Drug delivery device with vacuum assisted securement and/or feedback

A drug delivery device includes a housing with at least one pressure communication channel or aperture, which distributes a negative fluid pressure across its base to draw tissue against the device. The device can also include a porous, adhesive layer over the channel(s) or aperture(s), for attaching to tissue. The device can also include a pressure sensor for determining whether there is proper attachment. Further, a bladder may be used instead of the adhesive layer for attaching the device. The bladder, in a partially inflated state, can apply constant pressure across a contact surface causing a flexible adhesive layer attached to the bladder to confirm and adhere to the tissue. Subsequent evacuation of the bladder causes it to deflate and collapse or retract, thereby causing the flexible adhesive layer to pull and stretch the tissue toward the base.

FIELD OF THE DISCLOSURE

The present disclosure relates to drug delivery devices. More particularly, the present disclosure relates to drug delivery devices having vacuum assisted securement and patient/operator feedback.

BACKGROUND OF THE INVENTION

Some drug delivery devices may be configured to be temporarily attached to a patient to deliver a drug or other substance via an injection needle or some other means, over an extended period of time. The device may be attached to the tissue of the patient's abdomen, thigh, arm or some other portion of the patient's body.

Many of these devices have a rigid housing and may use an adhesive disposed on or over the base of the housing to adhere the device to the patient's body tissue. Many of these adhesives yield higher retention performance over an extended period of time when they are initially applied in a uniform manner with high pressure.

Applying a high uniform pressure across the adhesive, when attaching the device to the patient's body, can be difficult because body tissue is soft and often contoured or curved. Consequently, high performance retention of the device to the body over extended periods of time may not be achieved.

To overcome this difficulty, the soft body tissue may be pinched between the device and the bones or other structures behind the body tissue when attaching the device, to achieve device retention over an extended period of time. Unfortunately, pinching the soft body tissue may be uncomfortable or painful for the patient and may not uniformly apply high pressure across the adhesive.

Another method used to overcome low retention performance is to use a stronger adhesive. This method, however, increases discomfort or pain when the device is removed from the patient.

Accordingly, a drug delivery device with improved retention performance over extended periods of time and/or which allows the use of less aggressive adhesives to reduce discomfort or pain upon device removal, is desired.

SUMMARY OF THE INVENTION

Disclosed herein is a drug delivery device. Various embodiments of the drug delivery device may comprise a housing with a rigid base. The rigid base may have a surface defining at least one pressure communication channel or aperture, which distributes a negative fluid pressure across the base that draws body tissue against the base.

In various embodiments, the device may further comprise a porous, adhesive layer disposed over the at least one pressure communication channel or aperture, which adhesively attaches the device to the body tissue. The at least one pressure communication channel or aperture distributes a negative fluid pressure across the adhesive layer, thereby drawing the body tissue uniformly against the entire surface area of the adhesive layer.

In various embodiments, the porous, adhesive layer may be resilient.

In various embodiments, the drug delivery device may comprise a housing, at least one bladder disposed over a base of the housing, and a flexible adhesive layer disposed over the at least one bladder, which adhesively attaches the device to body tissue. The at least one bladder, in a partially inflated or expanded state, conforms to the contour of the body tissue when the device is applied thereto with an application force, the application force thereby being distributed uniformly across the entire surface area of the flexible adhesive layer. Collapsing the at least one bladder against the base, after the device is applied to the body tissue, causes the flexible adhesive layer to pull the body tissue toward the base, thereby stretching the body tissue.

In various embodiments, the at least one pressure communication channel may comprise a spiral-shaped groove having a first end disposed at a central area of the base and a second end which is disposed at a peripheral area of the base.

In various embodiments, the at least one pressure communication channel comprises two or more concentric grooves.

In various embodiments, the rigid base may include a port in fluid communication with the at least one pressure communication channel or aperture, the port for applying the negative pressure to the at least one pressure communication channel or aperture.

In various embodiments, the drug delivery device may further comprise a negative pressure source in fluid communication with the at least one pressure communication channel.

In various embodiments, the negative pressure source may be separate from the device.

In various embodiments, the negative pressure source may be integrated with the device.

In various embodiments, the negative pressure source may comprise a vacuum pump.

In various embodiments, the negative pressure supplied by the vacuum pump may be selected by changing one or more of a speed of the vacuum pump, a stroke length of the vacuum pump, and power to the vacuum pump.

In various embodiments, the drug delivery device may further comprise a valve for adjusting the negative fluid pressure generated by the vacuum pump.

In various embodiments, the valve may have a negative differential pressure setting that can be selected by varying at least one of a pre-compression of a valve biasing element and a valve area that negative fluid pressure is communicated across.

In various embodiments, the drug delivery device may further comprise a controller, wherein the valve may have a negative differential pressure setting that can be selected by the controller.

In various embodiments, the drug delivery device may further comprise at least two fixed-pressure valves connected between the vacuum pump and the at least one pressure communication channel or aperture, wherein the negative fluid pressure supplied by the active pump may be selected by including or excluding one or more of the fixed-pressure valves which alter a flow path of the negative fluid pressure between the active pump and the at least one pressure communication channel or aperture.

In various embodiments, the drug delivery device may further comprise one or more controller actuated valves connected with the one or more fixed-pressure valves, the one or more controller actuated valves may be operative for including or excluding the one or more fixed pressure valves.

In various embodiments, the drug delivery device may further comprise a user-selectable negative fluid pressure selector, which allows a user to select the negative fluid pressure supplied by the vacuum pump.

In various embodiments, the negative pressure source may comprise an oxygen absorber.

In various embodiments, the negative pressure source may comprise a syringe.

In various embodiments, the negative pressure source may comprise an air chamber that expands in volume from a minimum volume state to generate the negative pressure.

In various embodiments, the air chamber may comprise a biasing element for expanding the air chamber from the minimum volume state.

In various embodiments, the air chamber may comprise a flexible air chamber that expands and collapses.

In various embodiments, the drug delivery device may further comprise a user actuated first lever connected to the housing, the first lever for collapsing the air chamber.

In various embodiments, the first lever may compress the biasing element when the user moves the first lever in a first direction.

In various embodiments, the drug delivery device may further comprise a plunger and a cylinder, the plunger and cylinder movably disposed relative to one another. In some embodiments, the air chamber may be formed between the plunger and the cylinder.

In various embodiments, one of the plunger and the cylinder may be movable by the user for collapsing the air chamber.

In various embodiments, one of the plunger and the cylinder may compress the biasing element when pressed by the user.

In various embodiments, the air chamber may include a valve or vent that allows air contained within the air chamber to pass therethrough when the air chamber is collapsed to the minimum volume state and which does not allow air to pass therethrough when the chamber is expanded from the minimum volume state.

In various embodiments, the drug delivery device may further comprise a removable sealing film disposed over the adhesive layer for maintaining the adhesive layer in a sterile condition prior to use of the device. In some embodiments air exhausted from the air chamber when the air chamber is collapsed to the minimum volume state may break a seal between the sealing film and the adhesive layer to facilitate removal of the sealing film.

In various embodiments, activation of the device by the user may release the first lever from the air chamber to allow the biasing element to decompress and expand the air chamber thereby generating the negative pressure in the at least one channel or aperture.

In various embodiments, the movement of the first lever in the first direction may activate the device, the activation of the device thereby causing the first lever to be released from the air chamber to allow the biasing element to decompress and expand the air chamber, thereby generating the negative pressure in the at least one channel or aperture.

In various embodiments, the drug delivery device may further comprise a second lever which facilitates movement of the first lever in the first direction by the user pinching the first and second levers together.

In various embodiments, one of the plunger and the cylinder may allow the biasing element to decompress and expand the air chamber thereby generating the negative pressure in the at least one channel or aperture.

In various embodiments, releasing one of the plunger and the cylinder may expand the air chamber thereby generating the negative pressure in the at least one channel or aperture.

In various embodiments, the drug delivery device may further comprise a controller for controlling the amount of the negative pressure.

In various embodiments, the drug delivery device may further comprise a ballast volume between the plunger and a desired point of negative pressure application.

In various embodiments, the drug delivery device may further comprise a fluid pressure distribution structure for distributing fluid pressure to the at least one pressure communication channel or aperture.

In various embodiments, the fluid pressure distribution structure may comprise a serial structure.

In various embodiments, the serial structure may comprise a primary fluid pressure delivery conduit and two or more secondary fluid pressure delivery conduits extending from the primary fluid pressure deliver conduit.

In various embodiments, the primary fluid pressure delivery conduit may becoupled to a source of fluid pressure.

In various embodiments, the fluid pressure distribution structure may comprise a parallel structure.

In various embodiments, the parallel structure may comprise a plurality of fluid pressure delivery conduits extending from a source of fluid pressure.

In various embodiments, the drug delivery device may further comprise one or more valves disposed in the fluid pressure distribution structure.

In various embodiments, the valves may sequentially open to sequentially distribute the fluid pressure to the at least one pressure communication channel or aperture.

In various embodiments, the secondary fluid pressure conduits may be operative as pressure regulators.

In various embodiments, the secondary fluid pressure conduits may operate as pressure regulator by collapsing at a predetermined negative fluid pressure.

In various embodiments, the valves may have a higher opening negative fluid pressure than the predetermined negative fluid pressure at which the secondary fluid pressure conduits collapse at.

In various embodiments, the one or more valves may open at a predetermined negative fluid pressure.

In various embodiments, the predetermined negative fluid pressure may be higher than a negative fluid pressure applied to the body tissue.

In various embodiments, the drug delivery device may further comprise a sealing ring disposed around an injection needle entry site.

In various embodiments, the drug delivery device may further comprise a sealing ring partially embedded in or disposed on, the adhesive layer and surrounding an opening through which an injection needle of the device can extend through during needle insertion.

In various embodiments, the drug delivery device may further comprise a sealing ring partially embedded in or disposed on, the base of the housing and surrounding an opening through which an injection needle of the device can extend through during needle insertion.

In various embodiments, the drug delivery device may further comprise an injection apparatus including a container for a pharmaceutical product or drug.

In various embodiments, the pharmaceutical product or drug may be selected from the group consisting of TNF inhibitors, antibodies to the calcitonin gene-related peptide receptor, colony stimulating factors, erythropoiesis stimulating agents, apelin receptor agonists, anti-thymic stromal lymphopoietin antibodies, anti-thymic stromal lymphopoietinreceptor antibodies, antibodies that bind human Proprotein Convertase Subtilisin/Kexin Type 9 and tissue inhibitors of metalloproteinases.

In various embodiments, the drug delivery device may further comprise a pressure sensor for sensing the proximity of the body tissue to the device.

In various embodiments, the drug delivery device may further comprise a pressure sensor for sensing whether there is negative fluid pressure drawing the body tissue against the adhesive layer.

In various embodiments, the drug delivery device may further comprise a pressure sensor for sensing whether there is negative fluid pressure drawing the body tissue against the base.

In various embodiments, the pressure sensor senses the negative fluid pressure if the device is properly secured to the body tissue and wherein the pressure sensor does not sense or senses very little negative fluid pressure if the device is improperly secured to the body tissue.

In various embodiments, the pressure sensor outputs a signal which is used by the controller to determine if the device is properly secured to the body tissue of the patient.

In various embodiments, the pressure sensor may comprise an absolute pressure sensor or a differential pressure sensor.

In various embodiments, the pressure sensor may comprise a bellows.

In various embodiments, the bellows compresses when the pressure sensor senses the negative fluid pressure.

In various embodiments, the bellows expands when it senses positive fluid pressure.

In various embodiments, the bellows may include one or more contacts and further comprising a circuit which is closed by the one or more contacts of the bellows if the bellows senses a predetermined positive fluid pressure threshold.

In various embodiments, the drug delivery device may further comprise an element for biasing the bellows in compression and expansion.

In various embodiments, the pressure sensor may be integrated with the plunger and cylinder.

In various embodiments, the pressure sensor may comprise a strain sensor affixed to a predictably flexible surface subject to negative pressure.

In various embodiments, the pressure sensor monitors relative movement between the plunger and the cylinder after the air chamber has been collapsed by depressing one of the plunger and the cylinder.

In various embodiments, the pressure sensor, upon the release of one of the plunger and cylinder, senses a negative pressure if one of the plunger and the cylinder moves and then stops prior to the air chamber returning to a fully expanded state.

In various embodiments, the pressure sensor, upon the release of one of the plunger and cylinder, senses little or no negative pressure if one of the plunger and the cylinder moves to the fully expand the air chamber.

In various embodiments, the pressure sensor may comprise an optical source for generating and an optical signal and an optical receiver for receiving the optical signal.

In various embodiments, the optical receiver does not receive the optical signal generated by the optical source if the device is properly secured to the body tissue and wherein the optical receiver does receive the optical signal generated by the optical source if the device is improperly secured to the body tissue.

In various embodiments, the optical receiver does not receive the optical signal generated by the optical source if negative pressure is generated in the air chamber after the release of one of the plunger and the cylinder and wherein the optical receiver does receive the optical signal generated by the optical source if little or no negative pressure is generated in the air chamber upon the release of one of the plunger and cylinder.

Further disclosed herein is a drug delivery device comprising a housing including a rigid base, the base including a surface having a first pressure communication aperture; an adhesive layer disposed over or on the base, the adhesive layer for adhesively attaching the device to body tissue, the adhesive layer having a second pressure communication aperture aligned with first pressure communication aperture, the apertures exposing a portion of the body tissue; and a pressure sensor for determining whether the device is properly attached to the body tissue by the adhesive layer.

In various embodiments, the pressure sensor may comprise a bellows or a diaphragm.

In various embodiments, the bellows or diaphragm may be expanded to sense whether a negative fluid pressure can be generated between the exposed body tissue and the bellows or the diaphragm.

In various embodiments, the pressure sensor may further comprise a rod attached to the bellows or diaphragm and an electrically powered coil for pulling the rod to expand the bellows or the diaphragm when the coil is energized.

In various embodiments, the speed at which the rod is pulled by the energized coil to expand the bellows or diaphragm determines whether a negative pressure is generated between the exposed body tissue and the bellows or the diaphragm.

In various embodiments, a negative pressure is generated between the exposed body tissue and the bellows or the diaphragm if the rod does not move or moves slowly, thereby indicating that the device is properly attached to the body tissue by the adhesive layer.

In various embodiments, very little or no negative pressure is generated between the exposed body tissue and the bellows or the diaphragm if the rod moves or moves quickly, thereby indicating that the device is improperly attached to the body tissue by the adhesive layer.

In various embodiments, the speed of the rod may be monitored by monitoring the shape of a current through the coil over time.

In various embodiments, the circuit may further comprise an electrical circuit, the circuit including a contact, wherein the rod engages the contact to close the circuit if current applied to the coil creates a magnetic field that is sufficient to move the rod if very little or no negative fluid pressure is generated between the exposed body tissue and the bellows or diaphragm.

In various embodiments, the pressure sensor may further comprise a cable attached to the bellows or diaphragm and an electrically powered motor for pulling and winding the cable to expand the bellows or the diaphragm when the motor is energized.

In various embodiments, the energized motor generates torque to pull and wind the cable to expand the bellows or the diaphragm, wherein the amount of torque required to pull and wind the cable to expand the bellows or diaphragm determines whether a negative pressure is generated between the exposed body tissue and the bellows or diaphragm, and wherein the amount of torque generated by the motor is proportional to the amount of current drawn by the motor.

In various embodiments, a negative pressure may be generated between the exposed body tissue and the bellows or the diaphragm if the motor draws current above a predetermined threshold pulling and winding the cable, thereby indicating that the device is properly attached to the body tissue by the adhesive layer.

In various embodiments, very little or no negative pressure may be generated between the exposed body tissue and the bellows or the diaphragm if the motor draws current below a predetermined threshold pulling and winding the cable, thereby indicating that the device is improperly attached to the body tissue by the adhesive layer.

In various embodiments, the drug delivery device may further comprise a source of a positive fluid pressure, wherein the at least one pressure communication channel or aperture is further operative for distributing the positive fluid pressure across the adhesive layer at the end of injection to indicate dose delivery completion.

In various embodiments, the drug delivery device may further comprise a source of a positive fluid pressure for applying the positive fluid pressure between the device and the body tissue at the end of injection to indicate dose delivery completion.

In various embodiments, the drug delivery device may further comprise a source of a positive fluid pressure, wherein the at least one pressure communication channel or aperture is further operative for distributing the positive fluid pressure across the base at the end of injection to indicate dose delivery completion.

Further disclosed herein is a method for attaching a drug delivery device to a patient. In various embodiments the method may comprise placing the device above body tissue of the patient at a selected drug delivery site; applying a negative fluid pressure to at least one pressure communication channel or aperture provided in a base of a housing of the device, the at least one pressure communication channel or aperture distributing the negative fluid pressure across an adhesive layer disposed over the at least one pressure communication channel or aperture, thereby drawing the body tissue uniformly against the entire surface area of the adhesive layer.

In various embodiments the method may comprise placing the device on body tissue of the patient at a selected drug delivery site with an application force, the device having housing with a base, at least one bladder disposed over the base, and a flexible adhesive layer disposed over the at least one bladder, the at least one bladder being in a partially inflated state to conform to the contour of the body tissue, so that the application force is distributed uniformly across the entire surface area of the flexible adhesive layer; and collapsing the at least one bladder against the base to cause the flexible adhesive layer to pull the body tissue toward the base, thereby stretching the body tissue.

In various embodiments the method may comprise placing the device above body tissue of the patient at a selected drug delivery site; applying a negative fluid pressure to at least one pressure communication channel or aperture defined in a base of a housing of the device, the at least one pressure communication channel or aperture distributing the negative fluid pressure across the base; and drawing the body tissue of the patient against the base with the negative pressure.

In various embodiments, the method may further comprise applying a positive fluid pressure to the at least one pressure communication channel or aperture defined in the base of the housing of the device, the at least one pressure communication channel or aperture distributing the positive fluid pressure across the adhesive layer at the end of injection to indicate dose delivery completion.

In various embodiments, the method may further comprise applying a positive fluid pressure between the device and the body tissue at the end of injection to indicate dose delivery completion.

In various embodiments, the method may further comprise applying a positive fluid pressure to the at least one pressure communication channel or aperture defined in the base of the housing of the device, the at least one pressure communication channel or aperture distributing the positive fluid pressure across the base at the end of injection to indicate dose delivery completion.

The same reference numerals are used in the drawings to identify the same or similar elements and structures in the various embodiments.

DETAILED DESCRIPTION

The drug delivery device in various embodiments may comprise a disposable single use or reusable on-body injector or autoinjector, which automatically delivers a subcutaneous injection of a fixed or patient/operator-settable dose of a drug over a controlled or selected period of time. The drug delivery device is intended for self-administration by the patient, but can also be used by a caregiver or a formally trained healthcare provider (operator) to administer an injection.

In some embodiments, the drug delivery device may include an adhesive system for temporarily attaching the drug delivery device to body tissue (e.g., skin, organ, and muscle) of the patient, and a pneumatic system which generates a negative fluid pressure (i.e., a vacuum suction force) between the device and the body tissue of the patient, at least when the device is being initially applied to the body tissue with an application force. In some embodiments, the negative fluid pressure may be distributed across the entire surface of the adhesive system by the pneumatic system, thereby drawing the body tissue against the entire surface area of the adhesive system. This in turn, allows the application force to be uniformly applied across the entire surface area of the adhesive system, which improves its retention performance, particularly when the device is attached to contoured and/or soft body tissue. The use of the negative fluid pressure or vacuum suction force may be more comfortable for the patient, particularly when applied to soft body tissue, than pinching the tissue between the device and bones or other structures behind the body tissue. The pneumatic system may also allow a less aggressive adhesive system to be used, which reduces discomfort or pain upon device removal by sufficiently improving the performance of the less aggressive adhesive system, to enable short-term wearing of the device (e.g., a 10 minute application of the device). Further, there is a “wet-out” time where the retention performance of the adhesive system improves as the adhesive flows and covers the body tissue of the patient. The pneumatic system can provide additional retention force until the adhesive system has flowed and covered the body tissue and is fully performing. In other embodiments, the drug delivery device may include a pneumatic system which is configured to operate alone without the adhesive system to temporarily attach the device to the body tissue of the patient. In such embodiments, the patient feels no discomfort or pain when the device is removed from the patient's body because the adhesive system has been eliminated.

FIG. 1shows an embodiment of the drug delivery device10according to the present disclosure. The drug delivery device10comprises a housing12, a primary container14for a drug or medicament, a plunger drive mechanism16, an injection needle18, a needle drive mechanism20, a device activation mechanism24, a body proximity sensor26, a pneumatic system30, and an optional adhesive system60.

In various embodiments, the housing12may comprise a top wall12-1, a base or bottom wall12-2, and one or more side walls12-3connecting the top and bottom walls12-1,12-2. The housing12can be a single, unitary component or multiple components or sections that are combined into a single, unit. One or more of the top, bottom, and side walls12-1,12-2,12-3of the housing12may be constructed from a rigid or substantially rigid material including, but not limited to plastic and/or metal. The housing12may be sized to encase the primary container14, the plunger drive mechanism16, the injection needle18, the needle drive mechanism20, the device activation mechanism24, the body proximity sensor26, and one or more components of the pneumatic system30. If provided, the adhesive system60may be disposed on or over an outer surface12-2-1of the bottom wall12-2of the housing12. The housing12of reusable embodiments of the device10may be configured to allow removal and insertion of the primary container14. For example, in some embodiments, the housing12may have a closure (not shown) that allows insertion and removal of the primary container14. In other embodiments, the housing12may be configured so that the bottom wall12-2can be removed from the rest of the housing12to allow insertion and removal of the primary container14. In other embodiments, the housing12may be configured to receive or attach the primary container14or a cartridge module or a cassette containing the primary container14.

In various embodiments, the primary container14may comprise a cylindrical barrel14-1having a first end14-2and a second end14-3disposed opposite the first end14-2. The second end14-3of the barrel14-1may define an opening (not visible) and the first end14-2of the barrel member14-1may be occluded by an end wall14-4. The end wall14-4may include an opening (not visible) for dispensing the drug or medicament stored within the primary container14. The opening may be closed by a pierceable diaphragm or seal (not shown). A stopper14-5may be slidably disposed within the barrel member14-1for expelling the drug or medicament from the container barrel member14-1. In some embodiments, the primary container14may be pre-filled with a drug or medicament.

The primary container14may be coupled to the injection needle18by a tube22that may have a first end22-1connected to the end wall14-4of the primary container14and a second end22-2connected to or in fluid communication with a proximal end or other portion of the injection needle18. In various embodiments, the first end22-1of the tube22may include a piercing mechanism for piercing the seal (if provided) closing the opening in the end wall14-4of the primary container14to allow fluid communication between an interior14-6of the primary container14and the tube22.

In various embodiments, the needle drive mechanism20may be configured to move the injection needle18between first (concealed/withdrawn) and second (insertion) positions. In the first position, the injection needle18may be disposed entirely within the interior12-4of the housing12and concealed from view as shown inFIG. 1. In the second position, at least a portion of the injection needle18may extend out through an opening in the bottom wall12-2of the housing12to penetrate the body tissue of the patient as shown for example, inFIG. 4C. Some embodiments of the needle drive mechanism20may include one or more biasing elements20-1for driving the injection needle18from the first position to the second position to insert the needle18into the patient's body tissue at the injection site and, in some embodiments, for withdrawing the needle18from the patient's body tissue (i.e., return the injection needled18to the first position) after the plunger drive mechanism16completes the drug delivery process. In some embodiments, one or more of the biasing elements20-1can include a spring or other element capable of driving and, in some embodiments, withdrawing the needle18.

In various embodiments, the plunger drive mechanism16may comprise a plunger16-1and plunger drive (not shown) for driving the plunger16-1through the primary container14to expel the drug or medicament therefrom. The plunger drive may comprise a mechanical arrangement of one or more biasing elements such as springs, an electrical/mechanical arrangement comprising one or more motors and/or solenoids and a drive train or transmission, and/or a compressed or liquefied gas, and any combination thereof.

In some embodiments, the plunger drive mechanism16expels the drug or medicament from the primary container14and through the injection needle18into the body tissue of the patient after the needle drive mechanism20inserts the injection needle18into body tissue of the patient. As described earlier, upon completion of drug delivery, the needle drive mechanism20may withdraw the injection needle18from the body tissue and return it to the first position. In other embodiments, a needle safety guard may deploy around the extended injection needle18upon device removal to prevent inadvertent contact therewith. In some embodiments, the needle18can include a conventional rigid injection needle. In other embodiments, the needle18may comprise a soft cannula made, for example, of Teflon or PE, that is introduced with a sharp internal trocar that retracts immediately after insertion, thereby eliminating the need for retraction or protection of the needle18.

In some embodiments, a patient, operator, and/or manufacturer programmable controller17may be provided to control the operation of the plunger drive mechanism16. The controller17, in some embodiments, can comprise a microcontroller. In other embodiments, the controller17can comprise a microprocessor and a memory for storing instructions which are executed by the microprocessor to control the plunger drive mechanism16. In some embodiments, the controller17may be programmed to control the speed of the plunger mechanism to allow constant or variable drug delivery rates and/or to control the stroke of the plunger mechanism to deliver a desired dose of the medicament or drug. In some embodiments, the controller17may be programmed to control needle insertion and withdrawal speeds and/or needle motion.

In various embodiments, the device activation mechanism24may comprise a button24-1or other user interface mechanism, which allows the patient or operator to initiate, trigger, or otherwise activate the device10after it has been properly attached to the body tissue of the patient. The device activation mechanism24may be disposed in the top or side walls12-1,12-3of the housing12. In some embodiments, the activation mechanism24may operate in combination with the controller17to sequentially trigger or cause the activation and/or deactivation of one or more of the pneumatic system30, the needle drive mechanism20, and the plunger drive mechanism16. For example, in some embodiments, an input at the button24-1or other user interface may activate the pneumatic system30to attach or assist in the attachment of the device10to the body tissue of the patient. Once the device10is attached, the needle drive mechanism20may be activated to insert the injection needle18into the body tissue. After needle insertion, the plunger drive mechanism16may be activated to deliver the drug or medicament into the body tissue. Upon completion of drug delivery, the needle drive20may be activated to withdraw the injection needle18from the body tissue. In some embodiments, the pneumatic system30may be deactivated to allow the device10to be removed from the patient's body tissue.

In other embodiments, the activation mechanism24may operate alone without the controller17to sequentially activate one or more of the pneumatic system30, the needle drive20, and the plunger drive mechanism16.

In various embodiments, the body proximity sensor26may comprise an electromechanical sensor that monitors the device attachment process to prevent activation of the device10before it has been properly attached to the body tissue of the patient. In some embodiments, the body proximity sensor26may continue to monitor the device10to detect detachment thereof from the body tissue of the patient during the drug delivery process.

In some embodiments, the electromechanical type body proximity sensor26may include a sensing pin26-1or other depressible or deflectable member that extends through an aperture in the bottom wall12-2of the housing12. The sensing pin26-1may be biased in the extended position by a biasing element26-2, which in some embodiments may include without limitation a spring or other elastic element. As the device10and the body tissue are brought together during the attachment process, the extended sensing pin26-1may be the first part of the device10to contact the body tissue. As the distance or gap between the body tissue and the device10decreases, the extended sensing pin26-1may be pressed into the housing12of the device10or otherwise deflected. When the device10is properly attached and secured to the body tissue, via the pneumatic system30, the sensing pin26-1will have been moved into to a depressed position within the housing12, thereby allowing the operation of the activation mechanism24, followed by needle insertion, drug delivery, needle withdrawal (if applicable) and any other device function of the injection process. If the device10partially or completely disengages from the body tissue, the biasing element26-2pushes and moves the sensing pin26-1back to the extended position. In some embodiments, the moment the sensing pin26-1moves from the depressed position, the device10will terminate the injection process and withdraw the injection needle18from the body tissue and into the housing12. In some embodiments, the body proximity sensor26may be capable of communicating sensor information to the controller17so that the body proximity sensor26may be monitored and/or controlled by the controller17.

Electromechanical-type body proximity sensors26may include, but are not limited to switches and the like, which monitor the movement of the pin or other depressible or deflectable member as it is depressed or deflected during the body sensing process. Depressible and deflectable members can include, but are not limited to compressible pads. Such sensors may use capacitive or resistive methods to detect pad compression. In some embodiments, the body proximity sensor26may comprise an electrical sensor including, but not limited to a capacitive sensing device, an infrared proximity or distance sensor, which does not use depressible or deflectable pins or other moveable members. In some embodiments, the body proximity sensor26may comprise a mechanical sensor or an optical sensor for sensing contact between the device10and the body tissue of the patient.

In various embodiments, the optional adhesive system60may comprise an adhesive laminate62that is capable of allowing positive and negative fluid pressure to pass therethrough and which can, in some versions, conform to the contour of the patient's body tissue at the injection site, particularly soft body tissue. In some embodiments, the adhesive layer62may be a porous sheet layer with a uniform or non-uniform distribution of pores or can include a non-porous sheet layer having one or more openings with a geometrical configuration corresponding to a geometrical configuration of channels and/or apertures in the bottom wall12-2of the housing12of the drug delivery device, as will be described in more detail below. As discussed earlier, the retention performance of the adhesive system60may be assisted by the pneumatic system30.

In various embodiments, the pneumatic system30can comprise a fluid pressure source31which generates a negative fluid pressure (vacuum suction or pressure). The fluid pressure source31, in other embodiments, may be configured to generate positive fluid pressure (e.g., air pressure). In other embodiments, the fluid pressure source31of the pneumatic system30may be configured to generate negative fluid pressure in a first mode of operation and a positive fluid pressure in a second mode of operation.

As shown inFIG. 2A, the pneumatic system30in some embodiments of the device10ofFIG. 1, may further comprise a fluid pressure distribution arrangement formed by a plurality of channels or grooves42(vacuum grooves2) provided in the outer surface12-2-1of the bottom wall12-2of the housing12(illustrated without the optional adhesive system60). Each of the vacuum grooves42may include at least one vacuum port42-1that may extend through the bottom wall12-2of the housing12and pneumatically communicate with the fluid pressure source31of the pneumatic system30(FIG. 1), which supplies negative fluid pressure (e.g. device attachment and retainment) or positive fluid pressure (e.g., device removal). The vacuum grooves42distribute the fluid pressure force across the outer surface12-2-1of the bottom wall12-2of the device housing12. The vacuum grooves42may be separated from another as shown inFIG. 2A, connected to one another (not shown) or some of the vacuum grooves42may be separated from one another while others are connected to one another (not shown), depending upon the desired distribution of the fluid pressure across the bottom wall12-2of the housing12.

As shown inFIG. 2B, other embodiments of the vacuum distribution arrangement of the pneumatic system30may comprise a single continuous vacuum groove44formed in the outer surface12-2-1of the bottom wall12-2of the housing12(shown without the optional adhesive system60). The vacuum groove44may include at least one vacuum port44-1that may extend through the bottom wall12-2of the housing12and pneumatically communicate with the fluid pressure source31of the pneumatic system30(FIG. 1), which supplies negative or positive fluid pressure. As in the previous embodiment ofFIG. 2A, the vacuum groove44distributes the fluid pressure force across the outer surface12-2-1of the bottom wall12-2of the device housing12.

In other embodiments, as shown inFIG. 2C, the vacuum distribution arrangement of the pneumatic system30may comprise one or more apertures46that extend through the bottom wall12-2of the housing12(shown without the optional adhesive system60) and pneumatically communicate with the fluid pressure source31of the pneumatic system30(FIG. 1), which supplies negative or positive fluid pressure. As in the previous embodiments ofFIGS. 2A and 2B, the apertures46distribute the fluid pressure across the outer surface12-2-1of the bottom wall12-2of the device housing12. It should therefore be appreciated that the configuration and/or arrangement of pressure communication channel(s) and/or aperture(s) in the bottom wall12-2of the housing12can vary within the scope of the present disclosure and is not limited to those specific examples disclosed herein. Additional embodiments, in fact, will be disclosed below in reference toFIGS. 2D and 2E.

Referring now toFIG. 3A, the adhesive laminate62of the optionally provided adhesive system60may comprise a compressible porous layer64having a first face surface64-1, a second face surface64-2and one or more side surfaces64-3connecting the first and second face surfaces64-1,64-2. The first face surface64-1may be covered by or coated with a first adhesive layer66that adhesively attaches the laminate62to the outer surface12-2-1of the bottom wall12-2of the device housing12. The second face surface64-2may be covered by or coated with a second adhesive layer68that adhesively attaches the device10to the tissue T of the patient's body (FIG. 3C). The one or more side surfaces64-3may be covered by or coated with a sealing layer70that connects the first and second adhesive layers66,68and hermetically seals the side surface(s)64-3of the porous layer64. In other embodiments, the one or more side surfaces64-3may be sealed by a process that closes off the pores (e.g., a hot knife cutting process or a thermal reflow process). The first adhesive layer66may include one or more openings66-1that are aligned with, and dimensioned and configured to match respective ones of the one or more vacuum grooves or apertures42defined in or by the bottom wall12-2of the device housing12(such as the vacuum grooves or apertures shown inFIGS. 2A-2C, as well as2D and2E described below) to provide fluid communication with the porous layer64to distribute the negative and/or positive fluid pressure, supplied by the fluid pressure source31of the pneumatic system30, across the first surface64-1of the porous layer64of the laminate62. In other embodiments, the one or more openings66-1may be formed in any other suitable pattern which distributes the negative and/or positive fluid pressure supplied by the fluid pressure source31, across the first surface64-1of the porous layer64of the laminate62. The second adhesive layer68may include one or more openings68-1disposed across the second surface64-2of the porous layer64. The one or more openings68-1allow the negative and/or positive fluid pressure applied across the first surface64-1of the porous layer64and transmitted through the porous layer64to its second surface64-2, to be applied across the injection site to draw the body tissue T of the patient against the laminate62in the case of negative fluid pressure (FIG. 3C) or release the device10from the body tissue T of the patient. The one or more openings68-1may be aligned with, and dimensioned and configured to match respective ones of the one or more vacuum grooves or apertures42defined in or by the bottom wall12-2of the device housing12. In other embodiments, the one or more openings68-1may be formed in any other suitable pattern which allows the negative and/or positive fluid pressure to be applied across the body tissue T at the injection site. As shown inFIGS. 3B and 3C, the laminate62may also include openings63-1and63-2for allowing the injection needle18and the sensing pin26-1of the body proximity sensor26to pass therethrough.

The porous layer64of the laminate62can be constructed from an open cell foam material or any other suitable compressible porous material. Each of the first and second adhesive layers66and68of the laminate62can be a double sided, medical adhesive tape that has the one or more openings66-1or68-1punched through it. The first and second adhesive layers66and68can also be made using any other suitable adhesive material which can be formed with openings. A removable sterile liner or barrier film F (FIG. 3B) may be provided, which covers the second adhesive layer68of the laminate62prior to use of the device10. The film F may include a pull tab PT to facilitate removal thereof.

The fluid pressure source31of the pneumatic system30depicted in the device10shown inFIGS. 3A-3C, may comprise one or more vacuum storage receptacles, each of which stores a negative fluid pressure. One or more valves34may be provided for selectively connecting the vacuum storage receptacles31with vacuum ports (not visible) of the one or more vacuum grooves42(or to apertures if applicable) defined in or by the bottom wall12-2of the device housing12, for application of the negative fluid pressure or vacuum contained within the storage receptacles31. The negative fluid pressure stored in each of the vacuum storage receptacles31may be generated or supplied by an external vacuum pump or like mechanism (not shown) that can be removably connected to the receptacles31during the operation and/or manufacturing of the device10.

In operation, the pneumatic system30of the device10generates and distributes the negative fluid pressure across the entire surface area of the laminate62of the adhesive system60, thereby drawing the body tissue T against the entire surface area of the laminate62. This allows an initial application force to be uniformly applied across the entire surface area of the laminate62, which allows the rigid housing12of the device10to be adhered via the adhesive system60to soft tissue with curved and/or uneven contours. Accordingly, the retention performance of the adhesive system60may be improved and needle insertion challenges associated with non-planar tissue surfaces may be reduced.

FIG. 4shows another embodiment of the drug delivery device10-1. The device10-1is similar to the device10ofFIG. 1except it does not include the optional adhesive system60. The negative fluid pressure supplied by the fluid pressure source31of the pneumatic system30and applied to the bottom of the device10-1generates an air-flow or vacuum suction force which draws the body tissue T toward the device10-1. In accordance with the Bernoulli principle, the greater the gap G between the body tissue T and the bottom of the device10-1, the greater the air-flow or vacuum suction force requirement will be. The greater air-flow requirement, in turn, will require a larger reserve of negative fluid pressure or vacuum suction force.

Referring toFIGS. 1 and 4, embodiments of the drug delivery device10,10-1used, for example, in laboratory environments can be connected to a large vacuum pump31-1, which allows the fluid pressure source31to be omitted, bypassed, or supplemented. In such embodiments, large reserves of negative fluid pressure are not a problem. In portable embodiments of the device10, the negative fluid pressure must be supplied by the fluid pressure source31of the pneumatic system30disposed in the housing12of the device10,10-1. In some embodiments, the fluid pressure source31may comprise a small vacuum pump or a syringe. In other embodiments, the fluid pressure source31may comprise one or more oxygen absorbing packets or oxygen absorbers that can be punctured when the pneumatic system is activated. In some embodiments, the oxygen absorbers can be made from iron particles that react with moisture and oxygen to form rust. This process removes oxygen from the environment. One such oxygen absorber is marketed under the brand name Oxy-Sorb. Oxygen makes up approximately 21% of atmospheric content, which may generate up to about −3.0 psi (21%×14.7 psia at sea level) after isolating a volume and then removing the oxygen (at least in its gaseous form). The oxygen absorbers can be disposed within the vacuum distribution arrangement or be disposed remotely from it and connected therewith.

The size of the fluid pressure source31generally depends upon the size of the negative fluid pressure that is required to attach and secure the device10,10-1to the body tissue of the patient. If a larger negative fluid pressures is required, a larger and/or more complex fluid pressure source31may be required, which undesirably increases the mass, size, and/or cost of the device10,10-1. Therefore, it is desirable to minimize the negative fluid pressure requirements of the device10,10-1so that the size of the fluid pressure source31of the pneumatic system30can be kept to a minimum and therefore, minimize the mass, size, and/or cost of the device10,10-1.

FIG. 2Dshows another embodiment of the vacuum distribution arrangement of the pneumatic system30. This vacuum distribution system minimizes the negative fluid pressure requirements in mobile embodiments of the device10,10-1and comprises a spiral-shaped vacuum groove48formed in the outer surface12-2-1of the bottom wall12-2of the housing12. The vacuum groove48may be configured to spiral around the area of the bottom wall12-2where the injection needle18will protrude from the housing12during needle insertion, as this region of the device should be securely retained against the body tissue of the patient during the operation of the device. The vacuum groove48may include at least one vacuum port26-1that extends through the bottom wall12-2of the housing12and pneumatically communicates with the fluid pressure source31(FIGS. 1 and 4) of the pneumatic system30, which supplies negative fluid pressure. As in the previous embodiments of the vacuum distribution arrangement (FIGS. 2A-2C), the spiral-shaped vacuum groove48distributes the negative fluid pressure or vacuum suction force across the outer surface12-2-1of the bottom wall12-2of the device housing12.

Referring again toFIGS. 1 and 4 and 2D, once the device10,10-1with the vacuum distribution arrangement ofFIG. 2Dis attached to body tissue of the patient, particularly a convex area of body tissue T (e.g., the thigh or arm), the central-most portion48-2of the spiral-shaped groove48surrounding the injection needle region of the housing's bottom wall12-2should be positioned to contact the tissue first at the injection site, because the spiral-shaped groove48concentrates air-flow in the region with the smallest gap G1(FIG. 4). This rapidly pulls the tissue toward and engages the injection needle region of bottom wall12of the device10,10-1, thereby sealing the central-most portion of the groove48. The continued application of negative fluid pressure/vacuum suction force from this point enables a gradual distribution of the negative fluid pressure to an expanding area of the housing's bottom wall12-2, as the tissue at the injection site is brought into closer proximity, while not applying or expending the negative fluid pressure to the area with the greatest gap G. Since negative fluid pressure is efficiently used, the negative pressure supply requirements of the device10,10-1are minimized. This, in turn, allows for a smaller pneumatic system30, thus, reducing the mass, size, and/or cost of the device10,10-1.

FIG. 2Eshows another embodiment of the vacuum distribution arrangement of the pneumatic system30. In this embodiment, the bottom wall12-2of the device housing12may comprise a plurality of concentric vacuum grooves50,52,54formed in the outer surface12-2-1thereof (three grooves shown for ease of description and illustration only). Each of the grooves50,52,54may include at least one vacuum port50-1,52-1,54-1, that extends through the bottom wall12-2of the housing12and pneumatically communicates with the fluid pressure source31of the pneumatic system30(FIGS. 1 and 4), which supplies negative fluid pressure. The vacuum grooves50,52,54may be configured to encircle the area of the bottom wall12-2where the injection needle18protrudes from the housing12during needle insertion to securely retain the device against the patient's body tissues during the operation thereof. As in previous embodiments ofFIGS. 2A-2D, the concentric vacuum grooves50,52,54distribute the negative fluid pressure/vacuum suction force across the outer surface12-2-1of the bottom wall12-2of the device housing12.

Referring still toFIG. 2E, the vacuum ports50-1,52-1,54-1in some embodiments can be sequentially opened starting with vacuum port50-1of the smallest diameter groove50, and then opening the vacuum ports52-1and54-1of the larger diameter grooves in order of increasing diameter. Additionally, in some embodiments, the width of each of the grooves50,52,54can progressively decrease moving from the smallest diameter groove50to the largest diameter groove54. Progressively decreasing width of each groove moving from the smallest diameter groove50to the largest diameter groove54operates to normalize the volumes of the grooves50,52,54and their corresponding radial air-flow rates, which pull the body tissue toward the bottom wall12-2of the device housing12.

FIG. 5Ashows an embodiment of a sequential valve arrangement, comprising first, second and third valves50-2,52-2, and54-2, respectively, which prioritizes the application of negative fluid pressure to the body tissue of the patient by sequentially opening the vacuum ports50-1,52-1, and54-1of respective vacuum grooves50,52, and54, shown for example in the embodiment ofFIG. 2E. In some embodiments, the operation of the valves50-2,52-2, and54-2may be controlled by the device controller17(FIGS. 1 and 4). In other embodiments, the valves50-2,52-2, and54-2may comprise check valves including, but not limited to ball check valves, which operate automatically without the need for the controller17. The valve arrangement may further comprise a serial fluid pressure distribution structure extending between the fluid pressure source31and the vacuum ports50-1,52-1, and54-1of respective vacuum grooves50,52, and54. The serial fluid pressure distribution structure may comprise a vacuum supply line56and branch vacuum supply lines (branch lines)56-1,56-2, and56-3. The first valve50-2may be disposed in the vacuum supply line56before the branch line56-1, the vacuum port50-1of the smallest diameter vacuum groove50and the second valve52-2. The second valve52-2may be disposed in the vacuum supply line56before the branch line56-2, the vacuum port52-1of the intermediate vacuum groove52and the third valve54-2. The third valve54-2may be disposed in the vacuum supply line56before the branch line56-3and the vacuum port54-1of the largest diameter vacuum groove54. The first valve50-2can be configured to open at initial contact between the device10and the body of the patient including, but not limited to the threshold travel of the body proximity sensor, or any other similar triggering event. When body tissue is pulled up against the bottom wall12-2of the device housing12, the smallest diameter groove50(FIG. 2E), which encircles the region of the housing bottom wall12-2where the injection needle18protrudes through during needle insertion, seals against the body tissue first (because gap G1is the shortest distance as illustrated inFIG. 4) and the vacuum suction force in that vacuum groove50approaches the negative fluid pressure level of the fluid pressure source31. The second valve52-2can be configured to open in response to an increase in the negative fluid pressure level (increased vacuum suction force) indicating that gap G (FIG. 4) between the bottom wall12-2of the device housing12and the tissue has decreased because the smallest diameter and central-most vacuum groove50is sealed against the tissue. The third valve54-3can be configured to open in response to a further increase in the negative fluid pressure level (further increased vacuum suction force) indicating that gap G between the bottom wall12-2of the device housing12and the body tissue has decreased again because the prior vacuum groove52has sealed against the tissue and so on.

In some embodiments, the negative fluid pressure applied to the tissue of the patient's body can be approximately 0.5 to approximately 4 pounds per square inch gauge (psig) (approximately 3.4 kPa to approximately 27.6 kPa) and can typically be approximately 1.5 psig to approximately 2.5 psig (approximately 10.3 kPa to approximately 17.2 kPa). An approximately 1.5 psig to approximately 2.5 psig (approximately 10.3 kPa to approximately 17.2 kPa) negative fluid pressure may increase the ability of the fluid pressure source31to maintain negative fluid pressure during minor disruptions without exhaustion. In addition, the approximately 1.5 psig to approximately 2.5 psig (approximately 10.3 kPa to approximately 17.2 kPa) negative fluid pressure can provide a good compromise between providing adequate adhesive force while limiting capillary breakage in the body tissue of the patient. Applying a larger negative fluid pressure may allow more opening pressure tolerance in the valves50-2,52-2, and54-2and other components of the system. This in turn, may allow less expensive valves and other components with larger tolerances to be used, thereby reducing the cost of the system.

The fluid pressure distributed in the sequential valve arrangement can be regulated in some embodiments at the vacuum ports50-1,52-1,54-1or other points of application by implementing the branch lines56-1,56-2, and56-3with relatively flexible tubes that collapse upon themselves under the negative fluid pressure (the vacuum supply line56would be implemented with relatively inflexible tubing which does not collapse upon itself under the negative fluid pressure). The flexibility of the branch lines can be selected so that the branch lines56-1,56-2,56-3collapse upon themselves at a desired negative fluid pressure to substantially occlude fluid flow (e.g., air-flow) through the branch lines56-1,56-2,56-3. Accordingly, the flexible branch lines56-1,56-2,56-3operate as inexpensive fluid pressure regulators to limit or prevent the system from applying full negative fluid pressure to the body tissue. The tubing material, durometer, outside diameter, inside diameter, and any combination thereof can be selected to provide the branch tubes56-1,56-2,56-3with the appropriate flexibility so that they collapse and substantially occlude fluid flow at a desired negative fluid pressure. In some embodiments the desired negative fluid pressure can be, but is not limited to −1.5 pounds per square inch differential (psid) to ambient pressure (approximately −10.3 kPa to ambient pressure), i.e., 1.5 pounds per square inch (psi) less than ambient pressure (approximately 10.3 kPa less than ambient pressure).

FIG. 5Bis a table which shows the fluid pressure in pounds per square inch absolute (psia) at various points within the sequential valve arrangement and serial fluid pressure distribution structure (system) embodied inFIG. 5Aat different transitions of the valves and branch lines, according to an illustrative embodiment of the disclosure. The table assumes the system initially seals against the body tissue at vacuum ports50-1,52-1, and54-1and that the system is not constrained by vacuum supply P1. In this embodiment, the flexible branch lines56-1,56-2,56-3are set to close at approximately −1.5 psid to ambient pressure (approximately −10.3 kPa to ambient pressure) and the check valves50-2,52-2,54-2are set to open at approximately 2.0 psid across the valve (approximately 13.8 kPa across the valve). It should be understood that in various other embodiments, the fluid pressure at the various points within the sequential valve arrangement and serial fluid pressure distribution structure ofFIG. 5Acan vary from what is shown in the table ofFIG. 5B, depending upon factors including, but not limited to the closing fluid pressures of the flexible branch lines56-1,56-2,56-3, the opening fluid pressures of the valves50-2,52-2, and54-2, and the like.

If the fluid pressure source31fails, the check valves50-2,52-2, and54-2can maintain the negative fluid pressure. In some embodiments, it may be beneficial for the check valve opening pressure to be higher than the negative pressure applied to the body tissue so that it will be isolated from subsequent lines as well. Therefore, in such embodiments, the valves50-2,52-2, and54-2should have an opening pressure which is at least greater than the closing pressure of the branches lines56-1,56-2,56-3, and the branch line close pressure should be very close to or the same as the pressure applied to the patient. For example, in one non-limiting embodiment, the branch lines56-1,56-2,56-3may close at approximately 1.5 psid below ambient pressure (approximately 10.3 kPa below ambient pressure) and the check valves50-2,52-2, and54-2may open at approximately 2.0 psid differential pressure (approximately 13.8 kPa differential pressure). Accordingly, a loss of seal at the most distal branch line56-3from the fluid pressure source31can still maintain a negative fluid pressure at the body tissue if the check valve opening pressure of the vacuum supply line56is greater than net application of vacuum suction force at the body tissue. If the body tissue seal at the most distal branch line56-3is disturbed, then the next branch line56-2will only retain vacuum suction force equal to the check valve opening pressure. So if the target negative fluid pressure is for example, approximately −1.5 psig (approximately −103 kPa) at the body tissue, the check valves50-2,52-2,54-2along the vacuum supply line56should have an opening pressure of at least 1.5 psid or one breach will affect the subsequent branch line.

Alternatively, using the prior vacuum levels of the grooves as a reference pressure, but not in-line, may allow the grooves50,52,54, to be closed from the vacuum supply of the fluid pressure source31via their corresponding valves50-2,52-2,54-2and maintain vacuum suction even if the negative pressure level of the fluid pressure source31is exhausted due to faulty sealing or challenging tissue geometry.

In further embodiments, the fluid pressure distribution system may comprise a parallel structure of plural vacuum supply lines distributing fluid pressure to the vacuum ports (not shown). Although serial fluid pressure distribution structures may be less costly and simpler to implement than parallel fluid pressure distribution structures, parallel structures may reduce the effect of losing a seal at one or more of the application locations (e.g., vacuum ports) and may reduce the total pressure differential required of the system, because the parallel structures do not require multiple valves in series to minimize disruption impact.

In still further embodiments, the fluid pressure distribution system may comprise a combination of one or more serial and one or more parallel fluid pressure distribution structures.

FIG. 6shows another embodiment of the drug delivery device10-2. In this embodiment of the device10-2the fluid pressure source31comprises two flexible pressure-vacuum chambers70that can each be expanded (to a maximum volume state) and collapsed (to minimum volume state) by the patient or operator via a lever72. The flexible pressure-vacuum chambers70may each comprise a flexible bellows70-1sealed at a first end by a rigid end wall70-2and sealed at a second end by the bottom wall12-2of the device housing12. Each of the levers72may be pivotally attached to the top wall12-1of the device housing12and have a first end72-1that extends through an opening in the top wall12-1of the housing12and a second end72-2that engages the rigid end wall70-2of its respective flexible pressure-vacuum chamber70. Some embodiments of the device10-2may use only a single flexible pressure-vacuum chamber70and other embodiments of the device10-2may use three or more flexible pressure-vacuum chambers70. In addition, the levers72in some embodiments, may be configured to collapse more than one pressure-vacuum chamber70.

Each flexible pressure-vacuum chamber70may contain biasing element74including, but not limited to a coil spring, which assists in re-expanding the pressure-vacuum chamber70after it has been collapsed by the lever72. The second end72-2of each lever72may include a foot72-3that slides on the rigid end wall70-2of the flexible pressure-vacuum chamber70when the lever72pivots during the collapse and expansion of the chamber70.

The levers72may be arranged so that the first ends72-1of the levers72cross one another, thereby allowing the patient to pinch them together to compress or bend the biasing elements74and collapse the flexible pressure-vacuum chambers70to exhaust the air from inside the chambers70, prior to use of the device10-2. In some embodiments, the air can be exhausted through a one-way valve (not shown) provided in the bellows70-1or any other suitable portion of the flexible pressure-vacuum chamber70, which opens under a positive fluid pressure (collapse of the chamber70) and which closes under a negative fluid pressure (expansion of the chamber70). In other embodiments, the air exhausted from the flexible pressure-vacuum chambers70creates a positive fluid pressure which can be applied to the laminate62via the vacuum ports (not visible) of the one or more vacuum grooves42(or apertures42if applicable) defined in or by the bottom wall12-2of the device housing12, which in turn is applied to the removable sterile barrier film, which may cover the laminate62prior to use of the device10-2. The positive fluid pressure applied to the sterile barrier film breaks the seal between the film and the laminate62, thereby facilitating the removal of the film therefrom. When the device10-2is activated, the collapsed flexible pressure-vacuum chambers70(in the minimum volume state) are expanded by the biasing elements contained therein. As the flexible pressure-vacuum chambers70expand, they generate the negative fluid pressure or vacuum suction that is applied to the vacuum ports (not visible of the one or more vacuum grooves42(or apertures42if applicable) defined in or by the bottom wall12-2of the device housing12.

In some embodiments, the levers72can be decoupled from the flexible pressure-vacuum chambers70after activation of the device10-2. In other embodiments, the levers72can be configured to slide rather than pivot to collapse and expand the flexible pressure-vacuum chambers70. In other embodiments, the levers72can also be configured to activate the device10-2. The flexible pressure-vacuum chamber and lever arrangement described above can also be used in embodiments of the device that do not use an adhesive system or which use an adhesive system that comprises a double-sided medical adhesive.

FIG. 7Ashows another embodiment of the device10-3. The device10-3is similar to the devices described earlier except the device10-3comprises a bladder80(depicted in the unpressurized state) attached to the outer surface12-2-1of the bottom wall12-2of the device housing12, and the fluid pressure source of the pneumatic system30comprises a plunger pump82pneumatically coupled to the bladder80. The device10-3can further optionally include a conventional flexible adhesive layer62-1attached to a bottom surface80-1of the bladder80. The plunger pump82may be mounted on the bottom wall12-2of the device housing12and enclosed therein. The bottom wall12-2of the housing12includes one or more ports86, which allow the plunger pump82to pneumatically communicate with the interior of the bladder80to selectively provide negative and positive fluid pressures within the bladder80. One or more valves (not shown) may be provided to selectively close and open the ports86. Openings80-2and80-3extend through the bladder80and adhesive layer62to allow the injection needle18(not visible) and the sensing pin26-1of the body proximity sensor26to extend therethrough. Operation of the device10-3inFIG. 7Awill be described below after a discussion of the plunger pump82.

Referring toFIG. 8A, various embodiments of the plunger pump82may comprise a rigid cylinder82-1of any desired shape including, but not limited to round, elliptical, oval, square, and the like, closed at one end by an end wall82-1-1, and a correspondingly shaped plunger82-2reciprocally disposed in the cylinder82-1. The plunger82-2may include opposing free and working ends82-2-1and82-2-2, respectively. The free end82-2-1of the plunger82-2may extend out through an opening in the side wall of the housing12(FIG. 8D) to allow the patient or operator to depress and thereby actuate the pump82. The space between the working end82-2-2of the plunger82-2and the end wall82-1-1of the cylinder82-1defines a pressure-vacuum chamber82-3. A biasing element82-4including, but not limited to a spring, may be disposed between the working end82-2-2of the plunger82-2and the end wall82-1-1of the cylinder82-1. An elastomeric seal82-5including, but not limited to an O-ring, may be disposed in a groove formed in the inner wall surface of the cylinder82-1, at the opening thereof, or disposed in a groove formed in the outer wall surface of the plunger82-2adjacent to the working end82-2-2thereof, to pneumatically seal the chamber82-3.

As shown inFIG. 8A, the biasing element82-4normally maintains the plunger82-2of the plunger pump82in an extended position relative to the cylinder82-1prior to deployment of the bladder80. When the plunger82-2is pressed into the cylinder82-1to a depressed position by the patient or operator to pressurize and thereby deploy the bladder80or evacuate and thereby retract the bladder80(depending upon the selected operating mode of the pump82), the biasing element82-4is compressed between the working end82-2-2of the plunger82-2the end wall82-1-1of the cylinder82-1, as shown inFIG. 8B. When the plunger82-2is released, as shown inFIG. 8C, either by the patient or by actuation of the activation mechanism, the biasing element82-4moves the plunger82-2back to the extended position from the depressed position. In some embodiments, the releasing the plunger82-2may be used to evacuate and retract the bladder80.

As shown inFIG. 8D, the plunger82-2in some embodiments may include a low vacuum indicator83including, but not limited to a colored or marked section of the plunger82-2. In some embodiments, the indicator83may extend about one third of the way along the outer surface of the plunger82-2from the working end82-2thereof so that it becomes visible if the vacuum level drops below a desired threshold. If this occurs, the patient or operator can push the plunger82-2one or more times to re-establish the appropriate vacuum level which will conceal the indicator83within the device housing12.

FIG. 8Eshows another embodiment of the plunger pump92that comprises a movable cylinder92-1and a fixed plunger92-2disposed within the movable cylinder92-1. The movable cylinder92-1may be pressed by the patient or operator to activate the pump92. The biasing element92-4is disposed outside of the pressure-vacuum chamber92-3. In embodiments of the device that do not require positive pressure, the plunger pump92may include a valve92-5including, but not limited to a flapper valve, which opens under a positive fluid pressure and which closes under ambient or negative fluid pressure. Such a valve may also be used in the pressure pump depicted inFIGS. 8A-8D. A ballast chamber (not shown) may be provided inline after the flapper valve92-5to improve vacuum performance and allow multiple compressions of the plunger92-2.

In some embodiments, the plunger pump82shownFIGS. 8A-8Dor the plunger pump92shown inFIG. 8Emay also be used in the devices shown inFIGS. 1 and 4, which do not include the bladder.

FIGS. 7B-7Ddepict the operation of the device10-3ofFIG. 7Aaccording to an embodiment of the disclosure. Referring first toFIG. 7B, the device10-3may be operated by pressing the plunger82-2of the plunger pump82into the device housing12, which causes the plunger pump82to generate a positive fluid pressure in the interior of the bladder80, which pressurizes the bladder80and at least partially inflates or expands it. A valve (not shown) may be provided in the cylinder82-1or in any other suitable portion of the plunger pump82, to bleed off any excess pressure which may overinflate the bladder80.

InFIG. 7C, the device10-3may be applied to the body tissue T of the patient at a selected injection site with an application force. The partially inflated bladder80, and particularly the bottom wall80-1of the bladder80with the flexible adhesive layer62-1, conforms to the contour of the patient's body tissue T at the injection site when the device10-3is applied thereto. As the bottom wall80-1of the bladder80flexes, it conforms the flexible adhesive layer62-1to the contour of the body tissue T so that the application force is uniformly distributed across the entire surface area of the adhesive layer62-1to more uniformly adhere it to the body tissue T.

Once placed on the body tissue T, the plunger82-2may be released from the depressed position, either manually by the patient/user or by activation of the activation mechanism26. Once released, the plunger pump82generates a negative fluid pressure or vacuum suction force which evacuates air from the interior of the bladder80and causes the bladder80to deflate and retract against the outer surface12-2-1of the bottom wall12-2of the device housing12as shown inFIG. 7D. This causes the flexible adhesive layer62-1, which is adhered to the body tissue T at the injection site, to pull the body tissue T toward the bottom wall12-2of the device housing12, thereby conforming it to the contour of the bottom wall12-2and stretching it taut. In embodiments where the bottom wall12-2of the device housing12is substantially planar, the body tissue T may be stretched into a substantially planar orientation.

The device10-3described with reference toFIGS. 7A-7Dmay also use the pressure-vacuum chamber70and lever72arrangement illustratedFIG. 6instead of plunger pump82(FIGS. 8A-8D) or plunger pump92(FIG. 8E). Further, the plunger pumps82or92may be used as the fluid pressure source31in the devices10,10-1illustrated inFIGS. 1, 3A-3C and 4.

FIG. 9shows another embodiment of the drug delivery device10-4. The device10-4is similar to the device10-3shown inFIGS. 7A-7D, except the bladder100of the device10-4is pre-inflated during the manufacturing of the device10-4or inflated at the time of use to a small positive pressure including, but not limited to approximately 0.5 psig to approximately 8 psig (approximately 3.4 kPa to approximately 55.2 kPa), to hold the flexible adhesive layer62-1away from the bottom wall12-2of the device housing12, prior to the application of the device10-4to the body tissue of the patient. In addition, the bladder100may include an overpressure vent100-3that opens to allow the interior100-2of the bladder100to be evacuated once a minimum application pressure has been reached, thereby allowing the flexible adhesive layer62-1covering the bottom wall100-1of the bladder100to be mechanically retracted to draw the body tissue toward the bottom wall12-2of the device housing12and hold it flat against the device10-4. In some embodiments, the bladder100can be mechanically retracted by a plurality of rods102, provided within the device housing12, which extend through corresponding openings (not visible) formed in the bottom wall12-2of the device housing12and connect to the bottom wall100-1of the bladder100or a base62-1-1of the flexible adhesive layer62-1. Each of the rods92in the shown embodiment may be upwardly biased (toward the top wall12-1of the device housing12) by a biasing element106including, but not limited to a spring, which may be disposed between the bottom wall12-2of the device housing12and a retainer104fixedly disposed at the top of each rod102.

Prior to attaching the device10-4to the body tissue of the patient, the lightly pressurized bladder100of the device10-4pulls the rods102down, which compresses the springs106between the retainers104and the bottom wall12-2of the device housing12, and holds the flexible adhesive layer62-1away from the bottom wall12-2of the device housing12. When the device10-4is placed against the body tissue of the patient and a minimum application pressure is reached, the overpressure vent100-3opens to allow the interior100-2of the bladder100to be evacuated, thereby deflating the bladder100. As the bladder100deflates, the springs106expand and raise the rods102up, thereby retracting the flexible adhesive layer62-1covering the bottom wall100-1of the bladder100toward the bottom wall12-2of the device housing12and drawing the body tissue toward the bottom of the device10-4to hold it flat against the device10-4.

In other embodiments, the rods102may be made using an elastomeric material such as silicone. The elastomeric rods can now function as biasing elements, thereby allowing the separate biasing elements described above to be omitted. The elastomeric rods102can be molded with the base62-1-1of the flexible adhesive layer62-1to reduce the cost of the device10-4.

The inflation pressure of the bladder100may be selected so the bladder100does not completely load the biasing elements, thereby allowing the bladder100to conform to the contour and/or soft body tissue of the patient. Further, the biasing force generated by the biasing elements may be selected so that the peak retraction pressure is at least 15 percent lower than the predicted adhesive performance.

In some embodiments, one or more sealing rings may be provided around the injection needle entry site to isolate the negative fluid pressure from the injection site and to prevent the drug from being withdrawn from the entry site. The sealing ring(s) may comprise without limitation an O-ring made using an elastomeric material. As shown inFIG. 2C, the sealing ring(s)110in some embodiments may be partially embedded in or disposed on the bottom wall12-2of the device housing12. In other embodiments, the sealing ring(s)110may be partially embedded in or disposed on the adhesive laminate62as shown inFIG. 3A. In addition, the sealing ring(s) can be used in any of the embodiments disclosed herein.

FIG. 10Ashows another embodiment of the drug delivery device10-5with a pneumatic system fluid pressure source31comprising an electromechanical (active) pump132, a ballast cylinder or chamber136in fluid communication with the pump132, a user-selectable negative fluid pressure selector (vacuum regulator)134in fluid communication with the ballast chamber136and the vacuum distribution arrangement140in the bottom wall12-2of the device housing12, and a valve138(which can be actuated by the controller17in some embodiments) disposed between the vacuum regulator134and the ballast chamber136for activating and deactivating the fluid pressure source31of the pneumatic system30. The vacuum regulator134allows the patient or operator to select the negative fluid pressure/vacuum suction force supplied by the active pump132and/or ballast chamber136.

As shown inFIG. 10C, in some embodiments the vacuum regulator134may include a housing134-2which defines a chamber134-2-1. The housing134-2includes a chamber inlet134-2-2in fluid communication with the valve138and a chamber outlet134-2-3in fluid communication with the vacuum distribution arrangement140. The regulator chamber134-2-1is closed by a thin flexible cap134-3that flexes under negative fluid pressure/vacuum suction force. A rotatable adjustment knob or selector134-1is provided for allowing a patient or operator adjust or select the negative fluid pressure/vacuum suction force supplied to the vacuum distribution arrangement140by the active pump132and/or ballast chamber136. The selector134-1may have a shaft134-1-2that extends from the back134-1-1thereof. The shaft134-1-2may extend through the cap134-3and threadedly engage the regulator housing134-2. An O-ring seal134-4may be disposed between the back134-1-1of the selector134-1and the outer surface134-3-1of the cap134-3. When the selector134-1is rotated in a first direction, it presses the cap134-3and causes it flex inwardly toward the regulator chamber134-2-1, which increases the negative fluid pressure/vacuum suction force supplied to the vacuum distribution arrangement140by the active pump and/or ballast chamber136. When the selector134-1is rotated in a second opposite direction, it allows the cap134-3to relax and more easily flex in response to vacuum thus pulling in outside air, which decreases the negative fluid pressure/vacuum suction force supplied to the vacuum distribution arrangement140by the active pump and/or ballast chamber136. The selector134-1may be configured as a multi-position selector (not shown) or as an analog, continuously variable selector134-1shown inFIG. 10B.

The ballast chamber136is especially useful in embodiments that use a low-power version of the active pump132and can be omitted when a high-power version of the active pump132is used. The ballast chamber136can eliminate the need or reduce the number of the valves in the vacuum distribution arrangement140.

The negative fluid pressure supplied or generated by the active pump132can be selected or adjusted in some embodiments by changing the speed, stroke length, and/or power to the pump132. In other embodiments, the negative fluid pressure supplied by the active pump132can be selected or adjusted by changing the differential pressure setting of the valve138located before (not shown) or after the pump132(shown inFIG. 10A) via the controller17.

The differential pressure setting of the valve138can be changed mechanically if the valve comprises a check valve139, an embodiment of which is shown inFIG. 10D. The check valve139can comprise a housing139-1, a valve139-2disposed within an interior of the housing139-1, and a valve biasing arrangement139-3for biasing the valve139-2in a closed position. The housing139-1can include an internal partition wall139-1-1that divides the interior of the housing139-1into first and second chambers139-1-2and139-1-3, respectively. The valve139-2can include a head139-2-1and a stem139-2-2. The valve stem139-2-2extends through an opening139-1-1-3in the partition wall139-1-1and can include a threaded free end139-2-2-1. A first surface139-1-1-1of the partition wall139-1-1can include a concentric O-ring groove139-1-1-1-1, located, for example, at location L1or L2depending upon the desired vacuum level, which is disposed opposite the valve head139-2-1. An O-ring139-4is disposed in the O-ring groove139-1-1-1-1. The valve biasing arrangement139-3can include a spring retainer139-3-2for threadedly receiving the threaded free end139-2-2-1of the valve stem139-2-2(threaded coupling), and a spring139-3-1disposed between a second surface139-1-1-2of the partition wall139-1-1and the spring retainer139-3-2. The differential pressure P1/P2setting of the valve139may be selected by varying the pre-compression of the spring139-3-1or other valve biasing element and/or selecting the area of the valve head139-2-1that pressure is communicated across. The pre-compression of the spring139-3-1or O-ring139-4can be increased or decreased by lowering or raising the spring retainer height H, respectively, via the threaded coupling between the threaded free end139-2-2-1of the valve stem139-2-2and the spring retainer139-3-2. The area of the valve head139-2-1that the pressure is communicated across can be selected by locating the O-ring139-4and the O-ring groove139-1-1-1-1at location L1or L2. For example, the area of the valve head139-2-1that the pressure is communicated across can be decreased to area A1by locating the O-ring139-4and the O-ring groove139-1-1-1-1at location L1. The area of the valve head139-2-1that the pressure is communicated across can be increased to area A2by locating the O-ring139-4and the O-ring groove139-1-1-1-2at location L2.

As shown inFIG. 10E, in other embodiments, the negative fluid pressure supplied by the active pump132can be selected or adjusted by altering the flow path (flow routing) to include or omit none of or one or more of fixed-pressure check valves150,152,154either before the pump132, as shown, or after the pump132. The flow path may be altered by opening and/or closing one or more valves160,162,164, which allow the selection of none or one or more of the check valves150,152,154in series, thereby reducing the negative fluid pressure (vacuum level) in the rest of the system170. One or more of the one or more valves160,162,164may comprise controller actuated gate valves.

The body proximity sensor used in the drug delivery devices described earlier (e.g.,FIG. 1) is useful in preventing errors and providing the patient or operator with confidence that the device has been applied correctly. Some patients, however, may find the depressible or deflectable sensing pin26-1of the sensor26extending from the bottom wall12of the device housing somewhat intrusive. Although a capacitive or an optical type body proximity sensor, which has no sensing pin26-1, can be used in place of the pin sensor26, such sensors can require a significant amount of electrical energy to power. Further, some patients may find drug delivery device securement, via the negative fluid or vacuum pressure applied to their body tissue by the pneumatic system, objectionable.

Accordingly, in some embodiments of the drug delivery device, the pneumatic system can be implemented as a non-intrusive body proximity sensor, which replaces the pin, capacitive and optical body proximity sensors described previously. In such embodiments, the pneumatic system may apply a lower, less intrusive negative fluid or vacuum pressure than the pneumatic systems described in the previous embodiments, which apply a negative fluid or vacuum pressure that assists in attaching and retaining or solely attaches and retains the device to the body tissue of the patient.

FIG. 11shows an embodiment of the drug delivery device10-6where the pneumatic system30has been adapted and configured as a body proximity sensor. The device10-6is similar to the device10described earlier and shown inFIG. 1, and therefore can include a housing12, a primary container14for a drug or medicament, a plunger drive mechanism16, an injection needle (not visible), a needle drive mechanism20, a device activation mechanism24, the pneumatic system's fluid pressure source31, the pneumatic system's fluid pressure distribution arrangement (not visible), a controller17and an optional adhesive system60. The device10-6further includes a pressure sensor126in place of the body proximity sensor26ofFIG. 1. The bottom wall12-2of the device housing12may include an opening127(pressure sensing opening) which allows fluid pressure communication between pressure sensor126and the adhesive laminate62of the adhesive system60. The pressure sensor126senses, through the adhesive laminate62, any vacuum pressure (and additionally in some embodiments, the positive pressure) generated between the device10-6and the body tissue of the patient and outputs a signal which can be monitored, for example, by the controller17. If the device10-6is properly secured to the body tissue of the patient, the pressure sensor126should indicate a vacuum pressure between the device and the body tissue. If the device is not properly secured to the body tissue of the patient, the pressure sensor126may indicate very little or no vacuum pressure between the device and the body tissue. The controller17uses the pressure sensor signal to determine whether the device10-6is properly secured to the body tissue of the patient. If the device10-6is determined to be properly secured, the injection process can commence or continue on. If the device10-6is determined to not be properly secured, the injection process will not be commenced or can be terminated. In embodiments where vacuum pressure is not used to assist or solely attach and retain the device to the body tissue of the patient, the pneumatic system30of the device10-6may be adapted and configured to generate a lower negative fluid or vacuum pressure between the device10-6and the body tissue of the patient than the pneumatic system30of the device10described earlier and shown in, for example,FIG. 1. In some embodiments, the vacuum pressure can be generated between bottom wall12-2of the device housing12in area129surrounding the opening for the injection needle and the body tissue of the patient. In other embodiments, the vacuum pressure can be generated across the bottom wall12-2of the device housing12and the body tissue of the patient. In still further embodiments, the pressure sensor, may comprise a strain sensor128affixed to a predictably flexible surface subject to negative pressure such as a wall of the pressure chamber31.

The pneumatic system30may also be capable of generating a positive fluid pressure between the device10-6and the body tissue of the patient to aid in releasing the device10-6from the body tissue of the patient.

The pressure sensor126can be configured to measure absolute pressure or differential pressure, however, differential pressure sensing may allow lower vacuum pressures to be used without compromising sensitivity or increasing the risk of false readings due to using the device across a wide range of atmospheric pressures/altitudes.

FIG. 12Ashows another embodiment of the pressure sensor226of drug delivery device10-6. The pressure sensor226may comprise a flexible bellows226-1, made for example of an elastomeric or a rubber material, which is closed at one end closed by an end wall226-1-1. The bellows226-1is mounted on the device housing bottom wall12-2over the pressure sensing opening127. A coil spring226-2may be disposed within the bellows226-1between the end wall226-1-1and the bottom wall12-2of the device housing12. The pressure sensor226senses through the adhesive laminate62of the adhesive system60the pressure generated between the device10-6(FIG. 11) and the body tissue of the patient.

The pressure sensor226is shown in a neutral state inFIG. 12Awhere no vacuum or positive pressure is applied between the device10-6and the body tissue of a patient. In the neutral state, the bellows226-1may have height H wherein the spring226-2has substantially no compressive or tension force acting on it. As shown inFIG. 12B, if the pressure sensor226senses a vacuum pressure applied between the device10-6and the body tissue of the patient, the bellows226-1compresses the spring226-2and decreases in height to, for example, height HV. As shown inFIG. 12C, if the pressure sensor226senses a positive pressure applied between the device10-6and the body tissue of the patient, the226-1bellows expands the spring226-2and increases in height to, for example, height HP. The height H of the pressure sensor bellows226-1can be monitored using any well-known electrical, magnetic, or optical method to allow the determination of whether the device10-6is properly secured to the body tissue of the patient. In other embodiments, contacts226-3can be provided on the exterior surface of the bellows end wall226-1-1which engage corresponding contacts228-1-1of a circuit228-1provided on, for example, a printed circuit board228, if the positive pressure sensed by the sensor226is above a predetermine pressure (e.g., during release of the device10-6from the body tissue of the patient). In some embodiments, the circuit288-1may be used with the controller17(FIG. 1). In other embodiments, the circuit228-1can be adapted to include all the functionality of the controller17and therefore replace it.

FIGS. 13A-Dshow another embodiment of the drug delivery device10-7where the pneumatic system30has been adapted and configured as a body proximity sensor. The device10-7is similar to the devices10described earlier and shown inFIGS. 1, 2A-2E, and 3A-3C, except that the fluid pressure source of the pneumatic system30comprises a plunger pump182similar to that described earlier and shown inFIGS. 7A-7C. The plunger pump182is adapted and configured to include a pressure sensor183/184(FIGS. 13B-13D).

As shown inFIG. 13B, the plunger pump182may comprise a rigid cylinder182-1closed at one end by an end wall182-1-1, and a correspondingly shaped plunger182-2reciprocally disposed in the cylinder182-1. The plunger182-2may include opposing free and working ends182-2-1and182-2-2, respectively. The free end182-2-1of the plunger182-2extends out from the cylinder182-1to allow the patient or operator to depress and thereby actuate the pump182. The space between the working end182-2-2of the plunger182-2and the end wall182-1-1of the cylinder182-1defines a pressure-vacuum chamber182-3. A biasing element182-4including, but not limited to a spring, may be disposed between the working end182-2-2of the plunger182-2and the end wall182-1-1of the cylinder182-1. An elastomeric seal182-5including, but not limited to an O-ring, may be disposed in a groove formed in the inner wall surface of the cylinder182-1, at the opening thereof, or disposed in a groove (not visible) formed in the outer wall surface of the plunger182-2adjacent to the working end182-2-2thereof, to pneumatically seal the chamber182-3. The cylinder182-1applies vacuum pressure (and positive fluid pressure in some embodiments depending upon the selected pump mode) to the bottom wall12-2of the device housing12(FIG. 13A). The pressure sensor may include any device which is capable of monitoring the movement of the plunger182-2relative to the cylinder182-1. In the shown embodiment, the pressure sensor comprises an optical source183that generates an optical signal S, such as a light beam, and an optical receiver184that receives the optical signal, such as a light sensor. The optical source183can be embedded in or disposed on the surface of the cylinder182-1and the optical receiver184can be embedded in or disposed on the surface of the cylinder182-1opposite the optical source183and aligned therewith so that the optical source183and optical receiver184face one another across the bore of the cylinder182-1. The optical receiver184can be adapted to generate a first output signal that indicates that none or insufficient vacuum pressure is being generated between the device and the patient's body tissue when the optical receiver184receives the optical signal generated by the optical source183. The optical receiver184can also be adapted to generate a second output signal which indicates that sufficient vacuum pressure is being generated between the device and the patient's body tissue when the optical receiver184does not receive the optical signal generated by the optical source183. In some embodiments, the optical receiver184may transmit the output signals to the controller17, which in turn, uses the signals to determine whether to commence with or continue the injection process.

Prior to applying the device10-7to the patient's body tissue, the plunger182-2is pressed into the cylinder182-1to evacuate air from the cylinder182-1as shown inFIG. 13C. The device10-7is then applied to the patient's body tissue and the plunger182-2is released. If the device10-7is properly secured to the patient's body tissue (so that an appropriate vacuum pressure can be generated by the pump182between the device10-7and the body tissue), the biasing element182-4will attempt to move the plunger182-2back out of the cylinder182-1and return it to its original extended position (FIG. 13B) when the plunger182-2is released, thereby generating a vacuum pressure between the device10-7and the body tissue. As the plunger182-2moves back out of the cylinder182-1, the vacuum pressure will increase until the biasing element182-4can no longer move the plunger182-2. As shown inFIG. 13D, the vacuum pressure generated between the device and the patient's body tissue holds the plunger182-2in a partially returned position and blocks the optical signal generated by the optical source183so that the optical receiver184receives no signal. The optical receiver184, in turn, generates the second output signal which indicates that vacuum pressure is being sensed between the device10-7and the patient's body tissue. The distance the plunger182-2moves back from the fully depressed position within the cylinder182-1is determined by the relative vacuum pressure between the device10-7and the patient's body tissue, the relative ambient/atmospheric pressure and the force provided by the biasing element such as the compression spring182-4. The location of the optical source183and the optical receiver184in the cylinder182-1should be selected so that the plunger182-2moves back and holds a position relative to the cylinder182-1where it blocks the optical signal S generated by the optical source183so that the optical receiver184cannot receive it, when an appropriate vacuum pressure is generated between the device10-7and the patient's body tissue.

If the device10-7is not properly secured to the patient's body tissue, the biasing element182-4will easily move the plunger182-2back out of the cylinder182-1and return it to its original extended position when the plunger182-2is released, as shown inFIG. 13B, because no vacuum pressure is generated between the device10-7and the body tissue. As the plunger182-2moves back to the extended position, it moves past the location of the optical source183and optical receiver184and allows the optical signal S generated by the optical source183to be received by the optical receiver184. The optical receiver184, in turn, generates the first output signal which indicates that no vacuum pressure is being sensed between the device10-7and the patient's body tissue.

FIG. 14Ashows another embodiment of the pressure sensor326. The sensor326is described in conjunction with an embodiment of the drug delivery device10-8that does not include a pneumatic system and which includes a conventional adhesive layer62-1disposed on or over the housing bottom wall12-2to attach and retain the device10-8to the body tissue of the patient. The sensor326in such an application can be used to determine whether the drug delivery device10-8is properly attached to the body tissue of the patient by the adhesive layer62-1. The pressure sensor326may comprise a flexible bellows326-1, made for example of an elastomeric or a rubber material, having a one end closed by an end wall326-1-1. The bellows may be constructed to have a spring constant. The bellows326-1is mounted so that it is exposed to the body tissue at the injection site. In some embodiments, the bellows326-1can be mounted on the bottom wall12-2of the device housing12over the pressure sensing127opening, which is aligned with a corresponding opening127-1in the adhesive layer62-1. The aligned openings127,127-1expose the sensor326to the underlying body tissue when attached thereto. In some embodiments, the bellows326-1may be constructed to be flat when the sensor326is inoperative and no force is being applied thereto, so that the sensor326is not sensitive to gravity and/or patient orientation. In other embodiments, a diaphragm (not shown) can be used in place of the bellows326-1although the bellows326-1can be displaced a further distance and therefore, improves sensing performance. A magnetic or conductive rod328extends up from the end wall326-1-1of the bellows326-1. A selectively powered coil329surrounds the rod329. In some embodiments a stop (not shown) may be provided above and spaced from the free end328-1of the rod328. In other embodiments, the rod328may be electrically connected by a flexible wire330to a terminal332-2of a circuit332-1which is used to monitor the movement of the bellows326-1and therefore, vacuum pressure. The circuit332-1may be provided on a printed circuit332board disposed above and spaced from the free end328-1of the rod328. The printed circuit board332may include an electrical contact332-3which faces and is aligned with the free end328-1of the rod328. When the rod328engages the electrical contact332-3it closes the circuit332-1.

The pressure sensor326can be used to determine whether the drug delivery device328is properly attached to the body tissue of the patient. The pressure sensor328operates when the coil329is powered. The powered coil329generates a magnetic field (which provides a constant force) that pulls the rod328, which is attached to or unitary with the end wall326-1-1of the bellows328-1, toward the stop (not shown) or toward the overlying circuit contact332-3. If the device10-8is properly attached to the body tissue of the patient, the adhesive layer62-1generates an air seal which allows a vacuum pressure to be generated between the interior side of the bellows326-1-1end wall (the exterior side of the bellows end wall326-1-1is exposed to atmospheric pressure) and area of the body tissue exposed by the pressure sensing openings127,127-1in the housing bottom wall12-2and adhesive layer62-1, as the bellows326-1is pulled away from the body tissue by the rod328when the coil329is powered. In operation, the coil329is powered with a pre-determined and limited amount of electrical power and will pull the rod328a distance proportional to the vacuum pressure behind the bellows326-1. If the air seal is substantially leak-free, a significant and constant force will be required to pull bellows326-1due to the vacuum pressure generated behind the bellows326-1. In some embodiments, the pre-determined electric pulse through the coil329will not create a magnetic field or force that is sufficient to pull the rod328all the way to the circuit contact332-3(or stop); thereby indicating that the device10-8is securely placed on the body tissue and the injection may proceed. Consequently, if the seal generated by the adhesive layer62-1is not substantially leak-free, very little force will be required to pull bellows326because the vacuum pressure behind the bellows326-1will be very small or non-existent. Consequently, the magnetic force created by the coil329will be sufficient to pull the rod328until the free end328-1thereof contacts the circuit contact332-3(or the stop) as shown inFIG. 14B, thereby indicating that the device10-8is not securely placed on the body tissue and the injection should not proceed.

The strength of the magnetic field of the coil329depends upon many factors including, without limitation the geometry of the coil329, the number of turns of the coil329, the voltage (power) supplied to the coil329, and the material of the rod328. The coil329selected and the power supplied to the coil329should allow the free end328-1of the rod328to almost engage the stop (not shown) or the circuit contact332-3at a desired threshold of vacuum pressure.

The shape of the current profile through the coil329can be influenced by the rod328moving through the magnetic field. Therefore, in some embodiments pressure sensing can be performed indirectly by monitoring the shape of the current (I) through the coil329over time (t). If the rod328moves faster or slower through the magnetic field, it will carry inflections in the current waveform.FIG. 14Cshows an example of a current profile for a rod328that does not move or which moves slowly through the magnetic field, thereby indicating a proper seal between the device10-8and the body tissue of the patient. When such a determination is made, the injection process can commence or continue on.FIG. 14D, shows an example of a current profile for a rod328that moves or moves quickly through the magnetic field, thereby indicating an insufficient seal between the device10-8and the body tissue of the patient. If such a determination is made, the injection process should not commence or should not continue on. Differentiating between the current profiles of a proper versus insufficient seal may, in some embodiments, involve sensing the current (calculated using the voltage drop across a small, for example, less than 50 ohm resistor in series with the coil) at a specific time point (e.g., in a certain number of milliseconds) after the initiation of the pulse or as complicated as a nearly complete profile comparison. The current can be sensed in some embodiments by calculating the voltage drop across a small resistor (e.g., less than 50 ohms) which is in series with the coil.

If current profile monitoring is used for pressure sensing, the earlier mentioned stop (not shown) can be used instead of the circuit332-1and contact332-3arrangement described earlier, as it is not needed to monitor the end of the rod travel. In some embodiments, the stop can be cushioned to maintain quiet operation of the sensor326during the injection process.

The sensor326described above and shown inFIGS. 14A and 14Bmay also be used with any of the previously described drug delivery devices that include the pneumatic system.

Referring toFIG. 15A, some embodiments of the sensor426can use a flexible wire-like cable428and an electric motor429in place of the rod326and coil329described above and shown inFIGS. 14A and 14B. One end of the cable428attaches to the end wall426-1-1of the bellows426and the other end attaches to the shaft429-1of the electric motor429(e.g., a DC motor). When the motor429is powered, the shaft429thereof turns and winds-up the cable428, thereby pulling the bellows426-1away from the exposed area of the patient's body tissue, as shown inFIG. 15B. The motor429can be controlled to turn X number of revolutions as determined, for example, by an optical counter (not shown). Since the amount of current driving the motor429is proportional to the torque of the motor429, the current (used to pull and wind the cable428) can be used to indirectly monitor the sensor bellows426-1. For example, if the current used exceeds a predetermined current threshold, this can indicate a proper seal between the device10-8and the patient's body tissue. The optical counter counts the desired number of turns of the motor while monitoring current. The current can be monitored in some embodiments by monitoring the voltage (which is proportional to the current) across a small resistor less than, for example, 50 ohms placed in series with the motor. If a poor seal has been achieved, which causes a leak, this in turn reduces the current draw expected after X turns, whereas a good seal will begin to increase current draw quickly because it's harder for the motor to rotate against the pressure differential. In other embodiments, the displacement of the sensor bellows426-1can be monitored by a circuit432-1, which is closed when contacts426-2provided on the exterior surface of the bellows end wall426-1-1engage corresponding contacts432-2provided on the circuit432-1. The circuit432-1may be provided on a printed circuit board432disposed above and spaced from the end wall426-1-1of the bellows426.

FIG. 16is a flow chart illustrating an embodiment of a method for using the pneumatic system as body proximity sensor in a drug delivery device. The method commences in block300with the removal of the sterile liner from the adhesive laminate of the adhesive system. In block302, the device is applied to the body tissue of the patient and the pneumatic system is activated. In other embodiments, the pneumatic system may be activated prior to applying the device to the body tissue of the patient. Once activated, the pneumatic system generates a vacuum between the device and the body tissue of the patient. In block304, the vacuum pressure sensor monitors vacuum between the device and the body tissue of the patient. In block306a determination is made as to whether the vacuum pressure is at or above a predetermined vacuum pressure threshold. If the vacuum pressure is determined to be at or above the predetermined vacuum pressure threshold, the device will automatically commence or allow manual activation of needle insertion and drug delivery in block308. Once drug delivery is completed, the device will automatically retract the injection needle or enable the release of the needle safety guard in block310. In block312, the pneumatic system will release the vacuum pressure and in some embodiments apply a positive fluid pressure, which indicates to the patient that the injection process is completed. In some embodiments, the device may be constructed to also provide a visual (e.g., display text and/or activate a light) and/or an audible signal (e.g, a beep and/or word) that the injection process has been completed. In block314, the patient or operator removes the device from the body tissue.

The above description describes various systems and methods for use with a drug delivery device. It should be clear that the system, drug delivery device or methods can further comprise use of a medicament listed below with the caveat that the following list should neither be considered to be all inclusive nor limiting. The medicament will be contained in a reservoir. In some instances, the reservoir is a primary container that is either filled or pre-filled for treatment with the medicament. The primary container can be a cartridge or a pre-filled syringe.

For example, the drug delivery device or more specifically the reservoir of the device may be filled with colony stimulating factors, such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the drug delivery device may be used with various pharmaceutical products, such as an erythropoiesis stimulating agent (ESA), which may be in a liquid or a lyophilized form. An ESA is any molecule that stimulates erythropoiesis, such as Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxy polyethylene glycol-epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well as the molecules or variants or analogs thereof as disclosed in the following patents or patent applications, each of which is herein incorporated by reference in its entirety: U.S. Pat. Nos. 4,703,008; 5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422; 5,986,047; 6,583,272; 7,084,245; and 7,271,689; and PCT Publication Nos. WO 91/05867; WO 95/05465; WO 96/40772; WO 00/24893; WO 01/81405; and WO 2007/136752.

Examples of other pharmaceutical products for use with the device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); other biological agents such as Enbrel® (etanercept, TNF-receptor/Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such as Sensipar® (cinacalcet). The device may also be used with a therapeutic antibody, a polypeptide, a protein or other chemical, such as an iron, for example, ferumoxytol, iron dextrans, ferric glyconate, and iron sucrose. The pharmaceutical product may be in liquid form, or reconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins set forth below, including fusions, fragments, analogs, variants or derivatives thereof:

OPGL specific antibodies, peptibodies, and related proteins, and the like (also referred to as RANKL specific antibodies, peptibodies and the like), including fully humanized and human OPGL specific antibodies, particularly fully humanized monoclonal antibodies, including but not limited to the antibodies described in PCT Publication No. WO 03/002713, which is incorporated herein in its entirety as to OPGL specific antibodies and antibody related proteins, particularly those having the sequences set forth therein, particularly, but not limited to, those denoted therein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including the OPGL specific antibodies having either the light chain of SEQ ID NO:2 as set forth therein inFIG. 2and/or the heavy chain of SEQ ID NO:4, as set forth therein inFIG. 4, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;

Myostatin binding proteins, peptibodies, and related proteins, and the like, including myostatin specific peptibodies, particularly those described in U.S. Publication No. 2004/0181033 and PCT Publication No. WO 2004/058988, which are incorporated by reference herein in their entirety particularly in parts pertinent to myostatin specific peptibodies, including but not limited to peptibodies of the mTN8-19 family, including those of SEQ ID NOS:305-351, including TN8-19-1 through TN8-19-40, TN8-19 con1 and TN8-19 con2; peptibodies of the mL2 family of SEQ ID NOS:357-383; the mL15 family of SEQ ID NOS:384-409; the mL17 family of SEQ ID NOS:410-438; the mL20 family of SEQ ID NOS:439-446; the mL21 family of SEQ ID NOS:447-452; the mL24 family of SEQ ID NOS:453-454; and those of SEQ ID NOS:615-631, each of which is individually and specifically incorporated by reference herein in their entirety fully as disclosed in the foregoing publication;

IL-4 receptor specific antibodies, peptibodies, and related proteins, and the like, particularly those that inhibit activities mediated by binding of IL-4 and/or IL-13 to the receptor, including those described in PCT Publication No. WO 2005/047331 or PCT Application No. PCT/US2004/37242 and in U.S. Publication No. 2005/112694, which are incorporated herein by reference in their entirety particularly in parts pertinent to IL-4 receptor specific antibodies, particularly such antibodies as are described therein, particularly, and without limitation, those designated therein: L1H1; L1H2; L1H3; L1H4; L1H5; L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5; L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12; L2H13; L2H14; L3H1; L4H1; L5H1; L6H1, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;

Interleukin 1-receptor 1 (“IL1-R1”) specific antibodies, peptibodies, and related proteins, and the like, including but not limited to those described in U.S. Publication No. 2004/097712, which is incorporated herein by reference in its entirety in parts pertinent to IL1-R1 specific binding proteins, monoclonal antibodies in particular, especially, without limitation, those designated therein: 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the aforementioned publication;

Ang2 specific antibodies, peptibodies, and related proteins, and the like, including but not limited to those described in PCT Publication No. WO 03/057134 and U.S. Publication No. 2003/0229023, each of which is incorporated herein by reference in its entirety particularly in parts pertinent to Ang2 specific antibodies and peptibodies and the like, especially those of sequences described therein and including but not limited to: L1(N); L1(N) WT; L1(N) 1K WT; 2×L1(N); 2×L1(N) WT; Con4 (N), Con4 (N) 1K WT, 2×Con4 (N) 1K; L1C; L1C 1K; 2×L1C; Con4C; Con4C 1K; 2×Con4C 1K; Con4-L1 (N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N); TN8-14 (N); Con 1 (N), also including anti-Ang 2 antibodies and formulations such as those described in PCT Publication No. WO 2003/030833 which is incorporated herein by reference in its entirety as to the same, particularly Ab526; Ab528; Ab531; Ab533; Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551; Ab553; Ab555; Ab558; Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12; AblA1; AblF; AblK, AblP; and AblP, in their various permutations as described therein, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;

NGF specific antibodies, peptibodies, and related proteins, and the like including, in particular, but not limited to those described in U.S. Publication No. 2005/0074821 and U.S. Pat. No. 6,919,426, which are incorporated herein by reference in their entirety particularly as to NGF-specific antibodies and related proteins in this regard, including in particular, but not limited to, the NGF-specific antibodies therein designated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;

CD22 specific antibodies, peptibodies, and related proteins, and the like, such as those described in U.S. Pat. No. 5,789,554, which is incorporated herein by reference in its entirety as to CD22 specific antibodies and related proteins, particularly human CD22 specific antibodies, such as but not limited to humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, particularly including but not limited to human CD22 specific IgG antibodies, such as, for instance, a dimer of a human-mouse monoclonal hLL2 gamma-chain disulfide linked to a human-mouse monoclonal hLL2 kappa-chain, including, but limited to, for example, the human CD22 specific fully humanized antibody in Epratuzumab, CAS registry number 501423-23-0;

B-7 related protein 1 specific antibodies, peptibodies, related proteins and the like (“B7RP-1,” also is referred to in the literature as B7H2, ICOSL, B7h, and CD275), particularly B7RP-specific fully human monoclonal IgG2 antibodies, particularly fully human IgG2 monoclonal antibody that binds an epitope in the first immunoglobulin-like domain of B7RP-1, especially those that inhibit the interaction of B7RP-1 with its natural receptor, ICOS, on activated T cells in particular, especially, in all of the foregoing regards, those disclosed in U.S. Publication No. 2008/0166352 and PCT Publication No. WO 07/011941, which are incorporated herein by reference in their entireties as to such antibodies and related proteins, including but not limited to antibodies designated therein as follow: 16H (having light chain variable and heavy chain variable sequences SEQ ID NO:1 and SEQ ID NO:7 respectively therein); 5D (having light chain variable and heavy chain variable sequences SEQ ID NO:2 and SEQ ID NO:9 respectively therein); 2H (having light chain variable and heavy chain variable sequences SEQ ID NO:3 and SEQ ID NO:10 respectively therein); 43H (having light chain variable and heavy chain variable sequences SEQ ID NO:6 and SEQ ID NO:14 respectively therein); 41H (having light chain variable and heavy chain variable sequences SEQ ID NO:5 and SEQ ID NO:13 respectively therein); and 15H (having light chain variable and heavy chain variable sequences SEQ ID NO:4 and SEQ ID NO:12 respectively therein), each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;

IL-15 specific antibodies, peptibodies, and related proteins, and the like, such as, in particular, humanized monoclonal antibodies, particularly antibodies such as those disclosed in U.S. Publication Nos. 2003/0138421; 2003/023586; and 2004/0071702; and U.S. Pat. No. 7,153,507, each of which is incorporated herein by reference in its entirety as to IL-15 specific antibodies and related proteins, including peptibodies, including particularly, for instance, but not limited to, HuMax IL-15 antibodies and related proteins, such as, for instance, 146B7;

IFN gamma specific antibodies, peptibodies, and related proteins and the like, especially human IFN gamma specific antibodies, particularly fully human anti-IFN gamma antibodies, such as, for instance, those described in U.S. Publication No. 2005/0004353, which is incorporated herein by reference in its entirety as to IFN gamma specific antibodies, particularly, for example, the antibodies therein designated 1118; 1118*; 1119; 1121; and 1121*. The entire sequences of the heavy and light chains of each of these antibodies, as well as the sequences of their heavy and light chain variable regions and complementarity determining regions, are each individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115. In addition, description of the properties of these antibodies provided in the foregoing publication is also incorporated by reference herein in its entirety. Specific antibodies include those having the heavy chain of SEQ ID NO:17 and the light chain of SEQ ID NO:18; those having the heavy chain variable region of SEQ ID NO:6 and the light chain variable region of SEQ ID NO:8; those having the heavy chain of SEQ ID NO:19 and the light chain of SEQ ID NO:20; those having the heavy chain variable region of SEQ ID NO:10 and the light chain variable region of SEQ ID NO:12; those having the heavy chain of SEQ ID NO:32 and the light chain of SEQ ID NO:20; those having the heavy chain variable region of SEQ ID NO:30 and the light chain variable region of SEQ ID NO:12; those having the heavy chain sequence of SEQ ID NO:21 and the light chain sequence of SEQ ID NO:22; those having the heavy chain variable region of SEQ ID NO:14 and the light chain variable region of SEQ ID NO:16; those having the heavy chain of SEQ ID NO:21 and the light chain of SEQ ID NO:33; and those having the heavy chain variable region of SEQ ID NO:14 and the light chain variable region of SEQ ID NO:31, as disclosed in the foregoing publication. A specific antibody contemplated is antibody 1119 as disclosed in the foregoing U.S. publication and having a complete heavy chain of SEQ ID NO:17 as disclosed therein and having a complete light chain of SEQ ID NO:18 as disclosed therein;

TALL-1 specific antibodies, peptibodies, and the related proteins, and the like, and other TALL specific binding proteins, such as those described in U.S. Publication Nos. 2003/0195156 and 2006/0135431, each of which is incorporated herein by reference in its entirety as to TALL-1 binding proteins, particularly the molecules of Tables 4 and 5B, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publications;

Parathyroid hormone (“PTH”) specific antibodies, peptibodies, and related proteins, and the like, such as those described in U.S. Pat. No. 6,756,480, which is incorporated herein by reference in its entirety, particularly in parts pertinent to proteins that bind PTH;

Thrombopoietin receptor (“TPO-R”) specific antibodies, peptibodies, and related proteins, and the like, such as those described in U.S. Pat. No. 6,835,809, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind TPO-R;

Hepatocyte growth factor (“HGF”) specific antibodies, peptibodies, and related proteins, and the like, including those that target the HGF/SF:cMet axis (HGF/SF:c-Met), such as the fully human monoclonal antibodies that neutralize hepatocyte growth factor/scatter (HGF/SF) described in U.S. Publication No. 2005/0118643 and PCT Publication No. WO 2005/017107, huL2G7 described in U.S. Pat. No. 7,220,410 and OA-5d5 described in U.S. Pat. Nos. 5,686,292 and 6,468,529 and in PCT Publication No. WO 96/38557, each of which is incorporated herein by reference in its entirety, particularly in parts pertinent to proteins that bind HGF;

TRAIL-R2 specific antibodies, peptibodies, related proteins and the like, such as those described in U.S. Pat. No. 7,521,048, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind TRAIL-R2;

Activin A specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Publication No. 2009/0234106, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind Activin A;

TGF-beta specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Pat. No. 6,803,453 and U.S. Publication No. 2007/0110747, each of which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind TGF-beta;

Amyloid-beta protein specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in PCT Publication No. WO 2006/081171, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind amyloid-beta proteins. One antibody contemplated is an antibody having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6 as disclosed in the foregoing publication;

c-Kit specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Publication No. 2007/0253951, which is incorporated herein by reference in its entirety, particularly in parts pertinent to proteins that bind c-Kit and/or other stem cell factor receptors;

OX40L specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Publication No. 2006/0002929, which is incorporated herein by reference in its entirety, particularly in parts pertinent to proteins that bind OX40L and/or other ligands of the OX40 receptor; and

Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural processes. TIMP-3 is expressed by various cells or and is present in the extracellular matrix; it inhibits all the major cartilage-degrading metalloproteases, and may play a role in role in many degradative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequence of TIMP-3, and the nucleic acid sequence of a DNA that encodes TIMP-3, are disclosed in U.S. Pat. No. 6,562,596, issued May 13, 2003, the disclosure of which is incorporated by reference herein. Description of TIMP mutations can be found in U.S. Publication No. 2014/0274874 and PCT Publication No. WO 2014/152012.

Also included are antagonistic antibodies for human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecule that target the CGRP receptor and other headache targets. Further information concerning these molecules can be found in PCT Application No. WO 2010/075238.

Additionally, a bispecific T cell engager antibody (BiTe), e.g. Blinotumomab can be used in the device. Alternatively, included can be an APJ large molecule agonist e.g., apelin or analogues thereof in the device. Information relating to such molecules can be found in PCT Publication No. WO 2014/099984.

In certain embodiments, the medicament comprises a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody. Examples of anti-TSLP antibodies that may be used in such embodiments include, but are not limited to, those described in U.S. Pat. Nos. 7,982,016, and 8,232,372, and U.S. Publication No. 2009/0186022. Examples of anti-TSLP receptor antibodies include, but are not limited to, those described in U.S. Pat. No. 8,101,182. In particularly preferred embodiments, the medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated as A5 within U.S. Pat. No. 7,982,016.

Although the drug delivery devices, methods, and systems have been described in terms of illustrative embodiments, they are not limited thereto. Rather, the appended claims should be construed broadly to include other variants and embodiments of same, which may be made by those skilled in the art without departing from the scope and range of equivalents of the devices, methods, and systems.