Drug Therapy Delivery System and Method

Abstract

A drug delivery device for metering delivery of a drug to eye tissue over a period of time is provided. The device (100) includes a body portion (102) having a tube (104), a microporous core (106), and an outer surface (108) defining an internal reservoir (110). The outer surface defines a port (112) of the body portion arranged to provide a first passage of the drug from the reservoir. The tube length defines a second passage of the drug from a first end of the tube to a second end. The first end is coupled to the port to receive the first passage of the drug from the reservoir. The second end is spaced a distance from the first end and delivers the drug to the eye tissue. The microporous core is disposed within the lumen along at least a portion of the tube length and has a porosity to meter the second passage of the drug.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 395,501, filed Aug. 5, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Field The present disclosure generally relates to devices and methods for delivering a drug to a tissue region of a body. More specifically, the present disclosure relates to devices and methods for delivering a therapeutic drug to tissues associated with the eye.

Background Art

[0003] Background Aqueous humor is a fluid that fills the anterior chamber of the eye and contributes to intraocular pressure or the fluid pressure within the eye. Ocular hypertension is a condition of the eye in which the intraocular pressure or the fluid pressure within the eye increases. If left untreated, ocular hypertension can lead to diseases such as glaucoma, where the vision in the affected area gradually deteriorates and may sometimes be permanently lost.

[0004] Numerous attempts have been made to treat ocular hypertension, particularly glaucoma. Such attempts include implant procedures of drainage devices designed to lower the intraocular pressure in the affected area, as well as surgical procedures involving drug administration. The aim of these treatments is to improve the quality of life by reducing the intraocular pressure and to maintain visual function.

[0005] Drug administration is typically performed in the form of eye drops that the patient has to administer themselves, but in certain cases, implantable long - term drug delivery devices can be used. Implantable long - term drug delivery devices are typically placed outside the eye (such as an extra - ocular approach) or, alternatively, implanted into the anterior chamber of the eye (intra - anterior chamber approach).

[0006] There are various challenges associated with extraocular approaches to drug delivery. To be effective, an extraocular approach requires the transport of a sufficient amount of drug from the conjunctival layer of the eye into the anterior chamber of the eye through the eye's biological processes. Due to obvious natural mechanisms such as the continuous washing mechanism of the human tear film and the natural barrier formed by the conjunctiva against the interior of the eye, the effectiveness of the extraocular approach becomes complex, and the dosage becomes suboptimal over time. Therefore, the extraocular approach sometimes involves administering an excessive amount of drug to extend the effective period.

[0007] On the other hand, the intracameral approach is a more invasive approach that requires puncturing various tissue layers of the eye to access the anterior chamber of the eye and place a device. The intracameral approach becomes even more complex when administering a drug in combination with an absorbable (biodegradable) device, as the device may dislodge and float within the anterior chamber due to device degradation. Additionally, removal and repeated replacement of the device require trauma to the eye tissue. SUMMARY OF THE INVENTION

[0008] Abstract This specification discloses a drug delivery or metering device and method for metering the delivery of a drug to eye tissue over a period of time. Advantages of such devices and methods include controlling the rate at which the drug is delivered or distributed to a target site, such as a target tissue for a therapeutic treatment, and facilitating the transition of the drug from a first state to a second state as it moves along the delivery path and is delivered to the target site.

[0009] According to one example (Example 1), a drug delivery device for metering the delivery of a drug to eye tissue over a period of time is disclosed. The device includes a body portion having an outer surface that defines an internal reservoir. Here, the outer surface defines a port of the body portion that is arranged to provide a first passage for the drug from the reservoir, a first end, a second end opposite the first end, and a tube having a lumen extending along a tube length therebetween. Here, the tube length defines a second passage for the drug from the first end to the second end. The first end is coupled to the port to receive the first passage of the drug from the reservoir, and the second end is arranged at a distance from the first end to deliver the drug to the eye tissue. A microporous core is included that is arranged along at least a portion of the tube length within the lumen and has a porosity that meters the second passage of the drug.

[0010] In addition to Example 1, according to another example (Example 2), the drug has a first state when disposed at the first end of the tube and a second state when disposed at the second end of the tube. The drug transitions from the first state to the second state when moving through the microporous core along the second passage.

[0011] In addition to Example 2, according to another example (Example 3), the first state is a drug delivery state, and the second state is a drug treatment state.

[0012] In addition to Example 2, according to another example (Example 4), the first state is a non-treatment state of the drug, and the second state is a treatment state of the drug.

[0013] In addition to Example 2, according to another example (Example 5), the first state is a high-concentration state of the drug, and the second state is a low-concentration state of the drug. The low-concentration state has a lower concentration than the high-concentration state.

[0014] In addition to any one of Examples 1 to 5, according to another example ("Example 6"), the microporous core includes a plurality of nodes and fibrils configured to meter a second passage of the agent.

[0015] In addition to Example 6, according to another example ("Example 7"), the second passage of the agent is configured to be metered by the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

[0016] In addition to Example 6 or 7, according to another example ("Example 8"), the microporous core includes ePTFE fibers.

[0017] In addition to Example 8, according to another example ("Example 9"), the ePTFE fibers include a uniaxially stretched structure.

[0018] In addition to Example 8, according to another example ("Example 10"), the ePTFE fibers include a vortex or helical shape.

[0019] In addition to Example 6 or 7, according to another example ("Example 11"), the microporous core includes an ePTFE strip having a biaxially stretched structure.

[0020] In addition to any one of Examples 1 to 11, according to another example ("Example 12"), the tube includes a thermoplastic compound.

[0021] In addition to Example 12, according to another example ("Example 13"), the thermoplastic compound includes one or more of FEP, EFEP, ETFE, or PATT.

[0022] In addition to any one of Examples 1 to 11, according to another example ("Example 14"), the tube includes an elastomeric compound.

[0023] In addition to Example 14, according to another example ("Example 15"), the elastomeric compound includes silicone.

[0024] In addition to any one of Examples 1 to 15, according to another example ("Example 16"), the tube is a coating disposed on the outer surface of the microporous core.

[0025] In addition to any one of Examples 1 to 15, according to another example ("Example 17"), the tube is a tape wound around the outer surface of the microporous core.

[0026] In addition to any one of Examples 1 to 17, according to another example ("Example 18"), the porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular shape.

[0027] In addition to any one of Examples 1 to 17, according to another example ("Example 19"), the porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular weight.

[0028] In addition to any one of Examples 1 to 17, according to another example ("Example 20"), the porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular polarity.

[0029] In addition to any one of Examples 1 to 20, according to another example ("Example 21"), the outer surface of the body portion includes a first surface and a second surface opposite the first surface, and the port is disposed between the first surface and the second surface.

[0030] In addition to any one of Examples 1 to 20, according to another example ("Example 22"), the outer surface of the body portion includes a first surface and a second surface opposite the first surface, and the port is disposed on the first surface.

[0031] In addition to Example 22, according to another example ("Example 23"), the first end of the tube is disposed within the reservoir such that most of the tube length is disposed within the reservoir.

[0032] In addition to Example 23, according to another example (“Example 24”), most of the tube disposed within the reservoir is configured to partially cover the microporous core and provide a plurality of density diffusion openings.

[0033] In addition to Example 23 or 24, according to another example (“Example 25”), between 10% and 40% (inclusive) (or 10% - 40%) of the tube length is located outside the reservoir.

[0034] In addition to any one of Examples 1 - 25, according to another example (“Example 26”), the body portion includes a resealable opening through which the reservoir is configured to be replenished with the drug to be delivered.

[0035] According to one example (“Example 27”), a drug metering device for metering the delivery of a drug to eye tissue over a period of time is disclosed. The drug metering device includes a tube having a first end, a second end opposite the first end, and a lumen extending therebetween along a tube length, and a microporous core disposed within the lumen along at least a portion of the tube length. The microporous core has a porosity that provides for the metered passage of the drug through the microporous core from the first end of the tube toward the second end of the tube. The drug has a first state when disposed at the first end of the tube and a second state when disposed at the second end of the tube, and the drug transitions from the first state to the second state as it moves along the metering passage. The first end of the tube is sized to receive the drug in the first state and includes a drug receiving portion disposed to direct the drug in the first state to the microporous core.

[0036] In addition to Example 27, according to another example (“Example 28”), the first state is a delivery state of the drug and the second state is a therapeutic state of the drug.

[0037] In addition to Example 27, according to another example ("Example 29"), the first state is a non-treatment state of the drug, and the second state is a treatment state of the drug.

[0038] In addition to Example 27, according to another example ("Example 30"), the first state is a high-concentration state of the drug, the second state is a low-concentration state of the drug, and the low-concentration state has a lower concentration than the high-concentration state.

[0039] In addition to any one of Examples 27 to 30, according to another example ("Example 31"), the drug receiving portion includes a microporous drug receiving component having a porosity different from that of the microporous core.

[0040] In addition to any one of Examples 27 to 30, according to another example ("Example 32"), the first end is substantially closed, and the drug receiving portion is a drug receiving space in the lumen where the drug is temporarily stored for delivery.

[0041] In addition to any one of Examples 27 to 31, according to another example ("Example 33"), the first end is substantially open, and the drug receiving portion is configured to receive the drug from the surrounding environment outside the tube.

[0042] In addition to Example 33, according to another example ("Example 34"), the device further includes a filter membrane disposed at the first end and configured to filter the drug received from the surrounding environment.

[0043] In addition to Example 33, according to another example ("Example 35"), the first end is angled with respect to the tube length.

[0044] In addition to Example 33 or 35, according to another example ("Example 36"), the section of the microporous core near the first end of the tube is angled with respect to the tube length.

[0045] In addition to any one of Examples 33 to 36, according to another example ("Example 37"), the device further includes a body portion having an outer surface that defines an internal reservoir. The outer surface is coupled to the first end of the tube and defines a port of the body portion that is arranged to deliver the drug from the reservoir to the tube. The surrounding environment is the reservoir of the body portion.

[0046] In addition to any one of Examples 27 to 37, according to another example ("Example 38"), the microporous core includes a plurality of nodes and fibrils configured to control the metered passage of the drug.

[0047] In addition to Example 38, according to another example ("Example 39"), the second passage of the drug is configured to be metered by the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

[0048] In addition to Example 38 or 39, according to another example ("Example 40"), the microporous core includes ePTFE fibers.

[0049] In addition to Example 40, according to another example ("Example 41"), the ePTFE fibers include a uniaxially expanded structure.

[0050] In addition to Example 40, according to another example ("Example 42"), the ePTFE fibers include a helical or spiral geometry.

[0051] In addition to Example 38 or 39, according to another example ("Example 43"), the microporous core includes an ePTFE strip having a biaxially expanded structure.

[0052] In addition to any one of Examples 27 to 43, according to another example ("Example 44"), the tube includes a thermoplastic compound.

[0053] In addition to Example 44, according to another example ("Example 45"), the thermoplastic compound includes one or more of FEP, EFEP, ETFE, or PATT.

[0054] In addition to any one of Examples 27 to 43, according to another example ("Example 46"), the tube contains an elastomeric compound.

[0055] In addition to Example 46, according to another example ("Example 47"), the elastomeric compound contains silicone.

[0056] In addition to any one of Examples 27 to 47, according to another example ("Example 48"), the tube is a coating disposed on the outer surface of the microporous core.

[0057] In addition to any one of Examples 27 to 47, according to another example ("Example 49"), the tube is a tape wound around the outer surface of the microporous core.

[0058] In addition to any one of Examples 27 to 49, according to another example ("Example 50"), the porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular shape.

[0059] In addition to any one of Examples 27 to 49, according to another example ("Example 51"), the porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular weight.

[0060] In addition to any one of Examples 27 to 49, according to another example ("Example 52"), the porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular polarity.

[0061] According to one example (“Example 53”), a method of metering the delivery of a drug to an eye tissue is disclosed, the method comprising placing a drug delivery device near the eye tissue, wherein the drug delivery device includes an outer surface defining an internal reservoir and a port disposed to provide a first passage of the drug from the reservoir to the port, placing a drug delivery tube extending from the port at the first end of the tube to a location at a second end of the tube opposite the first end in fluid contact with the eye tissue to provide a second passage of the drug from the port to the second end of the tube, and delivering the drug from the second end of the tube through a microporous core disposed within the tube, wherein the microporous core has a porosity that meters the second passage of the drug.

[0062] According to another example (“Example 54”), a method of metering the delivery of a drug to an eye tissue is disclosed, the method comprising placing a first end of a drug delivery tube near the eye tissue, placing a second end of the drug delivery tube opposite the first end of the drug delivery tube in a position to establish fluid contact with the eye tissue, and delivering the drug from the second end of the tube through a microporous core disposed within the tube, wherein the microporous core has a porosity that meters the passage of the drug from the first end of the tube to the second end of the tube.

[0063] In addition to Example 53 or 54, according to an example (“Example 55”), the second end of the drug delivery tube is disposed within the anterior chamber of the eye.

[0064] In addition to Example 53 or 54, according to an example (“Example 56”), the second end of the drug delivery tube is disposed within the posterior chamber of the eye.

[0065] In addition to Example 53 or 54, according to an example (“Example 57”), the second end of the drug delivery tube is disposed within the vitreous humor of the eye.

[0066] In addition to Example 53 or 54, according to an example (Example 58), the second end of the drug delivery tube is disposed between the scleral tissue and the choroidal tissue of the eye.

[0067] The foregoing examples are illustrative only and should not be construed as limiting or narrowing the scope of any of the inventive concepts separately provided by the present disclosure. Although multiple examples are disclosed, other embodiments will become apparent to those skilled in the art from the following detailed description which illustrates exemplary examples. Accordingly, the drawings and the detailed description are to be considered as essentially illustrative rather than essentially limiting. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Brief Description of the Drawings The accompanying drawings are included to further understand the embodiments of the present disclosure, are incorporated herein and constitute a part thereof, and serve to illustrate examples and explain the principles of the present disclosure together with the description.

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[0088] It should be understood that, unless otherwise specified, the reproductions of the drawings and photographs are not necessarily to scale. In certain cases, details that are not necessary for understanding the disclosure, or details that make other details difficult to recognize, may be omitted. Of course, it should be understood that the disclosure is not necessarily limited to the specific examples or embodiments illustrated or described in this specification.

Mode for Carrying Out the Invention

[0089] Detailed Description Definitions and Terms The present disclosure should not be construed in a limiting sense. For example, the terms used in this application should be broadly construed in relation to the meanings given to such terms by those skilled in the art. A person skilled in the art can easily understand that the various embodiments of the inventive concept provided in the present disclosure can be realized by any number of methods and devices configured to perform the intended functions. Also, note that the attached drawings referred to in this specification are not necessarily drawn to scale (unless otherwise indicated), and may be exaggerated to explain various aspects of the present disclosure, and in that regard, the drawings should not be construed as limiting. However, some of the drawings represent anatomical structures and the positions of the embodiments relative to those anatomical structures, and such representations should be understood to be accurately scaled and positioned, and some deviation is allowed because the anatomical structures depicted vary in size and position from person to person.

[0090] Regarding the terms of inaccuracy, the terms "about" and "approximately" can be used interchangeably to refer to a measured value, including the stated measured value and measured values reasonably close to the stated measured value. Measured values reasonably close to the stated measured value deviate from the stated measured value by a reasonably small amount, as would be understood and readily confirmed by one of ordinary skill in the relevant art. Such deviations can arise, for example, from measurement errors, differences in calibration of measurement and / or manufacturing equipment, human error in reading and / or setting measured values, minor adjustments made to optimize performance and / or structural parameters in view of differences in measured values related to other components, specific implementation scenarios, inaccurate adjustment and / or operation of an object by a person or machine, and / or the like. If it is determined that one of ordinary skill in the relevant art cannot readily confirm the value of such a reasonably small difference, the terms "about" and "approximately" can be understood to mean plus or minus 10% of the stated value.

[0091] The phrases "at least one", "one or more", and "and / or" are open-ended expressions that have both conjunctive and disjunctive functions. For example, each of the expressions "at least one of A, B, and C", "at least one of A, B, or C", "one or more of A, B, and C", "one or more of A, B, or C", and "A, B, and / or C" means A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. When each of A, B, and C in the above expressions refers to an element such as X, Y, Z, or a class of elements such as X1-X n , Y1-Y m , Z1-Z o etc., this phrase is intended to refer to a single element selected from X, Y, and Z, combinations of elements selected from the same class (e.g., X1 and X2), and combinations of elements selected from two or more classes (e.g., Y1 and Z o ).

[0092] All numeric upper limits set forth throughout this disclosure are alternatively considered to include all lower numeric limits, as if such lower numeric limits were expressly recited herein. All numeric lower limits set forth throughout this disclosure are alternatively considered to include all higher numeric limits, as if such higher numeric limits were expressly recited herein. All numeric ranges set forth throughout this disclosure are considered to include all narrower numeric ranges subsumed therein, as if such narrower numeric ranges were all expressly recited herein.

[0093] Before describing embodiments of the disclosure in detail, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The disclosure is capable of other embodiments and of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of the terms "including," "comprising," "having," and variations thereof herein is intended to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0094] As used herein, the term "fibril" describes an elongate piece of material, such as a polymer, having a length and width that are substantially different from each other. For example, a fibril can resemble a string or fiber piece having a width (or thickness) that is much shorter or smaller than its length. In some instances, the width or thickness of a fibril can be smaller (microscopic) than a fiber piece.

[0095] As used herein, the term "node" describes a connection point of at least two fibrils. Here, the connection can be defined as the location where two fibrils contact each other permanently or temporarily. In some examples, a node is also used to represent a polymer with a volume larger than that of the fibril, and the fibril starts or ends via the node without the same fibril continuing clearly. In some examples, the node is wider and shorter than the fibril.

[0096] As used herein, "node" and "fibril" are not essential but are usually connected or interconnected and can be used to describe an object, for example, of microscopic size. A "microscopic" object has at least one dimension (width, length or height) that is substantially small, such that the object or details of the object are not visible to the naked eye or are difficult to observe without the aid of a microscope (including, but not limited to, a scanning electron microscope or SEM) or any suitable type of magnifying device.

[0097] Description of various embodiments The present disclosure relates to systems, devices, and methods for delivering a drug to a patient's eye. In various embodiments, the drug is an ophthalmic drug configured to treat, for example, ocular hypertension and / or glaucoma by reducing intraocular pressure from undesirably high levels that can lead to a gradual and possibly permanent loss of vision in the affected eye. In various embodiments, the drug delivery device according to the present disclosure is configured to meter the drug release rate of one or more different drugs and thus can be configured to provide a plurality of different release rates, including a plurality of different release rates for a plurality of drugs. Some examples of suitable ophthalmic drugs include therapeutic agents such as prostaglandin analogs (PGAs) (e.g., latanoprost), or beta blockers such as timolol, alpha-2 agonists such as brimonidine tartrate, or carbonic anhydrase inhibitors such as dorzolamide, compounds of carbonic anhydrase inhibitors and beta blockers, and therapeutic agents of other drug classes including compounds of alpha agonists and beta blockers that can be administered in combination with a PGA.

[0098] In some embodiments, such a drug delivery device is configured to be refillable in situ one or more times with minimal invasiveness without the need for an implant procedure and removal of the device from the implant site. Considering the size and subconjunctival target implant site, the implant procedure can be performed outside the operating room where needle punctures and small incisions are commonly performed. Further, some examples include features that help reduce the micro-movement between the device and the tissue into which the device is implanted. Micro-movement can be defined as small movement between the device and the tissue, and the movement can be on the scale of micrometers or millimeters, microseconds or milliseconds. Micro-movement can stimulate the surrounding tissue, which is known to lead to a foreign body tissue reaction and can cause excessive scarring, ultimately erosion of the implanted device, and / or site infection. In some examples, the target implant site can include subconjunctival and / or sub-Tenon's capsule locations of the eye.

[0099] A drug delivery device 100 for measuring the delivery of a drug to eye tissue over a period of time, according to some embodiments, is shown in FIG. 1 (photograph) and FIGS. 3A and 3B (schematic diagrams). The device 100 includes a body portion 102, a tube 104, and a microporous core 106. The body portion 102 has an outer surface 108 that defines an internal reservoir 110. The outer surface 108 defines a port 112 of the body portion 102 that is arranged to provide a first passageway "P1" for the drug from the reservoir 110. The tube 104 has a first end 114, a second end 116 opposite the first end 114, and a lumen 118 that extends between the two ends. The lumen 118 extends along a tube length "L" defined by the distance between the first end 114 and the second end 116.

[0100] In some examples, the body portion 102 can include a flap 120 to which the tube 104 can be attached or adhered, and a suture tab 122 that can be used to attach a suture to the body portion 102 without disturbing or affecting the reservoir 110.

[0101] The length L of the tube 104 defines a second passageway "P2" for the drug that passes through the lumen 118, or more specifically, through the microporous core 106 within the lumen 118. The second passageway P2 extends from the first end 114 to the second end 116, and the drug can exit the lumen 118 from the second end 116 via a third passageway "P3" and be delivered to the tissue at the target location. Thus, the first end 114 is coupled to the port 112 and receives the first passageway P1 of the drug from the reservoir 110, and the second end 116 is disposed at a distance (this distance is the tube length L) from the first end 114 to deliver the drug to the target eye tissue.

[0102] The microporous core 106 is disposed within the lumen 118 along at least a portion of the tube length L, and the core 106 has a porosity that measures a second passageway P2 of the agent as the agent passes through the core 106. In some examples, the core 106 can extend over the entire length L, but in other examples, the core 106 is a portion of the tube length L (e.g., as further described herein, depending on the amount for which it is necessary to meter the agent, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50% or any suitable range or value therebetween).

[0103] In some examples, the agent can be in a first state when disposed at the first end 114 of the tube 104 and in a second state when disposed at the second end 116 of the tube 104. The agent can transition from the first state to the second state as it moves through the core 106 along the second passageway P2.

[0104] In some examples, the first state is a delivery state of the agent that enables delivery of the agent from the reservoir 110 to the core 106, and the second state is a treatment state of the agent that enables the agent to effect a therapeutic treatment on the target tissue. In some examples, the first state is a non-treatment state of the agent and the second state is a treatment state. In some examples, the agent can transition from the first state to the second state while within the reservoir 110 before moving through the first passageway and along the second passageway through the core 106. In some examples, the first state is a high concentration state (or initial state) of the agent and the second state is a low concentration state (or subsequent state of the agent at a concentration lower than the initial state). The low concentration state is at a lower concentration than the high concentration state.

[0105] In some examples, the outer surface 108 of the device 100 can include a resealable opening 301 that can be used to fill or refill the agent in the reservoir 110. In some examples, the outer surface 108 of the device 100 can include a first surface 300 and a second surface 302 opposite the first surface 300. In some examples, the port 112 can be disposed between the first surface 300 and the second surface 302 as shown in FIG. 3B. In some examples, the first surface 300 and the second surface 302 are two components or material layers that are attached at the periphery 304 to form a single body portion 102 that defines the reservoir 110 therein. In some examples, after the device 100 is implanted, the first surface 300 is a surface close to or facing the eye, and the second surface 302 is a surface far from or away from the eye.

[0106] In some embodiments, one or more of the first surface 300 and the second surface 302 can include a microporous microstructure. For example, one or more of the first surface 300 and the second surface 302 can include a biocompatible material such as expanded polytetrafluoroethylene (ePTFE). Further, one or more of the first surface 300 and the second surface 302 can be formed from other biocompatible materials including, but not limited to, biocompatible polymers that may or may not be microporous, such as polyurethane, silicone, polysulfone, polyvinylidene fluoride (PVDF), polyhexafluoropropylene (PHFP), perfluoroalkoxy polymer (PFA), polyolefin, fluorinated ethylene propylene (FEP), acrylic copolymer, and polytetrafluoroethylene (PTFE).

[0107] The first surface and / or the second surfaces 300 and 302 can be in the form of one or more sheets or films, and can include knitted, woven, and / or non-woven fabrics containing individual fibers or multiple fiber strands. In some embodiments, the first surface and / or the second surfaces 300 and 302 can be formed from multiple sheets or films of a polymeric material. In some embodiments, the sheets or films can be laminated or mechanically joined to form the first surface and / or the second surfaces 300 and 302, as well as to form the body portion 102. The joining of the sheets or films can be accomplished by various mechanisms, including heat treatment, high-pressure compression, binders such as one or more adhesives, lamination, or other suitable methods known to those skilled in the art.

[0108] In some embodiments, the adjacent surfaces 300 and 302 and / or the layers of material forming such surfaces 300 and 302 can be partially or fully joined by a thermal method in which each of the polymers forming the material is brought above its melting point. In some embodiments, such a thermal process promotes the formation of adhesive or cohesive bonds between the materials or between the layers of material. In some embodiments, the adjacent surfaces 300 and 302 and / or the layers of material forming such surfaces 300 and 302 can be partially joined by a thermal method in which at least one of the materials is brought above its melting point. Such a thermal process can promote the formation of adhesive or cohesive bonds between the materials or between the layers of material. In some embodiments, one or more suitable adhesives are used to provide a sufficiently bonded interface. The adjacent surfaces 300 and 302, and / or the layers of material forming such surfaces 300 and 302, can be joined at one or more individual locations (such as the periphery 304) to form a stabilizing structure that extends throughout the resulting structure.

[0109] In some examples, the tube 104 and the core 106 can be formed from one or more materials including, but not limited to, PTFE, ePTFE, urethane, polyurethane, silicone (organopolysiloxane), polysulfone, PVDF, PHFP, PFA, polyolefin, FEP, ethylene fluorinated ethylene propylene (EFEP), ethylene tetrafluoroethylene (ETFE), 3'-(2-aminopyrimidyl)-2,2':5',2''-terthiophene (PATT), and acrylic copolymers. In some embodiments, the material can include other biocompatible polymers suitable for forming any one or more of the tube 104 and the core 106, including, but not limited to, silicone-urethane copolymers, styrene / isobutylene copolymers, polyisobutylene, polyethylene-co-poly(vinyl acetate), polyester copolymers, nylon copolymers, fluorinated hydrocarbon polymers, and any copolymers or mixtures of the foregoing can be used. In various embodiments, the elastomer or elastomeric material can include perfluoromethyl vinyl ether and tetrafluoroethylene, (per)fluoroalkyl vinyl ether (PAVE), a copolymer of tetrafluoroethylene and perfluoromethyl vinyl ether, silicone, fluoroelastomer, urethane, butyl rubber, styrene-butadiene, isobutylene-isoprene, or a TFE / PMVE copolymer.

[0110] In some examples, the core 106 is made of ePTFE fibers that have been uniaxially stretched or expanded to form a structure having nodes and fibrils as disclosed herein. In some examples, the core 106 can be stretched or expanded into a helical or spiral shape to form such a structure. In some examples, the core 106 can be formed from ePTFE strips that have been biaxially stretched or expanded to form a structure having nodes and fibrils as disclosed herein. The strip can have, for example, dimensions (e.g., a greater width or thickness) that are larger than those of the fibers. The tube 104 can be formed from an elastomeric compound including, but not limited to, silicone. In some examples, the elastomeric compound can be coated on the outer surface of the core 106 to form a coating disposed on the outer surface. In some examples, the elastomeric compound can be a tape that is wrapped around the outer surface of the core 106, thereby forming the tube 104 that surrounds the core 106. Other suitable methods for manufacturing or producing the tube 104 and the core 106 may also be used.

[0111] In some examples, device 100 can include one or more portions configured to promote and / or permit cell infiltration and / or tissue attachment. The agent can include a single therapeutic agent (e.g., drug) or can include a plurality of therapeutic agents. The agent can include additional materials (e.g., bioabsorbable polymers, pharmaceutically acceptable carriers) that affect the elution of the therapeutic agent (e.g., bioabsorbable polymer) from the delivery device. Throughout the description herein, the agent can be composed of both a therapeutic agent and / or additional materials for effective elution of the therapeutic agent, and thus is also referred to as a drug or a pharmaceutical composition or combination. For example, the agent can include bioabsorbable microparticles having a size in the range of about 0.1 micron to 50 microns, or about 1 micron to 50 microns, or about 5 microns to 50 microns, or about 15 microns to 50 microns, or about 10 microns to 40 microns, or about 15 microns to 25 microns, or about 18 microns to 23 microns. In some embodiments, the bioabsorbable microparticles have an average size of about 20 microns. In a further embodiment, the therapeutic agent retained in the bioabsorbable microparticles can be latanoprost. The bioabsorbable microparticles are retained within device 100 during use, while the agent is released from the bioabsorbable microparticles and thus can be released from device 100. Device 100 can be configured to meter the drug release rate at multiple different release rates for multiple different agents, as described herein.

[0112] As described above, the agent can be a pharmaceutical composition composed of at least one therapeutic agent and at least one additional material such as, but not limited to, bioabsorbable microparticles. The pharmaceutical composition can adopt a first state and can also adopt a second state, and can transition between the first state and the second state. For example, the pharmaceutical composition can transition from the first state to the second state when exposed to a fluid. In certain embodiments, the presence of the fluid can initiate the transition of the composition from the first state to the second state. In some embodiments, the first state corresponds to a non-therapeutic state and the second state corresponds to a therapeutic state, so that in the absence of a sufficient amount of fluid, the therapeutic agent may not be released from the composition (and thus not administered to a patient in need of the therapeutic agent). In the therapeutic state, the amount of the therapeutic agent released from the additional material can be increased compared to the amount released in the non-therapeutic state. In the therapeutic state, the therapeutic agent can be released in a pharmaceutically effective amount sufficient to treat a patient in need of the therapeutic agent. In some embodiments, there is substantially no fluid in the first state.

[0113] In certain embodiments, the fluid comprises water. However, in other embodiments, various other fluids may also be present. In some embodiments, the time required for the provided composition to be converted to the second state varies depending on the application and may be relatively short. For example, in some embodiments, the pharmaceutical composition transitions to the second state in a period of 10 seconds to 1 week after exposure to the fluid (e.g., 30 seconds to 6 days, 1 minute to 5 days, 1 minute to 4 days, 1 minute to 3 days, 1 minute to 2 days, or 1 minute to 1 day).

[0114] Similarly, the time for which the provided composition remains in the second state varies depending on the application and can be relatively long. For example, in some embodiments, the pharmaceutical composition can remain in the second state for a period of from 1 minute to 1 year after exposure to a fluid, and periods subsumed therein, such as 1 hour, 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 8 months, or 11 months. In other words, the daily influx of the drug from the reservoir to the patient's eye is consistent and controllable over that period. Without wishing to be bound by any particular theory, this can be achieved by using pharmaceutically acceptable carrier microparticles of various sizes and geometric complexities, and the conversion of the pharmaceutical composition occurs at different points over several months based on the degradation rate of the additional bioabsorbable material.

[0115] Figures 2A - 2F show several different examples of methods for implanting device 100 within the eye, such as between the conjunctiva and sclera of the eye. Also shown are the anterior chamber (AC), posterior chamber (PC), choroid, retina, lens, and vitreous body (VB) associated with the implant.

[0116] In Figure 2A, tube 104 of device 100 extends through the sclera into the AC, and since the second end 116 is disposed within the AC, tube 104 can deliver the drug to the AC. In Figure 2B, tube 104 of device 100 extends through the sclera into the PC, and since the second end 116 is disposed within the PC, tube 104 can deliver the drug to the PC.

[0117] In FIGS. 2C - 2E, the tube 104 of the device 100 extends through the sclera and choroid to the VB, and since the second end 116 is disposed within the VB, the tube 104 can deliver a drug to the VB. In FIG. 2C, the tube 104 is slightly curved such that the second end 116 of the tube 104 faces the center of the eye. In FIG. 2D, the tube 104 is angled or bent more than the tube 104 of FIG. 2C, and the second end 116 is directed towards the front of the eye, e.g., the lens. In FIG. 2E, the tube 104 is not angled or is straight as compared to the tube 104 of FIG. 2C, and the second end 116 is directed towards the back of the eye, e.g., the retina.

[0118] In FIG. 2F, the tube 104 is arranged such that the second end 116 is positioned between the choroid tissue and the sclera tissue, whereby a drug can be delivered, particularly to the region or area between them.

[0119] In an embodiment, the drug delivery device 100 can be useful for the treatment of glaucoma. Glaucoma is a progressive loss of vision associated with high eye pressure. For the treatment of glaucoma, the drug delivery device 100 can be implanted at least partially subconjunctivally (e.g., at or near the position from the limbus of the eye to the pars plana). Among other advantages, for example, by using the drug delivery system described herein for the treatment of glaucoma, which reduces tissue abrasion and has a refillable element of the drug delivery system, the common problem of patient compliance when using previously established treatment methods can be overcome. For example, using an implantable medical delivery system reduces the chance that a patient forgets to administer the drug daily, such as by using eye drops.

[0120] In some instances, macular degeneration of the retina can be treated using embodiments of the drug delivery device 100. Wet macular degeneration is a chronic eye disease with abnormal blood vessel growth under the macula, which is responsible for central vision in the eye. In conventional established treatments for macular degeneration, a needle is inserted into the eye to penetrate the blood-aqueous barrier. One advantage of the presently presented embodiments is that, among other advantages, this invasive technique can be eliminated and the treatment can be performed with minimal invasion. For the treatment of macular degeneration, the drug delivery device 100 can be implanted at least partially subconjunctivally and at least partially suprachoroidally (e.g., in the posterior part of the eye socket of the eye).

[0121] Other retinal diseases such as macular edema of the retina can be treated using embodiments of the drug delivery device 100. Macular edema is a chronic eye disease with distorted vision due to swelling of the macula, which is responsible for central vision in the eye. For the treatment of macular edema, the drug delivery device 100 is implanted at least partially subconjunctivally and at least partially suprachoroidally (e.g., in the posterior part of the pars plana of the eye). The drug delivery device 100 can be implanted and disposed at one or more implantation positions or sites for delivering a drug for the treatment of macular edema.

[0122] Another retinal disease that can be treated using embodiments of the drug delivery device 100 is retinitis. Retinitis is an eye disease with inflammation of the retina. For the treatment of retinitis, the drug delivery device 100 can be implanted at least partially subconjunctivally and at least partially suprachoroidally (e.g., in the posterior part of the ciliary body of the eye). In an embodiment, the drug delivery device 100 can be implanted and disposed at one or more implantation positions or sites for delivering a drug for the treatment of retinitis.

[0123] Yet another retinal disease that can be treated using an embodiment of the drug delivery device 100 is retinoblastoma, a form of eye cancer. For the treatment of retinoblastoma, the drug delivery device 100 can be implanted at least partially subconjunctivally and at least partially suprachoroidally (e.g., in the posterior portion of the pars plana of the eye). In an embodiment, the drug delivery device 100 can be implanted and positioned at one or more implantation locations or sites for delivering a drug for the treatment of retinoblastoma.

[0124] Retinal vein occlusion is a retinal disease that can be treated using an embodiment of the drug delivery device 100. Retinal vein occlusion, such as CRVO and BRVO, is an occlusion of one or more retinal veins. These occlusions can lead to excessive blood and fluid in the retina. For the treatment of retinal vein occlusion, the drug delivery system can be implanted at least partially subconjunctivally and at least partially suprachoroidally (e.g., in the posterior portion of the ciliary pars plana of the eye). In an embodiment, the drug delivery device 100 can be implanted and positioned at one or more implantation locations or sites for delivering a drug for the treatment of retinal vein occlusion.

[0125] The present disclosure includes devices and methods suitable for the treatment of corneal diseases. Some such corneal diseases include keratitis and dry eye. In some examples, the reservoir 110 or the tube 104 can dispense the drug from opposite sides of the reservoir 110 or the tube 104 such that the drug is released in the intraocular direction towards the eye and also in the conjunctival direction away from the eye.

[0126] Keratitis can be treated using an embodiment of the drug delivery device 100. Keratitis is an inflammation of the cornea. For the treatment of keratitis, the drug delivery device 100 can be implanted subconjunctivally (e.g., near the edge of the eye).

[0127] Dry eye is another corneal disease that can be treated using an embodiment of the drug delivery device 100. Dry eye is a condition where the lubrication of the eye's tear film is insufficient. For the treatment of dry eye, the drug delivery device 100 can be implanted subconjunctivally. In an embodiment, the drug delivery device 100 can be implanted and placed at one or more implant locations or sites for delivering a drug for the treatment of dry eye.

[0128] Yet another disease that can be treated using an embodiment of the drug delivery device 100 is presbyopia, which is the hardening of the lens of the eye. For the treatment of presbyopia, the drug delivery system can be implanted subconjunctivally. In an embodiment, the drug delivery device 100 can be implanted and placed at one or more implant locations or sites for delivering a drug for the treatment of presbyopia.

[0129] In some examples, the device 100 can be used when deploying gene therapy to prevent glaucomatous neurodegeneration for the treatment of age-related macular degeneration, retinitis pigmentosa, geographic atrophy, macular edema and diabetic retinopathy. In some examples, gene therapy is achieved by sustained administration of any of a viral transduction vector, an adeno-associated virus (AAV) vector, a polymer-based nanoparticle, a liposome or a compressed nucleic acid nanoparticle.

[0130] In view of the above, the drug delivery device 100 can be implanted at any suitable location in the eye according to the disease to be treated using the drug, whereby the drug to be administered can be effectively metered to the appropriate eye tissue. For example, the drug delivery device 100 can be disposed near the eye tissue. A tube 104, which can be a drug delivery tube, extends from a port 112 of the body portion 102 (providing a first passage P1 of the drug from the reservoir 110 to the port 112) at a first end 114 of the tube 104, and the second end 116 of the tube 104 is disposed in fluid contact with the eye tissue, providing a second passage P2 of the drug from the port 112 to the second end 116 of the tube 104. The drug is delivered from the second end 116 through a microporous core 106 disposed within the tube 104, and the microporous core 106 has a porosity that meters the second passage P2 of the drug.

[0131] In some examples, the tube 104 of the drug delivery device 100 can be disposed near the eye tissue. The second end 116 of the tube 104 can be disposed to establish fluid contact with the eye tissue. The drug is delivered from the second end 116 through a core 106 disposed within the tube 104. This core 106 has a porosity that meters the passage P2 of the drug from the first end 114 to the second end 116 of the tube 104.

[0132] As shown in FIGS. 3C and 3D, the core 106 is disposed within the tube 104 so as to substantially fill the interior of the tube 104 or, as shown, the lumen 118 of the tube 104 having an inner diameter “r”. The core 106 can include a plurality of nodes 306 and fibrils 308, which can be interconnected with each other and with the surrounding tube 104. In different examples, the nodes 306 and fibrils 308 are arranged and interconnected in different ways to control the flow of the second passage P2 of the agent in different ways, for example, to allow a faster flow or a slower flow, which will be further described herein. In some examples, the passage P2 of the agent is controlled or measured by the surface roughness and surface energy of the nodes 306 and fibrils 308 of the core 106. Frictional forces are generated by the surface roughness of the nodes 306 and fibrils 308, and the flow of the agent (fluid and particles) through the core 106 can be controlled or restricted. The intermolecular bonds of the agent are disrupted by the surface energy of the nodes 306 and fibrils 308, and thus the flow of the agent through the core 106 can be controlled or restricted.

[0133] Figures 4A - 4G show different examples of embodiments as disclosed herein, and the drug delivery device 100 includes a tube 104 and a microporous core 106, and may or may not include the body portion 102 as described above. When there is no body portion 102, the tube 104 and the core 106 facilitate the metering of the drug transported therethrough, and thus the device may be referred to as a "drug metering device". The tube 104 has a first end 114, a second end 116 opposite the first end 114, and a lumen 118 extending along the tube length L. The microporous core 106 is disposed within the lumen 118 along at least a portion (part or all) of the tube length L. The core 106 has a porosity that facilitates the metering passage of the drug from the first end 114 through the core 106 to the second end 116, as shown as P2 in the figure. The drug is in a first state when disposed at the first end 114, in a second state when disposed at the second end 116, and transitions from the first state to the second state when moving along the metering passage (P2).

[0134] The first end 114 of the tube 104 includes a drug receiving portion 400 sized to receive the drug in the first state. The drug receiving portion 400 is arranged to direct the drug in the first state to the core 106. The drug is directed from the drug receiving portion 400 to the core 106 via a first passage P1 as shown in the figure.

[0135] In Figure 4A, the drug receiving portion 400 includes a microporous drug receiving component 402 having a porosity different from that of the core 106. For example, the component 402 can be made of the same material or a different material as the material of the core 106, and is configured or manufactured to gradually release the drug stored in the component 402 to the core 106 via the first passage P1, and then the drug passes through the core 106 via the second / metering passage P2 and is finally released from the second end 116 of the tube 104 via a third passage P3.

[0136] It should be understood that the first end 114 may be substantially closed or substantially open. When substantially closed, the drug stored in the component 402 is prevented from being released into the environment through the first end 114. When substantially open, the component 402 may be formed as a seal that prevents the release of the drug through the substantially open first end 114. In some examples, such a seal may be formed by attaching or fusing the end of the component 402 that does not contact the core 106 to another component having a porosity of zero or very low compared to the porosity of the component 402 (the very low porosity is, for example, almost negligible compared to the porosity of the core 106 and the component 402). In some examples, the seal is formed by applying a specific treatment such as melting, disintegrating, binding, or other suitable means applicable to the end of the component 402, whereby the porosity of the treated end of the component 402 (the end that does not directly contact the core 106) is sufficiently reduced to facilitate the reduction of the drug released through the substantially open first end 114.

[0137] In FIG. 4B, the first end 114 is substantially closed, and the drug receiving portion 400 includes a drug receiving space 404 defined as a portion of the lumen 118 surrounded on one side by the closed first end 114 of the tube 104 and on the other side by the end of the core 106 close to the first end 114. The space 404 can initially or temporarily store the drug inside, whereby the drug gradually enters the core 106 through the first passage P1, then the drug passes through the core 106 through the second / measurement passage P2, and then is released from the lumen 118 of the tube 104 through the third passage P3.

[0138] In FIGS. 4C - 4F, the first end 114 is substantially open, and the drug receiving portion 400 (shown in some figures as including a drug receiving space 404, but alternatively or additionally may include a microporous drug receiving component 402 as appropriate) receives drug from the ambient environment 406 external to the tube 104. The environment 406 can be a body region different from the target region where the drug is delivered. For example, the environment 406 that initially temporarily stores the drug can be the subconjunctival space where the first end 114 is located, and the second end 116 can be placed at different locations such as AC (FIG. 2A), PC (FIG. 2B), VB (FIGS. 2C - 2E), or between the sclera and choroid (FIG. 2F) among other suitable places. Thus, the starting passage "P0" is defined in these examples as the passage through which the drug enters the drug receiving portion 400 from the environment 406, and then the drug enters the core 106 from the drug receiving portion 400 via the first passage P1.

[0139] In FIG. 4C, since the drug does not change state or properties from passage P0 to passage P1, the starting passage P0 and the first passage P1 can be considered substantially the same passage. However, in FIG. 4D, the drug is filtered as it passes through a filter or membrane 408 disposed at the first end 114 of the tube 104 via the starting passage P0. This portion or membrane 408 filters the drug when received from the environment 406, thereby filtering out undesired tissue or foreign matter and reducing the amount of undesired material allowed to enter the core 106.

[0140] In FIGS. 4E and 4F, either the first end 114 or one of the cores 106 can have an angled section that is cut or trimmed at a substantial angle to the longitudinal axis of the tube 104. In FIG. 4E, the first end 114 is angled, forming an angled first end 410. In FIG. 4F, the end of the core 106 near the first end 114 is angled, forming an angled section 412. The purpose of the angling is to increase the cross-sectional area of the angled end so that more drug can pass through compared to before angling (i.e., when the end is substantially perpendicular to the longitudinal axis of the tube 104). Specifically, the angled first end 410 increases the flow rate of the passage P0, and the angled section 412 of the core 106 increases the flow rate of the passage P1.

[0141] In FIG. 4G, both the first end 114 and the core 106 are angled, and the angled first end 410 of the tube 104 and the angled section 412 of the core 106 are flush with each other. This can be achieved by cutting or trimming both the first end 114 and the core 106 at an angle simultaneously.

[0142] FIGS. 5A - 5D show different configurations of the nodes 306 and fibrils 308 forming the core 106 according to the embodiments disclosed herein, and the diffusion directions are shown in FIGS. 5A - 5C. At the bottom of FIG. 5A, it is marked "5.0kV 13.1mm x1.00k LA1(UL) 2 / 15 / 2017", and the distance between two consecutive lines shown in the lower right corner represents 5.0μm. At the bottom of FIG. 5B, it is marked "10.0kV 9.0mm x500 SE 7 / 6 / 2022", and the distance between two consecutive lines shown in the lower right corner represents 10μm. At the bottom of FIG. 5C, it is marked "10.0kV 4.0mm x500 SE 7 / 7 / 2022", and the distance between two consecutive lines shown in the lower right corner represents 10μm.

[0143] FIG. 5D shows a cross-sectional view of the same core 106 as in FIG. 3D. At the bottom of FIG. 5D, it is marked with "5.0 kV 15.8 mm x1.00 k SE(UL) 2 / 16 / 2017", and the distance between the two continuous lines shown in the lower right corner represents 5.0 μm. As shown, node 306 is formed by aggregating or fusing a plurality of fibrils 308, and when the drug passes through core 106 in the diffusion direction, its diffusion rate can be reduced. In some examples, the diffusion direction defines a general direction in which the drug is configured to move through passage P2.

[0144] FIGS. 6A-6C show various examples of a method of metering the flow of a drug by nodes 306 and fibrils 308 affecting the transport rate of passage P2 through which the drug passes through core 106 in the diffusion direction as shown. The number of nodes 306 and fibrils 308 and their relative positions to each other can significantly affect the rate at which drug transport occurs (e.g., the rate at which the drug moves from the first end 114 to the second end 116 of tube 104).

[0145] According to Fick's first law, the flux, i.e., the amount of drug moving per unit area per unit time, can be expressed by the following equation

Equation

Equation

[0146] Therefore, based on the above formula, when the porosity of the core 106 decreases, the amount of material in the core 106 increases, and it operates such that the effective area of elution from the tube 104 decreases. Further, since the tube length (dx) is inversely proportional to the migration rate of the drug, increasing the tube length L also decreases the migration rate of the drug. Such an increase in length can be confirmed in the example shown in FIG. 7C, which will be further described here.

[0147] Furthermore, the velocity is proportional to the diffusion rate D, and the diffusion rate is affected by the curvature within the microstructure of the core 106 and can be controlled by changing the microstructure of the core 106, such as the positions and interconnectivities of the nodes 306 and fibrils 308 that make up the structure of the core 106.

[0148] In FIG. 6A, the dashed arrow lines each represent one possible passage P2 through the nodes 306 and fibrils 308 of the core 106 according to an example of the microstructure of the core 106. The line passes through the fibril 308 but cannot pass through the node 306, so it avoids the node 306 when passing around it. In FIG. 6B, the microstructure is changed such that the number of nodes 306 present in the core 106 increases, and compared to the example of FIG. 6A, the passage P2 is forced to move around each node 306 in the defined general direction of diffusion, and the drug transport rate decreases compared to FIG. 6A. In FIG. 6C, the microstructure is changed such that the number of nodes 306 present in the core 106 decreases, and compared to FIG. 6A, the passage P2 can move relatively linearly and there is less need for the passage P2 to bypass the node 306, thus increasing the drug transport rate through the microstructure. Therefore, the porosity of the nodes can define the drug transport rate and the node density. As the arrangement density of the nodes 306 increases, the drug transport rate becomes lower when the passage P2 moves in a more tortuous manner.

[0149] In some examples, the composition ratio and / or porosity or density of the node-to-fibril of the microstructure can affect the drug transport rate. For example, when there are fewer nodes and more fibrils, the transport rate increases. For example, when the microstructure has a more open configuration (high porosity and low density), the transport rate also increases.

[0150] Figures 7A - 7D show examples of drug delivery device 100 according to the embodiments disclosed herein. Device 100 includes a port 112 disposed on either of these surfaces, rather than between the first surface 300 or the second surface 302 at the periphery 304, as disclosed, for example, in FIG. 3B. The figures show port 112 disposed on the first surface 300 such that tube 104 extends from a surface close to the eye or a surface facing the eye after implantation, but in some examples, port 112 is disposed on the second surface �, and tube 104 extends around body portion 102 and then the second end 116 can reach the targeted tissue of the eye configured to be inserted as appropriate.

[0151] In FIG. 7B, a substantial portion (i.e., the majority) of the tube 104 (or the length of the tube) is disposed outside the reservoir 110. Thus, looking at FIG. 7B, more than 50%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, or any suitable range or value therebetween (including the end values) of the tube 104 can be disposed outside the reservoir. In FIG. 7C, a substantial portion of the tube 104 is disposed inside the reservoir 110 (referred to as the internal portion 700). The substantial portion can be defined as more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or any suitable range or value therebetween (including the end values) of the total length L of the tube 104. Thus, looking at FIG. 7C, less than about 40%, less than about 30%, less than about 20%, or any suitable range or value therebetween (including the end values) of the tube 104 can be disposed outside the reservoir. In some examples, 10% to 40% (including the end values) of the tube 104 can be disposed outside the reservoir, i.e., the internal portion 700 is 60% to 90% (including the end values) of the total length L of the tube 104. Thus, the tube 104 can be disposed within the reservoir 110 so as to increase the length L of the tube 104 in order to appropriately control the rate of migration of the agent through the core 106 that can extend through a part or all of the lumen 118 of the tube 104. This is because, as explained above with respect to Equation 2, increasing the length L of the tube promotes a decrease in the rate of migration of the agent therein.

[0152] In FIG. 7D, the internal portion 700 of the tube 104 has a plurality of density diffusion openings 702 through which the core 106 is exposed to the reservoir 110. Thus, these openings 702 in the tube 104 form a plurality of locations through which the agent can enter the core 106 by density diffusion via the first passage P1 and can provide, for example, additional means for controlling the metering of the agent through the core 106.

[0153] Figures 8A and 8B, 9A and 9B, and 10A and 10B show ways in which the device 100 can be positioned from outside the eye into different layers of the eye to effectuate intraocular drug delivery, in accordance with embodiments disclosed herein.

[0154] In FIGS. 8A and 9A, the body portion 102 is positioned subconjunctivally, the reservoir 110 is between the conjunctiva and the sclera, while the tube 104 extends through the sclera, choroid, and retina, and the second end 116 is positioned within the VB to deliver the drug intraocularly. These examples correspond to the examples shown in FIGS. 2C - 2E. In FIGS. 8B and 9B, the tube 104 extends only through the sclera, with a portion thereof between the sclera and the choroid, and the second end 116 can be positioned to effectuate intraocular drug delivery to a target space defined between the sclera and the choroid. These examples correspond to the example shown in FIG. 2F.

[0155] In FIG. 10A, the first end 114 of the tube 104 is positioned subconjunctivally, the microporous drug receiving component 402 is between the conjunctiva and the sclera, the tube 104 extends through the sclera, choroid, and retina, and the second end 116 is positioned within the VB to deliver the drug intraocularly. In FIG. 10B, the tube 104 extends only through the sclera, with a portion thereof between the sclera and the choroid, and the second end 116 can be positioned to effectuate intraocular drug delivery to a target space defined between the sclera and the choroid.

[0156] Component 402 is shown for illustrative purposes, but it should be understood that any suitable drug receiving portion 400, such as drug receiving space 404, can also be implemented. For example, the drug can be disposed in the region between the conjunctiva and the sclera, and the first end 114 of tube 104 can receive the drug from the region defined as the surrounding environment 406. In such a case, it should be understood that the surrounding environment 406 where the drug is initially temporarily stored is different from the target space where the drug is delivered. The target space can be any suitable region within the eye, including, but not limited to, VB (FIG. 10A) and the region between the sclera and the choroid (FIG. 10B) as shown.

[0157] FIGS. 11A-11D and 12A-12D show different ways of achieving drug delivery metering using different types of drug carrier polymers according to the embodiments disclosed herein. Any material and delivery process suitable for the drug carrier polymer can be implemented in the art, for example, as known in Sun T, Zhang YS, Pang B, Hyun DC, Yang M, Xia Y "Engineered Nanoparticles for Drug Delivery in Cancer Therapy", Angew Chem Int Ed Engl. 2014 Nov ten; 53(46):12320-64, doi: 10.1002 / anie.201403036. Epub 2014 Oct 7. PMID: 25294565, and the entire above-mentioned document is incorporated herein by reference.

[0158] In FIG. 11A, a non-biodegradable drug carrier polymer 1100 (or insoluble polymer film) that stores pre-loaded drug molecules 1102 internally for delivery is provided. In some examples, polymer 11o0 can also include an aqueous solution 1104 to facilitate the controlled delivery of drug molecules 1102 from polymer 1100 by diffusion. In some examples, instead of aqueous solution 1104, an internal polymer matrix is provided in polymer 1100 to prevent premature release of drug molecules 1102, as known in the art.

[0159] In FIG. 11B, polymer 1100 gradually releases drug molecule 1102 by controlled diffusion such that drug molecule 1102 is released and can no longer be trapped within polymer 1100. In FIG. 11C, the released drug molecule 1102 moves from the first end 114 into the microporous core 106 within tube 104 via the passage P1 shown in FIG. 11B, and drug molecule 1102 moves from the first end 114 to the second end 116 using diffusion through passage P2. In FIG. 11D, drug molecule 1102 is delivered to the target region via passage P3, while the non-biodegradable drug carrier polymer 1100 remains near the first end 114 on the opposite side of tube 104.

[0160] The drug molecule 1102 selectively permeates the core 106 and the access to the polymer 1100 is restricted due to the internal microstructure (e.g., nodes 306 and fibrils 308) of the core 106. Specifically, the internal microstructure is formed to pre-select the porosity of the core 106 in order to correspond to the molecular shape, molecular weight, and / or molecular polarity of the drug molecule 1102. For example, the internal microstructure can be pre-selected to allow the passage of a drug molecule 1102 having a predetermined molecular shape, a predetermined molecular weight, and / or a predetermined molecular polarity. That is, for each type of drug, the microstructure of the core 106 can be appropriately changed to prevent a compound or molecule having a larger molecular shape or molecular weight than the selected drug, or a molecular polarity different from the selected drug, from entering the core 106 or completely passing through the core 106 from the first end 114 to the second end 116. Thus, in some examples, nodes 306 and fibrils 308 can trap molecules of larger foreign particles therein, as shown in the embodiments of FIGS. 12A-12D, as further described herein.

[0161] In FIG. 12A, the drug molecule 1102 is pre-loaded into an erodible or biodegradable drug carrier polymer 1200 and initially stored. The polymer 1200 can be adjusted to control the erosion rate, whereby the polymer 1200 is decomposed at a predetermined rate and the drug molecule 1102 can be released. In FIG. 12B, the polymer 1200 is gradually eroded or decomposed into smaller degraded polymer particles 1202, while leaving the non-decomposed polymer 1204.

[0162] When released, as shown in FIG. 12C, the drug molecule 1102 enters the core 106 from the first end 114 via the passage P1 and moves towards the second end 116 via the passage P2. In this way, some of the decomposed polymer particles 1202 may also enter the microstructure of the core 106, while the non-decomposed polymer 1204 remains near the first end 114 outside the core 106, and all of the non-decomposed polymer 1204 is finally eroded into small particles 1202, at which point the particles 1202 can enter the core 106.

[0163] In FIG. 12D, the drug molecule 1102 is delivered from the second end 116 to the target region via the passage P3. In some examples, the microstructure of the core 106 traps the polymer particles 1202 therein and prevents the particles 1202 from entering the target region. This is beneficial for reducing the amount of carrier polymer entering the target region or preventing the carrier polymer from entering the target region until it is eroded small enough to pass through the microstructure. In any case, the microstructure of the core 106 can reduce the delivery of large foreign particles to the target region, thereby improving the safety for the user of the device 100.

[0164] In some examples, as shown in FIG. 13, the drug molecule 1102 can be delivered from the first end 114 to the second end 116 in response to a concentration difference (concentration gradient) of the drug molecule 1102 between the two ends 114, 116. The concentration gradient is widely used in the medical field to transport fluids and drugs, as described in Sulaiman, D & Suhaimi, H & Shamsuddin, Norazanita. (2020). “Estimating glucose diffusion coefficient of membranes for tissue engineering applications using Fick’s First Law.” IOP Conference Series: Materials Science and Engineering. 991. 012103. 10.1088 / 1757-899X / 991 / 1 / 012103, and the entire content of the above reference is incorporated herein by reference. Thus, due to the concentration gradient indicating that the concentration of the drug molecule 1102 is higher at the first end 114 (or the high-concentration region 1300 surrounding the first end 114) than at the second end 116 (or the low-concentration region 1302 surrounding the second end 116), the drug molecule 1102 is diffusively transported through the passage P2 through the core 106. Therefore, drug transport continues until the concentration gradient disappears, i.e., until the concentrations of the drug molecule 1102 in regions 1300 and 1302 are the same.

[0165] FIG. 14 shows a microscopic view of the microporous material on the outer surface 108 of the body portion 102 of the drug delivery device 100 according to some embodiments. Shown at the bottom of FIG. 14 is "5.00 kV 4.2 mm x500 SE 1 / 23 / 2018", and the distance between two consecutive lines shown in the lower right corner represents 10 μm. For example, the microporous material of FIG. 14 can be referred to throughout with respect to a medical implant device or system. As will be understood by those skilled in the art with reference to FIG. 14, the microporous aspects and parameters of the microporous material can be defined in various ways. When applying a microporous material to an ophthalmic device such as the drug delivery device 100 described herein, which is configured to be placed in situ within the eye tissue to facilitate drug delivery to the eye for the treatment of disease, the microporous properties of such a microporous material can generally be characterized by a volume porosity value defined as the ratio of the volume of air or fluid contained within the microporous material to the total volume (or gross volume) of the microporous material.

[0166] In another definition, the volume porosity can be defined as the percentage of the volume of the microporous material occupied by non-structural or transient elements such as air or other fluids. For example, if the total volume is 100 mm 3 and the chamber that holds air or fluid within it occupies a volume of 30 mm 3 the microporous material has a volume porosity value of 0.3 because 30% of the volume of the microporous material is empty or is a transient space filled with air or other fluid.

[0167] As can be understood, the two microporous materials can have the same volume porosity, but can have different pore sizes presented to the inflowing or outflowing air or fluid. For example, the first material can have a small number of large pores dispersed in a constant total volume, and the second material can have a relatively large number of relatively small pores dispersed in the same constant volume. If the air / fluid volumes of the two materials are the same, both microporous materials can have the same volume porosity.

[0168] As can be further understood, the properties of the microporous materials used in the device can be defined by the size of the passage through the microporous material, and can similarly be defined as the pore size measured at the location where the passage ends on the surface of the microporous material or along the length of the passage within the material. Microporous materials with small pores or passages can impede the flow through the material, and relatively large pores or passages can increase the passage of air or fluid into, out of, or within the microporous material.

[0169] As can still further be understood, the properties of the microporous material can also be defined by the curvature of the passages entering and passing through the material, and relatively small or large passages can impede the fluid flow path due to the frequency of passage curvature or the arrangement of obstacles within the fluid flow path. The air / fluid passage rate of the microporous material can be managed by controlling or defining any of the above properties of the material, and a material suitable for use in facilitating the delivery of a drug to the eye for the treatment of a disease can be provided.

[0170] For simplicity, the foregoing properties and variables of the microporous materials used in the various embodiments and examples described herein can be represented simply as porosities that can be based on volume porosity, pore or channel size, or tortuosity metric. Referring again to FIG. 14, the interior portion of the microporous material can have various porosities (or volume porosity or pore size or tortuosity). The interior portion can extend between the inner surface 1400 and the outer surface 108.

[0171] In any of these portions of the body portion 102, the porosity can be in the range of micropore size (SP), medium micropore size (MSP), mesopore size (MP), medium macropore size (MLP), and macropore size (LP) for comparison. For the purposes of the description herein, assuming that the delivery moves along a relatively straight passage through the microporous material such that the delivery engages the pores of the inner surface 1400, the uniform interior portion, and the outer surface 108 in sequence, the combined flow resistance can likewise be represented by connecting the respective pores. For example, the inner surface 1400 typically has a low porosity throughout (e.g., to resist ingrowth of tissue into the reservoir 110), and the interior portion and a portion of the outer surface 108 can have any of the foregoing porosities. Under these circumstances, when the interior portion has a medium porosity, for example, and the outer surface 108 has a high porosity, drug delivery through the microporous material from the reservoir 110 to the surrounding tissue of the device can be represented as SP-MP-LP. More examples will be described below.

[0172] Within the microporous material, various delivery channels can exist. Relatively straight flow channels can include, for example, the SP1-SP4-SP5 region, or the SP3-MLP1-MP1-MSP1 region. Some flow channels can be relatively straight, but there are also non-linear flow channels. For example, under certain conditions, at least a portion of the flow can continue to flow through regions where the resistance gradually decreases, such as SP1-LP1-LP2 or SP3-MLP1-LP1-LP2. As can be understood, the microstructure of the microporous material can undergo a modification process to obtain a specific type of flow through the microstructure. For example, the microstructure can have a relatively uniform layer across the inner layer of the microstructure, or, as shown here, can have variable portions throughout the thickness of the microporous material.

[0173] In some examples, the body portion 102 defines the thickness of a wall portion extending between the inner surface 1400 and the outer surface 108. The thickness of the wall portion can define an internal region of the body portion 102 having a transitional porosity between the porosity of the low-porosity surface of the inner surface 1400 (e.g., having a smaller pore size) and the porosity of the high-porosity surface of the outer surface 108 (e.g., having a larger pore size). Additionally or alternatively, the internal region can have an internal region porosity equal to the porosity of the low-porosity surfaces of the inner surface 1400 and the outer surface 108. Additionally or alternatively, the internal region can have an internal region porosity equal to the porosity of the low-porosity surface of the inner surface 1400. Additionally or alternatively, the internal region can have an internal region porosity equal to the porosity of the high-porosity surface of the external surface 108.

[0174] Referring further to the microporous material shown in FIG. 14, the fluid passage can also be affected by the concentration gradient between a fluid such as water and the agent in reservoir 110. More specifically, during the drug delivery process, the agent is first contained within reservoir 110. Next, the fluid is delivered to reservoir 110 through the microporous material, and the agent leaches out of the microporous material to reach the target delivery site. Although described herein as having layers or strata, the microporous material can have distinct discrete layers, or alternatively, as described above, can include regions of different porosities through which the fluid and agent pass. The drug delivery device 100, and more specifically the microporous material of drug delivery device 100, can also be optimized for target delivery. In other words, the region in which the microporous material is incorporated can be selected such that the agent can be delivered only to the target site surrounding device 100.

[0175] Without departing from the scope of the present disclosure, various changes and additions can be made to the exemplary embodiments described. For example, while the embodiments described above refer to specific features, the scope of the present disclosure includes embodiments having different combinations of features and embodiments that do not include all of the described features. Accordingly, the scope of the present disclosure is intended to encompass all such alternatives, modifications, and variations, and all equivalents thereof, that fall within the scope of the claims.

Claims

**Claim 1** A drug delivery device for metering the delivery of a drug to eye tissue over a period of time, the device comprising: a body portion having an outer surface defining an internal reservoir; a tube having a first end, a second end opposite the first end, and a lumen extending along a tube length therebetween; and a microporous core disposed within the lumen along at least a portion of the tube length; wherein the outer surface defines a port of the body portion arranged to provide a first passage for the drug from the reservoir; the tube length defines a second passage for the drug from the first end to the second end, the first end being coupled to the port for receiving the first passage of the drug from the reservoir, the second end being disposed at a distance from the first end for delivering the drug to eye tissue; the microporous core has a porosity for metering the second passage of the drug; a drug delivery device. **Claim 2** The device according to claim 1, wherein the drug has a first state when disposed at the first end of the tube and a second state when disposed at the second end of the tube, and the drug transitions from the first state to the second state when moving through the microporous core along the second passage. **Claim 3** The device according to claim 2, wherein the first state is a delivery state of the drug and the second state is a therapeutic state of the drug. **Claim 4** The device according to claim 2, wherein the first state is a non-therapeutic state of the drug and the second state is a therapeutic state of the drug. **Claim 5** The device according to claim 2, wherein the first state is a high-concentration state of the drug and the second state is a low-concentration state of the drug, and the low-concentration state has a lower concentration than the high-concentration state. **Claim 6** The device according to any one of claims 1 to 5, wherein the microporous core includes a plurality of nodes and fibrils configured to meter the second passage of the drug. **Claim 7** The device according to claim 6, wherein the second passage of the drug is configured to be metered by the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core. **Claim 8** The device according to any one of claims 1 to 7, wherein the tube is a coating disposed on the outer surface of the microporous core.

9. The device according to any one of claims 1 to 7, wherein the tube is a tape wound around the outer surface of the microporous core.

10. The device according to any one of claims 1 to 9, wherein the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular shape.

11. The device according to any one of claims 1 to 9, wherein the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular weight.

12. The device according to any one of claims 1 to 9, wherein the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular polarity.

13. The device according to any one of claims 1 to 12, wherein the outer surface of the body portion includes a first surface and a second surface opposite the first surface, and the port is disposed between the first surface and the second surface.

14. The device according to any one of claims 1 to 12, wherein the outer surface of the body portion includes a first surface and a second surface opposite the first surface, and the port is disposed on the first surface.

15. The device according to claim 14, wherein the first end of the tube is disposed within the reservoir such that a majority of the tube length is disposed within the reservoir.

16. The device according to claim 15, wherein a majority of the tube disposed within the reservoir is configured to partially cover the microporous core and provide a plurality of density diffusion openings.

17. The device according to claim 15 or 16, wherein 10% to 40% of the tube length is disposed outside the reservoir.

18. The device according to any one of claims 1 to 17, wherein the body portion includes a resealable opening through which the reservoir is configured to be refilled with the drug to be delivered.

19. A drug metering device for metering the delivery of a drug to eye tissue over a period of time, the drug metering device comprising A tube having a first end, a second end opposite the first end, and a lumen extending along the tube length therebetween, and, A microporous core disposed within the lumen along at least a portion of the tube length, A drug metering device comprising: The microporous core has a porosity that provides a metering passage for the drug through the microporous core from the first end of the tube towards the second end of the tube, The drug has a first state when disposed at the first end of the tube and a second state when disposed at the second end of the tube, and the drug transitions from the first state to the second state as it moves along the metering passage, and, The first end of the tube includes a drug receiving portion sized to receive the drug in the first state and positioned to direct the drug in the first state to the microporous core.

20. The device according to claim 19, wherein the first state is a delivery state of the drug and the second state is a therapeutic state of the drug.

21. The device according to claim 19, wherein the first state is a non-therapeutic state of the drug and the second state is a therapeutic state of the drug.

22. The device according to claim 19, wherein the first state is a high concentration state of the drug and the second state is a low concentration state of the drug, and the low concentration state is at a lower concentration than the high concentration state.

23. The device according to any one of claims 19 to 22, wherein the drug receiving portion includes a microporous drug receiving component having a porosity different from the porosity of the microporous core.

24. The device according to any one of claims 19 to 22, wherein the first end is substantially closed and the drug receiving portion is a drug receiving space within the lumen where the drug is temporarily stored for delivery.

25. The device according to any one of claims 19 to 23, wherein the first end is substantially open and the drug receiving portion is configured to receive the drug from the surrounding environment external to the tube.

26. The device according to claim 25, further comprising a filtration membrane disposed at the first end and configured to filter the drug received from the surrounding environment.

27. The device according to claim 25, wherein the first end portion is angled with respect to the tube length.

28. The device according to claim 25 or 27, wherein the section of the microporous core near the first end of the tube is angled with respect to the tube length.

29. The device according to any one of claims 25 to 28, further comprising a body portion having an outer surface defining an internal reservoir, the outer surface defining a port of the body portion being coupled to the first end of the tube and arranged to deliver a drug from the reservoir to the tube, wherein the surrounding environment is the reservoir of the body portion.

30. The device according to any one of claims 19 to 29, wherein the microporous core includes a plurality of nodes and fibrils configured to control the metering passage of the drug.

31. The device according to claim 30, wherein the second passage of the drug is configured to be metered by the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

32. The device according to any one of claims 19 to 31, wherein the tube is a coating disposed on the outer surface of the microporous core.

33. The device according to any one of claims 19 to 31, wherein the tube is a tape wound around the outer surface of the microporous core.

34. The device according to any one of claims 19 to 33, wherein the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular shape.

35. The device according to any one of claims 19 to 33, wherein the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular weight.

36. The device according to any one of claims 19 to 33, wherein the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular polarity.

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