Drug delivery systems and methods

Abstract

An ocular drug delivery device is disclosed. In various embodiments, the ocular drug delivery device includes a plurality of microporous layers arranged together to form a microporous body, the microporous layers being configured to meter the distribution of a drug to surrounding tissue. In some embodiments, the ocular drug delivery device includes one or more portions configured to resist tissue ingrowth, and one or more portions configured to allow tissue ingrowth. In some embodiments, the ocular drug delivery device delivers one or more drugs that can be used to treat glaucoma.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Provisional Patent Application No. 62 / 724,425, filed on August 29, 2018, which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] Aqueous humor is a fluid that fills the anterior chamber of the eye and contributes to the intraocular pressure, or fluid pressure within the eye. Ocular hypertension is a condition in which the intraocular pressure, or fluid pressure inside the eye, is elevated. Untreated ocular hypertension can lead to diseases including glaucoma, which can cause gradual and sometimes permanent loss of vision in the affected eye.

[0004] Many attempts have been made to treat ocular hypertension, particularly glaucoma. Such attempts include surgical procedures involving the implantation of drainage devices designed to reduce intraocular pressure in the affected eye, and the administration of medications. The goal of these treatments is to improve quality of life and preserve visual function by reducing intraocular pressure.

[0005] Although drug administration is typically carried out in the form of eye drops that must be self-administered by the patient, in some cases an implantable extended drug delivery device may be employed. An implantable extended drug delivery device is typically located outside the eye (e.g., an extraocular approach), or alternatively implanted within the anterior chamber of the eye (an intracameral approach).

[0006] Extraocular methods of drug delivery present various challenges. To be effective, extraocular methods require that sufficient amounts of drug be delivered through the conjunctival layer of the eye into the anterior chamber of the eye via the biological processes of the eye. Obvious natural mechanisms such as the continuous flushing mechanism of the human tear film, and the natural barrier to the interior of the eye formed by the conjunctiva, complicate the effectiveness of extraocular methods, resulting in suboptimal dose delivery over time. Therefore, extraocular methods sometimes involve administering an excess of drug to prolong the duration of efficacy.

[0007] On the other hand, the intracameral approach is a more invasive approach that requires puncture through various tissue layers of the eye to gain access to and place the device in the anterior chamber of the eye. In the case of combined absorbable (bioabsorbable) device administration, the intracameral approach is further complicated because the degradable nature of the device may cause the device to shift and float in the anterior chamber. In addition, removal and replacement of the device again requires trauma to the eye tissue. Summary of the invention

[0008] According to one example ("Example 1"), an implantable delivery device for dispensing a drug comprises: a first microporous layer comprising a plurality of pores sized to allow tissue ingrowth; a second microporous layer comprising a plurality of pores sized to allow tissue ingrowth; a third microporous layer coupled to the first microporous layer, the third microporous layer comprising a plurality of pores sized to resist tissue ingrowth; and a reservoir for receiving the drug, the reservoir being defined between the third microporous layer and the second microporous layer, wherein the third microporous layer is configured to meter the rate at which the drug is eluted from the reservoir when the delivery device is implanted.

[0009] According to another example ("Example 2") further relative to Example 1, the implantable delivery device further includes a fourth microporous layer coupled to the second microporous layer such that the reservoir is defined between the third microporous layer and the fourth microporous layer.

[0010] According to another example ("Example 3") further than Example 2, the fourth microporous layer includes a plurality of pores sized to resist tissue ingrowth, and wherein the fourth microporous layer is permeable to the drug.

[0011] According to another example ("Example 4") further than Example 2, the fourth microporous layer is impermeable to the drug.

[0012] According to another example (“Example 5”) further than Example 4, the fourth layer includes an elastomer.

[0013] According to another example (“Example 6”) that is further relative to any of the foregoing examples, the first microporous layer includes an aperture configured to expose the third microporous layer.

[0014] According to another example ("Example 7") further to any of the foregoing examples, the implantable delivery system includes one or more structural spacers disposed within the reservoir to maintain separation between the second microporous layer and the third microporous layer.

[0015] According to another example (“Example 8”) further to any of the preceding examples, the reservoir is configured to be refilled and emptied in situ.

[0016] According to another example ("Example 9") further relative to any of the aforementioned examples, the reservoir is configured to expand to contain the drug therein.

[0017] According to another example ("Example 10") further relative to any of the preceding examples, at least one of the first microporous layer and the second microporous layer includes an expanded polytetrafluoroethylene (ePTFE) membrane.

[0018] According to another example ("Example 11") further to any of the foregoing examples, a first portion of the third microporous layer is impermeable to the drug, and wherein a second portion of the third microporous layer is permeable to the drug.

[0019] According to another example (“Example 12”) further to any of the preceding examples, the first portion of the third microporous layer includes an elastomer.

[0020] According to another example ("Example 13") further than any of the preceding examples, the delivery device may be implanted within the eye.

[0021] According to another example ("Example 14") further than Example 13, the drug is an ophthalmic drug for treating glaucoma.

[0022] According to another example ("Example 15"), an implantable delivery device for dispensing a drug includes: a first microporous layer connected to a second microporous layer to define a storage portion including a first inner surface and an opposing second inner surface; and a body having an outer surface, wherein the first inner surface is separable from the second inner surface when the storage portion is filled with the drug, wherein the first inner surface is configured to meter the dispensing of the drug over a predetermined time period, and wherein the first inner surface is configured to resist tissue ingrowth, and wherein the outer surface of the body is configured to allow tissue ingrowth.

[0023] According to another example ("Example 16") further than Example 15, at least a portion of the first inner surface is permeable to the drug.

[0024] According to another example ("Example 17") further than Examples 15 to 16, the second inner surface is impermeable to the drug.

[0025] According to another example (“Example 18”) further than Example 17, the second inner surface includes an elastomer.

[0026] According to another example (“Example 19”) that is further relative to Examples 15 to 18, the reservoir is configured to be refilled and emptied in situ.

[0027] According to another example ("Example 20") further than Examples 15 to 19, the reservoir is configured to expand to accommodate the drug therein.

[0028] According to another example (“Example 21”) further than Examples 15 to 20, at least one of the first microporous layer and the second microporous layer includes an expanded polytetrafluoroethylene (ePTFE) membrane.

[0029] According to another example ("Example 22") further relative to Examples 15 to 21, a first portion of the first inner surface is impermeable to the drug, and wherein a second portion of the first inner surface is permeable to the drug.

[0030] According to another example ("Example 23") further relative to Example 22, the first portion of the first inner layer includes an elastomer.

[0031] According to another example ("Example 24") further than Examples 15 to 23, the delivery device can be implanted in the eye.

[0032] According to another example ("Example 25") further than Examples 15 to 24, the drug is an ophthalmic drug for treating glaucoma.

[0033] According to another example ("Example 26"), a delivery device for dispensing drugs includes a microporous body, which includes: a first microporous layer, a second microporous layer and a third microporous layer, the first microporous layer is located between the second microporous layer and the third microporous layer, the first microporous layer includes a plurality of pores sized to resist tissue ingrowth, wherein the second microporous layer and the third microporous layer both include a plurality of pores sized to allow tissue ingrowth; and a drug storage portion, which is located between the first microporous layer and the third microporous layer.

[0034] According to another example ("Example 27") further than Example 26, the first microporous layer includes a metering portion for dispensing the drug over a period of time.

[0035] According to another example ("Example 28") further than Examples 26 to 27, the second microporous layer and the third microporous layer define an exterior of the delivery device.

[0036] According to another example (“Example 29”) further than any one of Examples 26 to 28, the first microporous layer is coupled to the second microporous layer.

[0037] According to another example (“Example 30”) further than Example 29, the second microporous layer includes an aperture configured to expose the first microporous layer.

[0038] According to another example ("Example 31") further than Examples 26 to 30, the drug storage portion is configured to be refilled and emptied in situ.

[0039] According to another example ("Example 32") further than Examples 26 to 31, the drug storage portion is configured to expand to accommodate the drug therein.

[0040] According to another example (“Example 33”) further relative to Examples 26 to 32, at least one of the first microporous layer, the second microporous layer, and the third microporous layer includes an expanded polytetrafluoroethylene (ePTFE) membrane.

[0041] According to another example ("Example 34") further than Examples 26 to 33, wherein the first microporous layer includes a first portion permeable to the drug and a second portion impermeable to the drug, the second portion of the first microporous layer includes an elastomer.

[0042] According to another example ("Example 35") further than Examples 26 to 34, the delivery device is implantable within the eye.

[0043] According to another example ("Example 36") further than Examples 27 to 35, the drug is an ophthalmic drug for treating glaucoma.

[0044] According to another example ("Example 37"), a drug metering device having an exterior surrounding an interior defining a drug storage portion, the drug metering device comprising: a first layer comprising a first microporous layer and a second microporous layer, the first microporous layer being configured to resist tissue ingrowth and the second microporous layer being configured to allow tissue ingrowth, the first microporous layer defining a portion of the interior and the second microporous layer defining a portion of the exterior; and a second layer coupled to the first layer such that the drug storage portion is defined between the first layer and the second layer, a portion of the first microporous layer of the first layer being permeable to a drug that may be disposed in the drug storage portion.

[0045] According to another example ("Example 38") further relative to Example 37, the drug storage portion is defined between uncoupled portions of the first and second tiers such that the uncoupled portions of the first and second tiers are free to deflect relative to each other.

[0046] According to another example ("Example 39") that is further relative to Examples 37 to 38, the second layer includes a third microporous layer and a fourth microporous layer, the third microporous layer of the second layer is configured to resist tissue ingrowth, and the fourth microporous layer of the second layer is configured to allow tissue ingrowth, wherein the third microporous layer of the second layer defines a portion of the interior and the fourth microporous layer defines a portion of the exterior.

[0047] According to another example (“Example 40”) further than Examples 37 to 39, the first microporous layer and the second microporous layer of the first stage include an expanded polytetrafluoroethylene (ePTFE) membrane.

[0048] According to another example ("Example 41") further relative to Examples 37 to 40, the first microporous layer of the first level includes a plurality of pores sized to resist tissue ingrowth, and wherein the second microporous layer of the first level includes a plurality of pores sized to allow tissue ingrowth.

[0049] According to another example ("Example 42") further relative to Examples 39 to 41, the third microporous layer of the second level includes a plurality of pores sized to resist tissue ingrowth, and wherein the fourth microporous layer of the second level includes a plurality of pores sized to allow tissue ingrowth.

[0050] According to another example ("Example 43") further than Examples 39 to 42, the third microporous layer of the second level includes an elastomer, so that the third microporous layer of the second level is impermeable to the drug.

[0051] According to another example ("Example 44") further than Examples 37 to 43, the first microporous layer of the first stratum includes a first portion permeable to the drug and a second portion impermeable to the drug, and the second portion of the first microporous layer of the first stratum includes an elastomer.

[0052] According to another example ("Example 45") further than Examples 37 to 44, the delivery device can be implanted in the eye.

[0053] According to another example ("Example 46") further relative to Example 45, the drug is an ophthalmic drug for treating glaucoma.

[0054] According to another example ("Example 47") further than any of the preceding examples, the drug is included in the fluid suspension of the particles.

[0055] According to another example ("Example 48") further relative to Example 47, the first microporous layer of the first level comprises a plurality of pores, the sizes of which are designed to prevent particles from passing through the first microporous layer. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The accompanying drawings are included to provide a further understanding of embodiments of the present disclosure and are incorporated in and constitute a part of this specification, illustrate examples and together with the description serve to explain the principles of the present disclosure.

[0057] Figure 1A is a schematic diagram of a drug delivery system implanted in an eye, according to some embodiments.

[0058] Figure 1B yes Figure 1A Detailed view of a schematic diagram of a drug delivery system implanted into an eye, according to some embodiments.

[0059] Figure 2 According to some embodiments, the cutout is taken along line 2-2 and is in an expanded state. Figure 4 A cross-sectional view of the drug delivery system is shown.

[0060] Figure 3 According to some embodiments, the cutout is taken along line 2-2 and is in a deflated state. Figure 4 A cross-sectional view of the drug delivery system is shown.

[0061] Figure 4 is a front view of a drug delivery system according to some embodiments.

[0062] Figure 5 is a cross-sectional view of a drug delivery system according to some embodiments.

[0063] Figure 6 is a cross-sectional view of a drug delivery system according to some embodiments.

[0064] Figure 7 According to some embodiments, the cross-section is taken along line 7-7. Figure 6 A cross-sectional view of the drug delivery system is shown.

[0065] Figure 8 is a cross-sectional view of a drug delivery system according to some embodiments.

[0066] Fig. 9 According to some embodiments, the cross-section is taken along line 9-9 Figure 8 A cross-sectional view of the drug delivery system is shown. DETAILED DESCRIPTION

[0067] Those skilled in the art will readily appreciate that the various embodiments of the inventive concepts provided in the present disclosure may be implemented by any number of methods and devices configured to perform the intended functions. It should also be noted that the drawings referenced herein are not all drawn to scale, but may be enlarged to illustrate various aspects of the present disclosure, and in this regard the drawings should not be interpreted as limiting.

[0068] The present disclosure relates to systems, devices and methods for delivering drugs to the eyes of patients. In various embodiments, the drug is an ophthalmic drug configured to treat, for example, ocular hypertension and / or glaucoma by causing intraocular pressure to decrease from an undesirable high level, and high levels of intraocular pressure may cause the diseased eye to gradually and sometimes permanently lose vision. In various embodiments, the drug delivery system according to the present disclosure is configured to measure the drug release rate of one or more different drugs, and therefore can be configured to provide a variety of different release rates, including a variety of different release rates for a variety of drugs. Some examples of suitable ophthalmic drugs include therapeutic agents such as prostaglandin analogs (PGA) (e.g., latanoprost), or therapeutic agents from other drug classes, including, for example, 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 compounds of alpha-agonists and beta-blockers that can be administered in combination with PGA.

[0069] In some embodiments, such drug delivery systems are configured to be implanted and minimally invasively refilled one or more times in situ without the need to remove the drug delivery system from the implant site. Given the size and subconjunctival target implant location, the implantation procedure can be performed outside of an operating room, where needle punctures and small incision surgeries are typically performed. In addition, some system examples include features for helping to reduce micromotion between the drug delivery system and the tissue in which they are implanted. Micromotion sometimes results in irritation of the surrounding tissue, which is known to result in foreign body tissue reaction, eventual erosion of the implanted device, and / or site infection, which can lead to excessive scarring.

[0070] exist Figure 1A , a drug delivery system 1000 according to some embodiments is shown. As shown, the drug delivery system 1000 is implanted in the eye 5000 between the conjunctiva 5002 and the sclera 5004 of the eye 5000. Anterior chamber 5006 is also shown. The drug delivery system 1000 generally includes one or more parts configured to meter the drug released from the drug delivery system 1000, and one or more parts configured to promote or allow cell penetration and / or tissue attachment. The drug may include a single therapeutic agent (e.g., a drug), or may include multiple therapeutic agents. The drug delivery system 1000 may be configured to meter the drug release rate of multiple different drugs at multiple different release rates.

[0071] Figure 1B yes Figure 1ADetailed view of region 1B shown in FIG. 1 and showing drug delivery system 1000 implanted in subconjunctival space 5008. As shown, subconjunctival space 5008 is a recess formed between conjunctiva 5002 and sclera 5004 of eye 5000. Subconjunctival space 5008 may be formed according to known methods. Figure 1A and 1B 5008. In some embodiments, the drug delivery system 1000 can be implanted from the outside (e.g., from the outside of the eye), for example, through a conjunctival incision. In some embodiments, a conjunctival radial incision (radial incision) is performed near the limbal junction, and a blunt dissection of the conjunctiva is performed to expose the sclera and form a subconjunctival pocket for placement of the drug delivery system 1000. In other embodiments, the drug delivery system 1000 is implanted from the inside (e.g., from the inside of the eye), such as through a clear corneal incision, and is placed through the sclera 5004 and into the dissected subconjunctival space 5008.

[0072] In some embodiments, the drug delivery system 1000 may also be secured to the sclera 5004 or other surrounding tissue, such as by suturing, adhesives, or according to other known methods. Although the drug delivery system 1000 may be permanently or semi-permanently secured upon implantation, the drug delivery system 1000 may also be first temporarily secured (or not initially secured at all) and then secured to the sclera 5004 or other surrounding tissue by one or more portions of the drug delivery system 1000 that are configured to promote or allow cell penetration and tissue attachment.

[0073] Continue to refer Figure 1A and 1B , the drug delivery system 1000 includes at least a first layer 1100 and a second layer 1200. Figure 1B As depicted, the first level 1100 and the second level 1200 are generally coupled together in a manner that provides a drug reservoir 1300 defined between the first level 1100 and the second level 1200. The drug reservoir 1300 is generally an enclosed space in which a drug can be deposited for subsequent delivery by the drug delivery system 1000. Generally, the drug delivery system 1000 is configured to meter the release rate of the drug disposed within the drug reservoir 1300 over a specified period of time. For example, a drug can be disposed or deposited within the drug reservoir 1300, and the drug delivery system 1000 can be configured to release the drug according to a predetermined treatment regimen to treat one or more defects or symptoms of the eye.

[0074] In addition, the drug delivery system 1000 can be minimally invasively refillable and / or emptied in situ (e.g., without first removing the drug delivery system 1000 from the implant site). In some such embodiments, one or more of the first layer 1100 and the second layer 1200 are configured so that they can be repeatedly punctured with a cannula during a drug reservoir refill or emptying operation without significantly compromising the integrity of the first layer 1100 and / or the second layer 1200. In some embodiments, such integrity can be achieved by coating or absorbing the first layer 1100 and / or the second layer 1200 with an elastomeric material.

[0075] Reference now Figure 2-4 , a drug delivery system 1000 is shown. Figure 2 It is along Figure 4 2 and 3. A cross-sectional view of drug delivery system 1000 taken along line 2-2 of the drug delivery system shown in FIG. 1 and shown in an expanded state (i.e., drug reservoir 1300 is in an expanded state such that a separation is defined between first level 1100 and second level 1200). In some embodiments, the expanded state corresponds to the presence of a drug in drug reservoir 1300. Figure 3 It is along Figure 4 2 is a cross-sectional view of the drug delivery system 1000 taken along line 2-2 of the drug delivery system shown in FIG. 1 , which is shown in a deflated state, such as when the drug reservoir 1300 is empty or does not have a sufficient amount of drug to cause separation between the first level 1100 and the second level 1200. Figure 4 is a front view of drug delivery system 1000 .

[0076] like Figure 2 As depicted, the first and second tiers 1100, 1200 are coupled together along one or more portions of the first and second tiers 1100, 1200, while one or more other portions of the first and second tiers 1100, 1200 remain uncoupled. The uncoupled portions of the first and second tiers 1100, 1200 remain free to separate from one another. In various embodiments, the uncoupled portions of the first and second tiers 1100, 1200 are operable to separate from one another to define a drug depot 1300.

[0077] In some embodiments, the first layer 1100 and the second layer 1200 may be coupled together around the peripheral edge 1002 of the drug delivery system 1000, such as Figure 2As shown. However, it should be understood that the first layer 1100 and the second layer 1200 may be additionally or alternatively connected in other areas including one or more areas inside the peripheral edge 1002. The peripheral edge 1002 is generally an edge extending around the periphery of the drug delivery system 1000. The peripheral edge 1002 can be uniform, non-uniform, continuous or discontinuous. For example, in some embodiments, the peripheral edge 1002 may include one or more radially extending protrusions or flaps (e.g., the drug delivery system 1000 may include a scalloped peripheral edge). In some embodiments, these protrusions or flaps are operable as a connection area for connecting the drug delivery system 1000 to surrounding tissue (e.g., the sclera 5004).

[0078] like Figure 2 As shown, the first layer 1100 and the second layer 1200 are coupled together at the peripheral edge 1002 and / or along an area just radially inward of the peripheral edge 1002 to form a coupling area extending adjacent to the peripheral edge 1002. The coupling area can be annular and can extend radially inward from the peripheral edge 1002 as desired. Figure 2 As shown, the drug storage portion 1300 is defined between the first level 1100 and the second level 1200, wherein the first level 1100 and the second level 1200 remain uncoupled. It will be appreciated that the first level 1100 and the second level 1200 may additionally be coupled together at a plurality of discrete locations or regions, including one or more locations or regions radially inward of the peripheral edge 1002 of the drug delivery system 1000. Coupling together one or more additional regions within the peripheral edge may help control the expansion (inflation) curve of the drug delivery system 1000.

[0079] One or more of the first and second tiers 1100, 1200 can be configured to elastically or plastically deform when the drug depot 1300 expands. Additionally, in some embodiments, the first and second tiers 1100, 1200 can be inelastic, which can help control the expansion profile of the drug delivery system 1000.

[0080] In various embodiments, one or both of the first stratum 1100 and the second stratum 1200 include one or more regions configured to meter drug release. These metering regions can be in the form of membranes, layers or films or coatings. In some embodiments, one or more of the first stratum 1100 and the second stratum 1200 include one or more regions that are configured to allow or promote cell penetration or tissue ingrowth and attachment. Cell penetration and tissue attachment typically occur when the material has a sufficiently porous property to allow penetration of fibroblasts. Therefore, the drug delivery system 1000 may include a membrane, layer, film and / or coating configured to allow tissue ingrowth and attachment.

[0081] In at least one embodiment, the first layer 1100 and / or the second layer 1200 may be formed by a plurality of membrane layers. Figure 2 and 3 As shown, the first level 1100 may include a first diaphragm layer 1110 and a second diaphragm layer 1120. The first diaphragm layer 1110 and the second diaphragm layer 1120 of the first level 1100 together define the first level 1100. It will be understood that the first level 1100 may include diaphragm layers other than the first diaphragm layer 1110 and the second diaphragm layer 1120.

[0082] In some embodiments, one or more of the first diaphragm layer 1110 and the second diaphragm layer 1120 may include a microporous microstructure. For example, one or more of the first diaphragm layer 1110 and the second diaphragm layer 1120 may include a biocompatible material, such as expanded polytetrafluoroethylene (ePTFE). In addition, one or more of the first diaphragm layer 1110 and the second diaphragm layer 1120 of the first layer 1100 may be formed of other biocompatible materials including biocompatible polymers, which may or may not be microporous, including but not limited to polyurethane, silicone, polysulfone, polyvinylidene fluoride (PVDF), polyhexafluoropropylene (PHFP), perfluoroalkoxy polymer (PFA), polyolefin, fluorinated ethylene propylene (FEP), acrylic copolymer, and polytetrafluoroethylene (PTFE).

[0083] The first membrane layer and / or the second membrane layer can be in the form of one or more sheets or films, and they can include knitted, woven and / or non-woven forms, including individual strands or multiple fiber strands. In some embodiments, the first membrane layer 1110 and / or the second membrane layer 1120 can be formed from a variety of sheets or films of polymeric materials. In some embodiments, the sheets or films can be laminated or otherwise mechanically coupled together to form the first membrane layer 1110 and / or the second membrane layer 1120 of the first level 1100. The coupling of the sheets or films can be achieved by various mechanisms, including heat treatment, high pressure compression, a bonding agent such as one or more adhesives, lamination, or other suitable methods known to those skilled in the art.

[0084] In some embodiments, adjacently positioned diaphragm layers (e.g., first diaphragm layer 1110 and second diaphragm layer 1120) and / or material layers forming these diaphragm layers may be partially or completely combined via thermal methods when each polymer forming the material is brought to or above their melting temperature. In some embodiments, such thermal processes are conducive to forming an adhesive bond or a cohesive bond between each material or each material layer. In some embodiments, adjacently positioned diaphragm layers and / or material layers forming such diaphragm layers may be partially or completely combined via thermal methods when at least one of the materials is brought to or above its melting temperature. Such thermal processes may help to form an adhesive bond or a cohesive (cohesive) bond between each material or each material layer. In some embodiments, one or more suitable adhesives are utilized and a fully bonded interface is provided. Adjacently positioned diaphragm layers and / or material layers forming such diaphragm layers may be coupled together at one or more discrete locations to form a stable structure extending through the resulting structure.

[0085] In some embodiments, the first layer 1100, and / or the first membrane layer 1110 and the second membrane layer 1120, and / or the sheet or film forming the first membrane layer 1110 and the second membrane layer 1120 may undergo one or more processes to modify its microstructure. In some embodiments, such processes include, but are not limited to, material coating processes, surface pretreatment processes, and / or perforation processes. The material coating process may be used to apply one or more drugs or antimicrobial coatings to polymer materials (such as metal salts (e.g., silver carbonate) and organic compounds (e.g., chlorhexidine acetate). A hydrophilic coating that is capable of wetting, including immediately wetting the polymer matrix, may also be applied as a polymer surface, which is hydrophobic in nature. A surface coating including an antioxidant component may be additionally or alternatively applied to reduce the inflammatory response that occurs naturally in the human body during wound healing after surgery. The material surface may be additionally or alternatively modified with an anti-proliferative compound (e.g., mitomycin C, 5-fluorouracil) to reduce the surrounding tissue response.

[0086] In some embodiments, as explained in U.S. Pat. No. 9,849,629 to Zaggl, one or more surface pretreatment processes may be used to form layers exhibiting exemplary microstructures (e.g., wrinkles, folds, or other out-of-plane geometries). Such surface pretreatments may aid in the early, post-operative inflammatory phase, thereby providing an early, stable interface between the porous device and the tissue. In some embodiments, a heparin coating may additionally or alternatively be applied to help minimize cell formation, including fibrinogen accumulation, following surgical implantation.

[0087] In some embodiments, one or more perforation processes may be used to form a plurality of perforations or pores in one or more of the first membrane layer 1110 and the second membrane layer 1120 of the first layer 1100 to achieve a desired porosity. That is, in addition to relying on any gaps, pores (spaces between fibers and nodes that make up the microstructure), and / or channels naturally present within the polymer material, one or more perforation processes may be utilized.

[0088] It will be appreciated that the first membrane layer 1110 and the second membrane layer 1120 of the first level 1100 may be processed differently to achieve membrane layers with different material properties, such as different porosities and / or different cell permeability. In some embodiments, the first membrane layer 1110 and the second membrane layer 1120 of the first level may not undergo any processing steps.

[0089] In some embodiments, the first membrane layer 1110 (also referred to herein as the drug metering membrane layer) is configured to meter the rate at which the drug passes through the first membrane layer 1110, and thus the rate at which the drug is released by the drug delivery system 1000. In various embodiments, the first membrane layer 1110 is also configured to resist cell penetration and attachment. In some embodiments, the first membrane layer 1110 includes gaps, perforations, pores, channels, or combinations thereof that are sized and shaped to resist, hinder, or otherwise minimize cell penetration, while remaining permeable to one or more drugs. The gaps, perforations, pores, or channels of the first membrane layer 1110 of the first level 1100 may be, for example, less than about one (1) to about two (2) microns (or have an average size of less than about one to about two microns), although a variety of sizes may be selected based on the application. By resisting cell penetration and attachment, the first membrane layer 1110 of the first level 1100 operates to maintain separation between the drug disposed within the drug reservoir 1300 and the tissue surrounding the drug delivery system 1000. This separation operates to maintain a controlled and steady rate of release of the drug from the drug delivery system 1000 .

[0090] The second diaphragm layer 1120 (also referred to herein as the ingrowth diaphragm layer) is configured to promote or allow cell penetration and attachment. Therefore, the second diaphragm layer 1120 generally includes gaps, perforations, pores, channels, or combinations thereof, whose size and shape are designed to promote or allow cell penetration. Therefore, the second diaphragm layer 1120 generally includes gaps, perforations, pores, channels, or combinations thereof, whose average size exceeds the average size of the gaps, perforations, pores, or channels of the first diaphragm layer 1110 of the first level 1100. In some embodiments, the second diaphragm layer 1120 may include gaps, perforations, pores, or channels, whose size (or average size) ranges from twenty (20) microns to one hundred (100) microns, although various sizes are contemplated. For example, in other embodiments, the size (or average size) of the gaps, perforations, pores, or channels may exceed one hundred and fifty (150) microns. Thus, the first membrane layer 1110 operates to meter and maintain a controlled and steady rate of drug release from the drug delivery system 1000, while the second membrane layer 1120 helps promote biointegration of the drug delivery system 1000 by allowing cell ingrowth and tissue attachment. Cell ingrowth and tissue attachment help minimize micromotion.

[0091] In some embodiments, the interface between the first diaphragm layer 1110 and the second diaphragm layer 1120 of the first stratum 1100 operates as a boundary for cell penetration into the first diaphragm layer 1110. That is, in some embodiments, the first stratum 1100 is configured such that cell penetration and proliferation are confined within the second diaphragm layer 1120 and do not enter into the first diaphragm layer 1110. Therefore, in various embodiments, cell penetration and proliferation within the second diaphragm layer 1120 may generally propagate to the boundary between the first diaphragm layer 1110 and the second diaphragm layer 1120. In some embodiments, the first stratum 1100 may be configured to prevent or otherwise minimize the possibility of cell penetration and proliferation across the boundary between the first diaphragm layer 1110 and the second diaphragm layer 1120 of the first stratum 1100.

[0092] It should also be understood that while the first level 1100 (and the corresponding first membrane layer 1110 and second membrane layer 1120 of the first level 1100) of the drug delivery system 1000 shown in the figures are elliptical, the first membrane layer 1110 and second membrane layer 1120, and therefore the first level 1100, may be formed of other shapes and / or sizes, so long as the drug delivery system 1000 effectively meets its intended purpose of implantation in a tissue such as a subconjunctival pit, and may be operated to cause the drug disposed within the drug reservoir 1300 of the drug delivery system 1000 to be released to one or more regions of the tissue surrounding the drug delivery system 1000. For example, the first membrane layer 1110 and second membrane layer 1120, and therefore the first level 1100, may be square, rectangular, trapezoidal, or any other polygonal or non-polygonal shape (e.g., bean-shaped) as desired, so long as such shapes do not prohibit implantation or prevent the drug reservoir 1300 from dispensing the drug.

[0093] like Figure 2 and 3 As shown, the second level 1200 of the drug delivery system 1000 includes a first diaphragm layer 1210 and a second diaphragm layer 1220. The first diaphragm layer 1210 of the second level 1200 is similar to the first diaphragm layer 1110 of the first level 1100, so that the first diaphragm layer 1210 of the second level 1200 is configured to meter the rate at which the drug passes through the first diaphragm layer 1210 and, therefore, the rate at which the drug is released by the drug delivery system 1000. In various embodiments, the first diaphragm layer 1210 is also configured to resist cell penetration and attachment. Therefore, the first diaphragm layer 1210 generally includes gaps, perforations, pores, channels, or combinations thereof consistent with the gaps, perforations, pores, channels, or combinations thereof discussed above for the first diaphragm layer 1110 of the first level 1100.

[0094] The second membrane layer 1220 of the second stratum 1200 is similar to the second membrane layer 1120 of the first stratum 1100, such that the second membrane layer 1220 of the second stratum 1200 is configured to promote or allow cell penetration and attachment. Therefore, the second membrane layer 1220 generally includes gaps, perforations, pores, channels, or combinations thereof consistent with the gaps, perforations, pores, channels, or combinations thereof discussed above for the second membrane layer 1120 of the first stratum 1100. Therefore, in various embodiments, the drug delivery system 1000 includes the second stratum 1200 formed by the first membrane layer 1210 and the second membrane layer 1220, wherein the first membrane layer 1210 is permeable to the drug and is configured to resist cell penetration and tissue attachment, and the second membrane layer 1220 is permeable to the drug and is configured to promote or allow cell penetration and tissue attachment.

[0095] In some embodiments, the interface between the first diaphragm layer 1210 and the second diaphragm layer 1220 of the second stratum 1200 operates (functions) as a boundary for cell penetration into the first diaphragm layer 1210. That is, in some embodiments, the second stratum 1200 is configured such that cell penetration and proliferation are confined to the second diaphragm layer 1220 and do not enter into the first diaphragm layer 1210. Therefore, in various embodiments, cell penetration and proliferation within the second diaphragm layer 1220 may generally propagate to, but not through, the boundary between the first diaphragm layer 1210 and the second diaphragm layer 1220. In some embodiments, the second stratum 1200 may be configured to prevent or otherwise minimize the possibility of cell penetration and proliferation across the boundary between the first diaphragm layer 1210 and the second diaphragm layer 1220 of the second stratum 1200. It should be understood that the second stratum 1200 may include diaphragm layers other than the first diaphragm layer 1210 and the second diaphragm layer 1220.

[0096] Similar to the first level 1100 described above, the second level 1200 may be formed of shapes and / or sizes other than those depicted in the accompanying drawings (e.g., square, rectangular, trapezoidal, bean-shaped, or any other polygonal or non-polygonal shape), so long as the drug delivery system 1000 effectively meets its intended purpose of being implanted in tissue and is operable to cause the drug within the drug storage portion 1300 to be released into one or more regions of the tissue surrounding the drug delivery system 1000.

[0097] like Figure 2 and 3As shown, the first stratum 1100 is oriented such that the first diaphragm layer 1110 is positioned adjacent to the second stratum 1200 (and specifically the first diaphragm layer 1210 of the second stratum 1200), and includes a first face 1102 that faces or is otherwise exposed to the second stratum 1200 (and specifically the first diaphragm layer 1210 of the second stratum 1200). That is, in some embodiments, the first stratum 1100 is positioned such that the first diaphragm layer 1110 is positioned between the second diaphragm layer 1120 and the second stratum 1200. This configuration allows the first diaphragm layer 1110 of the first stratum 1100 to at least partially define the drug reservoir 1300. That is, in various embodiments, the drug reservoir 1300 is at least partially defined by one or more drug metering diaphragm layers (e.g., the first diaphragm layer 1110) that are configured to meter the rate at which the drug is released from the drug reservoir 1300. Such a configuration also allows the second membrane layer 1120 of the first level 1100 to include a second face 1104 opposite to the first face 1102 and partially define the exterior of the drug delivery system 1000. That is, in various embodiments, the exterior of the drug delivery system 1000 is at least partially defined by one or more tissue ingrowth membrane layers (e.g., second membrane layer 1120) that are configured to promote or allow cell penetration and tissue attachment, as described above. Promoting or allowing tissue ingrowth and attachment along one or more outer surfaces of the drug delivery system 1000 helps minimize micromotion between the drug delivery system 1000 and the surrounding tissues that the drug delivery system 1000 interfaces with.

[0098] Similarly, if Figure 2 and 3 As shown, the second layer 1200 is oriented such that the first diaphragm layer 1210 of the second layer 1200 is positioned adjacent to the first layer 1100 (and specifically the first diaphragm layer 1110 of the first layer 1100), and includes a first face 1202 that faces or is otherwise exposed to the first layer 1100 (and specifically the first face 1102 of the first diaphragm layer 1210 of the first layer 1100). That is, in some embodiments, the second layer 1200 is positioned such that the first diaphragm layer 1210 is positioned between the second diaphragm layer 1220 and the first layer 1100. This configuration allows the first diaphragm layer 1210 of the second layer 1200 to at least partially define the drug storage portion 1300. Such a configuration also allows the second diaphragm layer 1220 of the second layer 1200 to include a second face 1204 that is opposite to the first face 1202 and partially defines the exterior of the drug delivery system 1000. Therefore, as shown in FIG. Figure 2 and 3As shown, the exterior of the drug delivery system 1000 is at least partially defined by the first layer 1100 and the second membrane layers 1120 and 1220 of the second layer 1200, respectively. Figure 2 and 3 As shown, the drug storage portion 1300 is partially defined by the first diaphragm layers 1110 and 1210 of the first and second tiers 1100 and 1200, respectively. As shown, the drug storage portion 1300 is defined by the following portions of the first diaphragm layers 1110 and 1210 of the first and second tiers 1100 and 1200: those portions remain uncoupled or are not otherwise coupled to each other and are located radially inward of those portions of the first diaphragm layers 1110 and 1210 of the first and second tiers 1100 and 1200 that are coupled together.

[0099] In various embodiments, the first layer 1100 and the second layer 1200 (including their respective diaphragm layers) can be connected or coupled to each other according to known methods, such as by means of heat treatment, high pressure compression, bonding agents such as one or more adhesives, combinations thereof, or other techniques known to those skilled in the art.

[0100] In some embodiments, the first faces 1102 and 1202 of the first and second layers 1100, 1200, respectively, are coupled along the peripheral edge 1002 of the drug delivery system 1000 such that one or more portions of the first faces 1102 and 1202 of the first and second layers 1100, 1200 remain uncoupled from one another. In some embodiments, such uncoupled regions remain free to slide, translate, actuate, separate, or otherwise move relative to one another. Such relative movement between the uncoupled or unattached portions of the first and second layers 1100, 1200 allows the volume of the drug reservoir 1300 to vary with the amount of drug present in the drug reservoir 1300. For example, the drug delivery system 1000 may be switchable between states or configurations, including a first configuration in which the drug reservoir 1300 has a first volume and a second configuration in which the drug reservoir 1300 has a second volume greater than the first volume.

[0101] Figure 3 The drug delivery system 1000 is shown in a first configuration, wherein the drug depot 1300 is deflated (eg, lacking or including a negligible amount of drug), and Figure 2 The drug delivery system 1000 is shown in a second configuration, wherein the drug reservoir 1300 is expanded (e.g., completely or at least partially filled with a drug). In some embodiments, the drug delivery system 1000 in the deflated state has a relatively flat profile (e.g., a relatively uniform cross-section) compared to the profile of the drug delivery system 1000 in the expanded state. For example, Figure 4As shown, the drug delivery system 1000 can take the shape of a blister or pillow in an expanded state. However, the drug delivery system 1000 can be configured to take any desired shape or size when empty of any drug and / or when filled with a drug.

[0102] Because the drug delivery system 1000 is configured to deliver a drug, and because the drug delivery system 1000 can be refilled or emptied in situ, it will be appreciated that the drug delivery system 1000 can be converted between the first configuration and the second configuration in situ.

[0103] Furthermore, drug reservoir 1300 may be accessed in situ via a cannula, needle, or other suitable instrument or method to add or remove drug from drug reservoir 1300 .

[0104] Figure 2 The illustrated drug delivery system 1000 is configured such that a drug can be metered and dispensed from the drug delivery system 1000 through both the first layer 1100 and the second layer 1200. That is, in some embodiments, the drug delivery system 1000 includes a first layer 1100 and a second layer 1200 that are permeable to the drug. Specifically, in some embodiments, the drug is released from the drug delivery system 1000 by passing through first membrane layers 1110 and 1210 of the first layer 1100 and the second layer 1200, respectively, and passing through second membrane layers 1120 and 1220 of the first layer 1100 and the second layer 1200, respectively.

[0105] However, in other embodiments, the drug delivery system may be configured such that the drug is metered and dispensed from the drug delivery system through one or the other of the first and second strata but not both. That is, in some embodiments, the drug delivery system may be configured such that the first of the first and second strata is permeable to the drug and the other of the first and second strata is impermeable to the drug. For example, turning now to Figure 5 , shows a drug delivery system 2000 comprising a first layer 2100 permeable to a drug and a second layer 2200 impermeable to a drug. Figure 5 The first level 2100 of the drug delivery system 2000 is shown to be similar to Figure 2-4The first level 1100 is shown such that it includes a first membrane layer 2110 (similar to the first membrane layer 1110) and a second membrane layer 2120 (similar to the second membrane layer 1120), wherein the first membrane layer 2110 is permeable to the drug and is configured to meter the release rate of the drug disposed in the drug reservoir 2300 over a specified period of time and is configured to resist cell penetration and tissue attachment, and wherein the second membrane layer 2120 is permeable to the drug and is configured to promote or allow cell penetration and tissue attachment. Similar to the first level 1100 of the drug delivery system 1000 described above, the first level 2100 of the drug delivery system 2000 includes a first face 2102 and a second face 2104.

[0106] Figure 5 The second level 2200 of the illustrated drug delivery system 2000 includes a first face 2202 and a second face 2204 and is formed of a first membrane layer 2210 and a second membrane layer 2220, wherein the first membrane layer 2210 is drug impermeable. Figure 5 The second membrane layer 2220 of the drug delivery system 2000 is shown to be similar to Figure 2-4 The second diaphragm layer 1220 shown in FIG. Figure 5 The second membrane layer 2220 is shown to be configured to promote or allow cell penetration and tissue attachment. However, unlike the previous examples, the first membrane layer 2210 is impermeable to the drug disposed within the drug reservoir 2300. Alternatively, the drug delivery system 2000 may be configured such that the first tier 2100 is impermeable to the drug and the second tier 2200 is permeable to the drug. The drug permeable tier (e.g., the first tier 2100 or the second tier 2200) may include a first drug permeable membrane layer configured to resist cell penetration and tissue attachment and / or a second drug permeable membrane layer configured to promote or allow cell penetration and tissue attachment. Conversely, the drug impermeable tier (e.g., the first tier 2100 or the second tier 2200) may include a first drug impermeable membrane layer configured to resist cell penetration and tissue attachment and / or a second drug impermeable membrane layer configured to promote or allow cell penetration and tissue attachment.

[0107] Continue to refer Figure 5, the second membrane layer 2220 may be formed of any biocompatible material discussed herein, such as a biocompatible polymer, which is further combined with an elastomer or elastomeric material to form a composite material that is impermeable to drugs. For example, the second membrane layer 2220 may include a composite material comprising a microporous polymer membrane having nodes and fibrils and a sealing material such as an elastomeric material present therein, wherein the pores are spaces within the matrix of the fibrils (e.g., ePTFE). In some embodiments, the sealing material may be absorbed into the polymer membrane to form a membrane layer that is impermeable to drugs. It should be understood that various types of fluoropolymer (and non-fluoropolymer) membranes and various types of elastomeric materials may be combined to form a composite material while remaining within the scope of the present disclosure. It should also be understood that the elastomeric material may include a variety of elastomers and various types of non-elastomeric components, and include materials such as inorganic fillers, therapeutic agents, radiopaque markers, etc. while remaining within the scope of the present disclosure.

[0108] In some embodiments, the various membrane layers are formed from expanded polytetrafluoroethylene (ePTFE), although other biocompatible polymers suitable for forming drug-impermeable membrane layers may be used, including but not limited to urethanes, silicones (organopolysiloxanes), silicon-urethane copolymers, styrene / isobutylene copolymers, polyisobutylene, polyethylene-co-poly(vinyl acetate), polyester copolymers, nylon copolymers, fluorinated hydrocarbon polymers, and copolymers or mixtures of each of the foregoing.

[0109] In various embodiments, the elastomer or elastomeric material may include perfluoromethyl vinyl ether and tetrafluoroethylene, (per)fluoroalkyl vinyl ether (PAVE), copolymers of tetrafluoroethylene and perfluoromethyl vinyl ether, silicone, fluoroelastomer, urethane, or TFE / PMVE copolymers.

[0110] Continue to refer Figure 5In the drug delivery system 2000 shown in FIG. 2 , the drug delivery system 2000 can be configured to unidirectionally meter and distribute the drug disposed in the drug storage portion 2300 by including a first layer 2100 permeable to the drug and a second layer 2200 impermeable to the drug. That is, in some embodiments, the drug delivery system 2000 can be configured so that the drug is metered and released through one of the first layer 2100 and the second layer 2200 but not through the other of the first layer 2100 and the second layer 2200. Therefore, in these embodiments, the drug delivery system 2000 can be configured so that the drug is released in a first direction (e.g., through the first layer 2100) but not in a second direction (e.g., through the second layer 2200). Providing this type of controlled release helps provide for guiding the distribution of the drug to a designated tissue. For example, the drug can be released in a direction toward the scleral tissue while minimizing the release of the drug in a direction toward the conjunctival tissue, which may be useful for treating symptoms inside the eye. Alternatively, the drug may be released in a direction toward the conjunctival tissue while minimizing the release of the drug in a direction toward the scleral tissue, which may be useful for treating other symptoms of the eye, such as symptoms affecting the outside of the eye (e.g., dry eye). Releasing the drug in a direction toward the conjunctival tissue may be useful for treating other zones or regions of the body, since the drug distributed to the conjunctiva may be absorbed by the surrounding vasculature and transferred to other areas of the patient's anatomy. It should be understood that as used herein with respect to the first stratum 2100 and the second stratum 2200, the terms "first" and "second" are general designators, and thus, the stratum 2100 and 2200 may be combined with alternative designators such as "top," "bottom," "upper," "lower," "side," and the like. Thus, although the above is referred to as stratum 2100 in conjunction with the term "first," and the above is referred to as stratum 2200 in conjunction with the term "second," it should be understood that the stratum 2100 and 2200 may be referred to alternatively as the first stratum 2200 and the second stratum 2100. That is, the terms “first” and “second” should not be understood to represent any meanings other than designations commonly used for the hierarchies 2100 and 2200 .

[0111] In some embodiments, one or more of the first and second strata can be configured to include one or more drug permeable portions and one or more drug impermeable portions. Figure 6 and 7 , shows a drug delivery system 3000, which includes a first layer 3100 and a second layer 3200. The second layer 3200 is similar in form and structure to the first layer 3100 and the second layer 3200. Figure 5The second layer 2200 of the drug delivery system 2000 shown and described above is consistent and includes a first membrane layer 3210, a second membrane layer 3220, a first face 3202, and a second face 3204. In another aspect, the first layer 3100 differs from the previous first layer examples in that Figure 6 and Figure 7 The first layer 3100 shown includes a first membrane layer 3110 having a first portion 3112 that is permeable to the drug and a second portion 3114 that is not permeable to the drug. The first membrane layer 3110 is configured to meter the release rate of the drug disposed in the drug reservoir 1300 over a specified period of time. The second membrane layer 3120 is similar to the above-discussed, Figure 5 The second membrane layer 3120 of the drug delivery system 1000 is shown in FIG.

[0112] In various embodiments, the first portion 3112 of the first membrane layer 3110 generally includes gaps, perforations, pores, channels or other release features that are sized and shaped to allow the drug placed within the drug reservoir 3300 to be released through the first portion 3112. In some embodiments, the release of the drug metered into the drug reservoir 3300 through the first layer 3100 can be regulated or otherwise controlled by increasing (or alternatively decreasing) the surface area of ​​the metered first portion 3112 of the first membrane layer 3110. In some embodiments, increasing the surface area of ​​the metered first portion 3112 from a first surface area to a larger second surface area is associated with an increase in the amount of drug released by the drug delivery system 3000 per unit time. Similarly, decreasing the surface area of ​​the metered first portion 3112 from a first surface area to a smaller second surface area is associated with a decrease in the amount of drug released by the drug delivery system 3000 per unit time.

[0113] For example, if the drug delivery system includes a drug storage unit with a first size (e.g., volume) and a first drug metering diaphragm layer with a first surface area and including a first material with a first release rate per unit area, the drug delivery system is associated with the first drug release rate per unit time and the release of the metered drug in the first time period. If the size of the drug storage unit is increased from the first size to a larger second size, while maintaining the first surface area and the first material of the metering diaphragm layer, it should be understood that the drug delivery system is operable to meter the release of the drug in the second time period longer than the first time period. On the other hand, if the first surface area of ​​the metering diaphragm layer is reduced to a reduced second surface area, while maintaining the first material of the metering diaphragm layer and the first size of the drug storage unit, it should be understood that the drug delivery system is operable to meter the release of the drug in the third time period longer than the first time period. In addition, if the first material of the metering diaphragm layer is changed to a second material with a reduced second release rate per unit area, while maintaining the first size of the drug storage unit and the first surface area of ​​the metering diaphragm layer, it should be understood that the drug delivery system is operable to meter the release of the drug in the fourth time period longer than the first time period. Combinations of the above concepts can be utilized to maintain a drug release cycle while increasing the amount of drug released per unit time. For example, if the size of the drug reservoir is increased from a first size to a second, larger size, combined with an increase in the surface area of ​​the metering membrane layer from a first surface area to an increased second surface area while maintaining the first material of the metering membrane layer, it will be understood that the drug delivery system can be operated to increase the amount of drug released within a first period of time.

[0114] It should also be understood that different materials may have different flow rates per unit area, for example based on different microstructures (e.g., an increase in the number and / or size of gaps, perforations, pores, channels, or other release features present in the microstructures. Thus, different materials may additionally or alternatively be selected to regulate or otherwise control the degree or amount of release of a drug metered within a drug reservoir.

[0115] Thus, the various drug delivery systems discussed herein provide configurations that include a relatively large drug reservoir that also inherently does not have a high drug release rate due to an associated large drug metering surface area, or alternatively include a relatively small drug reservoir that also inherently does not have a low drug release rate due to an associated small drug metering surface area. A relatively large drug reservoir combined with a low release rate provides a drug delivery system 1000 that can be implanted for a long period of time (e.g., weeks, months, a year, or longer) without requiring intervention to refill the drug. Conversely, a relatively small drug reservoir combined with a high release rate provides a drug delivery system that can be implanted and dispensed at a very fast rate without being oversized and interfering with normal eye operation (e.g., blinking and eye movement).

[0116] In addition, it should be understood that drugs with thicker molecular structures generally require drug delivery systems to include microstructures with gaps, pores, channels and / or other release characteristics that are corresponding in size so that the drug can pass through the material of the drug metering diaphragm layer. Therefore, it will be understood that different drug delivery systems can be selected for use in administering different drugs.

[0117] Continue to refer to Figure 6 and 7 In the illustrated drug delivery system 3000, the first membrane layer 3110 of the first stratum 3100 may be formed of one or more sheets or films of a material, such as any of the biocompatible materials discussed herein, and wherein the one or more sheets or films of material have been further combined with a sealing material, such as an elastomer or elastomeric material, in the drug-impermeable second portion 3114. Thus, in some embodiments, the drug-impermeable second portion 3114 of the first membrane layer 3110 of the first stratum 3100 may include a composite structure. In some embodiments, the drug-impermeable second portion 3114 of the first membrane layer 3110 of the first stratum 3100 may correspond to a portion of the first membrane layer 3110 of the first stratum 3100 that has been selectively absorbed and / or coated with a sealing material. That is, in various embodiments, the first diaphragm layer 3110 of the first level 3100 may be configured such that one or more portions of the first diaphragm layer 3110 include a sealing material, and wherein one or more other portions of the first diaphragm layer 3110 do not have a sealing material, wherein those portions of the first diaphragm layer 3110 that include the sealing material correspond to the second portion 3114 that is impermeable to the drug, and wherein those portions of the first diaphragm layer 3110 that do not include the sealing material correspond to the first portion 3112 of the metered drug.

[0118] although Figure 6 and Figure 7The illustrated drug delivery system 3000 includes an oval-shaped first portion 3112 of metered drug, but the first portion 3112 of metered drug can be formed of other shapes and / or sizes other than those depicted in the drawings (e.g., square, rectangular, trapezoidal, bean-shaped, or any other polygonal or non-polygonal shape), as long as the first portion 3112 of metered drug effectively achieves its intended purpose of metered release of drug. Therefore, it should be understood that the boundary defined between the first portion 3112 of metered drug and the second portion 3114 of drug impermeable can define any suitable shape consistent with the above.

[0119] It should also be understood that although Figure 7 The illustrated drug delivery system 3000 includes only a single centrally located first portion 3112 of metered drug, but the first membrane layer 3110 of the first level 3100 may include a plurality of discrete first portions 3112 of metered drug. Similarly, it should be understood that the first portion 3112 of metered drug of the first membrane layer 3110 of the first level 3100 need not be centrally located, but may instead be positioned at an orientation offset from a central location.

[0120] In various embodiments, the drug delivery system may be configured such that one or more of the drug metering membrane layers discussed herein may be exposed to a tissue surface of a patient's anatomy. Figure 8 and 9 , shows a drug delivery system 4000, which includes a first layer 4100 and a second layer 4200. The second layer 4200 is similar to Figure 5 The second layer 2200 of the drug delivery system 2000 shown in and discussed above, such that the second layer 4200 is drug impermeable and includes a first membrane layer 4210 that is drug impermeable and a second membrane layer 4220 that is configured to promote or allow cell penetration and tissue attachment. Figure 5 In the illustrated drug delivery system 2000 , the second layer 4200 includes a first surface 4202 and a second surface 4204 .

[0121] However, Figure 8 and 9 The first level 4100 shown differs from the previous first level examples in that Figure 8 and 9 The first level 4100 shown includes an aperture or depression exposing a portion of the first membrane layer 4110. The first membrane layer 4110 is configured to meter the release rate of the drug disposed in the drug reservoir 4300 over a specified period of time. Figure 8 and 9As shown, the second membrane layer 4120 includes an aperture 4124 formed in a body 4122 of the second membrane layer 4120, wherein the aperture 4124 in the second membrane layer 4120 of the first level 4100 operates to expose the first membrane layer 4110. When implanted, one or more portions of the first membrane layer 4110 of the first level 4100 are directly exposed to tissue, while the second membrane layer 4120 operates to maintain separation between the first membrane layer 4110 and the tissue surface.

[0122] Direct exposure of the first membrane layer 4110 of the first level 4100 helps achieve more effective and efficient drug delivery to the tissue. Maintaining separation between the first membrane layer 4110 and the tissue surface helps minimize micromotion between the first membrane layer 4110 and the tissue. As described above, minimizing micromotion helps minimize microstimulation.

[0123] Thus, in various embodiments, the drug delivery system 4000 includes a first drug permeable layer 4100 and a second drug impermeable layer 4200, wherein the first layer 4100 includes a first diaphragm layer 4110 and a second diaphragm layer 4120, and wherein the first diaphragm layer 4110 is drug permeable and configured to resist cell penetration and tissue attachment, and wherein the second diaphragm layer 4120 is drug permeable and configured to promote or allow cell penetration and tissue attachment, and wherein the second diaphragm layer 4120 is configured such that when the first diaphragm layer 4110 is implanted, one or more portions of the first diaphragm layer 4110 are exposed to the tissue, and the second diaphragm layer 4120 is positioned between the tissue and one or more other portions of the first diaphragm layer 4110 when implanted.

[0124] In some embodiments, the various drug delivery systems discussed herein are formed as thin puck-shaped members. The drug delivery system may include a thickness between the outer opposing surfaces (e.g., the distance measured between the second face 1104 of the first level 1100 and the second face 1204 of the second level 1200) of less than or equal to half a millimeter (0.5 mm), such as, for example, between one tenth of a millimeter (0.1 mm) and half a millimeter (0.5 mm), although various sizes are contemplated. For example, given the different anatomical structures of the human body, the drug delivery system may exceed half a millimeter (0.5 mm) without departing from the spirit or scope of the present disclosure, as long as the thickness does not substantially interfere with normal eye function (e.g., pivoting and blinking).

[0125] In some embodiments, the various drug delivery systems disclosed herein may have a diameter (or width across the main axis) in the range of five (5) millimeters to fifteen (15) millimeters. In specific embodiments, the drug delivery systems disclosed herein may have a diameter (or width across the main axis) of ten (10) millimeters. In those embodiments where the drug delivery system is oval, the drug delivery system may include a major dimension (e.g., elliptical) of up to about thirty (30) millimeters and a corresponding minor dimension of up to about ten (10) millimeters. However, as described above, given the different anatomical structures of the human body, the drug delivery system may exceed such dimensions (e.g., fifteen (15), ten (10) and thirty (30) millimeters) without departing from the spirit or scope of the present disclosure, as long as the dimension does not substantially interfere with normal eye function (e.g., pivoting and blinking). Similarly, without departing from the spirit or scope of the present disclosure, the drug delivery system disclosed herein may include a diameter (or width across the main axis) of less than five (5) millimeters, as long as the drug delivery system can be operated to elute a sufficient degree of drug to be absorbed by the surrounding tissue. The shapes and sizes discussed herein should not be considered restrictive.

[0126] In addition, although the drug delivery systems discussed above are described as including a single drug storage portion, it should be understood that any of the above-mentioned drug delivery systems may include multiple storage portions. These storage portions may be fluidly coupled or isolated from each other. In some embodiments, each storage portion may be configured to accommodate the same or different drugs. Therefore, in some embodiments, the drug delivery systems discussed herein may be configured to deliver a variety of different drugs from the same storage portion or from a plurality of different storage portions.

[0127] In addition, in various embodiments, it should be understood that the drug can be loaded onto bioabsorbable particles or otherwise incorporated into bioabsorbable particles, which helps to meter the drug. In some embodiments, the size of the particles can make them into dispersions and be injected or otherwise delivered in situ to the drug storage unit (for example, when the drug delivery system is implanted in the patient's eyes). That is, in some examples, the drug can be included in the fluid suspension of the particles. In various embodiments, the filled or partially filled drug microporous storage unit can be entered in situ (for example, by a syringe or other suitable means), and the contents (for example, particles) in the storage unit can be removed and / or reloaded with fresh particles to maintain the constant delivery of the drug over a period of time. In various embodiments, the placement of the fluid suspension (liquid) of the particles in the drug storage unit can be completed via a syringe or other suitable delivery methods.

[0128] In some embodiments, the drug delivery system discussed herein is configured so that the drug microporous storage unit keeps particles in the drug storage unit and allows the dispersion carrier fluid (e.g., water) to leave the storage unit through one or more levels of the drug delivery system. For example, in some embodiments, the material (e.g., one or more of the first, second, third or fourth microporous layers) that limits the drug storage unit may include a microstructure that is configured to prevent particles of a fluid suspension (liquid) from passing through the material. For example, the first microporous layer may be configured to resist tissue ingrowth, and may include gaps, perforations, pores, channels or combinations thereof that prevent particles of a fluid suspension (liquid) from passing through the material. In some embodiments, particles are configured to decompose or degrade over time so that the drug (alone or in solution with a fluid) can penetrate, diffuse or otherwise pass through one or more levels of the microporous storage unit from the inside of the drug storage unit to the outside of the drug delivery system for body absorption. In some embodiments, the concentration of the solution of the dispersion carrier fluid and particles may vary or be changed over time. For example, particles may be added to the dispersion carrier fluid (e.g., in situ) to increase the concentration of particles in the storage unit. Additionally or alternatively, a dispersing carrier fluid may be added to reduce the particle concentration within the reservoir.

[0129] In certain embodiments, various drug delivery systems disclosed herein may additionally or alternatively include one or more structural spacers, such as one or more stents, pillars and / or reinforcing elements. One or more structural spacers may be incorporated into, integrated into, connected to or otherwise arranged in a storage portion to maintain the separation between those microporous layers forming a storage portion. Such structural spacers may be formed by any suitable biocompatible material (e.g., natural material or synthetic material such as metal and polymer) discussed herein.

[0130] The scope of the invention of the present application has been described above generally and with reference to specific embodiments and examples. It will be apparent to those skilled in the art that various modifications and changes may be made to the various embodiments and examples without departing from the scope of the present disclosure. Likewise, the various components discussed in the embodiments and examples discussed herein are combinable. Therefore, these embodiments and examples are intended to cover modifications and variations of the scope of the present invention.

Claims

1. An implantable delivery device for dispensing a drug, the delivery device comprising: a first microporous layer comprising a plurality of pores sized to allow tissue ingrowth, a second microporous layer comprising a plurality of pores sized to allow tissue ingrowth, a third microporous layer coupled to the first microporous layer, the third microporous layer comprising a plurality of pores sized to resist tissue ingrowth, and a reservoir for receiving a drug, the reservoir being defined by the opposing unattached portions of the third microporous layer and the second microporous layer and being disposed between the attached peripheral edges of the third microporous layer and the second microporous layer, the reservoir being capable of expanding to an expanded state when filled with a sufficient amount of the drug and being capable of contracting to a deflated state as the reservoir is emptied of the drug, wherein, in the expanded state, the second microporous layer and the third microporous layer are separated from each other between the unconnected portions, wherein the device has a relatively flat profile in a deflated state, so that the separation between the second microporous layer and the third microporous layer is reduced, and Wherein the third microporous layer is configured to meter the rate at which the drug is eluted from the reservoir when the delivery device is implanted.

2. The device according to claim 1, characterized in that Also included is a fourth microporous layer coupled to the second microporous layer such that the reservoir is defined between the third microporous layer and the fourth microporous layer.

3. The device according to claim 2, characterized in that The fourth microporous layer comprises a plurality of pores sized to resist tissue ingrowth, and wherein the fourth microporous layer is permeable to the drug.

4. The device according to claim 2, characterized in that The fourth microporous layer is impermeable to drugs.

5. The device according to claim 4, characterized in that The fourth microporous layer includes an elastomer.

6. The device according to any one of claims 1 to 5, characterized in that The first microporous layer includes pores configured such that the third microporous layer is exposed.

7. The device according to any one of claims 1 to 5, characterized in that The reservoir is configured to be refilled and emptied in situ.

8. The device according to any one of claims 1 to 5, characterized in that The reservoir is configured to expand to contain a drug therein.

9. The device according to any one of claims 1 to 5, characterized in that At least one of the first microporous layer and the second microporous layer includes an expanded polytetrafluoroethylene (ePTFE) membrane.

10. The device according to any one of claims 1 to 5, characterized in that A first portion of the third microporous layer is impermeable to the drug, and wherein a second portion of the third microporous layer is permeable to the drug.

11. The device according to claim 10, characterized in that The first portion of the third microporous layer includes an elastomer.

12. The device according to any one of claims 1 to 5, characterized in that The delivery device is capable of being implanted in the eye.

13. The device according to claim 12, characterized in that The drug is an ophthalmic drug for treating glaucoma.

14. The device according to claim 1, characterized in that The opposed uncoupled portions are operable to separate from one another to define the reservoir and thereby provide a volume of the reservoir that varies with the amount of drug present within the reservoir.

15. The device according to claim 1, characterized in that The delivery device is in the shape of a blister or pillow in the expanded state.

16. An implantable delivery device for dispensing a drug, the delivery device comprising: a first microporous layer coupled to a second microporous layer to define a reservoir, the reservoir being defined between opposing uncoupled portions of the first microporous layer and the second microporous layer and disposed between coupled peripheral edges of the first microporous layer and the second microporous layer; and a body having an outer surface, the reservoir comprising a first inner surface and an opposing second inner surface, wherein the first microporous layer comprises the first inner surface and the second microporous layer comprises the second inner surface, wherein the first inner surface is separable from the second inner surface when the reservoir is filled with the drug, and the first inner surface is operable to contract toward the second inner surface when the reservoir is emptied of the drug, wherein, in the expanded state, the first microporous layer and the second microporous layer are separated from each other between the unconnected portions, The device has a relatively flat profile in a deflated state, so that the separation between the first microporous layer and the second microporous layer is reduced. wherein the first interior surface is configured to meter dispensing of the drug over a predetermined period of time, and wherein the first interior surface is configured to resist tissue ingrowth, and Wherein, the outer surface of the body is configured to allow tissue ingrowth.

17. The device according to claim 16, characterized in that At least a portion of the first interior surface is permeable to the drug.

18. The device according to claim 16, characterized in that The second inner surface is impermeable to the drug.

19. The device according to claim 18, characterized in that The second inner surface includes an elastomer.

20. The device according to any one of claims 16 to 19, characterized in that The reservoir is configured to be refilled and emptied in situ.

21. The device according to any one of claims 16 to 19, characterized in that The reservoir is configured to expand to contain a drug therein.

22. The device according to any one of claims 16 to 19, characterized in that At least one of the first microporous layer and the second microporous layer includes an expanded polytetrafluoroethylene (ePTFE) membrane.

23. The device according to any one of claims 16 to 19, characterized in that A first portion of the first interior surface is impermeable to the drug, and wherein a second portion of the first interior surface is permeable to the drug.

24. The device according to claim 23, characterized in that The first portion of the first inner layer includes an elastomer.

25. The device according to any one of claims 16 to 19, characterized in that The delivery device is capable of being implanted in the eye.

26. The device according to any one of claims 16 to 19, characterized in that The drug is an ophthalmic drug for treating glaucoma.

27. A delivery device for dispensing a drug, comprising: a microporous body comprising a first microporous layer, a second microporous layer, and a third microporous layer, the first microporous layer being located between the second microporous layer and the third microporous layer, the first microporous layer comprising a plurality of pores sized to resist tissue ingrowth, wherein the second microporous layer and the third microporous layer each comprise a plurality of pores sized to allow tissue ingrowth; as well as a drug reservoir located between the first and third microporous layers, the drug reservoir being defined by opposing unattached portions of the first and third microporous layers and disposed between attached peripheral edges of the first and third microporous layers, the drug reservoir being operable to transition between an expanded state and a deflated state based on an amount of drug present in the drug reservoir, wherein, in the expanded state, the first microporous layer and the third microporous layer are separated from each other between the unconnected portions, wherein the device has a relatively flat profile in a deflated state, so that the separation between the first microporous layer and the third microporous layer is reduced, and wherein the plurality of pores in the first microporous layer are configured to correspond to the rate at which the metered drug is eluted from the drug storage portion, The first microporous layer includes a first portion that is permeable to drugs and a second portion that is not permeable to drugs.

28. The device according to claim 27, characterized in that The first microporous layer includes a metering portion for dispensing a drug over a period of time.

29. The device according to claim 27, characterized in that The second microporous layer and the third microporous layer define an exterior of the delivery device.

30. The device according to any one of claims 27 to 29, characterized in that The first microporous layer is coupled to the second microporous layer.

31. The device according to claim 30, characterized in that The second microporous layer includes openings configured to expose the first microporous layer.

32. The device according to any one of claims 27 to 29, characterized in that The drug depot is configured to be refilled and emptied in situ.

33. The device according to any one of claims 27 to 29, characterized in that The drug depot is configured to expand to contain a drug therein.

34. The device according to any one of claims 27 to 29, characterized in that At least one of the first microporous layer, the second microporous layer, and the third microporous layer includes an expanded polytetrafluoroethylene (ePTFE) membrane.

35. The device according to any one of claims 27 to 29, characterized in that The second portion of the first microporous layer includes an elastomer.

36. The device according to any one of claims 27 to 29, characterized in that The delivery device is capable of being implanted in the eye.

37. The device according to any one of claims 28 to 29, characterized in that The drug is an ophthalmic drug for treating glaucoma.

38. A drug metering device having an outer portion surrounding an inner portion, the inner portion defining a drug reservoir, the device comprising: a first stratum comprising a first microporous layer configured to resist tissue ingrowth and a second microporous layer configured to allow tissue ingrowth, the first microporous layer defining a portion of the interior and the second microporous layer defining a portion of the exterior, the first microporous layer and the second microporous layer comprising a microporous microstructure; as well as a second stratum coupled to the first stratum such that the drug depot is defined between opposing uncoupled portions of the first stratum and the second stratum and disposed between coupled peripheral edges of the first stratum and the second stratum, a portion of the first microporous layer of the first stratum being permeable to a drug capable of being disposed within the drug depot such that the first stratum is configured to meter a rate of elution of the drug from the drug depot, wherein the drug depot is operable to transition between an expanded state and a deflated state based on an amount of drug present in the drug depot, wherein, in the expanded state, the first layer and the second layer are separated from each other between the unconnected portions, and The device has a relatively flat profile in a deflated state, so that the separation between the first level and the second level is reduced.

39. The device according to claim 38, characterized in that The drug depot is defined between portions of the first and second tiers that are not coupled to each other such that the uncoupled portions of the first and second tiers are free to deflect relative to each other.

40. The device of claim 38, wherein: The second level includes a third microporous layer and a fourth microporous layer, the third microporous layer of the second level is configured to resist tissue ingrowth, and the fourth microporous layer of the second level is configured to allow tissue ingrowth, wherein the third microporous layer of the second level defines a portion of the interior and the fourth microporous layer defines a portion of the exterior.

41. The device according to any one of claims 38 to 40, characterized in that The first microporous layer and the second microporous layer of the first layer include expanded polytetrafluoroethylene (ePTFE).

42. The device according to any one of claims 38 to 40, characterized in that The first microporous layer of the first stratum includes a plurality of pores sized to resist tissue ingrowth, and wherein the second microporous layer of the first stratum includes a plurality of pores sized to allow tissue ingrowth.

43. The device according to claim 40, characterized in that The third microporous layer of the second stratum includes a plurality of pores sized to resist tissue ingrowth, and wherein the fourth microporous layer of the second stratum includes a plurality of pores sized to allow tissue ingrowth.

44. The device according to claim 40, characterized in that The third microporous layer of the second stratum includes an elastomer, such that the third microporous layer of the second stratum is impermeable to drugs.

45. The device according to any one of claims 38 to 40, characterized in that The first microporous layer of the first stratum includes a first portion permeable to drugs and a second portion impermeable to drugs, and the second portion of the first microporous layer of the first stratum includes an elastomer.

46. ​​The device according to any one of claims 38 to 40, characterized in that The drug dosing device is implantable in the eye.

47. The device according to claim 46, characterized in that The drug is an ophthalmic drug for treating glaucoma.

48. The device according to any one of claims 38 to 40, characterized in that The drug is included in a fluid suspension of particles.

49. The device according to claim 48, characterized in that The first microporous layer of the first stratum includes a plurality of pores sized to prevent the particles from passing through the first microporous layer.

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