Plungers for drug delivery devices

Abstract

To provide a plunger that provides geometry optimizations to minimize friction magnitude and variability during use by maintaining low deformation under large extrusion forces.SOLUTION: Plunger embodiments minimize a contact area between the plunger and a syringe or chamber, while also maintaining high contract pressures to maintain container closure integrity. Moreover, the plunger embodiments are configured to have minimal or no increase in the contact area under high loads associated with the delivery of viscous products.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 584,335, filed November 10, 2017, the entire contents of which are expressly incorporated herein by reference.

[0002] The present disclosure relates generally to plungers, and more particularly to plungers for drug delivery products. [Background technology]

[0003] Highly viscous products are increasingly being used in automated delivery devices, such as autoinjectors and on-body injectors. Automated delivery devices typically have requirements regarding drug delivery time. However, when using highly viscous products, automated delivery devices require large driving forces to achieve the required drug delivery time. In addition, automated delivery devices may have a driving mechanism that is separate from the plunger within the device and outputs up to five times the sustained injection force during initial impact and drug delivery.

[0004] Some conventional plungers have a cylindrical side surface that slides along and seals against the syringe or reservoir of a delivery device. Large driving forces exert large axial compressive forces on conventional plungers, which can cause them to deform radially outward during ejection. Such radial deformation can increase the contact area between the plunger and the syringe or reservoir, resulting in greater friction and unpredictability in the ejection process. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure describes plungers, drug delivery assemblies, drug delivery devices, and related methods that embody advantageous alternatives to conventional plungers and methods and that can address one or more of the problems or needs noted herein, as well as provide other benefits and advantages.

[0006] In some embodiments, a plunger for use in a drug delivery device is described herein, the plunger including a body portion having a generally cylindrical sidewall, a leading surface, and a trailing surface. The plunger further includes a plurality of ribs projecting radially outward from the sidewall of the body portion and axially spaced apart by recessed side surfaces. The plurality of ribs includes at least a trailing rib, a leading rib, and an intermediate rib, each having an annular configuration. The body portion is configured to assume a first configuration in the absence of an axial load and a second configuration in the presence of an axial load, the first and second configurations having substantially equal radial dimensions, and the second configuration having an axial dimension smaller than the axial dimension of the first configuration.

[0007] The plunger may further include one or more of the following: a trimmed edge of the body portion may be adjacent to the trailing surface of the body portion, and the trimmed edge may further have an outer diameter smaller than the outer diameter of the rib; the leading surface of the plunger may include a roughened portion and / or may have a generally conical configuration; one or both of the trailing rib and the intermediate rib may be axially smaller than the leading rib; at least one of the ribs may have a curved profile; at least one of the ribs may include a cylindrical portion extending between its curved axial end portions; a radial surface of the sidewall extending between the ribs may have a curved configuration; a radial surface of the body portion extending between the ribs may have a flat configuration; or the plunger may further include a plurality of protrusions extending away from the trailing surface of the body portion.

[0008] In some embodiments, described herein is a drug delivery assembly including a plunger configured as recited in any combination of the above paragraphs, the drug delivery assembly including a chamber having an annular sidewall extending between a first open end and a second end having a dispensing orifice, the plunger being received within the chamber such that the ribs of the plunger seal against an interior surface of the sidewall, and a drive member configured to drive the plunger within the chamber to the second end of the chamber.

[0009] The drug delivery assembly may further include one or more of the following: the contact area of the ribs on the inner side of the side wall remains substantially constant while the plunger is driven within the chamber; the trim edge of the plunger is spaced apart from the inner side of the side wall while the plunger is driven within the chamber; the ribs are axially spaced apart from each other by at least twice the distance the plunger travels within the chamber during air transport; or the ribs have a contact pressure with the inner side of the side wall of at least 0.8 MPa.

[0010] The above needs are met, at least in part, by the provision of plunger embodiments described in the following detailed description, particularly when studied in conjunction with the drawings. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a side cross-sectional view of an autoinjector device including a plunger made in accordance with various embodiments of the present disclosure. [Figure 2] 2 is a side cross-sectional detailed view of a first embodiment of a plunger for use in the autoinjector device of FIG. 1, in accordance with various embodiments of the present disclosure. FIG. [Figure 3] FIG. 3 is a side elevation view of the plunger of FIG. 2 showing the dimensional labels of Tables 1 and 2 according to various embodiments of the present disclosure. [Figure 4] 1 is a histrograph of upper rib diameter measurements for a first sample according to various embodiments of the present disclosure. [Figure 5]10 is a histograph of mid-rib diameter measurements for a first sample according to various embodiments of the present disclosure. [Figure 6] 10 is a histograph of lower rib diameter measurements for a first sample according to various embodiments of the present disclosure. [Figure 7] 10 is a histograph of the top inner diameter measurement of the first sample according to various embodiments of the present disclosure. [Figure 8] 10 is a histograph of the bottom inner diameter measurement of the first sample according to various embodiments of the present disclosure. [Figure 9] 10 is a histograph of total length measurements of a first sample according to various embodiments of the present disclosure. [Figure 10] 10 is a histograph of measurements from the top rib to the middle rib of a first sample according to various embodiments of the present disclosure. [Figure 11] 10 is a histograph of measurements from the middle rib to the bottom rib of a first sample according to various embodiments of the present disclosure. [Figure 12] 10 is a histograph of bottom lip diameter measurements for a first sample according to various embodiments of the present disclosure. [Figure 13] 10 is a histograph of inner lip diameter measurements for a second sample according to various embodiments of the present disclosure. [Figure 14] 10 is a histograph of upper rib diameter measurements for a second sample according to various embodiments of the present disclosure. [Figure 15] 10 is a histograph of mid-rib diameter measurements for a second sample according to various embodiments of the present disclosure. [Figure 16] 10 is a histograph of bottom rib diameter measurements for a second sample according to various embodiments of the present disclosure. [Figure 17] 10 is a histograph of the top inner diameter measurement of the second sample according to various embodiments of the present disclosure. [Figure 18] 10 is a histograph of the bottom inner diameter measurement of the second sample according to various embodiments of the present disclosure. [Figure 19] 10 is a histograph of total length measurements of a second sample according to various embodiments of the present disclosure. [Figure 20] 10 is a histograph of measurements from the top rib to the middle rib of a second sample according to various embodiments of the present disclosure. [Figure 21] 10 is a histograph of measurements from the middle rib to the bottom rib of a second sample according to various embodiments of the present disclosure. [Figure 22] 10 is a histograph of bottom lip diameter measurements for a second sample according to various embodiments of the present disclosure. [Figure 23] 10 is a histograph of inner lip diameter measurements for a second sample according to various embodiments of the present disclosure. [Figure 24] FIG. 2 is a side cross-sectional detailed view of a second embodiment of a plunger for use in the autoinjector device of FIG. 1, in accordance with various embodiments of the present disclosure. [Figure 25] FIG. 25 is a side elevation view of the plunger of FIG. 24 showing the dimensional label of Table 3 according to various embodiments of the present disclosure. [Figure 26] 10 is a histograph of seal diameter measurements for samples according to various embodiments of the present disclosure. [Figure 27] 10 is a histograph of upper rib diameter measurements for samples according to various embodiments of the present disclosure. [Figure 28] 10 is a histograph of top diameter measurements of samples according to various embodiments of the present disclosure. [Figure 29] 10 is a histograph of mean diameter measurements of samples according to various embodiments of the present disclosure. [Figure 30] 10 is a histograph of sample bottom diameter measurements according to various embodiments of the present disclosure. [Figure 31] 10 is a histograph of bottom rib diameter measurements for samples according to various embodiments of the present disclosure. [Figure 32] 10 is a histograph of bottom lip diameter measurements for samples according to various embodiments of the present disclosure. [Figure 33] 1 is a histograph of total length measurements of a sample according to various embodiments of the present disclosure. [Figure 34]10 is a histograph of measurements from the top to the top rib of a sample according to various embodiments of the present disclosure. [Figure 35] 10 is a histograph of rib-to-rib measurements of samples according to various embodiments of the present disclosure. [Figure 36] 1 is a graph illustrating infusion time study data according to various embodiments of the present disclosure. [Figure 37] 10 is another graph showing infusion time study data according to various embodiments of the present disclosure. [Figure 38] 1 is a graph illustrating injection friction force test data according to various embodiments of the present disclosure. [Figure 39] 1 shows a schematic cross-sectional view of one embodiment of an on-body drug delivery device including a plunger made in accordance with various embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0012] 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 so as not to overly 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 given to such terms and phrases by those skilled in the art, unless a different specific meaning is explained herein.

[0013] Plungers, also known as plunger stoppers or stoppers, configured as described herein offer optimized geometry that minimizes friction magnitude and variation during use compared to conventional plungers by providing less radial and contact area deformation under high ejection forces. Additionally, plunger embodiments described herein minimize the contact area between the plunger and syringe or reservoir by using ribs rather than cylindrical side contact surfaces, while also maintaining high contact pressure between the ribs and the syringe / reservoir to maintain the integrity of the container closure. Furthermore, plunger embodiments described herein are configured to minimize or eliminate an increase in contact area under the high loads associated with delivering viscous products. That is, the ribs and the plunger surface extending therebetween do not expand outward or expand a minimal amount during use, thereby maintaining a consistent contact area during use. In some approaches, the plunger includes three or more radial ribs that maintain a tight seal with the syringe or chamber, also avoiding disruption of sterility during storage and transport due to pressure changes, etc.

[0014] The combination of these features advantageously provides not only lower friction magnitude and variability during use compared to conventional plungers, but also reduces injection times by up to 30% compared to conventional plungers. Reduced friction variability also provides a more robust design space, enabling the development of high viscosity drug delivery devices such as autoinjectors and on-body injectors.

[0015] Autoinjector Disclosure Before providing further details of plunger embodiments, reference is made to FIG. 1 to describe an exemplary drug delivery device suitable for delivering highly viscous products. In a first example, autoinjector 100 includes a housing 102 having a syringe assembly 110 and an actuation mechanism 150. At least a portion of syringe assembly 110 and actuation mechanism 150 are disposed within housing 102. Syringe assembly 110 includes a syringe barrel 112, a needle assembly 114, and an optional filter member 120 disposed adjacent to needle assembly 114. Actuation mechanism 150 includes a frame member 152, a plunger assembly 160 including a plunger 200, which will be described in further detail below, a plunger rod guide 170, and a spiral spring (e.g., a watch spring) 180.

[0016] Syringe barrel 112 stores medicament 113 to be injected into a user and has first end 112a, second end 112b, and longitudinal axis "L." In the illustrated example, syringe barrel 112 further includes base 112c and sidewall 112d that define a cavity for storing the medicament. Additionally, syringe barrel 112 may include at least one opening 112e disposed through base 112c to allow delivery of the medicament to needle assembly 114. First end 112a of syringe barrel 112 may be open to accommodate plunger assembly 160, which will be described in more detail below.

[0017] It should be understood that syringe barrel 112 may be of any desired shape and / or size to accommodate various amounts of medication. In some examples, syringe barrel 112 may be made of cyclic olefin polymer ("COP"). Other example materials are possible.

[0018] Referring to FIG. 1 , needle assembly 114 is coupled to second end 112b of syringe barrel 112 via any type of coupling mechanism and / or structure and includes needle hub 116 and needle 118 attached to needle hub 116. Needle hub 116 defines a cavity that allows a medicament to enter needle 118 through any number of openings. Needle hub 116 is positioned below opening 112e formed in base 112c of syringe barrel 112. So configured, needle hub 116 receives the medicament as it exits syringe barrel 112, whereupon the medicament enters needle 118 and is administered to a user. It should be understood that injector 100 may include any number of additional components, such as a return spring, a needle shield and / or a guard, etc., to assist in administering the medicament to a user. For the sake of brevity, these additional components will not be described in particular detail.

[0019] Continuing to refer to FIG. 1 , filter member 120 is positioned adjacent to syringe barrel 112 and needle assembly 114. In some examples, filter member 120 may be positioned directly within opening 112e formed in base 112c of syringe barrel 112. In other examples, filter member 120 may be positioned within a portion of a cavity defined by needle hub 116 that extends distally beyond base 112c of barrel 112. In yet another example, filter member 120 may be positioned between base 112c of syringe barrel 112 and needle hub 116. Alternatively, filter member 120 may be positioned within syringe barrel 112, occupying substantially the entire cross-sectional area of syringe barrel 112.

[0020] 1, the frame member 152 of the actuation mechanism 150 may be securely coupled to the housing 102 in any number of ways. In some configurations, the frame member 152 may be integrally formed with the housing 102. The frame member 152 may include a first surface 152a, a second surface 152b, and a threaded opening 152c formed between the first surface 152a and the second surface 152b.

[0021] Plunger assembly 160 is movable along longitudinal axis L of syringe barrel 112 and includes a plunger rod 162 having a threaded portion 162a that is threadingly coupled to and disposed within threaded opening 152c of frame member 152. Threaded portion 162a of plunger rod 162, and similarly, threaded opening 152c of frame member 152, may have a thread pitch suitable for any desired drug delivery rate when driven by spiral spring 180. Plunger assembly 160 further includes a plunger face 164 disposed near first end 112a of syringe barrel 112.

[0022] Plunger rod guide 170 includes a rod portion 172 that is coupled to plunger assembly 160 in any number of ways, including, for example, by a splined connection or a grooved configuration that allows plunger assembly 160 to move axially relative to plunger rod guide 170. Thus, plunger rod guide 170 guides the rotational and axial movement of plunger assembly 160.

[0023] The inner portion 180a of the spiral spring 180 is coupled to the rod portion 172 of the plunger rod guide 170 by any known means to apply a force to the plunger rod guide 170 and rotate the plunger rod guide 170 about the axis L.

[0024] Plunger Disclosure Exemplary plungers 200 suitable for use in drug delivery devices to deliver highly viscous products are shown in FIGS. 2 and 3. Each plunger 200 includes a body portion 202 having a generally cylindrical sidewall 203 extending along a longitudinal axis L and having a leading surface 204 and a trailing surface 206 at its leading end 208 and trailing end 210, respectively. The plunger 200 is configured to be engaged on its trailing surface 206 and to be advanced within the syringe barrel 112 as described with reference to FIG. 1, thereby expelling the medicament 113 from the syringe barrel 112. In preferred embodiments, the body portions 202 described herein do not include a cavity for receiving a plunger rod or the like. Thus configured, the cross-section of each body portion 202 has a continuous configuration along its axial length between its leading surface 204 and trailing surface 206.

[0025] As shown, plunger 200 further includes annular ribs 216 extending radially outward from sidewall 203. Ribs 216 are spaced axially along body portion 202 and separated by side surfaces 226 that are radially recessed relative to ribs 216. Ribs 216 have outer diameters sized to provide contact areas 218 between plunger 200 and syringe barrel 112, thereby reducing the magnitude and variability of friction compared to conventional plungers in which the entire or a large majority of the sidewall contacts the container. Furthermore, the reduced diameter of body portion 202 along side surfaces 226 allows body portion 203 to compress under axial load, similar to a bellows, such that ribs 216 do not expand significantly radially outward and side surfaces 226 do not expand radially beyond ribs 216.

[0026] In one embodiment, the ribs 216 can be spaced apart by more than the travel distance of the plunger 200 caused by pressure changes during air transport, and in yet another embodiment, by more than twice this travel distance, thereby maintaining the integrity of the container closure during transport. In one example, the plunger 200 can travel from about 0.7 mm to about 1.12 mm, from about 1.0 mm to about 1.12 mm, and from about 0.7 mm to about 1.0 mm. Thus, the distance between the ribs 216 can have a corresponding range, can have twice the corresponding range, or can be spaced apart by more than twice the corresponding range, such as from about 2 mm to about 4 mm, or from about 2.5 mm to 3.1 mm. In another example, a break loose force of 6 N or greater can provide sufficient restraint to plunger travel during air transport.

[0027] In the illustrated form, the plunger 200 includes three annular ribs 216: a leading rib 220, a trailing rib 222, and an intermediate rib 224. It will be understood that in a particular application, the plunger 200 can include additional intermediate ribs as desired. The ribs 216 and the sidewall surfaces 226 extending therebetween can take any suitable form. Furthermore, the leading rib 220, the trailing rib 222, and the intermediate rib 224 need not have a fixed form.

[0028] In a first configuration, as shown in FIG. 2 , the ribs 216 can have a cross-sectional profile that is convexly curved along the longitudinal axis L. Additionally, the leading rib 220 and the trailing rib 222 can have a larger radius of curvature than the intermediate rib 224, such that the leading rib 220 and the trailing rib 220 provide a larger contact area 218 with the container 212 than the intermediate rib 224. If desired, although not shown, each rib 220, 222, 224 can have a curve with a different radius or each can have the same radius. In the configuration of FIG. 2 , the side surfaces 226 of the sidewall 203 extending between the ribs 216 have a cross-sectional profile that is concavely curved along the longitudinal axis L.

[0029] 3 shows another form of plunger 200 including a body portion 202 having a generally cylindrical sidewall 203 extending along a longitudinal axis L and having leading and trailing surfaces 204 and 206 at leading and trailing ends 208 and 210 thereof, respectively. The plunger 200 is configured to be engaged on its trailing surface 206 and urged within the syringe barrel 112 as described with reference to FIG. 1, thereby expelling the medicament 113 from the syringe barrel 112.

[0030] As shown, this form of plunger 200 includes annular ribs 216 extending radially outward from the sidewall 203. The ribs 216 are spaced axially along the body portion 202 and separated by side surfaces 226 that are radially recessed relative to the ribs 216. The ribs 216 have outer diameters sized to provide a contact area 218 between the plunger 200 and the syringe barrel 112. As shown, the plunger 200 may include three ribs 216: a leading rib 220, a trailing rib 222, and an intermediate rib 224. It will be understood that, for particular applications, the plunger 200 may include additional intermediate ribs as desired. The ribs 216 and the sidewall surfaces 226 extending therebetween may take any suitable form. As shown in FIG. 3, the plunger 200 may include ribs 216 having cylindrical portions 228 disposed between convex axial portions 230, as shown in the leading rib 220. The cylindrical portion 228 provides a larger contact area surface with the container 202 compared to curved ribs. Additionally, as shown, the intermediate rib 224 and the trailing rib 222 of the plunger 200 can have curved profiles with the same radius. Of course, combinations of the ribs 216 shown in Figures 2 and 3, as well as other suitable configurations, can also be used. In the configuration of Figure 3, the side surface 226 has a cylindrical intermediate portion 232 with frusto-conical portions 234, having a generally concave cross-section, located at either axial end thereof to transition between the side surface 226 and the adjacent rib 216.

[0031] As noted, leading surface 204 of plunger 200 is configured to engage and push medicament 113 within syringe barrel 112. As shown in Figures 2 and 24, leading surface 204 can have a pointed configuration to minimize the hold-up volume of medicament 113 within syringe barrel 112 by extending leading surface 204 into opening 112e of syringe barrel 112 and, optionally, needle hub 116 / needle 118, as described in more detail with reference to Figure 1.

[0032] The configuration of the leading surface 204 can take any desired shape, such as a cone with a concave curved surface 233 shown in the embodiment of FIG. 2, or a cone with flat sides 235 shown in the embodiment of FIG. 24. Additionally, the leading surface 204 can have a roughened texture over all or a portion of it. The roughened texture helps prevent the plungers 200 from sticking together during processing and storage. In another form, the leading surface 204 can have any suitable material applied to create the roughened texture.

[0033] 2 and 24 , in some embodiments, the plunger 200 can include a trim edge 236 adjacent the trailing surface 206. The trim edge 236 is the result of the individual plungers 200 being cut from a common sheet of material when the plungers 200 are formed as a batch. As shown, the trim edge 236 can also have an outer diameter smaller than the outer diameter of the rib 216 so that the trim edge 236 does not contact the container 212 during use, even when the plunger 200 is under axial load and retracted. Conventionally, plungers can be cut from a sheet of material such that the trim edge is at the front of the plunger. Furthermore, the trim edge 236 can have an outer diameter that engages with the syringe barrel during use. This additional contact area, especially with the uneven nature of the cut edge, can add magnitude and variability to friction on the drug delivery device during use. A plunger 200 configured as described herein advantageously avoids these challenges associated with trim edges.

[0034] According to some embodiments, the plunger 200 may include one or more protrusions 238 extending away from the trailing surface 206. The protrusions 238 are preferably arranged about the trailing surface 206 so that, in combination, the protrusions 238 provide stable contact for the plunger face 240 that pushes the plunger 200 within the container 212. For example, the protrusions 238 may be spaced apart about the trailing surface 206, such as in an array and / or symmetrically. The protrusions 238 may also be approximately centrally located on the trailing surface 206. It will be appreciated that the protrusions 238 may be provided in any suitable shape or configuration, such as a cone shape as in FIG. 2 or a dome shape as in FIG. 3. In the illustrated form, there are four protrusions 238 equally spaced apart from one another within a circle centered on the trailing surface 206.

[0035] The protrusions 238 may also be configured to advantageously shift the center of mass of the plunger 200 rearward, cushioning the initial impact of the plunger face 238 on the plunger 200 during a dispensing operation. Additionally, the protrusions 238 also help prevent the plungers 200 from sticking together during processing and storage. Thus, the combination of the roughened leading surface 204, the curved side surfaces 226, and the ribs 216 generally prevents the plungers 200 from sticking together during bulk processing and storage.

[0036] According to one example, the plunger 200 shown in Figures 2 and 3 may have the following dimensions: the upper rib 200-A- may have a diameter of approximately 9.4 mm, the middle rib 224-B- may have a diameter of approximately 9.1 mm, the lower rib 222-C- may have a diameter of approximately 9.2 mm, the upper inner surface 226-D1- may have a diameter of approximately 7.9 mm, the lower inner surface 226-D2- may have a diameter of approximately 7.9 mm, the overall length -E- may be approximately 9 mm, the distance from the upper rib 220 to the middle rib 224 may be approximately 3.18 mm, the distance from the middle rib 224 to the lower rib 222 may be approximately 3.08 mm, the bottom lip 236 may have a maximum diameter of approximately 8.8 mm, and the inner lip may have a diameter of approximately 8.4 mm. Other exemplary measurements may include: upper rib 220 and lower rib 222 may have a radius of about 0.5 mm, intermediate rib 224 may have a radius of about 0.3 mm, the distance from lower rib 222 to aft face 206 may be about 1.82 mm, protrusions 238 may have a radius of about 0.2 mm, a length of about 0.4 mm and may be spaced apart on a circle on aft face 206 having a diameter of about 6.0 mm.

[0037] Two sample groups of 2.25 mL plungers were measured as shown in Tables 1 and 2 below. The measurement standards in the upper part of the table are attached to plunger 200 in FIG. 3. Histograms of each measurement shown in Tables 1 and 2 are provided in FIGS. 3 to 23.

[0038] [Table 1]

[0039] [Table 2]

[0040] According to another example, the plunger 200 shown in Figures 24 and 25 can have the following dimensions: the seal outer diameter (upper rib 220) can have a diameter of approximately 9.10 mm, the upper rib outer diameter (middle rib 224) can have a diameter of approximately 8.90 mm, the upper outer diameter (side surface 226) can have a diameter of 8.50 mm, the middle outer diameter (side surface 226) can have a diameter of approximately 8.50 mm, the lower outer diameter (adjacent trim edge 236) can have a diameter of 8.40 mm, the lower rib 222 outer diameter can have a diameter of 9.00 mm, the bottom lip (trim edge 236) can have a maximum diameter of 8.70 mm, the overall length of the plunger 200 can be approximately 9.00 mm, the top to top (middle rib 224) can have a distance of approximately 4.40 mm, and the rib to rib (middle 224 to lower part 222) can have a distance of approximately 2.60 mm. Other exemplary measurements may include: the protrusions 238 may have a diameter of approximately 0.60 mm, a depth of approximately 0.25 mm, and may be spaced apart on the trailing surface 206 around a circle having a diameter of approximately 6.40 mm; the convex axial portion 230 of the leading rib 220 may have a leading radius of approximately 0.70 mm and a trailing radius of approximately 0.60 mm; the cylindrical portion 228 of the leading rib 220 may have a length of approximately 0.64 mm; the distance from the lower rib 222 to the trailing surface 206 may be approximately 2.00 mm; and the leading surface 204 may form an angle of approximately 7 degrees and have a radius of approximately 3.00 mm.

[0041] Measurements were made on a group of 2.25 mL plunger samples as shown in Table 3. The measurement standards in the upper row of the table are assigned to plunger 200 in FIG. 25. Histographs of the measurements in Table 3 are shown in FIGS. 26 to 35.

[0042] [Table 3]

[0043] In an autoinjector 100 configured with one of the plungers 200, when an axial load is applied to the rear surface to drive the plunger 200 within the container 212, the plunger 200 is configured to axially compress, similar to a bellows, without significant radial expansion beyond the original diameter of the ribs 216. Significant radial expansion may mean less than 5%, less than 3%, less than 2%, and less than 1% of its diameter. More specifically, the side surface 226 of the plunger 200 may be configured to collapse and compress axially so that the ribs 216 maintain their radial dimensions during use, thereby providing a consistent contact area with the syringe barrel 112 and minimizing frictional fluctuations. In some approaches, the plunger 200 may be configured to compress from about 10% to about 30% of its length when driven by a significant axial load. Typically, the more viscous the product, the greater the force required to administer the product within the desired administration time range. The plunger 200 described herein is suitable for use with drugs having a viscosity of 100 cP or less, and more preferably at least 300 cP or less. Furthermore, the plunger 200, as described herein, is configured to operate under an axial load of at least 500 N or less.

[0044] With respect to container closure integrity (meaning the container's ability to maintain a sterile barrier against potential contaminants), in a first example having a plunger configured as shown in Figure 2, the leading rib 220 can maintain the container closure integrity at a contact pressure of approximately 1.2 MPa, and the trailing rib 222 can maintain the container closure integrity at a contact pressure of approximately 1.1 MPa. In a second example having a plunger configured as shown in Figure 24, the leading rib 220 can maintain the container closure integrity at a contact pressure of approximately 0.8 MPa, and the trailing rib 222 can maintain the container closure integrity at a contact pressure of approximately 0.9 MPa.

[0045] The plunger 200 described herein is particularly suitable for use in the autoinjector described above with reference to Figure 1. The following data, reflected in the table below and the graphs shown in Figures 36-38, was obtained using an autoinjector device to test a plunger configured as shown in Figures 2 and 24 against a conventional threaded plunger.

[0046] Injection times were tested at 5°C and 23°C, as shown in Figures 36 and 37 and Table 4 below. The conventionally threaded plunger had an average injection time of 90.17 seconds with a standard deviation of 7.10 at 5°C and an average injection time of 19.00 seconds with a standard deviation of 1.23 at 23°C. The #1 plunger, configured as shown in Figure 2, had an average injection time of 49.45 seconds with a standard deviation of 3.63 at 5°C and an average injection time of 13.65 seconds with a standard deviation of 0.49 at 23°C. Thus, the #1 plunger had an average of 45% reduction and a standard deviation of 49% reduction at 5°C and an average of 32% reduction and a standard deviation of 60% reduction at 23°C compared to the conventionally threaded plunger. The #2 plunger had an average of 41% reduction and a standard deviation of 60% reduction at 5°C and an average of 33% reduction and a standard deviation of 73% reduction at 23°C compared to the conventionally threaded plunger.

[0047] [Table 4]

[0048] Conventional threaded plungers were also tested for average translational force and standard deviation along with plungers configured as shown in FIG. 2 (#1) and FIG. 24 (#2). FIG. 38 provides a graph showing the results of these tests. As shown in Table 5 below, both plungers configured as described herein performed better than the conventional plunger. More specifically, the plunger configured as shown in FIG. 2 had a 77% reduction in average translational force and a 95% reduction in standard deviation compared to the conventional plunger. The plunger configured as shown in FIG. 24 had a 17% reduction in average translational force and a 64% reduction in standard deviation compared to the conventional plunger.

[0049] [Table 5]

[0050] For all tests, syringe systems were prepared with 2.1 mL ± 0.1 mL of media, with plunger insertion corresponding to an air gap of at least 2 mm. The plunger was inserted so that the media contacted the entire surface of the syringe before pushing the plunger. For tests where release (BL) was critical (Friction, Release, and Ejection (BLE), Container Closure Integrity (CCI), and Simulated Air Transport), the syringe plunger system was preconditioned for 48 hours ± 3 hours prior to testing. The two-day sample conditioning period allowed for plunger settling and development of the initial BL force.

[0051] The BLE force acting on the plunger refers to the force required to expel the liquid from the syringe through the staked needle. The BLE test involves dosing at two different rates, and the BLE force is divided into two parts: Release: the initial force required to start the plunger moving, and Expulsion: the maximum force reached as the plunger moves through the syringe after the release effect has ended. Generally, the nominal and +0.2 plunger sizes have a frictional BL force close to or greater than that of the reference plunger.

[0052] On-body injector disclosure Although the plunger 200 shown in FIGS. 2 and 24 has been described with reference to use in the autoinjector drug delivery device 100 described above with reference to FIG. 1, the plunger 200 described herein is also suitable for use in other drug delivery devices, such as on-body injector devices. FIG. 39 is a schematic diagram of one embodiment of an on-body drug delivery device 10 constructed in accordance with the principles of the present disclosure. The drug delivery device 10 may be operated to deliver a drug to a patient subcutaneously or transdermally. In the illustrated embodiment, the drug delivery device 10 is configured as a wearable drug delivery device, such as an on-body injector or portable infusion pump, and is removably attached to the patient's tissue 11 (e.g., the patient's skin). In other embodiments (not shown), the drug delivery device 10 may be configured as a pen injector, such as an autoinjector or injection pen, that is temporarily pressed against the patient's tissue 11 for the course of an injection. The drug delivery device 10 may be configured to automatically deliver a fixed or patient / operator-settable dose of a drug over a controlled or selected period of time. Additionally, the drug delivery device 10 may be for self-administration by the patient or may be operated by medical personnel or other caregivers formally trained to administer injections.

[0053] Generally, the drug delivery device 10 may include an insertion mechanism 12, a reservoir 14, a fluid path assembly 22, a drive mechanism 24, and a controller 26, each of which may be disposed within the interior space of a main housing 29. An actuator 28 (e.g., a user-depressible button, a touchscreen, a microphone, etc.) may protrude from or be disposed on an exterior surface of the housing 29 and may be configured to initiate operation of the drug delivery device 10 by activating the insertion mechanism 12, the fluid path assembly 22, the drive mechanism 24, the controller 26, and / or other mechanisms and / or electronics by mechanical and / or electrical means (shown in dashed lines in FIG. 39 ). In embodiments in which the actuator 28 is a button that is pressed or otherwise physically operated by a user or patient, the actuator 28 may be configured to apply the motive force necessary to activate the insertion mechanism 12, the fluid path assembly 22, the drive assembly 24, the controller 26, and / or other mechanisms. In such embodiments, the actuator 28 may be physically connected, either directly or indirectly via a mechanical linkage, to the insertion mechanism 12, drive mechanism 24, fluid path assembly 22, and / or other mechanisms such that manually pushing or otherwise interacting with the actuator 28 provides the motive force necessary to activate the insertion mechanism 12, drive mechanism 24, fluid path assembly 22, and / or other mechanisms. For example, in some embodiments, manually pushing the actuator 28 may move the fluid path assembly 22 toward the fixed container 14, or move the container 14 toward the fixed fluid path assembly 22, thereby causing the container access needle to pierce the seal member and enter the reservoir or interior volume of the container 14. Additionally or alternatively, the actuator 28 may operate as an input device that sends electrical and / or mechanical signals to the controller 26, which may further execute programmable instructions to control the operation of the insertion mechanism 12, drive mechanism 24, fluid path assembly 22, and / or other mechanisms.In such embodiments, the controller 26 may include a processor (e.g., a microprocessor) and non-transitory memory for storing programmable instructions executed by the processor. Additionally, in such embodiments, the drug delivery device 10 may include internal actuators (e.g., electric motors, pneumatic or hydraulic pumps, and / or pressurized gas or liquid sources) separate from the actuators 28 that, in response to electrical control signals received from the controller 26, apply the motive force necessary to activate the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms.

[0054] 39 , the housing 29 may include a bottom wall 25 configured to be removably attached (e.g., adhered by an adhesive) to the patient's tissue 11 and a top wall 27 including one or more visual indicators 42 (e.g., lights, graphical displays, etc.) and / or a window 35 for viewing the container 14 and the medicament 113 contained therein. The one or more visual indicators 42 may be used to convey information to a user regarding the operational status of the drug delivery device 10 and / or the status of the medicament 113. An opening 31 may be formed in the bottom wall 25, and optionally, a pierceable sterility barrier 33, such as a pierceable septum, may extend across the opening 31 to seal the interior of the housing 29 prior to use. In some embodiments, the pierceable sterility barrier 33 may be omitted, and instead, a removable sealing member (not shown) may cover and seal close the opening 31 prior to use.

[0055] After the bottom wall 25 of the housing 29 is attached to the patient's tissue 13, the insertion mechanism 12 may be activated to move the delivery member from a retracted position within the housing 29 to a deployed position extending outside the housing 29. In this embodiment, this may involve the insertion mechanism 12 inserting the needle or trocar 21 and hollow cannula 23 surrounding the trocar 21 through a pierceable sterile barrier 33 and into the patient's tissue 11, as shown in FIG. 39 . Immediately or shortly thereafter, the insertion mechanism 12 may automatically retract the needle 21, leaving the distal open end of the cannula 23 inside the patient for subcutaneous delivery of the agent 113. The needle 21 may be solid and have a sharpened end for piercing the patient's skin 11. Additionally, the needle 21 may be made of a more rigid material than the cannula 23. In some embodiments, the needle 21 may be made of metal and the cannula 23 may be made of plastic or another polymer. The relative flexibility of cannula 23 may allow cannula 23 to be placed subcutaneously within the patient's tissue 11 for a period of time without causing pain or significant discomfort to the patient.

[0056] In some embodiments, the insertion mechanism 12 may include one or more springs (e.g., coil springs, torsion springs, etc.) that are initially held in a biased state and are released upon depression of the actuator 28 to insert the needle 21 and cannula 23 or hollow needle into the patient. Additionally, retraction of the needle 21 may be achieved by automatic release of another spring after the needle 21 and cannula 23 are inserted into the patient. Other power sources for insertion and / or retraction are also contemplated, including, for example, an electric motor, a hydraulic or pneumatic pump, or a canister that releases pressurized gas or liquid to provide actuation energy.

[0057] The container 14, which may be referred to in some contexts as a primary container, may include a wall 38 having an interior surface 43 and an exterior surface 47 that define a reservoir 30 that is filled with the medicament 113. In some embodiments, the reservoir 30 may be pre-filled with the medicament 113 by the drug manufacturer prior to attachment of the container 14 to the drug delivery device 10. In some embodiments, the container 14 may be rigidly connected to the housing 29 such that the container 14 cannot move relative to the housing, while in other embodiments, the container 14 may be slidably connected to the housing 29 such that the container 14 can move relative to the housing 29 during operation of the drug delivery device 10. The container 14 may have an elongated, barrel-like or cylindrical shape extending along a longitudinal axis A. In embodiments in which the drug delivery device 10 is configured as an on-body injector, the longitudinal axis A of the container 14 may be perpendicular, substantially perpendicular, or otherwise non-parallel to the direction in which the insertion mechanism 12 inserts a delivery member, such as the cannula 23, into a patient. This configuration may allow the on-body injector to have a generally flat, low-profile shape that can be worn by a patient without interfering with the patient's movement. First, a plunger 200 may be disposed within the reservoir 30 at the proximal end 36 of the container 14. The plunger 200 may sealingly and slidably engage an inner surface 43 of the wall 38 of the container 14 and may be movable relative to the wall 38 of the container 14.

[0058] The amount of drug 113 contained within reservoir 30 prior to delivery can be any amount within the range of about (e.g., ±10%) 0.5 to 20 mL, or any amount within the range of about (e.g., ±10%) 0.5 to 10 mL, or any amount within the range of about (e.g., ±10%) 1 to 10 mL, or any amount within the range of about (e.g., ±10%) 1 to 8 mL, or any amount within the range of about (e.g., ±10%) 1 to 5 mL, or any amount within the range of about (e.g., ±10%) 1 to 3.5 mL, or any amount within the range of about (e.g., ±10%) 1 to 3 mL, or any amount within the range of about (e.g., ±10%) 1 to 3 mL, or For example, the volume may be any volume within the range of about (e.g., ±10%) 1-2.5 mL, or any volume within the range of about (e.g., ±10%) 1-2 mL, or any volume up to about (e.g., ±10%) 4 mL, or any volume up to about (e.g., ±10%) 3.5 mL, or any volume up to about (e.g., ±10%) 3 mL, or any volume up to about (e.g., ±10%) 2.5 mL, or any volume up to about (e.g., ±10%) 2 mL, or any volume up to about (e.g., ±10%) 1.5 mL, or any volume up to about (e.g., ±10%) 1 mL. Reservoir 30 may be fully or partially filled with drug 113. Drug 113 may be one or more of the drugs described below, such as, for example, granulocyte colony-stimulating factor (G-CSF), PCSK9 (human proprotein convertase subtilisin / kexin type 9)-specific antibody, sclerostin antibody, or calcitonin gene-related peptide antibody (CGRP).

[0059] During operation of the drug delivery device 10, the drive mechanism 24 may push the plunger 200 along the longitudinal axis A from the proximal end 36 of the container 14 to the distal end 37 of the container 14 to expel the medicament 113 from the container 14. In some embodiments, the drive mechanism 24 may include one or more springs (e.g., coil springs, torsion springs, etc.) that are initially held in a biased state and released upon depression of the actuator 28. After their release, the springs may expand or contract to move the plunger 200 within the reservoir 30 along the longitudinal axis A from the proximal end 36 of the container 14 to the distal end 37 of the container 14. In other embodiments, the drive mechanism 24 may include an electric motor (not shown) that rotates a gear mechanism, including, for example, one or more sprocket gears, to cause axial movement of the plunger 200 within the reservoir 30. In yet other embodiments, the drive mechanism 24 may include both an electric motor and a spring, with the electric motor adjusting the extension of the spring via a tether or pulley system. In yet another embodiment, the drive mechanism 24 may include a canister that releases pressurized gas or liquid to provide the actuation energy. Other examples are possible.

[0060] The fluid pathway assembly 22 may be configured to establish fluid communication between the container 14 and the insertion mechanism 12 via a sterile fluid flow path during operation of the drug delivery device 10. The first end 44 of the fluid pathway assembly 22 may include a container access needle 60 and an overmold member 62. Generally, the overmold member 62 may serve as a mounting member or connection hub for the container access needle 60 and may provide an enlarged outer dimension, such as an enlarged outer diameter, to a portion of the container access needle 60 that does not access the reservoir 30. The container access needle 60 may have a sharpened end, or tip 63, corresponding to the proximal end of the container access needle 60 and a tip 64 in fluid communication with the fluid passageway 50.

[0061] The fluid pathway assembly 22 may include a first end 44 connected to the container 14, a second end 48 connected to the insertion mechanism 12, and a fluid pathway 50 extending between the first end 44 and the second end 48. As described in more detail below, in some embodiments, the first end 44 of the fluid pathway assembly 22 may be connected to the container 14 by a clip member 53. The fluid pathway 50 may be sterilized and may be made partially or entirely from flexible tubing 52. Initially, there may be slack in the flexible tubing 52 to allow the fluid pathway assembly 22 to move relative to the housing 29 and / or to allow components of the insertion mechanism 12 to which the fluid pathway assembly 22 is attached to move relative to the housing 29.

[0062] Drug Disclosure The above description describes various assemblies, devices, and methods for use with a drug delivery device. It should be clear that the system, drug delivery device, or method can further include the use of the drugs described below, but note that the following list should not be considered exhaustive or limiting. The drug is contained in a chamber or reservoir. In some cases, the reservoir is a primary container that is either filled or pre-filled with the drug for treatment. The primary container can be a cartridge or a pre-filled syringe.

[0063] 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® (filagrastim) and Neulasta® (pegfigrastim). In various other embodiments, the drug delivery device may be used with various pharmaceutical agents, 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® (methyoxy polyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (registered trademark), and others. any molecule that stimulates erythropoiesis, such as epoetin zeta, Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well as and the following patents or patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. No. 4,703,008, U.S. Pat. No. 5,441,868, U.S. Pat. No. 5,547,933, U.S. Pat. No. 5,618,698, U.S. Pat. No. 5,621,080, U.S. Pat. No. 5,756,349, U.S. Pat. No. 5,767,078, U.S. Pat. No. 5,773,569, U.S. Pat. No. 5,955,422, U.S. Pat. No. 5,986,047. and U.S. Patent Nos. 6,583,272, 7,084,245, and 7,271,689, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 96 / 40772, WO 00 / 24893, WO 01 / 81405, and WO 2007 / 136752, or variants or analogs thereof.

[0064] 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 causing receptor 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, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. 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, the entire disclosures of which are incorporated herein by reference), as well as the following patents or patent applications, the entire disclosures of which are incorporated herein by reference: U.S. Patent No. 4,703,008; U.S. Patent No. 5,441,868; U.S. Patent No. 5,547,933; U.S. Patent No. 5,547,933; Patent Nos. 5,618,698, 5,621,080, 5,756,349, 5,767,078, 5,773,569, 5,955,422, 5,830,851, 5,856,298, 5,986,047, 6,030,086, 6,310,078, 6,391,633, 6,583,272, 6,586,398, 6,900,292,U.S. Patent Nos. 6,750,369, 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, and U.S. Patent Application Publication Nos. 2004 / 0143202, 2004 / 0009902, 2004 / 0071694, and 2004 / 0143202. / 0091961, U.S. Patent Application Publication No. 2004 / 0143857, U.S. Patent Application Publication No. 2004 / 0157293, U.S. Patent Application Publication No. 2004 / 0175379, U.S. Patent Application Publication No. 2004 / 0175824, U.S. Patent Application Publication No. 2004 / 0229318, U.S. Patent Application Publication No. 2004 / 0248815, U.S. Patent Application Publication No. 2004 / 0266690, U.S. Patent Application Publication No. 2005 / 0019914, U.S. Patent Application Publication No. 2005 / 0026834, U.S. Patent Application Publication No. 2005 / 0096461, U.S. Patent Application Publication No. 2005 / 0107297, U.S. Patent Application Publication No. 2005 / 0107591, U.S. Patent Application Publication No. 2005 / 0124045, U.S. Patent Application Publication No. 2005 / 0124564, U.S. Patent Application Publication No. 2005 / 0137329, U.S. Patent Application Publication No. 2005 / 0142642, U.S. Patent Application Publication No. 2005 / 0143292, U.S. Patent Application Publication No. 2005 / 0153879, U.S. Patent Application Publication No. 2005 / 0158822, U.S. Patent Application Publication No. 2005 / 0158832, U.S. Patent Application Publication No. 2005 / 0170457, U.S. Patent Application Publication No. 2005 / 0181359, U.S. Patent Application Publication No. 2005 / 0181482, U.S. Patent Application Publication No. 2005 / 0192211, U.S. Patent Application Publication No. 2005 / 0202538, U.S. Patent Application Publication No. 2005 / 0227289, U.S. Patent Application Publication No. 2005 / 0244409, U.S. Patent Application Publication No. 2006 / 0088906,and U.S. Patent Application Publication No. 2006 / 0111279, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 99 / 66054, WO 00 / 24893, WO 01 / 81405, WO 00 / 61637, WO 01 / 36489, WO 02 / 014356, WO 02 / 19963, WO 02 / 20034, WO 02 / 49673, WO 02 / 085940, WO 03 / 029291, WO 2003 / 055526, WO 2003 / 084477, WO 2003 / 094858, WO 2004 / 002417, WO 2004 / 002424, WO 2004 / 009627, WO 2004 / 024761, WO 2004 / 033 651, WO 2004 / 035603, WO 2004 / 043382, WO 2004 / 101600, WO 2004 / 101606, WO 2004 / 101611, WO 2004 / 106373, WO 2004 / 018667, WO 2005 / 001025, WO 2005 / 001136, WO 2005 / 021579 Brochures, International Publication No. 2005 / 025606 pamphlet, International Publication No. 2005 / 032460 pamphlet, International Publication No. 2005 / 051327 pamphlet, International Publication No. 2005 / 063808 pamphlet, International Publication No. 2005 / 063809 pamphlet, International Publication No. 2005 / 070451 pamphlet, International Publication No. 2005 / 081687 pamphlet, International Publication No. 2005 / 084711 pamphlet, International Publication No. 2005 / 103076 pamphlet, International Publication No. 2005 / 100403 pamphlet,Examples include the erythropoietin molecules or variants or analogs thereof disclosed in WO 2005 / 092369, WO 2006 / 50959, WO 2006 / 02646, and WO 2006 / 29094.

[0065] Examples of other pharmaceuticals 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 filgastriim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-Met-G-CSF), and Nplate® (romiplostim); and small molecule drugs such as Sensipar® (cinacalcet). The device may also be used with other chemicals, such as therapeutic antibodies, polypeptides, proteins, or iron, e.g., ferumoxytol, iron dextran, ferric glyconate, and ferric iron oxide. The pharmaceutical agent may be in liquid form or may be reconstituted from a lyophilized form.

[0066] Among certain exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof.

[0067] As disclosed in PCT Publication WO 03 / 002713, each of which is individually and specifically incorporated herein by reference in its entirety, including OPGL-specific antibodies having either a light chain of SEQ ID NO:2 set forth in Figure 2 of said publication and / or a heavy chain of SEQ ID NO:4 set forth in Figure 4 of said publication; with regard to OPGL-specific antibodies and antibody-related proteins, in particular those having the sequences set forth in said publications, specifically but not limited to those set forth above (9H7, 18B2, 2D8, 2E11, 16E1, and 22B3), including but not limited to the antibodies described in said publications, which are incorporated herein in their entirety, OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies, and related proteins, including fully humanized and human OPGL-specific antibodies, in particular fully humanized monoclonal antibodies;

[0068] TN8-19-1 through TN8-19-40, TN8-19 con1, and TN8-19, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in U.S. Patent Application Publication No. 2004 / 0181033 and PCT Publication No. WO 2004 / 058988. myostatin-binding proteins, peptibodies, and related proteins, including myostatin-specific peptibodies, particularly those described in the above publications, which are incorporated herein by reference in their entirety, particularly in part, with particular reference to myostatin-specific peptibodies, including, but not limited to, the mTN8-19 family of peptibodies, including those of SEQ ID NOs: 305-351, including con2; the mL2 family of SEQ ID NOs: 357-383, the mL15 family of SEQ ID NOs: 384-409, the mL17 family of SEQ ID NOs: 410-438, the mL20 family of SEQ ID NOs: 439-446, the mL21 family of SEQ ID NOs: 447-452, the mL24 family of SEQ ID NOs: 453-454, and the peptibodies of SEQ ID NOs: 615-631;

[0069] 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, L2H15, L2H16, L2H17, L2H18, L2H19, L2H20, L2H21, L2H22, L2H23, L2H24, L2H25, L2H26, L2H27, L2H28, L2H29, L2H30, L2H31, L2H32, L2H33, L2H34, L2H35, L2H36, L2H37, L2H38, L2H39, L2H40, L2H41, L2H42, L2H43, L2H44, L2H45, L2H46, L2H47, L2H48, L2H49, L2H50, L2H51, L2H52, L2H53, L2H54, L2H55, L2H56, L2H57, L2H58, L2H59, L2H60, L2H61, L2H62, L2H63, L2H64, L2H65, L2H66, L2H67, L2H68, L2H69, L2H69, L2H70, L2H71, L2H72, L2H73, L2H74, L2H75, L2H76, L , L2H11, L2H12, L2H13, L2H14, L3H1, L4H1, L5H1, L6H1, IL-4 receptor-specific antibodies, particularly antibodies such as those described in the above publications, particularly those that inhibit activities mediated by IL-4 and / or IL-13 binding to the receptor, including those described in the above publications, which are particularly related in part to those set forth in the above publications and are incorporated herein by reference in their entirety, IL-4 receptor-specific antibodies, peptibodies, and related proteins,

[0070] Interleukin 1-receptor 1 ("IL1-R1")-specific antibodies, peptibodies, and related proteins, including, but not limited to, those set forth in U.S. Patent Application Publication No. 2004 / 097712, i.e., 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is individually and specifically incorporated by reference in its entirety, in part, IL1-R1-specific binding proteins, particularly those described in the above publications, which are incorporated by reference in their entirety, particularly with reference to monoclonal antibodies;

[0071] The sequences of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, in particular those sequences described in the following publications: 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 Ang2-specific antibodies and peptibodies, including, but not limited to, those described in PCT Publication No. WO 03 / 057134 and U.S. Patent Application Publication No. 2003 / 0229023, each of which is incorporated herein by reference in its entirety, particularly in part with respect to Ang2-specific antibodies and peptibodies, including, but not limited to, Ab526, Ab528, Ab531, Ab541, Ab542, Ab543, Ab544, Ab545, Ab546, Ab547, Ab548, Ab549, Ab550, Ab551, Ab552, Ab553, Ab554, Ab555, Ab556, Ab557, Ab558, Ab559 ... Ang2-specific antibodies, peptibodies, and related proteins, including anti-Ang2 antibodies and formulations such as those described in PCT Publication WO 2003 / 030833, which is incorporated by reference in its entirety with respect to Ab533, Ab535, Ab536, Ab537, Ab540, Ab543, Ab544, Ab545, Ab546, A551, Ab553, Ab555, Ab558, Ab559, Ab565, AbF1AbFD, AbFE, AbFJ, AbFK, AbG1D4, AbGC1E8, AbH1C12, AblA1, AblF, AblK, AblP, and those described in PCT Publication WO 2003 / 030833, which is incorporated by reference in its entirety with respect to AblP;

[0072] 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, each of which is individually and specifically incorporated herein by reference in its entirety, specifically including, but not limited to, the NGF-specific antibodies 4D4, 4G6, 6H9, 7H2, 14D10, and 14D11 set forth in the above publications, and NGF-specific antibodies and related proteins thereto, as disclosed in the above publications, each of which is individually and specifically incorporated herein by reference in its entirety, specifically including, but not limited to, the NGF-specific antibodies 4D4, 4G6, 6H9, 7H2, 14D10, and 14D11 set forth in the above publications,

[0073] humanized and fully human antibodies, including, but not limited to, humanized and fully human monoclonal antibodies, particularly including, but not limited to, human CD22-specific IgG antibodies, such as, for example, a dimer of human-mouse monoclonal hLL2 gamma chain disulfide linked to a human-mouse monoclonal hLL2 kappa chain, including, but not limited to, the human CD22-specific fully humanized antibody of epratuzumab (CAS Registry Number 501423-23-0); CD22-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 5,789,554, which is incorporated herein by reference in its entirety with respect to CD22-specific antibodies and related proteins;

[0074] IGF-1 specific antibodies L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, which are set forth in the following publications, each of which is individually and specifically incorporated by reference in its entirety herein: L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L 24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L3 IGF-1 receptor-specific antibodies, peptibodies, and related proteins, such as those described in PCT Publication WO 06 / 069202, which is incorporated by reference in its entirety with respect to IGF-1 receptor-specific antibodies and related proteins, including, but not limited to, 4H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments and derivatives thereof;

[0075] Also among the non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the present invention are each 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 therein. (ii) antibodies including, but not limited to, 2F8, A12, and IMC-A12, described in PCT Publication No. WO 06 / 138729 (published December 28, 2006) and PCT Publication No. WO 05 / 016970 (published February 24, 2005), and Lu et al. (2004), J. Biol. Chem. 279:2856-2865; (iii) PCT application publication numbers WO 07 / 012614 (published February 1, 2007), WO 07 / 000328 (published January 4, 2007), WO 06 / 013472 (published February 9, 2006), WO 05 / 058967 (published June 30, 2005), and WO 03 / 059951 (published July 24, 2003). (iv) Antibodies described in 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. (v) antibodies including, but not limited to, EM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1, huEM164 v1.2, and huEM164 v1.3, as described in U.S. Patent Application Publication No. 2005 / 0249728 (published November 10, 2005), U.S. Patent Application Publication No. 2005 / 0186203 (published August 25, 2005), U.S. Patent Application Publication No. 2004 / 0265307 (published December 30, 2004), and U.S. Patent Application Publication No. 2003 / 0235582 (published December 25, 2003), and Maloney et al. (2003), Cancer Res. 63:5073-5083; (vi) U.S. Pat. No. 7,037,498 (issued May 2, 2006), U.S. Patent Application Publication No. 2005 / 0244408 (published November 30, 2005), and U.S. Patent Application Publication No. 2004 / 0086503 (published May 6, 2004), and Cohen, et al. (2005), Clinical Cancer Res. 11:2063-2073, including, but not limited to, each of the antibodies produced by hybridomas having ATCC accession numbers PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, e.g., antibody CP-751,871, (vii) antibodies, including, but not limited to, antibody 19D12, as described in U.S. Patent Application Publication No. 2005 / 0136063 (published June 23, 2005) and U.S. Patent Application Publication No. 2004 / 0018191 (published January 29, 2004), comprising a heavy chain encoded by the polynucleotide of plasmid 15H12 / 19D12 HCA(γ4), deposited with the ATCC under accession number PTA-5214, and a light chain encoded by the polynucleotide of plasmid 15H12 / 19D12 LCF(κ), deposited with the ATCC under accession number PTA-5220; (viii) antibodies, including but not limited to, 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, which are described in U.S. Patent Application Publication No. 2004 / 0202655 (published October 14, 2004), each of which is incorporated herein by reference in its entirety, with respect to the aforementioned antibodies, peptibodies, and related proteins that specifically target the IGF-1 receptor;

[0076] B-7 related protein 1-specific antibodies, peptibodies, related proteins, and the like ("B7RP-1," also referred to in the literature 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 ICOS, the natural receptor for B7RP-1, particularly on activated T cells, and particularly as disclosed in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety: 16H (within which the light chain variable region sequence and heavy chain variable region sequence are SEQ ID NO: 1 and SEQ ID NO: 7, respectively); 5D (within which the light chain variable region sequence and heavy chain variable region sequence are SEQ ID NO: 1 and SEQ ID NO: 7, respectively); and SEQ ID NO:9), 2H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:3 and SEQ ID NO:10, respectively), 43H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:6 and SEQ ID NO:14, respectively), 41H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:5 and SEQ ID NO:13, respectively), and 15H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:4 and SEQ ID NO:12, respectively), and those disclosed in U.S. Patent Publication No. 2008 / 0166352 and PCT Publication No. WO 07 / 011941, each of which is incorporated by reference in its entirety, with respect to such antibodies and related proteins, including, but not limited to, the antibodies set forth in the following publications:

[0077] 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;

[0078] IFN-γ-specific antibodies, peptibodies, and related proteins, etc., particularly human IFN-γ-specific antibodies, particularly fully human anti-IFN-γ antibodies, such as, for example, IFN-γ-specific antibodies, particularly those described in the following patent publication, U.S. Patent Application Publication No. 2005 / 0004353, which is incorporated herein by reference in its entirety, with reference 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 specifically incorporated herein by reference in their entirety, as disclosed in the aforementioned 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, 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, as disclosed in the aforementioned publications. A specific antibody considered is antibody 1119, disclosed in the aforementioned U.S. Patent Application Publication, which has the complete heavy chain of SEQ ID NO: 17 disclosed in the aforementioned U.S. Patent Application Publication, and the complete light chain of SEQ ID NO: 18 disclosed in the aforementioned U.S. Patent Application Publication.

[0079] TALL-1 specific antibodies, peptibodies, and related proteins, such as those described in U.S. Patent Application Publication Nos. 2003 / 0195156 and 2006 / 0135431, each of which is incorporated herein by reference in its entirety, as disclosed in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety, and other TALL specific binding proteins, particularly those described in U.S. Patent Application Publication Nos. 2003 / 0195156 and 2006 / 0135431, each of which is incorporated herein by reference in its entirety with respect to TALL-1 binding proteins, particularly the molecules in Table 4 and Table 5B:

[0080] Parathyroid hormone ("PTH")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,756,480, which is incorporated herein by reference in its entirety, with particular reference in part to proteins that bind PTH;

[0081] 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 herein by reference in its entirety, with particular reference in part to proteins that bind to TPO-R;

[0082] 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;

[0083] 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 TRAIL-R2;

[0084] 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 incorporated herein by reference in its entirety, with particular reference to proteins that bind activin A;

[0085] TGF-β specific antibodies, peptibodies, related proteins, etc., including, but not limited to, those described in U.S. Pat. No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, each of which is incorporated by reference in its entirety, with particular reference in part to proteins that bind TGF-β;

[0086] 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 the antibody disclosed in the above publication having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6.

[0087] c-Kit-specific antibodies, peptibodies, related proteins, etc., including, but not limited to, those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated herein by reference in its entirety, with particular reference in part to proteins that bind c-Kit and / or other stem cell factor receptors;

[0088] 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, with particular reference in part to proteins that bind OX40L and / or other ligands of the OX40 receptor;

[0089] Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (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), Humatopeptide® (anti-HER2 / neu(erbB2) receptor mAb), Rope® (somatropin, human growth hormone), Humira® (adalimumab), insulin in 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-BlySmAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), Raptiva® (efalizumab), Cimzia® (certolizumab pegol, CDP870), Soliris™ (eculizumab), pexelizumab (anti-complement C5), Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Neulasta® (PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-Met-G-CSF), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP 1Ib / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Rituxan® (rituximab, anti-CD20mAb), Tarceva® (erlotinib), Roferon-A® (interferon alfa-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-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), CNTO148 (golimumab, anti-TNFα mAb), HGS-ETR1 (mapatuzumab, 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-CD30mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF idiopathic pulmonary fibrosis (FG-3019), anti-CTLA4 mAb, anti-eosin 1 mAb (CAT-213), anti-FGF8 mAb, anti-GD2 mAb, anti-GM2 mAb, anti-GDF-8 receptor 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-IL12 / IL23 mAb (CNTO1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-Iglycin receptor mAb (MDX-018, CNTO95), anti-IP10 ulcerative colitis mAb (MDX-1100), anti-LLY antibody, BMS-66513, anti-Mannos receptor / hCGβ mAb (MDX-1307), anti-methelin dsFv-PE38 complex (CAT-5001), anti-PD1 mAb (MDX-1106 (ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβ mAb (GC-1008), anti-TRAIL receptor-2 antibody (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), NVS antibody No. 1, and NVS antibody No. 2, and other exemplified materials.

[0090] Sclerostin antibodies, such as, but not limited to, romosozumab, brosozumab, or BPS804 (Novartis), may also be included. 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, a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9) may be included in the device.Such PCSK9-specific antibodies include those described in the following patents or patent applications, each of which is incorporated herein by reference in its entirety for all purposes: U.S. Patent No. 8,030,547, U.S. Patent Application Publication No. 2013 / 0064825, WO 2008 / 057457, WO 2008 / 057458, WO 2008 / 057459, WO 2008 International Publication No. / 063382, International Publication No. 2008 / 133647, International Publication No. 2009 / 100297, International Publication No. 2009 / 100318, International Publication No. 2011 / 037791, International Publication No. 2011 / 053759, International Publication No. 2011 / 053783, International Publication No. 2008 / 125623, International Publication No. 20 International Publication No. 11 / 072263, International Publication No. 2009 / 055783, International Publication No. 2012 / 0544438, International Publication No. 2010 / 029513, International Publication No. 2011 / 111007, International Publication No. 2010 / 077854, International Publication No. 2012 / 088313, International Publication No. 2012 / 101251, International Publication and 2001 / 031007, including, but not limited to, Repatha® (evolocumab) and Praluent® (alirocumab), and molecules, variants, analogs, or derivatives thereof, as disclosed in WO 2012 / 101252, WO 2012 / 101253, WO 2012 / 109530, and WO 2001 / 031007.

[0091] 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 (U.S. Pat. Nos. 7,223,593 and 7,537,924), OncoVEXGALV / CD (U.S. 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).

[0092] TIMPs are also included. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural processes. TIMP-3 is expressed by various cells or present in the extracellular matrix, inhibits all major cartilage-degrading metalloproteinases, and may play a role in many connective tissue degrading diseases, including rheumatoid arthritis and osteoarthritis, as well as cancer and cardiovascular conditions. 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 Application Publication No. WO 2014 / 152012.

[0093] 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 Publication No. WO 2010 / 075238.

[0094] Additionally, bispecific T cell-engaging (BiTE®) antibodies, such as BLINCYTO® (blinatumomab), can be used in the device. Alternatively, APJ large molecule agonists, such as apelin or analogs thereof, can be included in the device. Information regarding such molecules can be found in PCT Publication WO 2014 / 099984.

[0095] 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.

[0096] The plunger, drug delivery assembly, drug delivery mechanism, method, and elements thereof have been described in terms of exemplary, but not limited to, embodiments. The detailed description is to be construed as exemplary only and does not describe every possible embodiment of the present invention, as describing each and every possible embodiment would be impractical, if not impossible. Those skilled in the art will appreciate 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. Many alternative embodiments can 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 that define the present invention.

[0097] It should be understood that the legal scope of the present invention is defined by the language of the claims set forth at the end of this patent, and that the scope of the appended claims should be interpreted broadly to include other variations and embodiments thereof that may be made by those skilled in the art without departing from the scope of the embodiments described herein.

Claims

1. 1. A plunger for use in a drug delivery device, comprising: a body portion having a generally cylindrical sidewall, a leading surface, and a trailing surface; a plurality of ribs projecting radially outward from the sidewall of the body portion and spaced axially apart by recessed side surfaces, the plurality of ribs including at least a trailing rib, a leading rib, and a middle rib, each of the ribs including an annular configuration; Including, the body portion is configured to assume a first configuration in the absence of an axial load and a second configuration in the presence of an axial load, the first and second configurations having substantially equal radial dimensions, and the second configuration having an axial dimension that is smaller than the axial dimension of the first configuration; Plunger.

2. 2. The plunger of claim 1, wherein the radial surface of the sidewall extending between the ribs has a curved configuration.

3. 3. The plunger of claim 2, wherein the radial surface of the sidewall extending between the ribs is concave.

4. 2. The plunger of claim 1, wherein the radial surface of the body portion extending between the ribs includes a flat portion.

5. 5. The plunger of claim 4, wherein the radial surface of the body portion extending between the ribs further includes a frusto-conical portion at an axial end of the flat portion.

6. A plunger according to any preceding claim, wherein a trim edge of the body portion is adjacent the trailing surface of the body portion.

7. 7. The plunger of claim 6, wherein said trim edge has an outer diameter smaller than an outer diameter of said rib.

8. The plunger according to any one of claims 1 to 7, wherein the leading surface includes a roughened portion.

9. A plunger according to any preceding claim, wherein the leading surface is of a generally conical configuration.

10. A plunger according to any one of claims 1 to 9, wherein at least one of the trailing rib or the intermediate rib is axially smaller than the leading rib.

11. 11. The plunger of claim 10, wherein both the trailing rib and the intermediate rib are axially smaller than the leading rib.

12. A plunger according to any preceding claim, wherein at least one of the ribs has a curved axial profile.

13. A plunger according to any preceding claim, wherein at least one of the ribs includes a cylindrical portion extending between curved axial end portions of at least one of the ribs.

14. A plunger according to any preceding claim, further comprising a plurality of protrusions extending away from the trailing face of the body portion.

15. a body portion having a generally cylindrical sidewall, a leading surface, and a trailing surface; a plurality of ribs projecting radially outward from the sidewall of the body portion and spaced axially apart by recessed side surfaces, the plurality of ribs including at least a trailing rib, a leading rib, and a middle rib, each of the ribs including an annular configuration; Including, the body portion is configured to assume a first configuration in the absence of an axial load and a second configuration in the presence of an axial load, the first and second configurations having substantially equal radial dimensions, and the second configuration having an axial dimension that is smaller than the axial dimension of the first configuration; A plunger; a chamber having an annular sidewall extending between a first open end and a second end having a dispensing orifice, the plunger being received within the chamber such that the ribs of the plunger seal against an interior surface of the sidewall; a drive member configured to drive the plunger within the chamber to the second end of the chamber; A drug delivery assembly comprising:

16. 16. The drug delivery assembly of claim 15, wherein the contact area of the ribs on the inside of the sidewall remains substantially constant while the plunger is driven within the chamber.

17. 17. A drug delivery assembly according to claim 15 or 16, wherein a trim edge of the plunger is spaced from the inner side of the side wall while the plunger is driven within the chamber.

18. A drug delivery assembly according to any one of claims 15 to 17, wherein the ribs are axially spaced apart from each other by at least twice the distance of plunger travel within the chamber during air transport.

19. Housing and a syringe assembly including: a syringe barrel at least partially received within the housing and having an annular sidewall extending between a first open end and a second end having a dispensing orifice; and a needle assembly; an actuation mechanism at least partially received within the housing, a plunger received within the syringe barrel, a body portion having a generally cylindrical sidewall, a leading surface, and a trailing surface; a plurality of ribs projecting radially outward from the sidewall of the body portion and spaced axially apart from one another by recessed side surfaces, the plurality of ribs including at least a trailing rib, a leading rib, and a middle rib, each of the ribs including an annular configuration, the ribs sized to seal against an interior surface of the sidewall of the syringe barrel; Including, the body portion is configured to assume a first configuration in the absence of an axial load and a second configuration in the presence of an axial load, the first and second configurations having substantially equal radial dimensions, and the second configuration having an axial dimension that is smaller than the axial dimension of the first configuration; an actuation mechanism including a plunger; A drive mechanism; a drive member driven by the drive mechanism and configured to push the plunger within the syringe barrel to the second end of the syringe barrel, thereby forcing the medicament within the syringe barrel through the needle assembly; an autoinjector device.

20. a housing having an interior and a bottom wall within an opening extending into the housing, the housing configured to be secured to tissue of a user; a reservoir having an annular sidewall extending between a first open end and a second end having a dispensing orifice; A drive mechanism comprising: a plunger received within the reservoir, a body portion having a generally cylindrical sidewall, a leading surface, and a trailing surface; a plurality of ribs projecting radially outward from the sidewall of the body portion and spaced axially apart from one another by recessed side surfaces, the plurality of ribs including at least a trailing rib, a leading rib, and a middle rib, each of the ribs including an annular configuration, the ribs sized to seal against an interior surface of the sidewall of the reservoir; Including, a drive mechanism including a plunger, the body portion configured to assume a first configuration in the absence of an axial load and a second configuration in the presence of an axial load, the first and second configurations having substantially equal radial dimensions, the second configuration having an axial dimension that is smaller than the axial dimension of the first configuration; a drive member configured to drive the plunger within the reservoir to the second end of the reservoir; an insertion mechanism including a delivery member configured to move through the opening in the housing from a retracted position within the housing to a deployed position extending outside the housing; a fluid pathway assembly configured to fluidly couple the reservoir to the insertion mechanism; an actuator configured to, in response to actuation of the actuator, cause the drive mechanism to drive the plunger within the reservoir to the second end of the reservoir, thereby dispensing the medicament in the reservoir through the insertion mechanism; and 1. An on-body injector device comprising:

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