Low insertion force syringe stoppers, assemblies and related methods

Abstract

A plunger rod head and syringe stopper pocket design (e.g., for use in pre-filled syringe assembly) that facilitates reduced axial insertion force when coupling a plunger rod to a stopper. The desired axial insertion force can be lower than the associated breakaway force between the stopper and its associated syringe barrel, where the design ensures that the rod head and syringe stopper are coupled and requires a substantial, non-zero separation force to separate the components.

Description

[Background technology]

[0001] background A syringe typically includes a barrel, a stopper disposed within the barrel, and a plunger rod for moving the stopper. The stopper is typically air- and liquid-impermeable, forms an airtight and liquid-tight seal with the barrel, and also has low-friction sliding properties. Low-friction sliding properties are important for facilitating the discharge of liquid from the syringe.

[0002] Syringe assembly typically includes connecting a plunger rod to a stopper. In the assembly method of a prefilled syringe, the barrel can be filled with a therapeutic agent before inserting the stopper into the barrel. Once the stopper is inserted into the barrel, the plunger rod is connected to the stopper by applying an axial force to push the plunger rod head into the stopper, or by applying a torque or rotational force to screw the plunger rod head into the stopper.

[0003] Some have observed that the process of forming a connection between the plunger rod and the stopper during assembly, or the process of connecting the plunger rod and the stopper using a threaded or force-fit action, can deform or translate the stopper, compromising the seal integrity or sterility of the barrel and / or therapeutic agent, and / or increasing pressure within the barrel, potentially causing fluid leakage from the outlet end of the syringe. Some prior art designs attempt to overcome these concerns by assembling a pre-filled syringe without connecting the plunger rod to the stopper, thereby eliminating the need to manipulate or force-connect the plunger rod to the stopper. The concept disclosed in U.S. Patent No. 11,185,635 to Novartis AG employs such a non-bonding approach to address the aforementioned concerns. However, after initial assembly (e.g., inserting the plunger rod into the stopper within the barrel), the lack of coupling between the stopper and plunger rod means that the rod is free to translate an unacceptable amount from the stopper (e.g., completely disengage from the barrel) without the addition of an additional backstop to the barrel. Prior art assembly designs for such threaded or screw-type plunger rod assemblies include U.S. Patent No. 10,369,292 to W.L. Gore & Associates, Inc., which describes a stopper that supports the plunger rod assembly with a non-threaded, integral engagement with the stopper. In some embodiments, the threaded plunger rod is free to rotate within the interior cavity of the stopper. Summary of the Invention

[0004] Abstract Various embodiments relate to plunger rod head and syringe stopper pocket designs, and related methods and systems, that facilitate reducing the axial insertion force when coupling a plunger rod to a stopper in pre-filled syringe designs. Various embodiments ensure that the rod head and syringe stopper are coupled and require a substantial, non-zero separation force to separate the components, while requiring an axial insertion force that is lower than the breakaway force between the stopper and the associated syringe barrel.

[0005] According to one embodiment ("Embodiment 1"), a stopper for a syringe includes a body having a front end, a rear end, and an outer surface extending between the front end and the rear end, the outer surface being operable to sealingly and slidably engage a barrel of the syringe, the body of the stopper having an inner surface and a pocket having a first end and a second end, the pocket being defined by the inner surface, the body further having an opening to the second end of the pocket formed at the rear end of the body, the pocket including a trap portion having a first diameter, a relief portion having a second diameter, and a coupling portion between the trap portion and the relief portion having a third diameter smaller than the first diameter and the second diameter, the inner surface of the body including one or more coupling protrusions corresponding to the coupling portion of the pocket.

[0006] According to another embodiment ("Embodiment 2"), in addition to embodiment 1, the one or more coupling protrusions include a circumferential ridge.

[0007] According to another embodiment ("Embodiment 3"), in addition to embodiment 2, the circumferential ridge extends continuously along the periphery of the pocket.

[0008] According to another embodiment ("Embodiment 4"), in addition to any of Embodiments 1-3, the one or more coupling protrusions include longitudinal ridges.

[0009] According to another aspect ("Aspect 5"), in addition to any of aspects 1 to 4, the one or more coupling protrusions have a leading edge and a trailing edge, and further, at least the leading edge is at least one of angled and rounded.

[0010] According to another embodiment ("embodiment 6"), in addition to any of embodiments 1 to 5, the first diameter is approximately the same as the second diameter.

[0011] According to another embodiment (“Embodiment 7”), further to any of embodiments 1-6, the third diameter is at least 10% smaller than the first diameter and / or the second diameter, or optionally at least 13% smaller, or optionally at least 18% smaller.

[0012] According to another embodiment ("embodiment 8"), in addition to any of embodiments 1 to 7, the first diameter differs from the third diameter by about 0.3 mm.

[0013] According to another embodiment ("Embodiment 9"), further to any of embodiments 1-8, the second diameter differs from the third diameter by about 0.3 mm, or optionally by 0.1 mm to 0.6 mm, or optionally by 0.2 mm to 0.5 mm, or optionally by 0.3 mm to 0.4 mm.

[0014] According to another aspect ("Aspect 10"), a syringe includes: a barrel having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper disposed within the receiving chamber and slidably and sealingly engaging the inner surface of the barrel, wherein the stopper has a pocket including a trap portion having a first diameter, a relief portion having a second diameter, and a coupling portion between the trap portion and the relief portion, the coupling portion having a third diameter smaller than the first diameter and the second diameter, the stopper including one or more coupling protrusions corresponding to the coupling portion of the pocket; and a plunger rod having a head portion, a rear portion, and a rod portion extending between the head portion and the rear portion, wherein the head portion has a tapered crown and defines a retention feature that engages the coupling portion of the pocket to couple the plunger rod to the stopper, the head portion being received in the trap portion of the stopper.

[0015] According to another aspect ("Aspect 11"), in addition to aspect 10, the tapered crown has a smooth surface for slidably engaging with one or more coupling protrusions of the coupling portion when the head portion of the plunger rod is inserted into the pocket of the stopper.

[0016] According to another aspect ("Aspect 12"), in addition to aspects 10 or 11, the stopper and the barrel define a disengagement force, and the stopper and the plunger rod are configured such that, when the stopper is received in the barrel, the head portion of the plunger rod can be axially inserted into the stopper with an insertion force smaller than the disengagement force.

[0017] According to another embodiment ("embodiment 13"), in addition to embodiment 12, the separation force is 2N to 20N.

[0018] According to another aspect ("Aspect 14"), in addition to any of aspects 10 to 13, the stopper and the plunger rod require application of a longitudinal separation force to separate the plunger rod from the stopper.

[0019] According to another embodiment ("embodiment 15"), in addition to the features of embodiment 14, when embodiment 12 or 13 is included, the separation force is greater than the detachment force.

[0020] According to another aspect ("Aspect 16"), a method for coupling a plunger rod to a stopper disposed within a barrel of a syringe includes axially inserting a head portion of the plunger rod into a pocket of the stopper with an insertion force less than a separation force defined between the stopper and the barrel of the syringe, wherein the plunger rod is coupled to the stopper when the head portion of the plunger rod is axially inserted into a capture portion of the stopper.

[0021] According to another aspect ("Aspect 17"), in addition to aspect 16, inserting the head portion into the pocket includes sliding a tapered crown of the head portion of the plunger rod over one or more coupling protrusions corresponding to the coupling portions of the pocket to couple the plunger rod to the stopper.

[0022] According to another aspect ("Aspect 18"), in addition to aspect 17, the one or more coupling protrusions include one or more longitudinally extending ridges and / or one or more circumferentially extending ridges.

[0023] According to another aspect ("Aspect 19"), in addition to any of aspects 16 to 18, inserting the head portion into the pocket includes sliding the head portion of the plunger rod over one or more coupling protrusions having a leading edge and a trailing edge, and further, at least the leading edge is at least one of angled and rounded, and further, inserting the head portion into the pocket includes sliding the head portion longitudinally over the leading edges of the one or more coupling protrusions.

[0024] According to another embodiment ("embodiment 20"), in addition to embodiment 19, the separation force is 2N to 20N.

[0025] According to another aspect ("Aspect 21"), in addition to any of aspects 16-20, the stopper and the plunger rod require application of a longitudinal separation force to separate the plunger rod from the stopper.

[0026] According to another embodiment ("embodiment 22"), in addition to embodiment 21, the separation force is greater than the detachment force.

[0027] According to another aspect ("Aspect 23"), a stopper for a syringe includes a body having a front end, a rear end, and an outer surface extending between the front end and the rear end, wherein the outer surface includes a body operable to sealingly and slidably engage a barrel of the syringe, the body of the stopper having an inner surface and a pocket having a first end and a second end, the pocket being defined by the inner surface, the body further having an opening to the second end of the pocket formed at the rear end of the body, the pocket including a trap portion having a first diameter, a relief portion having a second diameter, and a coupling portion between the trap portion and the relief portion having a third diameter smaller than the first diameter and the second diameter, and the inner surface of the body includes one or more coupling recesses corresponding to the coupling portion of the pocket.

[0028] According to another embodiment ("Embodiment 24"), in addition to embodiment 23, the one or more coupling recesses include a circumferential recess.

[0029] According to another embodiment ("Embodiment 25"), in addition to embodiment 24, the circumferential recess extends continuously along the periphery of the pocket.

[0030] According to another embodiment ("Embodiment 26"), in addition to any of Embodiments 23-25, the one or more coupling recesses include longitudinal recesses.

[0031] According to another aspect ("Aspect 27"), in addition to any of aspects 23 to 26, the one or more coupling recesses have a leading edge and a trailing edge, and at least the leading edge is at least one of angled and rounded.

[0032] According to another embodiment ("embodiment 28"), in addition to any of embodiments 23 to 27, the first diameter is approximately the same as the second diameter.

[0033] According to another aspect ("Aspect 29"), further to any of aspects 23-28, the third diameter is at least 10% larger than the first diameter and / or the second diameter, or optionally at least 13% larger, or optionally at least 18% larger.

[0034] According to another embodiment ("Embodiment 30"), further to any of embodiments 23-29, the first diameter differs from the third diameter by about 0.3 mm, or optionally, by 0.1 mm to 0.6 mm, or optionally, by 0.2 mm to 0.5 mm, or optionally, by 0.3 mm to 0.4 mm.

[0035] According to another embodiment ("Embodiment 31"), further to any of embodiments 23-30, the second diameter differs from the third diameter by about 0.3 mm, or optionally, by 0.1 mm to 0.6 mm, or optionally, by 0.2 mm to 0.5 mm, or optionally, by 0.3 mm to 0.4 mm.

[0036] According to another aspect ("Aspect 32"), a method for coupling a plunger rod to a stopper disposed within a barrel of a syringe includes axially inserting a head portion of the plunger rod into a pocket of the stopper with an insertion force less than a separation force defined between the stopper and the barrel of the syringe, wherein the plunger rod is coupled to the stopper when the head portion of the plunger rod is axially inserted into a capture portion of the stopper.

[0037] According to another aspect ("Aspect 33"), in addition to aspect 32, inserting the head portion into the pocket also includes sliding enlarged segments of the head portion of the plunger rod into one or more coupling recesses corresponding to the coupling portions of the pocket to couple the plunger rod to the stopper.

[0038] According to another aspect ("Aspect 34"), in addition to aspect 33, the one or more coupling recesses include one or more longitudinally extending recesses and / or one or more circumferentially extending recesses.

[0039] According to another aspect ("Aspect 35"), in addition to aspect 34, each of the one or more coupling recesses has a leading edge and a trailing edge, at least the leading edge being at least one of angled and rounded, and inserting the head portion into the pocket includes sliding the head portion longitudinally over the leading edge of the one or more coupling recesses and seating an enlarged segment of the head portion in the one or more coupling recesses.

[0040] According to another aspect ("Aspect 36"), in addition to any of aspects 32 to 35, the separation force is 2N to 20N, and when the plunger rod is inserted into the stopper, the stopper and the plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper.

[0041] According to another embodiment ("Embodiment 37"), in addition to embodiment 36, the separation force is greater than the separation force.

[0042] According to another aspect ("Aspect 38"), a syringe includes: a barrel having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper disposed within the receiving chamber and slidably and sealingly engaging the inner surface of the barrel, the stopper having a pocket including a trapping portion having a first diameter, a relief portion having a second diameter, and a coupling portion between the trapping portion and the relief portion having a third diameter larger than the first diameter and the second diameter, the stopper including one or more coupling recesses corresponding to the coupling portion of the pocket; and a plunger rod having a head portion, a rear portion, and a rod portion extending between the head portion and the rear portion, the head portion defining a retention mechanism that engages with the coupling recess of the pocket to couple the plunger rod to the stopper, the retention mechanism being received in the one or more coupling recesses of the stopper.

[0043] According to another aspect ("Aspect 39"), in addition to aspect 38, the stopper and the barrel define a disengagement force, and the stopper and the plunger rod are configured such that, when the stopper is received in the barrel, the head portion of the plunger rod is axially insertable into the stopper with an insertion force less than the disengagement force.

[0044] According to another embodiment ("embodiment 40"), in addition to embodiment 39, the separation force is 2N to 20N.

[0045] According to another aspect ("Aspect 41"), in addition to any of aspects 38 to 40, the stopper and the plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper.

[0046] According to another embodiment ("embodiment 42"), in addition to the features of embodiment 41, when embodiment 39 or 40 is included, the separation force is greater than the detachment force.

[0047] According to any of the foregoing aspects, the stopper can be configured to exhibit an insertion force that is less than 75% of the breakaway force of the stopper when received in a syringe barrel, and in some cases, no greater than 50% of the breakaway force of the stopper when received in a syringe barrel.

[0048] According to any of the above-described aspects, the stopper can be characterized in that the Lp / L value or Lr / L value, which is a ratio defined in this specification, is greater than 0, optionally greater than 0.05, and is 0.5 or less, optionally 0.3 or less, or optionally 0.2 or less. According to any of the above-described aspects, the Lp / L value or Lr / L value is, for example, 0.1 to 0.2.

[0049] The foregoing aspects are merely exemplary and should not be construed as limiting or narrowing the scope of the inventive concepts otherwise provided by this disclosure. While multiple aspects are disclosed, still other embodiments and associated features will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative examples. Accordingly, the drawings and detailed description are to be regarded as illustrative and not restrictive in nature. [Brief explanation of the drawings]

[0050] BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification, illustrating embodiments and, together with the description, serving to explain the principles of the present disclosure.

[0051] [Figure 1] FIG. 1 is a side view of a syringe according to some embodiments.

[0052] [Figure 2] FIG. 2 is a side view of a syringe with the plunger rod and stopper disassembled or separated, according to some embodiments.

[0053] [Figure 3A]FIG. 3A is a longitudinal cross-sectional view showing a prior art stopper and plunger rod coupling mechanism. [Figure 3B] FIG. 3B is a longitudinal cross-sectional view showing a prior art stopper and plunger rod coupling mechanism.

[0054] [Figure 3C] FIG. 3C is a schematic diagram of a stopper design according to some embodiments. [Figure 3D] FIG. 3D is a schematic diagram of a stopper design according to some embodiments.

[0055] [Figure 3E] FIG. 3E is a close-up view of the end of the plunger rod of FIGS. 3A and 3B, according to some embodiments.

[0056] [Figure 4A] FIG. 4A shows a stopper and the stopper assembled to a plunger rod, according to some embodiments. [Figure 4B] FIG. 4B shows a stopper and the stopper assembled to a plunger rod, according to some embodiments. [Figure 4C] FIG. 4C shows a stopper and the stopper assembled to a plunger rod, according to some embodiments.

[0057] [Figure 5] FIG. 5 illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 6] FIG. 6 illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 7] FIG. 7 illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 8] FIG. 8 illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 9]FIG. 9 illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 10A] FIG. 10A illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 10B] FIG. 10B illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 11A] FIG. 11A shows various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 11B] FIG. 11B illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 12A] FIG. 12A shows various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 12B] FIG. 12B illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 13A] FIG. 13A shows various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 13B] FIG. 13B illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 14] FIG. 14 illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 15A] FIG. 15A shows various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 15B] FIG. 15B illustrates various stopper pocket designs for the syringe of FIGS. 1 and 2, according to some embodiments.

[0058] [Figure 16] FIG. 16 shows various plunger rod designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 17]FIG. 17 shows various plunger rod designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 18A] FIG. 18A shows various plunger rod designs for the syringe of FIGS. 1 and 2, according to some embodiments. [Figure 18B] FIG. 18B shows various plunger rod designs for the syringe of FIGS. 1 and 2, according to some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description Definitions and Terminology The present disclosure should not be construed in a limiting sense. For example, the terms used in this application should be interpreted broadly in accordance with the meaning that one of ordinary skill in the art would assign to such terms.

[0060] The use of headings is provided solely to facilitate review of the description and is not intended to distinguish or otherwise designate that concepts of one heading are inapplicable to or unrelated to concepts of another heading. In fact, the opposite is intended; the description is intended to be read and interpreted as a whole, and various features and aspects of a particular embodiment are applicable across and to various other embodiments described herein.

[0061] With respect to terms related to imprecision, the terms "about" and "approximately" may be used interchangeably to refer to measurements that include the stated measurement and measurements that are reasonably close to the stated measurement. A measurement that is reasonably close to the stated measurement deviates from the stated measurement by a reasonably small amount, as understood and easily ascertained by one of ordinary skill in the relevant art. Such deviations may result from, for example, measurement error, differences in the calibration of measuring and / or manufacturing equipment, human error in reading and / or setting measurements, fine-tuning made to optimize performance and / or structural parameters to account for variations in measurements associated with other components, specific implementation scenarios, imprecise adjustment and / or manipulation of objects by humans or machines, and / or the like. If it is determined that the value of such a reasonably small difference would not be readily ascertainable by one of ordinary skill in the relevant art, the terms "about" and "approximately" shall be understood to mean plus or minus 10% of the stated value.

[0062] As used herein, the terms "elastic" and "elastomeric" refer to a material property as understood in the context of stoppers used in injector devices (e.g., in FDA approved applications) and relate to the tendency of a material to spontaneously return to, or recover from, its undeformed shape after being subjected to a dimensional deformation (e.g., shrinkage, expansion, strain, etc.).

[0063] As used herein, the term "syringe" is intended to include any of a variety of devices that include a stopper received within a barrel and an actuation mechanism configured to displace the stopper within the barrel to expel or deliver contents held within the barrel. The concepts disclosed herein can be utilized in conjunction with syringes ranging from, for example, 0.5 mL to 20 mL, and can also be appropriately scaled to smaller or larger syringes.

[0064] As used herein, the term "proximal" means closer to the operator end of the device (e.g., the plunger rod end), while the term "distal" means further from the operator than proximal (e.g., the piercing element end).

[0065] As used herein, terms such as "rotate" (e.g., "rotation") are intended to mean circumferential movement.

[0066] As used herein, the terms "axial" insertion, translation, movement, etc. are intended to mean movement in the longitudinal direction.

[0067] As used herein, the terms "silicone" and "silicone oil" can be used interchangeably herein.

[0068] As used herein, the term "substantially free" is intended to mean that the specified substance (e.g., silicone, silicone oil, or other lubricant) is present in an unquantifiable or trace amount, or is not intentionally added to the system (e.g., no silicone oil is intentionally added to an injector device such as a barrel or stopper).

[0069] As used herein, the term "sealing rib" means a rib on a stopper that contacts the interior surface of the barrel to prevent air or other contaminants from entering the barrel or the contents of the barrel from exiting the barrel.

[0070] As used herein, the term "non-sealing rib" means a rib that does not contact the inner surface of the syringe barrel, or a rib that contacts the inner surface of the barrel in a manner that allows air (or other contaminants) and / or the contents of the barrel to pass through.

[0071] As used herein, the term "longitudinally extending" is intended to mean a feature that has a larger dimension in the axial or longitudinal direction, as opposed to the lateral (e.g., circumferential) direction.

[0072] As used herein, the term "circumferentially extending" is intended to mean a feature that has a greater lateral (e.g., circumferential) dimension than an axial or longitudinal dimension.

[0073] As used herein, the term "breakaway force" is intended to mean the force required to initiate relative movement between the stopper and the syringe barrel after the stopper is placed within the syringe barrel.

[0074] As used herein, the term "separation force" is intended to mean the longitudinal force required to separate the head of the plunger rod from the pocket in the stopper.

[0075] As used herein, the terms "ridge" and "rib" are synonymous, as are the terms "valley" and "recess."

[0076] Description of Various Embodiments Those skilled in the art will readily appreciate that the various aspects of the present disclosure can be implemented by any number of methods and apparatus configured to perform the intended functions. It should also be noted that the accompanying drawings referred to herein are not necessarily drawn to scale and may be exaggerated to illustrate various aspects of the present disclosure, and that in at least that respect the drawings should not be construed as limiting.

[0077] Various concepts herein relate to plunger rod head and syringe stopper pocket designs that facilitate reducing the axial insertion force when coupling a plunger rod to a stopper (e.g., when used in a prefilled syringe assembly). The desired axial insertion force can be lower than the associated separation force between the stopper and its associated syringe barrel, but still ensure that the plunger rod head portion and the syringe stopper are coupled and require a substantially non-zero separation force to separate the components. Generally, the coupling, or engagement, between the stopper and the head portion of the plunger rod is a non-threaded engagement. That is, these components are configured to be assembled by an axial insertion method rather than by screwing. In other words, at least one of the stopper pocket and the head portion of the plunger rod is not threaded, and preferably both the stopper pocket and the head portion of the plunger rod are not threaded or do not have a complementary thread mechanism for threaded engagement between the components. As described herein, a "thread" feature is generally a continuous or discontinuous helically extending feature that is engaged and advanced by a rotational motion. As shown and described herein, in various examples, the engagement features of the stopper and / or plunger are non-helically arranged (e.g., circumferentially continuous, circumferentially discontinuous, and / or longitudinally arranged).

[0078] 1 illustrates a syringe 10, according to some examples. The syringe 10 is generally operable to deliver contents 12 of the syringe 10 by pressurizing the contents 12 and expelling them from the syringe 10. The syringe contents 12 may include a therapeutic agent (e.g., a pharmaceutical agent) to be delivered to a patient in connection with a medical procedure. The syringe 10 may also be more commonly referred to as an injector or injection device, and while the syringe 10 may be configured as shown, the principles described herein are applicable to other configurations of the syringe 10, including automatic injector configurations.

[0079] As shown, syringe 10 includes a barrel 20, also referred to as a cartridge tube, a plunger rod 22, and a stopper 24. Syringe 10 may also include a piercing element 26, although it is within the scope of this disclosure for syringe 10 to be terminated with a "needleless" device, such as a Luer-Lok™ system (not shown).

[0080] In some embodiments, the barrel 20 includes a distal end 30, a proximal end 32, an exterior surface 34, and an interior surface 36 that bounds or otherwise defines a receiving chamber 38 for receiving the contents 12. The barrel 20 can be formed from a variety of materials, including relatively rigid materials. Some examples of suitable materials include glass materials (e.g., borosilicate glass), ceramic materials, polymeric materials (e.g., polypropylene, polyethylene and their copolymers, cyclic olefin polymers and cyclic olefin copolymers), metallic materials, and combinations thereof. In some embodiments, the barrel 20 includes a quantity of lubricant (not shown) on the interior surface 36 of the barrel 20. In other embodiments, the barrel 20 is lubricant-free or substantially lubricant-free. As shown, the contents 12 may be pre-filled into the barrel 20 as part of the syringe assembly process (i.e., as a pre-filled syringe). However, in other applications, the contents 12 may be drawn into the barrel 20 after assembly of the syringe 10. The inner diameter of syringe barrel 20 can have a variety of dimensions, such as about 3 mm to about 20 mm, or about 5 mm to about 20 mm. In one example, barrel 20 corresponds to a 0.5 ml syringe and has a diameter of, for example, 4.65 mm ± 0.1 mm or 6.85 mm ± 0.1 mm, although various dimensions are contemplated. In another example, barrel 20 corresponds to a 20 ml syringe and has a diameter of 19.05 mm ± 0.2 mm, although various dimensions are contemplated.

[0081] The plunger rod 22 of the syringe 10 is movable within the barrel 20, displacing the contents 12 by moving the stopper 24 toward the distal end 30 of the barrel 20. While shown prefilled in FIG. 1, in other applications, the barrel 20 may be primed or filled by pulling the stopper 24 proximally. FIG. 2 illustrates the syringe 10 in a partially assembled state, while FIG. 1 illustrates the syringe 10 in a fully assembled state. Some assembly methods include placing the stopper 24 within the barrel 20 with the contents 12 received within the barrel 20, as shown in FIG. 2. The plunger rod 22 can then be assembled to the stopper by applying an axial insertion force Fi to the plunger rod 22. As shown in FIG. 2, the plunger rod 22 includes a proximal end 42, a distal end 44, a head portion 46 at the distal end 44, a rear portion 48 at the proximal end 42, and a rod portion 50 extending between the head portion 46 and the rear portion 48. For reference, head 46 is generally designated by a box and an "X" as several different configurations of head 46 are possible and will be described in more detail below. Generally speaking, head 46 is configured to couple plunger rod 22 to stopper 24.

[0082] As shown in FIG. 2 , the stopper 24 is disposed within the receiving chamber 38 such that the stopper 24 slidably and sealingly engages the inner surface 36 of the barrel 20 (e.g., the contents of the syringe are generally unable to pass through the stopper 24 before and during actuation). The stopper 24 includes a body 60 having a front end 62, a rear end 64, and an outer surface 66 extending between the front and rear ends 62, 64, the outer surface 66 being operable to sealingly and slidably engage the barrel 20 of the syringe 10. The body 60 further includes an inner surface 68 and a pocket 70 having a first end 72 and a second end 74, the pocket 70 being defined by the inner surface 68. The body 60 includes an opening 76 to the second end 74 of the pocket 70, the opening 76 being formed in the rear end 64 of the body 60. As with head portion 46 of plunger rod 22, pocket 70 is shown in generalized form with a box and an "X" because several different configurations of pocket 70 are contemplated, which will be described in more detail below. Outer surface 66 of stopper 24 optionally defines one or more ridges (also called ribs), valleys (also called recesses), or other features to assist stopper 24 in sealingly and slidably engaging inner surface 36 of barrel 20.

[0083] The body 60 of the stopper 24 is formed from an elastomeric material. The stopper 24 may also include a thin film cover formed from a polymeric material, such as a fluoropolymer material, including PTFE, ePTFE, and variants thereof. Examples of suitable stopper and film cover materials can be found in U.S. Pat. No. 10,471,211 to W.L. Gore & Associates, Inc. In some instances, the thin film cover functions as a solid lubricant. The thin film cover may be provided on the stopper 24 in addition to, or as an alternative to, a lubricant (e.g., silicone oil) provided within the barrel 20. The stopper 24 should generally have low air and liquid permeability to minimize and prevent leakage of liquid within the barrel 20 and the intrusion of air between the stopper 24 and the inner surface 68 of the barrel 20 during filling and / or ejection of the contents 12 of the syringe 10. The overall diameter of the stopper 24 may be any of a variety of values. However, in some examples, the outer diameter is 5.2 mm to 5.5 mm ± 0.1 mm for a 0.5 ml barrel, and 19.9 mm to 21 mm ± 0.15 mm for a 20 ml barrel, although various dimensions are contemplated.

[0084] If desired, a thin film lubricant may be added in addition to the solid lubricant. In at least one embodiment, the thin film lubricant is coated directly onto the solid lubricant of the stopper by spray coating or by contacting the stopper 24 with another substrate (e.g., a coating tube) containing a quantity of thin film lubricant. The thin film lubricant may also be baked or crosslinked onto the solid lubricant of the stopper 24. Applying the thin film lubricant directly onto the solid lubricant of the stopper 24 may help prevent the thin film lubricant from diffusing into the therapeutic agent 150. As described further herein, the thin film lubricant may also be applied to the solid lubricant (e.g., ePTFE) of the stopper 200 through a vent or insertion tube (not shown) or through the barrel 20. In some embodiments, the thin film lubricant may be applied directly to the barrel 20. Furthermore, to reduce the total amount of thin film lubricant in the system, the thin film lubricant may be applied to a limited number of sections of the barrel 20.

[0085] The thin film lubricant may be either a solid or liquid lubricant. In some embodiments, the thin film lubricant is silicone oil. In other embodiments, the thin film lubricant may be other lubricants, such as polysorbate. Additionally, the thin film lubricant may be chemically or physically modified to improve its compatibility with the solid lubricant, thereby reducing the amount of thin film lubricant that may be removed from stopper 24. In some embodiments, the thin film lubricant is configured to have a higher affinity for the solid lubricant than the barrel 20 and / or the therapeutic agent.

[0086] The amount of thin film lubricant applied to stopper 24 can vary. In at least one embodiment, the thin film lubricant is applied at a "low" level, which can be in an amount of about 0.3 pg to about 100 pg per stopper 24. The amount of thin film lubricant applied to stopper 24 can be from about 0.3 pg to about 100 pg, from about 5 pg to about 100 pg, from about 0.3 pg to about 90 pg, from about 5 pg to about 90 pg, from about 0.3 pg to about 80 pg, from about 5 pg to about 80 pg, from about 0.3 pg to about 70 pg, from about 5 pg to about 70 pg, from about 0.3 pg to about 60 pg, or from about 5 pg to about 50 pg. The surface density can be about 60 pg, about 0.3 pg to about 50 pg, about 5 pg to about 50 pg, about 0.3 pg to about 40 pg, about 5 pg to about 40 pg, about 0.3 pg to about 30 pg, about 5 pg to about 30 pg, about 0.3 pg to about 20 pg, about 5 pg to about 20 pg, about 0.3 pg to about 10 pg, or about 5 pg to about 10 pg. 2 For a 1 mL stopper 200, the thin film lubricant has a concentration of about 0.15 pg / cm on the stopper 24. 2 ~about 50pg / cm 2 , about 2.5pg / cm 2 ~about 50pg / cm 2 , about 0.15pg / cm 2 ~Approx. 45pg / cm 2 , about 2.5pg / cm 2 ~Approx. 45pg / cm 2 , about 0.15pg / cm 2 ~about 40pg / cm 2 , about 2.5pg / cm2 ~about 40pg / cm 2 , about 0.15pg / cm 2 ~Approx. 35pg / cm 2 , about 2.5pg / cm 2 ~Approx. 35pg / cm 2 , about 0.15pg / cm 2 ~About 30pg / cm 2 , about 2.5pg / cm 2 ~About 30pg / cm 2 , about 0.15pg / cm 2 ~Approx. 25pg / cm 2 , about 2.5pg / cm 2 ~Approx. 25pg / cm 2 , about 0.15pg / cm 2 ~about 20pg / cm 2 , about 2.5pg / cm 2 ~about 20pg / cm 2 , about 0.15pg / cm 2 ~Approx. 15pg / cm 2 , about 2.5pg / cm 2 ~Approx. 15pg / cm 2 , about 0.15pg / cm 2 ~Approx. 10pg / cm 2 , about 2.5pg / cm 2 ~Approx. 10pg / cm 2 , about 0.15pg / cm 2 ~Approx. 5pg / cm 2 , about 2.5pg / cm 2 ~Approx. 5pg / cm 2 Of course, the surface density may vary depending on the size of the stopper 24.

[0087] As shown in FIG. 1 , stopper 24 contacts inner surface 36 of barrel 20 via one or more sealing ribs, although stopper 24 can have any number of sealing and / or non-sealing ribs. Generally, a breakaway force must be applied to initiate movement of stopper 24 within barrel 20. Breakaway force is often measured as a "wet" or "dry" value (i.e., filled with a liquid content, such as saline or water, and empty). Generally, such measurements are performed on a prefilled syringe ("wet") rather than an empty syringe ("dry"). Breakaway forces for prefilled syringes are typically 20 N or less. In various examples, the breakaway force is less than 15 N. In some prefilled syringes, the breakaway force is less than about 11 N, less than 9 N, less than 7 N, less than 5 N, or in the range of about 2 N to 5 N. For example, for a 0.5 mL syringe, the target breakout force (prefilled or "wet" syringe) is designed to be approximately 4 N, with an average range of 2 N to 8 N. Break or breakout force can be evaluated using a method similar to that described in Section 6 of ISO 11040-8. Also see Appendix E of ISO 11040-4 for sliding force measurement techniques that can be used to evaluate breakout force. Breakout force can be measured using a stopper travel speed of 250 mm / min within the barrel 20. U.S. Patent No. 10,369,292 to W.L. Gore & Associates, Inc. describes various expected breakout forces for prefilled syringes. U.S. Patent No. 9,220,631 to Juergen et al. also describes various expected breakout forces for prefilled syringes.

[0088] As shown, the piercing element 26 of the syringe 10 is coupled to the distal end 30 of the barrel 20. The piercing element 26 is optional, as the syringe 10 may be "needleless" and / or not be coupled to the barrel 20 if desired (e.g., in the case of an auto-injector device). When present, the piercing element 26 may be configured to pierce the patient's skin and inject the contents 12 into the patient.

[0089] 3A and 3B illustrate a prior art head design 46P for the head 46 of the plunger rod 22 (FIG. 1) and a prior art stopper design 24P for the stopper 24. FIGS. 3A and 3B are longitudinal cross-sectional views of the stopper 24P. The head 46P is configured to be axially inserted into a pocket 70P in the stopper 24P to couple the head 46P to the stopper 24P. FIG. 3A illustrates the head 46P in the pocket 70P when the stopper 24P is not in a compressed state, such as when disposed within the syringe barrel 20. In other words, FIG. 3A illustrates the stopper 24P in a relaxed state. FIG. 3B illustrates the shape and interface between the stopper 24P and the pocket 70P when the stopper 24P is received in a compressed state within the barrel 20 of the syringe 10. Thus, FIG. 3B is more representative than FIG. 3A with respect to the actual interaction between head portion 46P and stopper 24P when syringe 10 is assembled.

[0090] As shown, pocket 70P includes trap 80P having an enlarged diameter and coupling portion 84P having a reduced diameter relative to the enlarged diameter of coupling portion 84P. As shown, trap 80P has a constant diameter and is cylindrical, then tapers distally, i.e., is conical. Trap 80P extends the remainder of pocket 70P and is cylindrical and has a constant diameter.

[0091] The head portion 46P, in turn, includes a tapered crown 90P having a first diameter, an enlarged segment 94P defining a retention feature 96P, and a reduced diameter reduction segment 98P, which has a smaller diameter than the enlarged segment 94P. FIG. 3E shows an enlarged view of the head portion 46P. As shown in FIG. 3E, in one embodiment, the head portion 46P has an outer diameter of approximately 2.1 mm (e.g., 2.06 mm) at the retention feature 96P and a coupling length C of approximately 5.1 mm, for example. The combined length Lte of the tapered crown 90 and the enlarged feature 96P is approximately 1.6 mm, for example, although various dimensions are contemplated. As shown in FIG. 3B, the enlarged segment 94P engages with the catch 80P, the retention feature 96P engages with the coupling portion 84P, and the reduction segment 98P also engages with the coupling portion 84P. These various engagements couple stopper 24 to head 46P, but require a significant axial insertion force Fi to insert head 46P into pocket 70P. The insertion force Fi in the prior art design shown in FIG. 3B is expected to exceed the breakaway force associated with stopper 24.

[0092] With regard to the interaction of the prior art pocket 70P and head 46P, it has been observed that during insertion, if the axial insertion force Fi on the plunger rod 22 required to insert the head 46P into the pocket 70P exceeds the breakaway force between the stopper 24P and the barrel 20, the stopper 24P may move or be displaced within the syringe 10. If the breakaway force is exceeded, the prior art stopper design 24P may move distally within the barrel 20, risking ejection of the contents 12 and / or other undesirable effects (e.g., loss of the seal).

[0093] 3C and 3D illustrate stopper designs for the syringe of FIG. 1, shown in a more generalized manner for ease of reference. For example, in FIGS. 3C and 3D, the stopper is shown without sealing ribs, although such a feature is expressly contemplated. In general, FIGS. 3C and 3D illustrate improved stopper designs usable with heads similar to head 46P, or alternative head designs that facilitate assembly without requiring high axial insertion forces Fi (e.g., insertion forces Fi that are lower than the withdrawal forces associated with the design of stopper 24, and more generally, the design of syringe 10). The stopper design of FIG. 3C generally illustrates mating projections or ridges (also called ribs) for mating, while FIG. 3D generally illustrates mating recesses or valleys for mating to stopper rod 22.

[0094] As shown in the designs of FIGS. 3C and 3D , the stopper 24 is provided with a pocket 70 that facilitates reducing the insertion force Fi. As shown, the stopper 24 is in a relaxed, or uncompressed, state (compared to the compressed state of the stopper 24 after insertion into the barrel 20). Various features of the stopper 24 discussed above with reference to FIG. 1 can be applied to the designs of FIGS. 3C and 3D as desired. As shown, the pocket 70 includes a trap portion 80 having a first diameter D1, a relief portion 82 having a second diameter D2, and a coupling portion 84 having a third diameter D3 between the trap portion 80 and the relief portion 82. For reference, in the case of FIG. 3C , the diameter D3 is generally measured to correspond to the minimum diameter of the pocket 70 in the trap 80 defined by the coupling protrusion 88. In the case of FIG. 3C , the third diameter is smaller than the first and second diameters. In the case of FIG. 3D , the diameter D3 is generally measured to correspond to the maximum diameter of the pocket in the trap 80 defined by the coupling recess 88. 3C, the body 60 has an inner surface 68 including one or more coupling protrusions 88 corresponding to the coupling portions 84 of the pocket 70. In addition, in FIG. 3D, the body 60 has an inner surface 60 including one or more coupling recesses 88 corresponding to the coupling portions 84 of the pocket 70.

[0095] As shown, the first diameter is approximately the same as the second diameter. In some embodiments of the design of FIG. 3C , the third diameter (including the coupling protrusions 88) is at least 1% smaller, at least 2% smaller, at least 3% smaller, at least 4% smaller, at least 5% smaller, at least 6% smaller, at least 7% smaller, at least 8% smaller, at least 9% smaller, at least 10% smaller, at least 13% smaller, at least 15% smaller, at least 18% smaller, or at least 20% smaller than the first diameter and / or the second diameter, or any value or range between any of the foregoing values. In one non-limiting example, the first and second diameters are approximately 2.4 mm inner diameters and the third diameter is 2.05 mm inner diameter before being compressed within the barrel 20. In other examples, one or more coupling protrusions protrude approximately 0.175 mm (on each side) relative to the periphery of the stopper 24. Thus, in some embodiments of the coupling protrusion, the third diameter differs from the first diameter and / or the second diameter by, for example, about 0.3 mm, 0.1 mm to 0.6 mm, 0.2 mm to 0.5 mm, or 0.3 mm to 0.4 mm, although various dimensions are contemplated.

[0096] 3D design, the third diameter (including the bonding recess 88) is at least 1% larger, at least 2% larger, at least 3% larger, at least 4% larger, at least 5% larger, at least 6% larger, at least 7% larger, at least 8% larger, at least 9% larger, at least 10% larger, at least 13% larger, at least 15% larger, at least 18% larger, or at least 20% larger than the first diameter and / or the second diameter, or any value or range between any of the foregoing percentages. Thus, in some embodiments relating to the bonding recess, the third diameter differs from the first diameter and / or the second diameter by, for example, about 0.3 mm, 0.1 mm to 0.6 mm, 0.2 mm to 0.5 mm, or 0.3 mm to 0.4 mm, although various dimensions are contemplated.

[0097] As shown in FIG. 3C , one or more of the coupling protrusions 88 include a circumferential ridge (also referred to as a rib). As shown, a second coupling protrusion (designated by reference numeral 89 for ease of reference) having a larger diameter than coupling protrusion 88 may be provided. The circumferential ridge optionally extends continuously along the periphery of pocket 70. One or more of the coupling protrusions 88 may additionally or alternatively include a longitudinal ridge (not shown) similar to those described in connection with other pocket designs herein. As shown in FIG. 3C , coupling protrusion 88 has a leading edge 100 and a trailing edge 102. In some embodiments, at least leading edge 100 is at least one of angled and rounded. As shown in FIG. 3C , leading edge 100 and trailing edge 102 are each rounded. The rounding or angling of leading edge 100 can help reduce the axial insertion force Fi required to insert plunger rod 22 into stopper 24.

[0098] As shown in FIG. 3D , one or more of the bonding recesses 88 include a circumferential valley. As shown in FIG. 3D , there is a second bonding recess (designated with reference numeral 89 for ease of reference) that is smaller in diameter than the bonding recess 88. The circumferential valley optionally extends continuously along the periphery of the pocket 70. The one or more bonding recesses 88 may additionally or alternatively include a longitudinal recess or valley (not shown) similar to those described herein with respect to other pocket designs. For reference, the diameter D3 is generally measured to correspond to the maximum diameter of the pocket 70 at the catch 80 defined by the bonding recess 88. As shown in FIG. 3D , the bonding recess 88 has a leading edge 100 and a trailing edge 102. In some embodiments, at least the leading edge 100 is angled and / or rounded. As shown in FIG. 3D , the bonding recess 88 has a leading edge 100 and a trailing edge 102. 3D, the leading edge 100 and the trailing edge 102 are each rounded. The rounding or angling of the leading edge 100 and / or the trailing edge 102 can help reduce the axial insertion force Fi required to insert the plunger rod 22 into the stopper 24.

[0099] Generally, and in each of the following examples, the effectiveness of a coupling 84 is characterized by the overall length or axial dimension of the largest coupling protrusion or recess, as applicable. In Figure 3C, a second, smaller coupling protrusion (i.e., less inwardly protruding) is shown in dashed lines, and in Figure 3D, a second, smaller (i.e., less outwardly protruding) coupling recess is shown in dashed lines, but neither contributes to the calculation of the respective maximum coupling length ratios described below.

[0100] 3C and 3D, each pocket 70 can have a substantially smooth or feature-free surface, except for the mating protrusions 88, 89 or mating recesses 88, 89, respectively. In other words, the walls of the pocket 70 can be substantially cylindrical (e.g., a right cylinder, or a non-tapered cylinder, including a slight taper, such as 1-5 degrees, for ease of molding, or a conical or relatively more tapered cylinder, as desired), except for the mating protrusions / recesses. This smooth or feature-free pocket (except for variations introduced by the mating features) can be carried over to each design described below.

[0101] In the case of a circumferential ridge (also called a rib) or recess (also called a valley), the performance of the coupling protrusion 88 or coupling recess 88 can be evaluated as the ratio of the axial length of the largest ridge or recess to the overall length of the pocket. As shown in FIG. 3C , the largest coupling protrusion 88 (e.g., the protrusion defining the smallest overall diameter within the pocket) has a linear axial distance, or protrusion length Lp, corresponding to the overall height of the largest coupling protrusion 88. When multiple coupling protrusions 88 have the same diameter, the one with the longest or largest axial protrusion length Lp is used to determine Lp. For reference, Lp is measured from the proximal and distal transition points between the maximum diameters of the pocket 70 adjacent to the coupling protrusion 88. In other words, it is the edge where the coupling protrusion 88 begins to protrude inward into the pocket 70. On the other hand, the stop pocket defines an overall linear axial distance, or height L. The ratio of Lp to L, mathematically expressed as Lp / L, is called the "maximum coupling length ratio" and directly affects the insertion force Fi. For reference, FIG. 3A shows the protrusion length Lp corresponding to the narrowed region of the stopper 24P and the pocket length L of the stopper 24P.

[0102] Similarly, as shown in FIG. 3D , the largest coupling recess 88 has a linear axial distance, or recess length, Lr, that corresponds to the overall height of the largest coupling recess 88. Again, when multiple recesses have the same diameter, Lr is selected for the coupling recess 88 having the longest axial length. Lr is measured from the proximal and distal transitions between the smallest diameters of the pockets 70 adjacent to the coupling recess 88. In other words, it is the edge where the coupling recess 88 begins to protrude outward from the surrounding pocket 70. Meanwhile, the stop pocket 70 defines an overall linear axial distance, or height, L. The ratio of Lr to L, mathematically expressed as Lr / L, directly affects the insertion force, Fi, also referred to as the “maximum coupling length ratio.”

[0103] In various examples, stopper 24 is configured to exhibit an insertion force, Fi, that is less than 75% of the breakaway force of stopper 24 when received in syringe barrel 20, and in some cases, less than or equal to 50% of the breakaway force of stopper 24 when received in syringe barrel 20. For example, stopper 24 may be characterized by an Lp / L value that is greater than 0 (e.g., 0.05) and less than or equal to 0.5, optionally less than or equal to 0.3, optionally less than or equal to 0.2, or optionally less than or equal to 0.1 to achieve the reduced insertion force, Fi. In some embodiments, the Lp / L value is, for example, between 0.1 and 0.2, although various values ​​are contemplated. Substantially the same values ​​are also contemplated for Lr / L values. Specifically, stopper 24 may be characterized by an Lr / L value that is greater than 0 (e.g., 0.05) and less than or equal to 0.5, optionally less than or equal to 0.3, or optionally less than or equal to 0.2, or optionally less than or equal to 0.1 to achieve the reduced insertion force, Fi.

[0104] Examples 1 and 2 described below include various values ​​of maximum bond length ratio for various bond protrusion designs shown and described in the various figures.

[0105] The stopper 24 can include an elastomeric body defined by an outer surface, optionally having one or more ribs, and an inner surface that defines an internal cavity. The elastomeric body can be formed from a variety of elastomeric materials, including, but not limited to, butyl, bromobutyl, chlorobutyl, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomers, thermoplastic elastomers (TPEs), thermoplastic vulcanizates (TPVs), silicone, materials sold under the trademark VITON®, and combinations and blends thereof. Exemplary elastomeric materials include, but are not limited to, butyl rubber, bromobutyl rubber, chlorobutyl rubber, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomers, and combinations thereof.

[0106] In some embodiments, stopper 24 can include an outer layer material or coating to reduce friction as the stopper slides within the syringe barrel. Suitable materials for use as the outer layer include, but are not limited to, polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), densified expanded polytetrafluoroethylene, fluorinated ethylene propylene (FEP), perfluoroalkoxy (PFA), tetrafluoroethylene-hexafluoropropylene-vinylidene fluoride terpolymer (THV), polyethylene, polypropylene, polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymers, and copolymers and combinations thereof.

[0107] The outer layer can also include a composite fluoropolymer film having a barrier layer and a porous layer. The porous layer can be formed, for example, from ePTFE or other porous expanded fibrillating fluoropolymer (e.g., ePTFE as described in U.S. Pat. No. 6,541,589 to Baille). The ePTFE layer can be filled with organic or inorganic materials to provide color, lubricity, or other functionality.

[0108] As mentioned above, in some embodiments, the outer layer can comprise a densified expanded fluoropolymer, such as, but not limited to, densified expanded polytetrafluoroethylene (ePTFE). Densified ePTFE films can be produced by methods described in U.S. Patent No. 7,521,010 to Kennedy et al., U.S. Patent No. 6,030,694 to Dolan et al., U.S. Patent No. 5,792,525 to Fuhr et al., or U.S. Patent No. 5,374,473 to Knox et al. Expanded (expanded, expanded, stretched or foamed) copolymers of PTFE, such as those described in U.S. Pat. No. 5,708,044 to Branca et al., U.S. Pat. No. 6,541,589 to Baillie, U.S. Pat. No. 7,531,611 to Sabol et al., U.S. Pat. Publication No. 2009 / 0093602 to Ford, U.S. Pat. Application No. 12 / 410,050 to Xu et al., and U.S. Pat. Publication No. 2010 / 0248324 to Xu et al., are available if densified.

[0109] In some embodiments, the outer layer can also include an expanded polymer material comprising a functionalized tetrafluoroethylene (TFE) copolymer material having a microstructure characterized by nodes interconnected by fibrils, where the functionalized TFE copolymer material includes a functionalized copolymer of TFE and PSVE (perfluorosulfonyl vinyl ether), or a functionalized TFE copolymer material of TFE and other suitable functional monomers (such as, but not limited to, vinylidene fluoride (VDF), vinyl acetate, or vinyl alcohol). The functionalized TFE copolymer material can be prepared, for example, according to the methods described in U.S. Patent Publication No. 2010 / 0248324 to Xu et al. or U.S. Patent Publication No. 2012 / 035283 to Xu et al.

[0110] 4A-15C illustrate improved stopper designs that can be used with heads similar to head 46P, or alternative head designs that facilitate assembly without the need for high axial insertion forces F for rod coupling that exist in the prior art. In other words, the various stopper pocket designs shown in FIGS. 4A-15C facilitate rod insertion for coupling stopper rod 22 to stopper 24 without exceeding the breakaway force between stopper 24 and barrel 20.

[0111] 4A and 4C are longitudinal cross-sectional views of the stopper 24 of FIGS. 1 and 2, each including a pocket 70A that facilitates a reduced insertion force F. FIG. 4A shows the stopper 24 in a relaxed, or uncompressed, state. FIG. 4C shows the stopper 24 in a compressed state (the state typically found within the barrel 20) with the head portion 46P inserted into the pocket 70A. The various features of the stopper 24 discussed above with reference to FIG. 1 are applicable to the design of FIGS. 4A and 4C, except for the additional details shown and described for the pocket 70A, and will not be further described. For reference, additional pocket designs are provided, and similar reference numbers will be used to indicate similar features in the following description and / or drawings. For example, pocket 70B is also shown and described, and features similar to those of pocket 70A will be designated in the description and / or drawings with the same reference number as pocket 70A followed by a "B" to indicate the presence of a feature similar to or having similar properties as the previously described feature.

[0112] 4A, pocket 70A includes a trap portion 80A having a first diameter, a relief portion 82A having a second diameter, and a mating portion 84A between trap portion 80A and relief portion 82A and having a third diameter smaller than the first and second diameters. Inner surface 68A of body 60 includes one or more mating protrusions 88A that correspond to mating portion 84A of pocket 70A.

[0113] As shown, the first diameter is approximately the same as the second diameter. In some embodiments, the third diameter is at least 1% smaller than the first diameter and / or the second diameter. In one example, the first diameter and the second diameter are approximately 2.4 mm inner diameters, and the third diameter prior to compression within barrel 20 is 2.05 mm inner diameter. In other examples, one or more coupling projections protrude approximately 0.175 mm (on each side) relative to the periphery of stopper 24.

[0114] As shown in FIG. 4A , one or more coupling protrusions 88A include a circumferential ridge (also referred to as a rib). The circumferential ridge optionally extends continuously along the periphery of the pocket 70A. The one or more coupling protrusions 88A may additionally or alternatively include a longitudinal ridge (not shown), such as any of those described in connection with other pocket designs herein. As shown in FIG. 4A , the coupling protrusions 88A include a leading edge 100A and a trailing edge 102A. In some embodiments, at least the leading edge 100A is angled and / or rounded. As shown in FIG. 4A , the leading edge 100A and the trailing edge 102A are each rounded. The rounding or angling of the leading edge 100A can help reduce the axial insertion force Fi required to insert the plunger rod 22 into the stopper 24.

[0115] 4B is an enlarged view of the vicinity of coupling protrusion 88A. As shown, the largest (and only) coupling protrusion 88A has a linear axial distance, or protrusion length, Lp, corresponding to the overall height of coupling protrusion 88A. Lp is measured from the proximal and distal transitions between the maximum diameters of pocket 70 adjacent coupling protrusion 88. In other words, it is the edge where coupling protrusion 88 begins to protrude into pocket 70 (which roughly corresponds to the origin of leading edge 100A and trailing edge 102A). The stop pocket, in turn, defines the overall linear axial distance, or height, L. As previously mentioned, the ratio of Lp to L, mathematically expressed as Lp / L, is referred to as the "maximum coupling length ratio" and directly affects insertion force Fi.

[0116] 4C shows the compressed stopper 24, illustrating pocket 70A as it would typically appear when interacting with head 46 of plunger rod 22, for example, due to the design of head 46P. As shown, retention feature 96P engages mating portion 84A of pocket 70A, coupling plunger rod 22 to stopper 24 with head 46P received in catch 80A of stopper 24.

[0117] During insertion into pocket 70A, tapered crown 90P slidably engages coupling protrusion 88A of coupling portion 84A as head portion 46P is inserted into pocket 70A of stopper 24. Stopper 24, including pocket 70A, is configured such that, when stopper 24 is received in barrel 20 (FIG. 1), head portion 46P can be axially inserted into stopper 24 with an insertion force Fi, which is smaller than the removal force (e.g., when the removal force is 2N to 20N). After insertion, head portion 46P is captured by capture portion 80A of pocket 70A.

[0118] To separate the head portion 46P from the pocket 70A, a non-zero longitudinal separation force must be applied between the stopper 24 and the plunger rod 22, and the retention feature 96P must be pulled back onto the mating portion 84A of the pocket 70A to separate the components. As shown, the smooth surface of the tapered crown facilitates insertion of the retention feature 96P onto the mating projection 88A, reducing the required axial insertion force, while the relatively hard or angled edges of the retention feature 96P prevent the head portion 46P from being pulled back onto the mating projection 88A once it is seated in the catch 80A. In some embodiments, the separation force is greater than 2 N. In some embodiments, the separation force exceeds or is greater than the breakaway force. For reference, the axial insertion force is distinct from the rotational or torsional insertion force required for a threaded engagement. The embodiments described herein contemplate an axial insertion assembly method, rather than a threaded assembly method.

[0119] In various examples, the rod stopper assemblies described herein can rotate relative to one another without causing relative axial movement between the two components. Additionally, in various examples, the rod stopper assemblies described herein can rotate freely relative to one another after assembly (i.e., the absence of threads allows free rotation between the rod and stopper, according to some examples). In other embodiments, the interaction between the assembled plunger rod 22 and stopper 24 prevents relative rotation after the plunger rod 22 is inserted into the stopper 24 to couple the two components.

[0120] For reference, the embodiments described herein can be utilized with equipment used to attach a plunger rod to a stopper that includes a twisting / screw motion (where the barrel 20 and stopper 24 rotate on the plunger rod 22 with axial movement). This twisting motion can also be present in “push-in” plunger rods similar to those described herein. In any event, in various examples, the plunger rod 22, and more specifically the head portion 46, is pushed axially past one or more mating projections on the stopper 24 rather than threaded past the one or more mating projections on the stopper 24.

[0121] 5-10A are longitudinal cross-sectional views illustrating several design variations of pockets 70 configured to achieve a similar result of an axial insertion force Fi that is lower than the associated withdrawal force of stopper 24. FIG.

[0122] FIG. 5 is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, including a pocket 70B that facilitates a lower insertion force Fi than pocket 70P. FIG. 5 illustrates one or more coupling protrusions 88B that include a circumferential ridge (also called a rib) that is smaller (narrower) than coupling protrusion 88A (FIG. 4A). This ridge defines approximately the same inner diameter as the ridge of pocket 70A. From this (and from the additional examples below), it should be understood that various dimensions of the coupling protrusions are contemplated. Like coupling protrusion 88A, the circumferential ridge extends continuously around the periphery of pocket 70B. Pocket 70B otherwise operates similarly to pocket 70A, except that due to the smaller profile of coupling protrusion 88A, on average, pocket 70B will have a lower axial insertion force Fi than pocket 70A, and the associated separation force is expected to be similarly lower.

[0123] FIG. 6 is a longitudinal cross-sectional view of stopper 24 of FIGS. 1 and 2, including pocket 70C, which promotes a lower insertion force, F, than pocket 70P. FIG. 6 illustrates one or more coupling protrusions 88C, which include a circumferential ridge (also referred to as a rib) that is larger in size (wider) than coupling protrusions 88A (FIG. 4A) and 88B (FIG. 5). Like coupling protrusions 88A and 88B, the circumferential ridge extends continuously along the periphery of pocket 70C. Pocket 70C otherwise operates similarly to pockets 70A and 70B, except that due to the larger (wider) profile of coupling protrusion 88A, the axial insertion force, F, is expected to be higher on average than pockets 70A and 70B, and the associated separation force will be similarly higher.

[0124] FIG. 7 is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, which includes a pocket 70D that facilitates a lower insertion force Fi than pocket 70P. FIG. 7 illustrates one or more coupling protrusions 88D with a larger (wider) circumferential ridge (also called a rib) than coupling protrusions 88A (FIG. 4A), 88B (FIG. 5), and 88C (FIG. 6). Like coupling protrusions 88A, 88B, and 88C, this circumferential ridge extends continuously along the periphery of pocket 70D. In other respects, pocket 70D operates similarly to pockets 70A, 70B, and 70C. As shown, coupling protrusion 88D has a relatively flat peak, or apex. The flattening design of coupling protrusion 88D, in particular, allows this flattening to be applied to the narrower peak, or apex, of coupling protrusion 88A.

[0125] Flattening one or more of the coupling protrusions 88 can increase the stiffness of the coupling protrusions, help reduce insertion force, and / or increase separation force. In other variations, thickening and / or lengthening the coupling protrusions can improve the manufacturing process, the strength or robustness of the coupling protrusions, and / or help increase separation force between the stopper 24 and the plunger rod 22. In some instances, larger radial features may exhibit greater stiffness than relatively small radial features and may be more susceptible to tearing during molding, coupling to, or separation from, the plunger rod 22.

[0126] FIG. 8 is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, including a pocket 70E that facilitates a lower insertion force Fi than pocket 70P. FIG. 7 illustrates one or more coupling protrusions 88E that include circumferential ridges (also called ribs) of various sizes or configurations (narrower, wider, less pronounced, more pronounced, rounded peaks, flat peaks, etc.). However, as shown, coupling protrusion 88E is located more proximally than coupling protrusions 88A, 88B, 88C, and 88D. Like the coupling protrusions previously described, circumferential ridge 88E (also called ribs) extends continuously along the periphery of pocket 70E. Pocket 70E operates similarly to the previously described pockets, except that catch 80E is substantially longer than the other embodiments, thereby providing distal-to-proximal play or displacement for head 46P (not shown) when fully inserted into catch 80E, compared to other embodiments that include coupling protrusions that directly engage retention feature 96P (not shown). This feature facilitates a desired amount of proximal sliding or displacement before retention feature 96P engages coupling protrusion 88E and prevents further movement between the components. In this manner, stopper 24 and plunger rod 22 remain coupled and can only be separated by application of a separation force similar to that described above, while still allowing relative axial displacement between the two components.

[0127] FIG. 9 is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, including a pocket 70F that facilitates a lower insertion force F than the pocket 70P during mating of the stopper 24 and the plunger rod 22. FIG. 9 illustrates a plurality of mating projections 88F, which include a plurality of circumferential ridges (also called ribs) of any of the aforementioned sizes or configurations (narrower, wider, less pronounced, more pronounced, rounded peaks, flat peaks, or other variations). As shown, the plurality of mating projections 88F includes one more proximally located ridge (also called a rib) and a second more distally located ridge (e.g., in a position similar to that of mating projections 88A, 88B, 88C, and 88D). In at least this way, at least one mating projection 88F directly engages a retention feature 96P (not shown) when the head portion 46P (not shown) is fully inserted into the catch 80F. This mechanism can facilitate a higher degree of engagement (e.g., a higher separation force) without substantially increasing the attendant axial insertion force Fi required to insert the head portion 46P to couple the stopper 24 and plunger rod 22.

[0128] FIG. 10A is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, which includes a pocket 70G that facilitates a lower insertion force Fi when mating the stopper 24 with the plunger rod 22 than the pocket 70P of FIG. 3B. FIG. 10B is an end view of the pocket 70G, illustrating features of the pocket 70G from a different perspective than FIG. 10A. As shown, the pocket 70G includes one or more mating projections 88G, which include a plurality of longitudinal ridges (also called ribs) having any of the aforementioned sizes or configurations (narrower, wider, more or less pronounced, rounded peaks, flat peaks, or other variations). As shown, the plurality of mating projections 88G include a plurality of longitudinal ridges (also called ribs) circumferentially spaced apart from one another. In other words, the longitudinal ridges are discretely spaced apart around the periphery of the pocket 70G. As shown, the ridges are equidistant from one another and similarly configured (sized and shaped), although it should be understood that these configuration variables, including the number of ridges (e.g., six shown), can be varied as desired.

[0129] Each ridge has a leading edge 100G and a trailing edge 102G. As previously described, at least one of the leading edges 100G may be angled and / or rounded. As shown, each leading edge 100G and trailing edge 102G of each ridge is rounded. Making the leading edges 100G rounded or angled can help reduce the axial insertion force Fi required to insert the plunger rod 22 into the stopper 24. In various examples, the trailing edge 102G of each coupling protrusion 88G is positioned to directly engage a retention feature 96P (not shown) when the head 46P (not shown) is fully inserted into the catch 80G to couple the stopper 24 and plunger rod 22.

[0130] 11A-13B provide further examples of coupling protrusion designs or configurations according to some embodiments.

[0131] For example, Fig. 11A is a longitudinal cross-sectional view showing the stopper 24 of Figs. 1 and 2, with a modified number of coupling protrusions 70G compared to Figs. 10A and 10B. The pocket 70G of Fig. 11A facilitates not only the insertion force F of Figs. 10A and 10B but also a lower insertion force F than that exhibited by the pocket 70P when the stopper 24 is coupled to the head portion 70P. Fig. 11B is an end view of the pocket 70G showing features of the pocket 70G from a different perspective than Fig. 11A. As shown in Figs. 11A and 11B, the pocket 70G includes one or more coupling protrusions 88G, which include a plurality of longitudinal ridges (also called ribs) having any of the aforementioned sizes or configurations (narrower, wider, more or less pronounced, rounded peaks, flat peaks, etc.). In the example of FIGS. 11A and 11B, one or more coupling protrusions 88G include longitudinal ridges (also called ribs) configured similarly to those described in connection with FIGS. 10A and 10B, but with fewer ridges (three as shown). The number and configuration of the longitudinal ridges or grooves can generally be varied to help provide desired separation force performance while reducing the axial force of insertion. Such longitudinal ridges or grooves can also be useful in combined torsional and axial mounting (although such mounting is still in contrast to a threaded mounting). Otherwise, the pocket 70G of FIGS. 11A and 11B operates substantially similarly to the pocket 70G of FIGS. 10A and 10B, in some cases, and has similar features and functionality.

[0132] Because a fewer number of coupling protrusions 70G (e.g., three evenly spaced apart) than those shown in FIGS. 10A and 10B are incorporated, the modified pocket 70G according to FIGS. 11A and 11B may have a lower axial insertion force Fi and a lower separation force than the configurations of FIGS. 10A and 10B. In the examples of FIGS. 11A and 11B, the coupling protrusions are spaced apart (e.g., equally spaced) by a greater distance than shown in FIG. 10A. For example, in FIG. 10A, the coupling protrusions 88G may be spaced apart by 0.5 to 1.5 times the width of the coupling protrusions 88G. As shown in FIGS. 11A and 11B, the coupling protrusions 88G may be circumferentially spaced apart by a distance greater than twice the width of the coupling protrusions 88G.

[0133] FIG. 12A is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, which includes a pocket 70H that facilitates a lower insertion force Fi than the pocket 70P during mating of the stopper 24 with the head portion 46P. FIG. 12B is an end view of the pocket 70H, illustrating the features of the pocket 70H from a different perspective than that of FIG. 12A. As shown, the pocket 70H includes one or more mating projections 88H (e.g., three evenly spaced apart), which include a plurality of circumferentially extending ridges (also referred to as ribs) having any of the aforementioned sizes or configurations (narrower, wider, more or less pronounced, rounded peaks, flat peaks, etc.), which are aligned circumferentially and spaced apart from one another. Apart from the spacing between the ridges, the circumferential ridges operate substantially similarly and have similar function and characteristics to the pocket 70D ( FIG. 7 ) (which includes the wider, flatter shape of the circumferential ridges).

[0134] FIG. 13A shows another example longitudinal cross section of the stopper 24 of FIGS. 1 and 2, including a pocket 70J that facilitates a lower insertion force Fi than the pocket 70P during mating of the stopper 24 with the head portion 70P. FIG. 13B is an end view of the pocket 70J from a different perspective than FIG. 13A, illustrating the features of the pocket 70J. As shown, the pocket 70J includes one or more coupling protrusions 88J similar to the coupling protrusions 70J of FIGS. 12A and 12B, but with more segments (and thus more coupling protrusions 70J, e.g., six total) than in FIGS. 12A and 12B. The coupling protrusions 70J are circumferentially aligned and spaced a desired distance from one another. The ridges (also called ribs) shown in FIGS. 13A and 13B operate substantially similarly to the previous examples and have similar functions and characteristics, except that they have a relatively short longitudinal length and a wider, flatter shape than grooved or longitudinally extending ridge designs.

[0135] 10A-13B include circumferentially discontinuous and / or circumferentially spaced longitudinally extending coupling protrusions. Circumferentially spacing the coupling protrusions allows the coupling protrusions to radially expand or deform somewhat (or close the gaps between the coupling protrusions) during insertion of the plunger rod 22, helping to reduce the required axial insertion force. In other words, these grooved designs (spaced longitudinally oriented coupling protrusions) or discontinuous circumferential designs (spaced circumferentially oriented coupling protrusions) promote greater deformation of the stopper 24 at the coupling protrusions, reducing the expected insertion force.

[0136] 14-15B show an alternative design that includes a mating recess rather than a mating protrusion for engaging head portion 46P or other head portions as desired.

[0137] FIG. 14 is a longitudinal cross-sectional view of stopper 24 of FIGS. 1 and 2, which includes pocket 70K that facilitates a lower insertion force Fi during mating of stopper 24 with head portion 46P than pocket 70P.

[0138] 14, pocket 70K includes a trap portion 80K having a first diameter, a relief portion 82K having a second diameter, and a coupling portion 84K between trap portion 80K and relief portion 82K and having a third diameter greater than the first and second diameters in each of the one or more recesses associated with coupling portion 84K. In particular, inner surface 68K of body 60 includes one or more coupling recesses 88K corresponding to coupling portions 84A of pocket 70A.

[0139] As shown, the first diameter is approximately the same as the second diameter. In some embodiments, the third diameter is at least 10% larger than the first diameter and / or the second diameter. In some embodiments, the third diameter is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 13%, at least 15%, at least 18%, or at least 20% larger than the first diameter and / or the second diameter. In one example, when the stopper 24 is in a compressed state within the barrel 20, the third diameter is approximately 2.8 mm. In such an example, the stopper 24 can be mated with a plunger rod head having a retention feature defining an outer diameter of, for example, approximately 2.4 mm, 2.6 mm, or 2.8 mm, depending on the desired engagement between the stopper 24 and the plunger rod head 46. In another example, the first and second diameters have an outer diameter of about 2.05 mm and the third diameter has an outer diameter of 2.4 mm before being compressed within barrel 20. In some other examples, one or more of the coupling projections are recessed (on each side) relative to the periphery of stopper 24 by about 0.175 mm.

[0140] As shown in FIG. 14 , the one or more coupling recesses 88K include one or more circumferential recesses (e.g., generally valley-shaped recesses as shown). The circumferential recesses optionally extend continuously along the periphery of the pocket 70K. The one or more coupling recesses 88K may additionally or alternatively include longitudinal recesses (not shown), such as any of those described herein in connection with FIGS. 15A and 15B . As shown in FIG. 14 , the coupling recess 88K has a leading edge 100K and a trailing edge 102K. In some embodiments, at least the leading edge 100K is angled and / or rounded. As shown in FIG. 14 , the leading edge 100K and the trailing edge 102K are each rounded.

[0141] FIG. 14 shows the stopper 24 uncompressed, and therefore shows the pocket 70A as it would typically be seen prior to insertion into the barrel 20 and actual interaction with the head portion 46 of the plunger rod 22.

[0142] During insertion into the pocket 70K, the tapered crown 90P is slidably received within one or more coupling recesses 88K of the coupling portion 84K after the head portion 46P is inserted into the pocket 70K of the stopper 24. In particular, the retention feature 96P of the head portion 46P can be received in one of the one or more coupling recesses 88K. The stopper 24, including the pocket 70K, is configured such that, with the stopper 24 received in the barrel 20 (FIG. 1), the head portion 46P can be axially inserted into the stopper 24 with an insertion force Fi that is less than the removal force (e.g., when the removal force is 2 N to 20 N). After insertion, the head portion 46P can be captured in the capture portion 80K of the pocket 70K.

[0143] To separate the head portion 46P from the pocket 70K, a non-zero longitudinal separation force must be applied between the stopper 24 and the plunger rod 22 to separate the components by withdrawing the retention feature 96P from one or more of the mating recesses 88K in the pocket 70K. As shown, the smooth surface of the tapered crown facilitates insertion of the retention feature 96P into the mating portion 84K and one or more of the mating recesses 88K, reducing the required axial insertion force, while the relatively hard or angled edges of the retention feature 96P prevent backout of the head portion 46P from the mating portion 84K once it is seated in the catch 80A. As previously mentioned, in some embodiments, the separation force is greater than 2N. In some embodiments, the separation force exceeds or is greater than the breakaway force. For reference, the axial insertion force is distinct from the rotational or twisting insertion force required for threaded engagement.

[0144] As previously mentioned, the embodiments described herein are provided for an axial insertion assembly method, rather than a threaded screw-in assembly method. Again, the embodiments described herein can be utilized in devices with a twisting / threading motion (where the barrel 20 and stopper 24 rotate relative to the plunger rod 22 with axial movement) used to attach the plunger rod to the stopper. This twisting motion can also be present in “push-in” plunger rods similar to those described herein. In any event, in various examples, the plunger rod 22, and more specifically the head portion 46, is pushed axially past one or more mating projections on the stopper 24, rather than threaded thereover.

[0145] 15A and 15B show longitudinal cross-sectional views of design variations of the longitudinally oriented or grooved recesses of the pocket 70, which are also configured to achieve a similar result of an axial insertion force Fi that is lower than the associated breakaway force of the stopper 24.

[0146] FIG. 15A is a longitudinal cross-sectional view of the stopper 24 of FIGS. 1 and 2, including a pocket 70L that facilitates a lower insertion force Fi than pocket 70P. Other than the longitudinal orientation of the recess, the features of pocket 70L are substantially similar to the features of pocket 70K. FIG. 15A illustrates one or more mating recesses 88L that include one or more longitudinally extending mating recesses (e.g., valley-shaped recesses). The multiple longitudinal recesses may have any of the aforementioned sizes or configurations (narrower, wider, more or less pronounced, rounded peaks, flattened peaks, or other variations). As shown, the multiple mating recesses 88L include multiple longitudinal valley-like depressions or recesses circumferentially spaced from one another. As shown, the recesses are equidistant from one another and similarly configured (size and shape), but it should be understood that these configuration variables, including the number of recesses (e.g., four in the design of FIG. 15A), can be varied as desired. FIG. 15B is a cross section through one or more of the docking recesses 88L, showing how the recesses may be synchronously positioned or spaced apart from one another.

[0147] Each coupling recess 88L has a leading edge 100L and a trailing edge 102L. As previously described, the leading edge 100L can be angled and / or rounded. As shown, the leading edge 100L and the trailing edge 102L of each recess are each rounded. In various examples, the leading edge 100L and / or the trailing edge 102L of each coupling recess 88L can be positioned to directly engage the plunger rod 22 when the plunger rod 22 is fully inserted into the capture 80L and the stopper 24 and plunger rod 22 are coupled together.

[0148] Figures 16-18B show alternative head designs for plunger rod 22. Any of the stopper designs previously described can be used with the head designs shown in Figures 16-18.

[0149] FIG. 16 is a longitudinal cross-sectional view showing the head portion 46A of the plunger rod 22 (FIG. 1), which facilitates reducing the insertion force Fi when coupling the plunger rod 22 to the stopper 24. FIG. 16 shows a small portion of the stopper 24 in compression around the pocket 70F (see FIG. 9 and related description). In one example, the head portion 46A has a maximum outer diameter OD at the retention feature 96A of, for example, about 2.06 mm, 2.1 mm, 2.2 mm, or 2.3 mm, depending on the desired engagement with the corresponding design of the stopper 24, specifically the required axial insertion force Fi and separation force.

[0150] Head portion 46A is configured to be axially inserted into a pocket (e.g., pocket 70F) of stopper 24 to couple head portion 46A to stopper 24. FIG. 16 shows head portion 46A in pocket 70F with stopper 24 in a compressed state similar to when disposed within syringe barrel 20.

[0151] Head portion 46A has a first diameter, terminates in a flat end, and has a tapered crown 90A extending to a first enlarged segment 94A, which has an abruptly reduced diameter defining a first retention feature 96A, and a second tapered segment that expands proximally and abruptly reduces in diameter at a proximal engaging segment 98A defining a second retention feature 97A. Proximal engaging segment 98A has a smaller diameter than first enlarged segment 94A and second enlarged segment 98A.

[0152] 16 (showing stopper 24 in a compressed state), first retention feature 96A and second retention feature 97A are configured to engage with a plurality of mating projections 88F of pocket 70F. These various engagements couple stopper 24 to head portion 46A, but require a lower axial insertion force Fi to insert head portion 46A into pocket 70A (e.g., lower than the breakaway force between stopper 24 and barrel 20, as discussed above), while still requiring a substantial, non-zero separation force to separate stopper 24 from head portion 46A.

[0153] 17 is a side view showing the head portion 46B (FIG. 1) of the plunger rod 22. The head portion 46B is configured to facilitate an insertion force Fi that is lower than the separation force between the stopper 24 and the barrel 20 when coupling the plunger rod 22 to the stopper 24, as described above.

[0154] Head portion 46B is configured to be axially inserted into a pocket (e.g., pocket 70k or a variation thereof) of stopper 24 to couple head portion 46B to stopper 24. As shown, head portion 46B has a tapered crown 90B having a first diameter and terminating in a flat end, and an enlarged segment 94B that increases in diameter to a peak and then decreases in diameter to a proximal engagement segment 98B, which has a smaller diameter than enlarged segment 94B.

[0155] In contrast to the design of FIG. 16 , which includes one or more sharp transitions to define a retention feature, the enlarged segment 94B tapers or increases in width or diameter proximally to a peak, then tapers or decreases in width or diameter proximally to the proximal engagement segment 98B. The enlarged segment 94B is configured to engage with an engagement portion of the stopper, such as the engagement portion 84K ( FIG. 14 ). For example, the enlarged segment 94B can define a retention feature 96B that engages with one of the one or more mating recesses 88K. While a relatively sharp apex defining the retention feature 96B is shown, a rounded apex or a squared apex, for example, can also be implemented. Furthermore, to facilitate mating of the plunger rod 22 to the stopper 24, multiple similar retention features can be positioned along the length of the head portion 46B corresponding to one or more mating recesses 88K of the pocket 70K ( FIG. 14 ). These various engagements couple the stopper 24 to the head portion 46B, but require an axial insertion force Fi that is lower than the separation force between the barrel 20 and the stopper 24 to insert the head portion 46B into a pocket 70 (e.g., pocket 70K), while still requiring a substantially non-zero separation force to separate the stopper 24 from the head portion 46B.

[0156] 18A is a side view illustrating the head portion 46C of the plunger rod 22, which facilitates coupling the plunger rod 22 to the stopper 24 with an insertion force Fi that is lower than the separation force Fi exhibited between the barrel 20 and the stopper 24. As shown, the head portion 46C includes one or more (e.g., four) retention features 96C in the form of surface protrusions defining longitudinally extending ridges (also referred to as ribs). The one or more retention features 96C can be configured or otherwise sized and shaped to be complementary to a coupling portion of the stopper 24, such as one or more coupling recesses 88G of the pocket 70G. In other words, the one or more retention features 96C can define a complementary fit with one or more coupling recesses 88G.

[0157] Head portion 46C can be configured to be axially inserted into a pocket of stopper 24 (e.g., pocket 70G, FIGS. 15A and 15B) to couple head portion 46C to stopper 24. For example, FIG. 18B is a longitudinal cross-sectional view showing head portion 46C within pocket 70G, with stopper 24 shown in a compressed state as disposed within syringe barrel 20.

[0158] As shown, head portion 46C terminates in a cylindrical segment with a flat end and has an enlarged segment 94C that is expanded in diameter by longitudinal surface protrusions that define one or more retention features 96C. As shown, when plunger rod 22 is inserted into stopper 24 in a compressed state (e.g., as in the assembly of the pre-filled syringe example), enlarged segment 94C engages catch 80G. This engagement couples stopper 24 to head portion 46C, but requires an axial insertion force Fi that is lower than the breakaway force between stopper 24 and barrel 20 to insert head portion 46C into pocket 70G, while still requiring a substantially non-zero separation force to separate stopper 24 from head portion 46C.

[0159] It will be appreciated that the various head designs and features described above may be combined and / or utilized with any of the various pocket designs described above.

[0160] Considering the above explanation, the method of assembling the plunger rod to the stopper can be explained as follows.

[0161] A method for coupling a plunger rod to a stopper disposed within a barrel of a syringe includes axially inserting a head portion of the plunger rod into a pocket of the stopper with an insertion force less than a breakaway force defined between the stopper and the barrel of the syringe, wherein the head portion of the plunger rod is axially inserted into a capture portion of the stopper, coupling the plunger rod to the stopper.

[0162] Inserting the head portion into the pocket may include sliding a tapered crown of the head portion of the plunger rod over one or more mating projections corresponding to the mating projections of the pocket to couple the plunger rod to the stopper. The one or more mating projections may include one or more longitudinally extending ridges (also referred to as ribs) and / or one or more circumferentially extending ridges (also referred to as ribs). Each of the one or more mating projections may have a leading edge and a trailing edge, at least the leading edge being angled and / or rounded, and inserting the head portion into the pocket may include sliding the head portion longitudinally over the leading edge and / or the trailing edge of the one or more mating projections. As described above, the separation force may be, for example, 2N to 20N. Once the plunger rod is inserted into the stopper, the stopper and plunger rod must apply a longitudinal separation force to separate the plunger rod from the stopper. In various examples, the separation force is greater than the separation force.

[0163] Inserting the head portion into the pocket can also include sliding enlarged segments of the head portion of the plunger rod into one or more mating recesses corresponding to the mating portions of the pocket to couple the plunger rod to the stopper. The one or more mating recesses can include one or more longitudinally extending recesses and / or one or more circumferentially extending recesses. Each of the one or more mating recesses can have a leading edge and a trailing edge, at least the leading edge being angled and / or rounded, and inserting the head portion into the pocket can include sliding the head portion longitudinally over the leading edges of the one or more mating recesses to seat the enlarged segments of the head (e.g., one or more retention features) within the one or more mating recesses. Again, as described above, the separation force can be, for example, 2N to 20N. Also, once the plunger rod is inserted into the stopper, the stopper and plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper. Again, in various examples, the separation force is greater than the separation force. [Example]

[0164] Example 1: Manufacturing, test methods and test results

[0165] Syringe stoppers were manufactured according to the teachings of U.S. Patent No. 8,722,178 (hereinafter, the "'178 patent") assigned to W.L. Gore & Associates, Inc. Generally, samples were fabricated according to the respective designs shown in Figures 4A, 5, 6, and 7. The pocket dimensions selected for each design are shown in Table 1, and all of these values ​​were measured in the uncompressed state. The sample dimensions were measured using a Mitutoyo TM-505 Toolmaker's Microscope. As previously described, each pocket included a trap portion having a first diameter D1, a relief portion having a second diameter D2, and a junction portion between the trap portion and the relief portion having a third diameter. See the schematic diagrams in Figures 3C and 3D. For measurement purposes, the third diameter generally corresponds to the smallest diameter of the trap pocket defined by the junction projection. Furthermore, because the first and second diameters of each sample were fabricated to be the same, only the second diameter was measured, and the first diameter was assumed to be the same value as the measured second diameter.

[0166] Next, for reference, each stopper sample is manually inserted into a non-siliconized glass barrel (i.e., not coated with silicone lubricant) conforming to ISO 11040-4 with a nominal inner diameter of 4.65 mm with a vent tube along with 200 μL of water for injection (WFI).

[0167] The filled and stoppered syringes were stored at ambient conditions with the luer end of the glass barrel facing up for one week before testing.

[0168] A commercially available plunger rod having the dimensions described in connection with FIG. 3E was obtained and used to move the stopper within the barrel. When the plunger rod was inserted into the stopper, visual evaluation was performed to determine whether the insertion of the plunger rod caused longitudinal translation of the stopper. If the majority of evaluations were "No," no longitudinal translation of the stopper was observed during plunger rod insertion, indicating that the plunger rod insertion force was less than the withdrawal force.

[0169] After inserting the plunger rod into the stopper, a TA XT Plus Texture Analyzer (Hamilton, MA) was used to compress the plunger rod longitudinally (toward the tip of the syringe) at 100 mm / min, translating the stopper approximately 10 mm. The texture analyzer then retracted the plunger rod longitudinally (toward the flanged end of the syringe) at a rate of 10 mm / min, and the movement of the plunger toward the flanged end of the syringe was visually assessed. In each case, there was a nonzero separation force between the plunger and stopper sample. In other words, the two remained attached unless an external force was applied to separate them. Furthermore, a majority of the scores for each sample were "Yes," indicating that the stopper actually moved toward the flanged end of the syringe when the plunger rod was retracted, indicating not only that the separation force was nonzero, but that the separation force actually exceeded the separation force.

[0170] [Table 1]

[0171] For reference, the prior art plunger shown in FIG. 3A can be manufactured in accordance with ISO 1140-5 and does not have a relief portion defining the second diameter D2. The third diameter (the coupling portion) is 1.6-1.9 mm, and the first nominal diameter (the capture portion) is 2.5 mm. The nominal value of L is 5.3 mm, and Lp is 3.15 mm, resulting in an Lp / L ratio of 0.594. For reference, with the design of FIG. 3A (e.g., with the dimensions above), the insertion force of the plunger rod is expected to exceed the withdrawal force.

[0172] From the above, it is considered that an Lp / L value of less than 0.5, for example, less than 0.3, or less than 0.2, is advantageous in terms of reducing insertion force. Generally, the Lp / L value is expected to be greater than 0 (for example, 0.05) and less than or equal to 0.5, 0.3, or 0.2. For example, the Lp / L value can be in the range of 0.1 to 0.2.

[0173] Example 2: Manufacturing, test methods and test results

[0174] Syringe stoppers were again manufactured according to the teachings of the '178 patent. As in Example 1, the pocket dimensions of each stopper sample were measured in the uncompressed state and are shown in Table 2. The sample dimensions were measured using a Mitutoyo TM-505 Toolmaker's Microscope. Again, the first diameter, corresponding to the capture portion, was fabricated to be the same as the second diameter, corresponding to the relief portion, so only the second diameter was measured, assuming the first diameter was the same. Both samples were prepared generally according to the design in Figure 6. Selected pocket dimensions are shown in Table 2, and each value was measured in the uncompressed state.

[0175] As in Example 1, stopper samples were inserted through a vent tube into a non-siliconized glass barrel conforming to ISO 11040-4, with a nominal inner diameter of 4.65 mm and a water contact angle of approximately 80°, along with 200 μL of water for injection (WFI) at 120 mm / s using an AST CCS container closure system (Tacoma, WA).

[0176] The filled and stoppered syringes were stored at ambient conditions with the luer end of the glass barrel facing up for one week before testing.

[0177] A commercially available plunger rod with the dimensions described in connection with Figure 3E was obtained and used to move the stopper within the barrel. The plunger rod was automatically inserted into the stopper at a speed of approximately 0.5 mm / s, and the insertion force was measured using a TA XT Plus Texture Analyzer (Hamilton, MA). The maximum force was recorded. The same TA XT Plus Texture Analyzer (Hamilton, MA) was also used to test the removal force by moving the stopper toward the Luer end within the glass barrel at a speed of approximately 100 mm / min. The maximum force in each case was recorded.

[0178] [Table 2]

[0179] As shown in the data above, for the above designs, the recorded insertion forces were much lower than the withdrawal forces, in all cases less than 75% of the withdrawal force and even less than 50% of the withdrawal force.

[0180] Examples of syringe barrel contents The syringes of the present disclosure can be used in combination with a variety of therapeutic compounds, including, but not limited to, drugs and biologics such as clotting factors, cytokines, epigenetic protein families, growth factors, hormones, peptides, signaling molecules, and their variants, as well as amino acids, vaccines, and / or combinations thereof. Therapeutic compounds further include antibodies, antisense, RNA interference directed against the above biologics and their target receptors, and their variants. Additional therapeutic compounds include gene therapy, primary stem cells, and embryonic stem cells. Therapeutic compounds include antibodies, antisense, RNA interference against protein kinases, esterases, phosphatases, ion channels, proteases, structural proteins, membrane transport proteins, nuclear hormone receptors, and / or combinations thereof. Furthermore, it should be understood that at least one of the therapeutic compounds identified herein, as well as two or more of the therapeutic compounds listed in this application, used in the present disclosure, are also considered within the scope of the present disclosure.

[0181] Examples of clotting factors include, but are not limited to, fibrinogen, prothrombin, Factor I, Factor V, Factor X, Factor VII, Factor VIII, Factor XI, Factor XIII, protein C, platelets, thromboplastin, and co-clotting factor VIIa.

[0182] Examples of cytokines include, but are not limited to, lymphokines, interleukins, chemokines, monokines, interferons, and colony-stimulating factors.

[0183] Examples of epigenetic protein families include, but are not limited to, ATPase family AAA domain-containing protein 2 (ATAD2A), ATPase family-AAA domain-containing 2B (ATAD2B), ATPase family-AAA domain-containing-2B (ATAD2B), bromodomain adjacent to zinc finger domain-1A (BAZ1A), bromodomain adjacent to zinc finger domain-1B (BAZ1B), bromodomain adjacent to zinc finger domain-2A (BAZ2A), bromodomain adjacent to zinc finger domain-2A (BAZ2A), bromodomain adjacent to zinc finger domain-2B (BAZ2B), bromodomain-containing protein 1 (BRD1), bromodomain-containing protein 2-1st bromodomain (BRD2), Bromodomain-containing protein 2 - first and second bromodomains (BRD2), Bromodomain-containing protein 2 isoform 1 - bromodomain 2 (BRD2(2)), Bromodomain-containing protein 3 - bromodomain 1 (BRD3(1)), Bromodomain-containing protein 3 - first bromodomain (BRD3), Bromodomain-containing protein 3 - first and second bromodomains (BRD3), Bromodomain-containing protein 3 - bromodomain 2 (BRD3(2)), Bromodomain-containing protein 4 - first bromodomain (BRD4), Bromodomain-containing protein 4 isoform length - bromodomains 1 and 2 (BRD4(1-2)), Bromodomain-containing protein 4 isoform long-bromodomain 2 (BRD4(2)), bromodomain-containing protein 4 isoform short (BRD4(full-length-short-iso)), bromodomain-containing protein 7 (BRD7), bromodomain-containing 8-bromodomain 1 (BRD8(1)), bromodomain-containing 8-bromodomain 2 (BRD8(2)), bromodomain-containing protein 9 isoform 1 (BRD9), bromodomain-containing testis-specific-1 bromodomain (BRDT), bromodomain-containing testis-specific-1 and 2 bromodomain (BRDT), bromodomain testis-specific protein isoform b-bromodomain 2 (BRDT(2)), bromodomain and PHD finger-containing-1 (BRPF1),Bromodomain and PHD finger-containing-3 (BRPF3), bromodomain and PHD finger-containing-3 (BRPF3), bromodomain and WD repeat-containing 3-second bromodomain (BRWD3(2)), cat eye syndrome critical region protein 2 (CECR2), CREB binding protein (CREBBP), E1A binding protein p300 (EP300), EP300 (EP300), nucleosome remodeling factor subunit BPTF isoform 1 (FALZ), nucleosome remodeling factor subunit BPT (FALZ), euchromatin histone-lysine N-methyltransferase 2 (EHMT2), histone acetyltransferase-KAT2A (GCN5L2), euchromatin histone-lysine N-methyltransferase 1 (EHMT1), histone-lysine N-methyltransferase MLL (MLL), polybromo1-first bromodomain (PB1(1)), polybromo1- 2nd bromodomain (PB1(2)), polybromo l-bromodomain 2 (PBRM1(2)), polybromo l-bromodomain 5 (PBRM1(5)), histone acetyltransferase KAT2B (PCAF), PH interacting protein-1st bromodomain (PHIP(1)), PH interacting protein-2nd bromodomain (PHIP(2))), protein kinase C binding protein 1 (PRKCBP1), protein arginine N-methyltransferase SWI / SNF-related matrix-associated actin-dependent regulator of chromatin subfamily a member 2 (SMARCA2), SWI / SNF-related matrix-associated actin-dependent regulator of chromatin subfamily a member 4 (SMARCA4), nuclear body protein SP110 (SP110), nuclear body protein SP140 (SP140), transcription initiation factor TFIID subunit 1 (TAF1(1-2))), TAF1 RNA polymerase II TATA box-binding protein (TBP)-associated factor 250 kDa bromodomain 2 (TAF1(2)), transcription initiation factor TFIID subunit 1-like bromodomain 1 (TAF1L(1)), transcription initiation factor TFIID subunit 1-like bromodomain 2 (TAF1L(2)),These include tripartite motif-containing 24 (TRIM24(Bromo.)), tripartite motif-containing 24 (TRIM24(PHD-Bromo.)), E3 ubiquitin-protein ligase TRIM33 (TRIM33), tripartite motif-containing 33 (TRIM33(PHD-Bromo.)), WD repeat 9-first bromodomain (WDR9(1)), and WD repeat 9-second bromodomain (WDR9(2)).

[0184] Examples of growth factors include, but are not limited to, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), c-fos-induced growth factor (FIGF), platelet-activating factor (PAF), transforming growth factor beta (TGF-β), bone morphogenetic proteins (BMP), activin, inhibin, fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), glial cell line-derived neurotrophic factor (GDNF), growth differentiation factor-9 (GDF9), epidermal growth factor (EGF), transforming growth factor-α (TGF-α), growth factor (KGF), migration-stimulating factor (MSF), hepatocyte growth factor-like protein (HGFLP), hepatocyte growth factor (HGF), hepatoma-derived growth factor (HDGF), and insulin-like growth factor.

[0185] Examples of hormones include, but are not limited to, amino acid derived (such as melatonin and thyroxine), thyrotropin-releasing hormone, vasopressin, insulin, growth hormone, glycoprotein hormones, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, eicosanoids, arachidonic acid, lipoxins, prostaglandins, steroids, estrogens, testosterone, cortisol, and progestogens.

[0186] Examples of proteins and peptides and signaling molecules include, but are not limited to, ataxia telangiectasia variabile, tumor protein p53, checkpoint kinase 2, breast cancer susceptibility protein, double-strand break repair protein, DNA repair protein RAD50, nibrin, p53-binding protein, DNA damage checkpoint protein mediator, H2A histone family member X, microcephalin, C-terminal binding protein 1, chromosome integrity protein 1A, cell division cycle 25 homolog A (CDC25A), forkhead box O3, and B-cell inhibitor kappa kinase. These include nuclear factor of light polypeptide gene enhancer, alpha (NFKBIA), nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), natriuretic peptide receptor A (NPR1), tumor necrosis factor receptor superfamily, member 11a (TNFRSF11A), v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA), sterol regulatory element-binding transcription factor 2 (SREBF2), CREB-regulated transcriptional coactivator 1 (CRTC1), CREB-regulated transcriptional coactivator 2 (CRTC2), X-box binding protein 1 (XBP1), and catenin beta 1 (cadherin-associated protein or CTNNB1).

[0187] Examples of G protein-coupled receptors (GPCRs) include, but are not limited to, the adenosine receptor family, the adrenergic receptor family, the angiotensin II receptor, the apelin receptor, the vasopressin receptor family, the brain-specific angiogenesis inhibitor family, the bradykinin receptor family, the bombesin receptor family, the complement component 3a receptor 1, the complement component 5a receptor 1, the calcitonin receptor family, the calcitonin receptor-like family, the calcium-sensing receptor, the cholecystokinin A receptor (CCK1), the cholecystokinin B receptor (CCK2), the chemokine (CC motif) receptor family, the sphingosine 1-phosphate receptor family, the succinate receptor, and the choline receptor. Agonist receptor family, chemokine-like receptor family, cannabinoid receptor family, corticotropin-releasing hormone receptor family, prostaglandin D2 receptor, chemokine C-X3-C receptor family, chemokine (CXC motif) receptor family, Burkitt's lymphoma receptor, chemokine (CXC motif) receptor family, cysteinyl leukotriene receptor 2 (CYSLT2), chemokine receptor (FY), dopamine receptor family, G protein-coupled receptor 183 (GPR183), lysophosphatidic acid receptor family, endothelin receptor family, coagulation factor II (thrombin) receptor family, free fatty acid receptor family , formyl peptide receptor family, follicle-stimulating hormone receptor (FSHR), gamma-aminobutyric acid (GABA) B receptor, galanin receptor family, glucagon receptor, growth hormone-releasing hormone receptor (GHRH), ghrelin receptor (ghrelin), growth hormone secretagogue receptor 1b (GHSR1b), gastric inhibitory polypeptide receptor (GIP), glucagon-like peptide receptor family, gonadotropin-releasing hormone receptor (GnRH), pyroglutamylated RFamide peptide receptor (QRFPR), G protein-coupled bile acid receptor 1 (GPBA), hydroxycarboxylic acid receptor family, lysophosphatidic acid receptor 4 (LPA4), lysophosphatidic acid receptor 5 (GPR92), G protein-coupled receptor 79 pseudogene (GPR79), hydroxycarboxylic acid receptor 1 (HCA1), G protein-coupled receptor (C5L2, FFA4,FFA4, FFA4, GPER, GPR1, GPR101, GPR107, GPR119, GPR12, GPR123, GPR132, GPR135, GPR139, GPR141, GPR142, GPR143, GPR146, GPR148, GPR149, GPR15, GPR150, GPR151, GPR152, GPR157, GPR161, GPR162, GPR17, GPR171, GPR173, GPR176, GPR18, GPR182, GPR20, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR35, GPR37L1, GPR39, GPR4, GPR45, GPR50, GPR52, GPR55, GPR6, GPR61, GPR65, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR97,TM7SF1), metabotropic glutamate receptor family, gastrin-releasing peptide receptor (BB2), orexin receptor family, histamine receptor family, 5-hydroxytryptamine receptor family, KISS1-derived peptide receptor (kisspeptin), leucine-rich repeat-containing G protein-coupled receptor family, chorionic gonadotropin receptor (LH), leukotriene B4 receptor (BLT1), adenylate cyclase-activating polypeptide 1 receptor 1 (mPAC1), motilin receptor, melanocortin receptor family, melanin-concentrating hormone receptor 1 (MCH1), neuropeptide Y1 receptor (Y1), neuropeptide Y2 receptor (NPY2R), opioid receptor family, oxytocin receptor (OT), P2Y purinoceptor 12 (mP2Y12), P2Y purinoceptor 6 (P2Y6), pancreatic polypeptide receptor receptor family, platelet-activating factor receptor family, prostaglandin E receptor family, prostanoid IP1 receptor (IP1), MAS-related GPR, member family, rhodopsin (rhodopsin), relaxin family peptide receptor family, somatostatin receptor family, tachykinin receptor family, melatonin receptor family, urotensin receptor family, vasoactive intestinal peptide receptor 1 (mVPAC1), neuromedin B receptor (BB1), neuromedin U receptor 1 (NMU1), neuropeptide B / W receptor family, neuropeptide FF receptor 1 (NPFF1), neuropeptide S receptor 1 (NPS receptor), neuropeptide Y receptor family, neurotensin receptor 1 (NTS1), opsin 5 (OPN5), opioid receptor-like receptor (NOP), oxoeicosanoid(OXE) receptor 1 (OXE), oxoglutarate (α-ketoglutarate) receptor 1 (OXGR1), purinergic receptor family, pyrimidinergic receptor family, prolactin-releasing hormone receptor (PRRP), prokineticin receptor family, platelet-activating receptor (PAF), prostaglandin F receptor family, prostaglandin 12 (prostacyclin) receptor family, parathyroid hormone receptor family, muscarinic acetylcholine receptor (such as rM4), prostanoid DP2 receptor (rGPR44), prokineticin receptor family, relaxin family peptide receptor family, secretin receptor (secretin), Frizzled class receptor (Smoothened), trace amine-associated receptor family, tachykinin family, thromboxane A2 receptor (TP), thyrotropin-releasing hormone receptor (TRH1), and thyroid-stimulating hormone receptor (TSH).

[0188] Examples of nuclear hormone receptors include, but are not limited to, androgen receptor (AR), estrogen-related receptor alpha (ESRRA), estrogen receptor 1 (ESR1), nuclear receptor subfamily 1 - group H - member 4 (NR1H4), nuclear receptor subfamily 3 - group C - member 1 (glucocorticoid receptor) (NR3C1), nuclear receptor subfamily 1 - group H - member 3 (liver X receptor alpha) (NR1H3), nuclear receptor subfamily 1 - group H - member 2 (liver X receptor beta) (NR1H2), nuclear receptor subfamily 1 - group H - member 2 (liver X receptor beta) (NR1H2), nuclear receptor subfamily 3 - group C - member 2 (mineralocorticoid receptor). (NR3C2), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor gamma (PPARG), peroxisome proliferator-activated receptor delta (PPARD), progesterone receptor alpha (PGR), progesterone receptor beta (PGR), retinoic acid receptor alpha (RARA), retinoic acid receptor beta (RARB), retinoid X receptor alpha (RXRA), retinoid X receptor gamma (RXRG), thyroid hormone receptor alpha (THRA), thyroid hormone receptor beta (THRB), retinoic acid-related orphan receptor, liver X receptor, farnesoid X receptor, vitamin D receptor, pregnane X receptor, constitutive androstane receptor, hepatocyte nuclear factor 4, estrogen receptor, estrogen-related receptor, glucocorticoid receptor, and nerve growth factor-inducible receptor B, germline nuclear factor.

[0189] Examples of membrane transport proteins include, but are not limited to, the ATP-binding cassette (ABC) superfamily, solute carrier (SLC) superfamily, multidrug resistance protein 1 (P-glycoprotein), organic anion transporter 1, and proteins such as EAAT3, EAAC1, EAAT1, GLUT1, GLUT2, GLUT9, GLUT10, rBAT, AE1, NBC1, KNBC, CHED2, BTR1, NABC1, CDPD, SGLT1, SGLT2, NIS, CHT1, NET, DAT, GLYT2, CRTR, BOAT1, SIT1, XT3, y+LAT1, BAT1, NHERF1, NHE6, ASBT, DMT1, DCT1, NRAMP2, NKCC2, NCC, KCC3, NACT, MCT1, MCT8, MCT12, SLD, VGLUT3, THTR1, THTR2, PIT2, GLVR2, OCTN2, URAT1, NCKX1, NCKX5, CIC, PiC, ANTI, ORNT1, AGC1, ARALAR, Citrin, STLN2, aralar2, TPC, MUP1, MCPHA, CACT, GC1, PHC, DTD, CLD, DRA, PDS, Prestin, TAT1, FATP4, ENT3, ZnT2, ZnT10, AT1, NPT2A, N Examples of genes encoding the PT2B, HHRH, CST, CDG2F, UGAT, UGTL, UGALT, UGT1, UGT2, FUCT1, CDG2C, NST, PAT2, G6PT1, SPX4, ZIP4, LIV4, ZIP13, LZT-Hs9, FPN1, MTP1, IREG1, RHAG, AIM1, PCFT, FLVCR1, FLVCR2, RFT1, RFT2, RFT3, OATP1B1, OATP1B3, and OATP2A1.

[0190] Examples of structural proteins include, but are not limited to, tubulin, heat shock proteins, microtubule stabilizing proteins, tumor protein 18, stathmin, kinesin-8 and kinesin-14 families, Kip3 and Kif18A.

[0191] Examples of proteases include, but are not limited to, the ADAM (a disintegrin and metalloprotease) family.

[0192] Examples of protein kinases include, but are not limited to, AP2-related kinases, human ABL proto-oncogene 1-non-receptor tyrosine protein kinase family, c-abl oncogene 1 receptor tyrosine kinase family, v-abl Abelson murine leukemia viral oncogene homolog 2, activin A receptor family, ABC1 activity of chaperone-bc1 complex homolog (S. pombe) (ADCK3), aarF domain-containing kinase 4 (ADCK4), v-akt murine thymoma viral oncogene homolog family, anaplastic lymphoma receptor tyrosine kinase family, protein kinase A family, protein kinase B family, ankyrin repeat and kinase domain-containing 1 (ANKK1), NUAK family-SNF1-like kinase, mitogen-activated protein kinase kinase kinase family, Aurora kinase A (AURKA), Aurora kinase B (AURKB), aurora kinase C (AURKC), AXL receptor tyrosine kinase (AXL), BMP2-inducible kinase (BIKE), B lymphoid tyrosine kinase (BLK), bone morphogenetic protein receptor family, BMX non-receptor tyrosine kinase (BMX), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), protein tyrosine kinase 6 (BRK), BR serine / threonine kinase family, Bruton's agammaglobulinemia tyrosine kinase (BTK), calcium / calmodulin-dependent protein kinase family, cyclin-dependent kinase family, cyclin-dependent kinase-like family, CHK1 checkpoint homolog (S. pombe) (CHEK1), CHK2 checkpoint homolog (S. pombe) (CHEK2), insulin receptor, isoform A (INSR), insulin receptor, isoform B (INSR), rho-interacting serine / threonine kinase (CIT), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), CDC-like kinase family - hepatocyte growth factor receptor (MET), proto-oncogene tyrosine protein kinase receptor, colony-stimulating factor family receptor, c-src tyrosine kinase (CSK), casein kinase family,Megakaryocyte-associated tyrosine kinase (CTK), death-associated protein kinase family, doublecortin-like kinase family, discoidin domain receptor tyrosine kinase, dystrophy myotonic protein kinase (DMPK), dual specificity tyrosine-(Y)-phosphorylation-regulated kinase family, epidermal growth factor receptor family, eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1), EPH receptor family, ephrin type A receptor family, ephrin type B receptor family, v-erb-b2 erythroblastic leukemia viral oncogene homolog Milli, mitogen-activated protein kinase family, endoplasmic reticulum nuclear signaling 1 (ERN1), PTK2 protein tyrosine kinase 2 (FAK), fer (fps / fes-related) tyrosine kinase (FER), feline sarcoma oncogene (FES), fibroblast growth factor receptor family, Gardner-Rashid feline sarcoma virus (v-fgr) oncogene homolog (FGR), fms-related tyrosine kinase family, Fms-related tyrosine kinase family, fyn-related kinase (FRK), SRC-related FYN oncogene, cyclin G-associated kinase (GAK) , eukaryotic translation initiation factor 2 alpha kinase, growth hormone receptor, G protein-coupled receptor kinase 1 (GRK1), G protein-coupled receptor kinase family, glycogen synthase kinase family, germ cell-associated 2 (haspin) (HASPIN), hematopoietic cell kinase (HCK), homeodomain-interacting protein kinase family, mitogen-activated protein kinase kinase kinase kinase family, hormone-upregulated Neu-related kinase (HUNK), enterocyte (MAK-like) kinase (ICK), insulin-like growth factor 1 receptor (IGF1R), conserved helix-loop-helix ubiquitous kinase (IKK-α), inhibitor of kappa ray polypeptide gene enhancer in B-cell kinase beta family, insulin receptor (INSR), insulin receptor-related receptor (INSRR), interleukin-1 receptor-related kinase family, IL2-inducible T-cell kinase (ITK), Janus kinase family, kinase insert domain receptor, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog,Lymphocyte-specific protein tyrosine kinase (LCK), LIM domain kinase family, serine / threonine kinase family, leucine-rich repeat kinase family, v-yes-1 Yamaguchi sarcoma virus-associated oncogene homolog (LYN), male germ cell-associated kinase (MAK), MAP / microtubule affinity-regulating kinase family, e.g., microtubule-associated serine / threonine kinase family, maternal-fetal leucine zipper kinase, c-mer proto-oncogene tyrosine kinase (MERTK), met proto-oncogene (hepatocyte growth factor receptor), MAP kinase-interacting serine / threonine kinase family, myosin light chain kinase family, mixed lineage kinase domain-like protein isoform, CDC42-binding protein kinase family, serine / threonine kinase family, macrophage-stimulating receptor 1 receptor (c-met-related tyrosine kinase) (MST1R), mechanistic target of rapamycin (serine / threonine kinase family) threonine kinase) (MTOR), musculoskeletal receptor tyrosine kinase (MUSK), myosin light chain kinase family, NIMA (never in mitosis gene a)-related kinase family, serine / threonine protein kinase NIM1 (NIM1), nemo-like kinase (NLK), oxidative stress responsive 1 (OSR1), p21 (Cdc42 / Rac)-activated kinase family, PAS domain-containing serine / threonine kinase, platelet-derived growth factor receptor family, 3-phosphoinositide-dependent protein kinase-1 (PDPK1), calcium-dependent protein kinase 1, phosphorylase kinase gamma family, phosphatidylinositol 4,5-bisphosphate 3-kinase, phosphoinositide-3-kinase family, phosphatidylinositol 4-kinase family, phosphoinositide kinase, FYVE finger-containing, Pim-1 oncogene (PIM1), pim-2 oncogene (PIM2), pim-3 oncogene (PIM3), phosphatidylinositol-4-phosphate 5-kinase family, phosphatidylinositol-5-phosphate 4-kinase family protein kinase, membrane-associated tyrosine / threonine 1 (PKMYT1), protein kinase N family, polo-like kinase family, protein kinase C family,Protein kinase D family, cGMP-dependent protein kinase family, eukaryotic translation initiation factor 2-alpha kinase 2 (PRKR), X-linked protein kinase (PRKX), prolactin receptor (PRLR), PRP4 pre-mRNA processing factor 4 homolog B (yeast) (PRP4), PTK2B protein tyrosine kinase 2 beta (PTK2B), SIK family kinase 3 (QSK), v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1), neurotrophic tyrosine kinase receptor type family, receptor (TNFRSF)-interacting serine-threonine kinase family, dual serine / threonine and tyrosine protein kinase (RIPK5), Rho-associated coiled-coil-containing protein kinase family, c-ros oncogene 1, receptor tyrosine kinase (ROS1), ribosomal protein S6 kinase family, SH3-binding domain kinase 1 (SBK1), serum / glucocorticoid-regulated kinase tyrosine kinase family, putative uncharacterized serine / threonine protein kinase (Sugen kinase 110) (SgK110), salt-inducible kinase family, SNF-related kinase (SNRK), src-related kinase, SFRS protein kinase family, spleen tyrosine kinase (SYK), e.g., TAO kinase family, TANK-binding kinase 1 (TBK1), e.g., TEC protein tyrosine kinase (TEC), testis-specific kinase 1 (TESK1), transforming growth factor, beta receptor family, immunoglobulin-like and EGF-like domain 1-containing tyrosine kinase (TIE1), TEK tyrosine kinase, endothelial (TIE2), angiopoietin-1 receptor (Tie2), Tusle-like kinase family, TRAF2 and NCK-interacting kinase (TN IK), non-receptor tyrosine kinase family, TNNI3-interacting kinase (TNNI3K), transient receptor potential cation channel, testis-specific serine kinase family, TTK protein kinase (TTK), TXK tyrosine kinase (TXK), tyrosine kinase 2 (TYK2), TYRO3 protein tyrosine kinase (TYRO3), unc-51-like kinase family, phosphatidylinositol 3-kinase,These include vaccinia-related kinase 2 (VRK2), the WEE1 homolog family, the WNK lysine-deficient protein kinase family, the v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES), the sterile alpha motif and leucine zipper-containing kinase AZK (ZAK), and the zeta chain (TCR)-associated protein kinase 70 kDa (ZAP70).

[0193] Cell therapy primarily uses cells derived from endoderm such as exocrine secretory epithelial cells and hormone-secreting cells, keratinized epithelial cells, moist stratified barrier epithelial cells, sensory transduction cells, autonomic nerve cells, sensory organ and peripheral nerve supporting cells, central nervous system neurons and glial cells, ectoderm such as lens cells, metabolic and storage cells, barrier function cells (lung, intestine, exocrine glands and urogenital tract), mesoderm such as extracellular matrix cells, contractile cells, blood and immune system cells, germ cells, nurse cells, interstitial cells, and combinations thereof. Additionally, cells that have been genetically, chemically or physically altered or otherwise modified are also within the scope of the present invention.

[0194] Examples of exocrine secretory epithelial cells include, but are not limited to, salivary gland mucous cells, salivary gland number 1, von Ebner's gland cells of the tongue, mammary gland cells, lacrimal gland cells, ceruminous gland cells of the ear, eccrine sweat gland dark cells, eccrine sweat gland clear cells, apocrine sweat gland cells, Mohr's gland cells of the eyelid, sebaceous gland cells, Bowman's gland cells of the nose, Brunner's gland cells of the duodenum, seminal vesicle cells, prostate cells, bulbourethral gland cells, Bartholin's gland cells, Littré gland cells, endometrial cells of the uterus, isolated goblet cells of the respiratory and digestive tract, gastric mucosal cells, gastric gland zymogen cells, gastric gland oxidative cells, pancreatic acinar cells, Paneth cells of the small intestine, type II pneumocytes of the lung, and and Clara cells of the lung, hormone-secreting cells, such as, but not limited to, anterior pituitary cells, intermediate pituitary cells, magnocellular neurosecretory cells, cells of the intestinal and respiratory tracts, thyroid cells, parathyroid cells, adrenal gland cells, Leydig cells of the testes that secrete testosterone, theca cells of the ovarian follicle that secrete estrogen, luteal cells of ruptured follicles that secrete progesterone, juxtaglomerular cells, macula densa cells of the kidney, peripolar cells of the kidney, mesangial cells of the kidney, and pancreatic islets, keratinizing epithelial cells, such as, but not limited to, epidermal keratinocytes, epidermal basal cells, keratinocytes of the fingernails and toenails, nail bed Basal cells, medullary hair stem cells, cortical hair stem cells, epidermal hair stem cells, epidermal root sheath cells, root sheath cells of Huxley's layer, root sheath cells of Henle's layer, outer root sheath cells and hair matrix cells, moist stratified barrier epithelial cells, including but not limited to, surface epithelial cells of stratified squamous epithelium and basal cells of the epithelium of the cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, and urothelial cells, sensory transduction cells, including but not limited to, auditory inner hair cells of the organ of Corti, auditory outer hair cells of the organ of Corti, basal cells of the olfactory epithelium, cold-sensitive primary sensory neurons, heat-sensitive primary sensory neurons, Merkel cells of the epidermis , olfactory receptor neurons, pain-sensitive primary sensory neurons, photoreceptor cells in the retina of the eye, proprioceptive primary sensory neurons, touch-sensitive primary sensory neurons, type I carotid body cells, type II carotid body cells, type I hair cells of the vestibular system of the ear, type II hair cells and type I taste bud cells of the vestibular system of the ear, autonomic nerve cells, including but not limited to cholinergic neurons, adrenergic neurons and peptidergic neurons, sensory organ and peripheral neuron supporting cells, including but not limited to inner column cells of the organ of Corti, outer column cells of the organ of Corti, inner phalangeal cells of the organ of Corti,Ectophalangeal cells of the organ of Corti, border cells of the organ, Hensen's cells of the organ of Corti, vestibular organ supporting cells, taste bud supporting cells, olfactory epithelial supporting cells, Schwann cells, satellite glial cells and enteric glial cells, central nervous system neurons and glial cells, including but not limited to astrocytes, neuronal cells, oligodendrocytes and spindle neurons, lens cells, including but not limited to anterior lens epithelial cells and crystallin-containing lens fiber cells, metabolic and storage cells, including but not limited to adipocytes and hepatic adipocytes, barrier function cells, including but not limited to cells, including but not limited to kidney parietal cells, kidney glomerular podocytes, kidney proximal tubule brush border cells, loop of Henle's slice cells, kidney distal tubule cells, kidney collecting duct cells, chief cells, intercalated cells, type I pneumocytes, pancreatic duct cells, non-striated duct cells, chief cells, intercalated cells, duct cells, intestinal brush border cells, exocrine gland striated duct cells, gallbladder epithelial cells, efferent duct non-ciliated cells, epididymal chief cells and epididymal basal cells, extracellular matrix cells, including but not limited to ameloblast epithelial cells, meniscal epithelial cells of the vestibular system of the ear, organ of Corti interdental epithelial cells, loose connective tissue fibroblasts, corneal fibroblasts, tendon fibroblasts, Bone marrow reticular fibroblasts, other non-epithelial fibroblasts, pericytes, nucleus pulposus cells of the intervertebral disc, cementoblasts / cementocytes, odontoblasts / odontoblasts, hyaline cartilage chondrocytes, fibrocartilage chondrocytes, elastic cartilage chondrocytes, osteoblasts / osteocytes, osteoprogenitor cells, vitreous cells of the vitreous body of the eye, stellate cells of the perilymphatic space of the ear, hepatic stellate cells and pancreatic stellate cells, contractile cells, including but not limited to skeletal muscle cells, satellite cells, cardiac myocytes, smooth muscle cells, myoepithelial cells of the iris and myoepithelial cells of exocrine glands, blood cells and immune system cells, including but not limited to erythrocytes, megakaryocytes, monocytes, connective tissue cells, tissue macrophages, epidermal Langerhans cells, osteoclasts, dendritic cells, microglial cells, neutrophil granulocytes, eosinophil granulocytes, basophil granulocytes, hybridoma cells, mast cells, helper T cells, suppressor T cells, cytotoxic T cells, natural killer T cells, B cells, natural killer cells, reticulocytes, stem cells and progenitor cells of the blood and immune system, germ cells, including but not limited to oogonia, oocytes, spermatocytes, spermatocytes, spermatogonia and sperm, nurse cells, including but not limited to ovarian follicle cells and Sertoli cells, thymic epithelial cells,Stromal cells, including but not limited to interstitial renal cells, and any combination of the foregoing.

[0195] Non-limiting examples of other known biologics include, but are not limited to, Avosinagis, Abeglin, Actemra, AFP-Cyde, Antova, Alzera, Aurexis, Avastin, Benlysta, Vexar, Brontres, Bosatria, Campath, CEA-Cyde, CEA-Scan, Cimzia, Siramza, Ectomab, Erbitux, Fibricint, Gadiva, Herceptin, hPAM4-Cyde, HumaSPECT, HuMax-CD4, HuMax-EGFr, Humira, HuZAF, Hybri-Ceaker, Ilaris, Indimasys-125, Kadcyla, Lemtrada, Leucarest, Leukoscan, Lucentis, and Lin. These include Fomun, Lymphoscan, Lymphostat-B, MabThera, Mycograb, Mylotarg, Myosint, Neutrospec, Pneumax, Nuvion, Omnitarg, Opdivo, Orthochron OKT3, Ovalex, Panorex, Prolia, Prostasint, Raptiva, Remicade, Rimovab, Lencarex, LeoPro, Lexomun, Rituxan, Roactemra, Syntimun, Simponi, Simulect, Soliris, Stelara, Synagis, Taxless, Serasim, Theladgin, Thelalock, Tysabri, Vectibix, Verluma, Xolair, Yervoy, Zenapax and Zevalin, and combinations thereof.

[0196] Non-limiting examples of known monoclonal antibodies include, but are not limited to, 3F8, 8H9, abagovomab, abciximab, abituzumab, abrilumab, actotuzumab, adalimumab, adecatumumab, aducanumab, afacevicumab, afelimomab, afutuzumab, alacizumab pegol, ALD518, ALD403, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, AMG334, and anatumomab. Mafenatox, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, arcitumomab, ascribvacumab, acelizumab, atezolizumab, atinumab, atlizumab, atolimu-mab, avelumab, bapineuzumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezloxumab, biciromab, bimagrumab, bimekizumab, bivatuzumab mertansine, bleselumab, blinatumab, brontuzumab, brosozumab, bococizumab, brazikumab, blu- Lentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontuzumab, burosumab, cabilalizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, carotuximab, catumaxomab, cBR96-doxorubicin immunoconjugate, cedelizumab, sergituzumab amnaleukin, certolizumab pegol, cetuximab, sitatuzumab bogatox, cixutuzumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine, conatumumab, concizumab, CR6261, crenezumab, clotezumab, dacetuzumab, daclizumab, darotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, delrotuximab biotin, detumomab, zina Tuximab, dilidabumab, domaglotumab, dorlimomab-alitonox, drozitumab, durigotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elocinib, Limab, emactuzumab, emibetuzumab, emicizumab, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faretuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fivatuzumab, ficlatuzumab, figitumumab, filibumab, framvotumab, fretikumab, fontolizumab, foralumab, foravirumab, fresolimumab, furanumab, futuximab, galcanezumab, galiximab, ganitumab, gantenerumab, gavilimab, gemtuzumab ozogamicin, gevokizumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiusetan, icrucumab, idarucizumab, igovomab, IMA-638, IMAB362, imalumab, imciromab, imgatuzumab, incl. Mab, indatuximab ravtansine, indusatumab vedotin, inebilizumab, infliximab, inolimab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, isatuximab, itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, LBR-101 / PF0442g7429, lebrikizumab, remaresomab, lendali Ibuprofen, lentilumab, lerdelimumab, lexatumumab, ribivirumab, rifatuzumab vedotin, ligelizumab, rilotumab satetraxetan, lintuzumab, lirilumab, roderucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, lumiliximab, lumletuzumab, LY2951742, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretum Mab, mirvetuximab sorafutansine, mitumomab, mogamulizumab, monalizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab butafenatox, namirumab, naptumomab estafenatox, naratuximab emtansine, narunatumab, natalizumab, nabicixizumab, nabibumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesbacumab, nimotuzumab, nivolumab, nofetumomabMerpentan, obilutoxiaximab, obinutuzumab, occaratuzumab, ocrelizumab, odulimab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otreltuzumab, oxelumab, ozonazumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pasco Lisumab, pasotuximab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placuramab, prosalizumab, pogalizumab, polatuzumab vedotin, ponezumab, prezalizumab, priliximab, pritoximab, pritumumab, PRO140, kilimumab, racotumomab, radletumab, rafivirumab, ralpanizumab, ramucirumab, ranibizumab, raxibax Mab, refanezumab, regavirumab, reslizumab, rilotumab, rinukumab, risankizumab, rituximab, rivavazumab pegol, lobatumumab, loredumab, romosozumab, lontalizumab, rovalpituzumab tesirin, rovelizumab, ruplizumab, sacituzumab govitecan, samalizumab, sapelizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, cetoxiaximab, sevirumab, SGN-CD19A, SGN-CD33A, sibrotuzumab, sifalimumab , siltuximab, simtuzumab, siplizumab, sirukumab, sofituzumab vedotin, solanezumab, solitomab, soneptizumab, sontuzumab, stamulumab, sulesomab, suvismab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tamtubetomab, tanezumab, taplitumomab paptox, talexuzumab, tefibazumab, terimomab alitox, tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, ticilimumab, tigatuzumab, tildrakizumab, timolumab, tisotumab vedotin, TNX-650, tocilizumab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocuprumab, urelumab, urutoxazumab, usuteki These include numab, utomilumab, vadastaximab butarilin, bundletuzumab vedotin, vanticizumab, vanucizumab, bapaliximab, valilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, borsetuzumab mafodotin, votumumab, zentuzumab, zalutumumab, zanolimumab, zatuximab, diralimumab, and zolimomab alitox, and combinations thereof.

[0197] Examples of vaccines developed for viral diseases include, but are not limited to, hepatitis A vaccine, hepatitis B vaccine, hepatitis E vaccine, HPV vaccine, influenza vaccine, Japanese encephalitis vaccine, MMR vaccine, MMRV vaccine, polio vaccine, rabies vaccine, rotavirus, chickenpox vaccine, shingles vaccine, smallpox vaccine, yellow fever vaccine, adenovirus vaccine, coxsackie B virus vaccine, cytomegalovirus vaccine, human dengue fever vaccine, human eastern equine encephalitis virus vaccine, Ebola hemorrhagic fever vaccine, enterovirus 71 vaccine, Epstein-Barr vaccine, hepatitis C vaccine, HIV vaccine, and human HTLV-1 vaccine. Examples of vaccines for bacterial diseases include, but are not limited to, T lymphocytic leukemia vaccines, Marburg virus disease vaccines, norovirus vaccines, human respiratory syncytial virus vaccines, severe acute respiratory syndrome (SARS) vaccines, and human West Nile virus vaccines; examples of vaccines for bacterial diseases include, but are not limited to, anthrax vaccines, DPT vaccines, Q fever vaccines, Hib vaccines, tuberculosis (BCG) vaccines, meningococcal vaccines, typhoid vaccines, pneumococcal conjugate vaccines, pneumococcal polysaccharide vaccines, cholera vaccines, dental caries vaccines, ehrlichiosis vaccines, leprosy vaccines, Lyme disease vaccines, Staphylococcus aureus vaccines, Streptococcus pyogenes vaccines, syphilis vaccines, tularemia vaccines, and plague vaccines. Examples of parasitic disease vaccines include, but are not limited to, malaria vaccine, schistosomiasis vaccine, Chagas disease vaccine, hookworm vaccine, human onchocerciasis / river blindness vaccine, trypanosomiasis vaccine, and visceral leishmaniasis vaccine. Examples of non-infectious diseases include, but are not limited to, Alzheimer's disease amyloid protein vaccine, breast cancer vaccine, ovarian cancer vaccine, prostate cancer vaccine, and talimogene laherparepvec (T-VEC), including, but not limited to, vaccines under the following trade names: ACAM2000, ActHIB, Adacel, AFLURIA.QUADRIVALENT, AgriFlu, BCG vaccine, BEXSERO, Vislax, Boostrix, Cervarix, Comvax, DAPTACEL, DECAVAC, Engerix-B, FLUAD, Fluarix, Fluarix tetravalent, Flubloc, Flucervax, Flucervax tetravalent, Flulaval, Flumist, Flumist tetravalent, Fluvirin, Fluzone tetravalent, Fluzone, Fluzone high dose and Fluzone intradermal, Gardasil, Gardasil 9, Havrix, Hivex, Imovax, Infanrix, IPOL, Ixiaro, JE-Vax, KINRIX, Menactra, Menhybrix, Menomne-A / C / Y / W-135, Menoveo, MMR II, MM-Vax, Pediarix, Pedovax HIB, Pentacel, Pneumovax 23, Poliovax, Prevnar, Prevnar 13, ProQuad, Quadracel, Quadrivalent, RabAvert, RecombiVax HB, ROTARIX, RotaTeq, TENIVAC, TICE BCG, Tripedia, TRUMENBA, Twinrix, TYPHIM Vi, VAQTA, Varivax, Vaccola, Vivotif, YF-Vax, Zostavax and combinations thereof.

[0198] Examples of injectable drugs include, but are not limited to, Abravar (gadofosveset trisodium injection), Abarelix depot, abobotulinum toxin A injection (Dysport), ABT-263, ABT-869, ABX-EFG, Acretropine (somatropin injection), Acetadot (acetylcysteine ​​injection), Acetazolamide injection, Acetadot, Actemra (tocilizumab injection), Axrel (corticorelin ovine triflate for injection), Actamune, Activase, injectable acyclovir (Zovirax injection), Adacel, adalimumab, and Adenoscaine. Adenosine (adenosine injection), adenosine injection (Adenoscan), AdrenaClick, Adrevue (intravenous iobenguane 1123 injection), Afluria, Ak-Fluor (fluorescein injection), Aldurazyme (laronidase), alglucerase injection (Ceredase), Alkeran injection (melphalan HCl injection), allopurinol sodium for injection (Aloprim), Alloprim (allopurinol sodium for injection), alprostadil, Arsuma (sumatriptan injection), ALTU-238, amino acid injection, Aminosine, Apidra, Apremilast, injectable alprostadil dual chamber system (Caverject) Impulse), AMG 009, AMG 076, AMG 102, AMG 108, AMG 114, AMG 162, AMG 220, AMG 221, AMG 222, AMG 223, AMG 317, AMG 379, AMG 386, AMG 403, AMG 477, AMG 479, AMG 517, AMG 531, AMG 557, AMG 623, AMG 655, AMG 706, AMG 714, AMG 745, AMG 785, AMG 811, AMG 827, AMG 837, AMG 853, AMG 951, Amiodarone Hydrochloride Injection (Amiodarone Hydrochloride Injection), Amobarbital Sodium Injection (Amytal Sodium), Amytal Sodium (Amobarbital Sodium Injection), Anakinra, Anti-Aβ, Anti-β7, Anti-β20, Anti-CD4, Anti-CD20, Anti-CD40, Anti-IFNα, Anti-IL13, Anti-OX40L, Anti-oxLDS, Anti-NGF, Anti-NRP1,Arixtra, Amphadase (hyaluronidase injection), Ammonur (sodium phenylacetate and sodium benzoate injection), Anaprox, Anzemet injection (dolasetron mesylate injection), Apidra (insulin glulisine [rDNA-derived] injection), Apomab, Aranesp (darbepoetin alfa), Argatroban (argatroban injection), Arginine hydrochloride injection (R-Gene 10, Aristocort, Aristospan, arsenic trioxide injection (Trisenox), Altican hydrochloride and epinephrine injection (Septocain), Alzera (ofatumumab injection), Asclera (polidocanol injection), ataluren, ataluren-DMD, atenolol injection (Tenormin intravenous infusion), atracurium besilate injection (atracurium besilate injection), Avastin, Azactam injection (aztreonam injection), azithromycin (Zithromax) Injection), Aztreonam Injection (Azactam Injection), Baclofen Injection (Lioresal Intrathecal), Bacteriostatic Water (Bacteriostatic Water for Injection), Baclofen Injection (Lioresal Intrathecal), Valuin Oil Ampoule (Dimercarprol Injection), BayHepB, BayTet, Benadryl, Bendamustine Hydrochloride Injection (Trenda), Benztropine Mesylate Injection (Cogentin), Betamethasone Injectable Suspension (Celeston Solspan), Bexar, Bisilin CR 900 / 300 (Penicillin G Benzathine and Penicillin G Progain Injection), Blenoxan (Bleomycin Sulfate Injection), Bleomycin Sulfate Injection (Blenoxan), Boniva Injection (Ibandronate Sodium Injection), Botox Cosmetic (Onabotulinum Toxin A for Injection), BR3-FC, Bravere (Urofollitropin Injection), Bretylium (Bretylium Tosylate Injection), Brevital Sodium (Methohexital Sodium for Injection), Bretin, Briobercept, BTT-1023, Bupivacaine Hydrochloride, Byetta, Ca-DTPA (Calcium Pentetate Trisodium Injection), Cabazitaxel Injection (Jevtana), Caffeine Alkaloids (Caffeine and Sodium Benzoate Injection), Calcigex Injection (Calcitrol), Calcitrol (Calcigex Injection),Calcium chloride (Calcium chloride injection 10%), versenate calcium disodium (edetate calcium disodium injection), Campas (artemtuzumab), Camptosar injection (irinotecan hydrochloride), canakinumab injection (Ilaris), Capastatin sulfate (capreomycin for injection), Capreomycin for injection (capastatin sulfate), Cardiolite (preparation kit for technetium Tc99 sestamibi for injection), Carticel, Casflo, cefazolin and dextrose for injection (cefazolin injection), cefepime hydrochloride, cefotaxime, cefepime Futriaxone, Cerezyme, Carnitor Injection, Caverject, Celeston Solspan, Celsior, Cerebix (fosphenytoin sodium injection), Ceredase (alglucerase injection), Seretec (technetium Tc99m exametazyme injection), certolizumab, CF-101, chloramphenicol sodium succinate (chloramphenicol sodium succinate injection), chloramphenicol sodium succinate injection (chloramphenicol sodium succinate), Cholestagel (colesevelam HCl), Coligona Dotropin alfa injection (Ovidrel), Cimzia, Cisplatin (Cisplatin injection), Chlor (Clofarabine injection), Clomiphine citrate, Clonidine injection (Duraclone), Cogentin (Ventropine mesylate injection), Colistimeth injection (Colimycin M), Colistimeth M (Colistimeth injection), Compass, Conivaptan hydrochloride injection (Baprisol), Injectable conjugated estrogens (Premarin injection), Copaxone, Injectable corticorelin ovine triflate (Axrel), Colbert (Ibutilide fumarate) sodium chloride injection), Cubicin (daptomycin injection), CF-101, Cyanokit (hydroxocobalamin for injection), cytarabine liposome injection (DepoCyt), cyanocobalamin, Cytoven (ganciclovir), DHE45, dacetuzumab, Dacogen (decitabine injection), dalteparin, Dantrium IV (dantrolene sodium for injection), dantrolene sodium for injection (Dantrium IV), daptomycin injection (Cubicin), darbepoetin alfa, DDAVP injection (desmopressin acetate injection), Decabax,Decitabine Injection (Dacogen), Dehydrated Alcohol (Dehydrated Alcohol Injection), Denosumab Injection (Prolia), Delatestril, Delestrogen, Delteparin Sodium, Depacon (Sodium Valproate Injection), DepoMedrol (Methylprednisolone Acetate Injection Suspension), DepoCyte (Cytarabine Liposomal Injection), Depodur (Morphine XR Liposomal Injection), Desmopressin Acetate Injection (DDAVP Injection), Depoestradiol, DepoProvera 104mg / ml, DepoProvera 150mg / ml, DepoTestosterone, Dexrazoxane for Injection, Intravenous Infusion Only (Totect), Glucose / Electrolytes, Glucose and Sodium Chloride Injection (5% Glucose in 0.9% Sodium Chloride), Glucose, Diazepam Injection (Diazepam Injection), Digoxin Injection (Lanoxin Injection), Dilaudid HP (Hydromorphone Hydrochloride Injection), Dimer Carprol Injection (in oil inval ampoules), Diphenhydramine Injection (Benadryl Injection), Dipyridamole Injection (Dipyridamole Injection), DMOAD, Injectable Docetaxel (Taxotere), Dolasetron Mesylate Injection (Anzemet Injection), Dorivax (Injectable Doripenem), Injectable Doripenem (Drivax), Doxercalciferol Injection (Hectol Injection), Doxil (Doxorubicin Hcl Liposomal Injection), Doxorubicin Hcl Liposomal Injection (Doxil), Duramorph (Morphine Injection), Dysport (Abobotulinum Toxin A Injection), Ecallantide Injection ( Carbitol), EC-Naprosyn (naproxen), edetate calcium disodium injection (versenate calcium disodium), Edex (injectable alprostadil), Engelix, edrophonium injection (Enron), eliglustat tartrate, Eloxatin (oxaliplatin injection), Emend injection (fosaprepitant dimeglumine injection), enalaprilat injection (enalaprilat injection), Enron (edrophonium injection), enoxaparin sodium injection (Lavenox), Eovist (gadoxetate disodium injection), Enbrel (etanercept), enoxaparin, Epicel, epinepherine, Epipen, Epipen Junior, epratuzumab,Erbitux, Ertapenem Injection (Invanz), Erythropoietin, Essential Amino Acid Injection (Nephramin), Estradiol Cypionate, Estradiol Valerate, Etanercept, Exenatide Injection (Byetta), Ebrotra, Fabrazyme (Adalusidase β), Famotidine Injection, FDG (Fludeoxyglucose F18 Injection), Ferahem (Ferumoxytol Injection), Feridex IV (Ferumoxide Injection), Fertinex, Ferumoxide Injection (Feridex IV), Ferumoxytol Injection (Ferahem), Flagyl Injection (Metronidazole Injection), Fluarix, Fludara (Fludarabine Phosphate), Fludeoxyglucose F18 Injection (FDG), Fluorescein Injection (Ak-Fluor), Follitropin AQ Cartridge (Follitropin beta injection), follitropin alfa injection (Gonal-f RFF), follitropin beta injection (Follistim AQ cartridge), Folotin (pralatrexate intravenous solution), fondaparinux, Forteo (teriparatide (rDNA-derived) injection), fostamatinib, fosaprepitant dimeglumine injection (Emend injection), foscarnet sodium injection (Foscavir), Foscavir (foscarnet sodium injection), fosphenytoin sodium injection (Cerebyx), fosproporpol disodium injection (Lucedra), Fragmin, Fuzeon (enfuvirtide), GA101, gadobenat dimeglumine injection (Multihance), gadofosbecet trisodium injection (Ablavar), gadoteridol injection (ProHance), gadoversetamide injection (OptiMARK), gadoxetate disodium injection (Eovist), ganirelix (ganirelix acetate injection), Gardasil, GC1008, GDFD, gemtuzumab ozogamicin ion injection (Mylotarg), Genotropin, gentamicin injection, GENZ-112638, golimumab injection (Simponi injection), Gonal-f RFF (follitropin alfa injection), granisetron hydrochloride (Kytril injection), gentamicin sulfate, glatiramer acetate, Glucagen, glucagon, HAE1, Haldol (haloperidol injection),Havlix, Hector injection (doxercalciferol injection), hedgehog pathway inhibitor, heparin, Herceptin, hG-CSF, Humalog, human growth hormone, Humatrope, HuMax, Humegon, Humira, Humulin, ibandronate sodium injection (Boniva injection), ibuprofen lysine injection (Neoprofen), ibutilide fumarate injection (Corvert), idamycin PFS (idarubicin hydrochloride injection) drug), idarubicin hydrochloride injection (idamycin PFS), Ilaris (canakinumab injection), injectable imipenem and cilastatin (Primaxin IV), Imitrex, incobotulinumtoxinA injection (Xeomin), Increx (mecasermin [rDNA-derived] injection), Indocin IV (indomethacin injection), indomethacin injection (Indocin IV), Infanrix, Innohept, insulin, insulin aspart [rDNA-derived, ] Injection (NovoLog), Insulin glargine [rDNA-derived] Injection (Lantus), Insulin glulisine [rDNA-derived] Injection (Apidra), Interferon α-2b, Recombinant for Injection (Intron A), Intron A (Interferon α-2b, Recombinant for Injection), Invantz (Ertapenem Injection), Invega Sustena (Paliperidone Palmitate Extended-Release Injectable Suspension), Invirase (Saquinavir Mesilate), Lobenguan 1123 Intravenous Injection (AdreView), Iopromide Injection (Ultravist), Ioversol Injection (Optiray Injection), Iprex (Mecasermin Linfabate [rDNA-derived] Injection), Iprivasc, Irinotecan Hydrochloride (Camptosar Injection), Iron Sucrose Injection (Venofer), Istodax (Injection Romidepsin), Itraconazole Injection (Sporanox Injection), Jevtana (Cabazitaxel Injection), Jonexa, Carbitol (Ecallantide Injection), KCL in D5NS (Potassium Chloride and Sodium Chloride Injection in 5% Dextrose), KCL in D5W, KCL in NS, Kenalog 10 Injection (Triamcinolone Acetonide Injectable Suspension), Kepivance (Palifermin), Keppra Injection (Levetiracetam), Keratinocyte, KFG, Kinase Inhibitors, Kineret (Anakinra), Kinlytic (Urokinase Injection), Kinrix, Klonopin (Clonazepam), Kytril Injection (Granisetron Hydrochloride), Lacosamide Tablets and Injection (Vinpat), Lactated Ringer's Solution, Lanoxin Injection (Digoxin Injection), Injectable Lansoprazole (Prevacid IV), Lantus , Leucovorin calcium (leucovorin calcium injection), Lente (L), leptin, Levemir, leukinsargramostim, leuprolide acetate, levothyroxine, levetiracetam (Kepra injection), Labenox, levocarnitine injection (Carnitol injection), Rexcan (Regadenoson injection), Lioresal intrathecal (baclofen injection), liraglutide [rDNA] injection (Victoza), Labenox (enoxaparin sodium injection), Lucentis (ranibizumab injection), Lumizyme, Lupron (leuprolide acetate injection), Lucedra (fospropofol disodium injection), Machi,Magnesium sulfate (magnesium sulfate injection), mannitol injection (mannitol IV), Marcaine (bupivacaine hydrochloride and epinephrine injection), Maxipim (cefepime hydrochloride for injection), MDP multi-dose kit of technetium injection (technetium Tc99m medronate injection), mecasermin [rDNA-derived] injection (Inclelex), mecasermin rinfabate [rDNA-derived] injection (Iplex), melphalan hydrochloride injection (Alkeran injection), methotrexate, Menactra, Menopur (menotropin injection) ), Injectable Menotropin (Repronex), Injectable Methohexital Sodium (Brevital Sodium), Methyldoped Hydrochloride Injection, Liquid (Methyldoped Acid Hcl), Methylene Blue (Methylene Blue Injection), Methylprednisolone Acetate Injectable Suspension (Depo-Medrol), MetMab, Metoclopramide Injection (Reglan Injection), Metrodin (Urofollitropin Injection), Metronidazole Injection (Flagyl Injection), Miacalcin, Midazolam (Midazolam Injection), Minpara (Sinakare), Minocin Injection (Minocycline) Injection), Minocycline Injection (Minocin Injection), Mipomersen, Mitoxantrone Injectable Concentrate (Novantrone), Morphine Injection (Duramorph), Morphine Sulfate XR Liposomal Injection (Depodur), Sodium Morphate (Sodium Morphate Injection), Motesanib, Mozobil (Plerixafor Injection), Multihans (Gadobenate Dimeglumine Injection), Multiple Electrolytes and Dextrose Injection, Multiple Electrolytes Injection, Mylotarg (Gemtuzumab Ozogamicin for Injection), Myozyme (Alglucosidase Alfa), Nafcillin Injection (Nafcillin Sodium), Nafcillin Sodium (Nafcillin Injection), Naltrexone XR Injection (Vivitrol), Naprosyn (Naproxen), Neoprofen (Ibuprofen Lysine Injection), Nandrol Decanoate, Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection), NEO-GAA, Neotect (Technetium Tc99m Depreotide Injection), Nephlamin (Essential Amino Acid Injection), Neulasta (Pegfilgrastim), Neupogen (Filgrastim), Novolin, Novolog, Neolicormon,Nutrexin (Trimetrexate Glucuronate Injection), NPH(N), Nexsteron (Amiodarone Hydrochloride Injection), Norditropin (Somatropin Injection), Saline (Sodium Chloride Injection), Novantrone (Mitoxantrone Injection Concentrate), Novolin 70 / 30 Innolet (70% NPH, Human Insulin Isophane Suspension and 30% Regular Human Insulin Injection), Novolog (Insulin Aspart [rDNA-derived] Injection), Nplate (Romiplostim), Nutropin (Somatropin for Injection (rDNA-derived)), Nutropin AQ, Nutropin Depot (Somatropin for Injection (rDNA-derived)), Octreotide Acetate Injection (Sandostatin LAR), Ocrelizumab, Ofatumumab Injection (Arzerra), Olanzapine Sustained-Release Injectable Suspension (Zyprexa Relprevv), Omnitarg, Omnitrope (somatropin [rDNA-derived]) injection), ondansetron hydrochloride injection (Zofran injection), OptiMARK (gadoversetamide injection), Optiray injection (iobersol injection), Orencia, osmitrol injection in Aviva (mannitol injection in Aviva 250 plastic container), osmitrol injection in Viaflex (mannitol injection in Viaflex 250 plastic container), osteoprotegrin, Ovidrel (chorionic gonadotropin alfa injection), oxacillin (oxacillin for injection), oxaliplatin injection (Eloxatin), oxytocin injection (Pitocin), paliperidone palmitate sustained-release injectable suspension (Invegasus Tena), Pamidronate Disodium Injection (Pamidrone Disodium Injection), Intravenous Panitumumab Injection (Vectibix), Papaverine Hydrochloride Injection (Papaverine Injection), Papaverine Injection (Papaverine Hydrochloride Injection), Parathyroid Hormone, Paricalcitol Injectable Flip-Top Vial (Zemplar Injection), PARP Inhibitors, Pedialix, PEG Instron, Pegininterferon, Pegfilgrastim, Penicillin G Benzathine and Penicillin G Procaine, Calcium Pentetate Trisodium Injection (Ca-DTPA), Zinc Pentetate Trisodium Injection (Zn-DTPA), Pepcid Injection (Famotidine Injection),Pergonal, pertuzumab, phentolamine mesylate (phentolamine mesylate for injection), physostigmine salicylate (physostigmine salicylate (injection)), physostigmine salicylate (physostigmine salicylate (injection)), piperacillin and tazobactam injection (Zosyn), Pitocin (oxytocin injection), Plasma-Lite 148 (multiple electrolytes injection), Plasma-Lite 56 and dextrose (multiple electrolytes and glucose injection in a Viaflex 250 plastic container), Plasma-Lite, plerixafor injection (Mozobil), polidocanol injection (Asclera), potassium chloride, pralatrexate solution for intravenous use (Folotyn), pramlintide acetate injection (Symlin), Premarin injection (injectable conjugated estrogens), technetium Tc99 injection sestamibi preparation kit (Cardiolite), Prevacid IV (lansoprazole for injection), Primaxin IV (Imipenem and Cilastatin for injection), Prochimar, Procrit, Progesterone, Prohans (Gadoteridol injection), Prolia (Denosumab injection), Promethazine Hydrochloride Injection (Promethazine Hydrochloride Injection), Propranolol Hydrochloride Injection (Propranolol Hydrochloride Injection), Quinidine Gluconate Injection (Quinidine Injection), Quinidine Injection (Quinidine Gluconate Injection), R-Gene 10 (Arginine Hydrochloride Injection), Ranibizumab Injection (Lucentis), Ranitidine Hydrochloride Injection (Zantac Injection), Raptiva, Reclus (Zoledronic acid injection), Recombivarix HB, Regadenoson Injection (Rexiscan), Reglan Injection (metoclopramide injection), Remicade, Renagel, Renbella (sevelamer carbonate), Repronex (injectable menotropin), Retrovir IV (zidovudine injection), rhApo2L / TRAIL, Ringer's and 5% dextrose injection (Ringer's in dextrose), Ringer's injection (Ringer's injection), Rituxan, rituximab, Rocephin (ceftriaxone), rocuronium bromide injection (Zemron), Roferon-A (interferon alpha-2a), Romazicon (flumazenil), romidepsin for injection (Istodax), Saizen (somatropin injection), Sandostatin LAR (octreotide acetate injection),Sclerostin Ab, Sensipar (Cinacalcet), Sensakyne (Bupivacaine Hydrochloride Injection), Septokyne (Altican Hydrochloride and Epinephrine Injection), Serostim LQ (Somatropin (rDNA-derived) Injection), Simponi Injection (Golimumab Injection), Sodium Acetate (Sodium Acetate Injection), Sodium Bicarbonate (Sodium Bicarbonate 5% Injection), Sodium Lactate (Sodium Lactate Injection in AVIVA), Sodium Phenylactate and and sodium benzoate injection (Ammonul), injectable somatropin (rDNA-derived) (Nutropin), Sporanox injection (itraconazole injection), Stelara injection (ustekinumab), Stemgen, Sufenta (sufentanil citrate injection), sufentanil citrate injection (Sufenta), Smavel, sumatriptan injection (Arsma), Symlin, Symlin Pen, systemic hedgehog antagonist, Symviskwan (Hylan GF 20 single-agent intra-articular injection), Tarceva, Taxotere (docetaxel for injection), technetium Tc99m, injectable telavancin (Vibativ), temsirolimus injection (Toricel), Tenormin IV Injection (atenolol injection), teriparatide (rDNA-derived) injection (Forteo), testosterone cypionate, testosterone enanthate, testosterone propionate, tebutropin (somatropin, rDNA-derived, for injection), tgAAC94, thallium chloride, theophylline, thiotepa (thiotepa injection), thymoglobulin (antithymocyte globulin (rabbit)), thyrogen (thyrotropin alpha for injection), ticarcillin disodium and clavulanate potassium Galaxy (Timentin injection), Taigan injection (trimethobenz Amino acid (injection)), Trianda (bendamustine hydrochloride injection), Trelstar (triptorelin pamoate injection suspension), triamcinolone acetonide, triamcinolone diacetate,Triamcinolone hexacetonide injectable suspension (Aristospan Injection 20 mg), Trilicense (triamcinolone acetonide injectable suspension), trimethobenzamide hydrochloride injection (Tygan Injection), trimetrexate glucuronate injection (Nutrexin), triptorelin pamoate for injectable suspension (Trelstar), Twinject, Trivaris (triamcinolone acetonide injectable suspension), Trisenox (arsenic trioxide injection), Twinrix, Typhoid Vi, Ultravist (iopromide injection), urofollitropin for injection (Metrozine), urokinase injection (Kinlytic), Ustekinu, Mab (Stelara Injection), Ultralente (U), Valium (diazepam), Sodium Valproate Injection (Depacone), Valtropin (Somatropin Injection), Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection), Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride), Baprizol (Conivaptan Hydrochloride Injection), VAQTA, Vasovist (Gadofosbecet Trisodium Injection for Intravenous Use), Vectibix (Panitumumab Injection for Intravenous Use), Venofer (Iron Sucrose Injection) , verteporfin injection (Visudyne), Vibativ (telavancin for injection), Victoza (liraglutide "rDNA" injection), Vimpat (lacosamide tablets and injection), vinblastine sulfate (vinblastine sulfate injection), Vincasar PFS (vincristine sulfate injection), Victoza, vincristine sulfate (vincristine sulfate injection), Visudyne (verteporfin injection), vitamin B-12, Vivitrol (naltrexone XR injection), Voluven (hydroxyethyl starch injection in sodium chloride), Xeloda, Xenical (orlistat), Xeomin (incobotulinumtoxinA for injection), Xolair, Zantac injection (ranitidine hydrochloride injection), Zemplar injection (paricalcitol injectable flip-top vial), Zemlon (rocuronium bromide injection), Zenapax (daclizumab), Zevalin, zidovudine injection (retrovir IV), Zithromax injection (azithromycin), Zn-DTPA (zinc pentetate trisodium injection), Zofran injection (ondansetron hydrochloride injection), Zingo, zoledronic acid for injection (Zometa), zoledronic acid injection (Reclus), Zometa (zoledronic acid for injection), Zosyn (piperacillin and tazobactam injection), Zyprexarelprev (olanzapine extended-release injectable suspension), and combinations thereof.

[0199] Announcement The invention of this application has been described above both generically and with reference to specific embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments without departing from the scope of the present disclosure. Therefore, it is intended that the embodiments cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

1. 1. A stopper for a syringe, said stopper comprising: a body having a front end, a rear end, and an exterior surface extending between the front end and the rear end, the exterior surface being operable to sealingly and slidably engage a barrel of a syringe; the body of the stopper has an inner surface and a pocket having a first end and a second end, the pocket being defined by the inner surface, the body further having an opening to the second end of the pocket formed at a rear end of the body; the pocket includes a trap portion having a first diameter, a relief portion having a second diameter, and a junction portion between the trap portion and the relief portion having a third diameter smaller than the first diameter and the second diameter; A stopper for a syringe, wherein the inner surface of the body includes one or more coupling protrusions that correspond to the coupling portions of the pocket.

2. The stopper of claim 1 , wherein the one or more coupling projections include a circumferential ridge.

3. 3. The stopper of claim 2, wherein said circumferential ridge extends continuously around the periphery of said pocket.

4. The stopper of any one of claims 1 to 3, wherein the one or more coupling projections include longitudinal ridges.

5. The stopper of any one of claims 1 to 4, wherein the one or more coupling projections have a leading edge and a trailing edge, and further wherein at least the leading edge is at least one of angled and rounded.

6. The stopper of any one of claims 1 to 5, wherein the first diameter is approximately the same as the second diameter.

7. The stopper according to any one of claims 1 to 6, wherein the third diameter is at least 10% smaller than the first diameter and / or the second diameter.

8. The stopper of any one of claims 1 to 7, wherein the first diameter differs from the third diameter by about 0.3 mm.

9. The stopper of any one of claims 1 to 8, wherein the second diameter differs from the third diameter by about 0.3 mm.

10. 10. The stopper of any one of claims 1 to 9, wherein the stopper is configured to exhibit an insertion force that is less than 75% of the breakaway force of the stopper when received in a syringe barrel, and optionally no more than 50% of the breakaway force of the stopper when received in a syringe barrel.

11. 11. The stopper according to any one of claims 1 to 10, wherein the coupling projection is a circumferential ridge and the stopper is characterized by an Lp / L value that is greater than 0, optionally greater than 0.05 and equal to or less than 0.5, or optionally equal to or less than 0.3, or optionally equal to or less than 0.2, or optionally between 0.1 and 0.

2.

12. a barrel having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper disposed within the receiving chamber and slidably and sealingly engaging the inner surface of the barrel, the stopper having a pocket including a trap portion having a first diameter, a relief portion having a second diameter, and a mating portion between the trap portion and the relief portion having a third diameter smaller than the first diameter and the second diameter, the stopper including one or more mating protrusions corresponding to the mating portion of the pocket; a plunger rod having a head portion, a rear portion, and a rod portion extending between the head portion and the rear portion, wherein the head portion has a tapered crown and defines a retention feature that engages the coupling portion of the pocket to couple the plunger rod to the stopper, and wherein the head portion is received in the capture portion of the stopper; , a syringe.

13. 13. The syringe of claim 12, wherein the tapered crown has a smooth surface for slidably engaging one or more coupling protrusions of the coupling portion when the head portion of the plunger rod is inserted into the pocket of the stopper.

14. 14. The syringe of claim 12 or 13, wherein the stopper and the barrel define a separation force, and the stopper and the plunger rod are configured such that, when the stopper is received in the barrel, a head portion of the plunger rod can be axially inserted into the stopper with an insertion force smaller than the separation force.

15. 15. The syringe of claim 14, wherein the separation force is between 2N and 20N.

16. 16. The syringe of claim 14 or 15, wherein the stopper is configured to exhibit an insertion force of less than 75% of the withdrawal force of the stopper, and optionally no more than 50% of the withdrawal force.

17. The syringe of any one of claims 12 to 16, wherein the stopper and plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper.

18. A syringe according to claim 14 when dependent on any one of claims 14 to 17, wherein the separation force is greater than the breakaway force.

19. 19. The stopper according to any one of claims 12 to 18, wherein the Lp / L value is greater than 0, optionally greater than 0.05, and not greater than 0.5, optionally not greater than 0.3, or optionally not greater than 0.2, or optionally between 0.1 and 0.

2.

20. A method for coupling a plunger rod to a stopper disposed within a barrel of a syringe, the method comprising axially inserting a head portion of the plunger rod into a pocket of the stopper with an insertion force less than a separation force defined between the stopper and the barrel of the syringe, wherein the plunger rod is coupled to the stopper when the head portion of the plunger rod is axially inserted into a capture portion of the stopper.

21. 21. The method of claim 20, wherein inserting the head portion into the pocket includes sliding a tapered crown of the head portion of the plunger rod over one or more coupling protrusions corresponding to coupling portions of the pocket to couple the plunger rod to the stopper.

22. The method of claim 21 , wherein the one or more coupling protrusions include one or more longitudinally extending ridges and / or one or more circumferentially extending ridges.

23. 23. The method of any one of claims 20 to 22, wherein inserting the head portion into the pocket comprises sliding the head portion of the plunger rod over one or more coupling protrusions having a leading edge and a trailing edge, and wherein at least the leading edge is at least one of angled and rounded, and wherein inserting the head portion into the pocket comprises sliding the head portion longitudinally over the leading edges of the one or more coupling protrusions.

24. The method of claim 23, wherein the separation force is between 2N and 20N.

25. The method of any one of claims 20 to 24, wherein the stopper and plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper.

26. The method of claim 25 , wherein the separation force is greater than the breakaway force.

27. A method according to any one of claims 20 to 26, wherein the stopper is configured to exhibit an insertion force of less than 75% of the withdrawal force, and optionally no more than 50% of the withdrawal force.

28. 28. The method of any one of claims 20 to 27, wherein the stopper is characterized by an Lp / L value that is greater than 0, optionally greater than 0.05, and less than or equal to 0.5, or optionally less than or equal to 0.3, or optionally less than or equal to 0.2, or optionally between 0.1 and 0.

2.

29. 1. A stopper for a syringe, said stopper comprising: a body having a front end, a rear end, and an exterior surface extending between said front end and said rear end, said exterior surface operable to sealingly and slidably engage a barrel of a syringe; the body of the stopper has an inner surface and a pocket having a first end and a second end, the pocket being defined by the inner surface, the body further having an opening to the second end of the pocket formed at a rear end of the body; the pocket includes a trap portion having a first diameter, a relief portion having a second diameter, and a junction portion between the trap portion and the relief portion having a third diameter smaller than the first diameter and the second diameter; A stopper for a syringe, wherein the inner surface of the body includes one or more coupling recesses corresponding to the coupling portions of the pocket.

30. 30. The stopper of claim 29, wherein the one or more coupling recesses include a circumferential recess.

31. 31. The stopper of claim 30, wherein the circumferential recess extends continuously around the periphery of the pocket.

32. The stopper of any one of claims 29 to 30, wherein the one or more coupling recesses comprise longitudinal recesses.

33. The stopper of any one of claims 29 to 32, wherein the one or more coupling recesses have a leading edge and a trailing edge, and at least the leading edge is at least one of angled and rounded.

34. The stopper of any one of claims 29 to 33, wherein the first diameter is approximately the same as the second diameter.

35. The stopper according to any one of claims 29 to 34, wherein the third diameter is at least 10% larger than the first diameter and / or the second diameter.

36. The stopper of any one of claims 29 to 35, wherein the first diameter differs from the third diameter by about 0.3 mm.

37. The stopper of any one of claims 29 to 36, wherein the second diameter differs from the third diameter by about 0.3 mm.

38. 38. The stopper according to any one of claims 29 to 37, wherein the coupling recess is a circumferential recess and the stopper is characterized by an Lr / L value that is greater than 0, optionally greater than 0.05 and equal to or less than 0.5, or optionally equal to or less than 0.3, or optionally equal to or less than 0.2, or optionally between 0.1 and 0.

2.

39. A method for coupling a plunger rod to a stopper disposed within a barrel of a syringe, the method comprising axially inserting a head portion of the plunger rod into a pocket of the stopper with an insertion force less than a separation force defined between the stopper and the barrel of the syringe, wherein the plunger rod is coupled to the stopper when the head portion of the plunger rod is axially inserted into a capture portion of the stopper.

40. 40. The method of claim 39, wherein inserting the head portion into the pocket also includes sliding enlarged segments of the head portion of the plunger rod into one or more coupling recesses corresponding to coupling portions of the pocket to couple the plunger rod to the stopper.

41. 41. The method of claim 40, wherein the one or more coupling recesses include one or more longitudinally extending recesses and / or one or more circumferentially extending recesses.

42. 42. The method of claim 41, wherein each of the one or more coupling recesses has a leading edge and a trailing edge, at least the leading edge being at least one of angled and rounded, and inserting the head portion into the pocket comprises sliding the head portion longitudinally over the leading edge of the one or more coupling recesses and seating an enlarged segment of the head portion in the one or more coupling recesses.

43. 43. The method of any one of claims 39 to 42, wherein the separation force is between 2N and 20N, and when the plunger rod is inserted into the stopper, the stopper and the plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper.

44. 44. The method of claim 43, wherein the separation force is greater than the breakaway force.

45. 45. The method of claim 43 or 44, wherein the stopper is configured to exhibit an insertion force that is less than 75% of the breakaway force of the stopper when received in a syringe barrel, and optionally no greater than 50% of the breakaway force of the stopper when received in a syringe barrel.

46. 46. ​​The method of any one of claims 40 to 45, wherein the stopper is characterized by an Lr / L value that is greater than 0, optionally greater than 0.05, and less than or equal to 0.5, or optionally less than or equal to 0.3, or optionally less than or equal to 0.2, or optionally between 0.1 and 0.

2.

47. a barrel having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper disposed within the receiving chamber and slidably and sealingly engaging an inner surface of the barrel, the stopper having a pocket including a trap portion having a first diameter, a relief portion having a second diameter, and a mating portion between the trap portion and the relief portion having a third diameter greater than the first diameter and the second diameter, the stopper including one or more mating recesses corresponding to the mating portion of the pocket; a plunger rod having a head portion, a rear portion, and a rod portion extending between the head portion and the rear portion, the head portion defining a retention feature that engages a coupling recess in the pocket to couple the plunger rod to the stopper, the retention feature being received in one or more coupling recesses in the stopper; , a syringe.

48. 48. The syringe of claim 47, wherein the stopper and the barrel define a breakaway force, and the stopper and the plunger rod are configured such that, when the stopper is received in the barrel, a head portion of the plunger rod is axially insertable into the stopper with an insertion force less than the breakaway force.

49. 49. The syringe of claim 48, wherein the separation force is between 2N and 20N.

50. 50. The syringe of any one of claims 47 to 49, wherein the stopper and plunger rod require the application of a longitudinal separation force to separate the plunger rod from the stopper.

51. 51. The syringe of claim 50 when dependent on claim 48 or 49, wherein the separation force is greater than the breakaway force.

52. 50. The syringe of claim 48 or 49, wherein the stopper is configured to exhibit an insertion force of less than 75% of the breakaway force of the stopper when received in the syringe barrel, and optionally no more than 50% of the breakaway force of the stopper when received in the syringe barrel.

53. 53. The syringe of any one of claims 47 to 52, wherein the stopper is characterized by an Lr / L value that is greater than 0, optionally greater than 0.05, and less than or equal to 0.5, optionally less than or equal to 0.3, or optionally less than or equal to 0.2, or optionally between 0.1 and 0.2.

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