Drug delivery device having damping mechanism

Abstract

To provide an improved torque drive type injector with a damping mechanism.SOLUTION: An auto injector 100 includes a housing 102 defining an outer shell, a needle assembly 110 at least partially disposed within the outer shell 102, a drive assembly 120 at least partially disposed within the outer shell 102, and a damper mechanism 140 at least partially disposed within the outer shell 102. The outer shell 102 includes a proximal end 102a and a distal end 102b, and defines a longitudinal axis "L" extending between the proximal end 102a and the distal end 102b. The damper mechanism 140 acts to attenuate the effect of torque spring 136 on the drive assembly 120.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS Priority is claimed to U.S. Provisional Patent Application No. 62 / 745,813, filed October 15, 2018, which is incorporated by reference herein in its entirety.

[0002] The present disclosure relates generally to injectors, and more particularly to torque-driven injectors having a damping mechanism. [Background technology]

[0003] Autoinjectors and on-body injectors offer several advantages in the delivery of medications and / or therapies, including ease of use when compared to traditional delivery methods using, for example, conventional syringes.

[0004] Many injector systems use a coil spring structure to provide actuation energy for functions such as needle insertion and drug delivery. While the use of a spring can offer advantages of user simplicity and device automation, it can have certain limitations. For example, there is a linear relationship between force and displacement of a linear spring actuator. When initiating drug delivery, an excessive amount of energy may be input into the system to provide enough energy for drug delivery at the end of the plunger stroke.

[0005] Furthermore, when more viscous medications are delivered by an auto-injector, the required spring force is likely to increase. A spring with a higher spring constant imparts more force per travel distance to the medication product and primary container at the beginning of the movement. In many auto-injectors, an air gap exists between the plunger face and a reservoir that holds the medication prior to injection into the user. When the medication is administered, the spring propels the plunger face toward the medication within the air gap. Because the plunger face offers little resistance across the air gap, and the large force propelling the plunger may cause the plunger face to suddenly come into contact with the reservoir containing the medication. As the spring-driven plunger impacts the stopper of the primary container that holds the medication, the patient may experience this excess energy as a "slap" or similar physical "bump." Furthermore, the user may also experience a jerk, bounce, and / or a reaction force due to the sudden change in acceleration when the rotational movement begins. Such mechanical bumps can be confusing and / or unsettling to the injector user, thus potentially affecting proper administration. Furthermore, the "slaps" and "bumps" caused by excessive energy can potentially have catastrophic consequences, such as destruction of the primary container and damage to the drug product due to shear loads. Furthermore, high force springs can create unnecessarily high shear rates on the drug product.

[0006] Furthermore, patients may experience large variations in injection times due to variations in drug characteristics. These variations can be alarming to users, who may believe that something is wrong with the administration of the drug, and therefore may stop the injection before receiving the full dose. Variations in injection times may be caused by large variations in drug viscosity due to changes in drug temperature, large variations in friction between components within the device (e.g., between the syringe barrel and stopper), etc. Summary of the Invention [Means for solving the problem]

[0007] According to a first aspect, a drug delivery device includes a housing defining an outer shell having a proximal end and a distal end, a needle assembly at least partially disposed within the housing at the proximal end, a drive assembly at least partially disposed within the housing, and a damper mechanism at least partially disposed within the housing at the distal end. The housing further defines a longitudinal axis extending between the proximal end and the distal end. The needle assembly includes a syringe barrel containing a medicament and a needle or cannula. The drive assembly is operatively coupled to the needle assembly for propelling the medicament through the needle or cannula. The damper mechanism is operatively coupled to the drive assembly and the housing. When the drive assembly is actuated, the damper mechanism dampens its effect. In some embodiments, the syringe barrel can be constructed from a polymeric material. The medicament can have a viscosity of less than about 10 cP at about 21°C.

[0008] In this aspect, the damper mechanism includes a frame member, a damper member operably coupled to the drive assembly, a chamber formed between a portion of the frame member and the damper member, and a damper fluid disposed within the chamber. In some forms, the frame member may be integrally formed with the housing. Upon actuation of the drive assembly of the drug delivery device, the frame member and the damper member rotate relative to one another, and the damper fluid exerts an opposing force on at least one of the frame member and the damper member.

[0009] In some approaches, the drug delivery device may also include an excess chamber in fluid communication with the chamber. The excess chamber is adapted to receive excess damper fluid. Additionally, in some configurations, the device may include a seal disposed near the chamber to retain the damper fluid within the chamber. In some embodiments, the chamber is axially aligned with the longitudinal axis. In other approaches, the chamber may be partially axially aligned with the longitudinal axis and partially laterally aligned therewith. In yet other approaches, the chamber may be laterally aligned with the longitudinal axis.

[0010] In any of these embodiments, the drive assembly may include a plunger assembly including a threaded plunger rod and a plunger face, a plunger rod guide coupled to the plunger assembly, and a torque spring coupled to the plunger rod. The plunger face is disposed near the needle assembly and is movable along the longitudinal axis of the housing. The plunger rod guide guides the rotational movement of the plunger assembly and is operably coupled to one of the frame member or the damper member. The torque spring applies a force to the plunger rod guide, which causes the plunger rod guide to rotate. Rotation of the plunger rod guide advances the plunger assembly toward the proximal end of the housing, propelling the medicament through the needle assembly. The plunger assembly may additionally include a gap of more than about 10 mm between the threaded plunger rod and the plunger face. Furthermore, the syringe barrel may contain at least about 1 mL of medicament having a viscosity of at least about 4 cP. Other examples are possible.

[0011] Additionally, in any of the above embodiments, the damper mechanism may exert a counter force on the drive assembly or on at least one component operatively coupled to the drive assembly.

[0012] According to another aspect, a damper mechanism of a drug delivery device includes a frame member, a damper member operably coupled to a drive assembly of the drug delivery device, a chamber formed between a portion of the frame member and the damper member, and a damper fluid disposed within the chamber. Upon actuation of the drug delivery device to administer a medicament to a user, the frame member and the damper member rotate relative to each other and the damper fluid exerts an opposing force on at least one of the frame member and the damper member.

[0013] According to yet another aspect, an autoinjector includes a housing defining an outer shell having a proximal end, a distal end, and a longitudinal axis extending therebetween, a needle assembly disposed at least partially within the housing at the proximal end, and a drive assembly disposed at least partially within the housing. The needle assembly includes a syringe barrel containing a medicament and a needle or cannula. The drive assembly is operatively coupled to the needle assembly for propelling the medicament through the needle or cannula. The drive assembly includes a plunger assembly having a plunger rod and a plunger face disposed near the needle assembly and movable along the longitudinal axis of the housing. The syringe barrel is adapted to contain at least about 1 mL of medicament having a viscosity of at least about 4 cP. The plunger rod and plunger face have an initial clearance of greater than about 10 mm.

[0014] The above needs are met, at least in part, by the provision of a torque-driven drug delivery device as described in the detailed description below, particularly when studied in conjunction with the drawings. [Brief explanation of the drawings]

[0015] [Figure 1] 1A and 1B show cross-sectional views of an exemplary torque-driven drug delivery device having a damper mechanism, according to various embodiments. [Figure 2] 2 shows an enlarged cross-sectional view of the damper mechanism of the exemplary drug delivery device of FIG. 1, according to various embodiments. [Figure 3]10A-10C show cross-sectional views of a second exemplary drug delivery device having a chamber for excess damper fluid, according to various embodiments. [Figure 4] 10A-10C show cross-sectional views of a third exemplary drug delivery device having a damper fluid disposed between the discs of the damper mechanism, in accordance with various embodiments. [Figure 5] 10 shows a cross-sectional view of a fourth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 6a] 10A-10C show cross-sectional views of a fifth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 6b] 10A-10C show cross-sectional views of a fifth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 7] 10 shows a cross-sectional view of a sixth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 8] 10 shows a cross-sectional view of a seventh exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 9a] 10 shows a cross-sectional view of an eighth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 9b] 10 shows a cross-sectional view of an eighth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 9c] 10 shows a cross-sectional view of an eighth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 10] 10 shows a cross-sectional view of a ninth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 11] 13A shows a cross-sectional view of a tenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 12] 13 shows a cross-sectional view of an eleventh exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 13] 12 shows a cross-sectional view of a twelfth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 14] 13 shows a cross-sectional view of a thirteenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 15] 14 shows a cross-sectional view of a fourteenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 16] 15 shows a cross-sectional view of a fifteenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 17] 16A-16C show cross-sectional views of a sixteenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 18] 17 shows a cross-sectional view of a seventeenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 19] 19 shows a cross-sectional view of an eighteenth exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 20] 19 shows a cross-sectional view of a 19th exemplary damper mechanism of a drug delivery device, according to various embodiments. [Figure 21] 1 shows a graph depicting shear stress as a function of shear rate according to various embodiments. [Figure 22] 1 shows a graph depicting apparent viscosity as a function of shear rate according to various embodiments. [Figure 23] 1 shows a perspective view of an exemplary drug delivery device having gaps between components, according to various embodiments. [Figure 24] 10A-10C show diagrams of an example of the effect of a damper mechanism on drug expulsion, according to various embodiments. [Figure 25] 10A-10C show diagrams of an example of the effect of a damper mechanism on drug expulsion in a low friction environment, according to various embodiments. [Figure 26] 10A-10C show diagrams of an example of the effect of a damper mechanism on drug expulsion in a high friction environment, according to various embodiments. [Figure 27] 1 illustrates an exemplary model calculation of a drug delivery device, according to various embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0016] Those skilled in the art will understand that elements in the figures are drawn for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions and / or relative positions of some of the elements in the figures may be exaggerated relative to other elements to improve understanding of various embodiments of the present invention. Also, common but well-understood elements that are useful or necessary in commercially feasible embodiments are often not shown in order to unduly distract from the illustrations of these various embodiments. Furthermore, it will be appreciated that certain acts and / or steps may be described or shown in a particular chronological order, although those skilled in the art will understand that such specificity with respect to order is not actually required. It will also be understood that the terms and phrases used herein have the ordinary technical meaning, as set forth above, that would be ascribed to such terms and phrases by those skilled in the art, unless a different specific meaning is explained herein.

[0017] Broadly, in accordance with these various embodiments, a torque-driven injector includes a housing, a syringe assembly containing a medication to be injected into a user, and a rotatable actuation assembly that uses a torque spring to inject the medication into the user. As the rotatable actuation assembly rotates to administer the medication, a fluid damper is used to provide more consistent drug delivery times between medications of various viscosities, as well as medications that may exhibit viscosity changes based on different environmental changes (e.g., different temperatures).

[0018] Furthermore, as the actuation mechanism rotates, the damper mechanism can reduce or eliminate the "slap" or "bump" that occurs when the plunger face first contacts the medication and / or medication storage device. The damper mechanism can also reduce the "jerk" or bounce when the mechanism is released. Thus, the user does not feel this sudden movement during the drug delivery process, allowing for a comfortable and safe administration of medication. Furthermore, torque springs using a larger number of turns, as described in detail below, can maintain a more consistent start and end torque than conventional springs and springs with fewer turns. As a result, a smaller autoinjector can be used, improving overall user comfort. Furthermore, the damper can reduce and / or eliminate variability in injection time, minimizing the risk of the device stalling. The damper can also provide design flexibility to target optimal injection times for ease of use, potentially eliminating the need to customize devices for different drug doses.

[0019] 1 and 2, an exemplary autoinjector 100 includes a housing 102 defining an outer shell, a needle assembly 110 at least partially disposed within the outer shell 102, a drive assembly 120 also at least partially disposed within the outer shell 102, and a damper mechanism 140 also at least partially disposed within the outer shell 102. The outer shell 102 includes a proximal end 102a, a distal end 102b, and defines a longitudinal axis "L" extending between the proximal end 102a and the distal end 102b.

[0020] The needle assembly 110 is disposed generally at or near the proximal end 102a of the shell 102 and includes a syringe barrel 112 containing a medicament 113 and a needle or cannula 114. The needle assembly 110 may include any number of additional components, such as, for example, a sidewall or sidewalls, an opening that allows the medicament 113 to pass through the needle or cannula 114, a return spring, a shield member, a filter member, and the like, which will not be described in detail for the sake of brevity. A portion of the syringe barrel 112 may be open to accommodate a portion of the drive assembly 120, which is described in more detail herein below. The syringe barrel 112 may be of any desired shape and / or size to accommodate various amounts of the medicament 113. In some embodiments, the syringe barrel 112 may be constructed from a polymeric material, such as a cyclic olefin polymer ("COP"), a cyclic olefin copolymer ("COC"), or a glass material. Other examples are possible.

[0021] The drive assembly 120 may include a nut 122 positioned adjacent the syringe barrel 112, a trigger ring 124, a plunger rod guide 126, a plunger rod assembly 130, and a drive mechanism in the form of a torque or power spring 136. In general, portions of the drive assembly 120 may be securely coupled to the shell 102 via any number of approaches. In some configurations, the nut 122 may be integrally formed with the shell 102 and may include a threaded opening 122a. The trigger ring 124 is configured to selectively engage the nut 122 and move axially. In the illustrated embodiment, the trigger ring 124 is generally cylindrical in shape, having a generally circular inner surface and any number of ledges, protrusions, and grooves disposed around and / or within the outer periphery of the ring. The trigger ring 124 may be coupled to the housing 102 via any number of techniques.

[0022] Plunger rod guide 126 includes a rod portion 127 and a base portion 128 coupled thereto. Plunger rod guide 126 includes an opening 126a extending at least partially through rod portion 127 and base portion 128. Base portion 128 may have any number of protrusions or tabs extending therefrom that define a slidable engagement with trigger ring 124.

[0023] The plunger rod assembly 130 includes a plunger rod 131, a washer 132, and a plunger 133 that is movable along the longitudinal axis L of the housing 102. The plunger rod 131 has a threaded portion 131a that is threadedly coupled to the plunger rod guide 126 and the threaded opening 122a of the nut 122. The washer 132 minimizes friction losses between the rotation of the plunger rod 131 and the non-rotating plunger 133. In some approaches, the washer 132 can also be used to adjust the volume of the medicament 113 by making the washer 132 thicker or thinner. Thus, the washer 132 can be used to accommodate different fill volumes of the medicament 113 in the same device 100, thereby better controlling the air gap between the bottom of the washer 132 and the top of the plunger 133.

[0024] The rod portion 127 of the plunger rod guide 126 is coupled to the plunger rod assembly 130 via any number of approaches, including, for example, by a splined connection or a grooved configuration that allows the plunger rod assembly 130 to be axially displaced relative to the plunger rod guide 126. Thus, the plunger rod guide 126 guides the rotational movement of the plunger rod assembly 130. The threaded portion 131a of the plunger rod 131, and similarly the threaded opening 122a of the nut 122, may have a thread pitch suitable for any desired drug delivery rate or force / torque combination when driven by the drive mechanism 136. Relative rotation between the plunger rod 131 and the nut 122 advances the plunger rod 131 axially toward the proximal end 102a of the housing 102. The plunger 133 has an upper surface 133a disposed near the syringe barrel 112.

[0025] In the illustrated example, drive mechanism 136 is in the form of a power spring or torque spring 136 having an inner portion 136a coupled to rod portion 127 of plunger rod guide 126 via any known approach to apply torque on plunger rod guide 126 to rotate plunger rod guide 126 about axis L. In some embodiments, torque spring 136 may have a number of turns to provide the appropriate rotational movement necessary to expel medication from syringe barrel 112, although additional parameters of the spring design, such as material properties and any applied heat treatments, can affect the torque output of the spring. Pre-forming of torque spring 136 can also affect its performance. As an example, in an autoinjector, a pre-stressed spring may be preferred because the pre-stressing process generally increases the torque output of the spring by first coiling the spring in the opposite direction of the intended operating conditions, thereby creating a permanent strain in the steel band. This strain maximizes the stress in the material, thereby increasing torque. Such increased torque is advantageous in minimizing the size and weight of the device.

[0026] In some examples, the torque spring 136 may have about 1 to about 30 turns in a wound or loaded configuration, preferably about 12 turns. In some embodiments, the total number of turns of the spring may be greater by about 20% margin on both ends of the operating range, resulting in a range of about 1*1.4 = 1.4 to 30*1.4 = 42 turns. The number of turns of the dosing mechanism is derived from the pitch and the required travel length. As previously mentioned, a smaller pitch is preferred because it requires lower torque input and actuation force. Actuation force is correspondingly reduced. If high axial forces are not required, a larger pitch can be used, requiring fewer spring turns, thereby enabling a smaller device. In some embodiments, the torque spring 136 may have several initial or preload turns to provide a useful torque. After the preload turns, the torque spring 136 is wound with additional working turns, i.e., the number of turns used by the device during injection. As a non-limiting example, the torque spring 136 may have approximately 2.5 preload turns and approximately 6 working turns. Therefore, the total number of turns during assembly is approximately 8.5. However, due to potentially large tolerances in the angular positioning of the spring ends, the torque spring 136 may have initial slack before reaching a solid state and therefore may have a total of approximately 10 turns. Devices with different drug amounts and viscosities may require different average torques to be generated from the torque spring 136 if the same dosage is desired. The average torque output can be controlled by adjusting the width of the band used for the torque spring 136 (e.g., the axial length of the torque spring 136 when disposed within the device) and maintaining the same number of working turns. This may allow the amount and / or viscosity of the drug to be changed while still allowing different springs to be used in the same configuration as the device and have similar injection times.

[0027] In some embodiments, the energy (EFLOW) required to expel the medicament 113 through the needle 114 is determined by any combination of the drug amount, viscosity, needle channel dimensions, and target dosing time. The energy (ESPRING) delivered by the torque spring 136 may be determined by any combination of the number of functional turns (N) and the average spring torque (T) over the functional turns. The energy delivered by the spring can be calculated using the following formula: ESPRING = 2*π*N*T. If friction losses in the system are excluded, the following relationship exists: EFLOW = ESPRING = 2*π*N*T. Therefore, the following relationship is obtained: EFLOW / (2*π) = N*T. In other words, for the torque spring 136 to have enough energy to expel a given amount of a given drug through a given needle in a given time, higher torque can be translated into fewer functional turns since the product (N*T) remains constant.

[0028] The threaded connection between the plunger rod 131 and the nut 122 provides a translation between the input torque and the output axial force of the torque spring 136. Providing the torque spring 136 with a high turn count reduces the overall torque and the variation between the starting and ending torque compared to a linear spring with comparable transmission specifications or other torsion springs with fewer turns and a smaller pitch. In addition, the threads of the plunger rod 131 and the nut 122 can have a smaller pitch with an increased number of turns while still achieving similar linear motion of the plunger rod assembly 130. A smaller thread pitch requires less input torque to provide the same output as a higher-pitch thread and a higher-torque spring. Therefore, because actuation force is directly related to the input torque that must be used to drive the plunger rod assembly 130, the high-turn count (e.g., about 1 to about 30 turns) and low-torque systems described herein can reduce actuation force. Additionally, the reduced internal structural force required to resist torque from torque spring 136 during storage (e.g., prior to use) allows for the use of smaller injector designs and less expensive raw materials. Additionally, the threaded connection between plunger rod 131 and nut 122 allows threaded plunger rod 131 to be adjusted to accommodate different amounts of drug stored in syringe barrel 112. If desired, threaded plunger rod 131 may be initially installed at a lower position within injector 100 with a smaller amount of drug product disposed within syringe barrel 112, thus reducing the number of unique components and simplifying variability management. Threaded plunger rod 131 may also be adjustably installed at various depths as needed during the manufacturing and / or assembly process.

[0029] A damper mechanism 140 is also disposed at least partially within housing 102 at its distal end 102b. Damper mechanism 140 is operably coupled to a portion of drive assembly 120 (e.g., plunger rod guide 126) and housing 102. Damper mechanism 140 acts to dampen the effect of torque spring 136 on drive assembly 120.

[0030] Generally, to activate the device, a user presses device 100 against their skin, thereby disengaging trigger ring 124 from nut 122 and / or plunger rod guide 126. This disengagement allows plunger rod guide 126 to rotate relative to trigger ring 124. Because torque spring 136 is in a wound or compressed state, torque spring 136 begins to unwind, thereby rotating plunger rod guide 126. This rotation in turn rotates plunger rod 131, which, due to the threaded connection between plunger rod 131 and nut 122, advances plunger rod 131 and plunger 133 toward proximal end 102a of housing 102, thereby inserting needle or cannula 114 and administering medicament 113. By way of non-limiting example, U.S. Provisional Patent Application No. 62 / 719,367, filed August 17, 2018, describes in further detail the operating process and components of the drive assembly and is therefore incorporated by reference in its entirety.

[0031] 1 and 2, damper mechanism 140 includes a damper member 142, a frame member 150, a chamber 160 formed between a portion of damper member 142 and frame member 150, and a damper fluid 151 disposed within chamber 160. Damper member 142 may be coupled to plunger rod guide 126 via any number of approaches, such as, for example, via a friction fit or threaded engagement. Damper member 142 includes a body 143 having an inner surface 143a defining a central opening or bore 144 for accommodating a portion of plunger rod guide 126, and further including an outer surface 143b. Damper member 142 further includes wing portions 145 having inner surfaces 145a positioned away from body 143 and facing outer surface 143b. A channel 146 is formed between outer surface 143b of body 143 and inner surface 145a of wing portions 145.

[0032] Frame member 150 operably couples to housing 102. For example, frame member 150 may be in the form of a cylindrical member defining a body 152 and a coupling portion 153 for coupling to housing 102 via any number of approaches, such as, for example, adhesive, threaded, frictional connection, etc. In some embodiments, frame member 150 may be integrally formed with distal end 102b of housing 102.

[0033] The body 152 of the frame member 150 is adapted to be at least partially inserted into the channel 146 of the damper member 142. In the illustrated example, the frame member 150 further includes a ledge 155 that engages (e.g., by a frictional fit) with the inner surface 145a of the wing portion 145. A chamber 160 is defined by the body 152 of the frame member 150 and the body 143 of the damper member 140. In some embodiments, the shell 102 can further define an end surface of the chamber 160. A damper fluid 151 is disposed within the chamber 160.

[0034] As described above, relative rotation between the components of damper mechanism 140 causes damper fluid 151 to dampen this effect. Specifically, in this embodiment, as plunger rod guide 122 rotates, damper member 140 rotates relative to frame member 150. Because torque from torque spring 136 exists between damper member 142 and frame 150, the system accelerates from rest, thus increasing its velocity. During the relative rotation, damper fluid 151 experiences shear stress due to the rotation of damper member 142. In the disclosed embodiment, damper fluid 151 therefore exerts an opposing reaction torque on drive assembly 120, and in particular on plunger rod guide 126 of drive assembly 120. The velocity of drive assembly 120 increases until the opposing damper torque builds up to the same level as the applied torque and an equilibrium is reached. This balance occurs at a particular speed and torque and depends on many factors, such as the geometry of the damper mechanism 140, the fluid properties of the damper fluid 151, and the torque profile of the torque spring 136. Other examples are possible.

[0035] When configured in this manner, the damper mechanism 140 has a relatively simple design with a minimum of parts, reducing assembly and component costs and complexity. The damper mechanism 140 can be easily assembled, filled, and tested on a separate assembly line before insertion into the device 100. In some embodiments, it may also be of interest to have a robust and stable damper mechanism 140. There are many parameters that can affect the performance of the damper mechanism 140, and reducing the effects of these parameters can further improve the stability of the damper mechanism 140. For example, as also discussed above, a damper fluid 151 may be selected that has shear-thinning properties, i.e., a small variation in viscosity as a function of temperature. The shear stress of the damper fluid 151 is directly related to the damping torque. To achieve a relatively constant and predictable velocity at a particular required damping torque, it is desirable for the change in shear rate caused by changes in input torque (and therefore shear stress) to be minimal. In some embodiments, this can be best achieved by having a design with a lower shear rate, as shown in Figure 21, which depicts shear stress as a function of shear rate for damper fluid type "G," since the variation in shear rate y for a given input torque interval is smaller within this region. Note that the curves provided in and values ​​shown in Figure 21 represent example curves only; therefore, other curves may be used. Figure 22 shows the apparent viscosity of damper fluid type G. The shear-thinning properties can be seen by decreasing the apparent viscosity and increasing the shear rate.

[0036] Another parameter that can affect the robustness and stability of the damper mechanism includes a large gap at a small diameter. The level of shear rate is designed into and affected by the dimensions of the damper mechanism 140. The size of the gap defining the chamber 160 affects the shear rate. When the nominal chamber 160 size is at its largest, and when the chamber 160 is placed at its smallest diameter, the art tolerances can have a minimal effect on the size of the chamber 160.

[0037] Further, with brief reference to FIG. 23 , the described damper mechanism 140 can be activated to allow a large clearance “C” (e.g., about 10 mm or greater) between the plunger rod 131 and the plunger 133 without risking destruction of the syringe barrel 112 or other components of the device 100 when an impact occurs between the plunger rod 131 and the plunger 133. These devices can be adapted to expel at least about 1 mL of medicament 113 having a viscosity of at least about 4 cP. Such a large clearance advantageously reduces platform complexity, inventory variation, and / or process control. The damper mechanism 140 also provides a better user experience compared to devices without a damper mechanism, where the impact, feel, and sound may startle the user.

[0038] In some embodiments, it may be beneficial for a significant surface of the damper member to be in contact with the damper fluid. If the entire surface is not in contact with the damper fluid due to underfilling, the damping torque is reduced. Accordingly, FIG. 3 illustrates an alternative damper mechanism 240 for the drug delivery device 200 that is less sensitive to fill accuracy. It will be understood that the drug delivery device 200 includes any number of similar components and / or features as the drug delivery device 100 and, therefore, includes similar two-digit suffixes as used in connection with FIGS. 1 and 2 . Accordingly, these components will not be described in particular detail. In the drug delivery device 200, the damper member 242 includes a body 243 having an inner surface 243 a defining a central opening or bore 244 for receiving a portion of the plunger rod guide 226, and further includes an outer surface 243 b. The damper member 242 includes a wing portion 245 having an inner surface 245 a and a notch 245 b. The damper member 242 further defines a channel 246 between an outer surface 243 b of the body 243 and an inner surface 245 a of the wing portion 245 , and further includes an end cap portion 247 .

[0039] In this embodiment, the frame member 250 is integrally formed as an end cap of the housing 202. The frame member includes a generally cylindrical protrusion 252 having an inner surface 252a and an outer surface 252b. The cylindrical protrusion 252 defines a tab 253 on the outer surface 252b. When the damper mechanism 240 is installed on the drug delivery device 200, the cylindrical protrusion 252 is inserted into the channel 246. In this configuration, the notch 245b engages the tab 253, limiting relative axial movement between the damper member 242 and the frame member 250. Furthermore, because the concentric cylinders are radially constrained relative to one another, part tolerances have minimal effect on concentricity. However, relative rotation between the damper member 242 and the frame member 250 is still permitted. In this embodiment, a U-shaped chamber 260 is formed between the protrusion 252, the body 243, and the end cap portion 247 to contain the damper fluid 251. In such a configuration, the chamber is partially axially and partially laterally aligned with the longitudinal axis L. When constructed, the channel 246 further defines an excess chamber 248 for containing any excess damper fluid, which may be used to selectively adjust the damping torque generated or may simply be used as a “spillover” area if more fluid than desired is accidentally delivered. In these embodiments, the damper mechanism 240 may engage with the housing 202 and / or the drive assembly 220, as needed. Furthermore, the damper mechanism 240 may be assembled to the device 200 via an axial assembly process.

[0040] In these embodiments, it may be desirable to provide a seal to ensure that the damper fluid remains within the desired chamber to maintain a constant damping torque. Such a seal can create a resistance force between the frame and the damper member, which in turn creates a resistance torque. This may be undesirable during administration because the power source (i.e., torque spring) may need to be larger to overcome this additional resistance. Accordingly, FIG. 4 illustrates an alternative drug delivery device 300 having an alternative damper mechanism 340 that allows for simple filling of the damper fluid while preventing fluid escape. Drug delivery device 300 includes any number of similar components and / or features as drug delivery devices 100 and 200 and, therefore, includes the same two-digit suffixes used in connection with FIGS. 1-3. Accordingly, these components will not be described in particular detail. In drug delivery device 300, damper member 342 includes a body 343 and a disc portion 345 coupled to body 343. The disc portion 345 defines a first surface 345a, includes a number of grooves 345b positioned along its length, and terminates at an outer end 345c. The frame member 350 is also in the form of a generally cylindrical member having a generally disc-like base 352 defining a first surface 352a, and a sidewall portion 353 including tabs 353a. The disc-like base 352 further defines an opening 354.

[0041] In the illustrated embodiment, any number of sealing members 347 are disposed within or adjacent to the grooves 345b of the damper member 342. To assemble the damping mechanism, the disk damper member 342 is inserted into the opening 354 in the base 352 so that the outer end 345c engages the tab 353a on the sidewall portion 353. As a result, a chamber 360 is formed between the first surface 345a of the disk portion 345 and the first surface 352a of the base 352. In this embodiment, the chamber 360 is disposed in a lateral arrangement and sealed via the sealing members 347. Such damper mechanisms 340 can be assembled within the same power module, eliminating internal rotary play, thereby reducing and / or eliminating the risk of the device 300 jerking during operation.

[0042] 5, an alternative damper mechanism 440 for the drug delivery device 400 includes similar features to the damper mechanism 240 described above. Accordingly, these features have the same two-digit suffixes as those provided in FIG. 3 and, therefore, will not be described in detail. The damper mechanism 440 additionally includes a generally cylindrical extension 447a extending from the end cap portion 247 that mates with an inner cylinder 450a extending from the frame member 450. When the frame member 450 and the damper member 442 are coupled together, relative rotation is still permitted, but the concentric engagement between the extension 447a and the inner cylinder 450a improves centering of the components, resulting in less variance in the dimensions of the chamber 460.

[0043] Referring now to Figures 6a-8, alternative damper mechanisms are provided that effectively double the damping surface by creating two chambers containing damping fluid on multiple sides of a frame member. As a result, these damper mechanisms can generate approximately twice the damping torque compared to similar designs with a single chamber. Advantageously, these damper mechanisms can be manufactured more compactly compared to single-chamber designs when the same level of damping torque is required. These damper mechanisms include similar features to those described with reference to Figures 1-5 and, therefore, include similar two-digit suffixes. Therefore, for the sake of brevity, some of these components will not be described in detail.

[0044] 6a and 6b, the damper member 542 is generally U-shaped and defines a channel 546 between an inner wall 543a and an outer wall 543b. The damper member 542 may additionally include a tab 544 extending from the outer wall 543b and a ledge 545 extending from the inner wall 543a. The frame member 550 includes a base portion 552, a first generally cylindrical protrusion 553, and a second generally cylindrical protrusion 554 that receives a notch 554a.

[0045] In operation, ledge 545 of damper member 542 frictionally engages and rotatably couples with plunger rod guide 526. Channel 546 is filled with damper fluid 551, and frame member 550 couples to damper member 542 by inserting first cylindrical protrusion 553 into channel 546. Notch 554a then engages tab 544, securing damper member 542 to frame member 550. First cylindrical protrusion 553 further divides channel 546 into a U-shaped chamber 560, such that damper fluid 551 surrounds, and is thus disposed on either side of, first protrusion 553.

[0046] FIG. 7 shows a damper mechanism 640 similar to mechanism 540 described in FIGS. 6a and 6b, but additionally includes a third generally cylindrical protrusion 655. This protrusion 655 engages with inner wall 643a to form an additional channel 647 that functions as a fluid relief pathway. In FIG. 8, the components of damper mechanism 740 are essentially inverted. In other words, frame member 750 defines channel 757 between first side wall 756 and second side wall 758, while still including cylindrical protrusion 754 bearing notch 754a. Damper member 742 includes first protrusion 743, second protrusion 744 bearing tab 744a, and third protrusion 745 bearing ledge 745a. Damper fluid 751 is disposed within channel 757 and first protrusion 743 is inserted therein to define a chamber 760 surrounding first protrusion 743 .

[0047] 9a-9c show a similar damper mechanism 840 that allows for easy filling of the channel 857 of the frame member 850 with damper fluid 851. When the damper member 842 is subsequently applied, the angled protrusions 843 penetrate into the single channel 860, distributing the damper fluid 851 into the single channel 860 between the first protrusion 843 and the first and second side walls 856, 858. In this example, the protrusions 844a engage notches 858a formed on the second side wall 858. Similarly, in FIG. 10, the components of the damper mechanism 940 are essentially inverted. In other words, similar to FIGS. 6a-7, the damper member 942 is generally U-shaped and defines a channel 946 between an inner wall 943a and an outer wall 943b. The damper member 942 further includes a second channel 947 extending from the outer wall 943b. Frame member 950 includes a base portion 952, a first protrusion 953, a second protrusion 954, and a third protrusion 956. Damper fluid 951 is inserted within channel 946, with first protrusion 953 inserted into channel 946 to define chamber 960. In this example, second protrusion 954 is inserted into second channel 947.

[0048] 11-20 illustrate alternative damper mechanisms having a three-piece design. In these embodiments, fluid paths may be sealed and / or extended to ensure fluid is contained within a chamber or to allow fluid to be easily filled and collected. Additionally, these components may ensure concentricity between damping surfaces. These damping mechanisms include similar features to those described with reference to FIGS. 1-10 and, therefore, include similar two-digit suffixes. Therefore, for the sake of brevity, some of these components will not be described in detail.

[0049] As shown in FIG. 11 , the damper mechanism 1040 includes a first damper member 1042, a frame member 1050, and a second damper member 1062. The first damper member 1042 may be coupled to a plunger rod guide (not shown) via any number of approaches and includes a body 1043 having an inner surface 1043a defining a central opening or bore 1044 for accommodating a portion of the plunger rod guide, and further defining an outer surface 1043b. The first damper member 1042 further includes wing portions 1045 having inner surfaces 1045a positioned away from the body 1043 and facing the outer surface 1043b. A channel 1046 is formed between the outer surface 1043b of the body 1043 and the inner surface 1045a of the wing portions 1045.

[0050] The second damper member 1062 is in the form of a generally cylindrical body 1063 having an inner surface 1063a and an outer surface 1063b. The second damper member 1062 includes a ledge 1064 extending outward from the outer surface 1063b. The second damper member 1062 is adapted to be at least partially disposed within the channel 1046 and to at least partially surround the body 1043 of the first damper member 1042 to form a concentric cylinder. In this configuration, a chamber 1060 is formed between the outer surface 1043b of the first damper member 1042 and the inner surface 1063a of the second damper member 1062. The chamber 1060 contains a damper fluid 1051.

[0051] In this embodiment, the frame member 1050 is integrally formed with the distal end 1002b of the housing 1002 and includes a base portion 1052 and a generally cylindrical protrusion 1053 extending therefrom. In operation, the frame member 1050 is positioned within or near the channel 1046 and can engage a ledge 1064 on the second damper member 1062 to hold the second damper member in place. The frame member 1050 may include any number of additional notches, tabs, etc. for selectively engaging the first and / or second damper members 1042, 1062. As a result, the chamber 1060 may be defined by the outer surface 1043b of the first damper member 1042, the inner surface 1063a of the second damper member 1062, and the base portion 1052 of the frame member 1050. Furthermore, the first damper member 1042, the second damper member 1062, and the frame member 1050 form three concentric cylinders, thereby limiting relative movement (except relative rotation) therebetween. In some embodiments, the second damper member 1062 can be rigidly coupled to the frame member 1050 (which itself can be coupled to and / or integrally formed with the housing 1002) to ensure that the second damper member 1062 remains stationary while the first damper member 1042 rotates with the plunger rod guide. Furthermore, in some embodiments, the frame member 1050 can include detents 1055 that engage grooves 1045b on the wing portions 1045 of the first damper member 1042 to limit relative axial movement.

[0052] 12 is similar to damper mechanism 1040 (and thus similar features include similar two-digit suffixes), but differs in the placement of chamber 1160 and damper fluid 1151. Specifically, chamber 1160 is defined by inner surface 1145a of wing portion 1145, outer surface 1163b of body 1163 of second damper member 1162, and base portion 1152 of frame member 1150. In this example, frame member 1150 includes protrusion 1153 that inserts into channel 1164 defined by second damper member 1162 to secure frame member 1150 to second damper member 1162.

[0053] 13 is similar to damper mechanism 1140 (and thus similar features include similar two-digit suffixes), except that frame member 1250 includes a rotational locking protrusion 1253 in the form of a pin that engages with a cylinder or hole 1264 defined by second damper member 1262. Thus, relative rotation between frame member 1250 and second damper member 1262 is limited.

[0054] The example damper mechanism 1340 shown in FIG. 14 is similar to damper mechanism 1240 (and thus similar features include similar two-digit suffixes), except that damper mechanism 1340 includes any number of sealing components for sealing chamber 1360 to retain damper fluid 1351 therein. Specifically, frame member 1350 further includes resilient finger portions 1356 adapted to form a seal with outer surfaces 1345 b of wing portions 1345 of first damper member 1342. In this example, wing portions 1345 have a generally tapered or wedge-like shape that contacts outer surfaces 1345 b thereof to assist in properly positioning resilient fingers 1356. Additionally, first damper member 1342 includes an additional sealing portion in the form of a bump or detent 1343 for abutting base portion 1352 of frame member 1350.

[0055] 15 is similar to the three-piece damper mechanism described above (and thus similar features include similar two-digit suffixes), but advantageously can further include any number of alignment features to facilitate filling of chamber 1460 with damper fluid 1451 and to ensure proper alignment of components during installation. Specifically, protrusion 1453 formed by base portion 1452 of frame member 1450 can include ledge 1453a that assists in properly aligning first damper member 1442 against frame member 1450. An outer surface 1443a of the first damper member 1442 abuts the ledge 1453a to ensure that the frame member 1450 is properly concentrically aligned with the first damper member 1442 and additionally defines a chamber 1460 between the outer surface 1443a, the ledge 1453a, and the protrusion 1453. The chamber 1460 may then be filled with damper fluid 1451 and a second damper member 1462 in the form of a snap-on or press-fit lid may be applied.

[0056] The second damper member 1462 includes a base portion 1463, a first protrusion 1464, and a second protrusion 1465 that cooperate to define a channel 1466. When the second damper member 1462 is installed, the first protrusion 1464 abuts the protrusion 1453 of the frame member 1450, and the second protrusion 1465 additionally engages the ledge 1444 of the first damper member 1442. As a result, the protrusion 1453 of the base member 1450 and the ledge 1444 of the first damper member 1442 cooperate to guide the placement of the second damper member 1462 so as to reduce and / or eliminate relative misalignment of these components. The second damper member 1462 also serves as a seal to close the chamber 1460.

[0057] The exemplary damper mechanism 1540 shown in FIG. 16 is similar to the three-piece damper mechanism described above (and thus similar features include similar two-digit suffixes), but includes an alternative arrangement to ensure proper component alignment during installation. The damper mechanism 1540 includes a first damper member 1542 having a wing portion 1545 defining a first surface 1545a, a tab 1545b, and a second surface or ledge 1545c. The second damper member 1562 includes a cylinder or bore 1564 that couples to a rotation locking protrusion 1553 carried by a body portion 1552 of the frame member 1550. The second damper member 1562 further includes a facing surface 1562a and a ledge 1566. A first surface 1545c of the wing portion 1545 is adapted to abut the ledge 1566 of the second damper member 1562, and a second surface 1545c of the wing portion 1545 is adapted to abut the contact surface 1562a of the second damper member 1562, thereby creating two contact or ground planes, thus further ensuring proper displacement of the damper mechanism 1540.

[0058] 17 and 18 show damper mechanisms 1640, 1740 similar to damper mechanisms 1240, 1340, 1440, and 1540, except that they utilize features of their respective frame members 1650, 1750 as a contact surface (and thus similar features include similar two-digit suffixes). Specifically, in FIG. 17, a first damper member 1642 includes a finger portion 1645 having a first ledge or surface 1645a, a second surface 1645b, a finger 1645c, and a protrusion 1645d extending from the finger 1645c. The frame member 1650 includes a base portion 1652 bearing a first protrusion 1653 that locks relative rotation and a second protrusion 1654 having an outer surface 1654a. The frame member 1650 further includes a tab 1656. The second damper member 1662 includes a first surface 1662a, a channel or hole 1664, and a ledge 1666 defining a surface 1666a. A first protrusion 1653 of the frame member 1650 is inserted into the hole 1664 of the second damper member 1662 to prevent relative rotation therebetween. Furthermore, a surface 1666a of the ledge 1666 of the second damper member 1662 abuts the second protrusion 1654 of the frame member 1652. A first surface 1662a of the second damper member 1662 abuts a first ledge 1645a of the finger portion 1645 of the first damper member 1642, and a second surface 1645b of the finger portion 1645 of the first damper member 1642 abuts an outer surface 1654a of a second protrusion 1654 of the frame member 1650. Additionally, a finger 1645c of the finger portion 1645 engages a tab 1656 of the frame member 1650. Multiple contact points or ground planes are thereby created between the first damper member 1642, the frame member 1650, and the second damper member 1662, further ensuring proper displacement of the damper mechanism 1640. In FIG. 18, damper mechanism 1740 includes similar features, surfaces, and / or protrusions as damper mechanism 1640 shown in FIG. 17, but frame member 1750 further includes protrusion 1753 that carries bump 1753a that engages with channel 1745a in finger portion 1745 of first damper member 1742.

[0059] The exemplary damper mechanism shown in FIGS. 19 and 20 is similar to the damper mechanisms described above (and thus similar features include similar two-digit suffixes), but includes an additional sealing component. As shown in FIG. 19 , a sealing member 1870 is operably coupled (e.g., glued or otherwise affixed) to a frame member 1850. The sealing member 1870 can be molded using any number of conventional approaches and includes a number of resilient sealing fingers 1872. These fingers 1872 are at least partially inserted into the chamber 1860 to restrict the damper fluid 1851 from exiting the chamber 1860 when a gap is formed between the frame member 1850 and the first damper member 1842 and / or the second damper member 1862.

[0060] 20, resilient sealing fingers 1947 are carried by finger portions 1945 of first damper member 1945. These sealing fingers 1947 engage frame member 1950 to ensure that damper fluid 1951 does not leak into the rest of device 1900.

[0061] 24-26, in some embodiments, it may be advantageous to construct the syringe barrel 112 from different materials. Because of large friction variations in containers constructed from some materials, there may be large variances in delivery times. Friction between the plunger and syringe barrel can introduce significant variability, especially when the syringe is constructed from a polymeric material. As noted, the force required to expel a drug through a needle within a specified time, which is directly related to the axial plunger speed, varies depending on the viscosity of the drug. For high-viscosity drugs (e.g., greater than 10-15 cP), the force requirement is high, while for low-viscosity drugs, the force requirement is low. The force also depends on the rate at which the drug is expelled. During dispensing, an equilibrium dispensing rate is achieved where the speed-dependent resistance in the system matches the input torque from the power source. However, the range over which frictional force varies in the system is constant regardless of the viscosity of the drug. Consequently, for low-viscosity drugs, the ratio between frictional force and drug expulsion force is high. Furthermore, for polymer syringe barrels, high variability in frictional forces is expected, so the residual torque from the spring to expel the drug may be either too high or too low, resulting in a dosing time that is either too fast or too slow, which can result in either unacceptably high dosing time variability or complete failure of the device.

[0062] The use of a damper mechanism addresses these inconsistencies by acting as a buffer against excess torque. The speed of the dispensing mechanism is the result of a mechanical equilibrium, where the friction in the system, the torque required to expel the drug, and the torque acting on the mechanical damper are equal to the total input torque from the power source. Because the non-constant torque, the torque of the damper, and the torque required to expel the added drug dominate the frictional force, fluctuations in frictional force have a relatively small effect on the torque available for expulsion and therefore have a modest effect on speed. Generally, whenever resistance in the device increases during dispensing, whether due to friction and component tolerances or high drug viscosity, the speed in the device decreases. However, due to the speed-dependence of the damper, even a slight decrease in speed results in a decrease in damping torque, which releases the torque available to overcome the increased resistance.

[0063] As shown in Figures 24-26, the variance between plunger friction, the torque required to expel the drug, and the torque absorbed by the damper are added to provide the nominal input torque requirement. Note that the torque contribution in the device is not limited to these provided terms. If a damper is not used, the spring would be sized larger because the damper dissipates a significant amount of torque. The velocity-dependent terms (i.e., Tdamper and Tdrug) dissipate the majority of the energy in the device.

[0064] Because a small decrease in velocity corresponds to a large decrease in damper torque (and vice versa), only a small change in the torque available for drug ejection is observed. This is illustrated in Figures 25 and 26. In Case 1, shown in Figure 25, friction is at the low end of the expected range, resulting in an increase in the magnitude of the viscous term due to the increased available torque, where the damper term absorbs most of the torque, while the torque available for drug ejection increases only slightly. This results in only a slightly faster dosing time. Conversely, in Case 2, illustrated in Figure 26, the increased friction substantially reduces the damper torque, but only slightly reduces the torque available for drug ejection, resulting in only a slightly longer dosing time. In a device without a damper mechanism, a significant proportion of the input torque is used to overcome friction in the system. Variations in friction directly add to or subtract from the torque available for ejection. Therefore, large fluctuations in dosing time can be expected.

[0065] Referring to Figure 27, an example of high sensitivity is illustrated by model calculations. The first two columns, A and B, illustrate the range of dosing times for various friction values ​​when a mechanical damper mechanism is used. Both the high-viscosity (column A) and low-viscosity (column B) drug variant devices exhibit narrow dosing time variability due to the damper. For variants without a damper (columns C and D), variability for the high-viscosity drug variant is similarly low. This is due to the high proportion of input torque used to expel the drug compared to the torque used to overcome the constant friction. However, for the low-viscosity drug variant (column D) where no damper is used, dosing time varies dramatically due to frictional dispersion. In addition to the high dosing time sensitivity to frictional variability, in terms of the device platform, if no damper is used, any change in drug viscosity significantly changes the input torque requirements. Therefore, more power springs are required to achieve the desired dosing time window. On the other hand, having a damper introduces a buffering effect using a slightly larger spring.

[0066] Furthermore, certain materials may affect these forces. For example, when using a glass syringe, the glide force and glide force variability may be lower compared to a plastic syringe due to siliconization of the barrel and stopper. When administering high viscosity drugs, the resistance to flow through the needle tends to be the largest contributor to overall injection time. However, when administering drugs with low viscosity and volume, the glide force (and its relative variability) may be a significant contributor to the total required force in the system.

[0067] When configured in this manner, the damper design described above can reduce the number of spring variants required in an autoinjector platform, improving consistency of administration times for users and reducing the risk of syringe breakage. When using low-viscosity drugs, small variations in spring performance and / or drug viscosity can have a significant impact, so the damper mechanism described herein delays the overall administration time, thereby reducing the number of spring variants required. When using high-viscosity drugs, the damper mechanism described herein has a greater impact on the impact velocity of the plunger rod, especially when administering low-volume drug products. The damper mechanism reduces the impact velocity of the plunger rod to a safer level, reducing the risk of syringe breakage. The damper mechanism described herein requires fewer parts, thereby aiding in assembly and cost savings. Furthermore, the described damper mechanism does not rely on surface friction and relatively complex movement mechanisms, thereby further reducing system complexity.

[0068] The above description describes various assemblies, devices, and methods for use with a drug delivery device. It will be apparent that the assembly, drug delivery device, or method may further include the use of the agents listed below, although the following list should not be considered exhaustive or limiting. The agent is contained within a reservoir. In some instances, the reservoir is a primary container that is filled or pre-filled for treatment with the agent. The primary container can be a cartridge or a pre-filled syringe.

[0069] For example, the drug delivery device, or more specifically the reservoir of the device, may be loaded with a colony-stimulating factor, such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the drug delivery device may be used with a variety of pharmaceutical products, such as erythropoiesis-stimulating agents (ESAs), which may be in liquid or lyophilized form.ESAs include 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), and Silap®. o® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta. , any molecule that stimulates red blood cell production, as well as the following patents or patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. Nos. 4,703,008, 5,441,868, 5,547,933, 5,618,698, 5,621,080, 5,756,349, 5,767,078, 5,773,569, 5,955,422, 5,9 and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 96 / 40772, WO 00 / 24893, WO 01 / 81405, and WO 2007 / 136752, or variants or analogs thereof.

[0070] The ESA may be an erythropoiesis-stimulating protein. As used herein, "erythropoiesis-stimulating protein" refers to any protein that directly or indirectly activates the erythropoietin receptor, for example, by binding to the receptor and inducing dimerization. Erythropoiesis-stimulating proteins include erythropoietin and 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. Erythropoiesis-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, pseudopeptides (including EMP1 / hematide), and pseudoantibodies. Exemplary erythropoiesis-stimulating proteins include erythropoietin, darbepoietin, erythropoietin agonist variants, and peptides or antibodies that bind to and activate the erythropoietin receptor (as well as compounds reported in U.S. Patent Application Publication Nos. 2003 / 0215444 and 2006 / 0040858, each of which is incorporated herein by reference in its entirety), as well as erythropoietin molecules, or variants or analogs thereof, disclosed in the following patents or patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. No. 4,703,008; Specification No. 5,441,868, Specification No. 5,547,933, Specification No. 5,618,698, Specification No. 5,621,080, Specification No. 5,756,3 Specification No. 49, Specification No. 5,767,078, Specification No. 5,773,569, Specification No. 5,955,422, Specification No. 5,830,851, Specification No. 5,830,851, Specification No. 5,856,298, Specification No. 5,986,047, Specification No. 6,030,086, Specification No. 6,310,078, Specification No. 6,391, Specification No. 633, Specification No. 6,583,272, Specification No. 6,586,398, Specification No. 6,900,292, Specification No. 6,750,369,Nos. 7,030,226, 7,084,245, and 7,217,689, U.S. Patent Application Publication Nos. 2002 / 0155998, 2003 / 0077753, 2003 / 0082749, 2003 / 0143202, 2004 / 0009902, 2004 / 0071694, 2004 / 0091961, 2004 / 0143857, 2004 / 0157293, 2004 / 0175379, Specification No. 2004 / 0175824, Specification No. 2004 / 0229318, Specification No. 2004 / 0248815, Specification No. 2004 / 0266690 specification, 2005 / 0019914 specification, 2005 / 0026834 specification, 2005 / 009 Specification No. 6461, Specification No. 2005 / 0107297, Specification No. 2005 / 0107591, Specification No. 2005 / 0124045 Specification of No. 2005 / 0124564, Specification of No. 2005 / 0137329, Specification of No. 2005 / 0142642, Patent Nos. 2005 / 0143292, 2005 / 0153879, 2005 / 0158822, 2005 / 0158832, 2005 / 0170457, 2005 / 0181359, 2005 / 0181482, 2005 / 0192211, 2005 / 0202538, 2005 / 0227289, 2005 / 0244409, 2006 / 0088906, and 2006 / 0111279, and PCT International Publication Nos. 91 / 05867, 95 / 05465, 99 / 66054, 00 / 24893, 01 / 81405, 00 / 61637, 01 / 36489, 02 / 014356, 02 / 19963, 02 / 20034, 02 / 49673, 02 / 085940, and 03 / 029291;Brochure No. 2003 / 055526, Brochure No. 2003 / 084477, Brochure No. 2003 / 094858, Brochure No. 2004 / 002417, Brochure No. 2004 / 002424, Brochure No. 2004 / 009627, Brochure No. 2004 / 024761, Brochure No. 2004 / 033651 , pamphlet No. 2004 / 035603, pamphlet No. 2004 / 043382, pamphlet No. 2004 / 101600, pamphlet No. 2004 / 101606, pamphlet No. 2004 / 101611, pamphlet No. 2004 / 106373, pamphlet No. 2004 / 018667, pamphlet No. 2005 / 001025 , Brochure No. 2005 / 001136, Brochure No. 2005 / 021579, Brochure No. 2005 / 025606, Brochure No. 2005 / 032460, Brochure No. 2005 / 051327, Brochure No. 2005 / 063808, Brochure No. 2005 / 063809, Brochure No. 2005 / 070451 Brochures, pamphlets No. 2005 / 081687, pamphlets No. 2005 / 084711, pamphlets No. 2005 / 103076, pamphlets No. 2005 / 100403, pamphlets No. 2005 / 092369, pamphlets No. 2006 / 50959, pamphlets No. 2006 / 02646, and pamphlets No. 2006 / 29094.

[0071] Examples of other pharmaceutical products for use with the device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab), and Prolia™ (denosumab); other biologics such as Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such as Sensipar® (cinacalcet). The device may be used with other chemicals such as therapeutic antibodies, polypeptides, proteins, or iron, e.g., ferumoxytol, iron dextran, ferric glyconate, and iron sucrose. The pharmaceutical product may be in liquid form or may be reconstituted from a lyophilized form.

[0072] Among certain exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof.

[0073] and fully humanized and human OPGL-specific antibodies, particularly OPGL-specific antibodies, peptibodies, and related proteins (also referred to as RANKL-specific antibodies, peptibodies, etc.), including, but not limited to, the antibodies described in PCT Publication WO 03 / 002713 (the above publication is incorporated herein in its entirety with respect to OPGL-specific antibodies and antibody-related proteins, particularly those having the sequences described in the above publication, particularly, but not limited to, those set forth in the above publication, including OPGL-specific antibodies having either the light chain of SEQ ID NO: 2 set forth in Figure 2 of the above publication and / or the heavy chain of SEQ ID NO: 4 set forth in Figure 4 of the above publication (9H7, 18B2, 2D8, 2E11, 16E1, and 22B3), each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the above publication).

[0074] Myostatin-specific proteins, including myostatin-binding proteins, peptibodies, and related proteins, including those described in U.S. Patent Application Publication No. 2004 / 0181033 and PCT Publication No. WO 2004 / 058988 (these publications specifically describe the mTN8-19 family of peptibodies, including those in SEQ ID NOS: 305-351, including TN8-19-1 to TN8-19-40, TN8-19con1, and TN8-19con2; the mL2 family of SEQ ID NOS: 357-383; and the mL3 family of SEQ ID NOS: 384-409). The entire contents of the present specification are incorporated by reference in their entirety in their sections regarding myostatin-specific peptibodies, including, but not limited to, the mL15 family of SEQ ID NOs: 410-438, the mL17 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 the peptibodies of SEQ ID NOs: 615-631, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the above-mentioned publications.

[0075] IL-4 receptor-specific antibodies, peptibodies, and related proteins, including, in particular, those described in PCT Publication No. WO 2005 / 047331 or PCT International Application No. PCT / US2004 / 37242 and U.S. Patent Application Publication No. 2005 / 112694, which inhibit the effects mediated by binding of IL-4 and / or IL-13 to the receptor (the above publications are particularly directed to IL-4 receptor-specific antibodies, particularly those antibodies described in the above publications, and in particular, but not limited to, the antibodies specified in the above publications). and (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 herein by reference in its entirety as disclosed in the above-mentioned publications.

[0076] Interleukin 1-receptor 1 ("IL1-R1")-specific antibodies, peptibodies, and related proteins, including, but not limited to, those described in U.S. Patent Application Publication No. 2004 / 097712 (the above publication is incorporated by reference herein in its entirety, particularly in that portion relating to IL1-R1-specific binding proteins, monoclonal antibodies, particularly, but not limited to, those designated in the above publication (15CA, 26F5, 27F2, 24E12, and 10H7), each of which is individually and specifically incorporated by reference herein in its entirety as disclosed in the above publication).

[0077] These include, but are not limited to, those described in PCT Publication No. WO 03 / 057134 and U.S. Patent Application Publication No. 2003 / 0229023 (each of the foregoing publications is directed to, among other things, Ang2-specific antibodies and peptibodies, particularly those of the sequences described in the foregoing publications, including 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), which are incorporated herein by reference in their entirety in the section concerning antibodies, including but not limited to, Con4-L1(N), ... 537, Ab540, Ab543, Ab544, Ab545, Ab546, A551, Ab553, Ab555, Ab558, Ab559, Ab565, AbF1AbFD, AbFE, AbFJ, AbFK, AbG1D4, AbGC1E8, AbH1C12, AblA1, AblF, AblK, AblP, and AblP are incorporated herein by reference in their entireties), Ang2-specific antibodies, peptibodies, and related proteins (each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the above-mentioned publications).

[0078] In particular, NGF-specific antibodies, peptibodies, and related proteins, including but not limited to those described in U.S. Patent Application Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426 (the above publications are hereby incorporated by reference in their entirety in this regard, particularly with respect to NGF-specific antibodies and related proteins, including but not limited to the NGF-specific antibodies (4D4, 4G6, 6H9, 7H2, 14D10, and 14D11) designated in the above publications, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the above publication).

[0079] CD22-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 5,789,554 (the above publication is incorporated herein by reference in its entirety for its disclosure of CD22-specific antibodies and related proteins, particularly human CD22-specific antibodies, including but not limited to, humanized and fully human antibodies, including but not limited to, humanized and fully human monoclonal antibodies, particularly human CD22, particularly IgG antibodies, such as dimers of a human-mouse monoclonal hLL2 gamma chain disulfide linked to a human-mouse monoclonal hLL2 kappa chain, including but not limited to, epratuzumab, a human CD22-specific fully humanized antibody with CAS Registry Number 501423-23-0).

[0080] IGF-1 receptor-specific antibodies, peptibodies, and related proteins, such as those described in PCT Publication WO 06 / 069202 (the above publication includes, but is not limited to, the IGF-1 specific antibodies designated in the above publication (L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19 , L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30 and IGF-1R-binding fragments and derivatives thereof), each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the above publications.

[0081] Also among the non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the present invention are each and every one of those described below. (i) U.S. Patent Application 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 ACC 2586), Antibody 8 (DSMZ Accession No. DSM ACC 2589), Antibody 23 (DSMZ Accession No. DSM ACC 2588), and Antibody 18 described in the above publications); (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. 279:2856-2865 (including, but not limited to, antibodies 2F8, A12, and IMC-A12 described therein); (iii) PCT International Publication Nos. 07 / 012614 (published February 1, 2007), 07 / 000328 (published January 4, 2007), 06 / 013472 (published February 9, 2006), 05 / 058967 (published June 30, 2005), and 03 / 059951 (published July 24, 2003); (iv) U.S. Patent Application 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 described therein); (v) U.S. Patent Application 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. 63:5073-5083 (including, but not limited to, the antibodies EM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1, huEM164 v1.2, and huEM164 v1.3 described therein); (vi) U.S. Pat. No. 7,037,498 (issued May 2, 2006), U.S. Patent Application Publication Nos. 2005 / 0244408 (published November 30, 2005), and 2004 / 0086503 (published May 6, 2004), and Cohen, et al. (2005), Clinical Cancer Res. 11:2063-2073, such as antibody CP-751,871 (including, but not limited to, antibodies produced by hybridomas having ATCC deposit numbers PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793 described in the above publications, and each of antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3); (vii) U.S. Patent Application Publication Nos. 2005 / 0136063 (published June 23, 2005) and 2004 / 0018191 (published January 29, 2004) (including, but not limited to, antibody 19D12 and antibodies comprising a heavy chain encoded by the polynucleotide of plasmid 15H12 / 19D12 HCA(γ4), deposited with the American Type Culture Collection (ATCC) under serial no. PTA-5214, and a light chain encoded by the polynucleotide of plasmid 15H12 / 19D12 LCF(K), deposited with the American Type Culture Collection (ATCC) under serial no. PTA-5220); and (viii) U.S. Patent Application 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 described therein) (each and every one of which is incorporated by reference in its entirety, particularly with respect to the foregoing antibodies, peptibodies, and related proteins that target the IGF-1 receptor).

[0082] B-7 related protein 1-specific antibodies, peptibodies, related proteins, and the like ("B7RP-1" is also referred to herein as B7H2, ICOSL, B7h, and CD275), particularly B7RP-specific fully human monoclonal IgG2 antibodies, particularly fully human IgG2 monoclonal antibodies that bind to an epitope in the first immunoglobulin-like domain of B7RP-1, particularly those that inhibit the interaction of B7RP-1 with its natural receptor, ICOS, particularly on activated T cells, particularly those disclosed in all of the above respects in U.S. Patent Application Publication No. 2008 / 0166352 and PCT Publication No. WO 07 / 011941 (the above publications are incorporated by reference in their entirety with respect to such antibodies and related proteins, including, but not limited to, the following antibodies designated therein: all of which are incorporated by reference herein: 16H (having therein the light chain variable and heavy chain variable sequences SEQ ID NO:1 and SEQ ID NO:7, respectively); 5D (having therein the light chain variable and heavy chain variable sequences SEQ ID NO:2 and SEQ ID NO:9, respectively); 2H (having therein the light chain variable and heavy chain variable sequences SEQ ID NO:3 and SEQ ID NO:10, respectively); 43H (having therein the light chain variable and heavy chain variable sequences SEQ ID NO:6 and SEQ ID NO:14, respectively); 41H (having therein the light chain variable and heavy chain variable sequences SEQ ID NO:5 and SEQ ID NO:13, respectively); and 15H (having therein the light chain variable and heavy chain variable sequences SEQ ID NO:4 and SEQ ID NO:12, respectively) (each of which is individually and specifically incorporated by reference herein in its entirety as disclosed in the above publications).

[0083] IL-15 specific antibodies, peptibodies, and related proteins, particularly antibodies, particularly humanized monoclonal antibodies, such as those disclosed in U.S. Patent Application Publication Nos. 2003 / 0138421, 2003 / 023586, and 2004 / 0071702, and U.S. Patent Application Publication No. 7,153,507, each of which is incorporated herein by reference in its entirety, for IL-15 specific antibodies and related proteins, including, inter alia, peptibodies, including, but not limited to, HuMax IL-15 antibodies and related proteins, such as 146B7.

[0084] IFN-γ-specific antibodies, peptibodies, and related proteins, etc., particularly human IFN-γ-specific antibodies, particularly fully human anti-IFN-γ antibodies, such as those described in the following patent publications: U.S. Patent Application Publication No. 2005 / 0004353, which is incorporated herein by reference in its entirety with respect to the antibodies designated 1118, 1118*, 1119, 1121, and 1121*. The entire sequences of the heavy and light chains of each of these antibodies, as well as the sequences of their heavy and light chain variable regions and complementarity-determining regions, are each individually and expressly incorporated herein by reference in their entirety, as disclosed in the above publications and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115. Additionally, the descriptions of the properties of these antibodies provided in the above publications are also incorporated herein by reference in their entirety. Specific antibodies include those having a heavy chain of SEQ ID NO: 17 and a light chain of SEQ ID NO: 18, as disclosed in the above publications; those having a heavy chain variable region of SEQ ID NO: 6 and a light chain variable region of SEQ ID NO: 8; those having a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 20; those having a heavy chain variable region of SEQ ID NO: 10 and a light chain variable region of SEQ ID NO: 12; those having a heavy chain of SEQ ID NO: 32 and a light chain of SEQ ID NO: 20; those having a heavy chain variable region of SEQ ID NO: 30 and a light chain variable region of SEQ ID NO: 12; those having a heavy chain sequence of SEQ ID NO: 21 and a light chain sequence of SEQ ID NO: 22; those having a heavy chain variable region of SEQ ID NO: 14 and a light chain variable region of SEQ ID NO: 16; those having a heavy chain of SEQ ID NO: 21 and a light chain of SEQ ID NO: 33; and those having a heavy chain variable region of SEQ ID NO: 14 and a light chain variable region of SEQ ID NO: 31. A specific antibody contemplated is antibody 1119, which is disclosed in the above-mentioned U.S. patent application publication and has the complete heavy chain of SEQ ID NO: 17 disclosed therein and the complete light chain of SEQ ID NO: 18 disclosed therein.

[0085] TALL-1-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Patent Application Publication Nos. 2003 / 0195156 and 2006 / 0135431, as well as other TALL-specific binding proteins (the above publications are each incorporated by reference in their entirety herein with respect to TALL-1 binding proteins, particularly the molecules in Table 4 and Table 5B, and each of which is individually and specifically incorporated by reference in its entirety herein as if fully disclosed in the above publications).

[0086] Parathyroid hormone ("PTH")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,756,480, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind PTH.

[0087] Thrombopoietin receptor ("TPO-R")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,835,809, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind to TPO-R.

[0088] Hepatocyte growth factor ("HGF")-specific antibodies, peptibodies, and related proteins, including those that target the HGF / SF:c-Met axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / scatter (HGF / SF), as described in U.S. Patent Application Publication No. 2005 / 0118643 and PCT Publication No. WO 2005 / 017107, huL2G7, as described in U.S. Patent No. 7,220,410, and OA-5d5, as described in U.S. Patent Nos. 5,686,292 and 6,468,529 and PCT Publication No. WO 96 / 38557, each of which is incorporated by reference in its entirety with particular reference in part to proteins that bind HGF.

[0089] TRAIL-R2 specific antibodies, peptibodies, related proteins, etc., such as those described in U.S. Pat. No. 7,521,048, which is incorporated herein by reference in its entirety, with particular reference in part to proteins that bind to TRAIL-R2.

[0090] Activin A-specific antibodies, peptibodies, related proteins, etc., including, but not limited to, those described in U.S. Patent Application Publication No. 2009 / 0234106, which is particularly relevant in part to proteins that bind to activin A and is incorporated herein by reference in its entirety.

[0091] Particularly relevant to proteins that bind to TGF-β are TGF-β-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, each of which is incorporated by reference in its entirety.

[0092] Amyloid-β protein-specific antibodies, peptibodies, related proteins, etc., including, but not limited to, those described in PCT Publication WO 2006 / 081171, which is particularly related in part to proteins that bind to amyloid-β protein and is incorporated herein by reference in its entirety. One contemplated antibody is an antibody having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6, as disclosed in the aforementioned publication.

[0093] c-Kit-specific antibodies, peptibodies, related proteins, and others, including, but not limited to, those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated by reference in its entirety, particularly in the portion concerning proteins that bind c-Kit and / or other stem cell factor receptors.

[0094] OX40L-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2006 / 0002929, which is incorporated herein by reference in its entirety, particularly in the portion relating to proteins that bind OX40L and / or other ligands of the OX40 receptor.

[0095] Activase® (alteplase, tPA), Aranesp® (darbepoetin), 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® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-alpha4beta7 mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel (etanercept, TNF-receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Hum atrope® (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® (vidilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Neulasta® (pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP 11b / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alpha-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrinmAb), Valortim® (MDX-1303, anti-B, anthrax 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 IgG1 Fc), 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 antagonist), CNTO 148 (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-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adecatumumab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF idiopathic pulmonary fibrosis phase I fibrogen (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12 mAb (ABT-874), anti-IL 12 / IL23 mAb (CNTO 1275), anti-IL 13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO 95), anti-IP10 ulcerative colitis mAb (MDX-1100), anti-LLY antibody, BMS-66513, anti-mannose receptor / hCGβ mAb (MDX-1307), anti-mesothelin dsFv-PE38 conjugate (CAT-5001), anti-PD1 mAb (MDX-1106 (ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβ mAb (GC-1008), anti-TRAIL receptor 2 human mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), NVS antibody #1, and NVS antibody #2.

[0096] Also included may be sclerostin antibodies, such as, but not limited to, romosozumab, brosozumab, or BPS804 (Novartis). Further therapeutic agents may be included, such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA. Additionally, the device may include a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9).Such PCSK9-specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab), and molecules, variants, analogs, or derivatives thereof, as disclosed in the following patents or patent applications, each of which is incorporated herein by reference in its entirety for all purposes: U.S. Pat. No. 8,030,547; U.S. Patent Application Publication No. 2013 / 0064825; WO 2008 / 057457; WO 2008 / 057458; WO 2008 / 057459; WO 2008 / 063382; WO 2008 / 133647; WO 2009 / 100297; WO 2009 / 100318; WO 2011 / 063382; International Publication No. 037791, International Publication No. 2011 / 053759, International Publication No. 2011 / 053783, International Publication No. 2008 / 125623, International Publication No. 2011 / 072263, International Publication No. 2009 / 055783, International Publication No. 2012 / 0544438, International Publication No. 2010 / 029513, International Publication No. WO 2011 / 111007, WO 2010 / 077854, WO 2012 / 088313, WO 2012 / 101251, WO 2012 / 101252, WO 2012 / 101253, WO 2012 / 109530 and WO 2001 / 031007.

[0097] Also included are talimogene laherparepvec or other oncolytic HSVs for the treatment of melanoma or other cancers. Examples of oncolytic HSVs include, but are not limited to, talimogene laherparepvec (US Pat. Nos. 7,223,593 and 7,537,924); OncoVEXGALV / CD (US Pat. No. 7,981,669); OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143); G207, 1716; NV1020; NV12023; NV1034, and NV1042 (Vargehes et al. (2002), Cancer Gene Ther., 9(12):967-978).

[0098] Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) that are important in many natural processes. TIMP-3 is expressed by various cells or present in the extracellular matrix. It inhibits all major metalloproteinases that degrade cartilage, and may play a role in many degenerative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as cancer and cardiovascular disease. 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 Application Publication No. 2014 / 0274874 and PCT Publication No. WO 2014 / 152012.

[0099] Also included are antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecules that target the CGRP receptor and other headache targets. Further information regarding these molecules can be found in PCT International Application No. 2010 / 075238.

[0100] Additionally, bispecific T cell-engaging (BiTE®) antibodies, such as BLINCYTO® (blinatumomab), can be used in the device. Alternatively, an APJ macromolecule agonist, such as apelin or an analog thereof, can be included in the device. Information regarding such molecules can be found in PCT Publication WO 2014 / 099984.

[0101] In certain embodiments, the medicament comprises a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody. Examples of anti-TSLP antibodies that may be used in such embodiments include, but are not limited to, those described in U.S. Patent Nos. 7,982,016 and 8,232,372, and U.S. Patent Application Publication No. 2009 / 0186022. Examples of anti-TSLP receptor antibodies include, but are not limited to, those described in U.S. Patent No. 8,101,182. In a particularly preferred embodiment, the medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated A5 in U.S. Patent No. 7,982,016.

[0102] Drug delivery devices, methods, and their components have been described with respect to exemplary embodiments, but are not limited thereto. The detailed description is to be construed as an example only and does not describe every conceivable embodiment of the invention, as describing every single conceivable embodiment would be impractical, if not impossible. Many alternative embodiments may be implemented using either current technology or technology developed after the filing date of this patent, and such embodiments will still fall within the scope of the claims defining the invention. For example, components described herein with respect to a particular type of drug delivery device, such as an on-body injector drug delivery device or other type of drug delivery device, may also be utilized in other drug delivery devices, such as an autoinjector drug delivery device.

[0103] Those skilled in the art will understand that numerous modifications, variations, and combinations can be made to the above-described embodiments without departing from the scope of the present invention, and that such modifications, variations, and combinations are to be construed as falling within the scope of the inventive concept.

Claims

1. a housing defining an outer shell having a proximal end, a distal end, and a longitudinal axis extending between the proximal end and the distal end; a needle assembly disposed at least partially within the housing at the proximal end thereof, the needle assembly comprising a syringe barrel containing a medicament and a needle or cannula; a drive assembly at least partially disposed within the housing and operatively coupled to the needle assembly for propelling the medicament through the needle or cannula; a damper mechanism disposed at least partially within the housing adjacent the distal end thereof, the damper mechanism operably coupled to the drive assembly and the housing, and wherein the damper mechanism damps the effect of the drive assembly when actuated.

2. The damper mechanism includes: A frame member; a damper member operably connected to the drive assembly; a chamber formed between a portion of the frame member and the damper member; a damper fluid disposed in the chamber formed between the frame member and the damper member, 2. The drug delivery device of claim 1, wherein when the drive assembly of the drug delivery device is actuated, the frame member and the damper member rotate relative to each other and the damper fluid exerts an opposing force on at least one of the frame member and the damper member.

3. The drug delivery device of claim 2 , wherein the frame member is integrally formed with the housing.

4. 4. The drug delivery device of claim 2 or 3, further comprising an excess chamber in fluid communication with the chamber, the excess chamber adapted to receive excess damper fluid.

5. The drug delivery device of any one of claims 2 to 4, further comprising a seal disposed near the chamber to retain the damper fluid within the chamber.

6. A drug delivery device according to any one of claims 2 to 5, wherein the chamber is axially aligned with the longitudinal axis.

7. The drug delivery device of any one of claims 2 to 6, wherein the chamber is partially axially and partially laterally aligned with the longitudinal axis.

8. A drug delivery device according to any one of claims 2 to 5, wherein the chamber is aligned laterally with the longitudinal axis.

9. The drive assembly includes: a plunger assembly including a threaded plunger rod and a plunger face disposed adjacent the needle assembly and movable along the longitudinal axis of the housing; a plunger rod guide coupled to the plunger assembly to guide rotational movement of the plunger assembly, the plunger rod guide further operatively coupled to one of the frame member or the damper member; 9. The drug delivery device of claim 2, further comprising: a torque spring coupled to the plunger rod guide for applying a force to the plunger rod guide to rotate the plunger rod guide, wherein rotation of the plunger rod guide causes the plunger assembly to advance toward the proximal end of the housing and propel the medicament through the needle assembly.

10. 10. The drug delivery device of claim 9, wherein the plunger assembly includes a clearance of greater than 10 mm between the threaded plunger rod and the plunger face, and the syringe barrel is adapted to contain at least about 1 mL of a medicament having a viscosity of at least about 4 cP.

11. A drug delivery device according to any preceding claim, wherein the damper mechanism exerts an opposing force on the drive assembly.

12. A drug delivery device according to any preceding claim, wherein the damper mechanism exerts an opposing force on at least one component operatively connected to the drive assembly.

13. 1. A damper mechanism for a drug delivery device, comprising: A frame member; a damper member operatively connected to a drive assembly of the drug delivery device; a chamber formed between a portion of the frame member and the damper member; a damper fluid disposed in the chamber formed between the frame member and the damper member, A damper mechanism, wherein when the drug delivery device is actuated to administer medication to a user, the frame member and the damper member rotate relative to each other and the damper fluid exerts an opposing force on at least one of the frame member and the damper member.

14. The damper mechanism of claim 13 , wherein the frame member is integrally formed with a housing of the drug delivery device.

15. 15. A damper mechanism according to claim 13 or 14, wherein the damper member defines a channel and the frame member defines a protrusion extending inwardly into the channel.

16. 15. A damper mechanism according to claim 13 or 14, wherein the frame member defines an elongated platform having an opening, the damper member defines a circular plate having a protrusion disposed through the platform opening, and the chamber is formed by the volume between the elongated platform and the circular plate.

17. A damper mechanism according to any one of claims 13 to 16, further comprising an excess chamber in fluid communication with the chamber, the excess chamber adapted to receive excess damper fluid.

18. A damper mechanism according to any one of claims 13 to 17, further comprising a seal disposed near the chamber for retaining the damper fluid within the chamber.

19. A damper mechanism according to any one of claims 13 to 18, wherein the chamber is axially aligned with the longitudinal axis.

20. A damper mechanism according to any one of claims 13 to 19, wherein the chamber is partly axially aligned and partly laterally aligned with the longitudinal axis.

21. A damper mechanism according to any one of claims 13 to 18, wherein the chamber is aligned laterally with the longitudinal axis.

22. A damper mechanism according to any one of claims 13 to 21, wherein the damper assembly is adapted to engage with at least one of a housing of a drug delivery device or a drive assembly of the drug delivery device.

23. 23. The damper mechanism of claim 22, wherein the damper mechanism is adapted to be assembled to the drug delivery device via a shaft assembly.

24. a housing defining an outer shell having a proximal end, a distal end, and a longitudinal axis extending between the proximal end and the distal end; a needle assembly disposed at least partially within the housing at the proximal end thereof, the needle assembly comprising a syringe barrel containing a medicament and a needle or cannula; a drive assembly at least partially disposed within the housing and operatively coupled to the needle assembly for propelling the medicament through the needle or cannula, the drive assembly including a plunger assembly having a plunger rod and a plunger face disposed adjacent the needle assembly and movable along the longitudinal axis of the housing; The autoinjector, wherein the syringe barrel is adapted to contain at least about 1 mL of a medicament having a viscosity of at least about 4 cP, and the plunger rod and the plunger face have an initial clearance of greater than about 10 mm.

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