Apparatus for delivering therapeutic agents

Technical Field

0001In various embodiments, the invention relates to apparatus for delivering therapeutic agents to a patient's eye.

Background

0002Medical treatment often requires the administration of a therapeutic agent (e.g., medicament, drugs, etc.) to a particular part of a patient's body. Intravenous injection has long been a mainstay in medical practice to deliver drugs systemically. Some maladies, however, require administration of drugs to anatomical regions to which access is more difficult to achieve.

0003A patient's eye is a prime example of a difficult-to-reach anatomical region. Ocular pathologies, such as diabetic retinopathy and macular degeneration, are typically treated by administration of drugs to the vitreous humor, which has no fluid communication with the vasculature. Such administration not only delivers the drug directly to where it is needed, but also minimizes the exposure of the rest of the patient's body to the drug and, therefore, to its potential side effects.

0004Injection of drug into the patient's body (e.g., into the vitreous humor of the eye), while medically feasible, typically delivers a bolus of the drug. Bolus injections may, however, present several problems. First, their use in treating chronic eye conditions typically necessitates repeated injections into the eye, a painful procedure that generally requires repeated and expensive visits to a physician's office, and can cause trauma to the eye. Second, because a bolus injection intrinsically produces a sawtooth-profile dependence of drug concentration over time, the dosage of the injection tends to be near the threshold limit of toxicity. Injection of such dosages typically increases the likelihood of systemic side effects, as occurs, for example, with ranibizumab.

0005Document <patcit id="pcit0001" dnum="WO2007084765A"><text>WO2007084765</text></patcit> describes a device in which a first therapeutic agent is contained in a syringe, and a sustained release formulation comprising a second therapeutic agent is contained in a needle attached to the syringe.

0006A need therefore exists for apparatus of administering appropriately chosen therapeutic drugs to the eye so that the time variation of the concentrations of those drugs in the eye is minimized.

Summary of the Invention

0007According to the present invention, there is provided an implantable drug-delivery device for implantation on a patient's eye, as set forth in claim 1.

0008In various embodiments, the present invention features apparatus for delivering therapeutic agents to a patient's eye.

0009Accordingly, invention features the drug-delivery device of claim 1 that includes a first reservoir for containing a first liquid having a first therapeutic agent, a second reservoir for containing a second liquid having a second therapeutic agent different from the first therapeutic agent, and at least one cannula in fluid communication with the first and second reservoirs (e.g., a first cannula in fluid communication with the first reservoir and a second, separate cannula in fluid communication with the second reservoir). The at least one cannula may have an outlet for separately delivering the first and second liquids to the patient. In various embodiments, the first reservoir in fact includes the first liquid and the second reservoir includes the second liquid.

0010In various embodiments, each of the first and second therapeutic agents treats glaucoma and/or ocular hypertension. In such a case, the first and second therapeutic agents may each be selected from the group consisting of acetazolamide, betaxolol, bimatoprost, brimonidine, brinzolamide, carbidopa, carteolol, dorzolamide, epinephrine, latanoprost, levodopa, levobunolol, levobetaxolol, loratadine, metipranolol, pilocarpine, pseudoephedrine, timolol, travoprost, and unoprostone isopropyl. In another embodiment, the first and second therapeutic agents treat age-related macular degeneration, macular edema associated with diabetic retinopathy, and/or macular edema associated with retinovascular occlusive diseases. In this case, the first and second therapeutic agents may be selected from the group consisting of ranibizumab, pegaptanib, verteporfin, bevacizumab, a steroid, a drug that prevents beta amyloid deposition in the retina, an anti-human complement activation blocker that blocks complement H activation in the eye, and small interfering RNA (siRNA) molecules. In yet another embodiment, each of the first and second therapeutic agents treat cytomegalovirus retinitis and may be selected from the group consisting of valganciclovir, vitravene, and cidofovir. In still another embodiment, each of the first and second therapeutic agents treat itching and allergic conjunctivitis and may be selected from the group consisting of loteprednol etabonate, naphazoline, pheniramine maleate, pemirolast, and ketotifen fumarate.

0011In an alternative embodiment, the first and second therapeutic agents are chosen so as to treat two different maladies selected from the group consisting of glaucoma, ocular hypertension, age-related macular degeneration, macular edema associated with diabetic retinopathy, macular edema associated with retinovascular occlusive diseases, low tear production, cytomegalovirus retinitis, bacterial conjunctivitis, itching and allergic conjunctivitis, post-operative eye inflammation, inflammation of the cornea due to herpes simplex virus, postoperative inflammation after cataract extraction, corneal ulcers, and Sjögren's syndrome.

0012In general, embodiments of the invention feature a drug-delivery device that includes a first reservoir for containing a first liquid having a first therapeutic agent, a second reservoir for containing a second liquid having a second therapeutic agent different from the first therapeutic agent, memory for storing a drug-delivery regimen, and a microprocessor for controlling a delivery of the first and second liquids to a patient through at least one cannula based on an execution of the stored drug-delivery regimen.

0013In various embodiments, the drug-delivery device also includes a sensor for receiving feedback from the patient and/or a receiver for receiving wireless instructions (e.g., from a physician) that reprogram the drug-delivery regimen. The microprocessor may also modify the drug-delivery regimen based on the feedback. The feedback may be, for example, a measured eye pressure for the patient, a position of the patient, an activity being undertaken by the patient, and/or a measured residual amount of the first or second therapeutic agent present in a patient's tissue. In addition, execution of the drug-delivery regimen may be impacted by a variable such as the time of day, a patient-specific factor, and/or identities of the first and second therapeutic agents.

0014These and other objects, along with advantages and features of the embodiments of the present invention herein disclosed, will become more apparent through reference to the following description, the accompanying drawings, and the claims. Furthermore, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations.

Brief Description of the Drawings

0015In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which: <ul id="ul0001" list-style="none" compact="compact"><li><figref idref="f0001">FIG. 1A</figref> is an exploded view of a drug-delivery device;</li><li><figref idref="f0002">FIG. 1B</figref> is an assembled view of the exemplary drug-delivery device depicted in <figref idref="f0001">FIG. 1A</figref>;</li><li><figref idref="f0003">FIG. 2</figref> illustrates a drug-delivery device implanted in a patient's eye in accordance with one embodiment of the invention;</li><li><figref idref="f0004">FIG. 3</figref> is a cross-sectional view of a portion of the exemplary drug-delivery device depicted in <figref idref="f0002">FIG. 1B</figref>;</li><li><figref idref="f0005">FIGS. 4A and 4B</figref> are cross-sectional views illustrating the operation of a valve for a drug-delivery device in accordance with one embodiment of the invention;</li><li><figref idref="f0006">FIG. 5A</figref> is a top view of another drug-delivery device;</li><li><figref idref="f0007">FIG. 5B</figref> is a top view of yet another drug-delivery device in accordance with one embodiment of the invention;</li><li><figref idref="f0008">FIG. 6</figref> illustrates a drug-delivery device that utilizes electrolytic pumping in accordance with one embodiment of the invention;</li><li><figref idref="f0009">FIGS. 7A and 7B</figref> illustrate a top-cross-sectional view and a side-cross-sectional view, respectively, of an electrolysis micropump</li><li><figref idref="f0010">FIGS. 8A and 8B</figref> illustrate top and cut-away side views, respectively, of an electrolysis micropump,</li><li><figref idref="f0011">FIGS. 9A-9D</figref> illustrate successive cut-away views of a drug reservoir and pump chamber;</li><li><figref idref="f0012">FIG. 10</figref> illustrates a drug-delivery system with drug reservoir, cannula, valving, pump, refillable port, and suture tabs;</li><li><figref idref="f0013">FIG. 11</figref> illustrates the internal structure of one type of injection port on the reservoir</li><li><figref idref="f0014">FIGS. 12A-12K</figref> illustrate a process flow for fabricating a silicon mask and making a molded polydimethylsiloxane (PDMS) layer;</li><li><figref idref="f0015">FIGS. 13A-13M</figref> illustrate a process flow for fabricating the base layer of an implantable drug-delivery device that includes electrodes for electrolytic pumping and an integral cannula,</li><li><figref idref="f0016">FIG. 14</figref> illustrates (a) flow-rate testing results for an exemplary electrolysis pump; (b) ultra-low flow rate testing results for the exemplary electrolysis pump; (c) the pump efficiency as calculated from the flow delivery data; and (d) the typical gas recombination observed in the pump;</li><li><figref idref="f0017">FIG. 15</figref> illustrates bolus delivery of 250 nL doses using current pulses in an exemplary electrolysis pump; and</li><li><figref idref="f0018">FIG. 16</figref> illustrates the flow performance of an exemplary electrolysis pump under typical physiological back pressures.</li></ul>

Description

0016In general, embodiments of the present invention pertain to apparatus for delivering therapeutic agents to a patient's eye. In certain embodiments, the implantable drug-delivery device for the eye combines small size and a refillable reservoir. The small size minimizes discomfort from the device to the patient's eye, while the refillable reservoir allows the device to be refilled in situ, rather than being replaced. As such, a fluid, such as a solution of a drug, can be supplied to the patient's eye over extended periods of time.

0017The drug-delivery device may include a refillable reservoir, a cannula, and a valve. The refillable reservoir holds the fluid to be delivered, the cannula directs the fluid to the targeted site, and the valve controls the delivery of the fluid and prevents backflow. The refillable reservoir may have a self-resealing upper layer that can be pierced with a needle for refilling, and a lower layer that resists needle punctures and thereby protects the eye from accidental injury during the refilling process. For its part, the cannula may be tapered to facilitate its insertion into the patient's eye.

0018<figref idref="f0001">FIGS. 1A</figref> and <figref idref="f0002">1B</figref> schematically illustrate an exploded view and an assembled view, respectively, of a drug-delivery device 5. The device 5 includes a reservoir 100 that is configured to contain a liquid comprising a therapeutic agent (e.g., a drug), and a cannula 110 that is in fluid communication with the reservoir 100. At or near its distal end 117, the cannula 110, which is configured for insertion into a patient (e.g., into a patient's eye), includes an outlet 115 for delivering the drug to the patient. In addition, as described further below, the drug-delivery device 5 may also include a valve 120 positioned at or near the distal end 117 of the cannula 110. Alternatively, the valve 120 may be positioned elsewhere along the length of the cannula 110, such as at its end proximal the reservoir 100.

0019The reservoir 100 may be a refillable multi-layered structure having a first wall 10 that is puncturable by a needle and a second, opposite wall 50 that is generally unpuncturable by the needle. As explained further below, the needle is used in refilling the reservoir 100 with a liquid comprising a therapeutic agent, such as a drug. The first wall 10 may include a pliable, drug-impermeable polymer (e.g., silicone) layer that does not leak after being pierced by a needle, while the second wall 50 may include a layer having a less pliable and more mechanically robust material (e.g., a stiffer material, such as a polymer or a composite). Alternatively, the second wall 50 may include a greater thickness of the same material used to fabricate the first wall 10. When the drug-delivery device 5 is implanted on a patient's eye, the second wall 50 is placed adjacent to the sclera of the eye, and the greater mechanical strength of the second wall 50 limits the stroke of the needle used to puncture the first wall 10 to refill the reservoir 100. In this fashion, the eye is protected from accidental punctures. The reservoir 100 may be formed by bonding the first wall 10 and the second wall 50 either to each other or to one or more intervening layers 20, as described more fully below.

0020The reservoir 100 may include integral mechanical support structures 60 that reduce the possible contact area between the first wall 10 and the second wall 50 and that prevent the reservoir 100 from collapsing completely. The mechanical support structures 60 may be, or include, one or more protrusions (e.g., posts) extending from at least one of the first wall 10 and the second wall 50. Other mechanical support structures are also compatible with various embodiments described herein.

0021The cannula 110 may include an elongate first portion 70 and a wall 30 that together define a lumen 72 through the cannula 110. The cannula 110 may also include one or more integral mechanical support structures 74 in the lumen 72 to prevent the cannula 110 from collapsing and occluding the lumen 72. For example, the mechanical support structures 74 may be, or include, one or more protrusions (e.g., posts) extending from an inner surface of the first portion 70 of the cannula 110 towards the wall 30 of the cannula 110. In certain embodiments, the mechanical support structures 74 have a height that extends from the inner surface of the first portion 70 to the wall 30 and a width that extends less than the full width of the lumen 72. Other mechanical support structures are also compatible with various embodiments described herein.

0022The end 117 of the cannula 110 may be configured to be inserted into a patient's eye. For example, the end 117 of the cannula 110 may be tapered to facilitate insertion into the eye. The end 117 may have rounded corners that facilitate insertion into the eye. The outer diameter of the cannula 110 may be less than or equal to the outer diameter of a 25-gauge needle. The outer diameter of the cannula 110 may be less than 1 millimeter (e.g., 0.5 millimeters). When the drug-delivery device 5 is implantable on the eye, the outer diameter of the cannula 110 is sufficiently small to obviate the need for sutures at the insertion site to help maintain the integrity of the eye.

0023The cannula 110 may also include one or more flow-regulator structures (e.g., valves) to maintain a constant flow rate. In this way, the administered dosage of a drug depends on the duration that fluid containing the drug flows through the cannula 110, rather than on the magnitude of an applied pressure that drives fluid flow through the cannula 110. More accurate control of the administered dosage may thereby be obtained, and the dosage remains independent of external mechanical influence (e.g., if the patient rubs his or her eye). Instead of, or in addition to, the one or more flow-regulator structures of the cannula 110, the reservoir 100 may include one or more such flow-regulator structures.

0024In addition, the cannula 110 may include one or more fluid-flow isolation structures (e.g., valves) that isolate the reservoir 100 from a patient's eye during various operations that involve the reservoir 100 (e.g., purging, cleaning, and/or refilling), thereby preventing the exchange of fluid (in either direction) between the reservoir 100 and the patient's eye. Instead of, or in addition to, the one or more fluid-flow isolation structures of the cannula 110, the reservoir 100 may include one or more such fluid-flow isolation structures.

0025<figref idref="f0003">FIG. 2</figref> schematically illustrates the exemplary drug-delivery device 5 implanted in the eye of a patient in accordance with one embodiment of the invention. As illustrated, the device 5 is placed upon the conjunctiva of the eye, and cannula 110 is inserted therethrough in to the posterior chamber of the eye. As described more fully below, in certain embodiments, the reservoir 100 includes a needle-pierceable portion in the first wall 10 that serves as a fill port for the reservoir 100. The drug-delivery device 5 administers fluid to the posterior chamber of the eye through the cannula 110 and the valve 120. In other embodiments, the device 5 is used to administer fluid to the anterior chamber of the eye, which is separated from the posterior chamber by the lens.

0026As mentioned, in one embodiment, the drug-delivery device 5 is refillable. With reference again to <figref idref="f0001">FIG. 1A</figref>, the first wall 10 of the reservoir 100 may be puncturable by a needle (not shown), thereby allowing the reservoir 100 to be refilled through the needle. In one embodiment, at least a portion of the first wall 10 is self-sealing. For example, a self-sealing portion may include a soft plastic material that can be punctured with the needle and that reseals itself upon removal of the needle. In one embodiment, the self-sealing material advantageously provides a reservoir refill site that can withstand multiple punctures, and is biocompatible. Examples of materials that may be employed for the self-sealing material include, but are not limited to, PDMS, parylene C, parylene HT, polycarbonates, polyolefins, polyurethanes, copolymers of acrylonitrile, copolymers of polyvinyl chloride, polyamides, polysulphones, polystyrenes, polyvinyl fluorides, polyvinyl alcohols, polyvinyl esters, polyvinyl butyrate, polyvinyl acetate, polyvinylidene chlorides, polyvinylidene fluorides, polyimides, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polyethers, polytetrafluoroethylene, polychloroethers, polymethylmethacrylate, polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, gelatin, silicone rubbers and porous rubbers. Where the self-sealing material includes a plastic that is capable of leaching or absorbing drugs that come into contact with it (e.g., silicone), parylene may be coated over the plastic so that less drug is exposed to the plastic.

0027To illustrate the stability of PDMS as a material for the first wall 10, three different needle styles were inserted into a slab of PDMS: (i) a 20-gauge standard sharp-tipped needle, (ii) a 30-gauge non-coring needle, and (iii) a 30-gauge coring needle. The puncture sites were then observed using scanning electron microscopy and optical microscopy. The 20-gauge standard sharp-tipped needle and the 30-gauge non-coring needle allowed the PDMS to self-seal the puncture hole after the needle was removed. However, the 30-gauge coring needle left a channel in the PDMS after it was removed. The puncture mechanism in small-diameter needles of either standard or non-coring styles appears to tear and displace the PDMS material rather than removing material, thereby allowing the PDMS to reseal the puncture hole. In addition, the structural integrity of the PDMS was observed after multiple punctures with a 25-gauge needle. Table 1 shows the relationship between the thickness of the wall 70 and leakage for tests performed under atmospheric conditions with leakage determined through visual inspection. <tables id="tabl0001" num="0001"><table frame="all"><title>Table I</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="45mm" /><colspec colnum="2" colname="col2" colwidth="52mm" /><thead><row><entry valign="top">Wall Thickness (millimeters)</entry><entry align="center" valign="top">Number of Punctures Until Failure</entry></row></thead><tbody><row><entry>0.3557</entry><entry align="center">1</entry></row><row><entry>0.5080</entry><entry align="center">7</entry></row><row><entry>0.4826</entry><entry align="center">10</entry></row><row><entry>0.4578</entry><entry align="center">22</entry></row><row><entry>0.5334</entry><entry align="center">21</entry></row></tbody></tgroup></table></tables>

0028The refillable reservoir 100 may be used with a variety of drug-containing fluids, depending upon the type of malady being treated. Typically, the pharmaceuticals chosen for eye treatment will penetrate the protective physiological barriers of the eye such as the cornea, sclera, and the blood-retina barrier. In addition, the pharmaceuticals will target difficult-to-reach intraocular tissues such as the ciliary body, retina, and angle. As examples, fluids containing the following therapeutic agents, either alone or in proper combination, may be used with the drug-delivery devices described herein for the treatment of the following maladies: <ol id="ol0001" compact="compact" ol-style=""><li>i) acetazolamide, betaxolol, bimatoprost, brimonidine, brinzolamide, carbidopa, carteolol, dorzolamide, epinephrine, latanoprost, levodopa, levobunolol, levobetaxolol, loratadine, metipranolol, pilocarpine, pseudoephedrine, timolol, travoprost, and unoprostone isopropyl for the treatment of glaucoma and/or ocular hypertension;</li><li>ii) ranibizumab, pegaptanib, verteporfin, bevacizumab (e.g., Avastin®), steroids (such as fluocinolone and triamcinolone (e.g., Kenalog®)), drugs that prevent beta amyloid deposition in the retina (such as tarenflurbil (e.g., Flurizan®), anti-human complement activation blockers to block complement H activation in the eye, and siRNA molecules (the delivery of which may be appropriately titrated) for the treatment of age-related macular degeneration and/or the macular edema associated with diabetic retinopathy and retinovascular occlusive diseases;</li><li>iii) cyclosporine ophthalmic emulsion for the treatment of low tear production;</li><li>iv) valganciclovir, vitravene, and cidofovir for the treatment of cytomegalovirus retinitis;</li><li>v) levofloxacin for the treatment of bacterial conjunctivitis;</li><li>vi) loteprednol etabonate, naphazoline, pheniramine maleate, pemirolast, and ketotifen fumarate for the treatment of itching and allergic conjunctivitis;</li><li>vii) loteprednol etabonate for the treatment of post-operative eye inflammation;</li><li>viii) trifluridine for the treatment of inflammation of the cornea in children due to herpes simplex virus;</li><li>ix) ketorolac tromethamine for the treatment of postoperative inflammation after cataract extraction;</li><li>x) ofloxacin for the treatment of corneal ulcers;</li><li>xi) pilocarpine for the treatment of Sjögren's syndrome, an autoimmune disorder;</li></ol>

0029Because the refillable reservoir 100 can be used with a variety of different drug containing fluids, it may be, in some cases, desirable to remove any remaining fluid from the reservoir 100 before refilling. Remaining fluid in the reservoir 100 may be removed therefrom by, for example, inserting a needle or syringe through the self-sealing portion of the first wall 10 to suck out the fluid from the reservoir 100. Then, the reservoir 100 may be refilled with a new drug-containing fluid via another needle or syringe inserted through the self-sealing portion of the first wall 10. Purging, if desired, can be effected through repeated cycles of injection and removal of a purging fluid.

0030In one embodiment, the refillability of the reservoir 100 allows the drug-delivery device 5 to be smaller than it may otherwise be because the reservoir 100 need not be sufficiently large to hold a lifetime supply of the drug to be administered. The smaller size of the drug-delivery device 5 advantageously reduces the invasiveness of the device 5 both for implantation and daily use.

0031In addition, the refillability of the reservoir 100 may advantageously allow a physician to tailor a therapeutic regimen to a patient's changing needs or to take advantage of new advances in medicine. In one embodiment, the refillable reservoir 100 stores at least a one-month supply of the drug (e.g., a six-month supply) to reduce the number of refills required.

0032<figref idref="f0004">FIG. 3</figref> schematically illustrates a cross-sectional view of one embodiment of the valve 120 at the distal end 117 of the cannula 110. The cross-sectional view of <figref idref="f0004">FIG. 3</figref> is in the plane indicated by the dashed line of <figref idref="f0002">FIG. 1B</figref>. The valve 120 may include a valve seat 80 and an element movable between first and second positions. <figref idref="f0005">FIGS. 4A and 4B</figref> schematically illustrate cross-sectional views of the valve 120 with a movable element 122 in the first and second positions, respectively. In one embodiment, a flexible portion of the wall 30 of the cannula 110 forms the movable element 122, and the movable element 122 features an orifice 40 therethrough. The movable element 122 is movable between the first position (as schematically illustrated by <figref idref="f0005">FIG. 4A</figref>) in which the portion of the wall 30 does not contact the valve seat 80, and the second position (as schematically illustrated by <figref idref="f0005">FIG. 4B</figref>) in which the portion of the wall 30 contacts the valve seat 80 such that the orifice 40 is occluded. Liquid may flow through the orifice 40 to the outlet 115 of the cannula 110 when the movable element 122 is in the first position. However, the liquid is prevented from flowing through the orifice 40 to the outlet 115 when the movable element 122 is in the second position. As such, the valve 120 may prevent both unwanted diffusion of drug from the drug-delivery device 5 into the target organ and unwanted backflow of material from the patient's body into the cannula 110.

0033In one embodiment, the valve seat 80 is a protrusion (e.g., post) that extends from an inner surface of the cannula 110 towards the movable element 122 (e.g., the flexible portion of the wall 30), as shown schematically in <figref idref="f0005">FIGS. 4A and 4B</figref>. The protrusion may be substantially identical to the one or more integral mechanical support structures 74 in the lumen 72 of the cannula 110 described above.

0034In certain embodiments, the movable element 122 moves from the second position (<figref idref="f0005">FIG. 4B</figref>) to the first position (<figref idref="f0005">FIG. 4A</figref>) in response to pressure applied to the portion of the wall 30 by fluid within the cannula 110. For example, mechanical (e.g., manual) pressure applied to one or more walls 10, 50 of the reservoir 100 can force fluid through the cannula 110 such that the fluid pressure opens the valve 120. In certain embodiments, the valve 120 opens only when the fluid pressure inside the cannula 110 exceeds a predetermined threshold value greater than the fluid pressure outside the cannula 110. The valve 120 remains closed when the fluid pressure inside the cannula 110 is equal to or less than the fluid pressure outside the cannula 110, thereby preventing biological fluids from flowing backwards into the drug-delivery device 5.

0035<figref idref="f0006">FIG. 5A</figref> schematically illustrates a top view of another embodiment of a drug-delivery device 90. As illustrated, rather than featuring a single reservoir 100 having a single cannula 110 in fluid communication therewith, the drug-delivery device 90 includes two reservoirs 100A, 100B. Each reservoir 100A, 100B has a single, different cannula 110A, 110B in fluid communication therewith. In one embodiment, each reservoir 100A, 100B contains a different therapeutic agent in liquid form. This allows for the separate administration of two different drugs, for example in a staged or alternating fashion.

0036Each reservoir / cannula pair of the drug-delivery device 90 is contained in a separate pump that features one or all of the elements described above with reference to the drug-delivery device 5 depicted in <figref idref="f0001 f0002 f0003 f0004 f0005">FIGS. 1A through 4B</figref>, and that operates in an analogous fashion. For example each reservoir / cannula pair of the drug-delivery device 90 may in fact be implemented as a separate electrolytic pump, as described below with reference to the drug-delivery device 200 depicted in <figref idref="f0008 f0009 f0010 f0011 f0012">FIGS. 6 through 10</figref>, and be individually controlled in order to deliver to the patient an optimal therapeutic dosage of each of the different drugs.

0037While the drug-delivery device 90 is illustrated as having only two reservoir /cannula pairs, it may in fact be manufactured to have three, four, or any number of reservoir /cannula pairs. In addition, rather than having a single, separate cannula in fluid communication with each reservoir (as illustrated in <figref idref="f0006">FIG. 5A</figref>), a single cannula 110 may in fact be in fluid communication with two, three, four, or more reservoirs, as illustrated in <figref idref="f0007">FIG. 5B</figref>. In such a case, additional valves 112 may optionally be employed, as illustrated, in the different portions of the cannula 110 that branch off to each reservoir in order to prevent fluidic communication between the reservoirs.

0038In one embodiment, where the drug-delivery device 90 includes two reservoirs 100A, 100B, the volume of each reservoir ranges from, for example, 63µL to 105µL. For example, each reservoir 100A, 100B may have a width w of approximately 3mm, a depth d of approximately 7mm, and a height ranging from 3mm to 5mm. In such an embodiment, the overall dimensions of the drug-delivery device 90 may be within an 8mm x 8mm footprint with a height of 3mm to 5mm. Processes for manufacturing the drug-delivery device 90 may be as described below with reference to <figref idref="f0014">FIGS. 12A-12K</figref> and <figref idref="f0015">13A-13M</figref> for the single reservoir drug-delivery devices 5 and 200, respectively.

0039By utilizing two or more reservoirs, different combinations and/or sequences of different drugs may be appropriately employed to treat different maladies. For example, a drug-delivery device 90 featuring two, three, four, or more reservoirs may be employed to deliver appropriate amounts of ranibizumab, pegaptanib, verteporfin, bevacizumab, and/or a steroid, such as fluocinolone or triamcinolone, to treat age-related macular degeneration and/or the macular edema associated with diabetic retinopathy and retinovascular occlusive diseases. In addition, one or more reservoirs in such a device 90 may be employed to deliver, in combination with one or more of those drugs, drugs that prevent beta amyloid deposition in the retina (such as tarenflurbil), anti-human complement blockers to block complement H activation in the eye, and siRNA molecules. In another embodiment, two different isoforms of an anti vascular endothelial growth factor (anti-VEGF) are employed to treat the age-related macular degeneration. In many cases, age-related macular degeneration is caused by polymorphisms on chromosomes 1 and 10. Accordingly, embodiments of the invention may be employed to customize the dosage of different amounts of anti-VEGF variants in order to customize treatment for a patient based on his or her genetic make-up.

0040As another example, a drug-delivery device 90 featuring three reservoirs may be employed to deliver appropriate amounts of valganciclovir, vitravene, and cidofovir to treat cytomegalovirus retinitis, or a drug-delivery device 90 featuring two reservoirs may be employed to deliver appropriate amounts of two of those drugs to treat the cytomegalovirus retinitis. Similarly, a drug-delivery device 90 featuring two, three, or more reservoirs may be employed to deliver appropriate amounts of any of the drugs identified above for the treatment of glaucoma and/or ocular hypertension, or, alternatively, to deliver appropriate amounts of any of the drugs identified above for the treatment of itching and allergic conjunctivitis, in any combination deemed suitable by a physician. In addition still, two or more different maladies (for example of any of the types described above) may be treated in parallel by a drug-delivery device 90 featuring two, three, or more reservoirs containing different drugs targeted towards treating those different maladies.

0041In order to control (e.g., stagger or alternate) the delivery of drugs from the multiple reservoirs 100, the drug-delivery device 90 further includes microelectronics, such as a microcontroller or microprocessor 130, memory 132, a sensor 134, and a transceiver 136. More specifically, the memory 132 may store a drug-delivery regimen and the microprocessor 130 may control the delivery of the drugs from the reservoirs 100 to the patient through the one or more cannulas 110 by executing the stored drug-delivery regimen. During execution of the stored drug-delivery regimen, the microprocessor 130 may issue instructions to actuate mechanically, or through electrolysis (as described below), a reservoir /cannula pair (i.e., pump) to release drug therefrom. The stored drug-delivery regimen may be programmed to control, for example, the amount, frequency, and type of drug released based upon any applicable factor or variable. For example, the amount, frequency, and type of drug released may depend upon the time of day (e.g., larger amounts of a particular type of drug may be released more frequently at night when the patient is sleeping), or upon patient-specific factors, such as the severity of the patient's malady, the patient's tolerance for particular types of drugs, the patient's body weight, the patient's genetic make-up (which may be ascertained from, for example, a genetic screening of the patient), etc. In one embodiment, the stored drug-delivery regimen also includes programmable variables identifying the types of drugs contained in the reservoirs 110.

0042In one embodiment, the sensor 134 gathers feedback from the patient. The microprocessor 130 may then employ the feedback to modify the drug-delivery regimen stored in the memory 132. For example, the sensor 134 may measure the patient's eye pressure and the microprocessor 130 may thereafter increase or decrease the amount and/or frequency at which one or more of the multiple drugs being used in combination is released. As another example, the sensor 134 may determine the residual amount of a first drug that is left in the patient's tissue and then, when residues of the first drug have disappeared, the microprocessor 130 may issue instructions to cause a second drug may be delivered to the patient. In one embodiment, the sensor 134 determines the residual presence of the first drug in the patient's tissue by monitoring the physiological effects of that first drug on the patient. For example, the sensor 134 may measure the patient's reaction to the first drug by sampling and analyzing the patient's blood.

0043In yet another embodiment, the sensor 134 determines the patient's position (e.g., if the patient's is lying horizontal or standing upright), for example through the use of a device such as a gyroscope. Moreover, the sensor 134 may be employed to monitor the patient's heart rate to determine the patient's activity (e.g., whether the patient is exercising or resting). The microprocessor 130 may then employ such sensed information to deliver a drug, or combinations of drugs, to the patient at an optimal time. For example, upon determining that the patient is lying horizontal and is resting, and that the time of day is 3:00am, the microprocessor 130 may cause delivery of a drug to the patient that is best administered when one is sleeping. As another example, when the patient's sensed heart rate indicates that he or she is exercising, a drug requiring adequate mixing may delivered to the patient.

0044The functions described above may be implemented entirely within the drug-delivery device 90 or, alternatively, the microelectronics may also include a transceiver 136 so that, in addition to certain functions being implemented locally, functions may also be implemented remotely. In one embodiment, the transceiver 136 enables wireless communication between the local and remote portions. Moreover, the transceiver 136 may be employed to permit a physician to wirelessly reprogram the drug-delivery regimen.

0045In general, the microprocessor 130 may be any logic circuitry that responds to and processes instructions fetched from the memory 132. For example, the microprocessor 130 may be one of the many general-purpose microprocessor units manufactured by Intel Corporation of Mountain View, California. For its part, the memory 132 may be provided by one or more memory chips capable of storing data and allowing any storage location to be directly accessed by the microprocessor 130. The drug-delivery regimen stored in the memory 132 may programmed using any suitable programming language or languages (e.g., C++, C#, java, Visual Basic, LISP, BASIC, PERL, etc.). The transceiver 136 may be any hardware device, or software module with a hardware interface, that is capable of receiving and transmitting communications, including requests, responses, and commands, such as, for example, inter-processor communications and wireless communications.

0046The ability to customize therapy by prescribing two or more varying dosages in real-time (e.g., a doctor may wirelessly adjust dosages if needed) also minimizes uncomfortable and dangerous side effects for the patient. One powerful combination for the eye is the ability, using the delivery-device 90, to deliver combination therapy at different times of the day. For example, companies offer timolol and prostaglandin combination therapy (given topically in the same eye drop or in separate eye drops during different times of the day), but those drugs are not typically injected directly in to the eye because of inconvenience and discomfort to the patient. Timolol has a peak action in the eye approximately one hour after the drops are administered, while prostaglandins in the eye has a peak effect approximately four hours after topical administration. Therefore, in accordance with embodiments described herein, the drug-delivery device 90 may stagger drug delivery to match the approved dosing peak effects of combination therapies for diseases such as open-angle glaucoma.

0047In the prior art, for example, a patient may self administer at 7pm an FDA approved single eye drop that contains timolol and prostagladins for a peak action of each drug at approximately 8pm and 11pm, respectively. In contrast, the drug-delivery device 90 may be programmed to pump each respective drug at different staggered times to reach the same clinically desired effect when applied topically. Because drugs typically have different times of transport across the cornea when administered topically, but are not presented with that challenge when injected directly into the eye using the drug-delivery device 90, the drug-delivery device 90 may be employed to match optimal clinical effects with staggered intracameral injections.

0048Exemplary fixed combinations of drugs that may be administered to the patient using the drug-delivery device 90 include timolol 0.5%/dorzolamide 2.0%, timolol 0.5%/brimonidine 0.2%, and fixed combinations of prostaglandins plus timolol 0.5%, such as: timolol 0.5%/latanoprost 0.005%, timolol 0.5%/travoprost 0.005%, and timolol 0.5%/bimatoprost 0.03%.

0049Fixed combinations of drugs injected intracamerally with the drug-delivery device 90 help to avoid medication washout, which may occur when a patient on multiple single drugs instills his or her various medications with too short an interval between eye drops. In fact, with multiple eye drops for multiple drugs, a significant washout effect may occur when one drug causes another drug to be ineffective by increasing outflow before a therapeutic effect has occurred. Moreover, although large clinical trials have shown the fixed combination of timolol/dorzolamide to be equivalent to the unfixed combination (at most time points), real-world studies have demonstrated improved intraocular pressure (IOP) lowering for the fixed combination versus the unfixed combination.

0050Current limitations with topical combination therapies include the inability to tailor individualized therapy as flexibly as with the component drugs that can be administered using the drug-delivery device 90. The rigidity of topical fixed combination therapy may prevent the optimal dosing frequency or timing of some components (for example, having to use a beta-blocker twice daily when once daily may be sufficient). In various embodiments, the pumps of the drug-delivery device 90 allow for different combination therapies during the day (e.g., drug A and B in morning, drug B in the afternoon, and drug A in the evening). Patients, on the other hand, are not typically able to comply with such complicated dosing schedules. As a result, their doctor may give them one bottle having combination drugs A and B, and ask the patient to take that combination two or three times per day when it may not be necessary, for example, for some dosings of one drug in the evening. In addition, the side effects of drug components may be additive, and drug interactions are often compounded with combinations of therapy. The pumps of the drug-delivery device 90 may, however, achieve the same clinical effect without comprising one drugs efficacy and desired timing.

0051<figref idref="f0008">FIG. 6</figref> illustrates yet another drug-delivery device 200. The device 200 includes a reservoir 300, which is configured to contain a liquid comprising a therapeutic agent (e.g., a drug), and a cannula 310 that is in fluid communication with the reservoir 300. The cannula 310 may be manufactured from parylene or other suitable material. At or near its distal end 317, the cannula 310 includes an outlet 315 that is configured to be in fluid communication with a patient (e.g., a patient's eye). The device 200 also includes a first electrode 320, a second electrode 330, and a material 340 that is in electrical communication with the first and second electrodes 320, 330. At least one of the electrodes 320, 330 is planar. To ensure that the material 340 is in electrical communication with both electrodes 320, 330, the electrodes may be interdigitated with one another. In one embodiment, a voltage applied between the first electrode 320 and the second electrode 330 produces gas from the material 340. The produced gas forces the liquid to flow from the reservoir 300, through the cannula 310, to the outlet 315. In other words, the first and second electrodes 320, 330 operate an electrolytic pump that drives liquid from the reservoir 300, through the cannula 310, to the outlet 315.

0052In greater detail, electrolytic pumps use electrochemically-generated gases to generate pressure that dispenses fluid (e.g., a drug-containing liquid) from one location to another. For example, application of a suitable voltage across two electrodes (typically gold, palladium, or platinum) immersed in an aqueous electrolyte produces oxygen and hydrogen gases that can be used to apply pressure to a piston, membrane, or other transducer. Electrolysis of water occurs rapidly and reversibly in the presence of a catalyst such as platinum, which in the absence of an applied voltage catalyzes recombination of the hydrogen and oxygen to reform water. As described, in certain embodiments, the drug-delivery device 200 uses electrolytically-generated gas to pump the drug from the reservoir 300 through the cannula 310 to the patient. A check valve (not shown) at the distal end 317 of the cannula 310 may be employed to prevent forward flow of drug until enough pressure is generated by the pumping apparatus. Such electrolytic pumping can facilitate the electronic control of drug delivery.

0053Electrolytic pumps offer several advantages for drug delivery. Their low-temperature, low-voltage, and low-power operation suits them well for long-term operation in vivo. For ocular applications, electrolytic pumps produce negligible heat and can also achieve high stress-strain relationships. Moreover, they lend themselves readily to the use of microelectronics to control the voltage applied to the pump (and therefore the temporal pattern of pressure generation), which allows operation the device 200 in either bolus and/or continuous dosage mode. Radio-frequency (RF) transmission and reception may also be used to provide wireless power and control of the microelectronic circuitry that operates the pump.

0054Electrolysis in a chamber in fluid communication with its exterior generates gases that force working fluid out of the chamber. Reversing the polarity of the applied voltage can reverse the process, thereby restoring the chamber to its original state. Since a small trickle charge can prevent this reverse process, the drug-delivery device 200 can be held in place with little power (i.e., the device 200 is latchable).

0055With reference still to <figref idref="f0008">FIG. 6</figref>, the drug-delivery device 200 may be constructed of a first portion 250 and a second portion 260 mounted thereon. As illustrated, the first portion 250 may include the cannula 310, the first electrode 320, and the second electrode 330. By mounting the second portion 260 onto the first portion 250, the reservoir 300 is formed therebetween. In certain embodiments, the second portion 260 includes a liquid- and gas-impermeable material (e.g., silicone) that is self-sealing to repeated punctures, as described above.

0056<figref idref="f0009">FIGS. 7A and 7B</figref> schematically illustrate a top-cross-sectional view and a side-cross-sectional view, respectively, of the first portion 250 of the drug-delivery device 200. As illustrated, the first portion 250 includes a support layer 305, the first electrode 320, and the second electrode 330. The first and second electrodes 320, 330 are positioned over the support layer 305, and at least one of the first electrode 320 and the second electrode 330 is planar.

0057The support layer 305 may be liquid- and gas-impermeable and may also be electrically insulative such that, absent any conductive material above the support layer 305, the first electrode 320 and the second electrode 330 are electrically insulated from one another. The first electrode 320 and the second electrode 330 are configured to be in electrical communication with a voltage source (not shown) that applies a voltage difference across the first electrode 320 and the second electrode 330.

0058As illustrated in <figref idref="f0009">FIGS. 7A and 7B</figref>, the first and second electrodes 320, 330 are co-planar with one another. At least one of the first and second electrodes 320, 330 may be patterned to have elongations or fingers within the plane defined by the electrode. For example, as illustrated in <figref idref="f0009">FIG. 7A</figref>, the first electrode 320 may be elongate and extend along a generally circular perimeter with radial elongations 322 that extend towards the center of the circular perimeter. For its part, the second electrode 330 may have a center elongate portion 332 with generally perpendicular elongations 334 that extend therefrom. The elongations 334 may define a generally circular perimeter within the generally circular perimeter of the first electrode 320, as illustrated in <figref idref="f0009">FIG. 7A</figref>. Other shapes and configurations of the first electrode 320 and the second electrode 330 may also be compatible with embodiments of the drug-delivery device 200 described herein.

0059The first portion 250 may also include an outer wall 360 that is liquid- and gas-impermeable. As described more fully below, the outer wall 360 is configured to be bonded to a corresponding wall of the second portion 260 of the device 200.

0060The first portion 250 of the drug-delivery device 200 may also include a first structure 370 between the first electrode 320 and the second electrode 330. As illustrated in <figref idref="f0009">FIGS. 7A and 7B</figref>, the first structure 370 may be a generally circular wall extending generally perpendicularly from the support layer 305. The first structure 370 may include one or more fluid passageways 372 through which a liquid can flow between a first region 380 above the first electrode 320 and a second region 385 above the second electrode 330, as described more fully below. The first structure 370 may also include a liquid-permeable but gas-impermeable barrier between the first and second regions 380, 385.

0061The first portion 250 may also include a second structure 374 above the first electrode 320 and a third structure 376 above the second electrode 330. The second structure 374 may be mechanically coupled to the first structure 370 and the outer wall 360, as illustrated in <figref idref="f0009">FIG. 7B</figref>, such that the support layer 305, the outer wall 360, the first structure 370, and the second structure 374 define the first region 380 containing the first electrode 320. In addition, the third structure 376 may be mechanically coupled to the first structure 370, as illustrated in <figref idref="f0009">FIG. 7B</figref>, such that the support layer 305, the first structure 370, and the third structure 376 define the second region 385 containing the second electrode 330.

0062The second structure 374 and/or the third structure 376 may be flexible and liquid-and gas-impermeable. For example, the second structure 374 and/or the third structure 376 may include a flexible membrane (e.g., corrugated parylene film). The second structure 374 and/or the third structure 376 may be configured to expand and contract with increases and decreases in pressure in the corresponding first region 380 and/or second region 385. In some such embodiments, both the second and third structures 372, 374 include or represent portions of the same flexible membrane, as illustrated in <figref idref="f0009">FIG. 7B</figref>.

0063<figref idref="f0010">FIGS. 8A and 8B</figref> schematically illustrate a top view and a side-cross-sectional view, respectively, of a drug-delivery device 200 including the first and second portions 250, 260. The second portion 260 includes a liquid-impermeable wall that is configured to be bonded to the first portion 250 of the device 200. As illustrated in <figref idref="f0010">FIGS. 8A and 8B</figref>, the second portion 260 may be bonded to the outer wall 360 of the first portion 250 such that the second portion 260, the second structure 374, and the third structure 376 define the reservoir 300 configured to contain a drug.

0064The first region 380 and the second region 385 may contain a material 340 that emits gas when a sufficient voltage is applied to the material 340. For example, in certain embodiments, the material 340 includes water that is electrolytically separated by an applied voltage into hydrogen gas and oxygen gas. As illustrated in <figref idref="f0010">FIG. 8B</figref>, both the second and third structures 374, 376 may include liquid- and gas-impermeable flexible membranes. Gas generated at the first electrode 320 increases the pressure in the first region 380, thereby flexing the second structure 374 towards the reservoir 300. Furthermore, gas generated at the second electrode 330 increases the pressure in the second region 385, thereby flexing the third structure 376 towards the reservoir 300. The flexing of the second structure 374 and/or the third structure 376 forces liquid (e.g., containing a therapeutic agent, such as a drug) to flow from the reservoir 300, through the cannula 310, to the one or more outlets 315.

0065The device 200 may restrict gas produced at the first electrode 320 from mixing with gas produced at the second electrode 330. For example, as illustrated in <figref idref="f0010">FIG. 8B</figref>, when the material 340 comprises water, hydrogen gas produced at the first electrode 320 is generally restricted to the first region 380 and the hydrogen gas produced at the other, second electrode 330 is generally restricted to the second region 385.

0066<figref idref="f0011">FIGS. 9A-9D</figref> schematically illustrate various views of the drug-delivery device 200 of <figref idref="f0010">FIGS. 8A and 8B</figref>. <figref idref="f0011">FIG. 9A</figref> schematically illustrates a top view of the device 200 with the first electrode 320, the second electrode 330, the second portion 260, and the cannula 310. <figref idref="f0011">FIG. 9B</figref> schematically illustrates a top partially cut-away view that shows the first electrode 320, the second electrode 330, the second portion 260, the cannula 310, the second structure 374, and the third structure 376. As shown in <figref idref="f0011">FIG. 9B</figref>, the second structure 374 and the third structure 376 are portions of a membrane extending across the first portion 250 of the device 200. <figref idref="f0011">FIG. 9C</figref> shows a portion of the first region 380, the first electrode 320 in the first region 380, the second region 385, the second electrode 330 within the second region 385, the second structure 374, the third structure 376, the second portion 260, and the cannula 310. The device 200 shown in <figref idref="f0011">FIG. 9D</figref> does not contain either the material 340 or the drug, but otherwise corresponds to the filled device 200 shown in <figref idref="f0010">FIG. 8B</figref>.

0067<figref idref="f0012">FIG. 10</figref> schematically illustrates various views of the drug-delivery device 200 that includes an injection port 410 configured to receive an injection needle 420. In one embodiment, the injection port 410 is part of the first portion 250 of the device 200, while in another embodiment the injection port 410 is part of the second portion 260 of the device 200. The injection port 410 is in fluid communication with the reservoir 300 of the device 200 to facilitate refilling of the device 200 while the device 200 is implanted. In addition, as illustrated in <figref idref="f0012">FIG. 10</figref>, the device 200 may include suture tabs 400 for fastening the device 200 to the surface of the patient's eye.

0068<figref idref="f0013">FIG. 11</figref> schematically illustrates the internal structure of an exemplary injection port 410. Injection needle 420 pierces a surface 500 of the injection port 410 through needle injection guide 510, and thereby gains access to injection vestibule 520. Injection of fluid from the needle 420 into the vestibule 520 forces liquid through the injection port valve 530 and into the reservoir 540.

0069The device 200 may be powered by an internal battery (not shown), or the device 200 may be powered by an external source (not shown). Alternatively, both a battery and an external source may be used. For example, even though the power can be recharged wirelessly, a smaller battery may be used to store the power for a week, thereby advantageously keeping the device small and minimally invasive.

0070The external source can be electrically coupled to the device 200 using wires or by wireless means (e.g., by using RF transmitters and receivers). By utilizing an external source and avoiding the use of an internal battery, the device 200 can advantageously be made even smaller, and therefore less invasive. In addition, by wirelessly controlling the operation of the device 200 (e.g., turning it on and off), a handheld transmitter can be programmed to send a signal that communicates with the device to power the device when needed. For example, at times when less drug is needed, less power is transmitted, and less drug is pumped. There may also be some threshold cutoff on the external power applicator that limits the implant from pumping too much drug. Wireless power may be inductively imparted through the use of coils built into the implant and the external transmitter.

0071The device 200 may include an integrated circuit for controlling operation of the device 200. Examples of integrated circuits compatible with embodiments of the drug-delivery devices described herein include, but are not limited to, single-chip application specific integrated circuits (ASICs) and application specific standard products (ASSPs) that have become more common for implantable medical applications. In some embodiments, such integrated circuits consume as little power as possible to, for example, extend battery life and therefore lengthen the time between invasive replacement procedures. In addition, the device 200 may include microelectronics to control the dosage and release, sensors for feedback control, anchoring structures to hold the device in place, supports to keep the reservoir from collapsing on itself when emptied, filtering structures, additional valves for more accurate flow control, a flow regulator to remove the adverse effects of pressure on drug delivery, and a programmable telemetry interface.

0072As illustrated in <figref idref="f0001">FIGS. 1A</figref> and <figref idref="f0002">FIG. 1B</figref>, the drug-delivery device 5 includes three individual structural layers 10, 20, 50. One, two, or all three of the layers 10, 20, 50 may be made of a biocompatible polymer, such as PDMS or parylene. In one embodiment, at least one of the structural layers 10, 20, 50 is formed using a lithographic process (e.g., soft lithography). <figref idref="f0014">FIGS. 12A-12K</figref> schematically illustrate an exemplary lithographic process. As illustrated in <figref idref="f0014">FIG. 12A</figref>, a substrate (e.g., a silicon wafer) is provided. A photoresist layer may then be formed on the substrate (e.g., by spin-coating a light-sensitive liquid onto the substrate), as shown in <figref idref="f0014">FIG. 12B</figref> . Suitable photoresists are well-known to those skilled in the art and include, but are not limited to, diazonaphthoquinone, phenol formaldehyde resin, and various epoxy-based polymers, such as the polymer known as SU-8. As illustrated in <figref idref="f0014">FIG. 12C</figref>, the photoresist layer may then be patterned to cover a first portion of the substrate and to not cover a second portion of the substrate. For example, ultraviolet light may be shone through a mask onto the photoresist-coated wafer, thereby transferring the mask pattern to the photoresist layer. Treatment of the wafer by well-known photoresist development techniques can then be used to remove the portions of the photoresist layer that were exposed to the ultraviolet light. Persons skilled in the art of lithographic techniques are able to select appropriate materials and process steps for forming the patterned photoresist layer.

0073As illustrated in <figref idref="f0014">FIG. 12D</figref>, the portion of the substrate that is not covered by the patterned photoresist layer may be etched (e.g., by deep reactive-ion etching), thereby leaving untouched the portions of the silicon wafer protected by the photoresist layer. As illustrated in <figref idref="f0014">FIG. 12E</figref>, the patterned photoresist layer may then be removed. For example, after washing with a solvent, such as acetone, the photoresist layer is removed and the entire wafer can be cleaned through use of oxygen plasma to remove any remaining photoresist. As illustrated in <figref idref="f0014">FIG. 12F</figref>, a mold release layer (e.g., parylene, a widely-used polymer of p-xylene) may be formed on the substrate to facilitate removal of the PDMS layer from the silicon wafer. Other materials can be used as the mold release layer in other embodiments. As illustrated in <figref idref="f0014">FIG. 12G</figref>, a structural layer (e.g., PDMS silicone) may be formed on the mold release layer. For example, PDMS can be poured over the silicon wafer and allowed to cure either by standing at room temperature or accelerated by heating (e.g., to 75°C for 45 minutes). As illustrated in <figref idref="f0014">FIG. 12H</figref>, the structural layer may then be removed from the substrate, thereby providing the structural layer illustrated in <figref idref="f0014">FIG. 12I</figref>. In certain embodiments, the molded PDMS layer contains multiple copies of the structural layer, and each copy of the structural layer is separated from the others. Excess material can be removed from the structural layer, as illustrated in <figref idref="f0014">FIG. 12J</figref>, thereby providing the structural layer illustrated in <figref idref="f0014">FIG. 12K</figref>, which is ready for assembly with the other structural layers.

0074The individual structural layers can be assembled and bonded together in certain embodiments by treating the surface of one or more of the structural layers with oxygen plasma for about one minute, although the time is not critical. Oxygen plasma changes the surface of the PDMS from hydrophobic to hydrophilic.

0075With reference again to <figref idref="f0001">FIG. 1A</figref>, the bottom layer 50 and the middle layer 20 may be placed into a plasma chamber with the sides that are to be bonded facing the plasma. Once the surfaces have been treated, the two pieces 20, 50 may be aligned with the aid of a polar liquid (e.g., ethanol, water, etc.). The liquid preserves the reactive hydrophilic surface providing more time to align the two layers. It also makes the two pieces 20, 50 easier to manipulate for alignment since it lubricates the surfaces, which are otherwise sticky. The two-layer assembly can then be placed back into the chamber along with the top layer 10 and the treatment and alignment procedure repeated. The entire assembly can then be baked (e.g., at 100°C for 45 minutes) to reinforce the bonds. In practice, the bonded silicone appeared homogeneous by scanning electron microscopy and optical observation. Tests with pressurized N 2showed that the bonded silicone assembly withstood pressures of at least 25 psi.

0076With reference to <figref idref="f0001">FIGS. 1A</figref> and <figref idref="f0002">1B</figref>, the orifice 40 may be made by inserting a small diameter coring needle into a sheet of silicone rubber that later forms the upper surface of the cannula 110. Other methods can also be used to generate this feature. The coring needle removes material to create the orifice 40. The valve seat 80 may be a post that protrudes from the bottom of the cannula 110 and extends the height of the channel 72 to meet the top of the cannula 110. During assembly, the orifice 40 is centered over the valve seat 80 and rests on it to form the valve 120. In this configuration, the valve 120 is said to be "normally-closed" and fluid will not pass through. Fluid pressure in the cannula 110 exceeding a certain value (i.e., a cracking pressure) opens the valve 120 and allows fluid to exit the drug-delivery device 5 through a gap between valve seat 80 and the movable element 122, as illustrated in <figref idref="f0005">FIG. 4A</figref>.

0077<figref idref="f0015">FIGS. 13A-13M</figref> schematically illustrate one exemplary process for forming a drug-delivery device that includes electrolytic pumping, such as the drug-delivery device 200 depicted in <figref idref="f0008">FIG. 6</figref>, although other processes may also be employed in forming the drug-delivery device.

0078As illustrated in <figref idref="f0015">FIG. 13A</figref>, a bare silicon substrate may be provided and, as illustrated in <figref idref="f0015">FIG. 13B</figref>, a dielectric layer (e.g., a thermal silicon dioxide layer about 4000 Å thick) may be grown on the silicon substrate. This silicon oxide layer electrically insulates the substrate and electrolysis electrodes.

0079As illustrated in <figref idref="f0015">FIG. 13C</figref>, electrolysis electrodes (e.g., made of Ti/Pt, 200 Å and 2000 Å thick, respectively) may be then formed over the dielectric layer (e.g., deposited and lithographically patterned). The dielectric layer may be patterned and etched briefly with XeF₂ to remove a portion of the dielectric layer, thereby exposing a portion of the substrate. This process can also roughen the exposed silicon surface, as illustrated in <figref idref="f0015">FIG. 13D</figref>. A first sacrificial photoresist layer (e.g., 5 µm thick) can be spun and patterned on the substrate, as illustrated in <figref idref="f0015">FIG. 13E</figref>. The first sacrificial photoresist layer facilitates the release of the cannula from the supporting silicon substrate at the end of the fabrication process. A first structural layer (e.g., a 7.5 µm thick parylene layer) can then be deposited and patterned on the first sacrificial layer, as illustrated in <figref idref="f0015">FIG. 13F</figref>. The first structural layer will become the bottom wall of the drug-delivery cannula. As illustrated in <figref idref="f0015">FIG. 13G</figref>, a second sacrificial layer (e.g., a 25 µm thick photoresist layer, spun and patterned) can be formed over the first structural layer. As illustrated in <figref idref="f0015">FIG. 13H</figref>, a second structural layer (e.g., a 7.5 µm thick parylene layer) can then be deposited on the second sacrificial layer. The second structural layer will become the top and side walls of the cannula. The first and second structural layers can then be patterned, as illustrated in <figref idref="f0015">FIGS. 13I and 13J</figref>. For example, a Cr/Au etch mask layer for removing unwanted parylene (200Å and 2000Å thick, respectively) can be deposited and patterned on the substrate, as illustrated in <figref idref="f0015">FIG. 13I</figref>. The parylene can be patterned in an oxygen plasma through use of the Cr/Au masking layer, as schematically illustrated in <figref idref="f0015">FIG. 13J</figref>. A third structural layer (e.g., an SU-8 photoresist layer 70 µm thick) can be spun and patterned on the substrate, as illustrated in <figref idref="f0015">FIG. 13K</figref>. The SU-8 layer can support the cannula and prevent its collapse when a drug reservoir is attached to the base layer. The sacrificial photoresist layers are then removed by dissolving them in acetone, as illustrated in <figref idref="f0015">FIG. 13L</figref>. The cannula can then be peeled up from the surface of the roughened silicon substrate and broken off the silicon substrate directly beneath the cannula to form a free-standing cannula, as illustrated in <figref idref="f0015">FIG. 13M</figref>.

0080In one embodiment, the drug-delivery device 5, 90, 200 is implanted by attaching the main body of the device 5, 90, 200 to the top of a patient's eye and inserting the cannula 110, 310 into the anterior or the posterior segment of the eye. The device 5, 90, 200 may be affixed to the eye through use of current ophthalmic techniques such as sutures or eye tacks. In one embodiment, a method of using the device 200 includes applying a first voltage between the first and second electrodes 320, 330 to produce gas from the material 340 in electrical communication with the electrodes. The gas forces liquid to flow from the reservoir 300, through the cannula 310, to the outlet 315 of the device 200. In certain embodiments, the method also includes applying a second voltage between the first electrode 320 and the second electrode 330 to produce the material 340 from the gas. In this way, the device 200 is used in a reversible manner in which the material 340 is regenerated from the gases, thereby avoiding having to refill the device 200 with the material 340. In certain embodiments, the material 340 comprises water and the gas comprises hydrogen gas and oxygen gas. In certain embodiments, the first voltage and the second voltage are opposite in sign.

Example

0081A device having a flexible parylene transscleral cannula allowing for targeted delivery to tissues in both the anterior and posterior segments of a patient's eye is described below. This electrochemically driven drug-delivery device was demonstrated to provide flow rates suitable for ocular drug therapy (i.e., pL/min to µL/min). Both continuous and bolus drug-delivery modes were performed to achieve accurate delivery of a target volume of 250 nL. An encapsulation packaging technique was developed for acute surgical studies and preliminary ex vivo drug-delivery experiments in porcine eyes were performed.

0082The electrolysis of water results in the phase transformation of liquid to gas and provides the actuation used to drive drug delivery in this example device. The net result of the electrolysis is the production of oxygen and hydrogen gas that contributes to a volume expansion of about a thousand times greater than that of the water used in the reaction. This gas evolution process proceeds even in a pressurized environment (e.g., 200 MPa).

0083To drive gas generation and thus pumping, current control is useful due to its direct correlation to pump rate and volume. If current is used to drive the reaction, the theoretical pump rate (q_theoretical in m³/s) at atmospheric pressure is given by: <maths id="math0001" num=""><math display="block"><mrow><msub><mi mathvariant="normal">q</mi><mi mathvariant="normal">theoretical</mi></msub><mo>=</mo><mn mathvariant="normal">0.75</mn><msub><mrow><mfenced separators=""><mi mathvariant="normal">I</mi><mo>/</mo><mi mathvariant="normal">F</mi></mfenced><mi mathvariant="normal">V</mi></mrow><mi mathvariant="normal">m</mi></msub><mo>,</mo></mrow></math><img file="EP2242464B2_D0001.tif" /></maths> where I is current in amperes, F is Faraday's constant, and V_m is the molar gas volume at 25°C and atmospheric pressure. The theoretical generated or dosed gas volume (V_theoretical in m³) can be determined by: <maths id="math0002" num=""><math display="block"><mrow><msub><mi mathvariant="normal">V</mi><mi mathvariant="normal">theoretical</mi></msub><mo>=</mo><msub><mi mathvariant="normal">q</mi><mi mathvariant="normal">theoretical</mi></msub><mi mathvariant="normal">t</mi><mo>,</mo></mrow></math><img file="EP2242464B2_D0002.tif" /></maths> where t is the duration (in sec) that the current is applied. The efficiency (η) of an electrolysis actuator as a pump can be defined as: <maths id="math0003" num=""><math display="block"><mrow><mi mathvariant="normal">η</mi><mo>=</mo><msub><mi mathvariant="normal">V</mi><mi mathvariant="normal">experimental</mi></msub><mo>/</mo><msub><mi mathvariant="normal">V</mi><mi mathvariant="normal">theoretical</mi></msub><mo>,</mo></mrow></math><img file="EP2242464B2_D0003.tif" /></maths> where V_experimental is the actual volume of the generated hydrogen and oxygen gases. Efficiency in electrochemical systems is affected by a number of parameters including electrode parameters (e.g., material, surface area, geometry, and surface conditions), mass transfer parameters (e.g., transport mode, surface concentration, and adsorption), external parameters (e.g., temperature, pressure, and time), solution parameters (e.g., bulk concentration of electroactive species, concentration of other species and solvent), and electrical parameters (e.g., potential, current, and quantity of electricity).

0084The electrolysis pump included two interdigitated platinum electrodes immersed in an electrolyte. This electrode geometry improves pumping efficiency by reducing the current path through the solution, which serves to lower the heat generation. The gasses generated resulted in an internal pressure increase in the sealed reservoir, which caused drug to be delivered through the cannula and into the patient's eye. Electrolysis is a reversible process and ceases when the applied signal is turned off, thereby allowing the gradual recombination of hydrogen and oxygen to water.

0085Pumped drug entered the flexible transscleral cannula through a small port connected to the pump, while the generated gases remained trapped inside the reservoir. Parylene was selected as the cannula material for its mechanical strength, biocompatibility, and ease of integration. It is a USP Class VI material suitable for the construction of implants and is well-established as a MEMS material. The pump/cannula portion was fabricated using silicon micromachining and the reservoir portion by the casting of silicone rubber against a master mold.

0086More specifically, the fabrication process of the pump and cannula chip started with a thermally oxidized silicon substrate (5000 Å). LOR 3B (MicroChem Corporation, Newton, Massachusetts) was spun on at 3 krpm followed by AZ 1518 (AZ Electronic Materials, Branchburg, New Jersey) at 3 krpm. Ti-Pt (200/2000 Å) was e-beam evaporated and patterned by lift-off in a ST-22 photoresist stripper (ATMI, Danbury, Connecticut) to define the interdigitated electrodes. A second lithography step was performed (AZ 1518 at 3 krpm) to define the cannula footprint. The oxide layer was etched using buffered HF acid to expose the Si below. The photoresist was stripped and then the exposed Si was roughened by two cycles of XeF₂ etching. The first sacrificial photoresist layer (AZ 4620 spun at 2.75 krpm and hard baked to yield a 5 micron thick layer) was applied to facilitate release of the cannula from the substrate. The first parylene C layer (7.5 microns) forming the bottom of the cannula was deposited followed by thermal evaporation of a 2000 Å thick Cr etch mask. Following lithography (AZ 4620 at 500 rpm), the Cr was etched in Cr-7 (Cyanteck, Fremont, California) and the photoresist stripped. The parylene layer was then patterned in an oxygen plasma and the Cr etch mask was removed using Cr-7. A second photoresist sacrificial layer was deposited (AZ 4620 spun at 450 rpm and hard baked to yield a 25 micron thick layer) to define the channel height. A second parylene layer of 7.5 microns was deposited to complete the cannula. To define the cannula from the parylene/photoresist/parylene sandwich, Ti/Au (200/2000 Å) was deposited as an etch mask. The etch mask was patterned (AZ 4620 spun at 425 rpm) and etched first with Au etchant TFA (Transene Company, Inc., Danvers, Massachusetts) and then 10% HF. Finally, the sandwich was etched in oxygen plasma and the masking layer was stripped (Au etching TFA and 10% HF). Following the etch, the entire wafer was cleaned in 5% HF dip and by exposure to oxygen plasma. SU-8 2200 (MicroChem Corporation, Newton, Massachusetts) was spun at 2200 rpm resulting in a 70 micron thick layer after post baking. The sacrificial photoresist was removed by dissolving in a 40°C acetone solution for one day. The individual cannulae were released manually by gently lifting them off the substrate. Finally, individual dies were separated and the remaining silicon beneath each cannula was removed by scribing and breaking it off.

0087The pump chip containing the electrolysis actuator and cannula was combined with the drug reservoir and electrical wiring. Electrical wires were bonded to the electrode contact pads using OHMEX-AG conductive epoxy (Transene Company, Inc., Danvers, Massachusetts). The epoxy was cured at 150°C for 15 hours under vacuum. The pump chip and reservoir were then assembled using an encapsulation technique based on silicone soft lithography as described above.

0088To shape the package to fit comfortably on the curved contour of the eyeball, a silicone spacer (SYLGARD 184, Dow Corning, Midland, Michigan) was casted against a stainless steel sphere of 17.5 mm in diameter. This layer of partially cured silicone (10:1 base to curing agent ratio) was cured at 65°C for 20 minutes. The sphere was removed and the resulting crater was filled with wax. A silicone reservoir was prepared by casting against a conventionally machined acrylic mold, partially cured at 65°C for 20 minutes. The mold produced a reservoir with internal dimensions of 6 mm x 6 mm x 1.5 mm. The silicone reservoir was aligned to the chip and spacer and the parylene cannula was then immersed in DI water, which serves as a mask to prevent coating by silicone rubber during the encapsulation step, thereby exploiting the hydrophobicity of silicone rubber. The stack was immersed in silicone prepolymer and cured at room temperature for 24 hours. Extraneous silicone material was removed from the device to complete the assembly process.

0089To investigate the performance of the electrolysis pump, experiments examining continuous delivery, bolus delivery, pump efficiency, gas recombination, and backpressure were conducted. For these tests, a custom testing apparatus was laser-machined (Mini/Helix 8000, Epilog, Golden, Colorado) in acrylic. The experimental setup included a computer-controlled CCD camera (PL-A662, PixeLINK, Ottawa, Ontario, Canada) for collecting flow data from a calibrated micro-pipette (Accu-Fill 90, Becton, Dickinson and Company) attached to the output port of the test fixture. Testing was performed using deionized water as the electrolyte. The electrolysis was initiated under constant current conditions (50 µA to 1.25 mA) for continuous delivery operation. The relationship between efficiency and recombination of hydrogen and oxygen to water was studied.

0090Bolus delivery was also examined. A constant current pulse (0.5, 1.0, and 1.5 mA) was applied for 1, 2, and 3 seconds. Repeated trials were performed (n=4) to obtain average dosing volume. Normal IOP ranges from 5-22 mmHg (15.5 ± 2.6 mmHg (mean ±SD)). Values outside this range correspond to abnormal IOP, which is a characteristic of glaucoma (>22 mmHg). Thus, it is helpful to characterize pump performance under these physiologically relevant conditions. The experimental setup was modified to include a water column attached to the outlet of the micro-pipette. Backpressure was applied to the drug-delivery device by adjusting the height of the water column. Data was collected for backpressures corresponding to normal IOP (20 mmHg) and abnormal IOP (0 and 70 mmHg).

0091The prototype drug-delivery devices were implanted in enucleated porcine eyes. Preliminary ex vivo surgical modeling in enucleated porcine eyes is useful to prepare for device demonstration in vivo. The operation of each surgical device was tested prior to the surgical experiment to check for clogs and integrity of the electrical connections. The drug reservoir was filled with dyed deionized water and then the reservoirs were manually depressed, which generates sufficient pressure to expel the fluid from the reservoir. A second test was conducted to verify operation of the electrolysis pump by connecting to an external power supply and driving fluid from the reservoir by electrolysis pumping. An enucleated porcine eye was prepared for the surgical study and a limbal incision was made (between the cornea and sclera). The cannula was implanted through the incision into the anterior chamber. The enucleated porcine eye was pressurized at 15 mmHg by using an infusion line. Constant current (0.5 mA) was applied for 1 minute. The device was surgically removed after the experiment.

0092The electrolysis pump was operated at flow rates in the µL/min to µL/min range using driving currents from 5 µA to 1.25 mA (<figref idref="f0016">FIGS. 14A and 14B</figref>). The highest rate was 7 µL/min for 1.25 mA and the lowest was 438 pL/min at 5 µA. Both data sets are corrected to compensate for the evaporation of fluid during testing. Flow rates below about 2 µL/min are preferred for ocular drug delivery. This is consistent with naturally occurring flow rates in the eye; the ciliary body of the eye produces aqueous humor at 2.4 ±0.6 µL/min in adults. As current decreases, it was observed that pumping efficiency, which ranged from 24-49%, also decreased (<figref idref="f0016">FIG. 14C</figref>). Electrolysis-driven pumping efficiency is affected by the competitive recombination of hydrogen and oxygen gases to water. This effect is further enhanced by exposure to the platinum electrolysis electrodes that serve to catalyze the recombination reaction. In <figref idref="f0016">FIG. 14D</figref>, a typical accumulated volume curve is shown that illustrates the effect of recombination after the applied current is turned off. The measured recombination rate was 62 nL/min.

0093Bolus delivery mode was also evaluated (<figref idref="f0017">FIG. 15</figref>). If the desired dosing regimen is 250 nL per dose, this volume can be obtained by driving the pump for a short duration that is determined by the magnitude of the applied current. For example, a 1.0 mA driving current will dose 250 nL in 2.36 seconds. For 1.5 mA current, the pulse time can be set as 1.75 seconds. Under normal operation in the eye, the drug-delivery device will experience a backpressure equivalent to the IOP of the eye. Benchtop experiments indicated that the pump was able to supply sufficient drug flow over the range of normal and abnormal IOP equivalent backpressures (<figref idref="f0018">FIG. 16</figref>). The flow rates varied 30% compared to normal IOP over the tested backpressure range.

0094Initial surgical results showed promising results in enucleated porcine eyes. Following removal of the device after the surgical experiment, post surgical examination of the cornea revealed a small blue spot above the iris near the position of the cannula tip indicating that dye was delivered into the eye.

0095Additional details on some of the drug-delivery devices described herein may be found in <patcit id="pcit0002" dnum="US11686310B"><text>United States Patent Application No. 11/686,310</text></patcit> entitled "MEMS Device and Method for Delivery of Therapeutic Agents," published as <patcit id="pcit0003" dnum="WO2007106557A"><text>WO 2007106557</text></patcit>.

0096Having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. Accordingly, the described embodiments are to be considered in all respects as only illustrative and not restrictive.