Patent Publication Number: US-2011060280-A1

Title: Adhesive skin patch with pump for subcutaneous drug delivery

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to and the benefit of, and incorporates herein by reference in its entirety, U.S. Provisional Patent Application No. 61/239,836, which was filed on Sep. 4, 2009. 
    
    
     TECHNICAL FIELD 
     In various embodiments, the invention relates to pumps for delivering a drug, and in particular to pumps configurable as a skin patch. 
     BACKGROUND 
     As patients live longer and are diagnosed with chronic and often debilitating ailments, the result will be an increased need for improvements to the speed, convenience, and efficacy of drug delivery. For example, many chronic conditions, including multiple sclerosis, diabetes, osteoporosis, and Alzheimer&#39;s disease, are incurable and difficult to treat with currently available therapies: oral medications have systemic side effects; injections may require a medical visit, can be painful, and risk infection; and sustained-release implants must typically be removed after their supply is exhausted (and offer limited ability to change the dose in response to the clinical picture). In recent decades, several types of portable drug delivery devices have been developed, including battery-powered mini pumps, implantable drug dispensers, and diffusion-mediated skin patches. 
     Drug-delivery devices configured as adhesive skin patches provide several advantages over competing delivery technologies for the treatment of chronic diseases. They are compact, disposable, and incur relatively low manufacturing costs. Relative to other drug-delivery options, they are non-invasive since they require the simple adhesion to the skin of a patch-type device containing a reservoir that stores a drug or therapeutic agent. This type of device also provides flexibility in terms of where it can be applied, since the skin serves as a large accessible surface for the patch device. In several existing applications, patch-based devices rely on transdermal absorption for drug delivery, e.g., diffusion of the drug across the skin. However, because the skin exhibits low permeability and functions as a barrier to prevent molecular transport of foreign agents into the body, effective diffusion-based drug penetration is generally limited to drugs with low molecular weights. Accordingly, transdermal drug delivery is typically compatible with only a limited number of pharmaceutical agents and suitable only for the handful of diseases they treat. Another limitation of transdermal skin patches is that penetration across the contact area can often be heterogeneous and uncontrolled. Treatments for a number of chronic diseases currently require the administration of a drug or therapeutic agent either continuously or at specific times or time intervals in high controlled doses. 
     Several chronic diseases are currently treatable only with drugs that require subcutaneous drug delivery. Subcutaneous injections take advantage of the lack of blood flow to the subcutaneous layer, which allows the administered drug to be absorbed more slowly over a longer period of time. However, these types of injections typically must be administered either by the patient or a medical practitioner anywhere from several times a day to once every few weeks. Frequent injections can result in discomfort, pain, and inconvenience to the patient. Self-administration also leaves open the possibility for non-compliance or errors in dosage events. 
     There is a need, therefore, for a skin patch-based delivery system capable of delivering highly controlled dosages of drug at regular intervals or intermittently, depending on the needs of the patient. 
     SUMMARY OF THE INVENTION 
     In general, in one aspect, embodiments of the invention feature a drug-delivery device that includes a patch adherable to a patient&#39;s skin. An exterior surface of the patch defines an envelope within which are disposed at least one programmable drug pump including a reservoir, a cannula for conducting liquid from the reservoir to a delivery vehicle integrated with the patch, and a mechanism for forcing liquid from the reservoir through the cannula and into the delivery vehicle. All of these components are integral with the patch. A sensor associated with the cannula monitors a parameter of a fluid within the cannula and feedback circuitry, responsive to the sensor, adjusts operation of the drug pump. 
     In one embodiment, the delivery vehicle is a sponge positioned for contact with the skin with the patch affixed thereto. In an alternative embodiment, the delivery vehicle is a lancet insertable into the skin with the patch affixed thereto. The lancet may be retractable or wirelessly actuable. In an alternative embodiment, the cannula and catheter can be separated from the body of the pump while using an external needle lancet system to drive the catheter into the skin. In various embodiments, the pump may be electrolytically driven and the reservoir may be refillable. 
     In some embodiments, the patch includes first and second opposed surfaces, where the first surface is adherable to the skin and the second surface is under a hydrophobic layer to retain moisture within the patch. The patch may also be flexible, and the sensor may be one or more of a flow sensor, a pressure sensor, or a thermal sensor. 
     In general, in another aspect, embodiments of the invention feature a drug-delivery device including a patch adherable to a patient&#39;s skin and a plurality of drug pumps integral with the patch and residing within an envelope defined by the patch. Some embodiments feature a common reservoir and at least one cannula for conducting liquid therefrom to at least one delivery vehicle in fluid communication with the drug pumps, so that the pumps may force liquid from the common reservoir through the cannula(s) and into the delivery vehicle(s). A controller for selectively activating the pumps to achieve a programmed dosage may also be included. In other embodiments, multiple reservoirs allow for two or more drugs to be delivered at different intervals using the same or separate cannulas. 
     In one embodiment, each of the pumps fluidly communicates with a separate delivery vehicle (forming, for example, an array of microneedles that results in less perceived pain by the patient). In an alternative embodiment, each of the pumps fluidly communicates with a common delivery vehicle. The drug-delivery device may also include a sensor associated with each at least one cannula for monitoring a parameter of a fluid therein and feedback circuitry, responsive to the at least one sensor, for adjusting operation of the drug pumps. 
     In general, in yet another aspect, embodiments of the invention feature a drug-delivery device including a patch adherable to a patient&#39;s skin and, integral with the patch and residing within an envelope defined by the patch, at least one programmable drug pump including a reservoir, a cannula for conducting liquid from the reservoir to a delivery vehicle integrated with the patch, and a mechanism for forcing liquid from the reservoir through the cannula and into the delivery vehicle. The drug-delivery device may also include a flexible bladder downstream of the reservoir and upstream of an outlet of the cannula for receiving fluid from the reservoir and discharging it into the cannula. This has the advantage of saving power, since the power-hungry electrolysis system is active just long enough to pump fluid from the drug reservoir into the flexible bladder reservoir; the bladder compresses the drug out the catheter (a check valve is used to prevent backflow into the reservoir) even while the electrolysis is turned off. 
     In various embodiments, the drug-delivery device may also include a check valve between the reservoir and the flexible bladder, a sensor associated with the flexible bladder, and feedback circuitry, responsive to the sensor, for adjusting operation of the drug pump. The sensor may detect depletion of the flexible bladder and the feedback circuitry may cause the drug pump to operate so as to fill the flexible bladder. 
     In general, in another aspect, the invention features a drug-delivery device including a patch adherable to a patient&#39;s skin, and, integral with the patch and residing within an envelope defined by the patch, a lancet wirelessly actuable for insertion into a patient&#39;s skin in contact with the patch. The device also includes at least one programmable drug pump including a reservoir, a cannula for conducting liquid from the reservoir to the lancet, and a mechanism for forcing liquid from the reservoir through the cannula and into a delivery vehicle. 
     These 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, even if not made explicit herein. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In 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: 
         FIG. 1  schematically illustrates, in bottom view, a drug-delivery device in accordance with one embodiment of the invention; 
         FIGS. 2A and 2B  schematically illustrate, in isometric views, a drug-delivery used in accordance with one embodiment of the invention; 
         FIG. 2C  schematically illustrates, in schematic elevational cross-section, a delivery mechanism for use with various embodiments of the invention; 
         FIG. 3  schematically illustrates, in elevational cross-section, an electrolysis pump for use with the device illustrated in  FIG. 1 ; 
         FIG. 4  schematically illustrates, in a block diagram, the configuration of a drug-delivery device in accordance with one embodiment of the invention; 
         FIGS. 5A and 5B  schematically illustrate, in cut-away isometric views, a drug-delivery device in accordance with an alternative embodiment of the invention; 
         FIGS. 6A-6C  schematically illustrate, in top view, drug-delivery devices with multiple pumps in accordance with other embodiments of the invention; and 
         FIG. 7  schematically illustrates, in bottom view, a drug-delivery device with a flexible downstream bladder in accordance with yet another embodiment of the invention. 
     
    
    
     DESCRIPTION 
     In general, embodiments of the present invention pertain to patches adherable to the skin of a patient with integral drug-delivery pumps, and may be employed in connection with various types of skin patches. Refer first to  FIG. 1 , which illustrates an embodiment  100  of a drug-delivery device in accordance with the invention. The drug-delivery device  100  includes an adhesive patch  102  (e.g., an adhesive bandage) and, affixed to a bottom surface thereof, a programmable drug pump assembly  104 . A delivery vehicle  106  extends from the pump assembly  104  to facilitate transfer of drug from the pump to the wearer. A clear portion (not shown) of the adhesive patch  102  may be provided about the delivery vehicle  106  so a patient can confirm that the delivery vehicle  106  did not pierce a vein when applied to the skin, as evidenced by a lack of hematoma or blood bruising visible through the window. 
     The adhesive patch  102  is generally fabricated from a flexible material that conforms to the contours of the patient&#39;s skin and attaches via an adhesive on the illustrated backside surface that contacts a patient&#39;s skin. The adhesive may be any material suitable and safe for application to and removal from human skin Many versions of such adhesives are known in the art, though utilizing an adhesive with gel-like properties may afford a patient particularly advantageous comfort and flexibility. The adhesive may be covered with a removable layer to preclude premature adhesion prior to the intended application. As with commonly available bandages, the removable layer should not reduce the adhesion properties of the adhesive when removed. 
     On the bottom surface of the patch  102 , the various components of the drug pump assembly  104  are held within a housing  108  that is either fully self-contained or, if defined as discrete, intercommunicating modules, reside within a spatial envelope that is wholly within (i.e., which does not extend beyond in any direction) the perimeter of the patch  102 . For example, the housing  108  may be fully sealed and watertight except for where the delivery vehicle  112  extends from the patch  102 . The housing  108  protects the components of the drug pump assembly  104  and prevents the unintentional disassembly of the drug-delivery device  100 . 
     In one embodiment, where the patch  102  is made from a flexible material, the portion of the upper surface opposite the housing  108  may be constructed from or capped with an inflexible material. The inflexible material may effectively form a shell to protect the drug pump assembly  104  and prevent disruption of its operation from a number of causes, such as changes in the external environment (e.g., pressure) and accidental contact. 
     Alternatively or in addition, the upper surface of the patch  102  may have thereon (or may consist of) a layer made of silicone rubber, glass, or a hydrophobic coating to retain moisture within the patch  102 . Covering the drug pump assembly  104  with a protective material, such as silicone or epoxy, also protects the pump components. The protective material may be applied to the flexible material of the patch  102  to adhere thereto, sandwiching the housing  108  therebetween. Adhesion between the protective and flexible materials may be achieved with any of a number of known manufacturing steps for combining materials, such as applying epoxy to the materials or heat-sealing the materials together. 
     The delivery vehicle  106  may be any device suitable for delivering a fluid to a patient. In various embodiments, the delivery vehicle  106  is configured to deliver fluid to the skin surface for absorption (e.g., via a sponge) or to deliver fluid to the subcutaneous layer directly (e.g., via a lancet). For direct subcutaneous delivery applications, the delivery vehicle  106  must be of sufficient strength and flexibility to penetrate the subcutaneous layer without breaking or bending. Examples of such materials include, but are not limited to, stainless steel, silicon, polyurethane, and various composite materials as are well-known in the art. 
     The delivery vehicle  106  may be manually forced to or through the surface of the skin, as depicted in  FIGS. 2A and 2B , depending on the application. In certain embodiments, the delivery vehicle  106  is a delivery vehicle biased away from the skin  109  and driven into the skin against the bias. The delivery vehicle  106  may be actuated by a manual trigger, such as a button  111 . Pressing the button  111  drives the delivery vehicle  106  into the skin and also activates the pump electronics (described below), e.g., by bringing electrical contacts together. The button  111  may be hinged by, for example, a living hinge  117  that biases it in the retracted position. When the button  111  is pressed, overcoming the hinge bias, a catch holds it in place (and the delivery vehicle  106  in position) until the button  111  is pressed again. In addition to manual release by means of a second depression of the button  111 , the catch may be electromagnetically configured for release in response to a signal from the pump circuitry (after a predetermined amount of drug is sensed to have been delivered to the wearer) or from a wireless device. 
     A suitable mechanism  150  facilitating retractable insertion of the delivery vehicle  106  through the skin is depicted in  FIG. 2C . The mechanism  150  may operate mechanically or electromechanically. In the illustrated configuration, the delivery vehicle  106  is a lancet coupled to a lancet support  152  held in a retracted position by a pair of first catch elements  154  against a first biasing elastic element  156 , such as a spring or a sponge. The lancet  106  is actuated (or released), either manually or in response to a signal from the pump or a wireless device, by briefly opening the first catch elements  154 , and also a pair of second catch elements  158 , about associated hinges  160 . The first elastic element  152  quickly forces the lancet  106  into the skin, where the lancet support  152  is restrained by the second catch elements  158 . Additional second elastic elements  162 , biasing the lancet  106  toward the patch  102 , may be included to retract the lancet  106  at a desired time, such as following the administration of a full dose. The lancet  106  may be actuated for retraction either manually or, once again, by means of a signal (received from a wireless source or from the pump, e.g., when a full dose has been dispensed) by briefly opening the second catch elements  158  and the first catch elements  154  about hinges  160 . The second elastic elements  162  quickly force the lancet  106  back within the patch  102 , where the lancet support  152  is again retained by the first catch elements  154 . To facilitate automatic operation, the first and second catch elements  154 ,  158  may be mounted on a piezoelectric material, which undergoes strain upon application of voltage thereto, thus opening the first and second catch elements  154 ,  158 . Removal of the voltage from the piezoelectric material relieves the strain, thereby restoring the first and second catch elements  154 ,  158  to a closed configuration. 
     As shown in  FIGS. 1 and 3 , the drug pump assembly  104  may include a reservoir  110 , a cannula  112 , and a pump  114 . The reservoir  110  is a chamber configured to store a drug in liquid form. The reservoir  110  may also include a refill port  111  to allow for the introduction of additional drug. In some embodiments, the reservoir  110  is capable of holding between approximately one and ten mL of a drug and has an active operational lifetime of, e.g., 30 minutes to 75 hours, though the capacity and operational lifetime of the reservoir  110  is easily adjusted by altering the size of the reservoir  110  and the rate at which the drug is administered. The cannula  112  is fluidically coupled to the reservoir  110  to provide a fluid path from the reservoir  110  to (and through) the delivery vehicle  106 . The cannula  112  may contain a check valve  113  (see  FIG. 3 ) to prevent blood or interstitial fluid from entering the reservoir  110  and spoiling the drug. The cannula  112  can be made of substantially impermeable tubing, such as medical-grade plastic. 
     The cannula  112  may include a sensor  115  for monitoring a parameter, such as flow rate, of a fluid within the cannula  112 . In general, the sensor  115  may be a flow, thermal, time of flight, pressure, or other sensor, as are well-known in the art. In one embodiment, the sensors  115  are fabricated, at least in part, from parylene, which is a biocompatible, thin-film polymer. Advantageously, this enables the sensors  115  to be fully integrated into a parylene-based drug pump  100  (as described below). It may be desirable for parylene to be the only material in contact with the fluid flowing through the cannula  112  (e.g., to ensure biocompatibility and also to protect the other elements in the sensors  115 ). 
     A thermal flow sensor uses a resistive heater to locally heat the fluid flowing in proximity to the sensor  115 . The temperature of the flowing fluid can then be measured using one or more miniature resistive temperature devices, providing an indication of the flow rate. A time-of-flight sensor generates a tracer pulse in the fluid flowing within the cannula  112 , and then measures the time that it takes for this pulse to traverse a certain distance. This measured time is defined as the “time of flight” and corresponds to the linear fluid velocity, which may be translated into a volumetric flow rate. Multiple pressure sensors may be used to detect a difference in pressure and calculate the flow rate based on a known laminar relationship. 
     A pressure sensor located in or on the cannula  112 , or within the reservoir  110  (e.g., at the outlet port leading to the cannula), can also be used to measure and monitor the local pressure. Pressure sensing can be used to warn of improper pump operation or as an indirect measure of flow rate. For example, if knowledge of the pressure in the delivery vehicle  106  is required during dosing, then the sensor  115  can be placed in either of two places: (i) inside the cannula  112  and at its distal tip, or (ii) outside the cannula  112  and at its distal tip. Advantageously, placement of the sensor  115  at the distal tip of the cannula  112  prevents flow-related pressure drops inside the cannula  112  from causing an error in the pressure reading. 
     The pump  114  forces liquid from the reservoir  110  through the cannula  112  and into the delivery vehicle  106 . In various embodiments, the pump  114  is an electrolytic pump, as depicted in  FIG. 3 . A suitable electrolytic pump  114  includes an electrolysis chamber  116 , one surface of which is defined by a diaphragm  118 . The reservoir  110  is located on one side of the electrolysis chamber  116  (and within the housing  108 ). The diaphragm  118  defines the lower boundary of the reservoir  110  as well as the upper boundary of the electrolysis chamber  116 . A portion of the outer surface of the housing  108  defines the upper boundary of the reservoir  110 . The diaphragm  118  may be molded out of parylene (or microfabricated). The electrolysis chamber  116  contains a series of electrolysis electrodes  120  and an electrolyte  122  in liquid form. In operation, when current is supplied to the electrolysis electrodes  120 , the electrolyte  122  evolves gas  124 , expanding the diaphragm  118  (i.e., moving the diaphragm  118  upwards in  FIG. 3 ) and forcing liquid (e.g., drug) out of the drug reservoir  110 , into and through the cannula  112 , and out the distal end thereof to the delivery vehicle  106  (see  FIG. 1 ). The diaphragm  118  may be corrugated or otherwise folded to permit a large degree of expansion without sacrificing volume within the drug reservoir  110  when the diaphragm  118  is relaxed. When the current is stopped, the electrolyte gas  124  condenses back into its liquid state  122 , and the diaphragm  118  recovers its space-efficient corrugations. The electrolytic pump  114  may be smaller and more portable than other pumps because of its lack of rigidly moving parts. A high degree of pressure (i.e., greater than 20 psi) can be generated, allowing the drug pump assembly  104  to overcome any biofouling or blockages in the system. 
     The diaphragm  118  may be made with or from parylene polymer using microfabrication techniques. The electrodes  120  may be any suitable metal, such as platinum, titanium, gold, and copper, among others. Titanium has the advantage of not causing recombination of hydrogen and oxygen gas, making for a more efficient system compared to platinum, which causes hydrogen and oxygen gas to combine into water in its presence. It may be desirable, however, for some refillable devices to employ platinum electrodes. 
     The drug-delivery device  100  also includes a control system  130 , as depicted in  FIG. 4 . The illustrated control system  130  includes a battery  132  for powering the drug-delivery device  100 , a programmable system controller  134  for controlling the drug-delivery device  100 , a pump driver  136  for controlling the pump  114 , a system memory  138 , a flow interface  140  for relaying information obtained through feedback circuitry  142  from the sensor  114  to the system controller  134 , and as appropriate to the application, other electronics and monitoring components generically indicated at  144 . A multi-LED display  146  (see  FIG. 1 ) may also be included to indicate the current status of the device  100 . The components of system  130  may be mounted on a circuit board, which is desirably flexible and/or may be an integral part of the pump housing. 
     The system controller  134  receives signals from the flow sensor  115  and interprets these to measure the amount of liquid dispensed through the cannula  112 . Executable instructions in the system memory  138 , which are straightforwardly provided without undue experimentation, dictates the actions of the system controller  134  in general and in response to the received signals in particular. For example, the system controller may be programmed to dispense a particular amount of liquid at fixed intervals. As these intervals occur, the system controller  134  actuates the delivery vehicle  106  and then the electrolysis pump  114 . When the signals from the flow sensor  115  indicate that the proper dosage has been administered, the system controller  134  terminates the operation of the pump  114  and, if appropriate, causes retraction of the delivery vehicle  106 . 
     The system controller  134  also assesses the flow through the cannula  112  as reported by the flow sensor  115  and takes corrective action should the flow rate deviate sufficiently from a programmed or expected rate. For example, where the system controller  134  determines that a higher flow rate of drug is needed, it may increase the current to the electrolysis electrodes  120  to evolve greater gas in the electrolysis chamber  116 , thereby more rapidly expanding the diaphragm  118  and increasing the fluid flow rate through the cannula  112 . Alternatively, where the system controller  134  determines that a lower flow rate of drug is needed, it may decrease the current to the electrolysis electrodes  120  to evolve less gas in the electrolysis chamber  116 , thereby reducing the rate of expansion of the diaphragm  118  and decreasing the fluid flow rate through the cannula  112 . Depending upon the particular application for which the drug-delivery device  100  is employed, the flow rate requirements for fluid flowing through the cannula  112  may range from the nL/min to the μL/min flow scales. 
     The control system  130  is capable of controlling the drug-delivery device  100  to deliver either continuous infusion or intermittent drug delivery to the subcutaneous layer. For example, the stored instructions may implement a “dinner pump” where a 150 μL dose of insulin is needed immediately after dinner, but another 850 μL is dispensed at a “basal rate” over 6 hours while the patient sleeps. The drug-delivery device  100  may be configured to achieve sustained drug release over periods ranging from several hours to several months. The dosage events may be programmed to occur at specific times or time intervals, or they may take place in response to changing conditions in the patient. For example, in some embodiments, electronics  144  includes a conventional microelectronic communication module facilitating bidirectional wireless data transfer with an external transceiver, allowing a clinician to alter the programming in system memory  138  should the patient&#39;s condition change. 
     In one embodiment, the drug-delivery device  100  is automatically activated once the skin patch  102  is unwrapped and moisture is sensed. Other embodiments of the drug-delivery device  100  may be manually activated as described above. In some of these embodiments, for example, the pump  114  can be toggled on and off with a manual push. Optionally, the pump  114  can also be manually forced to speed up or slow down by means of wirelessly transmitted commands or manual control of user-accessible controls. In alternative embodiments, the pump  114  is activated when the lancet  106  is inserted into the skin. The device  100  may alert the patient that drug delivery is complete by, for example, issuing a signal or retracting the lancet  106 , as previously discussed. 
     The battery  132  may be a non-rechargeable lithium battery approximating the size of batteries used in wristwatches, though rechargeable Li—PON, lithium polymer batteries, nickel-metal-hydride, and nickel cadmium batteries may also be used. Other devices for powering the drug-delivery unit  100 , such as a solar cell or motion-generated energy system, may be used either in place of the battery  132  or supplementing a smaller battery. This can be useful in cases where the patient needs to keep the drug-delivery device  100  on for several days or more. 
     In another embodiment, as depicted in  FIGS. 5A and 5B , a drug-delivery device  200  includes the same components as the drug-delivery device  100 , but in a different configuration. The drug-delivery device  200  includes an adhesive patch in two parts, a drug pump portion  202   a  and a removable, replaceable infusion set portion  202   b ;  FIG. 5B  shows the device with the shell or case removed from the portion  202   a . That portion includes a drug pump  204 , a reservoir  210 , a cannula  212 , and an electrolytic pump  214  to move fluid from the reservoir  210  to the cannula  212  into a delivery vehicle which is part of an infusion set  250  on device portion  202   b . A control system  230  is disposed below electrodes  220 . The infusion set portion  202   b  includes the infusion set  250  and a fluid coupling for removably but sealably receiving the cannula  212 . The infusion set  250  also includes a delivery vehicle and any of the mechanisms that may be associated with it, as discussed above in relation to the delivery vehicle  106 . Both parts of the patch  202   a ,  202   b  each reside within a small, planar envelope, and each overlies a discrete adhesive patch  208 . All operations of the drug-delivery device  200  may be identical to that of the drug-delivery device  100 , as previously described. An advantage to the device  200  is the ability to leave the pump portion  202   a  in place while changing the infusion set  250 , merely by manually disengaging the device portion  202   b  from the cannula  212  and lifting the portion  202   b  (and its adhesive patch) from the skin. 
     Some embodiments, as illustrated in  FIGS. 6A-6C , contain multiple pumps on a single patch. Various configurations are possible: each pump with its own reservoir but sharing a delivery with one or more (or all) other pumps; each pump with its own reservoir and delivery vehicle; and a common reservoir accessed by all pumps, which may use one or more shared delivery vehicles or may each have its own delivery vehicle. With reference to  FIG. 6A , a drug-delivery device  300  contains a plurality of reservoirs  310  and pumps  314  (each with the components shown in  FIG. 1 , but controlled by a single pump controller) that reside on a single adhesive patch  316 . The patch  316  may have a sandwich configuration retaining a sponge or pad impregnated with saline solution (i.e., approximately 0.9% saline) for osmotic control. This may augment the flexibility of the patch  316  while also protecting the pumps  314  from mechanical damage and discouraging evaporation of drug. Each of the reservoirs  310  and the pumps  314  empty into a single conduit  318 , which is in turn connected to a single cannula and delivery vehicle as indicated at  320 . A control system  330  coordinates the operation of the pumps  314  in the manner described above. The volume of drug stored in each pump  314  may be the same or varied, and may be as little as 50 μL or less. The pumps  314  are arranged in an array and can function either independently or collectively to deliver variable dosage volumes, essentially achieving controllable dosage resolution equal to an average dosage delivered by each pump  314 . The pumps  314  can be arrayed adjacent to each other on the same surface or stacked on top of one another (or both). In any arrangement, all of the pumps  314  and the reservoirs  310  remain within an envelope within the borders of the patch  316 . 
     The reservoirs  310 , each actuated by one or more individual pumps  314 , can store different drugs, facilitating variable drug mixing through selective pump activation. Different drugs can be administered together as part of a drug “cocktail” or separately at different times, depending on the treatment regimen. These multiple reservoirs  310  may also facilitate mixing of agents, such as in the case where a first reservoir stores a first agent and a second reservoir stores a second agent. The first agent may be a drug that is stored in a “dormant” state with a half-life of several months, and the second agent may be a catalyst required for activating the first agent. By controlling the amount of the second agent that reacts with the first agent, the drug-delivery device  300  is able to regulate the potency of the delivered dosage. As noted, the drug-delivery device  300  may be programmed to deliver different drugs at different times, depending on the treatment regimen, and as explained above, in some embodiments pump operation can be altered through commands issued wirelessly to the pump. The array of pumps  314  can be broken into subsets, each of which administers a specific drug at an appropriate time. 
     In another embodiment, the drug-delivery device  300  includes only a single reservoir. The array of pumps  314  draw on the single reservoir to provide highly variable flow rates. If a very high flow rate is desired, all of the pumps  314  can simultaneously active. This allows fine, modular control over the overall flow rate, as well as potentially providing redundancy should any of the pumps fail. 
       FIGS. 6B and 6C  depict another embodiment  400  in which each pump  414  has its own cannula  412  and delivery vehicle  406  on a single adhesive-backed patch  418 . Each pump  414  may also be coupled to its own reservoir  410  (as shown in  FIG. 6B ), or all of the pumps  414  may share a common reservoir  420  (as shown in  FIG. 6C ). The multiple-outlet arrangement can provide uniform dosing throughout a contact area of the delivery vehicles  406 . Parallel operation of the pumps  414  may lead to faster response times and better dosage control. This arrangement also improves the safety and efficacy of patch-based drug delivery by including redundant components that are capable of functioning independently. This prevents the failure of a single pump  414  from interrupting the operation of the drug-delivery device  400 . Side effects, such as scarring and damage to the subcutaneous tissue layer, that result from frequently administered injections may be reduced or avoided, thereby improving quality of life for the patient. Administering several smaller doses over a larger surface area using multiple delivery vehicles  406  may also help to reduce systemic side effects occurring due to a high concentration of drug being delivered to a small target area. 
     In each of the drug-delivery devices  300 ,  400 , other types of drug pumps  314 ,  414  may be used instead of the described electrolytic pumps, particularly those that rely on electro-osmotically actuated, pressure-driven, or mechanically driven mechanisms. Additionally, the pump microarrays may be microfabricated using MEMS processing. Titanium and steel are useful metals in this process. 
       FIG. 7  depicts another embodiment of a drug-delivery device  500  with components identical to those of the drug-delivery device  100 , including a housing  502  and a pump  514 , with the addition of a flexible bladder  560  and a pair of check valves  562 . The flexible bladder  560  may be made of an elastic polymer such as parylene, and is typically disposed between a reservoir  510  and a delivery vehicle  506  to serve as a variable-volume, intermediate storage reservoir. This allows a pump  514  to operate for a shorter duration (e.g., ten minutes) in order to fill the flexible bladder  560 . Once the flexible bladder  560  is sufficiently full, the pump  514  can shut down and allow the flexible bladder  560  to force drug to the delivery vehicle  506  (either a single lancet or an array of machined needles) for an extended period of time (e.g., 50 minutes). In this manner, the drug-delivery device  500  can provide a constant flow rate without constant power. The check valves  562  may be disposed in a cannula  512  between the reservoir  510  and the flexible bladder  560  to prevent backflow, and in the cannula  512  between the flexible bladder  560  and the delivery vehicle  506  to prevent blood or interstitial fluid from entering the reservoir  510  and spoiling the drug. A sensor  515 , such as a pressure sensor, may be disposed in the cannula  512  or the flexible bladder  560  to communicate to the pump control system when the pump  514  needs to restart to fill the flexible bladder  560 . The sensor  515  may be of the types previously described, though using a pressure sensor can increase the consistency of the flow rate improving regulation of the filling cycles of the pump  514 . 
     Having 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.