Drug therapy delivery systems and methods

Abstract

To provide a preferable medical device such as an implantable medical device.SOLUTION: An implantable delivery device is provided for dispensing a medicament that includes a first microporous material that is bonded to a second microporous material. The first microporous material has a first microporous layer including a plurality of pores sized to permit tissue ingrowth and a second microporous layer including a plurality of pores sized to permit tissue ingrowth. The second microporous material has a third microporous layer including a plurality of pores sized to resist tissue ingrowth and a fourth microporous layer including a plurality of pores sized to permit tissue ingrowth. The second microporous layer is bonded to the third microporous layer to thereby form a reservoir for receiving the medicament. The first and second microporous materials are configured to meter a rate at which the medicament is dispensed from the reservoir when the delivery device is implanted.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] Cross - Reference to Related Applications This application is a continuation of U.S. Patent Application Publication No. 17 / 825,909, filed on May 26, 2022, which claims the benefit of Provisional Application No. 63 / 194,152, filed on May 27, 2021, and also claims the benefit of Provisional Application No. 63 / 345,595, filed on May 25, 2022, and these applications are hereby incorporated by reference in their entirety for all purposes.

Background Art

[0002] Aqueous humor is a fluid that fills the anterior chamber of the eye and contributes to intraocular pressure (IOP) or the fluid pressure within the eye. Ocular hypertension is a condition of the eye in which the IOP or the fluid pressure within the eye is elevated. If ocular hypertension is left untreated, it can lead to diseases such as glaucoma, and as a result, the vision of the affected eye may be gradually and sometimes permanently lost.

[0003] Many attempts have been made to treat ocular hypertension, particularly glaucoma. Such attempts include surgical procedures involving implanting drainage devices designed to lower the IOP of the affected eye, as well as drug administration. The aim of these treatments is to improve the quality of life by lowering the IOP and to maintain visual function.

[0004] Drug administration is typically carried out in the form of eye drops that require self - administration by the patient, but in some cases, an implantable extended drug delivery device can also be employed. Implantable extended drug delivery devices are typically either located outside the eye (e.g., an extra - ocular approach) or implanted within the anterior chamber of the eye (an intra - anterior - chamber approach).

[0005] There are various challenges in the extraocular approach in drug delivery. To perform an effective extraocular approach, it is necessary to transport a sufficient amount of drug 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, as well as the natural barrier to the interior of the eye formed by the conjunctiva, complicate the effectiveness of the extraocular approach and, as a result, impede the optimization of long-term dosage delivery. Therefore, in the extraocular approach, administration of an excessive amount of drug may be included to extend the period of effectiveness.

[0006] On the other hand, the intracameral approach is a more invasive approach that requires puncturing through various tissue layers of the eye and accessing the anterior chamber of the eye to place a device. When a drug is administered in relation to an absorbable (biodegradable) device, the intracameral approach becomes even more complicated because the degradability of the device may cause the device to dislodge and float within the anterior chamber. Furthermore, repeated removal and replacement of the device requires trauma to the eye tissue.

[0007] Examples of the above approaches established for treating eye conditions are described herein.

[0008] For example, Allergan has developed a biodegradable pellet for drug delivery to the anterior chamber of the eye and sells it under the trade name DURYSTA. The delivery method is described in U.S. Patent No. 10,398,707 to Allergan Inc., filed at least on October 2, 2022. The drug, bimatoprost, is filled within a biodegradable pellet implanted in the eye and dissolves within the anterior chamber to deliver the filled bimatoprost. However, wear may occur during the dissolution process, which may have an adverse effect on the endothelial cells in the cornea.

[0009] Similarly, Allergan Inc. is developing a device described as "ENV515," a fully bioabsorbable device loaded with travoprost, as disclosed in U.S. Patent Application Publication No. 2022 / 0080049, filed March 25, 2021. After implantation of the device in the anterior chamber, water bioerodes at least a portion of the device through which the active agent is released. However, this may result in damage to endothelial cells due to wear during bioerosion of the device.

[0010] Glaukos, Inc. has a device in development called "iDose." It is a metal plug that is inserted into the anterior chamber to deliver a glaucoma medication or drug, such as travoprost. The device is described at least in Glaukos Corp's U.S. Patent Application Publication No. 2021 / 0315806(A1), filed March 26, 2021. However, the device is not bioabsorbable and cannot be refilled while in the eye. This requires removal of the device, refilling the device, and re-implanting the device. This results in additional work for the patient and subsequent procedures.

[0011] Allergan has also developed an extraocular ring that elutes a glaucoma drug onto the surface of the eye. The drug eluted by the ring can be bimatoprost. The device is a relatively large silicone ring that is positioned within the fornix of the eye. The drug is released from the ring and transported through the cornea for drug delivery. However, this delivery method involves a device worn around the eye rather than within the eye, so direct delivery can be uncomfortable for patients and is not as effective.

[0012] With reference to established glaucoma treatments, Mati Therapeutics developed a punctal plug that is worn at the punctum on the outside of the user's eye. The drug can then leach out from the device and reach the delivery target through the eye. This device is described in U.S. Patent No. 9,216,108 of Mati Therapeutics, filed at least on February 17, 2009. Similar to the extraocular devices described above, since devices are worn intraocularly and periorbitally, it may cause discomfort to the user. This method is also not as effective as drug delivery by direct delivery.

[0013] Drug delivery methods have also been established for various other eye diseases. For example, Genentech has established a drug delivery device for exudative age-related macular degeneration via a port delivery system, which is described in U.S. Patent No. 10,398,593 to ForSight Vision4 Inc., filed on December 21, 2016. The port delivery system requires access to the eye as an access port is worn under the conjunctiva to replenish the drug. This can cause discomfort to the patient or any other complications associated with invasive drug delivery.

[0014] The treatment or prevention of eye diseases can be achieved by gene therapy. In gene therapy, the genetic properties of target cells or target tissues in the eye are changed to improve or affect the disorder. Genome therapy can be realized in various ways. By gene transfer, specific genetic materials required to supplement the defective protein function can be added. Genome editing makes it possible to accurately correct the DNA modifications that are the cause of the disorder. By introducing new genetic capabilities, diseased tissues can produce the necessary proteins.

[0015] Gene therapy is achieved by transduction using genetically engineered vectors. These vectors are preferably modified viruses or viral capsids used to transport different genetic materials to target cells and tissues. Viruses are useful because they can deliver nucleic acid material by infecting cells. In gene therapy strategies, it can be envisioned that new genetic material is integrated into the host cell's DNA, as enabled by modified retroviruses, or that new genetic material is introduced into the host cell nucleus but not integrated into the chromosome, as supported by adenoviruses. Since a patient's immune system can respond to the presence of viral material, the use of unmodified viruses is not without drawbacks. Furthermore, there is also a possibility of clinical complications due to the systemic spread of unmodified virus particles.

[0016] Like adenoviruses, adeno-associated virus (AAV) vectors can transduce various host cell types without integrating into the host genome. Adeno-associated virus is not known to cause serious complications or diseases. The immune response that the virus can induce is not significant. AAV vectors have gained a reputation as optimal transduction vectors. AAV vectors are small and non-pathogenic while retaining the ability to infect non-dividing cells. At least these attributes make AAV vectors very attractive for use in gene therapy. AAV capsids have proven successful in many preclinical and clinical applications in gene therapy and have received regulatory approval worldwide. Furthermore, additional inducers such as orally administered inducers (developed by MeiraGTx) have been proposed for controlled gene expression and regulation. The progress of gene therapy using AAV vectors has been shown to be particularly promising for the treatment of retinal diseases and is being studied by many companies such as Adverum and RegenXBio. The goal of gene therapy is for the transduced retinal cells to express the therapeutic DNA sequence over a long period of time.

[0017] In the field of ophthalmology, retinal gene therapy is considered applicable to several conditions, such as the prevention of glaucomatous neurodegeneration and the protection of retinal ganglion cells (interventions not related to IOP), or the support of photoreceptors and retinal pigment epithelium for the treatment of age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Other target diseases include geographic atrophy (GA), diabetic macular edema (DME), and diabetic retinopathy (DR). Once cells are transduced, AAV persists for a long time, and expression of the therapeutic DNA sequence is expected over several months and in some cases for several years.

[0018] Gene therapy vectors are generally administered by bolus injection into the subretinal space, intravitreally, or suprachoroidally. These administration routes exhibit a certain degree of invasiveness that can lead to clinical complications. Furthermore, they are not suitable for the gradual introduction of the transduction vector over a long period, and treatment cannot be administered gradually.

[0019] In contrast, the drug therapy delivery systems and methods disclosed herein introduce unique advantages for the administration of gene therapy, enabling the permanent and sustained distribution of the transduction vector over time and to a wider surrounding area. Thus, the systems and methods disclosed herein enhance cell uptake and dosage control while optimizing tissue targeting. Embodiments of the system enable a subconjunctival or sub-Tenon's capsule administration route designed to prevent vascular clearance through the conjunctiva, and a minimally invasive implantation procedure avoids damage to and clearance by the choroidal capillaries. Thus, exposure to existing neutralizing antibodies (Nabs) against the AAV capsid antigen is minimized.

[0020] Furthermore, the drug therapy delivery systems and methods disclosed herein are consistent with alternative methods for gene therapy (e.g., methods for predicting the delivery of genetic material to host cells without viruses). Polymer-based nanoparticles (less than 100 nm), liposomes, and compressed DNA or RNA nanoparticles (DNPs) can be adjusted according to various release rates, hydrophilicity, and lipophilicity, and can be designed to enhance specificity for specific cell types. Gene delivery by nanoparticles is less likely to induce a reaction from the immune system. Also, these vectors can accommodate larger holding capacities (i.e., 20 kb) and larger genes compared to AAV with a plasmid size up to 5 kb.

[0021] The above publications provide some examples of drugs and / or delivery systems applicable to the condition of the eye, and various other approaches are also being pursued. There is still a need for a minimally invasive drug delivery method that provides drug delivery to the local eye at a measured delivery rate over a desired period without patient participation and without breaching the blood-eye barrier.

Summary of the Invention

[0022] According to one example (Example 1), a method of treating an eye disease, the method comprising an implantable delivery device comprising a first microporous material bound to a second microporous material, the first microporous material having a first microporous layer comprising a plurality of pores sized to permit tissue ingrowth and a second microporous layer comprising a plurality of pores sized to permit tissue ingrowth, the second microporous material having a third microporous layer comprising a plurality of pores sized to resist tissue ingrowth and a fourth microporous layer comprising a plurality of pores sized to permit tissue ingrowth, the second microporous layer being bound to the third microporous layer thereby forming a reservoir for receiving at least one agent, the first microporous material and the second microporous material being configured to meter the rate at which the agent is dispensed from the reservoir when the delivery device is implanted; selecting an implantable delivery device; filling the reservoir with an agent for treating one or more eye diseases; implanting the implantable delivery device at an implantation site; and enabling the agent to be dispensed from the reservoir to one or more treatment sites.

[0023] In addition to Example 1, according to another example (Example 2), the implantation site is an anterior reservoir location.

[0024] In addition to Example 2, according to another example (Example 3), the one or more eye diseases include at least one of glaucoma, keratitis, dry eye, or presbyopia.

[0025] In addition to Example 3, according to another example (Example 4), when the one or more diseases are glaucoma, the agent has an API class that includes at least one of a prostaglandin, a prostaglandin structural analog, a beta blocker, an alpha agonist, or a carbonic anhydrase inhibitor.

[0026] In addition to Example 3, according to another example (Example 5), when the one or more diseases are keratitis, the agent has an API class that includes at least one of an antibiotic, a steroid, or an antifungal agent.

[0027] In addition to Example 3, according to another example ("Example 6"), when one or more diseases are dry eye, the drug has an API class corresponding to at least one of prostaglandins, beta blockers, alpha agonists, or carbonic anhydrase inhibitors.

[0028] In addition to Example 3, according to another example ("Example 7"), when one or more diseases are presbyopia, the drug has an API class including miotics.

[0029] In addition to Example 1, according to another example ("Example 8"), the implantation position is the posterior reservoir position.

[0030] In addition to Example 1, according to another example ("Example 9"), one or more eye diseases include at least one of age-related macular degeneration, geographic atrophy lesion, macular edema, uveitis, retinitis, keratitis, retinoblastoma, central retinal vein occlusion, or branch retinal vein occlusion.

[0031] In addition to Example 9, according to another example ("Example 10"), when one or more diseases are age-related macular degeneration, the drug has an API class including monoclonal antibodies, antibody-mimetic proteins, peptides, or small binding molecules.

[0032] In addition to Example 9, according to another example ("Example 11"), when one or more diseases are macular edema, the drug has an API class including monoclonal antibodies, antibody-mimetic proteins, peptides, small binding molecules, or steroids.

[0033] In addition to Example 9, according to another example ("Example 12"), when one or more diseases are uveitis, the drug has an API class including corticosteroids.

[0034] In addition to Example 9, according to another example ("Example 13"), when one or more diseases are retinitis, the drug has an API class including antibiotics or antiviral drugs.

[0035] In addition to Example 9, according to another example ("Example 14"), when one or more diseases are retinoblastoma, the agent has an API class that includes a cytotoxic chemotherapy compound.

[0036] In addition to Example 9, according to another example ("Example 15"), when one or more diseases are central retinal vein occlusion or branch retinal vein occlusion, the agent has an API class that includes a monoclonal antibody or a steroid.

[0037] In addition to Example 1, according to another example ("Example 16"), the implantation position is an anterior-posterior reservoir position.

[0038] In addition to Example 16, according to another example ("Example 17"), one or more eye diseases include at least one of age-related macular degeneration, geographic atrophy lesion, macular edema, uveitis, retinitis, central retinal vein occlusion, or branch retinal vein occlusion.

[0039] In addition to Example 17, according to another example ("Example 18"), when one or more diseases are age-related macular degeneration, the agent has an API class that includes a monoclonal antibody.

[0040] In addition to Example 17, according to another example ("Example 19"), when one or more diseases are macular edema, the agent has an API class that includes a monoclonal antibody or a steroid.

[0041] In addition to Example 17, according to another example ("Example 20"), when one or more diseases are uveitis, the agent has an API class that includes a corticosteroid.

[0042] In addition to Example 17, according to another example ("Example 21"), when one or more diseases are retinitis, the agent has an API class that includes an antibiotic or an antiviral agent.

[0043] In addition to Example 17, according to another example ("Example 22"), when one or more diseases are central retinal vein occlusion or branch retinal vein occlusion, the agent has an API class that includes a monoclonal antibody or a steroid.

[0044] In addition to Example 1, according to another example ("Example 23"), the implantable delivery device includes a refillable reservoir and a delivery arm.

[0045] In addition to Example 23, according to another example ("Example 24"), the method further includes refilling the refillable reservoir.

[0046] In addition to Example 1, according to another example ("Example 25"), the implantable delivery device has one or more filling ports for refilling the reservoir.

[0047] In addition to Example 1, according to another example ("Example 26"), the implantable delivery device is configured to dispense the agent in a single direction.

[0048] In addition to Example 1, according to another example ("Example 27"), the implantable delivery device is configured to dispense the agent in a plurality of directions.

[0049] In addition to Example 1, according to another example ("Example 28"), the implantable delivery device has a plurality of chambers defined within the reservoir, and a first and a second chamber within the plurality of chambers are in fluid communication with each other.

[0050] In addition to Example 1, according to another example ("Example 29"), the implantable delivery device has a plurality of chambers defined within the reservoir, and a first and a second chamber within the plurality of chambers are fluidly isolated from each other.

[0051] In addition to Example 1, according to another example ("Example 30"), the implantable delivery device has a plurality of chambers defined within the reservoir, and the implantable delivery device has one or more filling ports for refilling the reservoir.

[0052] In addition to Example 30, according to another example (“Example 31”), the number of filling ports corresponds to the number of chambers.

[0053] In addition to Example 31, according to another example (“Example 32”), embedding the implantable delivery device at the implantation site includes placing the device at the implantation site such that the implantable delivery device is subconjunctival.

[0054] In addition to Example 1, according to another example (“Example 33”), embedding the implantable delivery device at the implantation site includes placing the device at the implantation site such that the implantable delivery device is suprachoroidal.

[0055] In addition to Example 1, according to another example (“Example 34”), the implantation site is a reservoir position in the anterior vitreous.

[0056] In addition to Example 34, according to another example (“Example 35”), the one or more eye diseases include at least one of age-related macular degeneration, geographic atrophy lesion, macular edema, uveitis, retinitis, central retinal vein occlusion, or branch retinal vein occlusion.

[0057] In addition to Example 35, according to another example (“Example 36”), when the one or more diseases are age-related macular degeneration, the drug has an API class that includes a monoclonal antibody.

[0058] In addition to Example 35, according to another example (“Example 37”), when the one or more diseases are macular edema, the drug has an API class that includes a monoclonal antibody or a steroid.

[0059] In addition to Example 35, according to another example (“Example 38”), when the one or more diseases are uveitis, the drug has an API class that includes a corticosteroid.

[0060] In addition to Example 35, according to another example ("Example 39"), when one or more diseases are retinitis, the agent has an API class that includes an antibiotic or an antiviral agent.

[0061] In addition to Example 35, according to another example ("Example 40"), when one or more diseases are central retinal vein occlusion or branch retinal vein occlusion, the agent has an API class that includes a monoclonal antibody or a steroid.

[0062] In addition to Example 23, according to another example ("Example 41"), the implantation position is the anterior - anterior chamber reservoir position.

[0063] In addition to Example 41, according to another example ("Example 42"), one or more eye diseases include at least one of age - related macular degeneration, macular edema, uveitis, retinitis, central retinal vein occlusion, or branch retinal vein occlusion.

[0064] In addition to Example 42, according to another example ("Example 43"), when one or more diseases are glaucoma, the agent has an API class that includes at least one of a prostaglandin, a beta - blocker, an alpha - agonist, or a carbonic anhydrase inhibitor.

[0065] In addition to Example 42, according to another example ("Example 44"), when one or more diseases are keratitis, the agent has an API class that includes at least one of an antibiotic, a steroid, or an antifungal agent.

[0066] In addition to Example 42, according to another example ("Example 45"), when one or more diseases are dry eye, the agent has an API class corresponding to at least one of a prostaglandin, a beta - blocker, an alpha - agonist, or a carbonic anhydrase inhibitor.

[0067] In addition to Example 42, according to another example ("Example 46"), when one or more diseases are presbyopia, the agent has an API class that includes a miotic agent.

[0068] In addition to Example 1, according to another example ("Example 47"), gene therapy is developed for the treatment of age-related macular degeneration, retinitis pigmentosa, geographic atrophy, diabetic macular edema, and diabetic retinopathy, and to prevent glaucomatous neurodegeneration.

[0069] In addition to Example 1, according to another example ("Example 48"), gene therapy is achieved by continuous 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.

[0070] According to another example ("Example 49"), the pharmaceutical composition includes at least one therapeutic agent and at least one additional material, and the pharmaceutical composition has the ability to take on a first state and a second state, and the ability to transition between the first state and the second state when exposed to a fluid. The pharmaceutical composition further includes not allowing the movement of at least one therapeutic agent through the additional material in the first state of the pharmaceutical composition, and allowing the movement of at least one therapeutic agent through the additional material in the second state.

[0071] In addition to Example 49, according to another example ("Example 50"), at least one additional material includes a polymer and optionally includes bioabsorbable microparticles.

[0072] In addition to Example 49, according to another example ("Example 51"), in the second state, at least one therapeutic agent is released from at least one additional material at a predetermined rate.

[0073] In addition to Example 49, according to another example ("Example 52"), the bioabsorbable microparticles have an average size of 15 micrometers to 25 micrometers.

[0074] In addition to Example 49, according to another example ("Example 53"), in the second state, the composition can absorb fluid and release the therapeutic agent.

[0075] In addition to Example 49, according to another example (“Example 54”), the therapeutic agent includes at least one of a prostaglandin analog, a β-blocker, an α2 agonist, and a carbonic anhydrase inhibitor.

[0076] In addition to Example 54, according to another example (“Example 55”), the therapeutic agent includes at least one of latanoprost, timolol, brimonidine, or dorzolamide.

[0077] In addition to Example 49, according to another example (“Example 56”), the first state includes a non-treatment state and the second state includes a treatment state.

[0078] According to another example (“Example 57”), the pharmaceutical composition includes at least one therapeutic agent and at least one additional material, and the pharmaceutical composition has the ability to take on a first state and a second state, and the ability to transition between the first state and the second state when exposed to a fluid. The composition further includes, in the first state, that the pharmaceutical composition includes a non-treatment state.

[0079] In addition to Example 57, according to another example (“Example 58”), the second state includes a treatment state.

[0080] In addition to Example 57, according to another example (“Example 59”), the therapeutic agent includes at least one of a prostaglandin analog, a β-blocker, an α2 agonist, and a carbonic anhydrase inhibitor.

[0081] In addition to Example 57, according to another example (“Example 60”), the additional material includes a polymer and optionally includes a bioabsorbable material.

[0082] According to another example ("Example 61"), a pharmaceutical composition disposed within a reservoir defined by at least one additional material includes at least one therapeutic agent, and the pharmaceutical composition has the ability to take on a first state and a second state, and the ability to transition between the first state and the second state when exposed to a fluid. The composition further includes, in a first state of the pharmaceutical composition, that at least one additional material inhibits the movement of at least one therapeutic agent through the additional material, and in a second state of the pharmaceutical composition, that at least one additional material permits the movement of at least one therapeutic agent through the additional material.

[0083] In addition to Example 61, according to another example ("Example 62"), the transition between the first state and the second state is initiated by at least one additional material that permits the passage of a fluid from the external environment to the pharmaceutical composition in the first state.

[0084] In addition to Example 61, according to another example ("Example 63"), the at least one additional material includes a polymer and optionally includes bioabsorbable microparticles.

[0085] In addition to Example 61, according to another example ("Example 64"), in the second state, the at least one therapeutic agent is released from the at least one additional material at a predetermined rate.

[0086] In addition to Example 61, according to another example ("Example 65"), the bioabsorbable microparticles have an average size of 15 micrometers to 25 micrometers.

[0087] In addition to Example 61, according to another example ("Example 66"), in the second state, the composition is capable of absorbing a fluid and releasing a therapeutic agent.

[0088] In addition to Example 61, according to another example ("Example 67"), the therapeutic agent includes at least one of a prostaglandin analog, a beta blocker, an alpha2 agonist, and a carbonic anhydrase inhibitor.

[0089] In addition to Example 67, according to another example ("Example 68"), the therapeutic agent includes at least one of latanoprost, timolol, brimonidine, or dorzolamide.

[0090] In addition to Example 61, according to another example ("Example 69"), the first state includes a non-treatment state and the second state includes a treatment state.

[0091] According to another example ("Example 70"), the pharmaceutical composition disposed within a reservoir defined by at least one additional material includes at least one therapeutic agent, and the pharmaceutical composition has the ability to take on a first state and a second state, and the ability to transition between the first state and the second state when exposed to a fluid. The composition further includes that in the first state of the pharmaceutical composition, at least one material inhibits the movement of at least one therapeutic agent in the first state, whereby the pharmaceutical composition includes a non-treatment state.

[0092] In addition to Example 70, according to another example ("Example 71"), in the second state, at least one material allows the movement of at least one therapeutic agent in the second state, whereby the pharmaceutical composition includes a treatment state.

[0093] In addition to Example 70, according to another example ("Example 72"), the transition between the first state and the second state is initiated by at least one additional material that allows the passage of fluid from the external environment to the pharmaceutical composition in the first state.

[0094] In addition to Example 70, according to another example ("Example 73"), in the second state, at least one therapeutic agent is released from at least one additional material at a predetermined rate.

[0095] In addition to Example 70, according to another example ("Example 74"), the bioabsorbable microparticles have an average size of 15 micrometers to 25 micrometers.

[0096] In addition to Example 70, according to another example ("Example 75"), in the second state, the composition can absorb fluid and release a therapeutic agent.

[0097] In addition to Example 70, according to another example ("Example 76"), the therapeutic agent includes at least one of a prostaglandin analog, a β-blocker, an α2 agonist, and a carbonic anhydrase inhibitor.

[0098] In addition to Example 76, according to another example ("Example 77"), the therapeutic agent includes at least one of latanoprost, timolol, brimonidine, or dorzolamide.

[0099] In addition to Example 78, according to another example ("Example 78"), the first state includes a non-treatment state, and the second state includes a treatment state.

[0100] According to another example ("Example 79"), an implantable medical device pre-loaded with a therapeutic agent includes a first microporous material bonded to a second microporous layer and defining a reservoir disposed therebetween, the reservoir being configured to contain the therapeutic agent, and the implantable medical device being configured to release the therapeutic agent at a predetermined rate. The device further includes that the therapeutic agent is at least one of latanoprost, timolol, brimonidine, or dorzolamide.

[0101] According to another example ("Example 80"), an implantable medical device for delivering a therapeutic agent for the treatment of a disease includes a first microporous material bonded to a second microporous layer and defining a reservoir disposed therebetween, the reservoir containing a pharmaceutical composition and being configured to deliver the therapeutic agent to a target site for treating the disease. The device further includes that the treatment is configured to treat one or more of glaucoma, macular degeneration, macular edema, retinitis, retinoblastoma, retinal vein occlusion, keratitis, and dry eye.

Brief Description of the Drawings

[0102] The accompanying drawings are included to provide a further understanding of the embodiments of the present disclosure, are incorporated herein, form a part of this specification, serve to illustrate examples, and together with the description of this specification, serve to explain the principles of the present disclosure.

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DETAILED DESCRIPTION OF THE INVENTION

[0150] One skilled in the art will readily understand that the various embodiments of the inventive concepts provided in this disclosure can be implemented by any number of methods and devices configured to perform the intended functions. Also, the accompanying drawings referred to herein are not necessarily drawn to scale and may be exaggerated to show various aspects of the disclosure, and in that regard, it should be noted that the drawings should not be construed as limiting. However, some of the figures represent anatomical structures and the positioning of embodiments relative to those anatomical structures, and such representations, while some deviation is allowed since the depicted anatomical structures vary in size and position from person to person, should be understood to be accurately scaled and positioned.

[0151] 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, glaucoma and / or ocular hypertension by reducing intraocular pressure from an undesirably high level that can lead to progressive and in some cases permanent vision loss in the affected eye. 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 thus can be configured to provide multiple different release rates, including multiple different release rates of multiple drugs. Some examples of suitable ophthalmic drugs include therapeutic agents such as prostaglandin analogs (PGAs) (e.g., latanoprost), or beta blockers such as timolol, alpha2 agonists such as brimonidine tartrate, or carbonic anhydrase inhibitors such as dorzolamide, compounds of carbonic anhydrase inhibitors and beta blockers, and therapeutic agents from other drug classes including compounds of alpha agonists and beta blockers that can be administered in combination with a PGA.

[0152] In some embodiments, such drug delivery systems are configured to be implanted and refillable in situ in a minimally invasive manner one or more times without the need to remove the drug delivery system from the implantation site. Considering the size and subconjunctival target implantation location, the implantation procedure can be performed outside of an operating room where needle punctures and small incisions are commonly performed. Additionally, some system examples include features to help reduce micromotion between the drug delivery system and the tissue into which they are implanted. Micromotion can be defined as small movement between the drug delivery system and the tissue, and the movement can be on the scale of micrometers or millimeters and microseconds or milliseconds. Micromotion is sometimes known to cause irritation of the surrounding tissue, leading to excessive scarring, ultimately erosion of the implanted device, and / or a foreign body tissue reaction that can cause site infection.

[0153] A drug delivery system 1000 according to some embodiments is shown in FIG. 1A. As shown, the drug delivery system 1000 is implanted within the eye 5000 between the conjunctiva 5002 and the sclera 5004 of the eye 5000. The anterior chamber 5006 is also shown. The drug delivery system 1000 generally includes one or more portions configured to meter drug release from the drug delivery system 1000, and one or more portions configured to facilitate or permit cell infiltration and / or tissue attachment. The drug may include a single therapeutic agent (e.g., a pharmaceutical), or may include a plurality of therapeutic agents. The drug may include additional materials (e.g., a bioabsorbable polymer, a pharmaceutically acceptable carrier) to affect the elution of the therapeutic agent (e.g., a bioabsorbable polymer) from the delivery system. Throughout this description, the drug may also be composed of both a therapeutic agent and / or additional materials for effective elution of the therapeutic agent, and thus may be referred to as a pharmaceutical composition or combination. For example, the drug may include bioabsorbable microparticles having a size in the range of about 0.1 micrometers to 50 micrometers, or about 1 micrometer to 50 micrometers, or about 5 micrometers to 50 micrometers, or about 15 micrometers to 50 micrometers, or about 10 micrometers to 40 micrometers, or about 15 micrometers to 25 micrometers, or about 18 micrometers to 23 micrometers. In some embodiments, the bioabsorbable microparticles have an average size of about 20 micrometers. In further embodiments, the therapeutic agent retained within the bioabsorbable microparticles can be latanoprost. As further described herein, the bioabsorbable microparticles can be retained within the drug delivery system 1000 during use, while the drug can be released from the bioabsorbable microparticles and the drug delivery system 1000 itself. The drug delivery system 1000 can be configured to measure the drug release rate at a plurality of different release rates for a plurality of different drugs.

[0154] As described above, the agent can be a pharmaceutical composition composed of at least one therapeutic agent and at least one additional material (e.g., but not limited to, bioabsorbable microparticles). The pharmaceutical composition can take a first state, can take 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, such 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 thereof). 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 thereof. In some embodiments, the first state is substantially free of fluid.

[0155] In certain embodiments, the fluid includes water. However, in other embodiments, various other fluids may be present. In some embodiments, the time required for the provided composition to convert to the second state may vary in a manner suitable for the application and may be relatively short. For example, in some embodiments, the pharmaceutical composition converts to the second state within a period of 10 seconds to 1 week (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) after exposure to the fluid.

[0156] Similarly, the time for which the provided composition remains in the second state may vary in a manner suitable for the application and may be relatively long. For example, in some embodiments, the pharmaceutical composition may be in the second state for a period of 1 minute to 1 year after exposure to a fluid, and for any time frame included therein, such as 1 hour, 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 8 months, or 11 months. Stated another way, the daily influx of the agent from the reservoir to the patient's eye is consistent and controllable over a period of time. Without wishing to be bound by any particular theory, this can be achieved by using pharmaceutically acceptable carrier microparticles having various sizes and geometric complexities, in which case the conversion of the pharmaceutical composition occurs at different times over a period of months based on the pace of degradation in the additional biodegradable material.

[0157] Figure 1B is a detailed view of region 1B of Figure 1A and shows a drug delivery system 1000 implanted within the subconjunctival space 5008. As shown, the subconjunctival space 5008 is a pocket formed between the conjunctiva 5002 and the sclera 5004 of the eye 5000. The subconjunctival space 5008 shown in Figures 1A and 1B can be formed according to known methods. In some embodiments, the drug delivery system 1000 can be implanted externally (ab-externally) (e.g., from outside the eye), such as through a conjunctival incision. In some embodiments, a radial incision of the conjunctiva is made near the limbus of the cornea, blunt dissection of the conjunctiva is performed to expose the sclera, and a subconjunctival pocket for placing the drug delivery system 1000 is formed. In other embodiments, the drug delivery system 1000 is implanted internally (ab-internally) (e.g., from inside the eye), such as through a clear corneal incision, and is placed into the dissected subconjunctival space 5008 through the sclera 5004.

[0158] In some embodiments, the drug delivery system 1000 can be further secured to the sclera 5004 or other surrounding tissue, such as by suturing, by an adhesive, or according to other known methods. For example, suture threads can be used to place the drug delivery system 1000 on the sclera 5004. The drug delivery system 1000 can be secured permanently or semi - permanently upon implantation, but the drug delivery system 1000 can also be initially temporarily secured (or not secured at all initially), and then secured to the sclera 5004 or other surrounding tissue by one or more portions of the drug delivery system 1000 configured to promote or allow cell infiltration and tissue attachment.

[0159] Continuing to refer to FIGS. 1A and 1B, the drug delivery system 1000 includes at least a first layer 1100 and a second layer 1200. The first layer 1100 and the second layer 1200 are generally connected to each other to provide a drug reservoir 1300 defined between the first layer 1100 and the second layer 1200, as shown in FIG. 1B. The drug reservoir 1300 is generally a sealed space into which a drug can be deposited for subsequent delivery by the drug delivery system 1000. Generally, the drug delivery system 1000 is configured to measure the rate of release of the drug placed within the drug reservoir 1300 over a specified period of time. For example, a drug can be placed 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 plan to treat one or more defects or conditions of the eye.

[0160] Furthermore, the drug delivery system 1000 can be minimally invasively refillable and / or drainable in situ (e.g., without the need to first remove the drug delivery system 1000 from the implantation site). In some such embodiments, one or more of the first layer 1100 and the second layer 1200 are configured to be repeatedly punctured with a cannula during the operation of refilling or draining the drug reservoir without significantly compromising the integrity of the first layer 1100 and / or the second layer 1200. In some embodiments, this integrity can be achieved by coating or absorbing the first layer 1100 and / or the second layer 1200 with an elastomeric material.

[0161] Referring now to FIGS. 2-4, a drug delivery system 1000 is shown. FIG. 2 is a cross-sectional view of the drug delivery system 1000 shown in an inflated state (i.e., a state in which the drug reservoir 1300 is inflated such that a separation is defined between the first layer 1100 and the second layer 1200), obtained along line 2-2 of the drug delivery system shown in FIG. 4. In some embodiments, the inflated state corresponds to the presence of drug within the drug reservoir 1300. FIG. 3 is a cross-sectional view of the drug delivery system 1000 obtained along line 2-2 of the drug delivery system shown in FIG. 4, shown in a deflated state, such as when the drug reservoir 1300 is empty or there is not enough drug to cause a separation between the first layer 1100 and the second layer 1200. FIG. 4 is a front view of the drug delivery system 1000.

[0162] As shown in FIG. 2, the first layer 1100 and the second layer 1200 are connected to each other along one or more portions of the first layer 1100 and the second layer 1200, but one or more other portions of the first layer 1100 and the second layer 1200 are not connected. The unconnected portions of the first layer 1100 and the second layer 1200 are in a state where they can freely separate from each other. In various embodiments, the unconnected portions of the first layer 1100 and the second layer 1200 are operable to separate from each other to define the drug reservoir 1300.

[0163] In some embodiments, the first layer 1100 and the second layer 1200 can be connected to each other around the periphery 1002 of the drug delivery system 1000, as shown in FIG. 2. However, it will be appreciated that the first layer 1100 and the second layer 1200 may be additionally or alternatively connected in other regions including one or more regions inside the periphery 1002. The periphery 1002 is generally an edge extending around the drug delivery system 1000. The periphery 1002 can be uniform, non-uniform, continuous, or discontinuous. For example, in some embodiments, the periphery 1002 can include one or more radially extending tabs or frilly shapes (e.g., the drug delivery system 1000 can include a scalloped periphery). In some embodiments, these tabs or frilly shapes can be operated as connection regions for connecting the drug delivery system 1000 to surrounding tissues such as the dura mater 5004.

[0164] As shown in FIG. 2, the first layer 1100 and the second layer 1200 are connected to each other at the periphery 1002 and / or along a region immediately radially inside the periphery 1002 to form a connection region extending adjacent to the periphery 1002. The connection region may be formed in a ring shape and may extend radially inward from the periphery 1002 as desired. As shown in FIG. 2, the drug reservoir 1300 is defined between the first layer 1100 and the second layer 1200 and the first layer 1100 and the second layer 1200 are not connected. It will be appreciated that the first layer 1100 and the second layer 1200 can be further connected together at a plurality of discrete positions or regions including one or more positions or regions radially inside the periphery 1002 of the drug delivery system 1000. Connecting one or more additional regions inside the periphery together can help control the expanded outer shape of the drug delivery system 1000.

[0165] One or more of the first layer 1100 and the second layer 1200 can be configured to deform elastically or plastically as the drug reservoir 1300 expands. Further, in some embodiments, one of the first layer 1100 and the second layer 1200 can be inelastic, which can help control the expanded outer shape of the drug delivery system 1000.

[0166] In various embodiments, one or both of the first layer 1100 and the second layer 1200 include one or more regions configured to meter the release of the drug. These metering regions can be in the form of membranes, layers, or films, or coatings. In some embodiments, one or more of the first layer 1100 and the second layer 1200 include one or more regions configured to permit or promote cell infiltration or tissue ingrowth and tissue attachment. Cell infiltration and tissue attachment generally occur when the material is porous enough to permit fibroblast infiltration. Thus, the drug delivery system 1000 can include membranes, layers, films, and / or coatings configured to permit tissue ingrowth and tissue attachment.

[0167] In at least one embodiment, the first layer 1100 and / or the second layer 1200 can be formed from a plurality of membrane layers. For example, as shown in FIGS. 2 and 3, the first layer 1100 can include a first membrane layer 1110 and a second membrane layer 1120. The first membrane layer 1110 and the second membrane layer 1120 of the first layer 1100 collectively define the first layer 1100. It will be understood that the first layer 1100 can include additional membrane layers in addition to the first membrane layer 1110 and the second membrane layer 1120.

[0168] In some embodiments, one or more of the first membrane layer 1110 and the second membrane layer 1120 may include a microporous microstructure. For example, one or more of the first membrane layer 1110 and the second membrane layer 1120 may include a biocompatible material such as expanded polytetrafluoroethylene (ePTFE). Additionally, one or more of the first membrane layer 1110 and the second membrane layer 1120 of the first layer 1100 may be formed of other biocompatible materials including biocompatible polymers that may or may not be microporous, examples of which include polyurethane, silicone, polysulfone, polyvinylidene fluoride (PVDF), polyhexafluoropropylene (PHFP), perfluoroalkoxy polymer (PFA), polyolefin, fluorinated ethylene propylene (FEP), acrylic copolymer, and polytetrafluoroethylene (PTFE), but are not limited thereto.

[0169] The first membrane layer and / or the second membrane layer may be in the form of one or more sheets or films, and may include a knitted, woven, and / or non-woven form including individual fiber strands or multi-fiber strands. In some embodiments, the first membrane layer 1110 and / or the second membrane layer 1120 may be formed from a plurality of sheets or films of a polymeric material. In some embodiments, the sheets or films may be laminated or otherwise mechanically connected to each other to form the first membrane layer 1110 and / or the second membrane layer 1120 of the first layer 1100. The connection of the sheets or films can be achieved 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.

[0170] In some embodiments, adjacent film layers (e.g., a first film layer 1110 and a second film layer 1120) and / or layers of materials forming such film layers may be partially or fully bonded via a thermal method in which each of the polymers forming the materials is brought to a temperature above its melting temperature. In some embodiments, such thermal processes facilitate the formation of adhesive or cohesive bonds between the materials or layers of materials. In some embodiments, adjacent film layers and / or layers of materials forming such film layers may be partially or fully bonded via a thermal method in which at least one of the materials is brought to a temperature above its melting temperature. Such thermal processes can facilitate the formation of adhesive or cohesive bonds between the materials or layers of materials. In some embodiments, one or more suitable adhesives are utilized to provide a sufficiently bonded interface. Adjacent film layers and / or layers of materials forming such film layers may be joined at one or more discrete locations to form a stabilizing structure extending through the resulting structure.

[0171] In some embodiments, the first layer 1100, and / or the first film layer 1110 and the second film layer 1120, and / or the sheet or film on which the first film layer 1110 and the second film layer 1120 are formed may be subjected to one or more processes to modify their microstructure. In some embodiments, such processes include, but are not limited to, a material coating process, a surface pretreatment process, and / or a perforation process. The material coating process can be used to apply one or more drug or antibacterial coatings to a polymeric material (such as a metal salt (e.g., silver carbonate) and an organic compound (e.g., chlorhexidine diacetate)). A hydrophilic coating that enables wet-out (including immediate wet-out) of the polymer matrix can also be applied to a polymer surface that is generally hydrophobic. A surface coating containing an antioxidant component can be applied additionally or alternatively to mitigate the body's inflammatory response that naturally occurs during wound healing after surgery. The material surface can be modified additionally or alternatively with an anti-proliferative compound (e.g., mitomycin C, 5-fluoracil) to mitigate the surrounding tissue response.

[0172] In some embodiments, as described in Zaggl's U.S. Patent No. 9,849,629, one or more surface pretreatment processes can be utilized to form a layer exhibiting an exemplary microstructure (e.g., wrinkles, folds, or other geometric out-of-plane structures). Such surface pretreatment can more aggressively promote the initial inflammatory stage after surgery and provide an initially stable interface between the porous device and the tissue. In some embodiments, a heparin coating can be applied additionally or alternatively to help minimize cellular formation, including fibrinogen accumulation, after a surgical implantation procedure.

[0173] In some embodiments, one or more perforation processes can be utilized to form a plurality of perforations or holes 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, holes (voids between fibrils and nodes that make up the microstructure), and / or channels that naturally exist within the polymeric material, one or more perforation processes can be utilized.

[0174] It will be appreciated that the first membrane layer 1110 and the second membrane layer 1120 of the first layer 1100 can be treated differently to achieve membrane layers having different material properties such as different porosities and / or different cell infiltration capabilities. In some embodiments, the first membrane layer 1110 and the second membrane layer 1120 of the first layer may not be subjected to any processing steps.

[0175] 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 a 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 infiltration and cell attachment. In some embodiments, the first membrane layer 1110 includes gaps, perforations, holes, channels, or combinations thereof that are sized and shaped to resist, impede, or otherwise minimize cell infiltration while maintaining permeability to one or more drugs. The gaps, perforations, holes, or channels of the first membrane layer 1110 of the first layer 1100 may be, for example, less than about 1 to about 2 micrometers (or may have an average size less than that), although various dimensions can be selected based on the application. By being resistant to cell proliferation and cell attachment, the first membrane layer 1110 of the first layer 1100 operates to maintain a separation between the drug in the drug reservoir 1300 and the tissue surrounding the drug delivery system 1000. This separation operates to maintain a controlled and stable rate at which the drug is released by the drug delivery system 1000.

[0176] The second membrane layer 1120 (also referred to herein as the ingrowth membrane layer) is configured to promote or permit cell infiltration and cell attachment. Thus, the second membrane layer 1120 generally includes gaps, perforations, pores, channels, or combinations thereof that are sized and shaped to promote or permit cell infiltration. Thus, the second membrane layer 1120 generally includes gaps, perforations, pores, channels, or combinations thereof having an average size that exceeds the average size of the gaps, perforations, pores, or channels of the first membrane layer 1110 of the first layer 1100. In some embodiments, the second membrane layer 1120 may include gaps, perforations, pores, or channels having a size (or average size) in the range of 20 micrometers to 100 micrometers, although various dimensions are contemplated. For example, in other embodiments, the size (or average size) of the gaps, perforations, pores, or channels may exceed 150 micrometers. Thus, while the first membrane layer 1110 operates to meter and maintain a controlled and stable rate at which the drug is released by the drug delivery system 1000, the second membrane layer 1120 serves to facilitate the biocompatibility of the drug delivery system 1000 by allowing cell ingrowth and tissue attachment. Cell ingrowth and tissue attachment can minimize micromotion.

[0177] In some embodiments, the interface between the first membrane layer 1110 and the second membrane layer 1120 of the first layer 1100 operates as a boundary against cell infiltration into the first membrane layer 1110. That is, in some embodiments, the first layer 1100 is configured such that cell infiltration and cell proliferation are limited within the second membrane layer 1120 and not within the first membrane layer 1110. Thus, in various embodiments, cell infiltration and cell proliferation within the second membrane layer 1120 can generally propagate up to the boundary between the first membrane layer 1110 and the second membrane layer 1120. In some embodiments, the first layer 1100 can be configured to prevent or otherwise minimize the potential for cell infiltration and cell proliferation across the boundary between the first membrane layer 1110 and the second membrane layer 1120 of the first layer 1100.

[0178] The first layer 1100 of the drug delivery system 1000 (as well as the corresponding first membrane layer 1110 and second membrane layer 1120 of the first layer 1100) shown in the attached drawings is oval, but the first membrane layer 1110 and the second membrane layer 1120, and thus the first layer 1100, may be formed in other shapes and / or sizes, provided that the drug delivery system 1000 can be implanted into tissue such as a subconjunctival pocket and is operable to release the drug placed in the drug reservoir 1300 of the drug delivery system 1000 into one or more regions of the tissue surrounding the drug delivery system 1000. It should also be understood that this is conditional upon effectively achieving the intended purpose. For example, the first membrane layer 1110 and the second membrane layer 1120, and thus the first layer 1100, may be square, rectangular, trapezoidal, or any other polygonal or non-polygonal shape (e.g., kidney-shaped) as desired, provided that the shape does not prevent implantation or render the drug reservoir 1300 unable to distribute the drug.

[0179] As shown in FIGS. 2 and 3, the second layer 1200 of the drug delivery system 1000 includes a first membrane layer 1210 and a second membrane layer 1220. The first membrane layer 1210 of the second layer 1200 is similar to the first membrane layer 1100 of the first layer 1100 in that the first membrane layer 1210 of the second layer 1200 is configured to measure the rate at which the drug passes through the first membrane layer 1210 and thus the rate at which the drug is released by the drug delivery system 1000. In various embodiments, the first membrane layer 1210 is also configured to resist cell infiltration and cell attachment. Thus, the first membrane layer 1210 generally includes gaps, perforations, pores, channels, or combinations thereof that are consistent with those described above for the first membrane layer 1110 of the first layer 1100.

[0180] In that the second membrane layer 1220 of the second layer 1200 is configured to promote or permit cell infiltration and cell adhesion, the second membrane layer 1220 of the second layer 1200 is similar to the second membrane layer 1120 of the first layer 1100. Thus, the second membrane layer 1220 generally includes gaps, perforations, pores, channels, or combinations thereof that are consistent with those described above for the second membrane layer 1120 of the first layer 1100. Thus, in various embodiments, the drug delivery system 1000 includes a second layer 1200 formed from a first membrane layer 1210 and a second membrane layer 1220, the first membrane layer 1210 being permeable to the drug and configured to resist cell infiltration and tissue adhesion, and the second membrane layer 1220 being permeable to the drug and configured to promote or permit cell infiltration and tissue adhesion.

[0181] In some embodiments, the interface between the first membrane layer 1210 and the second membrane layer 1220 of the second layer 1200 operates as a boundary against cell infiltration into the first membrane layer 1210. That is, in some embodiments, the second layer 1200 is configured such that cell infiltration and cell proliferation are limited to the second membrane layer 1220 and not to the first membrane layer 1210. Thus, in various embodiments, cell infiltration and cell proliferation within the second membrane layer 1220 can generally propagate up to but not through the boundary between the first membrane layer 1210 and the second membrane layer 1220. In some embodiments, the second layer 1200 can be configured to prevent or otherwise minimize the potential for cell infiltration and cell proliferation across the boundary between the first membrane layer 1210 and the second membrane layer 1220 of the second layer 1200. It should be understood that the second layer 1200 can include membrane layers in addition to the first membrane layer 1210 and the second membrane layer 1220.

[0182] Similar to the first layer 1100 described above, the second layer 1200 may be formed in a shape and / or size other than those shown in the accompanying drawings (e.g., square, rectangular, trapezoidal, kidney-shaped, or any other polygon or non-polygon), provided that the drug delivery system 1000 can be implanted into the tissue and is operable to release the drug placed within the drug reservoir 1300 into one or more regions of the tissue surrounding the drug delivery system 1000, on the condition that the intended purpose is effectively achieved.

[0183] As shown in FIGS. 2 and 3, the first layer 1100 is oriented such that the first film layer 1110 is placed adjacent to the second layer 1200 (and in particular the first film layer 1210 of the second layer 1200), and includes a first surface 1102 that faces or is otherwise exposed to the second layer 1200 (and in particular the first film layer 1210 of the second layer 1200). That is, in some embodiments, the first layer 1100 is arranged such that the first film layer 1110 is positioned between the second film layer 1120 and the second layer 1200. Such a configuration provides that the first film layer 1110 of the first layer 1100 at least partially defines the drug reservoir 1300. That is, in various embodiments, the drug reservoir 1300 is at least partially defined by one or more drug metering film layers (e.g., the first film layer 1110) configured to meter the rate at which the drug is released from the drug reservoir 1300. Such a configuration also provides that the second film layer 1120 of the first layer 1100 includes a second surface 1104 opposite the first surface 1102 and at least partially defines 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 film layers (e.g., the second film layer 1120) and is configured to promote or permit cell infiltration and tissue attachment as described above. Promoting or permitting tissue ingrowth and tissue attachment along one or more of the outer surfaces of the drug delivery system 1000 helps to minimize micromotion between the drug delivery system 1000 and the surrounding tissue with which the drug delivery system 1000 contacts. Permitting tissue ingrowth and tissue attachment along one or more of the outer surfaces of the drug delivery system 1000 further aids in the targeted delivery of the drug from the device by ensuring that the drug is delivered to the desired location within the eye through the desired portion of the device.

[0184] Similarly, as shown in FIGS. 2 and 3, the second layer 1200 is oriented such that the first film layer 1210 of the second layer 1200 is placed adjacent to the first layer 1100 (and in particular the first film layer 1110 of the first layer 1100), and includes a first surface 1202 that faces or otherwise is exposed to the first layer 1100 (and in particular the first surface 1102 of the first film layer 1210 of the first layer 1100). That is, in some embodiments, the second layer 1200 is arranged such that the first film layer 1210 is positioned between the second film layer 1220 and the first layer 1100. Such a configuration provides that the first film layer 1210 of the second layer 1200 at least partially defines the drug reservoir 1300. Such a configuration also provides that the second film layer 1220 of the second layer 1200 includes a second surface 1204 opposite the first surface 1202 and at least partially defines the exterior of the drug delivery system 1000. Thus, as shown in FIGS. 2 and 3, the exterior of the drug delivery system 1000 is at least partially defined by the second film layers 1120 and 1220 of the first layer 1100 and the second layer 1200, respectively. Further, as shown in FIGS. 2 and 3, the drug reservoir 1300 is at least partially defined by the first film layers 1110 and 1210 of the first layer 1100 and the second layer 1200, respectively. As shown, the drug reservoir 1300 is defined by portions of the first film layers 1110 and 1210 of the first layer 1100 and the second layer 1200 that are unconnected or otherwise not connected to each other, and is disposed radially inward of portions of the first film layers 1110 and 1210 of the first layer 1100 and the second layer 1200 that are connected to each other.

[0185] In various embodiments, the first layer 1100 and the second layer 1200 (including their various film layers) can be interconnected or coupled to each other according to known methods in heat treatment, high-pressure compression, binders such as one or more adhesives, combinations thereof, or other techniques known to those skilled in the art.

[0186] In some embodiments, the first surfaces 1102 and 1202 of the first layer 1100 and the second layer 1200 are each connected along the periphery 1002 of the drug delivery system 1000 such that one or more portions of the first surfaces 1102 and 1202 of the first layer 1100 and the second layer 1200 are not connected to each other. In some embodiments, such non - connected regions are in a state of being free to slide, translate, actuate, separate, or otherwise move relative to each other. This relative movement between the unconnected or unbonded portions of the first layer 1100 and the second layer 1200 can cause the volume of the drug reservoir 1300 to change along with the amount of drug present within the drug reservoir 1300. For example, the drug delivery system 1000 can transition between 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 that is larger than the first volume.

[0187] FIG. 3 shows the drug delivery system 1000 in a first configuration where the drug reservoir 1300 is contracted (e.g., empty or containing a negligible amount of drug), while FIG. 2 shows the drug delivery system 1000 in a second configuration where the drug reservoir 1300 is expanded (e.g., completely or at least partially filled with drug). In some embodiments, the drug delivery system 1000 assumes a relatively flat outer shape (e.g., a relatively uniform cross - section) in the contracted state as compared to the outer shape of the drug delivery system 1000 in the expanded state. For example, as shown in FIG. 4, the drug delivery system 1000 can assume a blister shape or a pillow shape in the expanded state. However, the drug delivery system 1000 can be configured to assume any desired shape or size when empty of drug and / or when filled with drug.

[0188] The drug delivery system 1000 is configured to deliver a drug, and since the drug delivery system 1000 can be refilled or emptied in situ, it will be understood that the drug delivery system 1000 can transition between the first configuration and the second configuration in situ.

[0189] Furthermore, the drug reservoir 1300 can be accessed in situ by a cannula, needle, or other suitable instrument or method to add or remove drugs from the drug reservoir 1300.

[0190] The drug delivery system 1000 shown in FIG. 2 is configured such that the drug is measurable and distributable 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. In particular, in some embodiments, the drug is released from the drug delivery system 1000 by passing through the first membrane layers 1110 and 1210 of the first layer 1100 and the second layer 1200, respectively, and by passing through the second membrane layers 1120 and 1220 of the first layer 1100 and the second layer 1200, respectively.

[0191] However, in other embodiments, the drug delivery system can be configured such that the drug is metered and dispensed from the drug delivery system through one or the other, but not both, of the first and second layers. That is, in some embodiments, the drug delivery system can be configured such that the first of the first and second layers is permeable to the drug and the other of the first and second layers is impermeable to the drug. For example, referring now to FIG. 5, a drug delivery system 2000 is shown, which includes a drug-permeable first layer 2100 and a drug-impermeable second layer 2200. The first layer 2100 of the drug delivery system 2000 shown in FIG. 5 is similar to the first layer 1100 shown in FIGS. 2-4 in 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). The first membrane layer 2110 is permeable to the drug and is configured to measure the release rate of the drug placed within the drug reservoir 2300 over a specified period of time and to resist cell infiltration and tissue adhesion. The second membrane layer 2120 is permeable to the drug and is configured to promote or permit cell infiltration and tissue adhesion. Similar to the first layer 1100 of the drug delivery system 1000 mentioned above, the first layer 2100 of the drug delivery system 2000 includes a first surface 2102 and a second surface 2104.

[0192] The second layer 2200 of the drug delivery system 2000 shown in FIG. 5 includes a first surface 2202 and a second surface 2204, and is formed from a first membrane layer 2210 and a second membrane layer 2220. The first membrane layer 2210 is impermeable to the drug. The second membrane layer 2220 of the drug delivery system 2000 shown in FIG. 5 is similar to the second membrane layer 1220 shown in FIGS. 2-4 in that the second membrane layer 2220 shown in FIG. 5 is configured to promote or permit cell infiltration and tissue attachment. However, unlike the previous example, the first membrane layer 2210 is impermeable to the drug placed within the drug reservoir 2300. Alternatively, the drug delivery system 2000 may be configured such that the first layer 2100 is drug impermeable while the second layer 2200 is drug permeable. The drug permeable layer (e.g., the first layer 2100 or the second layer 2200) may include a first drug permeable membrane layer configured to resist cell infiltration and tissue attachment, and / or a second drug permeable membrane layer configured to promote or permit cell infiltration and tissue attachment. Next, the drug impermeable layer (e.g., the first layer 2100 or the second layer 2200) may include a first drug impermeable membrane layer configured to resist cell infiltration and tissue attachment, and / or a second drug impermeable membrane layer configured to promote or permit cell infiltration and tissue attachment.

[0193] Continuing to refer to FIG. 5, the second membrane layer 2220 may be formed from any biocompatible material described herein, such as a biocompatible polymer, and the biocompatible polymer may be 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 including a microporous polymer membrane having nodes and fibrils, where the pores are spaces within a matrix of fibrils (e.g., ePTFE) and a sealing material such as an elastomeric material is present therein. In some embodiments, the sealing material can be absorbed into the polymer membrane to form a drug-impermeable membrane layer. It should be understood that while remaining within the scope of the present disclosure, multiple types of fluoropolymer (and non-fluoropolymer) membranes and multiple types of elastomeric materials can be combined to form composite materials. It should also be understood that the elastomeric material can include, while remaining within the scope of the present disclosure, not only multiple elastomers but also multiple types of non-elastomeric components, such as inorganic fillers, therapeutic agents, radiopaque markers, and the like.

[0194] In some embodiments, the various membrane layers are formed from expanded polytetrafluoroethylene (ePTFE), but other biocompatible polymers suitable for use in forming the drug-impermeable membrane layer can be used. The drug-impermeable membrane layer includes, but is not limited to, urethane, silicone (organopolysiloxane), silicone-urethane copolymers, styrene / isobutylene copolymers, polyisobutylene, polyethylene-co-poly(vinyl acetate), polyester copolymers, nylon copolymers, fluorinated hydrocarbon polymers, and any copolymer or mixture of the foregoing.

[0195] 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, or a TFE / PMVE copolymer.

[0196] Continuing to refer to the drug delivery system 2000 shown in FIG. 5, by including a first layer 2100 that is permeable to the drug and a second layer 2200 that is impermeable to the drug, the drug delivery system 2000 can be configured to meter and dispense the drug placed within the drug reservoir 2300 in one direction. That is, in some embodiments, the drug delivery system 2000 can be configured such 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. Thus, in these embodiments, the drug delivery system 2000 can be configured to release the drug in a first direction (e.g., through the first layer 2100) without releasing the drug in a second direction (e.g., through the second layer 2200). Performing such release control helps to distribute the drug to a specified tissue. For example, the drug can be released in the direction towards the scleral tissue while minimizing the release of the drug in the direction towards the conjunctival tissue, which can be useful for treating the internal state of the eye. Alternatively, the drug can be released in the direction towards the conjunctival tissue while minimizing the release of the drug in the direction towards the scleral tissue, which can be useful for treating other conditions of the eye, such as conditions that affect the outside of the eye (e.g., dry eye). Releasing the drug in the direction towards the conjunctival tissue can be used to treat other areas or regions of the body because the drug distributed to the conjunctiva can be absorbed by the surrounding vascular system and transported to other regions in the patient's anatomy. The terms "first" and "second" as used herein with respect to the first layer 2100 and the second layer 2200 are general identifiers, and thus it should be understood that the layers 2100 and 2200 can be referred to in conjunction with alternative general identifiers such as top, bottom, upper, lower, side, etc. Thus, the layer 2100 is referred to above in conjunction with the term "first" and the layer 2200 is referred to above in conjunction with the term "second", but it should be understood that the layers 2100 and 2200 can alternatively be referred to as the first layer 2200 and the second layer 2100.That is, the terms "first" and "second" should not be understood to represent anything more than general identifiers for layers 2100 and 2200.

[0197] In some embodiments, one or more of the first and second layers may be configured to include one or more drug-permeable portions and one or more drug-impermeable portions. Referring now to FIGS. 6 and 7, a drug delivery system 3000 is shown, including a first layer 3100 and a second layer 3200. The second layer 3200 is identical in form and structure to the second layer 2200 of the drug delivery system 2000 shown and described above with reference to FIG. 5, and includes a first membrane layer 3210, a second membrane layer 3220, a first surface 3202, and a second surface 3204. In contrast, the first layer 3100 is different from the example of the first layer described above in that the first layer 3100 shown in FIGS. 6 and 7 includes a first membrane layer 3110 having a first portion 3112 that is permeable to the drug and a second portion 3114 that is impermeable to the drug. The first membrane layer 3110 is configured to measure the release rate of the drug placed within the drug reservoir 1300 over a specified period of time. The second membrane layer 3120 is the same as the second membrane layer 3120 of the drug delivery system 1000 shown in FIG. 5 described above.

[0198] In various embodiments, the first portion 3112 of the first membrane layer 3110 includes gaps, perforations, holes, channels, or other release features that are generally sized and shaped to allow the agent disposed within the agent reservoir 3300 to be released through the first portion 3112. In some embodiments, the metering of the release of the agent disposed within the agent reservoir 3300 by the first layer 3100 can be adjusted or otherwise controlled by increasing (or alternatively decreasing) the surface area of the metering first portion 3112 of the first membrane layer 3110. In some embodiments, increasing the surface area of the metering first portion 3112 from a first surface area to a second, larger surface area causes an increase in the amount of agent released per unit time by the drug delivery system 3000. Similarly, decreasing the surface area of the metering first portion 3112 from a first surface area to a second, smaller surface area causes a decrease in the amount of agent released per unit time by the drug delivery system 3000.

[0199] For example, when a drug delivery system includes a drug reservoir having a first size (e.g., volume) and a first drug metering film layer including a first material having a first surface area and a first release rate per unit area, the drug delivery system is associated with a first drug release rate per unit time and the metering of the drug release over a first period. It should be understood that when the size of the drug reservoir is increased from the first size to a second larger size while maintaining the first surface area and the first material of the metering film layer, the drug delivery system is operable to meter the drug release over a second period longer than the first period. On the other hand, it should be understood that when the first surface area of the metering film layer is decreased to a second decreased surface area while maintaining the first material of the metering film layer and the first size of the drug reservoir, the drug delivery system is operable to meter the drug release over a third period longer than the first period. Further, it should be understood that when the first material of the metering film layer is changed to a second material having a second decreased release rate per unit area while maintaining the first size of the drug reservoir and the first surface area of the metering film layer, the drug delivery system is operable to meter the drug release over a fourth period longer than the first period. By utilizing combinations of the above concepts, the drug release period can be maintained while increasing the amount of drug released per unit time. For example, when increasing the size of the drug reservoir from the first size to a second larger size in combination with increasing the surface area of the metering film layer from the first surface area to a second increased surface area while maintaining the first material of the metering film layer, it should be understood that the drug delivery system is operable to increase the amount of drug released during the first period.

[0200] It should also be understood that different materials can have different flow rates per unit area, for example, based on different microstructures (e.g., an increase in the amount and / or size of gaps, perforations, pores, channels, or other release features present within the microstructure). Thus, different materials can be additionally or alternatively selected to adjust or otherwise control the extent or amount to which the release of the drug disposed within the drug reservoir is metered.

[0201] Accordingly, the various drug delivery systems described herein include a configuration that includes a relatively large drug reservoir that does not inherently have a high drug release rate due to the associated large drug metering surface area, or a relatively small drug reservoir that does not inherently have a low drug release rate due to the 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 over a long period of time (e.g., weeks, months, one year, or more) without the need for intervention to replenish the drug. Conversely, a relatively small drug reservoir combined with a high release rate provides a drug delivery system that can be implanted and distribute the drug at a fast rate without becoming excessive and without interfering with normal eye movements (e.g., blinking and eye movement).

[0202] Furthermore, it should be understood that drugs having a coarser molecular structure generally require a microstructure in the drug delivery system that includes gaps, pores, channels, and / or other release features corresponding to a size such that the drug can pass through the material of the drug metering film layer. Accordingly, it will be understood that different drug delivery systems can be selected for use when administering different drugs.

[0203] Continuing to refer to the drug delivery system 3000 shown in FIGS. 6 and 7, the first membrane layer 3110 of the first layer 3100 may be formed from one or more sheets or films of a material such as any biocompatible material described herein, provided that the one or more sheets or films of the material are further combined with a sealing material such as an elastomer or elastomeric material at the drug-impermeable second portion 3114. Thus, in some embodiments, the drug-impermeable second portion 3114 in the first membrane layer 3110 of the first layer 3100 may include a composite structure. In some embodiments, the drug-impermeable second portion 3114 in the first membrane layer 3110 of the first layer 3100 may correspond to the portion of the first membrane layer 3110 of the first layer 3100 where the sealing material is selectively absorbed and / or coated with the sealing material. That is, in various embodiments, the first membrane layer 3110 of the first layer 3100 is in a state where one or more portions of the first membrane layer 3110 include a sealing material and one or more other portions of the first membrane layer 3110 do not include a sealing material, and the portion of the first membrane layer 3110 including the sealing material corresponds to the drug-impermeable second portion 3114, and the portion of the first membrane layer 3110 not including the sealing material corresponds to the drug metering first portion 3112.

[0204] The drug delivery system 3000 shown in FIGS. 6 and 7 includes an oval drug metering first portion 3112, provided that the drug metering first portion 3112 may be formed in other shapes and / or sizes (e.g., square, rectangular, trapezoidal, bean-shaped, or any other polygon or non-polygon) other than those shown in the accompanying drawings, provided that it effectively serves its intended purpose of metering the release of the drug. Thus, it will be understood that the boundary defined between the drug metering first portion 3112 and the drug-impermeable second portion 3114 may define any suitable shape consistent with the above.

[0205] Also, it should be understood that the drug delivery system 3000 shown in FIG. 7 includes only a single centrally located first drug metering portion 3112, but the first membrane layer 3110 of the first layer 3100 may include a plurality of discrete first drug metering portions 3112. Similarly, it should be understood that the first drug metering portions 3112 of the first membrane layer 3110 of the first layer 3100 need not be centrally located and may instead be positioned at a location offset from the central position.

[0206] In various embodiments, the drug delivery system may be configured such that one or more of the drug metering membrane layers described herein can be exposed to the tissue surface of the patient's anatomical structure. For example, referring now to FIGS. 8 and 9, a drug delivery system 4000 is shown, which includes a first layer 4100 and a second layer 4200. The second layer 4200 is similar to the second layer 2200 of the drug delivery system 2000 shown and described above with respect to FIG. 5 in that the second layer 4200 includes a first membrane layer 4210 that is impermeable to the drug and a second membrane layer 4220 configured to promote or permit cell infiltration and tissue attachment. Similar to the drug delivery system 2000 shown in FIG. 5, the second layer 4200 includes a first surface 4202 and a second surface 4204.

[0207] However, the first layer 4100 shown in FIGS. 8 and 9 is different from the previous example of the first layer in that the first layer 4100 shown in FIGS. 8 and 9 includes an opening or relief that exposes a portion of the first membrane layer 4110. The first membrane layer 4110 is configured to measure the release rate of the drug placed within the drug reservoir 4300 over a specified period of time. In particular, as shown in FIGS. 8 and 9, the second membrane layer 4120 includes an opening 4124 formed within the body 4122 of the second membrane layer 4120, and the opening 4124 within the second membrane layer 4120 of the first layer 4100 operates to expose the first membrane layer 4110. When implanted, one or more portions of the first membrane layer 4110 of the first layer 4100 are directly exposed to the tissue, while the second membrane layer 4120 operates to maintain a separation between the first membrane layer 4110 and the tissue surface.

[0208] The direct exposure of the first membrane layer 4110 of the first layer 4100 serves to enable more effective and efficient drug delivery to the tissue. Maintaining the separation between the first membrane layer 4110 and the tissue surface helps to minimize micromotion between the first membrane layer 4110 and the tissue. As described above, minimizing micromotion helps to minimize microstimulation.

[0209] Thus, in various embodiments, the drug delivery system 4000 includes a drug-permeable first layer 4100 and a drug-impermeable second layer 4200, the first layer 4100 includes a first membrane layer 4110 and a second membrane layer 4120, the first membrane layer 4110 is permeable to the drug and is configured to resist cell invasion and tissue adhesion, the second membrane layer 4120 is permeable to the drug and is configured to promote or permit cell invasion and tissue adhesion, the second membrane layer 4120 is configured such that when implanted, one or more portions of the first membrane layer 4110 are exposed to the tissue, while the second membrane layer 4120 is positioned between the tissue and one or more other portions of the first membrane layer 4110 while implanted.

[0210] Next, various implementations related to the treatment of a particular disease and various implementations related to the corresponding configurations of the embodiments disclosed herein will be described. As described below, some configurations of an implantable medical system 9000, such as a drug delivery system (e.g., the implantable medical system 9000 below), are disclosed along with the disease to be treated and examples of the corresponding implantation and device positions of the drug delivery system. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this specification, including drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and positioned at one or more implantation positions or sites to deliver a drug for the treatment of a given disease. In addition to glaucoma, diseases for which a drug delivery system may be useful for treatment include age-related macular degeneration, macular edema, uveitis, retinitis, keratitis, retinoblastoma, retinal vein occlusion (''RVO'', e.g., central RVO (''CRVO'') and branch RVO (''BRVO'')), dry eye, and presbyopia. These diseases can be treated using various active pharmaceutical ingredients (APIs) from various API classes, as will be further described below. However, it should be understood that the exemplary implementations described herein are only a part of many exemplary implementations of the drug delivery systems disclosed herein, and that additional diseases can be treated using such implementations without departing from the scope of the present disclosure. Details of these implementations will be described later.

[0211] Figures 10 and 10A - 10D show some examples of an implantable medical system 9000 that is useful in adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. Some examples of the implantable delivery devices disclosed herein have a delivery arm, as described below, while some do not. FIG. 10A shows an inflated reservoir 9100. FIGS. 10A - 1 and 10A - 2 show respective microscopic views of first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10B shows the reservoir 9100 of FIG. 10A in a state of being replenished through the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In particular, FIG. 10C shows an inflated reservoir 9100 with a delivery arm 9103. FIGS. 10C - 1 and 10C - 2 show respective microscopic views of first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the reservoir 9100 of FIG. 10C in a state of being replenished through the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In an example, the main portion 9101 and the delivery arm 9103 may comprise the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A - 1 and 10A - 2, for the sake of convenience of explanation, exemplary microporous materials are shown as schematic diagrams. The exemplary images provided in FIGS. 10A - 1, 10A - 2, 10C - 1, and 10C - 2 are representative of the microscopic images presented in FIG. 18. Further consideration of suitable microporous materials for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0212] The drug delivery devices shown in FIGS. 10A - 10D herein may be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense drugs as described above. The implantable medical system 9000 is presented in FIGS. 10A - 1, 10A - 2, 10C - 1, and 10C - 2 and may include the material structures shown in FIG. 18. The implantable medical system 9000 may also include material structures, selective permeability, and porous materials, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided particularly in FIGS. 3 - 10 and each of the incorporated documents. The implantable medical system 9000 may further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving drugs. The first microporous material 9201 and the second microporous material 9202 can be configured to meter the rate at which drugs are dispensed from the reservoir 9100 when the delivery device is implanted. Although mainly discussed herein as receiving a single drug, in some embodiments, an impermeable material is included within the reservoir 9100 to form a separate or distinct chamber or sub - reservoir that is not in fluid communication with the device 9000. In this way, the reservoir 9100 can accommodate a plurality of drugs that can be selectively delivered to the patient. These embodiments can enhance the customizability of the device 9000 and increase and / or expand the treatments available with the device 9000.

[0213] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat various diseases, as further described below. Generally, a method of treating a disease is disclosed that uses an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 that includes a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 that includes a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving the drug. The first microporous material 9201 and the second microporous material 9202 can be configured to measure the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0214] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating one or more diseases of the eye. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so as to be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at the implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0215] Figures 11A-11D show various features of the reservoir 9100 in an example of a drug treatment device. In particular, FIG. 11A shows a first configuration (configuration "A") of the reservoir 9100 in which the reservoir 9100 includes only the main portion 9101. FIG. 11B shows a second configuration (configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. FIG. 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of FIG. 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. FIG. 11D shows a fourth configuration (configuration "D") of the reservoir 9100, which is similar to that of FIG. 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or an implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. In some embodiments, one or more of the filling ports 9310 are made of a transparent, semi-permeable, translucent, or light-transmissive material. In this way, the device and / or accessory used to replenish the reservoir 9100 or the reservoir chamber can be observed when the device and / or accessory is inserted into the filling port 9310. As further described below, the plurality of chambers 9300 (e.g., FIGS. 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within a page) or multiple directions (e.g., within a page, out of a page, in-plane with a page, or any combination thereof).

[0216] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a generally polyhedral shape.

[0217] In certain examples, the physical characteristics of the reservoir 9100 can facilitate the functionality of the drug delivery system 1000. For example, the reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of the drug delivery system 1000 so as to deliver the drug to a pinpoint location relative to the reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more positions in the reservoir 9100 can function as a filling port 9310 for filling the reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of the reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. In some embodiments, the delivery arm 9103 can be flexible so as not to kink or compress during use. After implantation, the drug can flow or be discharged from the filling port 9310 of the reservoir 9100 to the treatment location. In an example, the reservoir 9100 can contain therein a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0218] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 may be formed. In this regard, the reservoir 9100 may include a reservoir main portion 9101 and an extended delivery arm 9103 extending from the reservoir main portion 9101. For example, the extended delivery arm 9103 may include a port that enables the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main portion 9101 and the extended delivery arm 9103.

[0219] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A that includes only the main portion 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 that includes the main portion 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the prevention of dispensing is shown as a swirling arrow inside the reservoir 9100. Dispensing can be performed only at the permeable portions of the implantable medical system 9000, and the prevention of dispensing can be performed at the impermeable portions of the implantable medical system 9000. Further, the flow and direction into the page are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0220] As will be described in more detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or multiple directions. Under these circumstances, the dispensing can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further under these circumstances, the directionality of the dispensing at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and, when reading the present disclosure as a whole, will recognize that certain variations and modifications of these examples are logical extensions of the examples described below.

[0221] Starting with FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0222] Referring to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally, outside and inside the page in FIG. 12E, and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing outside the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing inside the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner of similarly concentrated dispensing in a plurality of directions, it should be understood that some examples include dispensing in a manner scattered in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or different amounts in each dispensing direction. As described above, the dispensing amount may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. FIGS. 12G and 12H show a similar dispensing operation (generally, dispensing outside and inside the page in FIG. 12G, and upward and downward in FIG. 12H), but in a more scattered manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E to 12G, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0223] As described above, FIGS. 12I to 12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be the same as that described above with reference to FIGS. 12A to 12H. The main portion 9101 of the implantable medical system 9000 may be the same as that described with respect to FIGS. 12A to 12H. The examples shown in FIGS. 12I to 12P may include, additionally or alternatively, dispensing from the delivery arm 9103, as further described below. Specific examples will be described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0224] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in multiple directions. For example, the main portion 9101 can dispense the drug in a manner similar to that described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in a manner similar to that described with respect to FIGS. 12I and 12J.

[0225] Referring to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing, and the main portion 9101 is configured for focused dispensing. For example, the main portion 9101 can dispense the drug in a manner similar to that described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in a manner similar to that described with respect to FIGS. 12I and 12J.

[0226] The placement of the implantable medical system 9000 at the implantation location or site can vary depending on the disease being treated. In an example, the implantable medical system 9000 can be placed at a position in front of the eye, a position behind the eye, or both a position in front of and behind the eye. For example, the implantable medical system 9000 can be placed in the anterior chamber of the eye, the posterior chamber (at the anterior position) of the eye, or both a position in front of and behind the eye. When placed at a position in front of the eye, in some examples, a part of the implantable medical system 9000 can be placed within the anterior chamber. When placed at a position behind the eye, in some examples, the implantable medical system 9000 can have a part thereof placed for intravitreal administration of a drug. In an example, the portion of the reservoir 9100 placed within the anterior chamber or placed for intravitreal administration of a drug can be the delivery arm 9103 of the reservoir 9100.

[0227] The various implantation positions or sites and configurations of the reservoir 9100 can be seen in FIGS. 13A, 13B, 14A, 14B, 15A, 15B, 16A, 16B, 17A, and 17B. As described above, the implantable medical system 9000 can, in an example, have a refillable reservoir 9100 and a delivery arm 9103. In other examples, the reservoir 9100 can have a refillable reservoir 9100 without a delivery arm 9103. Of course, in an example, the reservoir 9100 may not be refillable. In particular, FIGS. 13A, 13B, 14A, and 14B relate to a reservoir without a delivery arm 9103, and FIGS. 15A, 15B, 16A, 16B, 17A, and 17B relate to a reservoir with a delivery arm 9103. As described elsewhere in this specification, the implantable medical system 9000 can be configured such that a drug is dispensed from the reservoir 9100 towards the eye (e.g., through the main portion 9101, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103), optionally away from the eye 5000.

[0228] More specifically, FIGS. 13A and 13B show a drug delivery system implanted at the location of the anterior reservoir 9100 (e.g., under the conjunctiva 5002 between the edge and the pars plana). As discussed below, such an implantation may be useful for glaucoma, dry eye, presbyopia, or keratitis. FIGS. 14A and 14B show a drug delivery system implanted at the location of the posterior reservoir 9100 (e.g., beyond the pars plana and suprachoroid). As will be described later, such an implantation may be useful for macular degeneration, uveitis, retinitis, macular edema, CRVO, and BRVO. FIGS. 15A and 15B show a drug delivery system implanted at the anterior-posterior reservoir 9100 location (e.g., the reservoir 9100 is between the edge and the pars plana and the delivery arm 9103 extends beyond the pars plana and suprachoroid). As will be described later, such an implantation may be useful for macular degeneration, uveitis, retinitis, macular edema, CRVO, and BRVO. FIGS. 16A and 16B show a drug delivery system implanted at the anterior-vitreous reservoir 9100 location, with the refillable reservoir 9100 positioned near the edge and the delivery arm 9103 positioned within the vitreous cavity of the eye 5000. As discussed below, such an implantation may be useful for macular edema, uveitis, retinitis, or macular degeneration. FIGS. 17A and 17B show a drug delivery system implanted at the reservoir 9100 location in the anterior chamber 5006, with the refillable reservoir 9100 positioned near the edge and the delivery arm 9103 positioned within the anterior chamber 5006. As discussed below, such an implantation may be useful for glaucoma, keratitis, and presbyopia.

[0229] FIG. 18 shows a microscopic view of a microporous material according to several embodiments presenting a microscopic image of the material structure illustratively represented in the portions of FIGS. 10A and 10C. For example, the microporous material of FIG. 18 may be referred to throughout with respect to a medical implant system. As will be understood by those skilled in the art, the microporous aspects and parameters of the microporous material can be defined in various ways. In the application of a microporous material in an ophthalmic device such as a drug delivery system described herein configured to be placed in situ within eye tissue to facilitate delivery of a drug to the eye for treatment of a disease, the microporous properties of such a microporous material can generally be characterized by a value of volumetric porosity defined as the ratio of the volume of air or fluid defined by and contained within the microporous material compared to the total volume (or gross volume) of the microporous material.

[0230] In another definition, volumetric porosity can be defined as the proportion 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 30 mm 3 of that volume contains chambers that hold air or fluid, the microporous material has a volumetric porosity value of 0.3 because 30% of the volume of the microporous material is empty or a transient space filled with air or other fluid.

[0231] As can be understood, two microporous materials can have the same volumetric porosity but can have different pore sizes presented to the inflowing or outflowing air or fluid. For example, a first material can have a few large pores distributed over a given total volume, and a second material can have a relatively large number of relatively small pores distributed over the same given volume, and both microporous materials can have the same volumetric porosity if the air / fluid volume of both materials is the same.

[0232] As can be further understood, the properties of the microporous material used in the eye drainage device can also be defined by the size of the passageways through the microporous material, or, similarly, as the pore size measured where the passageways terminate at the surface of the microporous material or along the length of the passageways within the material. Microporous materials with small pores or passageways can impede flow through the material, and relatively large pores or passageways can increase the passage of air or fluid into, out of, or within the microporous material.

[0233] As can be further understood, the properties of the microporous material can also be defined by the tortuosity of the passageways that enter and pass through the material, and relatively small or large passageways are impeded due to the frequency of bends within the passageways or the placement of obstacles within the fluid path. The air / fluid permeability of the microporous material can be managed by controlling or defining any of the aforementioned properties of the material, and a material can be provided that is suitable for use in facilitating the delivery of drugs to the eye for the treatment of diseases.

[0234] For simplicity, the aforementioned properties and variabilities of the microporous material used in the various embodiments and examples described herein can be presented simply as porosity based on a measure of volume porosity, the size of the pores or passageways, or tortuosity. Referring again to FIG. 18, the interior portion of the microporous material can have various porosities (or volume porosities, or pore sizes, or tortuosities). The interior portion can extend between an inner surface 9508 and an outer surface 9510.

[0235] In any of these parts of the body portion 9502, the porosity can vary relatively widely among a small pore size (SP), a medium-small pore size (MSP), a medium pore size (MP), a medium-large pore size (MLP), and a large pore size (LP). For the purposes of the description herein, assuming that delivery moves along a relatively straight path through the microporous material such that the delivery is sequentially linked to the porosity of the inner surface 9508, the uniform inner portion, and the outer surface 9510, the combined flow resistance can be represented by similarly connecting their respective porosities. For example, the inner surface 9508 typically has a low porosity throughout (e.g., to resist the ingrowth of tissue into the reservoir 9504), and the portions of the inner portion and the outer surface 9510 can have any of the aforementioned degrees of porosity. Under these circumstances, when the inner portion has a medium porosity, for example, and the outer surface 9510 has a high porosity, drug delivery through the microporous material from the reservoir 9504 to the tissue surrounding the device can be represented as SP-MP-LP. Further examples are described below.

[0236] Various delivery paths can exist within the microporous material. A relatively straight flow path can include, for example, regions SP1-SP4-SP5, or SP3-MLP1-MP1-MSP1. Some flow paths can be relatively straight, but non-linear flow paths also exist. For example, under certain conditions, at least a portion of the flow can proceed to flow through regions of decreasing resistance such as SP1-LP1-LP2 or SP3-MLP1-LP1-LP2. As will be understood, the microstructure of the microporous material can be subject to a modification process to obtain a particular type of flow through the microstructure. For example, the microstructure may have relatively uniform layers across the layers within the microstructure, or, as shown herein, may have variable portions across the thickness of the microporous material.

[0237] In some examples, the body portion 9502 defines the thickness of a wall portion that extends between an inner surface 9508 and an outer surface 9510. The thickness of the wall portion can define an internal region of the body portion 9502 that has a transitional porosity between the porosity of the low-porosity surface of the inner surface 9508 (e.g., having a smaller pore size) and the porosity of the high-porosity surface of the outer surface 9510 (e.g., having a larger pore size). Additionally, or alternatively, the internal region can have an internal region porosity that is equal to the porosity of the low-porosity surfaces of the inner surface 9508 and the outer surface 9510. Additionally, or alternatively, the internal region can have an internal region porosity that is equal to the porosity of the low-porosity surface of the inner surface 9508. Additionally, or alternatively, the internal region can have an internal region porosity that is equal to the porosity of the high-porosity surface of the outer surface 9510.

[0238] Referring further to the microporous material shown in FIG. 18, the fluid path can also be affected by a concentration gradient between a fluid such as water and a drug within the reservoir 9100. More specifically, in the process of drug delivery, the drug or medicament is first contained within the reservoir 9100. Then, fluid is delivered into the reservoir 9100 through the microporous material, whereby the drug can leach out of the microporous material and reach the target delivery site. Although described herein as having layers or strata, the microporous material can be without distinct separate layers and instead can include regions of different porosities for the fluid and drug to move through as described above. The drug delivery system 9000, and more specifically the microporous material of the drug delivery system 9000, can also be optimized for target delivery. In other words, the region in which the microporous material is incorporated can be selected to enable drug delivery only at the target location surrounding the system 9000.

[0239] Figures 19A - 19D illustrate different ways of implanting an exemplary embodiment of an implantable medical system described in other embodiments disclosed herein. Although the implantable medical system 9000 of FIGS. 17A - 17B has been described, the methods described herein can also be used with the system 1000 of FIGS. 1A - 1B. Further, FIGS. 19A - 19D illustrate the implantation of a device into one exemplary location within the eye; however, the implantation process can be applied to various locations within the eye as desired and will be described as necessary for the above - described embodiments.

[0240] In FIG. 19A, the implantable medical system 9000 is laid flat and held by an appropriate tool such as toothless forceps at the proximal end (or the leading edge near the intake conduit 9506), and with the pocket left open, the implantable medical system 9000 is advanced into the subconjunctival cavity formed by the incision 17 and inserted into the cut or incision 17 within the eye tissue. To prevent the device 9000 from folding or bending on its own, a support member as disclosed herein can be implemented.

[0241] In FIG. 19B, the implantable medical system 9000 is held using forceps such that the distal end (or trailing edge) of the device 9000 is held parallel to the conduit 9506. This method facilitates the delivery of the device 9000 at the desired depth with little undesirable longitudinal folding or bending, i.e., folding or bending along the longitudinal axis defined by the forceps. In some examples, the implantable medical system 9000 may experience folding or bending along the transverse axis during the procedure; however, such folding or bending is less detrimental than longitudinal folding or bending and can be corrected, for example, by using forceps or another tool to "smooth out" such folding or bending after delivery.

[0242] In FIG. 19C, the implantable medical system 9000 undergoes axial folding or bending (i.e., the folding or bending occurs along the longitudinal axis or along a line parallel to the axis), and the distal end or trailing edge of the device 9000 is grasped using forceps such that the forceps are substantially parallel to the conduit 9506. The device 9000 is pushed forward into the subconjunctival space inside the pocket formed by the incision 17. This method also facilitates delivery of the device 9000 at a desired depth with little unwanted axial folding or bending.

[0243] In FIG. 19D, the implantable medical system 9000 is grasped at one side edge using forceps that are substantially parallel to the conduit 9506. The device 9000 is then wound or wrapped around the body of the forceps and then pushed into the subconjunctival space. After the device 9000 is inserted, it is expanded in situ or the packaging is removed within the subconjunctival space. This method also facilitates delivery of the device 9000 at a desired depth with sufficient axial rigidity and little unwanted axial folding or bending. Glaucoma

[0244] In an exemplary implementation, the drug delivery system may be useful for treating glaucoma. As described elsewhere herein, glaucoma is a progressive loss of vision associated with high intraocular pressure. For the treatment of glaucoma, the drug delivery system can be implanted subconjunctivally (e.g., at or around the location between the edge of the eye 5000 and the pars plana (see, e.g., FIG. 13)). Among other advantages, such as reduced tissue abrasion, refillable elements of the drug delivery system, etc., using the drug delivery system described herein for the treatment of glaucoma can overcome the normal problems of patient compliance when using previously established treatment methods. For example, by using an implantable medical delivery system, the patient can reduce the likelihood of forgetting to administer daily medications, such as by using eye drops.

[0245] In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be an implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and re - described herein. These implantable medical systems 9000 can be similar to other ones disclosed elsewhere in this specification, including drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and disposed at one or more implantation positions or sites to deliver a drug for the treatment of glaucoma.

[0246] As described above, FIGS. 10 and 10A-10D illustrate some examples of an implantable medical system 9000 that is useful for adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of a first and a second microporous material 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 each show a microscopic view of a first and a second microporous material 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In the example, the main portion 9101 and the delivery arm 9103 may comprise the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of suitable microporous materials for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0247] The drug delivery devices shown in FIGS. 10A - 10D in this specification may be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense a drug as described above. The implantable medical system 9000 may include the material structures presented in Details 10A - 1 and 10C - 1 and shown in FIG. 18. The implantable medical system 9000 may also include a material structure, selective permeability, and a porous material, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3 - 10 and each of the incorporated documents. The implantable medical system 9000 may further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 may be configured to meter the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0248] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat glaucoma. Generally, a method of treating a disease is disclosed using an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 that includes a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 that includes a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving the drug. The first microporous material 9201 and the second microporous material 9202 can be configured to measure the rate at which a glaucoma drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0249] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating glaucoma. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so that they can be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at the implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0250] Figures 11A - 11D show various features of the reservoir 9100 in an example of a drug treatment device. In particular, FIG. 11A shows a first configuration (configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. FIG. 11B shows a second configuration (configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. FIG. 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of FIG. 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. FIG. 11D shows a fourth configuration (configuration "D") of the reservoir 9100, which is similar to that of FIG. 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or an implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As further described below, the plurality of chambers 9300 (e.g., FIGS. 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within a page) or in multiple directions (e.g., within a page, out of a page, in - plane with a page, or any combination thereof).

[0251] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a substantially polyhedral shape.

[0252] In certain examples, the physical characteristics of the reservoir 9100 can facilitate the functionality of the drug delivery system 1000. For example, the reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of the drug delivery system 1000 so as to deliver the drug to a pinpoint location relative to the reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more locations of the reservoir 9100 can function as a filling port 9310 for filling the reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of the reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can flow or be discharged from the filling port 9310 of the reservoir 9100 to the treatment location. In an example, the reservoir 9100 can contain within it a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0253] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main portion 9101 and an extended delivery arm 9103 extending from the reservoir main portion 9101. For example, the extended delivery arm 9103 may include a port that enables the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main portion 9101 and the extended delivery arm 9103.

[0254] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A that includes only the main portion 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 that includes the main portion 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the dispensing prevention is shown as a swirling arrow inside the reservoir 9100. The dispensing can be performed only at the permeable portions of the implantable medical system 9000, and the dispensing prevention can be performed at the impermeable portions of the implantable medical system 9000. Further, the flow into and the direction within the page are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0255] As will be described in further detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or multiple directions. In these situations, the dispensing can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further in these situations, the directionality of the dispensing at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed herein. One of ordinary skill in the art will understand this fact and will recognize that certain variations and modifications of these examples are logical extensions of the examples described below when reading the present disclosure as a whole.

[0256] Referring again to FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0257] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E, and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner that is similarly concentratedly dispensed in a plurality of directions, it should be understood that some examples include dispensing in a manner scattered in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or may be different amounts in each dispensing direction. As described above, the dispensing amount may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As previously described, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G, and upward and downward in FIG. 12H), but in a manner that is more scattered in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E - 12G, prevention of dispensing in various other directions and positions is shown, except where dispensing is possible.

[0258] As described above, FIGS. 12I - 12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be the same as that described above with reference to FIGS. 12A - 12H. The main portion 9101 of the implantable medical system 9000 may be the same as that described with respect to FIGS. 12A - 12H. The examples shown in FIGS. 12I - 12P may include, additionally or alternatively, dispensing from the delivery arm 9103, as further described below. Specific examples will be described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0259] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in a plurality of directions. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0260] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing, and the main portion 9101 is configured for centralized dispensing. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0261] Any of the above configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of glaucoma. Under these circumstances, the drug delivery system can be placed at a position in front of the eye 5000 and optionally within the anterior chamber 5006 of the eye 5000 (see, e.g., FIG. 17). For example, when the drug delivery system is arranged to treat glaucoma, the API class can include prostaglandins such as latanoprost, bimatoprost, and XALATAN. In certain cases, the API class can include beta blockers such as timolol or BETIMOL; alpha agonists such as brimonidine or ALPHAGEN; or carbonic anhydrase inhibitors such as dorzolamide, brinzolamide, or AZOPT. Macular degeneration

[0262] The present disclosure includes devices, systems, and methods suitable for the treatment of retinal diseases. In particular, age-related macular degeneration of the retina can be treated using an exemplary implementation of the implantable medical system 9000. Exudative age-related macular degeneration is a chronic eye disorder associated with abnormal blood vessel growth under the macula that affects central vision in the eye 5000. In previously established treatments for age-related 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 things, this invasive technique can be eliminated and the treatment can be performed in a minimally invasive manner, as further described herein.

[0263] For the treatment of age-related macular degeneration, the drug delivery system can be implanted suprachoroidally (e.g., behind the pars plana of the eye 5000). In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be the implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and re-described herein. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this document, including the drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and placed at one or more implant positions or sites for delivering a drug for the treatment of age-related macular degeneration.

[0264] As described above, FIGS. 10 and 10A - 10D show some examples of an implantable medical system 9000 that is useful for adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A - 1 and 10A - 2. FIGS. 10A - 1 and 10A - 2 each show a microscopic view of a first and a second microporous material 9202 within the implantable medical system 9000. FIG. 10B shows the state where the reservoir 9100 of FIG. 10A is being replenished through the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C - 1 and 10C - 2 each show a microscopic view of the first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the state where the reservoir 9100 of FIG. 10C is being replenished through the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In the example, the main portion 9101 and the delivery arm 9103 may comprise the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In Details A and B, exemplary microporous materials are schematically shown for convenience of explanation. The exemplary images provided in FIGS. 10A - 1, 10A - 2, 10C - 1, and 10C - 2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of suitable microporous materials for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0265] The drug delivery devices shown in FIGS. 10A-10D herein may be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense a drug as described above. The implantable medical system 9000 is presented in FIGS. 10A-1 and 10C-1 and may include the material structure shown in FIG. 18. The implantable medical system 9000 may also include a material structure, selective permeability, and a porous material, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3-10 and each of the incorporated documents. The implantable medical system 9000 may further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 may be configured to meter the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0266] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat macular degeneration. Generally, a method of treating a disease is disclosed that uses an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 that includes a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 that includes a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 can be configured to measure the rate at which a drug for macular degeneration is dispensed from the reservoir 9100 when the delivery device is implanted.

[0267] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating macular degeneration. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so that they can be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at an implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0268] Figures 11A - 11D show various features of the reservoir 9100 in an example of a drug treatment device. In particular, Figure 11A shows a first configuration (configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. Figure 11B shows a second configuration (configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. Figure 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of Figure 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. Figure 11D shows a fourth configuration (configuration "D") of the reservoir 9100, which is similar to that of Figure 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or an implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As further described below, the plurality of chambers 9300 (e.g., Figures 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within the page) or in a plurality of directions (e.g., within the page, out of the page, in - plane with the page, or any combination thereof).

[0269] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a substantially polyhedral shape.

[0270] In certain examples, the physical characteristics of reservoir 9100 can facilitate the functionality of drug delivery system 1000. For example, reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of drug delivery system 1000 so as to deliver the drug to pinpoint locations with respect to reservoir 9100. In this regard, it can be said that implantable medical system 9000 can have unidirectional distribution (e.g., on one side of implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of implantable medical system 9000). In an example, one or more positions of reservoir 9100 can function as filling port 9310 for filling reservoir 9100 with the drug. In this regard, implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of reservoir 9100 can function as a refillable chamber, and delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can flow or be discharged from filling port 9310 of reservoir 9100 to the treatment location. In an example, reservoir 9100 can include within it a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. Chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0271] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main portion 9101 and an extended delivery arm 9103 extending from the reservoir main portion 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main portion 9101 and the extended delivery arm 9103.

[0272] Figures 12A to 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A to 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A that includes only the main portion 9101. Figures 12I to 12P show Configuration B of the reservoir 9100 that includes the main portion 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the prevention of dispensing is shown as a swirling arrow inside the reservoir 9100. Dispensing can be performed only at the permeable portion of the implantable medical system 9000, and the prevention of dispensing can be performed at the impermeable portion of the implantable medical system 9000. Further, the flow and direction into the page are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0273] As will be described in further detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or multiple directions. Under these circumstances, the dispensing can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further under these circumstances, the directionality of the dispensing at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and will recognize that certain variations and modifications of these examples are logical extensions of the examples described below when reading the present disclosure as a whole.

[0274] Referring again to FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0275] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E, and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner of similarly concentrated dispensing in a plurality of directions, it should be understood that some examples include dispensing in a manner scattered in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or different amounts in each dispensing direction. As described above, the amount of dispensing may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As previously described, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G, and upward and downward in FIG. 12H), but in a more scattered manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E - 12G, prevention of dispensing in various other directions and positions is shown, except where dispensing is possible.

[0276] As described above, FIGS. 12I - 12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be the same as that described above with reference to FIGS. 12A - 12H. The main portion 9101 of the implantable medical system 9000 may be the same as that described with respect to FIGS. 12A - 12H. The examples shown in FIGS. 12I - 12P may include, additionally or alternatively, dispensing from the delivery arm 9103, as further described below. Specific examples will be described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0277] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing in the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in a plurality of directions. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0278] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing in the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing, and the main portion 9101 is configured for focused dispensing. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0279] Any of the above configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of macular degeneration. Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be placed at a rear position of the eye 5000 (e.g., see FIG. 14), and optionally (e.g., in Configurations B and D) can be placed at a front position of the eye 5000 (e.g., see FIG. 15). In some such circumstances, the drug delivery system (e.g., in Configurations B and D) is positioned in front of the eye 5000 and is arranged for intravitreal administration. The API class can include monoclonal antibodies, such as bevacizumab, ranibizumab, aflibercept, AVASTIN, LUCENTIS, or EYLEA. Macular edema

[0280] Other retinal diseases such as macular edema of the retina can be treated using an exemplary implementation of the implantable medical system 9000. Macular edema is a chronic eye disorder accompanied by visual distortion due to swelling of the macula involved in the central vision of the eye 5000. For the treatment of macular edema, the drug delivery system can be implanted suprachoroidally (e.g., behind the pars plana of the eye 5000). In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be the implantable medical system 9000 as described above throughout with reference to FIGS. 10A - 12P and re - described herein. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this specification, including the drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and arranged at one or more implantation positions or sites for delivering a drug for the treatment of macular edema.

[0281] As described above, FIGS. 10 and 10A-10D illustrate some examples of an implantable medical system 9000 that is useful for employing these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of first and second microporous materials 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. Details C and D each show a microscopic view of the first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In the example, the main portion 9101 and the delivery arm 9103 may include the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of microporous materials suitable for employing the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0282] The drug delivery devices shown in FIGS. 10A - 10D herein may be similar to the implanted delivery device 9000 described above. For example, this device can be used to dispense drugs as described above. The implanted medical system 9000 is presented in FIGS. 10A - 1 and 10C - 1 and may include the material structure shown in FIG. 18. The implanted medical system 9000 may also include a material structure, selective permeability, and porous materials, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3 - 10 and each of the incorporated documents. The implanted medical system 9000 may further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving drugs. The first microporous material 9201 and the second microporous material 9202 may be configured to meter the rate at which drugs are dispensed from the reservoir 9100 when the delivery device is implanted.

[0283] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat macular edema. Generally, a method of treating a disease is disclosed using an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 may be configured to measure the rate at which a drug for macular edema is dispensed from the reservoir 9100 when the delivery device is implanted.

[0284] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating macular edema. In certain cases, some or all of the first and second microporous materials 9202 may be elastomers so as to be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at an implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0285] Figures 11A - 11D show various features of the reservoir 9100 in an example of a drug treatment device. In particular, Figure 11A shows a first configuration (configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. Figure 11B shows a second configuration (configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. Figure 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of Figure 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. Figure 11D shows a fourth configuration (configuration "D") of the reservoir 9100, which is similar to that of Figure 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or an implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As further described below, the plurality of chambers 9300 (e.g., Figures 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within a page) or in multiple directions (e.g., within a page, out of the page, in - plane with the page, or any combination thereof).

[0286] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a generally polyhedral shape.

[0287] In certain examples, the physical characteristics of reservoir 9100 can facilitate the functionality of drug delivery system 1000. For example, reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of drug delivery system 1000 so as to deliver the drug to a pinpoint location with respect to reservoir 9100. In this regard, it can be said that implantable medical system 9000 can have unidirectional distribution (e.g., on one side of implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of implantable medical system 9000). In an example, one or more locations of reservoir 9100 can function as filling port 9310 for filling reservoir 9100 with the drug. In this regard, implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of reservoir 9100 can function as a refillable chamber, and delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can flow or be discharged from filling port 9310 of reservoir 9100 to the treatment location. In an example, reservoir 9100 can include within it a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. Chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0288] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main body 9101 and an extended delivery arm 9103 extending from the reservoir main body 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main body 9101 and the extended delivery arm 9103.

[0289] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A which includes only the main body 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 which includes the main body 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the prevention of dispensing is shown as a winding arrow inside the reservoir 9100. Dispensing can be performed only at the permeable part of the implantable medical system 9000, and the prevention of dispensing can be performed at the impermeable part of the implantable medical system 9000. Further, the flow into and the direction within the page are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0290] As will be described in more detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or in multiple directions. In these situations, the dispensing can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further, in these situations, the directionality of the dispensing at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different, depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and, when reading the present disclosure as a whole, will recognize that certain variations and modifications of these examples are logical extensions of the examples described below.

[0291] Referring again to FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A-12D, prevention of dispensing in various other directions and positions is shown, except where dispensing is possible.

[0292] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner that is similarly concentratedly dispensed in a plurality of directions, it should be understood that some examples include dispensing in a manner dispersed in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or may be different amounts in each dispensing direction. As described above, the amount of dispensing may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As described above, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G and upward and downward in FIG. 12H), but in a more dispersed manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E-12G, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0293] As described above, FIGS. 12I-12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be the same as that described above with reference to FIGS. 12A-12H. The main portion 9101 of the implantable medical system 9000 may be the same as that described with respect to FIGS. 12A-12H. The examples shown in FIGS. 12I-12P may include, additionally or alternatively, dispensing from the delivery arm 9103 as further described below. Specific examples are described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0294] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in a plurality of directions. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0295] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing and the main portion 9101 is configured for focused dispensing. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0296] Any of the above configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of macular edema. Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be positioned posterior to the eye 5000 and optionally (e.g., in Configurations B and D) can be positioned anterior to the eye 5000. In some such circumstances, the drug delivery system (e.g., in Configurations B and D) is positioned anterior to the eye 5000 and is arranged for intravitreal administration. The API class can include monoclonal antibodies such as ranibizumab, aflibercept, LUCENTIS, and EYLEA. The API class can include steroids such as dexamethasone, fluocinolone acetonide, OZURDEX, or RETISERT. The drug delivery vehicle can be used during administration of the API. For example, with respect to RETISERT, such a drug delivery vehicle can include a silicone cup having a poly(vinyl alcohol) (“PVA”) membrane, which can deliver the drug over a period of about 2 to 3 years. The delivery vehicle for OZURDEX can include a poly(lactic-co-glycolic acid) (“PLGA”) matrix with the drug. The API class can also include small binding molecules defined as antagonist molecules that enable inhibition of angiogenic growth factors including VEGF or PDGF or inhibit protein kinases. In a further example, the API class can include antibody mimetic proteins and peptides. Retinitis

[0297] Another retinal disease that can be treated using the exemplary implementation of the implantable medical system 9000 is retinitis. Retinitis is a disease of the eye 5000 accompanied by inflammation of the retina. For the treatment of retinitis, a drug delivery system can be implanted suprachoroidally (e.g., behind the pars plana of the eye 5000). In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be the implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and described again herein. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this specification, including the drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and positioned at one or more implantation locations or sites to deliver a drug for the treatment of retinitis.

[0298] As described above, FIGS. 10 and 10A-10D are useful for adopting these aspects of the present disclosure and show some examples of an implantable medical system 9000 that can be used to treat retinitis. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of first and second microporous materials 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished through the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 each show a microscopic view of the first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished through the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In the example, the main portion 9101 and the delivery arm 9103 may comprise the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for the sake of convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of suitable microporous materials for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0299] The drug delivery devices shown in FIGS. 10A-10D herein may be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense a drug. The implantable medical system 9000 is presented in FIGS. 10A-1 and 10C-1 and may include the material structures shown in FIG. 18. The implantable medical system 9000 may also include material structures, selective permeability, and porous materials, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3-10 and each of the incorporated documents. The implantable medical system 9000 may further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 may be configured to meter the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0300] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat retinitis. Generally, a method of treating a disease is disclosed using an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 can be configured to measure the rate at which a retinitis drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0301] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating retinitis. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so as to be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at an implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0302] Figures 11A - 11D show various features of the reservoir 9100 in an example of a drug treatment device. In particular, FIG. 11A shows a first configuration (configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. FIG. 11B shows a second configuration (configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. FIG. 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of FIG. 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. FIG. 11D shows a fourth configuration (configuration "D") of the reservoir 9100, which is similar to that of FIG. 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or an implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As will be further described below, the plurality of chambers 9300 (e.g., FIGS. 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as will be further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within the page) or in a plurality of directions (e.g., within the page, out of the page, in - plane with the page, or any combination thereof).

[0303] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be increased or decreased compared to other configurations of the drug delivery system 1000. These variations can depend, inter alia, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, a circle, a polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a substantially polyhedral shape.

[0304] In certain examples, the physical characteristics of the reservoir 9100 can facilitate the functionality of the drug delivery system 1000. For example, the reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of the drug delivery system 1000 so as to deliver the drug to pinpoint locations relative to the reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multi-directional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more locations of the reservoir 9100 can function as a filling port 9310 for filling the reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of the reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can be flowed or discharged from the filling port 9310 of the reservoir 9100 to the treatment location. In an example, the reservoir 9100 can include therein a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0305] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main portion 9101 and an extended delivery arm 9103 extending from the reservoir main portion 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main portion 9101 and the extended delivery arm 9103.

[0306] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A that includes only the main portion 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 that includes the main portion 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include a plurality of chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the dispensing prevention is shown as a swirling arrow inside the reservoir 9100. Dispensing can be performed only at the permeable portion of the implantable medical system 9000, and dispensing prevention can be performed at the impermeable portion of the implantable medical system 9000. Further, the flow and direction into the page are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0307] As will be described in more detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or in multiple directions. Under these circumstances, the dispensing can be performed at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further under these circumstances, the directionality of the dispensing at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and will recognize that certain variations and modifications of these examples are logical extensions of the examples described below when reading the present disclosure as a whole.

[0308] Referring again to FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0309] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner that is similarly concentratedly dispensed in a plurality of directions, it should be understood that some examples include dispensing in a manner dispersed in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or different amounts in each dispensing direction. As described above, the amount of dispensing may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As previously described, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G and upward and downward in FIG. 12H), but in a more dispersed manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E-12G, prevention of dispensing in various other directions and positions is shown, except where dispensing is possible.

[0310] As described above, FIGS. 12I-12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing with respect to the main portion 9101 in these examples may be similar to that described above with reference to FIGS. 12A-12H. The main portion 9101 of the implantable medical system 9000 may be similar to that described with respect to FIGS. 12A-12H. The examples shown in FIGS. 12I-12P may include, additionally or alternatively, dispensing from the delivery arm 9103, as further described below. Specific examples are described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0311] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in a plurality of directions. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0312] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing, and the main portion 9101 is configured for centralized dispensing. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J. Any of the above-described configurations of the dispensing mechanism of the implantable medical system 100 can be applied for use in the treatment of retinitis.

[0313] Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be placed at a position behind the eye 5000 and optionally (e.g., in Configurations B and D) can be placed at a position in front of the eye 5000. In some such circumstances, the drug delivery system (e.g., in Configurations B and D) is positioned in front of the eye 5000 and is arranged for intravitreal administration. The API class can include antibiotics and antiviral drugs (for cytomegalovirus (“CMV”)), such as ganciclovir or VITRASERT. The drug delivery vehicle can be used during administration of the API. For example, with respect to ganciclovir and VITRASERT, such a drug delivery vehicle can include a silicone cup with a PVA membrane, which can deliver the drug over a period of about 2 to 3 years. Retinoblastoma

[0314] Another retinal disease that can be treated using an exemplary implementation of the implantable medical system 9000 is retinoblastoma, a form of eye cancer. For the treatment of retinoblastoma, the drug delivery system can be implanted suprachoroidally (e.g., behind the pars plana of the eye 5000). In the example, the drug delivery system can be either Configuration A or C. For example, the drug delivery system can be the implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and described again herein. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this specification, including the drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and arranged at one or more implant positions or sites for delivering a drug for the treatment of retinoblastoma.

[0315] As described above, FIGS. 10 and 10A-10D illustrate several examples of an implantable medical system 9000 that is useful in adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of a first and a second microporous material 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 each show a microscopic view of a first and a second microporous material 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In the example, the main portion 9101 and the delivery arm 9103 may comprise the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for the sake of convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further considerations of suitable microporous materials for adopting the principles of the present disclosure are shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0316] The drug delivery devices shown in FIGS. 10A - 10D herein can be similar to the implanted delivery device 9000 described above. For example, this device can be used to dispense a drug as described above. The implanted medical system 9000 is presented in FIGS. 10A - 1 and 10C - 1 and can include the material structures shown in FIG. 18. The implanted medical system 9000 can also include material structures, selective permeability, and porous materials, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided particularly in FIGS. 3 - 10 and each of the incorporated documents. The implanted medical system 9000 can further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 can have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 can have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 can have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 can have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 can be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 can be configured to meter the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0317] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat retinoblastoma. Generally, a method of treating a disease is disclosed using an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving the drug. The first microporous material 9201 and the second microporous material 9202 can be configured to meter the rate at which the drug for retinoblastoma is dispensed from the reservoir 9100 when the delivery device is implanted.

[0318] The administration of the drug may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating retinoblastoma. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so as to be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at the implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0319] Figures 11A and 11C show various features of the reservoir 9100 in an example of a drug treatment device that can be used to treat retinoblastoma. In particular, Figure 11A shows a first configuration (configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. Figure 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of Figure 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with the drug.

[0320] Many factors can affect the physical characteristics of the drug treatment device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be increased or decreased compared to other configurations of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a generally polyhedral shape.

[0321] In certain examples, the physical characteristics of reservoir 9100 can facilitate the functionality of drug delivery system 1000. For example, reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of drug delivery system 1000 so as to deliver the drug to pinpoint locations with respect to reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more locations of reservoir 9100 can function as filling port 9310 for filling reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can flow or be discharged from the filling port 9310 of reservoir 9100 to the treatment location. In an example, reservoir 9100 can contain within it a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0322] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main portion 9101 and an extended delivery arm 9103 extending from the reservoir main portion 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main portion 9101 and the extended delivery arm 9103.

[0323] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A, which includes only the main portion 9101. For the sake of brevity, the dispensing operations described are shown with respect to Configuration A, but those skilled in the art will understand that these dispensing operations are equally applicable to Configuration C. In this regard, the difference would be that Configuration C includes multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configuration A. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the dispensing prevention is shown as a winding arrow inside the reservoir 9100. Dispensing can be performed only at the permeable part of the implantable medical system 9000, and dispensing prevention can be performed at the impermeable part of the implantable medical system 9000. Further, the flow and direction into the page are shown as an X surrounded by a circle, and the direction out of the page is shown as a point surrounded by a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used in this specification to clarify the description.

[0324] As will be described in more detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or multiple directions. In these situations, the dispensing can be performed at the main portion 9101. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and will recognize that certain variations and modifications of these examples are logical extensions of the examples described below when reading the present disclosure as a whole.

[0325] Referring again to FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0326] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E, and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner of being similarly concentratedly dispensed in a plurality of directions, it should be understood that some examples include dispensing in a manner scattered in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or may be different amounts in each dispensing direction. As described above, the dispensing amount may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As described above, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G, and upward and downward in FIG. 12H), but in a more scattered manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E-12G, prevention of dispensing in various other directions and positions is shown, except where dispensing is possible.

[0327] Any of the above configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of retinoblastoma. Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be disposed at a posterior position of the eye 5000. The API class may include cytotoxic chemotherapy compounds such as vincristine or ONCOVIN. Retinal vein occlusion

[0328] Retinal vein occlusion is a retinal disease that can be treated using an exemplary implementation of an implantable medical system 9000. Retinal vein occlusions, such as CRVO and BRVO, are occlusions of one or more retinal veins. These occlusions can result in excessive blood and fluid within the retina. For the treatment of retinal vein occlusion, a drug delivery system can be implanted suprachoroidally (e.g., behind the pars plana of the eye 5000). In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be an implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and described again herein. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this specification, including drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and positioned at one or more implantation locations or sites for delivering a drug for the treatment of retinal vein occlusion.

[0329] As described above, FIGS. 10 and 10A-10D illustrate some examples of an implantable medical system 9000 that is useful for adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of first and second microporous materials 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 each show a microscopic view of the first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In the example, the main portion 9101 and the delivery arm 9103 may include the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of microporous materials suitable for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0330] The drug delivery devices shown in FIGS. 10A-10D herein can be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense a drug as described above. The implantable medical system 9000 is presented in FIGS. 10A-1 and 10C-1 and can include the material structures shown in FIG. 18. The implantable medical system 9000 can also include material structures, selective permeability, and porous materials, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3-10 and each of the incorporated documents. The implantable medical system 9000 can further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 can have a first microporous layer 9203 that includes a plurality of pores sized to permit ingrowth of tissue. The first microporous material 9201 can have a second microporous layer 9205 that includes a plurality of pores sized to permit ingrowth of tissue. The second microporous material 9202 can have a third microporous layer 9205 that includes a plurality of pores sized to resist ingrowth of tissue. The second microporous material 9202 can have a fourth microporous layer 9207 that includes a plurality of pores sized to permit ingrowth of tissue. The second microporous layer 9205 can be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 can be configured to meter the rate at which a drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0331] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat retinal vein occlusion. Generally, a method of treating a disease is disclosed using an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving the drug. The first microporous material 9201 and the second microporous material 9202 can be configured to meter the rate at which a drug for retinal vein occlusion is dispensed from the reservoir 9100 when the delivery device is implanted.

[0332] The administration of the drug may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating retinal vein occlusion. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so as to be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at the implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0333] Figures 11A - 11D show various features of the reservoir 9100 in an example of a drug treatment device. In particular, Figure 11A shows a first configuration (Configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. Figure 11B shows a second configuration (Configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. Figure 11C shows a third configuration (Configuration "C") of the reservoir 9100, which is similar to that of Figure 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. Figure 11D shows a fourth configuration (Configuration "D") of the reservoir 9100, which is similar to that of Figure 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or of the implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As further described below, the plurality of chambers 9300 (e.g., Figures 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within the page) or in multiple directions (e.g., within the page, out of the page, in - plane with the page, or any combination thereof).

[0334] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a generally polyhedral shape.

[0335] In certain examples, the physical characteristics of the reservoir 9100 can facilitate the functionality of the drug delivery system 1000. For example, the reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of the drug delivery system 1000 so as to deliver the drug to pinpoint locations relative to the reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more positions of the reservoir 9100 can function as a filling port 9310 for filling the reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of the reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can be flowed or discharged from the filling port 9310 of the reservoir 9100 to the treatment location. In an example, the reservoir 9100 can include therein a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0336] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main part 9101 and an extended delivery arm 9103 extending from the reservoir main part 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main part 9101 and the extended delivery arm 9103.

[0337] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 during dispensing when the reservoir 9100 is in Configuration A that includes only the main part 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 that includes the main part 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the prevention of dispensing is shown as a coiled arrow inside the reservoir 9100. Dispensing can be performed only at the permeable part of the implantable medical system 9000, and the prevention of dispensing can be performed at the impermeable part of the implantable medical system 9000. Further, the flow and direction into the page are shown as an X enclosed in a circle, and the direction out of the page is shown as a point enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0338] As will be described in more detail below, the distribution of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is distributed generally in one direction or multiple directions. In these situations, the distribution can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further in these situations, the directionality of the distribution at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and will recognize that certain variations and modifications of these examples are logical extensions of the examples described below when reading the present disclosure as a whole.

[0339] Referring again to FIGS. 12A and 12B, unidirectional distribution is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution pattern of the distribution is shown by a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar distribution operation (generally distribution into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of distribution in various other directions and positions is shown except where distribution is possible.

[0340] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner of similarly concentrated dispensing in a plurality of directions, it should be understood that some examples include dispensing in a manner scattered in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or may be different amounts in each dispensing direction. As described above, the dispensing amount may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As described above, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G and upward and downward in FIG. 12H), but in a more scattered manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E-12G, prevention of dispensing in various other directions and positions is shown except at the locations where dispensing is possible.

[0341] As described above, FIGS. 12I-12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be similar to that described above with reference to FIGS. 12A-12H. The main portion 9101 of the implantable medical system 9000 may be similar to that described with respect to FIGS. 12A-12H. The examples shown in FIGS. 12I-12P may include, additionally or alternatively, dispensing from the delivery arm 9103, as further described below. Specific examples are described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0342] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in a plurality of directions. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0343] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing and the main portion 9101 is configured for centralized dispensing. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0344] Any of the above configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of retinal vein occlusion. Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be placed at a rear position of the eye 5000 and optionally (e.g., in Configurations B and D) at a front position of the eye 5000. The API includes monoclonal antibodies such as bevacizumab, ranibizumab, AVASTIN, or LUCENTIS. In an example, the API includes steroids such as dexamethasone or OZURDEX. The drug delivery vehicle can be used during administration of the API. For example, with respect to steroids, such a drug delivery vehicle can include a PLGA matrix having a drug implanted in the vitreous body. The API class can also include small binding molecules defined as antagonist molecules that enable inhibition of angiogenic growth factors including VEGF or PDGF, or inhibit protein kinases. In a further example, the API class can include antibody mimetic proteins and peptides. Keratitis and dry eye

[0345] The present disclosure includes devices, systems, and methods suitable for the treatment of corneal diseases. Some such corneal diseases include keratitis and dry eye. In some examples, the reservoir 9100 can dispense the drug from both sides of the reservoir 9100 such that the drug is released in a direction towards the eye 5000 and into the eye 5000, as well as in a direction away from the eye 5000 and into the conjunctiva 5002. Keratitis

[0346] Keratitis can be treated using an exemplary implementation of the implantable medical system 9000. Keratitis is an inflammation of the cornea. For the treatment of keratitis, the drug delivery system can be implanted subconjunctivally (e.g., near the edge of the eye 5000). In an example, the drug delivery system can be any of Configurations A - D.

[0347] For example, the drug delivery system can be an implantable medical system 9000 as described above throughout with reference to FIGS. 10A - 12P and as further described herein. These implantable medical systems 9000 can be similar to other ones disclosed elsewhere herein, including drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and disposed at one or more implantation positions or sites for delivering a drug for the treatment of keratitis.

[0348] As described above, FIGS. 10 and 10A-10D illustrate some examples of an implantable medical system 9000 useful in adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 respectively show microscopic views of first and second microporous materials 9202 within the implantable medical system 9000. FIG. 10B shows the state where the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 respectively show microscopic views of the first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the state where the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In the example, the main portion 9101 and the delivery arm 9103 may include the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of suitable microporous materials for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0349] The drug delivery devices shown in FIGS. 10A-10D herein can be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense a drug as described above. The implantable medical system 9000 is presented in FIGS. 10A-1 and 10C-1 and can include the material structure shown in FIG. 18. The implantable medical system 9000 can also include a material structure, selective permeability, and a porous material, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3-10 and each of the incorporated documents. The implantable medical system 9000 can further include a first microporous material 9201 coupled to a second microporous material 9202. The first microporous material 9201 can have a first microporous layer 9203 that includes a plurality of pores sized to permit ingrowth of tissue. The first microporous material 9201 can have a second microporous layer 9205 that includes a plurality of pores sized to permit ingrowth of tissue. The second microporous material 9202 can have a third microporous layer 9205 that includes a plurality of pores sized to resist ingrowth of tissue. The second microporous material 9202 can have a fourth microporous layer 9207 that includes a plurality of pores sized to permit ingrowth of tissue. The second microporous layer 9205 can be coupled to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 can be configured to meter the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0350] According to the principles of the present disclosure, the implantable medical system 9000 can be used to treat keratitis. Generally, a method of treating a disease is disclosed that uses an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 that includes a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 that includes a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 can be configured to measure the rate at which a keratitis drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0351] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating keratitis. In certain cases, some or all of the first and second microporous materials 9202 may be elastomers so that they can be resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at an implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0352] Figures 11A-11D illustrate various features of the reservoir 9100 in an example of a drug treatment device. In particular, FIG. 11A shows a first configuration (configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. FIG. 11B shows a second configuration (configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. FIG. 11C shows a third configuration (configuration "C") of the reservoir 9100, which is similar to that of FIG. 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. FIG. 11D shows a fourth configuration (configuration "D") of the reservoir 9100, which is similar to that of FIG. 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 can be a feature of the injection site in the reservoir 9100 or of the implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As further described below, the plurality of chambers 9300 (e.g., FIGS. 11C and 11D) can be in fluid communication with each other or can be fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can dispense the drug in one direction (e.g., within the page) or in multiple directions (e.g., within the page, out of the page, in-plane with the page, or any combination thereof).

[0353] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to a particular exemplary implementation of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a substantially polyhedral shape.

[0354] In certain examples, the physical characteristics of the reservoir 9100 can facilitate the functionality of the drug delivery system 1000. For example, the reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of the drug delivery system 1000 so as to deliver the drug to pinpoint locations with respect to the reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multi-directional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more positions of the reservoir 9100 can function as a filling port 9310 for filling the reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of the reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can flow or be discharged from the filling port 9310 of the reservoir 9100 to the treatment location. In an example, the reservoir 9100 can contain within it a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0355] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main portion 9101 and an extended delivery arm 9103 extending from the reservoir main portion 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main portion 9101 and the extended delivery arm 9103.

[0356] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 being dispensed when the reservoir 9100 is in Configuration A that includes only the main portion 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 that includes the main portion 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the dispensing prevention is shown as a swirling arrow inside the reservoir 9100. The dispensing can be performed only at the permeable part of the implantable medical system 9000, and the dispensing prevention can be performed at the impermeable part of the implantable medical system 9000. Further, the flow into the page and the direction are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0357] As will be described in further detail below, drug distribution can vary between and within configurations when used to treat keratitis. For example, as described above, the implantable medical system 9000 can be configured such that the drug is distributed generally in one direction or multiple directions. Under these circumstances, the distribution can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further under these circumstances, the directionality of the distribution at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 can be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and, when reading the present disclosure as a whole, will recognize that specific variations and modifications of these examples are logical extensions of the examples described below.

[0358] Referring again to FIGS. 12A and 12B, unidirectional distribution is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution profile is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar distribution operation (generally distribution into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A - 12D, prevention of distribution in various other directions and positions is shown except where distribution is possible.

[0359] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E, and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner that is similarly concentratedly dispensed in a plurality of directions, it should be understood that some examples include dispensing in a manner dispersed in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or may be different amounts in each dispensing direction. As described above, the dispensing amount may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As previously described, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G, and upward and downward in FIG. 12H), but in a manner that is more dispersed in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E-12G, prevention of dispensing in various other directions and positions is shown, except where dispensing is possible.

[0360] As described above, FIGS. 12I-12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be the same as that described above with reference to FIGS. 12A-12H. The main portion 9101 of the implantable medical system 9000 may be the same as that described with respect to FIGS. 12A-12H. The examples shown in FIGS. 12I-12P may include, additionally or alternatively, dispensing from the delivery arm 9103, as further described below. Specific examples will be described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0361] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing in the delivery arm 9103 can be performed in various directions (e.g., at the distal portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in multiple directions. For example, the main portion 9101 can dispense the drug in a manner similar to that described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in a manner similar to that described with respect to FIGS. 12I and 12J.

[0362] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing in the delivery arm 9103 can be performed in various directions only at the distal portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the distal portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing and the main portion 9101 is configured for centralized dispensing. For example, the main portion 9101 can dispense the drug in a manner similar to that described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in a manner similar to that described with respect to FIGS. 12I and 12J. Any of the above-described configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of keratitis.

[0363] Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be placed at a forward position of the eye 5000 and optionally (e.g., in Configurations B and D) can be placed within the anterior chamber 5006 of the eye 5000. Examples of APIs include antibiotics, steroids, or antifungal agents. Dry eye

[0364] Dry eye is another corneal disease that can be treated using an exemplary implementation of the implantable medical system 9000. Dry eye is the insufficient lubrication of the tear film of the eye 5000. In the treatment of dry eye, a drug delivery system can be implanted subconjunctivally. In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be the implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and described again herein. These implantable medical systems 9000 can be similar to others disclosed elsewhere in this specification, including the drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and positioned at one or more implantation locations or sites to deliver a drug for the treatment of dry eye.

[0365] As described above, FIGS. 10 and 10A-10D illustrate several examples of an implantable medical system 9000 that is useful in adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of first and second microporous materials 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 each show a microscopic view of the first and second microporous materials 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may be used). In the example, the main portion 9101 and the delivery arm 9103 may include the same or similar materials. Under these circumstances, the delivery arm 9103 can be integrated with or attachable to the main portion 9101 such that the delivery arm 9103 and the main portion 9101 are in fluid communication with each other. In FIGS. 10A-1 and 10A-2, exemplary microporous materials are schematically shown for convenience of explanation. The exemplary images provided in FIGS. 10A-1, 10A-2, 10C-1, and 10C-2 are representative examples of the microscopic images presented in FIG. 18. Further consideration of suitable microporous materials for adopting the principles of the present disclosure is shown and described in U.S. Patent Application Publication No. 2018 / 0263817, the entire content of which is incorporated herein by reference.

[0366] The drug delivery devices shown in FIGS. 10A-10D herein may be similar to the implantable delivery device 9000 described above. For example, this device can be used to dispense a drug as described above. The implantable medical system 9000 is presented in FIGS. 10A-1 and 10C-1 and may include the material structures shown in FIG. 18. The implantable medical system 9000 may also include material structures, selective permeability, and porous materials, which are shown and described in U.S. Patent No. 10,849,731 (Cully) and U.S. Patent Application Publication No. 2018 / 0126134 (Cully), both of which are incorporated by reference in their entirety by reference to the accompanying descriptions provided in particular in FIGS. 3-10 and each of the incorporated documents thereof. The implantable medical system 9000 may further include a first microporous material 9201 bonded to a second microporous material 9202. The first microporous material 9201 may have a first microporous layer 9203 including a plurality of pores sized to permit tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 including a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 including a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 including a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving a drug. The first microporous material 9201 and the second microporous material 9202 may be configured to meter the rate at which the drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0367] According to the principles of the present disclosure, an implantable medical system 9000 can be used to treat dry eye. Generally, a method of treating a disease is disclosed using an implantable medical system 9000 configured to measure the rate at which a drug is dispensed from a reservoir 9100 when a delivery device is implanted. This method may include selecting an implantable medical system 9000 similar to the implantable medical system 9000 described above. For example, the first microporous material 9201 may have a first microporous layer 9203 that includes a plurality of pores sized to resist tissue ingrowth. The first microporous material 9201 may have a second microporous layer 9205 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous material 9202 may have a third microporous layer 9205 that includes a plurality of pores sized to resist tissue ingrowth. The second microporous material 9202 may have a fourth microporous layer 9207 that includes a plurality of pores sized to permit tissue ingrowth. The second microporous layer 9205 may be bonded to the third microporous layer 9205, thereby forming a reservoir 9100 for receiving the drug. The first microporous material 9201 and the second microporous material 9202 can be configured to measure the rate at which the dry eye drug is dispensed from the reservoir 9100 when the delivery device is implanted.

[0368] Drug administration may include several steps. For example, the method may include filling the reservoir 9100 with a drug for treating dry eye. In certain cases, some or all of the first and second microporous materials 9202 may be elastomeric so that they are resealed after insertion of a syringe 9110 or other similar device. The method may include implanting the implantable medical system 9000 at the implantation site. The method may include enabling the drug to be dispensed from the reservoir 9100 to one or more treatment sites.

[0369] Figures 11A-11D illustrate various features of the reservoir 9100 in an example of a drug therapy device. In particular, FIG. 11A shows a first configuration (Configuration "A") of the reservoir 9100, where the reservoir 9100 includes only the main portion 9101. FIG. 11B shows a second configuration (Configuration "B") of the reservoir 9100, where the reservoir 9100 includes the main portion 9101 and the delivery arm 9103. FIG. 11C shows a third configuration (Configuration "C") of the reservoir 9100, which is similar to that of FIG. 11A and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. FIG. 11D shows a fourth configuration (Configuration "D") of the reservoir 9100, which is similar to that of FIG. 11B and further includes a plurality of chambers 9300 and a plurality of filling ports 9310 for filling the corresponding chambers with a drug. In the example, the filling port 9310 may be a feature of the injection site in the reservoir 9100 or an implantable medical system 9000 that facilitates filling the reservoir 9100 with a drug. As further described below, the plurality of chambers 9300 (e.g., FIGS. 11C and 11D) can be in fluid communication with each other or fluidly isolated. In the example, as further described elsewhere in this specification, the reservoir 9100 can distribute the drug in one direction (e.g., within the page) or multiple directions (e.g., within the page, out of the page, in-plane with the page, or any combination thereof).

[0370] Many factors can affect the physical characteristics of a drug delivery device. Depending on at least one of the implantation location and the disease being treated, one or both of the geometry and functionality of the reservoir 9100 of the drug delivery system 1000 can vary in the example. For example, the dimensions of the reservoir 9100 can be made larger or smaller compared to other components of the drug delivery system 1000. These variations can depend, among other things, on the amount of drug delivered for treatment, the manner in which the drug is delivered, and the resistance to drug delivery presented by the implantation location. As described herein, in the example, the reservoir 9100 can have a generally uniform shape (e.g., similar to an ellipse, circle, polygon, etc.). In other examples, the reservoir 9100 can have an irregular shape (e.g., a generally uniform shape with one or more protrusions or projections, an eccentric shape, etc.). Some exemplary shapes of the reservoir 9100 are described below with respect to specific exemplary implementations of the drug delivery system 1000. In the example, when the reservoir 9100 expands, the reservoir 9100 can expand along the length of the reservoir 9100. In some cases, due to the swelling, the reservoir 9100 may swell or expand into a generally polyhedral shape.

[0371] In certain examples, the physical characteristics of the reservoir 9100 can facilitate the functionality of the drug delivery system 1000. For example, the reservoir 9100 can be formed to generally disperse the drug across the treatment site on one or more sides of the drug delivery system 1000 so as to deliver the drug to a pinpoint location relative to the reservoir 9100. In this regard, it can be said that the implantable medical system 9000 can have unidirectional distribution (e.g., on one side of the implantable medical system 9000) or multidirectional distribution (e.g., on multiple sides of the implantable medical system 9000). In an example, one or more positions of the reservoir 9100 can function as a filling port 9310 for filling the reservoir 9100 with the drug. In this regard, the implantable medical system 9000 can be refillable with the drug as described above. For example, the main portion 9101 of the reservoir 9100 can function as a refillable chamber, and the delivery arm 9103 can function as a conduit for delivering fluid from the refillable chamber. After implantation, the drug can flow or be discharged from the filling port 9310 of the reservoir 9100 to the treatment location. In an example, the reservoir 9100 can contain within it a plurality of chambers 9300 for storing the drug to be delivered. Under these circumstances, one of the plurality of chambers 9300 can contain a first drug, and another of the plurality of chambers 9300 can contain a second drug that is the same as or different from the first drug. The chambers 9300 within the plurality of chambers 9300 can be in fluid communication with each other or isolated from each other depending on the implementation form.

[0372] Around the reservoir 9100, an extended delivery arm 9103 capable of administering the agent from the reservoir 9100 can be formed. In this regard, the reservoir 9100 may include a reservoir main body 9101 and an extended delivery arm 9103 extending from the reservoir main body 9101. For example, the extended delivery arm 9103 may include a port that allows the agent to exit the reservoir 9100 in a limited manner. In other cases, the agent may be able to exit the reservoir 9100 at any part of the extended delivery arm 9103 (e.g., not limited to the port). Additionally, or alternatively, the agent may be able to exit the reservoir 9100 in both the reservoir main body 9101 and the extended delivery arm 9103.

[0373] Figures 12A - 12P show various dispensing configurations of the reservoir 9100. In particular, Figures 12A - 12H show the implantable medical system 9000 during dispensing when the reservoir 9100 is in Configuration A that includes only the main body 9101. Figures 12I - 12P show Configuration B of the reservoir 9100 that includes the main body 9101 and the delivery arm 9103. For the sake of brevity, the dispensing operations herein are shown with respect to Configurations A and B, but those skilled in the art will understand that these dispensing operations are equally applicable to Configurations C and D. In this regard, the difference would be that Configurations C and D would include multiple chambers that can be similarly dispensed into the single chamber described below with respect to Configurations A and B. For illustrative purposes, the dispensing direction is shown as a straight arrow flowing out of the reservoir 9100, and the dispensing prevention is shown as a swirling arrow inside the reservoir 9100. The dispensing can be performed only at the permeable part of the implantable medical system 9000, and the dispensing prevention can be performed at the impermeable part of the implantable medical system 9000. Further, the flow into the page and the direction are shown as an X enclosed in a circle, and the direction out of the page is shown as a dot enclosed in a circle. Of course, these are only schematic diagrams of more complex phenomena, but are used herein to clarify the description.

[0374] As will be described in more detail below, the dispensing of the agent may vary between and within configurations. For example, as described above, the implantable medical system 9000 can be configured such that the agent is dispensed generally in one direction or multiple directions. In these situations, the dispensing can occur at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103. Further in these situations, the directionality of the dispensing at the main portion 9101 of the implantable medical system 9000, the delivery arm 9103, or both the main portion 9101 and the delivery arm 9103 may be the same or different depending on the example. The examples shown and described in these figures are only a part of many examples disclosed in this specification. Those skilled in the art will understand this fact and, when reading the present disclosure as a whole, will recognize that certain variations and modifications of these examples are logical extensions of the examples described below.

[0375] Referring again to FIGS. 12A and 12B, unidirectional dispensing is shown (generally into the page in FIG. 12A and downward in FIG. 12B). The distribution of the dispensing is shown in a scatter pattern, and the directions of the arrows are generally offset from each other but generally in the same direction. In contrast, FIGS. 12C and 12D show a similar dispensing operation (generally dispensing into the page in FIG. 12C and downward in FIG. 12D), but in a more concentrated manner where the directions of the arrows are generally not offset from each other and are in the same direction. In FIGS. 12A-12D, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0376] Referring back to FIGS. 12E and 12F, a multi-directional dispensing operation is shown (e.g., generally out of and into the page in FIG. 12E and upward and downward in FIG. 12F). The distribution of the dispensing is shown concentrated in a plurality of directions (similar to FIGS. 12C and 12D). As indicated by the number of arrows, the dispensing out of the page in FIG. 12E and the dispensing upward in FIG. 12F are less than the dispensing into the page in FIG. 12E and the dispensing downward in FIG. 12F. Although shown in a manner of being similarly concentratedly dispensed in a plurality of directions, it should be understood that some examples include dispensing in a manner scattered in one direction and dispensing in a concentrated manner in another direction. It should also be understood that the dispensing may be the same amount in each dispensing direction or may be different amounts in each dispensing direction. As described above, the dispensing amount may be proportional to the permeability in the dispensing portion of the implantable medical system 9000. As described above, FIGS. 12G and 12H show a similar dispensing operation (generally dispensing out of and into the page in FIG. 12G and upward and downward in FIG. 12H), but in a more scattered manner in a plurality of directions (similar to FIGS. 12A and 12B). In FIGS. 12E-12G, prevention of dispensing in various other directions and positions is shown except where dispensing is possible.

[0377] As described above, FIGS. 12I-12P show Configuration B of the reservoir 9100, where the reservoir 9100 includes a main portion 9101 and a delivery arm 9103. The dispensing regarding the main portion 9101 in these examples may be the same as that described above with reference to FIGS. 12A-12H. The main portion 9101 of the implantable medical system 9000 may be the same as that described with respect to FIGS. 12A-12H. The examples shown in FIGS. 12I-12P may include, as an addition or alternative, dispensing from the delivery arm 9103 as further described below. Specific examples will be described below, but it should be understood that those skilled in the art will recognize many other examples and combinations thereof in light of the present disclosure.

[0378] Referring to FIGS. 12I and 12J, the multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions (e.g., at the tip portion of the delivery arm 9103, along the length of the delivery arm 9103). Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000. In contrast, in the examples shown in FIGS. 12M and 12N, both the delivery arm 9103 and the main portion 9101 are configured to dispense in a plurality of directions. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12G and 12H, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0379] As previously described with reference to FIGS. 12K and 12L, the guided multi-directional dispensing operation in the delivery arm 9103 is shown. In this regard, the dispensing by the delivery arm 9103 can be performed in various directions only at the tip portion of the delivery arm 9103. Although specific to this example, no dispensing occurs in the main portion 9101 of the implantable medical system 9000 or along the length of the delivery arm 9103 away from the tip portion. In contrast, in the examples shown in FIGS. 12O and 12P, the delivery arm 9103 is configured for guided multi-directional dispensing, and the main portion 9101 is configured for centralized dispensing. For example, the main portion 9101 can dispense the drug in the same manner as described with respect to FIGS. 12C and 12D, and the delivery arm 9103 can dispense the drug in the same manner as described with respect to FIGS. 12I and 12J.

[0380] Any of the above configurations of the implantable medical system 100 and the dispensing mechanism can be applied for use in the treatment of dry eye. Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be placed at a position in front of the eye 5000 and optionally (e.g., in Configurations B and D) can be placed within the anterior chamber 5006 of the eye 5000. Examples of APIs include cyclosporine, lifitegrast, RESTASIS, or XIIDRA. Uveitis

[0381] Uveitis is yet another disease that can be treated using an exemplary implementation of the implantable medical system 9000. Uveitis is a disease of the eye 5000 that involves inflammation of the uvea. For the treatment of uveitis, a drug delivery system can be implanted suprachoroidally (e.g., posterior to the pars plana of the eye 5000). In an example, the drug delivery system can be any of Configurations A - D. Under these circumstances, the drug delivery system (e.g., in Configurations A and C) can be placed at a position posterior to the eye 5000 and optionally (e.g., in Configurations B and D) can be placed at a position in front of the eye 5000. In some such circumstances, the drug delivery system (e.g., in Configurations B and D) is positioned in front of the eye 5000 and is arranged for intravitreal administration. The API class can include corticosteroids such as fluocinolone acetonide and RETISERT. A drug delivery vehicle can be used during the administration of the API. For example, with respect to RETISERT, such a drug delivery vehicle can include a silicone cup with a PVA membrane, which can deliver the drug over a period of about 2 - 3 years. Presbyopia

[0382] Yet another disease that can be treated using the exemplary implementation of the implantable medical system 9000 is presbyopia, which is the hardening of the lens crystals of the eye 5000. For the treatment of presbyopia, a drug delivery system can be implanted subconjunctivally. In an example, the drug delivery system can be any of Configurations A - D. For example, the drug delivery system can be the implantable medical system 9000 as described previously throughout with reference to FIGS. 10A - 12P and described again herein. These implantable medical systems 9000 can be similar to other ones disclosed elsewhere in this specification, including the drug delivery systems 1000, 2000, 3000. In this regard, the implantable medical system 9000 can be implanted and positioned at one or more implant locations or sites for delivering a drug for the treatment of presbyopia.

[0383] As described above, FIGS. 10 and 10A-10D illustrate several examples of an implantable medical system 9000 useful in adopting these aspects of the present disclosure. In particular, FIG. 10 is an isometric view of an implantable medical system 9000 having a reservoir 9100 with a main portion 9101 and a delivery arm 9103. FIG. 10A shows the inflated reservoir 9100 of FIGS. 10A-1 and 10A-2. FIGS. 10A-1 and 10A-2 each show a microscopic view of a first and a second microporous material 9202 within the implantable medical system 9000. FIG. 10B shows the state in which the reservoir 9100 of FIG. 10A is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In particular, FIG. 10C shows the inflated reservoir 9100 with the delivery arm 9103. FIGS. 10C-1 and 10C-2 each show a microscopic view of a first and a second microporous material 9202 in the implantable medical system 9000. FIG. 10D shows the state in which the reservoir 9100 of FIG. 10C is being replenished via the insertion of a syringe 9110 (however, other suitable means for replenishing the reservoir 9100 in situ may also be used). In the example, t...

Claims

1. 1. A method of treating an eye disease, the method comprising: selecting an implantable delivery device comprising a first microporous material bonded to a second microporous material, the first microporous material having a first microporous layer including a plurality of pores sized to permit tissue ingrowth and a second microporous layer including a plurality of pores sized to permit tissue ingrowth, the second microporous material having a third microporous layer including a plurality of pores sized to resist tissue ingrowth and a fourth microporous layer including a plurality of pores sized to permit tissue ingrowth, the second microporous layer bonded to the third microporous layer thereby forming a reservoir for receiving at least one agent, the first microporous material and the second microporous material being configured to meter a rate at which the agent is dispensed from the reservoir when the delivery device is implanted; loading the reservoir with a drug for treating one or more eye conditions; implanting the implantable delivery device at an implantation site; and allowing the agent to be distributed from the reservoir to one or more treatment sites.

2. The method of claim 1 , wherein the implantation location is an anterior reservoir location.

3. The method of claim 2 , wherein the one or more eye diseases include at least one of glaucoma, keratitis, dry eye, or presbyopia.

4. 4. The method of claim 3, wherein when the one or more diseases is glaucoma, the agent has an API class including at least one of a prostaglandin, a prostaglandin structural analog, a beta blocker, an alpha agonist, or a carbonic anhydrase inhibitor.

5. 4. The method of claim 3, wherein when the one or more diseases is keratitis, the agent has an API class including at least one of an antibiotic, a steroid, or an antifungal agent.

6. 4. The method of claim 3, wherein when the one or more diseases is dry eye, the medication has an API class corresponding to at least one of a prostaglandin, a beta blocker, an alpha agonist, or a carbonic anhydrase inhibitor.

7. 4. The method of claim 3, wherein when the one or more diseases is presbyopia, the agent has an API class that includes miotics.

8. The method of claim 1 , wherein the implantation location is a posterior reservoir location.

9. 9. The method of claim 8, wherein the one or more ocular diseases comprise at least one of macular degeneration, geographic atrophy lesions, macular edema, uveitis, retinitis, keratitis, retinoblastoma, central retinal vein occlusion, or branch retinal vein occlusion.

10. 10. The method of claim 9, wherein when the one or more diseases is macular degeneration, the agent has an API class comprising a monoclonal antibody, an antibody mimetic protein, a peptide, or a small binding molecule.

11. 10. The method of claim 9, wherein when the one or more diseases is macular edema, the agent has an API class that includes a monoclonal antibody, an antibody mimetic protein, a peptide, a small binding molecule, or a steroid.

12. 10. The method of claim 9, wherein when the one or more diseases is uveitis, the agent has an API class that includes a corticosteroid.

13. 10. The method of claim 9, wherein when the one or more diseases is retinitis, the agent has an API class that includes an antibiotic or an antiviral agent.

14. 10. The method of claim 9, wherein the agent has an API class that includes a cytotoxic chemotherapeutic compound when the one or more diseases is retinoblastoma.

15. 10. The method of claim 9, wherein when the one or more diseases is central retinal vein occlusion or branch retinal vein occlusion, the agent has an API class that includes a monoclonal antibody or a steroid.

16. The method of claim 1 , wherein the implantation location is an anterior-posterior reservoir location.

17. 17. The method of claim 16, wherein the one or more ocular diseases comprise at least one of macular degeneration, geographic atrophy lesions, macular edema, uveitis, retinitis, central retinal vein occlusion, or branch retinal vein occlusion.

18. 20. The method of claim 17, wherein when the one or more diseases is macular degeneration, the agent has an API class that includes a monoclonal antibody.

19. 18. The method of claim 17, wherein when the one or more diseases is macular edema, the agent has an API class that includes a monoclonal antibody or a steroid. 。

20. 18. The method of claim 17, wherein when the one or more diseases is uveitis, the agent has an API class that includes a corticosteroid.

21. 20. The method of claim 17, wherein when the one or more diseases is retinitis, the agent has an API class that includes an antibiotic or an antiviral agent.

22. 18. The method of claim 17, wherein when the one or more diseases is central retinal vein occlusion or branch retinal vein occlusion, the agent has an API class comprising a monoclonal antibody or a steroid.

23. The method of claim 1 , wherein the implantable delivery device comprises a refillable reservoir and a delivery arm.

24. 24. The method of claim 23, further comprising refilling the refillable reservoir.

25. The method of claim 1 , wherein the implantable delivery device has one or more filling ports for refilling the reservoir.

26. The method of claim 1 , wherein the implantable delivery device is configured to dispense the agent in a single direction.

27. The method of claim 1 , wherein the implantable delivery device is configured to dispense the agent in multiple directions.

28. The method of claim 1 , wherein the implantable delivery device has a plurality of chambers defined within the reservoir, a first and a second chamber within the plurality of chambers being in fluid communication with one another.

29. 10. The method of claim 1, wherein the implantable delivery device has a plurality of chambers defined within the reservoir, a first and a second chamber within the plurality of chambers being fluidly isolated from one another.

30. The method of claim 1 , wherein the implantable delivery device has multiple chambers defined within the reservoir, the implantable delivery device having one or more fill ports for refilling the reservoir.

31. 31. The method of claim 30, wherein the number of fill ports corresponds to the number of chambers.

32. The method of claim 1 , wherein implanting the implantable delivery device at an implantation location comprises positioning the implantable delivery device at the implantation location such that the device is subconjunctival.

33. The method of claim 1 , wherein implanting the implantable delivery device at an implantation location comprises positioning the implantable delivery device at the implantation location such that the device is suprachoroidal.

34. The method of claim 1 , wherein the implantation location is an anterior-intravitreal reservoir location.

35. 35. The method of claim 34, wherein the one or more ocular diseases comprise at least one of macular degeneration, geographic atrophy lesions, macular edema, uveitis, retinitis, central retinal vein occlusion, or branch retinal vein occlusion.

36. 36. The method of claim 35, wherein when the one or more diseases is macular degeneration, the agent has an API class that includes a monoclonal antibody.

37. 36. The method of claim 35, wherein when the one or more diseases is macular edema, the agent has an API class that includes a monoclonal antibody or a steroid.

38. 36. The method of claim 35, wherein when the one or more diseases is uveitis, the agent has an API class that includes a corticosteroid.

39. 36. The method of claim 35, wherein when the one or more diseases is retinitis, the agent has an API class that includes an antibiotic or an antiviral agent.

40. 36. The method of claim 35, wherein when the one or more diseases is central retinal vein occlusion or branch retinal vein occlusion, the agent has an API class that includes a monoclonal antibody or a steroid.

41. The method of claim 23, wherein the implantation location is an anterior-anterior chamber reservoir location.

42. 42. The method of claim 41, wherein the one or more ocular diseases comprises at least one of macular degeneration, macular edema, uveitis, retinitis, central retinal vein occlusion, or branch retinal vein occlusion.

43. 43. The method of claim 42, wherein when the one or more diseases is glaucoma, the agent has an API class including at least one of a prostaglandin, a beta blocker, an alpha agonist, or a carbonic anhydrase inhibitor.

44. 43. The method of claim 42, wherein when the one or more diseases is keratitis, the agent has an API class including at least one of an antibiotic, a steroid, or an antifungal agent.

45. 43. The method of claim 42, wherein when the one or more diseases is dry eye, the agent has an API class corresponding to at least one of a prostaglandin, a beta blocker, an alpha agonist, or a carbonic anhydrase inhibitor.

46. 43. The method of claim 42, wherein when the one or more diseases is presbyopia, the agent has an API class that includes miotics.

47. 10. The method of claim 1, wherein the gene therapy is deployed for the treatment of age-related macular degeneration, retinitis pigmentosa, geographic atrophy, diabetic macular edema, and diabetic retinopathy, and for preventing glaucomatous neurodegeneration.

48. 10. The method of claim 1, wherein gene therapy is achieved by sustained administration of either a viral transduction vector, an adeno-associated viral (AAV) vector, a polymer-based nanoparticle, a liposome, or a compressed nucleic acid nanoparticle.

49. 1. A pharmaceutical composition comprising: a pharmaceutical composition comprising at least one therapeutic agent and at least one additional material, the pharmaceutical composition having the ability to assume a first state and a second state and to transition between the first state and the second state upon exposure to a fluid; A pharmaceutical composition, wherein in said first state of said pharmaceutical composition, said composition does not allow migration of said at least one therapeutic agent through said additional material, and in said second state of said pharmaceutical composition, said pharmaceutical composition allows migration of said at least one therapeutic agent through said additional material.

50. 50. The pharmaceutical composition of claim 49, wherein the at least one additional material comprises a polymer and optionally a bioabsorbable microparticle.

51. 50. The pharmaceutical composition of claim 49, wherein in said second state, said at least one therapeutic agent is released from said at least one additional material at a predetermined rate.

52. 50. The pharmaceutical composition of claim 49, wherein the bioabsorbable microparticles have an average size of 15 micrometers to 25 micrometers.

53. 50. The pharmaceutical composition of claim 49, wherein in the second state, the composition is capable of absorbing fluid and releasing the therapeutic agent.

54. 50. The pharmaceutical composition of claim 49, wherein the therapeutic agent comprises at least one of a prostaglandin analog, a beta blocker, an alpha 2 agonist, and a carbonic anhydrase inhibitor.

55. 55. The pharmaceutical composition of claim 54, wherein the therapeutic agent comprises at least one of latanoprost, timolol, brimonidine, or dorzolamide.

56. 50. The pharmaceutical composition of claim 49, wherein the first condition comprises an untreated condition and the second condition comprises a treated condition.

57. 1. A pharmaceutical composition comprising: a pharmaceutical composition comprising at least one therapeutic agent and at least one additional material, the pharmaceutical composition having the ability to assume a first state and a second state and to transition between the first state and the second state upon exposure to a fluid; The pharmaceutical composition, wherein in said first condition, said pharmaceutical composition comprises an untreated condition.

58. 58. The pharmaceutical composition of claim 57, wherein the second condition comprises a therapeutic condition.

59. 58. The pharmaceutical composition of claim 57, wherein the therapeutic agent comprises at least one of a prostaglandin analog, a beta blocker, an alpha 2 agonist, and a carbonic anhydrase inhibitor.

60. 58. The pharmaceutical composition of claim 57, wherein the additional material comprises a polymer and optionally a bioabsorbable material.

61. A pharmaceutical composition disposed within a reservoir defined by at least one additional material, comprising: at least one therapeutic agent, wherein the pharmaceutical composition has the ability to assume a first state and a second state and to transition between the first and second states upon exposure to a fluid; A pharmaceutical composition, wherein in said first state of said pharmaceutical composition, said at least one additional material inhibits migration of said at least one therapeutic agent through said additional material, and in said second state of said pharmaceutical composition, said at least one additional material permits migration of said at least one therapeutic agent through said additional material.

62. 62. The pharmaceutical composition of claim 61, wherein the transition between the first state and the second state is initiated by the at least one additional material that allows passage of the fluid from the external environment to the pharmaceutical composition in the first state.

63. 62. The pharmaceutical composition of claim 61, wherein the at least one additional material comprises a polymer and optionally a bioabsorbable microparticle.

64. 62. The pharmaceutical composition of claim 61, wherein in the second state, the at least one therapeutic agent is released from the at least one additional material at a predetermined rate.

65. 62. The pharmaceutical composition of claim 61, wherein the bioabsorbable microparticles have an average size of 15 micrometers to 25 micrometers.

66. 62. The pharmaceutical composition of claim 61, wherein in the second state, the composition is capable of absorbing fluid and releasing the therapeutic agent.

67. 62. The pharmaceutical composition of claim 61, wherein the therapeutic agent comprises at least one of a prostaglandin analog, a beta blocker, an alpha 2 agonist, and a carbonic anhydrase inhibitor.

68. 68. The pharmaceutical composition of claim 67, wherein the therapeutic agent comprises at least one of latanoprost, timolol, brimonidine, or dorzolamide.

69. 62. The pharmaceutical composition of claim 61, wherein the first condition comprises an untreated condition and the second condition comprises a treated condition.

70. A pharmaceutical composition disposed within a reservoir defined by at least one additional material, comprising: at least one therapeutic agent, wherein the pharmaceutical composition has the ability to assume a first state and a second state and to transition between the first and second states upon exposure to a fluid; A pharmaceutical composition, wherein in said first state of said pharmaceutical composition, said at least one material inhibits migration of said at least one therapeutic agent in said first state, such that said pharmaceutical composition comprises a non-therapeutic state.

71. 71. The pharmaceutical composition of claim 70, wherein in the second state, the pharmaceutical composition comprises a therapeutic state by virtue of the at least one material permitting movement of the at least one therapeutic agent in the second state.

72. 71. The pharmaceutical composition of claim 70, wherein the transition between the first state and the second state is initiated by the at least one additional material that allows passage of the fluid from the external environment to the pharmaceutical composition in the first state.

73. 71. The pharmaceutical composition of claim 70, wherein in the second state, the at least one therapeutic agent is released from the at least one additional material at a predetermined rate.

74. 71. The pharmaceutical composition of claim 70, wherein the bioabsorbable microparticles have an average size of 15 micrometers to 25 micrometers.

75. 71. The pharmaceutical composition of claim 70, wherein in the second state, the composition is capable of absorbing fluid and releasing the therapeutic agent.

76. 71. The pharmaceutical composition of claim 70, wherein the therapeutic agent comprises at least one of a prostaglandin analog, a beta blocker, an alpha 2 agonist, and a carbonic anhydrase inhibitor.

77. 77. The pharmaceutical composition of claim 76, wherein the therapeutic agent comprises at least one of latanoprost, timolol, brimonidine, or dorzolamide.

78. 71. The pharmaceutical composition of claim 70, wherein the first condition comprises an untreated condition and the second condition comprises a treated condition.

79. 1. An implantable medical device preloaded with a therapeutic agent, comprising: a first microporous material bonded to a second microporous layer defining a reservoir disposed therebetween; the reservoir is configured to contain the therapeutic agent and the implantable medical device is configured to release the therapeutic agent at a predetermined rate; An implantable medical device, wherein the therapeutic agent is at least one of latanoprost, timolol, brimonidine, or dorzolamide.

80. 1. An implantable medical device for delivering a therapeutic agent for the treatment of a disease, comprising: a first microporous material bonded to a second microporous layer defining a reservoir disposed therebetween; the reservoir is configured to contain a pharmaceutical composition and deliver the therapeutic agent to a target site to treat the disease; The implantable medical device, wherein the treatment is configured to treat one or more of glaucoma, macular degeneration, macular edema, retinitis, retinoblastoma, retinal vein occlusion, keratitis, and dry eye.

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