Drug delivery system with temperature-sensitive control

Abstract

To provide a drug delivery system including temperature-sensitive control.SOLUTION: A drug delivery system includes a reservoir 102 and a drug delivery device 104 combined with the reservoir 102. The drug delivery device 104 also may include at least one temperature-sensitive component, and a safety device 112 having locked and unlocked states. The system further includes an output device 108, a controller 110 combined with the safety device 112 and the output device 108. The controller 110 may also include a temperature sensor, or may be combined with the temperature sensor. The controller 110 is configured to determine if the temperature of a drug in the reservoir 102 or of the temperature-sensitive component is above an upper limit, below a lower limit, or between the upper and lower limits, and to activate the safety device 112 in either event. The controller 110 is configured to determine, directly or indirectly, if the temperature subsequently is between the upper and lower limits, and to unlock the safety device 112 according to a consequence thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 61 / 895,285, filed October 24, 2013, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] This patent relates to drug delivery systems, and more particularly to drug delivery systems that include temperature sensitive control of drug delivery and / or the drug delivery system.

[0003] Patients are administered medications for the treatment of a wide variety of medical conditions. Some medications are administered orally, topically, transmucosally, or by inhalation, while others are administered by injection or infusion. These injections or infusions may be administered intradermally, subcutaneously, intramuscularly, intravenously, or intraperitoneally. Typically, injections or infusions use a hollow cannula or needle through which the medication passes from a reservoir to the patient.

[0004] For subcutaneous and intramuscular injections, there has been a great deal of interest in achieving reproducibility in the insertion of the cannula or needle through the skin, positioning the needle at the appropriate depth in the body, and in achieving reproducibility in the rate of delivery when administering the cannula or needle to the patient. Often, achieving reproducibility in the rate of delivery involves reproducibility in the movement of the plunger inside the syringe or cartridge. Various mechanical devices have been designed to controllably release stored energy to insert the needle into the patient and to push the plunger into the syringe or cartridge. Springs, motors, chemical reactions, and phase change materials have all been considered as the driving force for moving the needle and / or plunger. Reproducibility of movement is considered crucial for consistent drug delivery.

[0005] When such a drug delivery device includes a controller, the controller controls the stored energy source to ensure that the energy is released in a repeatable manner, which may involve activating various springs and motors such that each of their movements occurs in a predetermined sequence, thereby ensuring safe and effective drug delivery to the patient through the cannula or needle. Summary of the Invention

[0006] According to one aspect of the disclosure, a drug delivery system includes a reservoir adapted to receive a drug and a drug delivery device coupled to the reservoir for delivering the drug from the reservoir. The drug delivery device further includes a safety device having a locked state in which drug delivery from the reservoir is restricted and an unlocked state in which drug delivery from the reservoir is not restricted. The system further includes a temperature sensor, an output device, and a controller coupled to the safety device, the temperature sensor, and the output device. The controller is programmed to (a) determine whether a temperature of the drug disposed in the reservoir is higher than an upper limit, and if the temperature is higher than the upper limit, activate the output device at least once and place the safety device in the locked state, (b) determine whether a temperature of the drug disposed in the reservoir is lower than a lower limit, and if the temperature is lower than the lower limit, activate the output device at least once and place the safety device in the locked state, and (c) determine whether the drug temperature is between the upper and lower limits after (b), and place the safety device in the unlocked state if the temperature is between the upper and lower limits.

[0007] According to another aspect of the present disclosure, a drug delivery system includes a reservoir adapted to receive a drug and a drug delivery device coupled to the reservoir for delivering the drug from the reservoir. The drug delivery device also includes at least one temperature sensitive component and a safety device having a locked state in which drug delivery from the reservoir is restricted and an unlocked state in which drug delivery from the reservoir is not restricted. The system further includes a temperature sensor, an output device, and a controller coupled to the safety device, the temperature sensor, and the output device. The controller is programmed to: (a) determine whether a temperature of the at least one temperature sensitive component is higher than an upper limit, and if the temperature is higher than the upper limit, activate the output device at least once and place the safety device in the locked state; (b) determine whether a temperature of the at least one temperature sensitive component is lower than a lower limit, and if the temperature is lower than the lower limit, activate the output device at least once and place the safety device in the locked state; and (c) determine whether a temperature of the at least one temperature sensitive component is between an upper limit and a lower limit after (b), and place the safety device in the unlocked state if the temperature is between the upper limit and the lower limit.

[0008] According to yet another aspect of the present disclosure, a drug delivery system includes a reservoir adapted to receive a drug and a drug delivery device coupled to the reservoir for delivering the drug from the reservoir. The drug delivery device also includes a safety device having a locked state in which drug delivery from the reservoir is restricted and an unlocked state in which drug delivery from the reservoir is not restricted. The system further includes a temperature sensor, an output device, and a controller coupled to the safety device, the temperature sensor, and the output device. The controller is programmed to (a) determine whether a temperature of the drug disposed in the reservoir is higher than an upper limit, and if the temperature is higher than the upper limit, activate the output device at least once and set the safety device to the locked state, (b) determine whether a temperature of the drug disposed in the reservoir is lower than a lower limit, and if the temperature is lower than the lower limit, activate the output device at least once and set the safety device to the locked state, and (c) determine whether a certain amount of time has elapsed since (b), and if the time has elapsed, set the safety device to the unlocked state.

[0009] According to yet another aspect of the present disclosure, a drug delivery system includes a reservoir adapted to receive a drug and a drug delivery device coupled to the reservoir for delivering the drug from the reservoir. The drug delivery device also includes a safety device having a locked state in which drug delivery from the reservoir is restricted and an unlocked state in which drug delivery from the reservoir is not restricted. The system further includes an output device and a controller coupled to the safety device and the output device. The controller includes a temperature sensor and is configured to (a) determine whether a temperature of the drug disposed in the reservoir is below a lower limit, and if the temperature is below the lower limit, activate the output device at least once and place the safety device in the locked state, and (b) determine whether the drug temperature is between an upper limit and a lower limit after (a), and place the safety device in the unlocked state if the temperature is between the upper limit and the lower limit. Additionally or alternatively, the controller may be configured to determine whether the drug exceeds the upper limit and take appropriate action if so.

[0010] According to yet another aspect of the present disclosure, a method of delivering a pharmaceutical product includes determining whether a temperature of a pharmaceutical product disposed in a reservoir is below a lower limit, activating an output device at least once if the temperature is below the lower limit, and instructing a user of the pharmaceutical delivery system, if the output device is activated, to wait a certain amount of time after activation of the output device before operating the pharmaceutical delivery device.

[0011] The present disclosure will be more fully understood from the accompanying drawings and the following description. Some drawings may be simplified by omitting selected elements in order to more clearly show other elements. For any exemplary embodiment, such omission of elements does not necessarily indicate the presence or absence of a particular element unless clearly distinguished by a corresponding textual description. None of the drawings are drawn to scale. [Brief description of the drawings]

[0012] [Figure 1] 1 is a schematic diagram of a drug delivery system according to one embodiment of the present disclosure. [Diagram 2]2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment that accommodates hot and cold drug conditions and controls delivery in direct response to temperature. [Diagram 3] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment in which delivery is controlled in response to hot and cold drug conditions, directly in response to elapsed time, and indirectly in response to temperature. [Figure 4] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment that accommodates hot and cold drug conditions and controls delivery in response to temperature. [Diagram 5] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment that responds to high drug temperature conditions by removal / replacement. [Figure 6] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment incorporating a heater to accommodate low drug temperatures. [Figure 7] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment that accommodates hot drug conditions through removal / replacement and cold drug conditions through the incorporation of a heater. [Figure 8] FIG. 1 is a perspective view of a drug delivery system according to one embodiment of the present disclosure, accompanied by a syringe that may be used to fill the device. [Figure 9] 9 is a cross-sectional view of the drug delivery device taken along line 9-9 of FIG. 8. [Figure 10] 10 is a cross-sectional view of the drug delivery device taken along line 10-10 of FIG. 9. [Figure 11] FIG. 9 is a schematic diagram of a drive section of the drug delivery system of FIG. 8. [Figure 12] FIG. 1 is an enlarged partial cross-sectional view of a barrier system according to the present disclosure for use with a needle, the needle being in a retracted position. [Figure 13] FIG. 13 is an enlarged partial cross-sectional view of the barrier system of FIG. 12 with the needle in the use position. [Figure 14] FIG. 4 is a cross-sectional view showing the position of a temperature sensor. [Figure 15]FIG. 1 is a schematic diagram of a mechanical control according to the present disclosure; [Figure 16] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment that accommodates hot and cold drug conditions and controls delivery in direct response to temperature. [Figure 17] 2 is a block diagram illustrating the operation of the drug delivery system shown in FIG. 1 in an embodiment that accommodates hot and cold drug conditions and controls delivery in passive response to temperature. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The drug can be injected or infused using a wide variety of methods, techniques, and systems. For example, the drug can be filled into a reservoir, such as a syringe, which can be used for subcutaneous administration (injection). Alternatively, the drug can be filled into a reservoir in the form of a syringe or other suitable primary container, such as a cartridge, and the pre-filled syringe or other container can be used in combination with an automatic injector to automate the movement of the plunger inside the syringe or container, and the insertion of the cannula or needle into the patient, as the case may be. As an example, the automatic injector may include a drive (e.g., a motor, a spring, a pressurized reservoir, etc.) for moving the container within the housing and / or moving the plunger within the container by operation of an actuator (e.g., pressing a button). As yet another alternative, the drug can be filled into a reservoir (or container), and a pump or drive (which may take the form of a motor, a spring, a pressurized reservoir, etc.) can operate the reservoir to inject the drug into the patient via a needle, cannula, or catheter. The pump and reservoir may be disposed within a housing, and the housing may be attached to the patient, for example as a body-worn drug delivery system.

[0014] Regardless of the drug delivery system, it is important to take precautions regarding the proper storage of injected or infused drugs. Failure to do so may result in incomplete delivery of the drug and / or therapeutic failure. For example, some medicines require storage at low temperatures (2-8°C), i.e., refrigeration. Exposure to temperatures outside the recommended range may result in degradation of the medicine and require disposal. Exposure to the environment may naturally expose the medicine to temperatures outside the recommended range.

[0015] As drugs are delivered by a wide variety of methods, techniques and systems, there are many different options for storing the drug and the associated drug delivery device. For example, the drug can be refrigerated in a (primary) container or reservoir (e.g., pre-filled syringe, cartridge, etc.) and the associated drug delivery device (e.g., auto-injector, body-mounted drug delivery system) can be stored at room temperature, with the reservoir being combined with the other parts of the drug delivery device when in use. Alternatively, the drug (in a container or reservoir) and the associated drug delivery device can be refrigerated together. For example, the reservoir can be combined with the associated drug delivery device before or during refrigeration, and already assembled when removed from storage. Also, the drug-filled container and drug delivery device can be stored in the same package (e.g., as a kit), while the drug-filled reservoir is not placed in the drug delivery device.

[0016] Cold storage of certain drug products (with or without an associated drug delivery device) may be important to prevent loss of efficacy or incomplete or suboptimal delivery. For example, cold storage may affect the physical properties of the drug product or the operation of the drug delivery device. Some drug products exhibit increased viscosity at low temperatures, which may impede or reduce the predictability of delivery immediately after removal from cold. Some drug products also increase in viscosity with increasing temperature, making delivery more difficult or less predictable the longer they are left at room temperature. Furthermore, cold storage may affect the performance of the drug delivery device when stored in a refrigerator with the drug. For example, it is known that battery discharge varies with temperature, providing less energy as temperatures drop, and if the device uses an internal battery, drug delivery may be more difficult or less predictable immediately after removal from refrigerated storage. Cold storage may also cause discomfort to the patient upon administration. Some patients experience discomfort when administering cold fluids. Additionally, the effect of low temperature on the medication and / or device may slow down the injection / infusion rate, causing discomfort to the patient.

[0017] When the drug product (and possibly the drug delivery device) is removed from storage, exposure to high temperatures may result in suboptimal delivery or delivery of a degraded drug product. As noted above, depending on storage precautions, drug products exposed to high temperatures may require disposal. Exposure to high temperatures may also affect components of the drug delivery device, such as the battery.

[0018] The present disclosure focuses on a drug delivery system that senses temperature changes experienced by the drug and / or delivery device and takes temperature changes into account in controlling the drug delivery and / or operation of the drug delivery device. As a result, a drug delivery system according to the present disclosure can vary the drug and / or device operation in response to temperature, ensuring safe, comfortable and predictable drug delivery over a wide range of environmental and operating conditions.

[0019] 1 is a schematic diagram of a drug delivery system 100 according to one embodiment of the present disclosure. The drug delivery system 100 includes components or subassemblies such as a reservoir 102, a drug delivery device 104, a temperature sensor 106, an output device 108, and a controller 110. Details of these components or subassemblies are described below using a series of non-limiting examples.

[0020] The reservoir 102 is adapted to receive a drug. The drug delivery device 104 is coupled to the reservoir 102 to deliver the drug from the reservoir 102. The drug delivery system 100 includes a safety device 112 having a locked state in which drug delivery from the reservoir 102 is restricted and an unlocked state in which drug delivery from the reservoir 102 is not restricted. In certain embodiments, the safety device 112 substantially prevents drug delivery from the reservoir 102 by placing or maintaining a physical barrier between the drug delivery device 104 and the reservoir 102 or by impeding operation of the drug delivery device 104. In some embodiments, substantially preventing drug delivery from the reservoir 102 may mean that the drug flow rate from the drug reservoir 102 through the delivery device 104 is less than about 15%, 10%, 5%, or 1% of the drug flow rate from the drug reservoir 102 through the delivery device 104 in the unlocked state. Further, in some embodiments, the safety device 112 in an unlocked state may move or remove a physical barrier between the drug delivery device 104 and the reservoir 102, or allow operation of the drug delivery device 104. In certain embodiments, allowing delivery of drug from the reservoir 102 may mean that the drug flow rate from the reservoir 102 through the drug delivery device 104 is at least about 85%, 90%, 95%, or 99% of the maximum drug flow rate from the reservoir 102 through the drug delivery device 104.

[0021] In some embodiments, the controller 110 is combined with the safety device 112, the temperature sensor 106, and the output device 108. The controller 110 may include a processor and a memory, and the processor may be programmed to receive one or more signals from the temperature sensor 106 and control (e.g., activate) the output device 108 and the safety device 112. Alternatively, the controller 110 may be a mechanical or assembled device that integrates the functions of the temperature sensor 106 and the safety device 112 and controls or activates the output device 108. For example, the controller 110 may include a piece of shape memory alloy that assumes a specific shape at a temperature above or below a certain threshold, and the piece of metal may be fixed to a fluid flow path (e.g., a tube) connecting the reservoir 102 and the drug delivery device 104, such that when the piece of metal assumes the shape, it presses against the fluid flow path to open or close the fluid flow path. In this case, the piece of metal functions as the temperature sensor 106 and the safety device 112 and is also part of the controller 110. It will be appreciated that the control unit may include not only mechanical and electrical components or subassemblies, but also chemical or biological components or subassemblies.

[0022] 1 and 2, the controller 110 may be configured (e.g., in an electrical embodiment, programmed to determine) whether the temperature of the drug disposed in the reservoir 102 is above an upper limit, block 130. In some embodiments, this determination may be made based on a signal received by the controller 110 from the temperature sensor 106. If the temperature is above the upper limit, block 130, the controller 110 may activate the output device 108 at least once (e.g., to warn a user that the drug temperature is unsafely high), block 132, and may lock the safety device 112, block 134. If the temperature is below the upper limit in block 130, the controller 110 determines (or is programmed to determine) whether the temperature of the drug disposed in the reservoir 102 is below the lower limit in block 136, and if so, activates the output device 108 at least once in block 138 (e.g., to warn the user that the drug temperature is low enough to compromise safety and / or comfort during delivery and / or predictability of delivery) and locks the safety device 112 in block 140. The controller 110 further determines (or is programmed to determine) whether the drug temperature is between the upper and lower limits in block 142 after block 136 (and blocks 138, 140), and if the temperature is between the upper and lower limits, unlocks the safety device 112 in block 144 and allows operation in block 146. This final step may be coupled with activation of the output device 108 to inform the user that the device is within the acceptable range for delivery.

[0023] 1 and 3, the controller 110 may determine whether the temperature of the drug disposed in the reservoir 102 is higher than an upper limit (e.g., by receiving a signal from the temperature sensor 106) in block 150, and if the temperature is higher than the upper limit, activate the output device 108 at least once in block 152 and lock the safety device 112 in block 154. The controller 110 may also be programmed to determine whether the temperature of the drug disposed in the reservoir 102 is lower than a lower limit (e.g., by receiving a signal from the temperature sensor 106) in block 156, and if the temperature is lower than the lower limit, activate the output device 108 at least once in block 158 and lock the safety device 112 in block 160. Additionally, control unit 110 may determine in block 162 whether a predetermined time has elapsed since block 156 (and 158, 160), and if so, place safety device 112 in an unlocked state in block 164 and permit operation in block 166. In some embodiments, if control unit 110 includes a processor, control unit 110 may be programmed or configured to perform the above-described determinations and activations shown in FIG.

[0024] 1 and 4, the drug delivery device 104 may optionally include at least one temperature sensitive component ("temperature sensitive component") 114 and a safety device 112 having a locked state in which drug delivery from the reservoir 102 is limited and an unlocked state in which drug delivery from the reservoir 102 is not limited. In such an embodiment, the controller 110, in combination with the safety device 112, the optional (or additional) temperature sensor 106, and the output device 108, determines whether the temperature of the at least one temperature sensitive component 114 is greater than an upper limit in block 170, and if so, activates the output device 108 at least once in block 172 and places the safety device 112 in a locked state in block 174. The controller 110 may also determine whether the temperature of the at least one temperature sensitive component 114 is below a lower limit in block 176, and if the temperature is below the lower limit, activate the output device 108 at least once in block 178 and lock the safety device 112 in block 180. The controller 110 may also determine whether the temperature of the at least one temperature sensitive component 114 is between an upper limit and a lower limit after block 176 in block 182, and if the temperature is between the upper limit and the lower limit, unlock the safety device 112 in block 184 and allow operation in block 186. Again, if the controller 110 includes a processor, the controller 110 may be programmed to perform the above-described determinations and activations, or may be otherwise configured to perform these operations. In such an embodiment, the at least one temperature sensitive component 114 may be a battery.

[0025] Further improvements can be made to any of the above embodiments.

[0026] For example, the reservoir 102 may be removable from the drug delivery system 100. In such an embodiment, as shown in Figures 1 and 5, the controller 110 may be configured or programmed to determine whether the temperature of the drug in the reservoir 102 exceeds a particular temperature in block 190. After determining that the temperature exceeds a threshold temperature in block 190 (and after activating an output device in block 192 and a safety device in block 194), the controller 110 may determine (or be programmed to determine) whether the reservoir 102 has been removed and replaced with another reservoir 102 containing the drug since block 190 in block 196. If the reservoir 102 has been removed and replaced with another reservoir 102, the controller 110 may place the safety device 112 in an unlocked state in block 198. Thereafter, the device may again determine in block 190 whether the temperature of the drug disposed in the reservoir 102 is higher than the upper limit, and if not, determine in block 200 whether the temperature of the drug disposed in the reservoir 102 is lower than the lower limit. If the drug temperature in the reservoir 102 is lower than the lower limit, the device may activate the output device 108 at least once in block 202 and lock the safety device 112 in block 204. Additionally, the controller 110 may determine (or be programmed to determine) whether the drug temperature is between the upper and lower limits in block 206 after block 200 (and after blocks 202, 204), and if the drug temperature is between the upper and lower limits, unlock the safety device 112 in block 208 and allow operation in block 210. It will be appreciated that such a method may also be adapted to determine a high temperature condition of a temperature sensitive component 114 (e.g., a battery) of a temperature drug delivery system, monitor a battery replacement, and subsequently operate the system 200.

[0027] In another embodiment, the drug delivery system 100 may include a heater 116 coupled to the controller 110 (see FIG. 1 ) near the reservoir 102 and / or the drug delivery device 104. As shown in FIGS. 1 and 6, the controller 110 may determine (or in the case of an electronic embodiment, may be programmed to determine) whether the temperature of the drug placed in the reservoir 102 exceeds, for example, an upper limit, in block 230. If the temperature is higher than the upper limit, the controller 110 may activate the output device 108 at least once in block 232 and lock the safety device 112 in block 234. If the temperature is lower than the upper limit, the controller 110 may determine (or may be programmed to determine) whether the temperature of the drug placed in the reservoir 102 is lower than a lower limit, in block 236, and if the temperature is lower than the lower limit, may activate the output device 108 at least once in block 238 and lock the safety device 112 in block 240. Additionally, the controller 110 determines (or is programmed to determine) in block 242 whether the drug temperature is between the upper and lower limits after block 236 (and after blocks 238, 240), and if the drug temperature is below the lower limit, the controller 110 activates the heater 116 in block 244, and if the drug temperature is between the upper and lower limits, the controller 110 deactivates the heater 116 in block 246. After or simultaneously with deactivating the heater 116 in block 246, the controller 110 disarms the safety device 112 in block 248 and permits operation in block 250.

[0028] It will be appreciated that the methods of operation of the system 100 described in Figures 2-6 may be combined with one another. For example, the system may implement any of the methods of Figures 2 and 3 in combination with the method of Figure 4, and similarly, Figure 4 may be implemented with reference to a particular time course (as shown for the reservoir in Figure 3) instead of a particular range of temperatures in block 182. Additionally, the steps of blocks 156-164 of Figure 3 may be interchanged with blocks 200-208 of Figure 5. It will also be appreciated from the above that the steps of starting and stopping the heater as shown in blocks 244 and 246 of Figure 6 may be combined with any of the methods of operation shown in Figures 2-5 (e.g., see Figure 7 in comparison with Figure 5).

[0029] Having generally described the construction and operation of the drug delivery system (see Figures 1-7), further exemplary details of the reservoir, drug delivery device, temperature sensor, output device, control, safety devices, and heater are described. In particular, an embodiment of a drug delivery system 300 incorporating features of Figure 1 and adding further details is shown in Figures 8-10.

[0030] 8 illustrates a drug delivery system 300. The system 300 is a wearable, disposable system. The system 300 may include a disposable housing 302 that is attached to the patient or wearer, for example, with an adhesive.

[0031] The disposable housing 302 may be made of a plastic material. As shown in Figure 9, the housing 302 may be made of two sections: a plate 304 that rests against the wearer's skin, and a dome 306 that is attached to the plate 304. The dome is preferably attached by sealing the interface between a periphery 308 of the plate 304 and a periphery 310 of the dome 306.

[0032] 9, the housing 302 has an interior surface 312 and an exterior surface 316 that define an interior space 314. In particular, the plate 304 has an interior surface 318 and an exterior surface 320, and the dome 306 has an interior surface 322 and an exterior surface 324. In the illustrated embodiment, the interior surface 312 of the housing 302 is defined by the interior surfaces 318, 322 of the plate 304 and the dome 306, and the exterior surface 316 of the housing 302 is defined by the exterior surfaces 320, 324 of the plate 304 and the dome 306.

[0033] As described above, the housing 302 may be adapted to be attached to the skin of the wearer. In some embodiments, an adhesive may be used. The adhesive may be adapted to secure and remove the housing from the skin during a single use. As shown in FIG. 9 , the adhesive is disposed on the exterior surface 316 of the housing 302, specifically in a layer 326 on a portion 328 of the exterior surface 320 of the plate 304. Prior to attachment of the housing 302 to the skin of the wearer, the adhesive is covered with a removable disposable sheet 330.

[0034] As shown in Figures 9 and 10, a reservoir 340, a driver 342, a needle 344, and an injector 346 are disposed within the housing 302. In the context of the embodiment shown in Figure 1, the reservoir 340 may correspond to the reservoir 102, and the driver 342, needle 344, and injector 346 may correspond to the drug delivery device 104. It will be appreciated that additional components and subassemblies corresponding to the drug delivery device 104 may be provided.

[0035] In some embodiments, the reservoir 340 is defined, at least in part, by a combination of a rigid-walled cylinder or bore 360 ​​having a port 362 at a first end 364, and a plunger 366 movably fitted along a longitudinal axis 368 of the cylinder 360 between a second end 370 and the first end 364 to expel the medicament from the reservoir 340 through the port 362 (FIG. 9). The plunger 366 can be actuated by manipulation of a driver 342.

[0036] The actuator 342 may be similar in structure and operation to the actuators for moving a plunger of a cylinder as found in U.S. Patent Nos. 6,656,158, 6,656,159, 7,128,727, and 7,144,384, which are incorporated herein by reference for all purposes. As shown in FIG. 11, the actuator 342 may include a plunger arm 372, a motor 374, a transmission 376, and a battery 378. The plunger arm 372 contacts the plunger 366 at at least a first end and pushes the plunger 366 along the cylinder 360. The transmission 376 is coupled to the plunger arm 366 and the motor 374 and moves the plunger arm 372 in response to the operation of the motor 374. The battery 378 provides a power source for the motor 374. The combination of the motor 374, the transmission 376, and the battery 378 may also be considered an actuator.

[0037] In other embodiments, the rigid walled cylinder 360 and plunger 366 of FIG. 9 may be replaced by a deformable, non-rigid pouch. It will be appreciated that if the reservoir 360 is a deformable, non-rigid pouch, a spring-based mechanical system may be used to compress and pressurize the reservoir. In still other configurations, a non-mechanical system may be used to move the plunger 366 or compress the bag. For example, a gas generating system may be used, including a two-component system in which the components are kept separate and combined when gas generation is required. In other embodiments, a swellable gel may be used, where water is introduced from a source internal to the device to increase the gel's volume and move the plunger or compress the pouch. As a further example, a pressurizing agent reservoir may be opened to release the pressurizing agent to move the plunger 366 or compress the pouch. Examples of such devices can be found in U.S. Patent Nos. 5,957,895, 5,858,001, and 5,814,020, which are incorporated herein by reference for all purposes.

[0038] In certain embodiments, the reservoir 340 may be a pre-filled container, such as a pre-filled cartridge or a pre-filled syringe. Alternatively, the delivery system 300 may include a fill port 380 in fluid communication with the reservoir 340. The fill port 380 is adapted to receive a luer tip of a syringe (such as the syringe shown in FIG. 8), but may alternatively be a rubber septum, for example. In use, a healthcare provider can inject medication from a syringe through the fill port 380 into the reservoir 340. The syringe may be provided to the healthcare provider as a pre-filled syringe (which may be filled with any of the materials described herein) with the system 300 as a kit.

[0039] Needle 344 has a retracted position in which tip 390 (actually the entire needle 344) is retracted within housing 302, and a use position in which tip 390 protrudes from housing 302 (see Figures 12 and 13), and an injector 346 moves needle 344 from the retracted position to the use position. Examples of exemplary injectors can be found in U.S. Patent Nos. 7,128,727 and 714,4384, which are incorporated herein by reference for all purposes.

[0040] The needle 344 may be hollow and may be used to administer the agent directly to the patient. Alternatively, the needle 344 may be used in conjunction with a cannula or catheter 392, where the needle 344 is used to insert the catheter 392 into the patient at the injection site, and the agent flows through the catheter 392 into the patient during administration (see Figures 9 and 10). In other words, in certain exemplary embodiments, the system 300 may automatically insert a soft cannula into the subcutaneous tissue.

[0041] As shown in Figures 9, 12, and 13, the housing 302 (specifically the plate 304) may have an opening or hole 394 formed therein through which the needle 344 (and catheter 392) may pass. In certain embodiments, the opening 394 may be unobstructed, i.e., without impediment or impediment to movement of the needle 344 (and catheter 392) through the hole 394. However, a septum 396 (shown in Figures 12 and 13) may be positioned to cover the opening 394 to better maintain sterility of the needle 344 and container integrity (CCI) of the device.

[0042] Septum 396, which may be made of rubber, is disposed between needle 344 (and space 314) and the patient's skin. Needle 344 is in a retracted position (FIG. 12). In a use position (FIG. 13), at least a portion of needle 344 (i.e., tip 390) descends from space 314 through septum 396. Thus, septum 396 always exists as a barrier between interior space 314 and the outside environment.

[0043] The system 300 also includes at least one temperature sensor 400 .

[0044] As shown in FIG. 14, at least one temperature sensor 400 can be located in various locations on the housing 302. For example, in an embodiment in which the reservoir 340 includes a cylinder 360 with a port 362 and a plunger 366 movable within the cylinder 360 relative to the port 362 to expel the drug from the port 362, the temperature sensor 400 can be attached to the plunger 366. In that case, the temperature sensor 400 can be in direct contact with the drug (e.g., placed on an inner surface of the plunger 366 in direct contact with the drug) or indirect contact (e.g., placed or embedded within the plunger 366). Alternatively, the sensor 400 can be located near or in contact with the reservoir 340, for example, near or in contact with a wall of the reservoir 340. This can be particularly useful when the reservoir is removable from the rest of the system 300. Additionally, the sensor can be located near or embedded in the controller. The sensor 400 can also be located near or in contact with the battery 378 (see FIG. 11). The temperature sensor 400 may be associated with a cannula if the reservoir 340 includes a cannula or tube in fluid communication with the reservoir 340. In Figure 14, the temperature sensor 400 is associated with a cannula in the form of a needle 344.

[0045] The temperature sensor 400 can take a variety of forms. For example, the temperature sensor can be a resistive temperature detector, a thermocouple, an infrared thermopile, and / or an assembly with a heat sensitive label and an optical detector. These sensors can be solid-state devices, but can also be of the RFID type. RFID sensors have the advantage over solid-state devices in that they do not require a power source or electrical contact with the device. A solid-state device can be connected to a power source (e.g., a battery) through a set of contacts.

[0046] Regarding the above example, some processor chips typically include a temperature sensor. During operation, heat is generated within the processor, and this local temperature rise can be calculated when determining the temperature using the built-in sensor. The built-in sensor can be used to infer the temperature of other parts of the delivery device, even the temperature of the reservoir, based on the distance of the sensor. If the heat generated is so great that it would affect the temperature determination of a distant part too much, the thermal transfer characteristics of the device and / or reservoir can be calculated and used to create a reference map of the internal temperature at various locations. This reference map can be stored in the controller for use in determining the temperature of the part and / or reservoir.

[0047] For embodiments in which the temperature sensor is affixed to the plunger, even if the sensor is placed in indirect contact with the pharmaceutical product (e.g., the sensor is embedded in the plunger), the sensor and pharmaceutical product will equilibrate at the same temperature, especially during long-term refrigerated storage. As the temperature of the pharmaceutical product increases, the determined temperature at the plunger should generally track the temperature change of the pharmaceutical in the reservoir. A highly thermally conductive material can be used as an intermediary between the pharmaceutical in the reservoir and the sensor affixed to the plunger so that the difference between the two temperatures is small. In addition to the measured temperature, rate of change information (e.g., temperature rate of change) may be used to improve accuracy and / or correlation with pharmaceutical product temperature.

[0048] For embodiments involving a temperature sensor (or temperature sensing component) associated with or in close proximity to the reservoir, the sensor may be, for example, an infrared thermopile chip. Such sensors measure the infrared signature of the heat source and do not require direct contact with the heat source. These infrared thermopiles operate in the 0.7 μm to 1000 μm wavelength band and may have a footprint of 2 mm×2 mm or less. An exemplary thermopile chip is the TMP006 chip from Texas Instruments (Dallas, Texas), which is optimized for low power consumption and requires less than 200 μA of supply current. Such sensors typically provide a determination of the outside temperature, which can be used to predict the time it will take for the drug (or temperature sensing component) to reach a temperature above a threshold. This prediction may be based on the thermal mass and heat transfer properties of the drug (or temperature sensing component) in addition to the outside temperature, and the processor may be programmed to perform the calculations or a reference table may be stored in memory that the processor accesses when the outside temperature is determined.

[0049] Similarly, for embodiments involving a temperature sensor (or temperature sensing component) associated with or in close proximity to the reservoir, the sensor may be a temperature sensitive label used in conjunction with an optical pickup or optical sensor. The temperature sensitive label changes appearance when a threshold temperature is reached. The label may be in the form of, for example, a solid label, a wax, a lacquer-like paint, or a liquid crystal polymer film. An optical pickup may be used to determine this change in appearance. This change in appearance may then be correlated with a threshold temperature to determine the temperature. The optical pickup may have a footprint of 2.5 mm by 2.5 mm and consume less than 20 μA in active mode and less than 0.5 μA in low power inactive mode. An example of an optical pickup or optical sensor is the MAX44005 sensor available from Maxim Integrated (San Jose, Calif.). In such an embodiment, the label and pickup combination is non-contact, preventing physical interaction between the label and the pickup.

[0050] Regarding the relevant embodiment of a temperature sensor fixed to the cannula or needle, such a sensor can be formed using thin film sensors (RTDs) or thin wires (thermocouples). Such technology allows integration with the needle assembly to place the sensor in thermal contact with the needle but indirectly in contact with the drug product. Needle assembly is often made of a material with high thermal conductivity, so placing the sensor on the needle reduces the temperature difference between the needle and the drug product passing through the needle. Additionally, placing the sensor on the cannula may allow monitoring of the patient's body / tissue temperature at the injection site.

[0051] The system 300 further includes a controller 450 coupled to the driver 342 and the injector 346, with the controller 212 operating the driver 342 to deliver a predetermined amount of drug from the reservoir 340 and the injector 346 to move the needle 344 between the retracted and use positions. As shown in FIG. 10, the controller is also coupled to a sensor 400, an output device 452, a safety device 454, and a heater 456.

[0052] In the embodiment shown in FIG. 10, the controller 450 may include a programmable microprocessor 470, a memory 472, and a power source 474. The power source 474 may include one or more batteries. In certain embodiments, the controller 450 may be programmed to determine whether the temperature sensor 400 is accurate before determining whether the temperature of the drug or drug delivery device (e.g., driver 342, injector 346) located in the reservoir 340 is above an upper limit, below a lower limit, or between an upper limit and a lower limit. This determination of accuracy may include determining whether the temperature sensor 400 is connected or may include comparing the temperature determination using the signal from the temperature sensor 400 to temperature determination using signals from other temperature sensors. Additionally, the controller 450 may be programmed to modify the temperature determination by consulting a table stored in memory or using a correction factor if the temperature sensor is not accurate.

[0053] The output device 452 may include at least one of a display, a light emitter, and a speaker. According to some embodiments, the output device 452 may include two or more of a display, a light emitter, and / or a speaker. The purpose of the output device 452 is to warn the user of a change in the operating state of the system, and in the above embodiment, the output device 452 issues a warning to the user for at least two different operating states, i.e., high temperature and low temperature. Therefore, the output device 452 may include multiple displays, light emitters, and / or speakers to issue different warnings to the user for a change in the operating state due to high temperature and a change in the operating state due to low temperature. A single output device 452 may be controlled by the control unit 450 to perform different operations (e.g., display different colors and emit different sounds or tones) depending on whether the change in the operating state is due to high temperature or low temperature.

[0054] The heater 456 can be one of many different types. For example, the heater 456 can be a mechanical heater (e.g., heat from a shape memory actuator), an electrical heater, a chemical heater, and / or a selectable combination of heat sources. In some embodiments, the electrical heater can include at least one of a resistive heater and a thermoelectric heater (i.e., a heater that uses infrared heating). In some embodiments, the heat source can include at least one of a controller (e.g., waste heat from a processor circuit board) and / or a patient wearing the drug delivery system (in which case a thermally conductive adhesive may be used). Whatever heater is used, the fluid flow path may be extended or widened near the heater to improve heating between the fluid reservoir and the injection / infusion site. Alternatively, the package may provide heating capabilities or the adhesive liner may be used for heating (e.g., an acrylic adhesive that heats when the adhesive liner is peeled off).

[0055] For resistive heaters, such heaters are constructed by applying power to a relatively high resistance resistor, which converts electrical energy into thermal energy. This heat is transferred by conduction or convection from the heat source to the adjacent pharmaceutical product or temperature sensing components. Waste heat from the processor circuit board can be generated, for example, from resistive heating of conductor traces.

[0056] Regarding thermoelectric heaters, such heaters utilize the Peltier effect to apply electrical energy to two dissimilar metals, causing a heat transfer at the junction. Thermoelectric heaters have certain advantages in the sense that the same structure can be used for heating as well as cooling, depending on the case. Furthermore, since there are no moving parts, the structure is simple and can be expected to have a long life.

[0057] For chemical heaters, such heaters may contain two or more chemicals that react exothermically. For example, one may utilize the crystallization of supersaturated sodium acetate. This reaction is initiated by nucleation during use and can provide heat for anywhere from 20 minutes to 2 hours depending on the amount of reactants.

[0058] The controller 450 can be a mechanical device, a combination of mechanical devices, a combination of electrical devices (hardwired circuitry or circuit components), or a combination of mechanical and electrical devices. FIG. 15 shows a specific embodiment of a mechanical controller 500 in combination with a reservoir 502, a needle 504, and a valve 506 disposed in a fluid flow path 508 between the reservoir 502 and the needle 504. The device including the controller 500, the reservoir 502, the needle 504, and the valve 506 may further include other devices (such as a drive for the reservoir 502 and / or an actuator for the needle 504), but these structures are omitted for ease of explanation. In the above embodiment, the valve 506 may function as a safety device, with a closed state of the valve corresponding to a locked state and an open state of the valve corresponding to an unlocked state.

[0059] The control unit 500 includes an actuator 510 formed of a temperature sensitive material that can be used to change the locked state of the valve / safety device 506, the actuator 510 being located in proximity to the drug being monitored and / or the temperature sensing components. The actuator 510 may include a piece of shape memory alloy, such as Nitanol (nickel-titanium), that assumes a first shape or a second shape depending on temperature. The temperature at which the piece changes between the first and second shapes may correspond to a lower temperature threshold. When the piece is in the first shape, the piece may abut against the valve 506 such that the valve 506 is in a closed state. When the piece is in the second shape, the piece may move away from the valve 506 such that the valve 506 is in an open state. Thus, when the piece is below the low temperature threshold, the piece ensures that the valve 506 is closed (locked), and when the piece is above the lower temperature threshold, the piece ensures that the valve 506 is open (unlocked).

[0060] 2 and 4, the controller 500 determines whether the temperature of the drug or temperature sensing component is below the low temperature threshold based on the shape of the shape memory alloy. If the temperature of the metal piece is below the temperature at which the shape of the metal piece changes, the metal piece activates the valve 506, which corresponds to activating the safety device. If the shape of the metal piece changes from a first shape to a second shape, the controller 500 determines whether the temperature of the drug or temperature sensing component is above the low temperature threshold. If this occurs, the metal piece moves away from the valve 506, causing the controller 500 to release the safety device, which opens the valve, at which point drug can flow from the reservoir 402 to the needle 504.

[0061] In various embodiments, activation of the safety does not require that the safety be in an unlocked state prior to activation. In some embodiments, activation of the safety may include or involve maintaining the safety in a default locked state. As shown in FIG. 16, the controller may determine (or, in the case of an electronic embodiment, be programmed to determine) whether the temperature of the drug disposed in the reservoir is above an upper limit in block 530. If the temperature exceeds the upper limit, the controller may activate an output device at least once in block 532 (e.g., to warn a user that the drug temperature is too high and thus unsafe) and place the safety in a locked state in block 534. In some embodiments, because the safety is in a locked state by default, placing the safety in a locked state in block 534 involves the controller doing nothing. If the temperature is below the upper limit, the controller may determine (or be programmed to determine) whether the temperature of the drug disposed in the reservoir is below the lower limit in block 536, and if so, activate the output device at least once in block 538 (e.g., to warn the user that the drug temperature is low enough to compromise safety and / or comfort during delivery and / or predictability of delivery) and lock the safety in block 540. As above, in some embodiments, locking the safety in block 540 involves the controller doing nothing, since the safety is locked by default. Additionally, the controller may determine (or be programmed to determine) whether the drug temperature is between the upper and lower limits in block 542 after block 536 (and after blocks 538, 540). If the temperature is between the upper and lower limits, the controller may unlock the safety in block 544 and allow operation in block 546. In embodiments where the safety is in a locked state by default, the controller may also need to place the safety in an unlocked state at block 548 .

[0062] The steps of the method of Figure 16 may be expressed similarly to the method of Figure 2, except that the controller must perform steps to unlock the safety device if, for example, it is determined that the temperature of the drug or temperature sensing component is not greater than an upper temperature threshold or less than a lower temperature threshold. Step 548 may be incorporated into any of the methods shown in Figures 2-7 to provide similar effect in embodiments in which the safety device is in a locked state by default.

[0063] Further embodiments of the method of operation of the device are shown in FIG. 17. These embodiments differ from the previously described embodiments in that the safety device is not necessarily activated. Thus, as shown in FIG. 17, the controller may determine (or be programmed to determine) whether the temperature of the drug placed in the reservoir is higher than an upper limit in block 560. If the temperature exceeds the upper limit, the controller may activate the output device at least once (e.g., to warn the user that the drug temperature is too high, compromising safety) in block 562 and lock the safety device in block 564. If the temperature is lower than the upper limit, the controller may determine (or be programmed to determine) whether the temperature of the drug placed in the reservoir is lower than a lower limit in block 566 and, if so, activate the output device at least once (e.g., to warn the user that the drug temperature is low enough to compromise safety and / or comfort and / or predictability of delivery) in block 568. Indicia (e.g., a warning) on ​​the exterior surface (e.g., cover) of the device may inform the user, for example, that if the output device is activated, the user must wait a certain period of time (e.g., 5, 10, or 20 minutes) before operating the device. However, as shown in block 570, the device is not locked and can be operated after the output device is activated in block 568.

[0064] The assumptions underlying the embodiment as shown in FIG. 17 are similar to those of the embodiment of FIG. 3, namely that ambient heat will raise the temperature of the drug or sensing component above a lower temperature threshold if sufficient time passes. Unlike the embodiment of FIG. 3, there is no activation of a safety device that would prevent use of the system. Optionally, the method embodiment of FIG. 17 can be further simplified by omitting the step of block 564, in which case activation of an output device alerts the user that the drug or temperature sensing component has exceeded an upper temperature threshold. In such an embodiment, activation of the output device at block 562 may be different from activation of the output device at block 568, allowing the user to distinguish between the two alerts. Additionally, operation of the device may be permitted after activation of the output device at block 562 or block 568.

[0065] Having described the structure and operation of the device, exemplary drugs, medications, or pharmaceutical agents contained within the reservoirs will now be described.

[0066] For example, the drug delivery device, and more specifically, the reservoir of the device, can be filled with colony stimulating factors, such as G-CSF. Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim), Neulasta® (pegfilgrastim). In various other embodiments, the drug delivery device can be used with a variety of pharmaceutical agents, such as erythropoietin stimulating agents (ESAs). The ESAs can be in liquid or lyophilized form. ESA refers to any molecule that stimulates erythropoiesis, such as, for example, Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol-epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binoc (epoetin zeta), and cyclosporine. rit® (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 molecules disclosed in the following patents or patent applications, each of which is incorporated by reference in its entirety: U.S. Patent 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, 7,271,689, PCT Publication Nos. 91 / 05867, 95 / 05465, 96 / 40772, 00 / 24893, 01 / 81405, and 2007 / 136752.

[0067] The ESA may be an erythropoietin stimulating protein. As used herein, "erythropoietin stimulating protein" refers to any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to and dimerizing the receptor. Erythropoietin stimulating proteins include erythropoietin, its variants, analogs or derivatives that bind to and activate the erythropoietin receptor, antibodies that bind to and activate the erythropoietin receptor, or peptides that bind to and activate the erythropoietin receptor. Erythropoietin stimulating proteins include, but are not limited to, epoetin alpha, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta, and analogs thereof, pegylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. Exemplary erythropoietin stimulating proteins include erythropoietin, darbepoietin, agonist variants of erythropoietin, peptides or antibodies that bind to and activate the erythropoietin receptor (including the compounds described in U.S. Publication Nos. 2003 / 0215444 and 2006 / 0040858, the disclosures of each of which are incorporated by reference in their entireties). Additionally, the erythropoietin molecules or variants or analogs thereof disclosed in the following patents or patent applications, each of which is incorporated by reference in its entirety: U.S. Patent 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, 5,830,851, 5,856,298, 5,986,047, 6,030,086, 6,310,078, 6 ,391,633, 6,583,272, 6,586,398, 6,900,292, 6,750,369, 7,030,226, 7,084,245, and 7,217,689; U.S. Publication Nos. 2002 / 0155998, 2003 / 0077753, 2003 / 0082749, 2003 / 0143202, 2004 / 0009902;No. 2004 / 0071694, No. 2004 / 0091961, No. 2004 / 0143857, No. 2004 / 0157293, No. 2 No. 004 / 0175379, No. 2004 / 0175824, No. 2004 / 0229318, No. 2004 / 0248815, No. 200 No. 4 / 0266690, No. 2005 / 0019914, No. 2005 / 0026834, No. 2005 / 0096461, No. 2005 / No. 0107297, No. 2005 / 0107591, No. 2005 / 0124045, No. 2005 / 0124564, No. 2005 / 013 No. 7329, No. 2005 / 0142642, No. 2005 / 0143292, No. 2005 / 0153879, No. 2005 / 01588 No. 22, No. 2005 / 0158832, No. 2005 / 0170457, No. 2005 / 0181359, No. 2005 / 0181482 , 2005 / 0192211, 2005 / 0202538, 2005 / 0227289, 2005 / 0244409, 2006 / 0088906, and 2006 / 0111279, and PCT International Publication Nos. 91 / 05867, 95 / 05465, 9 No. 9 / 66054, No. 00 / 24893, No. 01 / 81405, No. 00 / 61637, No. 01 / 36489, No. 02 / 01435 No. 6, No. 02 / 19963, No. 02 / 20034, No. 02 / 49673, No. 02 / 085940, No. 03 / 029291, No. 20 No. 03 / 055526, No. 2003 / 084477, No. 2003 / 094858, No. 2004 / 002417, No. 2004 / 002 No. 424, No. 2004 / 009627, No. 2004 / 024761, No. 2004 / 033651, No. 2004 / 035603, No. 2 No. 004 / 043382, No. 2004 / 101600, No. 2004 / 101606, No. 2004 / 101611, No. 2004 / 10 No. 6373, No. 2004 / 018667, No. 2005 / 001025, No. 2005 / 001136, No. 2005 / 021579, No. 2005 / 025606, 2005 / 032460, 2005 / 051327, 2005 / 063808, 2005 / 0 No. 63809, No. 2005 / 070451, No. 2005 / 081687, No. 2005 / 084711, No. 2005 / 103076,Nos. 2005 / 100403, 2005 / 092369, 2006 / 50959, 2006 / 02646 and 2006 / 29094.

[0068] Examples of pharmaceutical agents for use with the device include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab), Prolia™ (denosumab), biologics such as Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF inhibitor), Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), Nplate® (romiplostim), and small molecule drugs such as Sensipar® (cinacalcet). The device may be used with therapeutic antibodies, polypeptides, proteins, or other chemical agents such as iron, e.g., ferumoxytol, ferrous dextran, ferric gluconate, ferrous sucrose, etc. The pharmaceutical agent may be used in liquid form or reconstituted from a lyophilized form.

[0069] Specific exemplary proteins include the specific proteins listed below and fusions, fragments, analogs, variants and derivatives thereof.

[0070] Antibodies, peptibodies, and related proteins specific for OPGL (also referred to as RANKL-specific antibodies, peptibodies, etc.), including fully humanized and human antibodies specific for OPGL, particularly fully humanized monoclonal antibodies, including, but not limited to, those described in PCT Publication WO 03 / 002713, which is incorporated herein by reference in its entirety with respect to OPGL-specific antibodies and antibody-related proteins, particularly those having the sequences set forth therein, and particularly those named therein, i.e., 9H7, 18B2, 2D8, 2E11, 16E1, and 22B3, but not limited thereto, including OPGL-specific antibodies having a light chain of SEQ ID NO:2 as set forth in Figure 2 of said publication and / or a heavy chain of SEQ ID NO:4 as set forth in Figure 4 of said publication, each of which is individually and specifically incorporated herein by reference in its entirety as set forth therein.

[0071] Proteins, peptibodies, and related proteins that bind to myostatin, 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 in their entireties, particularly with respect to their portions relating to myostatin-specific peptibodies. These include, but are not limited to, the following: Peptibodies of the mTN8-19 family, e.g., those in SEQ ID NOs: 305-351, TN8-19-1 through TN8-19-40, TN8-19con1, and TN8-19con2, as well as 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 in SEQ ID NOs: 615-631, each of which is individually and specifically incorporated by reference in its entirety in its entirety as disclosed in said documents.

[0072] Antibodies, peptibodies, and related proteins specific for the IL-4 receptor, particularly those that inhibit activity 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 / 037242, and U.S. Publication No. 2005 / 112694 (which are incorporated by reference in their entirety, particularly with respect to the portions relating to IL-4 receptor-specific antibodies), particularly the antibodies described in said documents. and in particular, but without limitation, those named therein, namely, 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 in its entirety as if fully disclosed in said reference.

[0073] and antibodies, peptibodies, and related proteins specific for interleukin 1-receptor 1 ("IL1-R1"), including, but not limited to, those described in U.S. Publication No. 2004 / 097712A1, which is incorporated by reference in its entirety, particularly with respect to its portion relating to IL1-R1 specific binding proteins, monoclonal antibodies, and specifically, also those identified therein, including, but not limited to, 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the U.S. publication.

[0074] Antibodies, peptibodies, and related proteins specific for Ang2, 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 by reference in its entirety, particularly with respect to portions relating to antibodies, peptibodies, and the like specific for Ang2), particularly those sequences described in these documents, including, but not limited to, the following: L1(N), L1(N)WT, L1(N)1K WT, 2xL1(N), 2xL1(N)WT, Con4(N), Con4(N)1K WT, 2xCon4(N)1K, L1C, L1C 1K, 2xL1C, Con4C, Con4C 1K, 2xCon4C 1K, Con4-L1(N), Con4-L1C, TN-12-9(N), C17(N), TN8-8(N), TN8-14(N), Con1(N). Also included are anti-Ang2 antibodies and formulations, including those described in PCT Publication WO 2003 / 030833. (Said references are incorporated herein by reference in their entirety for the same purposes.) In particular, 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, AblP, and various substitutions thereof, each of which is individually and specifically incorporated by reference in its entirety as disclosed in said references.

[0075] and NGF-specific antibodies, peptibodies, and related proteins, including, but not limited to, those specifically described in U.S. Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426, which are incorporated by reference herein in their entireties, particularly with respect to their portions relating to NGF-specific antibodies and related proteins. These specifically include, but are not limited to, the NGF-specific antibodies identified therein, namely, 4D4, 4G6, 6H9, 7H2, 14D10, 14D11, each of which is individually and specifically incorporated by reference in its entirety as disclosed therein.

[0076] Antibodies, peptibodies and related proteins specific for CD22, such as those described in U.S. Pat. No. 5,789,554, which is incorporated herein by reference in its entirety for human CD22-specific antibodies and related proteins. In particular, human CD22-specific antibodies, such as humanized and fully human antibodies, but not limited to, including humanized and fully human monoclonal antibodies, in particular, including, but not limited to, human CD22-specific IgG antibodies, such as dimers of human-mouse monoclonal hLL2 gamma chain disulfide linked to human-mouse monoclonal hLL2 kappa chain, and the like, including, but not limited to, the human CD22-specific fully humanized antibody in epratuzumab (CAS Registry No. 501423-23-0).

[0077] IGF-1 receptor-specific antibodies, peptibodies and related proteins, such as those described in PCT Publication WO 06 / 069202, which is incorporated by reference in its entirety for its IGF-1 receptor-specific antibodies and related proteins, including, but not limited to, the following IGF-1 specific antibodies identified therein: L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H1 6, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29 , L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-IR binding fragments and derivatives thereof, each of which is individually and specifically incorporated by reference in its entirety herein as disclosed in said international publications.

[0078] Furthermore, non-limiting examples of anti-IGF-1R antibodies that may be used with the methods and constructs of the present invention include each and every one of those described in the following documents: (i) U.S. Publication Nos. 2006 / 0040358 (published February 23, 2006), 2005 / 0008642 (published January 13, 2005), and 2004 / 0228859 (published November 18, 2004), including, but not limited to, Antibody 1A (DSMZ Accession No. DSM ACC2586), Antibody 8 (DSMZ Accession No. DSM ACC2589), Antibody 23 (DSMZ Accession No. DSM ACC2588), and Antibody 18, all of which are described herein. (ii) PCT Publication Nos. WO 06 / 138729 (published December 28, 2006) and WO 05 / 016970 (published February 24, 2005), and Lu et al., 2004, J. Biol. Chem. 279:2856-65, including, but not limited to, the antibodies 2F8, A12, and IMC-A12 described therein. (iii) PCT International Publication Nos. 07 / 012614 (published on February 1, 2007), 07 / 000328 (published on January 4, 2007), 06 / 013472 (published on February 9, 2006), 05 / 058967 (published on June 30, 2005), and 03 / 059951 (published on July 24, 2003). (iv) U.S. Publication No. 2005 / 0084906, published April 21, 2005, including, but not limited to, antibody 7C10, chimeric antibody C7C10, antibody h7C10, antibody 7H2M, chimeric antibody *7C10, antibody GM607, humanized antibody 7C10 version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version 3, and antibody 7H2HM, which are described therein. (v) U.S. Publication Nos. 2005 / 0249728 (published November 10, 2005), 2005 / 0186203 (published August 25, 2005), 2004 / 0265307 (published December 30, 2004), and 2003 / 0235582 (published December 25, 2003), and Maloney et al., 2003, Cancer Res. 63:5073-83, including, but not limited to, antibodies EM164, resurfaced EM164, humanized EM164, huEM164v1.0, huEM164v1.1, huEM164v1.2, and huEM164v1.3, as described supra. (vi) U.S. Patent No. 7,037,498, issued May 2, 2006, U.S. Publication Nos. 2005 / 0244408, published November 30, 2005, and 2004 / 0086503, published May 6, 2004, and Cohen, et al., 2005, Clinical Cancer Res. 11:2063-73. For example, antibody CP-751,871. Examples include, but are not limited to, antibodies produced by hybridomas having ATCC deposit numbers PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, and PTA-2793, as well as antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3. (vii) U.S. Publication Nos. 2005 / 0136063 (published June 23, 2005) and 2004 / 0018191 (published January 29, 2004), including, but not limited to, antibody 19D12 and an antibody comprising an H chain encoded by a polynucleotide of plasmid 15H12 / 19D12 HCA(γ4) deposited under ATCC No. PTA-5214 and an L chain encoded by a polynucleotide of plasmid 15H12 / 19D12 LCF(κ) deposited under ATCC No. PTA-5220, as described above. (viii) U.S. Publication No. 2004 / 0202655 (published October 14, 2004), including, but not limited to, the antibodies PINT-6A1, PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3, PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2, PINT-12A3, PINT-12A4, and PINT-12A5, each and every of which is incorporated herein by reference in its entirety, particularly with respect to antibodies, peptibodies, and related proteins that target the IGF-1 receptor.

[0079] Antibodies, peptibodies, related proteins, and the like, specific for B-7 related protein 1 ("B7RP-1" is also referred to in the literature as B7H2, ICOSL, B7h, and CD275). In particular, B7RP-specific fully human monoclonal IgG2 antibodies, in particular fully human IgG2 monoclonal antibodies that bind to an epitope in the first immunoglobulin-like domain of B7RP-1. In particular, those that inhibit the interaction of B7RP-1 with its innate receptor ICOS in activated T cells. In particular, those disclosed in U.S. Publication No. 2008 / 0166352 and PCT Publication No. WO 07 / 011941, all of which are incorporated by reference in their entirety for the purposes of such antibodies and related proteins. These include, but are not limited to, the following antibodies identified in the above documents: 16H (having a light chain variable sequence of SEQ ID NO:1 and a heavy chain variable sequence of SEQ ID NO:7), 5D (having a light chain variable sequence of SEQ ID NO:2 and a heavy chain variable sequence of SEQ ID NO:9), 2H (having a light chain variable sequence of SEQ ID NO:3 and a heavy chain variable sequence of SEQ ID NO:10), 43H (having a light chain variable sequence of SEQ ID NO:6 and a heavy chain variable sequence of SEQ ID NO:14), 41H (having a light chain variable sequence of SEQ ID NO:5 and a heavy chain variable sequence of SEQ ID NO:13), and 15H (having a light chain variable sequence of SEQ ID NO:4 and a heavy chain variable sequence of SEQ ID NO:12), each of which is individually and specifically incorporated by reference in its entirety herein as disclosed in said U.S. publication.

[0080] IL-15 specific antibodies, peptibodies, and related proteins, such as, for example, particularly humanized monoclonal antibodies, particularly those disclosed in U.S. Publication Nos. 2003 / 0138421, 2003 / 023586, and 2004 / 0071702, and U.S. Patent No. 7,153,507, each of which is incorporated by reference in its entirety for its antibodies and related proteins, including peptibodies, specific for IL-15. Particularly, including, but not limited to, HuMax IL-15 antibodies, and related proteins, such as 146B7.

[0081] Antibodies, peptibodies, and related proteins specific for IFN gamma, in particular human IFN gamma specific antibodies, particularly fully human anti-IFN gamma antibodies, such as those described in US Publication No. 2005 / 0004353, which is incorporated herein by reference in its entirety for IFN gamma specific antibodies, in particular the 1118, 1118*, 1119, 1121, and 1121* antibodies identified therein. The complete sequences of the heavy and light chains of each of these antibodies, as well as the sequences of the variable regions and complementarity determining regions of the heavy and light chains, are each individually and specifically incorporated herein by reference in their entirety as disclosed in the US publications and in Thakur et al., Mol. Immunol. 36:1107-1115 (1999). Furthermore, the descriptions of the properties of these antibodies in the US publications are also incorporated herein in their entirety. Specific antibodies include the following antibodies disclosed in the US document: one having an H chain of SEQ ID NO: 17 and an L chain of SEQ ID NO: 18, one having an H chain variable region of SEQ ID NO: 6 and an L chain variable region of SEQ ID NO: 8, one having an H chain of SEQ ID NO: 19 and an L chain of SEQ ID NO: 20, one having an H chain variable region of SEQ ID NO: 10 and an L chain variable region of SEQ ID NO: 12, one having an H chain of SEQ ID NO: 32 and an L chain of SEQ ID NO: 20, one having an H chain variable region of SEQ ID NO: 30 and an L chain variable region of SEQ ID NO: 12, one having an H chain sequence of SEQ ID NO: 21 and an L chain sequence of SEQ ID NO: 22, one having an H chain variable region of SEQ ID NO: 14 and an L chain variable region of SEQ ID NO: 16, one having an H chain of SEQ ID NO: 21 and an L chain of SEQ ID NO: 33, and one having an H chain variable region of SEQ ID NO: 14 and an L chain variable region of SEQ ID NO: 31. One specific antibody contemplated is antibody 1119 disclosed in the US patent application, which has the complete heavy chain of SEQ ID NO: 17 disclosed in the same application and the complete light chain of SEQ ID NO: 18 disclosed in the same application.

[0082] Antibodies, peptibodies, and related proteins specific for TALL-1, as well as other TALL-specific binding proteins, such as those described in U.S. Publication Nos. 2003 / 0195156 and 2006 / 0135431, each of which is incorporated by reference in its entirety for purposes of TALL binding proteins. In particular, the molecules of Tables 4 and 5B, each of which is individually and specifically incorporated by reference in its entirety in this specification as if fully disclosed therein.

[0083] Antibodies, peptibodies, and related proteins specific for parathyroid hormone ("PTH"), such as those described in U.S. Patent No. 6,756,480, which is incorporated by reference herein in its entirety, particularly with respect to the PTH binding protein related portions.

[0084] Antibodies, peptibodies, and related proteins specific for the thrombopoietin receptor ("TPO-R"), such as those described in U.S. Patent No. 6,835,809, which is incorporated by reference herein in its entirety, particularly with respect to TPO-R binding protein related portions.

[0085] Antibodies, peptibodies, and related proteins specific for hepatocyte growth factor ("HGF"), including those targeting the HGF / SF:cMet axis (HGF / SF:c-Met). For example, fully human monoclonal antibodies neutralizing hepatocyte growth factor / scatter factor (HGF / SF), described in U.S. Publication No. 2005 / 0118643 and PCT Publication No. WO 2005 / 017107, huL2G7, described in U.S. Patent No. 7,220,410, OA-5d5, described in U.S. Patent Nos. 5,686,292 and 6,468,529, and PCT Publication No. WO 96 / 38557. Each of these documents is incorporated herein by reference in its entirety, particularly with respect to the HGF binding protein-related portions.

[0086] Antibodies, peptibodies, related proteins, etc. specific for TRAIL-R2, such as those described in U.S. Patent No. 7,521,048, which is incorporated by reference herein in its entirety, particularly with respect to the TRAIL-R2 binding protein related portions.

[0087] Antibodies, peptibodies, related proteins, etc. specific for activin A, including but not limited to those described in U.S. Publication No. 2009 / 0234106, which is incorporated by reference herein in its entirety, particularly with respect to activin A binding protein related portions.

[0088] Antibodies, peptibodies, related proteins, and the like specific for TGF beta, including but not limited to those described in U.S. Patent No. 6,803,453 and U.S. Publication No. 2007 / 0110747, each of which is incorporated by reference herein in its entirety, particularly with respect to TGF beta binding protein related portions.

[0089] Antibodies, peptibodies, related proteins, etc. specific for amyloid beta protein, including but not limited to those described in PCT Publication WO 2006 / 081171, which is incorporated herein by reference in its entirety, particularly with respect to portions related to proteins that bind to amyloid beta protein. One contemplated antibody is the antibody disclosed in said international publication having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6.

[0090] Antibodies, peptibodies, related proteins, and the like specific for c-Kit, including but not limited to those described in U.S. Publication No. 2007 / 0253951, which is incorporated by reference herein in its entirety, particularly with respect to protein-related moieties that bind c-Kit and / or other stem cell factor receptors.

[0091] Antibodies, peptibodies, related proteins, etc. specific for OX40L, including but not limited to those described in U.S. Application No. 11 / 086,289, which is incorporated by reference in its entirety, particularly with respect to proteinaceous moieties that bind OX40L and / or other OX40 receptor ligands.

[0092] Other exemplary proteins include: Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (erythropoietin), poetin delta), Velcade® (bortezomib), MLN0002 (anti-α4β7 mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF-receptor / Fc fusion protein, TNF inhibitor), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab , anti-HER2 / neu (erbB2) receptor mAb), Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), insulin solution, Infergen® (interferon alfacon-1), Natrecor® (nesiritide, recombinant human B-type natriuretic peptide (hBNP), Kineret® (anakinra), Leukine® (sargamostim, rhuGM-CSF), LymphoCide® (epratuzumab), (anti-CD22 mAb), Benlysta™ (lymphostat B, belimumab, anti-BlyS mAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), Raptiva® (efalizumab), Cimzia® (certolizumab pegol, CDP870), Soliris™ (eculizumab), pexelizumab (anti-C5 complement),Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Neulasta® (pegylated filgustidine), Lim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-Met G-CSF), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP IL6 receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolibumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alpha-2a), Simulect® (basiliximab), Prexige® (lumiraco Xyxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-B. anthracis protective antigen mAb), ABthrax®, Vectibix® (panitumumab), Xolair® (omalizumab), ETI211 (anti-MRSA mAb),IL-1 Trap (the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF Trap (the Ig domain of VEGFR1 fused to the Fc of IgG1), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23 mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF inhibitor), CNTO148 (golimumab, anti-TNFα mAb), HGS-ETR1 (mapatumumab), human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (zalutumumab), M200 (volociximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin BC mAbs MDX-066 (CDA-1 and MDX-1388), anti-CD22dsFv-PE38 complex (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax- TAC), anti-CD3mAb (NI-0401), adecatumumab, anti-CD30mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38mAb (HuMax CD38), anti-CD40LmAb, anti-crypto mAb, anti-CTGF idiopathic pulmonary fibrosis stage I fibrogen (FG-3019), anti-CTLA4mAb, anti-eotaxin 1mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2mAb, anti-ganglioside GM2mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepCmAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1RmAb, anti-IGF-1RmAb (HuMax-Inflam), anti-IL12mAb (ABT-874), anti-IL12 / IL23mAb (CNTO1275),Anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO95), anti-IP10 ulcerative colitis mAb (MDX-1100), anti-LLY antibody, BMS-66513, anti-mannos receptor / hCGβ mAb (MDX-1307), anti-mesoterin dsFv-PE38 complex (CAT-5001), Anti-PD1 mAb (MDX-1106 (ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβ mAb (GC-1008), anti-TRAIL receptor-2 mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), NVS antibody #1, and NVS antibody #2.

[0093] Also included may be, but are not limited to, sclerostin antibodies such as romosozumab, brosozumab, or BPS804 (Novartis).Further included may be therapeutic agents such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, buzupplant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA. Also included in the device are monoclonal antibodies (IgG) that bind to human proprotein convertase subtilisin / kexin type 9 (PCSK9), such as those described in US 8,030,547, US 13 / 469,032, WO 2008 / 057457, WO 2008 / 057458, WO 2008 / 057459, WO 2008 / 063382, WO 2008 / 133647, WO 2009 / 100297, WO 2009 / 100318, WO 2011 / 037791, WO 2011 / 053759, WO2011 / 053783, WO2008 / 125623, WO2011 / 072263, WO2009 / 055783, WO2012 / 0544438, WO2010 / 029513, WO2011 / 111007, WO2010 / 077854, WO2012 / 088313, WO2012 / 101251, WO2012 / 101252, WO2012 / 101253, WO2012 / 109530, and WO2001 / 031007.

[0094] Also included are talimogene laherparepvec or other oncolytic HSVs for the treatment of cancers such as melanoma. Examples of oncolytic HSVs include, but are not limited to, talimogene laherparepvec (US 7,223,593 and US 7,537,924), OncoVEXGALV / CD (US 7,981,669), OrienX010 (Lei et al., 2013, World Journal of Gastroenterology, 19:5138-5143), G207, 1716, NV1020, NV12023, NV1034, and NV1042 (Vargehes et al. 2002, Cancer Gene Ther, 2002, 9 (12): 967-978).

[0095] This also includes TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteases (TIMPs) that are important in many natural processes. TIMP-3 is expressed by a variety of cells and is present in the extracellular matrix. It inhibits all major cartilage-degrading metalloproteases and may play a role in many connective tissue degrading diseases, including rheumatoid arthritis, osteoarthritis, as well as cancer and cardiovascular pathologies. The amino acid sequence of TIMP-3 and the nucleic acid sequence of DNA encoding TIMP-3 are disclosed in U.S. Patent No. 6,562,596, issued May 13, 2003, the disclosure of which is incorporated herein by reference. Descriptions of TIMP mutations can be found in U.S. Patent Nos. 61 / 782,613, 61 / 798,160, 61 / 802,988, and 61 / 940,67.

[0096] Also included are antibodies that inhibit the human calcitonin gene-related peptide (CGRP) receptor, as well as bispecific antibody molecules that target the CGRP receptor and other headache-related targets. Additional information regarding these molecules can be found in WO2A075238A1.

[0097] Additionally, bispecific T cell-inducing antibodies (BiTe), such as brinotumomab, can be used in the device. Alternatively, APJ large molecule agonists, such as apelin or analogs thereof, can be included in the device. Information regarding such molecules can be found in PCT / 2013 / 075773.

[0098] Although various embodiments have been described in detail in the text above, it should be understood that the legal scope of the present invention is defined by the language of the claims set forth at the end of this patent. The detailed embodiments should be construed as examples only, and not every possible embodiment will be described, since describing every possible embodiment would be impractical, if not impossible. Many alternative embodiments are possible using current technology or technology developed after the filing date of this patent, which would still fall within the scope of the claims that define the present invention.

[0099] Additionally, unless a term is expressly defined in this patent using the phrase "In this specification, the word '---' is hereby defined to mean ..." or similar language, it should be understood that no express or implied limitation of meaning beyond the plain and ordinary meaning of the term is intended, and that the term should not be construed as limiting in scope based on any statement in any part of this patent (except the claim language). If any term recited in the claims at the end of this patent is uniformly referred to in accordance with a single meaning in this patent, this is done solely for clarity to avoid confusing the reader, and is not intended, implicitly or otherwise, to limit such claim language to that single meaning. Finally, it is not intended that the scope of any claim element be construed under 35 U.S.C. ...

Claims

1. 1. A drug delivery system comprising: a reservoir adapted to contain a drug; a medication delivery device coupled to the reservoir for delivering medication from the reservoir, the safety device having a locked state in which medication delivery from the reservoir is restricted and an unlocked state in which medication delivery from the reservoir is not restricted; A temperature sensor; Output device and a control unit combined with a safety device, a temperature sensor, and an output device; The control unit (a) determining whether the temperature of the drug placed in the reservoir is higher than an upper limit, and if the temperature is higher than the upper limit, activating the output device at least once and locking the safety device; (b) determining whether the temperature of the drug placed in the reservoir is below a lower limit, and if the temperature is below the lower limit, activating the output device at least once and locking the safety device; (c) determining whether the drug temperature is between the upper and lower limits after (b), and programming the safety device to be in an unlocked state if the temperature is between the upper and lower limits; Drug delivery systems.

2. 2. The drug delivery system of claim 1, wherein the reservoir is removable from the drug delivery system, and the control unit is programmed to determine whether the reservoir has been removed after (a) and replaced with another reservoir that can hold a drug, and to unlock the safety device if the reservoir has been removed and replaced with another reservoir.

3. 3. The drug delivery system of claim 1 or 2, further comprising a heater associated with the control unit near at least one of the reservoir and the drug delivery device, the control unit being programmed to activate the heater when the drug temperature is below a lower limit and to deactivate the heater when the drug temperature is between the upper and lower limits.

4. 4. The drug delivery system of claim 1, wherein the control unit is programmed to determine whether the temperature sensor is accurate before determining whether the temperature of the drug placed in the reservoir is above the upper limit, below the lower limit, or between the upper and lower limits.

5. 5. The drug delivery system of claim 4, wherein the control unit is programmed to adjust the temperature determination if the temperature sensor is inaccurate.

6. 6. A drug delivery system according to any one of claims 1 to 5, wherein the reservoir comprises a pre-filled container.

7. 7. The drug delivery system of claim 6, wherein the pre-filled container is a pre-filled syringe or a pre-filled cartridge.

8. 8. A drug delivery system as claimed in any one of claims 1 to 7, wherein the reservoir comprises a hole and a plunger that can be moved relative to the hole within the reservoir to push the drug through the hole, and the drug delivery device comprises a plunger arm whose first end contacts the plunger and an actuator associated with the plunger arm.

9. 9. The drug delivery system of claim 8, wherein the actuator comprises an assembly of an electric motor associated with the plunger arm and a battery associated with the electric motor.

10. 10. A drug delivery system according to claim 8 or 9, wherein the reservoir comprises a cannula in fluid communication with the bore.

11. 11. A drug delivery system according to any one of claims 1 to 10, wherein the temperature sensor comprises at least one of a resistance temperature detector, a thermocouple, an infrared thermopile, or a temperature sensitive label and optical detector assembly.

12. 12. The drug delivery system according to claim 1, wherein a temperature sensor is built into the control unit.

13. 13. A drug delivery system according to any preceding claim, wherein the reservoir comprises a cannula in fluid communication with the reservoir, and the temperature sensor is associated with the cannula.

14. 14. The drug delivery system of claim 13, wherein the cannula comprises a needle.

15. 15. A drug delivery system as claimed in any one of claims 1 to 14, wherein the drug or substance is disposed in a reservoir, the reservoir having a hole and a plunger movable relative to the hole within the reservoir to push the drug through the hole, and a temperature sensor attached to the plunger.

16. 16. The drug delivery system of claim 15, wherein the temperature sensor is in direct contact with the drug.

17. 17. The drug delivery system of claim 16, wherein the temperature sensor is located on an inner surface of the plunger that is in direct contact with the drug.

18. 16. The drug delivery system of claim 15, wherein the temperature sensor is not in direct contact with the drug.

19. 19. The drug delivery system of claim 18, wherein the temperature sensor is located inside the plunger.

20. 20. The drug delivery system of any one of claims 3 to 19, wherein the heater comprises at least one of an electrical heater, a chemical heater, and a selectable combination of heat sources.

21. 21. The drug delivery system of claim 20, wherein the heater comprises at least one of a resistive heater and a thermoelectric heater.

22. 21. The drug delivery system of claim 20, wherein the heat source comprises at least one of the control unit and a patient to which the drug delivery system is attached.

23. 23. The drug delivery system of any one of claims 1 to 22, wherein the output device comprises at least one of a display, a light emitter, and a speaker.

24. 24. A drug delivery system according to any one of claims 1 to 23, wherein the drug or substance is disposed in a reservoir.

25. 1. A drug delivery system comprising: A reservoir that can be filled with medicine coupled to the reservoir to deliver the drug from the reservoir; a medication delivery device comprising at least one temperature sensitive component and a safety device having a locked state in which medication delivery from the reservoir is restricted and an unlocked state in which medication delivery from the reservoir is not restricted; A temperature sensor; Output device and a control unit combined with a safety device, a temperature sensor, and an output device; The control unit (a) determining whether the temperature of at least one temperature-sensing component is higher than an upper limit, and if the temperature is higher than the upper limit, activating the output device at least once and locking the safety device; (b) determining whether the temperature of at least one temperature-sensitive component is below a lower limit, and if the temperature is below the lower limit, activating the output device at least once and locking the safety device; (c) determining whether the temperature of the at least one temperature-sensing component is between upper and lower limits after (b), and programming the safety device to an unlocked state if the temperature is between the upper and lower limits; Drug delivery systems.

26. 26. The drug delivery system of claim 25, wherein the at least one temperature sensitive component comprises a battery.

27. 27. The drug delivery system of claim 25 or 26, wherein the drug or agent is disposed in a reservoir.

28. 1. A drug delivery system comprising: a reservoir adapted to contain a drug; a medication delivery device coupled to the reservoir for delivering medication from the reservoir, the safety device having a locked state in which medication delivery from the reservoir is restricted and an unlocked state in which medication delivery from the reservoir is not restricted; A temperature sensor; Output device and a control unit combined with a safety device, a temperature sensor, and an output device; The control unit (a) determining whether the temperature of the drug placed in the reservoir is higher than an upper limit, and if the temperature is higher than the upper limit, activating the output device at least once and locking the safety device; (b) determining whether the temperature of the drug placed in the reservoir is below a lower limit, and if the temperature is below the lower limit, activating the output device at least once and locking the safety device; (c) determining whether a certain time has elapsed since (b), and if so, programming the safety device to be in an unlocked state; Drug delivery systems.

29. 30. The drug delivery system of claim 28, wherein the drug or agent is disposed in a reservoir.

30. 1. A drug delivery system comprising: a reservoir adapted to contain a drug; a medication delivery device coupled to the reservoir for delivering medication from the reservoir, the safety device having a locked state in which medication delivery from the reservoir is restricted and an unlocked state in which medication delivery from the reservoir is not restricted; Output device and a control unit combined with a safety device and an output device; The control unit includes a temperature sensor, (a) determining whether the temperature of the drug placed in the reservoir is below a lower limit, and if the temperature is below the lower limit, activating the output device at least once and locking the safety device; (b) determining whether the drug temperature is between the upper and lower limits after (a), and configured to unlock the safety device if the temperature is between the upper and lower limits; Drug delivery systems.

31. 31. The drug delivery system of claim 30, wherein the drug or agent is disposed in a reservoir.

32. A method for delivering a pharmaceutical product, comprising: determining whether a temperature of a pharmaceutical product placed in a reservoir is lower than a lower limit; activating an output device at least once if the temperature is lower than the lower limit; and instructing a user of the pharmaceutical delivery system, if the output device is activated, to wait a certain time after activation of the output device before operating the pharmaceutical delivery device.

33. 33. The method of claim 32, wherein providing instructions includes marking a cover of the medication delivery system with one or more indicia indicating that, when the output device is activated, a certain time period should elapse after activation of the output device before operating the medication delivery device.

Images