water-soluble polymer (e.g., PEO) can reinforce the mucin layer. The mucin layer is the deepest layer of tear fluid, which adheres to the underlying corneal and conjunctival epithelial cells.

[0385] Dispersion matrices (such as those described herein) typically have three commonly operative release mechanisms: Drug diffusion through non-degrading polymers (diffusion-controlled systems), Drug release due to polymer degradation and erosion (erosion-controlled systems), and Enhanced drug diffusion due to polymer swelling (swelling-controlled systems). Studies of various drugs incorporated into drug inserts described herein indicate that the release kinetics appear to follow the Higuchi model for the early stages of drug release.

[0386] The compositions described herein are particularly suitable for ocular administration. However, the compositions described herein can also be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, intradermally, by inhalation, topically, rectally, nasally, and vaginally), or bucally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraocular, intravitreal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal, and intracranial injection or infusion techniques.

[0387] As used herein, "local administration" refers to the administration of a substance to one or more specific locations on or in a subject's body, regardless of the location of the substance's effect, if any. Thus, the effect of a formulation containing a formulation base described herein can be local or systemic. Non-limiting examples of routes of local administration include transdermal, transmucosal (e.g., oral, nasal, vaginal, urethral), sublingual, buccal, nasal, and ocular routes of administration.

[0388] The described compositions are particularly suitable for administration that contacts the composition with bodily fluids (e.g., lacrimal fluid, rectal fluid, saliva, etc.) Thus, in some embodiments, the compositions described herein are administered to a subject's mucosa (e.g., to the oral mucosa, to the nasal mucosa, to the vaginal mucosa, to the urethral mucosa), sublingually, buccally, nasally, and / or ocularly.

[0389] The compositions described herein can be in any dosage form suitable for the intended mode of administration. For example, the compositions described herein can be in the form of a semi-erodible polymer matrix, e.g., for ocular administration. The compositions described herein can also be in solid form, e.g., for ocular administration. The compositions provided herein can be orally administered in any orally acceptable dosage form, including, but not limited to, solid dosage forms (e.g., capsules, tablets, pills, powders, granules), aqueous suspensions, dispersions, and solutions. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles. For rectal or lower intestinal administration, the formulation can be in the form of a suppository. Suppositories are typically formulated with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum. Such excipients include cocoa butter, beeswax, and polyethylene glycol. For ophthalmic use, the formulation may be provided as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the formulation may be formulated as an ointment (e.g., with petrolatum). For nasal administration (e.g., inhalation), the formulation may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0390] The compositions described herein may further comprise an excipient (e.g., a pharmaceutically acceptable excipient), which may, for example, increase the stability or other physical properties of the composition. Typically, such carriers are non-bioactive, meaning that they have little or no biological activity and / or that they produce little or no biological effect, for example, in the amount administered. Examples of excipients include preservatives, flavor enhancers, diluents, solvents, glycerin, gelatin, albumin, lactose, starch, stabilizers, melting agents, emulsifiers, suspending agents, salts, and buffers. Excipients may be organic or inorganic.

[0391] The compositions described herein can be formulated for immediate or non-immediate release (e.g., delayed, sustained, or extended release). The compositions described herein can also be formulated to provide controlled release of the pharmaceutically active agent contained therein. In some embodiments, the compositions described herein are formulated for extended release, e.g., release over about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 5 days, about 6 days, or about 7 days. In some embodiments, the compositions described herein are formulated for release over about 12 hours to about 48 hours (e.g., about 12 hours, about 24 hours).

[0392] The amount of pharmaceutically active agent in a single dosage form will vary depending on the subject being treated, the particular mode of administration, and the activity of the agent being used. Preferably, the composition should be formulated so that a dosage of about 0.01 mg / kg to about 100 mg / kg of body weight per day of the compound (or a pharmaceutically acceptable salt thereof) can be administered to the subject receiving the composition. For example, in some embodiments, the dosage can be in the range of about 0.5 mg / kg to about 100 mg / kg of body weight, or alternatively, in the range of about 1 mg / dose to about 1000 mg / dose. Other suitable dosages can be in the range of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.01 mg / kg to about 1 mg / kg of body weight per treatment. In some embodiments, the compositions are formulated such that a dosage of the pharmaceutically active agent described herein can be administered to a subject receiving the composition.

[0393] The desired dose may be conveniently administered in a single dose, e.g., so that the drug is administered once daily, as in daily ocular wear applications, or as multiple doses administered at appropriate intervals, e.g., so that the drug is administered two, three, four, five, six, or more times daily. The daily dose may be divided, particularly when relatively large amounts are being administered, or may be divided into several (e.g., two, three, four, five, six, or more) administrations, as deemed appropriate.

[0394] It should also be understood that the specific dosage and treatment regimen for any particular subject will depend on a variety of factors (e.g., the activity of the specific agent used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease, disorder, or condition being treated). The amount of agent in the composition will also depend on the specific agent in the composition. Determining a dosage for a particular agent, subject, and disease, disorder, or condition is well within the ability of one of ordinary skill in the art. Preferably, the dosage of the dosage does not cause or produce minimal adverse side effects.

[0395] Treatment method

[0396] The devices and inserts described herein can be used to treat ocular conditions. Accordingly, methods for treating ocular conditions in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition described herein, are also provided herein. Examples of ocular conditions that can be beneficially treated using the devices and / or compositions described herein include dry eye, glaucoma, allergies, infections (e.g., bacterial, viral, and other infections), chronic inflammatory conditions (e.g., rosacea keratitis, cyclitis, and blepharitis), selected retinal conditions (e.g., diabetic retinopathy, age-related macular degeneration, and other retinal conditions), post-surgery, and amblyopia. Pharmaceutically active agents useful in treating the conditions described herein are as described throughout.

[0397] As used herein, "treating" refers to taking steps to deliver agents to a subject to obtain a desired or beneficial result (e.g., by administering one or more therapeutic agents to the subject). Non-limiting examples of beneficial results include inhibiting a disease or condition (e.g., by slowing or halting its progression or causing regression of the disease or condition), and alleviating one or more symptoms resulting from a disease or condition. Those skilled in the art will be able to identify beneficial results specific to the particular disease or condition being treated.

[0398] As used herein, "administering" refers to taking steps to deliver an agent to a subject (e.g., a mammal) in need thereof (e.g., by administering one or more pharmaceutically active agents to the mammal). Administering can be performed, for example, once, multiple times, and / or over one or more extended periods of time. Administering includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a physician who instructs a patient to self-administer a drug or to have the drug administered by another person, and / or who provides a patient with a prescription for a drug, is administering the drug to the patient. Routes of administration consistent with the compositions and methods described herein are as discussed in the context of the insert compositions.

[0399] A "therapeutically effective amount" is an amount effective, at the dosage and over the period of time required, to achieve the desired therapeutic result (e.g., treatment, suppression, or amelioration of a disease or condition). The full therapeutic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount will vary according to factors such as the disease state, age, sex, and weight of the mammal, mode of administration, and the potency of the therapy or combination of therapies, and is capable of eliciting the desired response in an individual. The therapeutically effective amount of an agent to be administered can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art.

[0400] As used herein, "subject" refers to a mammal, including humans and non-human mammals (e.g., dogs, monkeys, pigs, rats, cats, dogs, rabbits, cattle, sheep, goats, horses, etc.). A "patient" is a human subject. In some embodiments, the subject is human.

[0401] example Example 1. Preparing the insert Inserts were prepared for testing with the compositions of water-insoluble polymer [A] percent (A%), water-soluble polymer (if any) [B] percent (B%), and drug of interest [C] percent (C%) to be evaluated, as identified in the table below. Components [A], [B], and [C] were obtained in powder form.

[0402] The compositions began as dry-mixed, weight-controlled blends of the identified components, with the ratios listed in the respective tables. The blended dry mixture was then transferred into a cylindrical injection chamber with thermal controls to heat the mixture to a set process temperature. Thermal heating was used to heat the low-melting point A% and B% polymer materials and pour the dispersed C% into a metal forming mold, creating an insert without affecting or degrading the C% (drug), which has a higher melting point and therefore remains dispersed in particulate form throughout the mixture. Once the desired process temperature was reached, a plunger or solid rod was inserted into the chamber. The exit orifice of the heated injection chamber was physically engaged and sealed with the empty metal mold chamber. Force was applied by the plunger to the molten material, transferring the fluid-like particle-filled polymer mixture from the injection chamber into the metal forming mold chamber. The previously empty metal mold chamber was thereby filled by the transfer of the mixture. The plunger solid rod was retracted. The injection chamber was released from the metal forming mold. After a predetermined time period for cooling to solidify the mixture, the metal forming mold was opened. The resulting insert, in solid form and shaped to the geometric size provided by the metal mold chamber and of the composition shown in the respective tables that follow, was removed from the metal mold chamber for testing.

[0403] In the tables that follow, "Rod" refers to results of testing the insert not in an ophthalmic device, and "In Device" refers to testing the insert in an ophthalmic device.

[0404] Example 2. Testing Protocol Used for Therapeutic Agents The following table provides, for illustrative purposes, the results of in vitro testing performed on a number of compositions using a UV scanning spectrophotometer calibrated to the therapeutic agent to detect the concentration of that therapeutic agent in a 2-3 ml volume of phosphate buffer at pH 7, and assessing the percent "daily" release of the drug for Ocular Daily Wear (e.g., about 12 to about 24 hours of wear). Ocular Daily Wear is defined by FDA Class II CFR 866.5925 products currently designated for ocular use and scleral tissue contact.

[0405] To begin testing, a UV scanning spectrophotometer concentration calibration curve for the therapeutic agent was established. Inserts were prepared to specifications in the specified table, and a time duration sample schedule for measurements was determined. The inserts were weighed to establish T=0. The inserts were immersed in a fixed volume of phosphate buffer. A mean body temperature of 37°C (e.g., from about 36.5°C to about 37.5°C) was simulated for identified time intervals. At the end of each time period, the inserts were transferred and immersed in a new phosphate buffer test container. The simulated mean body temperature of 37°C continued until the next time interval. UV scanning spectrophotometer data was generated for each time interval sample. Release rates were calculated versus time for the therapeutic agent, and graphical data plots were generated.

[0406] [Table 8]

[0407] Figures 28A and 28B are plots of data obtained from inserts in the ternary devices described in Table 7, showing the cumulative amounts of ciprofloxacin FB and ciprofloxacin hydrochloride, respectively, released from the inserts over a period of several days. The 10.23% daily release of ciprofloxacin FB (Table 7) compares favorably with the daily release of ciprofloxacin from the binary EVA blends (1.45% and 4.06%).

[0408] [Table 9]

[0409] Figures 29A and 29B are plots of data obtained from the ternary inserts described in Table 8, showing the cumulative amounts of dexamethasone FB and dexamethasone phosphate, respectively, released from the inserts over several days. The 82.7% daily release of dexamethasone phosphate compares favorably with the binary dexamethasone blend in EVA (3.39%, 6.14%, and 1.89%).

[0410] [Table 10]

[0411] Figure 30 is a plot of data obtained from the three-component insert described in Table 9, showing the cumulative amount of olopatadine FB released from the insert over several days. The olopatadine release curve follows a consistent pattern and timing of previous therapeutic examples with similar component ratios.

[0412] Example 3. Testing protocol used for EVA / PEO matrix The EVA / PEO matrix testing method followed the same sequence as the testing protocol for therapeutic agents described above, with a few exceptions. EVA / PEO matrix testing was performed on a two-component mixture: A% + B% = 100%. PEO is a well-known lubricant for its ophthalmic therapeutic benefits, but is not detectable using a UV scanning spectrophotometer. Therefore, the mass loss method was used for PEO.

[0413] The inserts were manufactured to specifications in the matrix formulation table.

[0414] A time duration sample schedule for the measurements was established. Samples were weighed to determine T=0. Test samples were placed in fresh phosphate buffer at a fixed volume. An average body temperature of 37°C was simulated for identified time intervals. Test samples were transferred into dry containers at the end of each time interval. Inserts were tapped dry and weighed to establish their hydrated mass. Inserts were air-dried for two days and then dried in an oven at 37°C for an additional day. The inserts (which had reached "dry weight") were weighed. Release rates versus time for the PEO component were calculated, and graphical plots were generated.

[0415] Tables 10A, 10B, 10C, and 10D summarize experiments to evaluate the release rate of water-soluble polymer [B%] in the combination of A% (structural) + B% (erodible) = 100%. PEO release kinetics was investigated as a function of EVA%, PEO%, and PEO molecular weight (which were systematically varied).

[0416] [Table 11]

[0417] [Table 12]

[0418] [Table 13]

[0419] The kinetic studies illustrated by Tables 10A, 10B, and 10C and corresponding Figures 31A, 31B, and 31C illustrate the ability of the PEO component to drive release in the first 12 to 24 hours of first insert wear.

[0420] Table 10D (Table 14) is a summary of the results of Table 10A (Table 11), Table 10B (Table 12), and Table 10C (Table 13).

[0421] [Table 14]

[0422] Table 10E (Table 15) and corresponding Figure 31D provide a comparison of the percentage of Polyox released in the first 12 hours as a function of initial Polyox loading for Polyox Mw 100K, 200K, and 300K with EVA4030AC (EVA40, meaning 40% vinyl acetate EVA block copolymer) and for Polyox Mw 100K and 200K with EVA2816 (EVA28, meaning 28% vinyl acetate EVA block copolymer).

[0423] [Table 15]

[0424] The release rate of Polyox from the matrix reaches a lower limit around 200,000 Mw when combined with 40% EVA and becomes more rapid over the same time period when combined with 28% EVA. The data also showed that combinations of 40% EVA and Polyox for molecular weights above 200,000 are capable of releasing from the matrix at roughly the same overall rate as demonstrated by the 300,000 Mw data over a 12-hour time period.

[0425] From a formulation perspective, a viable molecular weight range for 12- to 24-hour release using an EVA / PEO matrix includes PEO at or below 300,000 MW. Furthermore, blends of different PEO molecular weights below 300,000 can be an additional rate control tool for adjusting the erosion rate (of the drug) from the matrix, which is an important tool for achieving desired therapeutic design goals for drug delivery. The ability to control drug delivery using the disclosed materials and methods is important for precise drug delivery, which is important for many drugs.

[0426] Example 4. Demonstration of Ciprofloxacin FB Delivery Rate Control Using EVA / PEO Matrix Table 10F summarizes the matrix composition and delivery rate of ciprofloxacin FB over a 7-day period, where the PEO concentration of the ternary system is corrected. The first data (Series 1) is shown in Table 7 as part of the ciprofloxacin group of drugs. The last data (Series 4) is a binary system that is nearly identical to the two-component (EVA + drug) formulation from Table 7.

[0427] [Table 16]

[0428] Table 10D (Table 14) and Table 10F (Table 16) and corresponding Figure 32 demonstrate the range of drug delivery rate control that the EVA / PEO matrix system can provide as a function of formulation concentration, PEO molecular weight selection blending, and EVA vinyl acetate concentration.

[0429] This disclosure is supplemented by the following references, which are incorporated herein by reference in their entireties:

[0430] [1] Quaia, C; Optican, L; (2001)“Three Dimensional Rotations of the Eye”, Chapter for Alder's Physiology of the Eye, 10th Edition. Kauffman & Alm, Eds. National Eye Institute; NIH

[0431] [2] Doughty MJ, Laiquzzaman M, Oblak E, Button N.; (2002)“The tear (lacrimal) meniscus height in human eyes: a useful clinical measure or an unusable variable sign?”, Cont Lens Anterior Eye. 2002 Jun; 25(2):57-65

[0432] [3] Bekerman, I; Gottlieb, P; & Vaiman, M; (2014)“Variations in Eyeball Diameters of the Healthy Adults”, Journal of Ophthalmology, vol. 2014, Article ID 503645, 5 pages, 2014

[0433] [4] Atchison,D; Jones, C.E;, Schmid, K.L; Pritchard, N; Pope, J; Strugnell, W; Riley,R; (2004)“Eye Shape in Emmetropia and Myopia”, Investigative Ophthalmology & Visual Science; October 2004 Vol 45,No.10 PP 3380-3386

[0434] [5] Vojnikovic,B; Gabric, N; Dekaris, I; Juric, B (2013)“Curvature Analysis of the Corneal Front and Back Surface”, Coll. Antropol. 37 (2013) Suppl. 1:93-96

[0435] [6] Hashemi, H; Khabazkhoob,M; Emamian, M.H; Shariati, M;Yekta, A; Fotouhi,A;“White to white corneal diameter distribution in an adult population”, Journal of Current Ophthalmology 27 (2015) 21 -24 http: / / dx.doi.org / 10.1016 / j.joco.2015.09.001

[0436] [7] Khan, I.J; Abdul-Jabbar, G; Hodson, J; Edmunds, M.R; Cottrell, P; Evans, S; Williams, G.P; Rauz, S; (2014)“Defining the limits of Normal Conjunctival Fornix Anatomy in a Healthy South Asian Population”, Opthamology 2014;121:492-497 http: / / dx.doi.org / 10.1016 / j.optha.2013.09.033

[0437] [8] Vasanthakumar, P; Kumar, P; Rao, M; (2013)“Anthropometric Analysis of Palpebral Fissure Dimensions and its Position in South Indian Ethnic Adults”, Oman Medical Journal (2013) Vol.28, No 1:26-32 DOI 10.5001 / omj.2013.06

[0438] [9] Robinson DA; (1964)“The Mechanics of Human Saccadic Eye Movement”, J. Physiol

[1964] 174 PP 245-264

[0439]

[10] Laurutis, V.P; Robinson, D.A; (1986)“The Vestibulo-Ocular Reflex during Human Saccadic Eye Movements”, J. Physiol. (1986) 373, pp. 209-233

[0440]

[11] Findlay, J; & Walker, R (2012)“Human Saccadic Eye Movements”, Scholarpedia, 7(7):5095

[0441]

[12] Castelhano, M; & Henderson, J (2008)“Stable Individual Differences Across Images in Human Saccadic Eye Movements”, Canadian Journal of Experimental Psychology: 2008 Vol. 62 No.1 PP 1-14

[0442]

[13] Bentivolgio AR; Bressman S; Cassetta E; Carretta, D; Tonali, T; Albanese, A: “Analysis of Blink Rate Patterns in Normal Subjects” Movement Disorders Vol. 12 No. 6, 1996 PP 1028-1034

[0443]

[14] Abelson, M; ORA, Andover, MA. “It’s Time to Think About the Blink”, Pub 13-June 2011

[0444]

[15] Ousler. GW.; Abelson, M; Johnston, P; Rodriguez, J; Lane, K; Smith, L: 2014“Blink patterns and lid contact times in dry-eye and normal subjects”, Clinical Ophthalmology (Auckland N.Z.) 8 (1): 869-874

[0445]

[16] Francis, IC; Stapelton, F; Ehrmann, K; Coroneo, MT; (2006)“Lower eyelid tensometry in younger and older normal subjects”, Eye (2006) 20 (pp166-172)

[0446]

[17] S.K. Savale Technical operations / services Scientist at Mylan Laboratories LTD Nasik, Maharashtra, India: Department of Pharmaceutics, Slide Presentation 2015-2016‘Slide #4’. https: / / www.slideshare.net / sagarsavale1 / drug-release-kinetics

[0447]

[18] C. Mircioiu, V. Voicu, V. Anuta, A.Tudose, C. Celia, D. Paolino, M. Fresta, R. Sandulovici, I. Miricioiu Modeling“Mathmatical Modeling of Release Kinetics from Supramolecular Drug Delivery Systems”, Pharmaceutics 2019, 11,140 doi: 10.3390 / pharmaceutics11030140 www.mdpi.com / journal / pharmaceutics

[0448]

[19] X. Huang, & C. S. Brazel:“On the importance and mechanisms of burst release in matrix-controlled drug delivery systems”, Journal of Controlled Release 73 (2001) pp121-136

[0449]

[20] C.Brazel & X.Huang, “The Cost of Optimal Drug Delivery: Reducing and preventing the Burst Effect in Matrix Systems”, Carrier-Based Drug Delivery Chapter 19; DOI: 10.1021 / bk-2004-0879.ch019

[0450]

[21] Mishmia, S.; Gasset, P.; Klyce, D. Jr.; & Baum,J.L; (1966)“Determination of tear volume and tear flow”, Investigative Ophthalmology, Vol. 5, Number 3, 1966, pp.264-276

[0451]

[22] Brecher, Jonathan (2006) “Graphical representation of stereochemical configuration (IUPAC Recommendations 2006)” (PDF). Pure Appl. Chem. 78 (10): 1897-1970. doi:10.1351 / pac200678101897

[0452]

[23] Brecher, Jonathan (2008) “Graphical representation standards for chemical structure diagrams (IUPAC Recommendations 2008)”. Pure and Applied Chemistry. 80 (2): 277-410. doi:10.1351 / pac200880020277. ISSN 1365-3075

[0453]

[24] Almeida, et al., “Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide”, European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 526-533.

[0454] The teachings of all patents, published applications, and references cited herein are incorporated herein by reference in their entirety.

[0455] While exemplary embodiments have been specifically shown and described, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the embodiments as encompassed by the appended claims. [Explanation of symbols]

[0456] 001 Horizontal (vertically protruding) axis 003 Vertical (perpendicular to the horizontal plane) axis 004 Axis at one end 006 Axis at the other end 008 Twisting Arrow 009 Twisting arrow 011 Cross Axis 012 Horizontal axis 013 Vertical "torsion" axis 015 Arrow 016 Arrow 017 Arrow 018 Inner eyelid surface 021 Cross Axis 022 Horizontal axis 023 Vertical "torsion" axis 025 Arrow 026 Arrow 027 Arrow 060 Eyelid force direction vector arrow 061 Eyelid force direction vector arrow 062 Eyelid force direction vector arrow 072 Orifice, hole 089 Offset Space 090 Eyeball 091 Emmetropic eyeball 092 Myopic (nearsighted) eyeball 093 Hyperopic (farsighted) eyeball 094 Largest eyeball volume 095 Smallest eyeball volume 096 Eyeball 097 Eyeball 098 Eyeball 100 Origin 101 Cornea 102 Sclera 103 sagittal plane 104 Transverse plane 105 Optical axis line (“X”) 106 Vertical Axis (“Z”) 107 Horizontal (“Y”) Axis 108 Vertical axis rotation arrow 109 Right 110 Left 111 Horizontal Rotating Arrow 112 top 113 lower 114 Iris 115 Transverse (horizontal) width 116 Length in the optical axis direction 117 Conjunctival tissue 118 Lower eyelid 119 Upper eyelid 120 canthus 121 Clinical Measurement Location of Palpebral Fissure Height ("PFH") 122 Palpebral fissure width (“PFW”) 123 Upper eyelid (119) vault depth 124 Lower eyelid (118) vault depth 125 Eyeball 126 Ophthalmic Devices 128 lines 130 outer angle 132 angle 139 line 250 Open Space 270 Ophthalmic Devices 280 Ophthalmic Devices 299 Ophthalmic Devices 300 Planar Curved Surface 301 Slender support members 302 lower side 303 Arch 304 Sweep Curve 306 Vertical Section 310 Protrusion 311 Protrusion 312 Posterior surface 320 Protrusion 321 Protrusion 322 Posterior surface 330 Posterior surface 331 Protrusion 332 Posterior surface 333 Sealing Membrane 341 Protrusion 342 Posterior surface 350 Posterior surface 351 Protrusion 352 Posterior surface 353 Sealing Membrane 411 Flexible Connector 421 Flexible Connector 431 Flexible Connector 432 Plate Connector 441 Flexible Connector 451 Flexible Connector 452 Plate Connector 471 Flexible Connector 472 points 481 Flexible Connector 482 points 511 Plate 521 Plate 531 Plate 541 Plate 551 Plate 587 Ophthalmic Devices 591 Ophthalmic Devices 592 Ophthalmic Devices 593 Ophthalmic Devices 594 Ophthalmic Devices 595 Ophthalmic Devices 596 Ophthalmic Devices 597 Ophthalmic Devices 598 Ophthalmic Devices 611 Insert Pocket 612 Pocket 620 Pocket 621 Insert Pocket 622 Pocket 630 Pocket 631 Insert Pocket 632 Pocket 633 Pocket 641 Insert Pocket 642 pocket 650 pockets 651 Insert Pocket 652 pocket 653 Pocket 70 Orifice 711 Insert 712 Insert 713 Sealing membrane 721 Insert 722 Insert 723 Sealing membrane 731 Insert 732 Insert 733 Sealing Membrane 741 Insert 742 Insert 743 Sealing Membrane 751 Insert 752 Insert 753 Sealing membrane 800 Ophthalmic Devices 801 Slender support member 810 Flexible Connector 811 Plate 812 Plate, rear surface 813 Protrusion 820 Flexible Connector 821 Plate 822 Plate, rear surface 823 Protrusion 830 Flexible Connector 831 Plate 832 Plate, rear surface 833 Protrusion 840 Flexible Connector 841 Plate 842 Plate, rear surface 843 Protrusion 850 Flexible Connector 851 Plate 852 Plate, rear surface 853 Protrusion 860 Flexible Connector 861 Plate 862 Plate, rear surface 863 Protrusion 871 Pocket 875 Radius 876 Retaining Lip 877 Retaining Element 881 Pocket 889 Transverse width 900 cases 901 wells 902 interior space 903 Post 904 stabilizer 905 Joint 906 Lid 907 Keys 908 Receiver 909 port 910 Ridge 911 Peel Strip 911 plate 912 tabs 912 Posterior surface 913 Toroidal Protrusion 921 Plate 922 Posterior surface 923 Protrusion 931 Plate 932 Posterior surface 933 Protrusion 934 Dome-shaped curved surface 941 Plate 942 Posterior surface 943 Protrusion 944 Dome-shaped curved surface 951 Plate 952 Posterior surface 953 Protrusion 954 Anterior surface 955 Contact surfaces 961 Plate 962 Posterior surface 963 Protrusion 964 Anterior surface 965 Contact surfaces 971 Plate 972 Posterior surface 973 Protrusion 974 Anterior surface 975 Contact surfaces 975A Curved Surface 975B Generally planar surfaces 975C Curved Surface 976 Protrusion 977 Contact surfaces 977A Contact Surface 977B Contact Surface 977C Contact Surface 997 points 998 points 999 Local Origin 1000 Ophthalmic Devices 1001 Slender support member 1008 Ophthalmic devices 1010 Protrusion 1011 Plate 1013 Projection 1021 Plate 1023 Protrusion 1030 Posterior surface 1031 Plate 1033 Protrusion 1043 Projection 1125 acute angle 1201 Ophthalmic Devices 1202 Ophthalmic Devices 1203 Ophthalmic Devices 1204 Ophthalmic devices 1301 Support curve 1302 horizontal surfaces 1303 Arch 1304 Support curve 1311 Protrusion 1312 Posterior surface 1331 Protrusion 1332 Posterior surface 1511 Plate 1521 Plate 1531 Plate 1551 Plate 1631 Pocket 1651 Pocket 1871 surface 1876 ​​Retaining Lip 1889 Span 1900 insert 1901 Well 1902 Interior Space 1903 Post 1904 Stabilizer 1905 Joint 1906 Lid 1907 Key 1908 receiver 1909 port 1990 Case 2126 Ophthalmic Devices 2400 bottles 2405 Liquid 3015 Slender support members 3016 Slender support members 3017 Slender support members 3018 Slender support member 3103 Protrusion 3114 Posterior surface 3115 Protrusion 3116 Protrusion 3117 Protrusion 3118 Protrusion 3125 Posterior surface 3126 Posterior surface 3127 Posterior surface 3128 Posterior surface 3214 Posterior surface 3217 Protrusion 3215 Protrusion 3225 Posterior surface 3227 Posterior surface 3303 Posterior surface 3311 Protrusion 3331 Protrusion 3332 Retaining Lip 3511 Plate 3521 Plate 3531 Plate 3551 Plate 3592 Ophthalmic Devices 3631 Pocket 3651 Pocket 4112 Flexible Connector 4212 Flexible Connector 5102 Plate 5103 Plate 5105 Plate 5106 Plate 5107 Plate 5108 Plate 5114 Plate 5202 Plate 5203 Plate 5205 Plate 5207 Plate 5214 Plate 9100 Round Insert 9348 Surface

Claims

1. An ophthalmic device that is placed under the eyelid, comprising: a plate including a posterior surface; An ophthalmic device, wherein the posterior surface has at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate.

2. The ophthalmic device of claim 1 , wherein the plate is connected to an elongated support member of flexible material including a first end and a second end.

3. the plate is connected proximate to a first end of the elongated support member; The ophthalmic device of claim 2 , further comprising a plate connected proximate to the second end of the elongate support member.

4. The ophthalmic device of claim 2 or 3, wherein a flexible connector connects at least one plate to the elongate support member.

5. The ophthalmic device of claim 4 , wherein the connection between the flexible connector and the elongated support member is configured to be positioned adjacent to the canthus of the eye when the ophthalmic device is under the eyelid.

6. The ophthalmic device according to claim 1 , wherein the contact surface forms a boundary around the offset space.

7. The ophthalmic device according to claim 1 , wherein the at least one protrusion is a complete ring.

8. The ophthalmic device according to claim 1 , wherein the at least one protrusion is toroidal.

9. 9. An ophthalmic device according to any one of claims 1 to 8, wherein the posterior surface has at least three protrusions, the at least three protrusions having contact surfaces for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate.

10. 10. An ophthalmic device according to any one of claims 1 to 9, wherein the contact surface of the at least one protrusion on the posterior surface is a convex contact surface.

11. 11. An ophthalmic device according to any one of claims 1 to 10, wherein each plate further comprises an anterior surface on the other side of the plate from the posterior surface, the anterior surface having at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the anterior surface of the plate.

12. The ophthalmic device of claim 11 , wherein the contact surface of the at least one protrusion on the anterior surface is a convex contact surface.

13. An ophthalmic device according to any one of claims 1 to 12, wherein the periphery of at least one plate is curved.

14. 14. The ophthalmic device of claim 2, wherein at least one plate extends laterally from the elongate support member.

15. 15. The ophthalmic device of claim 2, wherein the length of the elongate support member is between about 3 millimeters and about 24 millimeters.

16. 16. The ophthalmic device of claim 15, wherein the length of the elongate support member is between about 3 millimeters and about 8 millimeters.

17. 16. The ophthalmic device of claim 15, wherein the length of the elongate support member is between about 4 millimeters and about 10 millimeters.

18. 16. The ophthalmic device of claim 15, wherein the length of the elongate support member is between about 6 millimeters and about 16 millimeters.

19. 19. An ophthalmic device according to any one of claims 3 to 18, wherein the elongated support member, the plate connected proximate to a first end of the elongated support member, and the plate connected proximate to a second end of the elongated support member are substantially coplanar, flexibly interconnected, and configured to adapt to irregular surfaces.

20. 20. An ophthalmic device according to any one of claims 2 to 19, wherein at least one plate is connected to the elongated support member between a first end and a second end of the elongated support member, and the at least one plate is substantially flush with the elongated support member.

21. 21. The ophthalmic device of claim 1, wherein the ophthalmic device comprises at least three plates.

22. 22. An ophthalmic device according to any one of claims 19 to 21, wherein each plate is connected to the elongate support member by a flexible connector.

23. 23. An ophthalmic device according to any one of claims 2 to 22, wherein at least two plates are connected to the elongated support member by curved flexible connectors and at least two additional plates are connected to the elongated support member by substantially straight flexible connectors.

24. 24. An ophthalmic device according to any one of claims 3 to 23, wherein the thickness from anterior to posterior of at least one plate decreases with distance from a central area of ​​the ophthalmic device.

25. 25. An ophthalmic device according to any one of claims 3 to 24, wherein the plates are connected to the same side of the elongate support member.

26. 23. The ophthalmic device of any one of claims 2 to 22, wherein the elongate support member is curved.

27. 27. The ophthalmic device of claim 26, wherein the elongate support member has a smoothly curved outer surface.

28. 28. An ophthalmic device according to any one of claims 1 to 27, wherein at least one plate is substantially circular.

29. 29. An ophthalmic device according to any one of claims 1 to 28, wherein the widest portion of the posterior surface of at least one plate is between about 2 millimeters and about 7 millimeters.

30. 29. The ophthalmic device of claim 28, wherein the plates are substantially circular, and the diameter of the at least one substantially circular plate is from about 2 millimeters to about 7 millimeters.

31. 31. The ophthalmic device of any one of claims 1 to 30, wherein the elongate support member comprises an arch portion and a plurality of outer sweep portions, each outer sweep portion extending from the arch portion.

32. 32. The ophthalmic device of claim 31, wherein the arched portion has a radius of curvature between about 0.0 millimeters and about 6.0 millimeters.

33. 33. The ophthalmic device of claim 32, wherein the arch portion is an arcuate arch positioned in a central area of ​​the ophthalmic device between the ends of the elongate support members.

34. 34. The ophthalmic device of any one of claims 1 to 33, wherein the ophthalmic device further comprises a substance in at least one plate to be delivered to the eye.

35. 35. An ophthalmic device according to any one of claims 1 to 34, wherein at least one plate provides at least one pocket for holding a substance to be delivered to the eye.

36. The ophthalmic device of claim 35 , wherein the at least one pocket is cylindrical in shape.

37. 37. The ophthalmic device of claim 35 or 36, wherein the ophthalmic device further comprises a substance in the at least one pocket to be delivered to the eye.

38. 38. The ophthalmic device of any one of claims 35 to 37, wherein the at least one pocket includes an opening configured to receive a substance to be delivered to the eye.

39. 39. The ophthalmic device of any one of claims 35 to 38, wherein an insert is present in the at least one pocket, the insert containing a substance to be delivered to the eye.

40. 40. The ophthalmic device of claim 39, wherein the ophthalmic device further comprises a retaining element for retaining the insert in the pocket.

41. The ophthalmic device of claim 40, wherein the retaining element is a sealing membrane coupled to the ophthalmic device, to the insert, or to the ophthalmic device and the insert.

42. 42. The ophthalmic device of claim 41, wherein the sealing membrane comprises at least one aperture.

43. 43. The ophthalmic device of any one of claims 40 to 42, wherein the retaining element comprises a lip at the opening of the pocket.

44. 44. An ophthalmic device according to any one of claims 38 to 43, wherein the opening is substantially polygonal in shape.

45. 45. An ophthalmic device according to any one of claims 38 to 44, wherein the opening is substantially hexagonal in shape.

46. 46. ​​The ophthalmic device of any one of claims 39 to 45, wherein the ophthalmic device further comprises an orifice in the plate, and the ophthalmic device is configured to dispense the substance from an insert through the orifice to the eye, providing a bidirectional drug delivery system.

47. 42. The ophthalmic device of any one of claims 1 to 41, wherein at least a portion of the ophthalmic device is made from a polymeric material.

48. An ophthalmic device for placement under the eyelid, comprising: an elongated support member of flexible material; at least one plate connected to the elongated support member; An ophthalmic device, wherein the plate includes a posterior surface, the posterior surface having at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate.

49. 49. The ophthalmic device of claim 48, wherein the contact surface is convex.

50. 50. The ophthalmic device of claim 48 or 49, wherein the elongate support member and the plate are substantially coplanar.

51. 51. An ophthalmic device according to any one of claims 48 to 50, wherein the at least one plate is connected to the elongate support member proximate an end of the elongate support member.

52. An ophthalmic device according to any one of claims 48 to 51, wherein the ophthalmic device comprises at least two plates connected to the elongated support member proximate the ends of the elongated support member, and the elongated support member and the two plates are substantially coplanar.

53. 53. An ophthalmic device according to any one of claims 48 to 52, wherein the ophthalmic device comprises at least three plates connected to the elongate support member.

54. 1. An ophthalmic device for placement under the eyelid to deliver a material to the eye, comprising: an elongated support member; a plate connected proximate each end of the elongated support member, the plate being substantially coplanar with the elongated support member; An ophthalmic device, wherein each plate includes a posterior surface, the posterior surface having at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate.

55. 55. The ophthalmic device of claim 54, wherein the contact surface is convex.

56. 56. The ophthalmic device of claim 54 or 55, wherein the ophthalmic device further comprises a pharmaceutically active agent.

57. 57. The ophthalmic device of claim 56, wherein the pharmaceutically active agent is disposed in at least one plate.

58. 58. An ophthalmic device according to any one of claims 54 to 57, wherein at least a portion of the ophthalmic device is formed from a pharmaceutically active agent blended with other materials.

59. 59. An ophthalmic device according to any one of claims 54 to 58, wherein at least one plate provides a pocket capable of receiving a pharmaceutically active agent.

60. 60. The ophthalmic device of claim 59, wherein the ophthalmic device further comprises a pharmaceutically active agent in the pocket.

61. 61. The ophthalmic device of claim 59 or 60, wherein the ophthalmic device further comprises a removable insert in at least one pocket, the insert containing a pharmaceutically active agent.

62. 62. The ophthalmic device of claim 61, wherein the plate further comprises a retaining element for retaining the insert in the pocket.

63. 1. An ophthalmic device for placement under an eyelid of an eye, comprising: a sclera contact surface having at least three contact points configured to contact the sclera of the eye; a remote surface configured to be maintained remote from the sclera of the eye by the at least three contact points; An ophthalmic device wherein the remote surface and the at least three contact points provide an offset space configured to retain tear fluid.

64. 64. The ophthalmic device of claim 63, wherein the ophthalmic device further comprises a pharmaceutically active agent delivered to the eye.

65. 65. The ophthalmic device of claim 64, wherein the pharmaceutically active agent is delivered to the eye by the tear fluid when the ophthalmic device is placed under the eyelid.

66. 66. An ophthalmic device according to any one of claims 63 to 65, wherein the surface area of ​​the sclera-contacting surface is less than about 20% of the surface area of ​​the remote surface.

67. 67. The ophthalmic device of any one of claims 63 to 66, wherein the ophthalmic device is flexible and adaptable to the sclera-contacting surface.

68. 1. A method for delivering a pharmaceutically active agent to the eye, comprising: Providing an ophthalmic device, the ophthalmic device comprises: an elongated support member; and a plate connected proximate each end of the elongated support member, the plate being substantially coplanar with the elongated support member; at least one plate including a posterior surface, the posterior surface having at least one protrusion, the at least one protrusion having a contact surface for contacting the sclera of the eye and for providing an offset space between the sclera and the posterior surface of the plate; adding a pharmaceutically active agent to at least one plate; placing the ophthalmic device under an eyelid of the eye.

69. 69. The method of claim 68, wherein the contact surface is convex.

70. 70. The method of claim 68 or 69, wherein adding the pharmaceutically active agent to the at least one plate comprises disposing the pharmaceutically active agent in at least one pocket of the at least one plate.

71. 71. The method of claim 70, wherein the step of disposing the pharmaceutically active agent in the at least one pocket comprises inserting an insert into the at least one pocket, the insert containing the pharmaceutically active agent.

72. 72. The method of any one of claims 68 to 71, wherein the ophthalmic device is placed under the eyelid with the posterior surface of the at least one plate facing the sclera of the eye.

73. 72. The method of any one of claims 68 to 71, wherein the ophthalmic device is placed under the eyelid with the anterior surface of the at least one plate facing the sclera of the eye.

74. 74. The method of any one of claims 68 to 73, wherein the ophthalmic device is placed under the eyelid with the elongate support member facing the fornix.

75. 74. The method of any one of claims 68 to 73, wherein the ophthalmic device is placed under the eyelid with the at least one plate facing the fornix.

76. An ophthalmic device as described in any one of claims 39 to 47, or a method as described in any one of claims 71 to 75, wherein the insert comprises, consists essentially of, or consists of a composition comprising the pharmaceutically active agent and a pharmaceutically acceptable carrier.

77. 77. The ophthalmic device or method of claim 76, wherein the pharmaceutically acceptable carrier comprises a water soluble polymer.

78. 78. The ophthalmic device or method of claim 76 or 77, wherein the pharmaceutically acceptable carrier comprises a water-insoluble polymer.

79. 79. The method of any one of claims 76 to 78, wherein the pharmaceutically acceptable carrier forms a matrix and the pharmaceutically active agent is dispersed within the matrix.

80. A composition comprising one or more pharmaceutically active agents, about 20% to about 80% by weight of a water-insoluble polymer, and about 20% to about 80% by weight of a water-soluble polymer.

81. 81. The composition of claim 80, wherein the composition comprises from about 25% to about 70% by weight of the water-insoluble polymer.

82. 82. The composition of claim 80 or 81, wherein the composition comprises about 40% to about 75% by weight of the water-soluble polymer.

83. 83. The composition of any one of claims 80 to 82, wherein the water-insoluble polymer is ethylene vinyl acetate (EVA).

84. 84. The composition of claim 83, wherein the weight percent of vinyl acetate in the ethylene vinyl acetate (EVA) is 25% or greater.

85. 85. The composition of any one of claims 80 to 84, wherein the water-soluble polymer is polyethylene oxide (PEO).

86. 86. The composition of claim 85, wherein the polyethylene oxide (PEO) has a molecular weight of about 100,000 to about 300,000.

87. 87. The composition of any one of claims 80 to 86, wherein the water-insoluble polymer has a melting temperature of about 99°C or less.

88. 88. The composition of any one of claims 80 to 87, wherein the water-soluble polymer has a melting temperature of about 99°C or less.

89. 89. The composition of any one of claims 80 to 88, wherein the composition comprises from about 0.5% to about 50% by weight of the one or more pharmaceutically active agents.

90. 90. The composition of any one of claims 80-89, wherein each of the one or more pharmaceutically active agents has a melting temperature greater than about 99°C and is water soluble.

91. 91. The composition of any one of claims 80 to 90, wherein the one or more pharmaceutically active agents are in the form of particles.

92. 92. The composition of any one of claims 80 to 91, wherein the one or more pharmaceutically active agents comprise ciprofloxacin, dexamethasone, olopatadine, pilocarpine, hyaluronic acid, hydroxypropyl cellulose, or a pharmaceutically acceptable salt thereof.

93. 93. The composition of any one of claims 80 to 92, wherein the composition is formulated for administration to the eye.

94. 94. The composition of any one of claims 80 to 93, wherein the composition is in the form of a semi-erodible polymer matrix.

95. 95. The composition of any one of claims 80 to 94, wherein the composition is formulated to provide controlled release of the one or more pharmaceutically active agents.

96. 96. A method of making the composition of any one of claims 80 to 95, comprising: hot-melt blending the one or more pharmaceutically active agents, the water-insoluble polymer, and the water-soluble polymer to form a hot-melt blend; and cooling said hot melt blend to produce said composition.

97. 97. The method of claim 96, wherein said hot melt blending is carried out at a temperature of less than about 99°C.

98. 98. The method of claim 96 or 97, wherein the hot melt blending is performed at a temperature below the melting temperature of the one or more pharmaceutically active agents.

99. 1. A case for holding and dispensing an ophthalmic device, comprising: a well configured to hold a fluid, the well having an open top; a stabilizer connected to the well; a lid connected to the well, the lid being rotatable between a position covering the open top of the well and a position in which the well is uncovered, the lid having a port in fluid communication with the interior of the well when the lid is covering the open top of the well; A case including a receiver protruding from the lid, configured to receive and hold an ophthalmic device in proximity to the port, and located within the well when the well is covered by the lid.

100. 100. The case of claim 99, wherein the receiver forms a channel that is open on at least one side of the receiver.

101. The case of claim 100, wherein the channel is open on two sides of the receiver and the channel is configured to allow the ocular device to be applied from either of the two sides of the receiver and to maintain the orientation of the applied ocular device.

102. 102. The case of claim 100 or 101, wherein the channel is shorter than the ophthalmic device.

103. 103. A case according to any one of claims 99 to 102, wherein the receiver further comprises a restraining element configured to hold the ophthalmic device in a particular orientation.

104. 104. The case of claim 103, wherein the restraining element is a ridge.

105. 105. A case according to any one of claims 99 to 104, wherein the lid is removably secured to the well when the lid is in a position covering an open top of the well.

106. 106. A case according to any one of claims 99 to 105, wherein the lid is configured to extend past the well when the lid is in a position covering an open top of the well.

107. 107. The case of any one of claims 99 to 106, wherein the case further comprises a latch for releasably securing the lid in position covering the open top of the well.

108. 108. The case of claim 107, wherein the latch includes a latch post and a key.

109. 109. The case of any one of claims 99 to 108, wherein the lid is connected to the well by a hinge made of a flexible material.

110. 110. The case of any one of claims 99 to 109, wherein the stabilizer forms a ring surrounding the well.

111. 111. A case according to any one of claims 99 to 110, wherein the well, the stabilizer, the lid and the receiver are of unitary construction.

112. 112. The case of any one of claims 99 to 111, wherein the port is configured to allow fluid to enter the well when the lid is in a position covering an open top of the well.

113. 113. A case according to any one of claims 99 to 112, wherein the port has a length sufficient for degassing from the well and for the entry of fluid into the well.

114. 114. The case of any one of claims 99 to 113, wherein the case further comprises a removable peel strip that seals the port.

115. 115. The case of any one of claims 99 to 114, wherein the case is made of a high melt flow polypropylene material.

116. 116. A case according to any one of claims 99 to 115, wherein the case comprises the ophthalmic device therein.

117. 117. A case according to any one of claims 99 to 116, wherein the case further comprises a feature for orienting the ophthalmic device.

118. The case of claim 117, wherein the features for orienting the ophthalmic device are tactile and visual features.

119. 99. The case of claim 99, wherein the ophthalmic device is an ophthalmic device according to any one of claims 1 to 67.

120. 119. The case of any one of claims 99 to 118, wherein the receiver further comprises a restraining element.

121. 121. The case of claim 120, wherein the restraining element is a ridge.

122. 1. A case for holding and dispensing an ophthalmic device, comprising: a well configured to hold a fluid, the well having an open top; a stabilizer connected to the well; a lid connected to the well, the lid being rotatable between a position covering the open top of the well and a position in which the well is uncovered; A case including a receiver protruding from the lid, configured to receive and hold an ophthalmic device, the receiver being within the well when the well is covered by the lid.

123. 123. The case of claim 122, wherein the case further comprises a port.

124. 124. The case of claim 123, wherein the port is on the lid and is fluidly connected to the interior of the well when the lid is in the position covering the open top of the well.

125. 125. The case of claim 123 or 124, wherein the receiver is further configured to hold the ophthalmic device in proximity to the port.

126. A case as described in any one of claims 123 to 125, wherein the port is configured to allow liquid to enter the well through the port and flow across the ophthalmic device when the lid is in a position covering the open top of the well.

127. an ophthalmic device; A case according to any one of claims 99 to 126; and a substance for administration to the eye of a user.

128. 128. The kit of claim 127, wherein the substance comprises a pharmaceutical agent.

129. 129. The kit of claim 127 or 128, wherein the substance comprises a pharmaceutical agent.

130. 130. The kit of any one of claims 127 to 129, wherein the substance comprises a drug.

131. 131. The kit of any one of claims 127 to 130, wherein the kit further comprises a solution for wetting the ophthalmic device.

132. A method of inserting an ophthalmic device held in a case by a receiver into a user's eye, the ophthalmic device having a surface for contacting the sclera of the eye; positioning the case on a substantially flat surface in front of the user with the surface of the ophthalmic device that will contact the sclera oriented towards the user; rotating a lid covering the open top of the case well to remove the receiver from the case well and reveal the ophthalmic device held by the receiver; removing the ophthalmic device from the receiver while maintaining the orientation of the ophthalmic device; and inserting the ophthalmic device under an eyelid of the user's eye.

133. 133. The method of claim 132, further comprising sterilizing the ophthalmic device sealed in the well with the lid in position covering the open top of the well.

134. 134. The method of claim 132 or 133, further comprising the step of adding a substance to the well to be administered to the user's eye.

135. 135. The method of claim 134, wherein the substance is added through a port.

136. 136. The method of claim 134 or 135, wherein the substance is added directly to the interior space of the well through the open top of the well.

137. 137. The method of any one of claims 134 to 136, further comprising removing a peel strip from the lid to leave the port unsealed.

138. 138. The method of any one of claims 135 to 137, wherein the lid covers the open top of the well and the port is in fluid communication with the interior space of the well.

139. A method according to any one of claims 132 to 138, wherein the step of removing the ophthalmic device includes grasping a protruding portion of the ophthalmic device from the right or left side of the receiver with the right or left hand, whichever hand is used to pull.

140. 140. The method of claim 139, wherein the step of removing the ophthalmic device further comprises the step of directing a protruding portion of the ophthalmic device with a pushing hand toward a pulling hand.

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