Low insertion force syringe stops, assemblies, and related methods

Abstract

The design of the plunger rod head and the syringe stop pocket helps reduce axial insertion forces while coupling the plunger rod to a stop (e.g., for a pre-filled syringe assembly). The desired axial insertion force may be lower than the associated struggling force between the stop and its associated syringe barrel, while these designs still ensure coupling of the stem head and the syringe stop and require considerable non-zero separation forces to disengage the components.

Description

Background Art

[0001] A syringe typically includes a barrel, a stopper positioned within the barrel, and a plunger rod for displacing the stopper. The stopper is typically air- and liquid-impermeable and forms an air- and liquid-tight seal with the barrel while also having low-friction slidability. Low-friction slidability is important for facilitating the discharge of liquid from the syringe.

[0002] Assembly of a syringe typically includes coupling the plunger rod to a stopper. In the assembly method of a prefilled syringe, the syringe may be filled with the therapeutic agent before the stopper is inserted into the syringe. Once the stopper has been inserted into the syringe, the plunger rod is coupled to the stopper by applying an axial force to press the plunger rod tip into the stopper, or by applying a torque or rotational force to screw the plunger rod tip into the stopper.

[0003] Some have observed that creating a connection between the plunger rod and the stopper during assembly, or the process of coupling the plunger rod and the stopper, using a screw-in or push-fit action, can cause the stopper to deform or translate (move), thereby compromising the seal integrity or sterility effectiveness of the syringe and / or therapeutic agent, and / or causing pressure within the syringe to increase, thereby causing fluid to leak from the syringe's outlet end. Some prior art designs aim to overcome these problems by assembling prefilled syringes without coupling the plunger rod to the stopper, thereby eliminating the need to manipulate or force the plunger rod to couple with the stopper. The concept disclosed by Novartis AG in U.S. Patent No. 11,185,635 employs this non-coupling approach in an effort to address the aforementioned issues. However, after initial assembly (e.g., placing the plunger rod into the syringe against the stopper), the lack of coupling between the stopper and the plunger rod means that without adding an additional stopper to the syringe, the rod is free to translate away from the stopper by an unacceptable amount (e.g., completely out of the syringe). Additional prior art assembly designs for such threaded or screw-type plunger rod assemblies include U.S. Patent No. 10,369,292, issued to WL Gore & Associates, Inc., which describes a stopper for supporting a plunger rod assembly, wherein the assembly forms an integral, non-threaded engagement with the stopper. In some embodiments, the threaded plunger rod is free to rotate within a cavity within the stopper. Summary of the Invention

[0004] Various embodiments relate to plunger rod tip and syringe stopper recess designs that facilitate reducing axial insertion force when coupling a plunger rod to a stopper in prefilled syringe designs, and associated methods and systems. Various embodiments provide for an axial insertion force that is lower than the breakaway force between the stopper and the associated syringe barrel, while still securing the rod tip and syringe stopper, and requiring a substantial non-zero separation force to disengage the components.

[0005] According to one aspect ("Aspect 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 seal and slidably engage the barrel of the syringe; wherein the body of the stopper has an inner surface and a recess having a first end and a second end, the recess being defined by the inner surface, and the body also having an opening to the second end of the recess, the opening being formed in the rear end of the body; wherein the recess includes a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion between the capture portion and the release portion, the coupling portion having a third diameter smaller than the first diameter and the second diameter; and wherein the inner surface of the body includes one or more coupling protrusions corresponding to the coupling portion of the recess.

[0006] According to another aspect (“Aspect 2”) further to Aspect 1, one or more coupling protrusions include a circumferential ridge.

[0007] According to another aspect ("Aspect 3") further to Aspect 2, the circumferential ridge extends continuously around the periphery of the pocket.

[0008] According to another aspect ("Aspect 4") further to any one of Aspects 1 to 3, one or more coupling protrusions include a longitudinal ridge.

[0009] According to another aspect (“Aspect 5”) further to any one of Aspects 1 to 4, one or more coupling protrusions have a leading edge and a trailing edge, and further wherein at least the leading edge is at least one of chamfered and rounded.

[0010] According to another aspect (“Aspect 6”) further to any one of Aspects 1 to 5, the first diameter is substantially the same as the second diameter.

[0011] According to another aspect (“Aspect 7”) further to any one of Aspects 1 to 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 aspect ("Aspect 8") further to any one of Aspects 1 to 7, the first diameter differs from the third diameter by about 0.3 mm.

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

[0014] According to another aspect ("Aspect 10"), a syringe includes a syringe having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper positioned in the receiving chamber so that the stopper can slide and sealingly engage with the inner surface of the syringe, the stopper having a recess, the recess including a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion located between the capture portion and the release 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 recess; and a plunger rod having a head, a rear portion, and a rod portion extending between the head and the rear portion, the head having a tapered crown and defining a retaining feature that engages with the coupling portion of the recess to couple the plunger rod to the stopper, wherein the head is received in the capture portion of the stopper.

[0015] According to another aspect ("Aspect 11") further to Aspect 10, the tapered crown has a smooth surface for slidably engaging with the one or more coupling protrusions of the coupling portion during insertion of the plunger rod head into the recess of the stopper.

[0016] According to another aspect ("Aspect 12") further than Aspect 10 or 11, the stopper and the syringe limit a break-away force, and the stopper and the plunger rod are configured so that the plunger rod head can be axially inserted into the stopper, wherein the stopper is received in the syringe with an insertion force less than the break-away force.

[0017] According to another aspect (“Aspect 13”) further than Aspect 12, the breakaway force is 2N to 20N.

[0018] According to another aspect (“Aspect 14”) further to any one of Aspects 10 to 13, the plunger rod and the stopper require a separation force to be applied in a longitudinal direction to disengage the plunger rod from the stopper.

[0019] According to another aspect (“Aspect 15”) further than Aspect 14, when the features of Aspect 12 or 13 are included, the separation force is greater than the break-away force.

[0020] According to another aspect ("Aspect 16"), a method of coupling a plunger rod to a stopper positioned within a barrel of a syringe includes axially inserting a head of the plunger rod into a recess of the stopper using an insertion force that is less than a break-away force defined between the stopper and the barrel of the syringe, wherein the plunger rod is coupled to the stopper when the head of the plunger rod is axially inserted into a capture portion of the stopper.

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

[0022] According to another aspect ("Aspect 18") further 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") further than any one of Aspects 16 to 18, inserting the head into the recess comprises sliding the head of the plunger rod over one or more coupling protrusions having a leading edge and a trailing edge, and further wherein at least the leading edge is at least one of chamfered and rounded, and further wherein inserting the head into the recess comprises sliding the head longitudinally over the leading edge of the one or more coupling protrusions.

[0024] According to another aspect (“Aspect 20”) further than Aspect 19, the breakaway force is 2N to 20N.

[0025] According to another aspect (“Aspect 21 ”) further to any one of Aspects 16 to 20 , the plunger rod and the stopper require a separating force to be applied in a longitudinal direction to disengage the plunger rod from the stopper.

[0026] According to another aspect (“Aspect 22”) further than Aspect 21, the separation force is greater than the break-away 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, the outer surface being operable to seal and slidably engage the barrel of the syringe; wherein the body of the stopper has an inner surface and a recess having a first end and a second end, the recess being defined by the inner surface, and the body also having an opening to the second end of the recess, the opening being formed in the rear end of the body; wherein the recess includes a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion between the capture portion and the release portion, the coupling portion having a third diameter smaller than the first diameter and the second diameter; and wherein the inner surface of the body includes one or more coupling recesses corresponding to the coupling portion of the recess.

[0028] According to another aspect (“Aspect 24”) further to Aspect 23, the one or more coupling recesses include circumferential recesses.

[0029] According to another aspect (“Aspect 25”) further to Aspect 24, the circumferential recess extends continuously around the periphery of the pocket.

[0030] According to another aspect ("Aspect 26") further to any one of Aspects 23 to 25, the one or more coupling recesses include longitudinal recesses.

[0031] According to another aspect (“Aspect 27”) further to any one 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 chamfered and rounded.

[0032] According to another aspect (“Aspect 28”) further to any one of Aspects 23 to 27, the first diameter is substantially the same as the second diameter.

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

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

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

[0036] According to another aspect ("Aspect 32"), a method of coupling a plunger rod to a stopper positioned within a barrel of a syringe comprises axially inserting a head of the plunger rod into a recess of the stopper using an insertion force, wherein the insertion force is less than a break-away force defined between the stopper and the barrel of the syringe, wherein the plunger rod is coupled to the stopper when the head of the plunger rod is axially inserted into a capture portion of the stopper.

[0037] According to another aspect ("Aspect 33") further to Aspect 32, inserting the head into the recess also includes sliding the enlarged section of the head of the plunger rod into one or more coupling recesses corresponding to the coupling portion of the recess so as to couple the plunger rod to the stopper.

[0038] According to another aspect (“Aspect 34”) further 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") further than Aspect 34, each of the one or more coupling recesses has a leading edge and a trailing edge, wherein at least the leading edge is one of chamfered or rounded, and inserting the head into the recess includes sliding the head longitudinally over the leading edge of the one or more coupling recesses so that the enlarged section of the head is seated in the one or more coupling recesses.

[0040] According to another aspect ("Aspect 36") further than any one of Aspects 32 to 35, the break-away force is 2N to 20N, and once the plunger rod is inserted into the stopper, the stopper and the plunger rod require a separation force applied in the longitudinal direction to separate the plunger rod from the stopper.

[0041] According to another aspect ("Aspect 37") further than Aspect 36, the separation force is greater than the break-away force.

[0042] According to another aspect ("Aspect 38"), a syringe includes a syringe having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper positioned in the receiving chamber so that the stopper can slide and sealingly engage with the inner surface of the syringe, the stopper having a recess, the recess including a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion located between the capture portion and the release portion, the coupling portion having a third diameter greater than the first diameter and the second diameter, the stopper including one or more coupling recesses corresponding to the coupling portion of the recess; and a plunger rod having a head, a rear portion, and a rod portion extending between the head and the rear portion, the head defining a retaining feature that engages with the coupling recess of the recess to connect the plunger rod to the stopper, wherein the retaining feature is received in the one or more coupling recesses of the stopper.

[0043] According to another aspect ("Aspect 39") further than Aspect 38, the stopper and the syringe limit a break-away force, and the stopper and the plunger rod are configured so that the plunger rod head can be axially inserted into the stopper, wherein the stopper is received in the syringe with an insertion force less than the break-away force.

[0044] According to another aspect (“Aspect 40”) further than Aspect 39, the break-away force is 2N to 20N.

[0045] According to another aspect (“Aspect 41 ”) further to any one of Aspects 38 to 40 , the plunger rod and the stopper require a separating force to be applied in a longitudinal direction to disengage the plunger rod from the stopper.

[0046] According to another aspect (“Aspect 42”) further than Aspect 41 , when the features of Aspect 39 or 40 are included, the separation force is greater than the break-away force.

[0047] In accordance with any of the foregoing aspects, the stopper can be configured to exhibit an insertion force that is less than 75% of the break-away force of the stopper when received in the syringe barrel, and optionally, to exhibit an insertion force that is less than 50% or less of the break-away force of the stopper when received in the syringe barrel.

[0048] According to any of the preceding aspects, the stopper may be characterized by an Lp / L or Lr / L value that is greater than 0, optionally 0.05, and 0.5 or less, optionally 0.3 or less, or optionally 0.2 or less, these ratios being as defined herein. According to any of the preceding aspects, the Lp / L or Lr / L value is, for example, 0.1 to 0.2.

[0049] The foregoing aspects are merely aspects and should not be construed as limiting or otherwise narrowing the scope of any inventive concept otherwise provided by this disclosure. Although multiple aspects have been disclosed, other embodiments and related features of the present application 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 should be considered illustrative in nature and not restrictive in nature. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The accompanying drawings are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments and together with the description serve to explain the principles of the disclosure.

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

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

[0053] 3A and 3B are longitudinal cross-sectional views illustrating prior art stopper and plunger rod coupling features.

[0054] Figure 3C and 3Dis an overview diagram of a stopper design according to some embodiments.

[0055] Figure 3E is an enlarged view of one end of the plunger rod of Figures 3A and 3B, according to some embodiments.

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

[0057] Figures 5 to 15B Shown is a diagram for use according to some embodiments Figure 1 and 2 Various stopper recess designs for syringes.

[0058] Figures 16 to 18B Shown is a diagram for use according to some embodiments Figure 1 and 2 Various plunger rod designs for syringes. DETAILED DESCRIPTION Definitions and Terminology

[0059] This disclosure is not intended to be read in a limiting manner.For example, the terms used in this application should be read broadly in the context of the meaning that one skilled in the art would attribute to such terms.

[0060] The use of headings is provided solely to facilitate reference to the specification and is not intended to isolate or otherwise designate concepts under one heading as inapplicable or otherwise unrelated to concepts under another heading. In fact, the opposite is intended, and the specification is intended to be read and interpreted as a whole, with various features and aspects of certain embodiments being applicable to various other embodiments described herein.

[0061] Regarding imprecise terms, the terms "about" and "approximately" are used interchangeably to refer to a measurement value including the stated measurement value and also any measurement value that is reasonably (fairly) close to the stated measurement value. As understood and readily determined by a person of ordinary skill in the relevant art, a measurement value that is reasonably (fairly) close to the stated measurement value deviates from the stated measurement value by a reasonably small amount. Such deviations may be due to, for example, measurement errors, differences in measurement value and / or manufacturing equipment calibration, human error in reading and / or setting the measurement value, fine-tuning performed to optimize performance and / or structural parameters taking into account differences in measurement values associated with other components, specific implementation scenarios, imprecise adjustments and / or manipulations of an object by a person or machine, and / or the like. Where it is determined that a person of ordinary skill in the relevant art would not easily determine a value for such a reasonably small difference, the terms "about" and "approximately" may be understood to mean the stated value plus or minus 10%.

[0062] As used herein, the terms "elastic" and "elastomeric" refer to a material property as understood with reference to a stopper used in an injector device (e.g., in FDA-approved applications) and relates to the tendency of a material to spontaneously recover, or return to its pre-deformation shape after being deformed dimensionally (e.g., contracted, expanded, twisted, etc.).

[0063] As used herein, the term "syringe" is intended to include any of a variety of devices including a stopper received in a barrel and an actuating mechanism configured to displace the stopper within the barrel to eject or deliver the contents held within the barrel from within the barrel. The concepts disclosed herein can be used in conjunction with syringes ranging from 0.5 mL (milliliter) to 20 mL, for example, 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 (eg, the plunger rod end), while the term "distal" means further from the operator than proximal (eg, the piercing element end).

[0065] As used herein, the term "rotation" and the like (eg, "rotation (noun)") are intended to refer to circumferentially oriented motion.

[0066] As used herein, the terms "axial" insertion, translation, movement, and the like are intended to mean longitudinally oriented movement.

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

[0068] As used herein, the term "substantially free" is intended to mean an unquantifiable amount or trace amount of an identified substance (e.g., silicone, silicone oil, or other lubricant), or any amount that has not been intentionally added to the system (e.g., silicone oil has not been intentionally added to an injector device, such as a syringe or stopper).

[0069] As used herein, the term "sealing rib" refers to the rib of the stopper that contacts the inner surface of the syringe to prevent air or other contaminants from entering the syringe, or to prevent the contents of the syringe from leaving the syringe.

[0070] As used herein, the term "non-sealing rib" is intended to mean a rib that does not contact the interior surface of the syringe barrel or a rib that does not contact the interior surface of the barrel such that air (or other contaminants) and / or barrel contents may pass therethrough.

[0071] As used herein, the term "longitudinally extending" means a feature having a greater dimension in the axial or longitudinal direction than in the transverse (eg, circumferential) direction.

[0072] As used herein, the term "circumferentially extending" means a feature having a greater dimension in the transverse (eg, circumferential) direction than in the axial or longitudinal direction.

[0073] As used herein, the term "break-away force" is intended to mean the force required to initiate relative movement between the stopper and the syringe barrel after the stopper is disposed in the syringe barrel.

[0074] As used herein, the term "breakaway force" refers to the longitudinal force required to disengage the head of the plunger rod from the recess of the stopper.

[0075] As used herein, the terms "ridge" and "rib" are synonymous, as are the terms "valley" and "depression." Description of various embodiments

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

[0077] Various concepts disclosed herein relate to designs for plunger rod heads and syringe stopper recesses that help reduce axial insertion force when coupling the plunger rod to a stopper (e.g., for prefilled syringe assemblies). The desired axial insertion force can be lower than the associated breakaway force between the stopper and its associated syringe barrel, while still ensuring that the plunger rod head and syringe stopper are coupled and requiring a substantial, non-zero separation force to disengage the components. Typically, the coupling or engagement between the stopper and the plunger rod head is a non-threaded engagement. That is, the components are configured to be assembled via an axial insertion method, rather than being threaded together. In other words, at least one of the stopper recess and the plunger rod head is non-threaded, and preferably, both the stopper recess and the plunger rod head are unthreaded or do not include complementary threaded features for threaded engagement between the components. As described herein, "threaded" features are generally continuous or discontinuous, helically extending features that engage and advance via a rotational motion. As shown and described herein, in various examples, the stop and / or plunger engagement features are non-helical (eg, circumferentially continuous, circumferentially discontinuous, and / or longitudinally).

[0078] Figure 1A syringe 10 according to some examples is shown. The syringe 10 is generally operable to deliver the contents 12 of the syringe 10 by pressurizing the contents 12 so that they are expelled from the syringe 10. The syringe contents 12 may include a therapeutic agent (e.g., a medicament) delivered to a patient in association with a medical treatment. The syringe 10 may be more generally referred to as an "injector" or "injection device," and although the syringe 10 may be configured as shown, the principles described herein may be applicable to other configurations of the syringe 10, including automatic injector configurations.

[0079] As shown, the syringe 10 includes a barrel 20, also known as a "barrel," a plunger rod 22, and a stopper 24. The syringe 10 may also include a piercing element 26, but the syringe 10 is a "needle-free" device, such as a Luer-Lok syringe. TM ) system (not shown) is also within the scope of the present disclosure.

[0080] In some embodiments, the syringe 20 includes a distal end 30, a proximal end 32, an outer surface 34, and an inner surface 36, which defines or otherwise defines a receiving chamber 38 for receiving the contents 12. The syringe 20 can be made of a variety of materials, including relatively hard materials. Some suitable material examples include glass materials (e.g., borosilicate glass), ceramic materials, polymer materials (e.g., polypropylene, polyethylene, and copolymers thereof, cycloolefin polymers, and cycloolefin copolymers), metal materials, and combinations thereof. In some embodiments, the syringe 20 includes a certain amount of lubricant (not shown) present on the inner surface 36 of the syringe 20. In other embodiments, the syringe 20 does not contain a lubricant, or does not contain substantially a lubricant. As shown, the contents 12 can be pre-filled into the syringe 20 as part of the syringe assembly process (i.e., as a pre-filled syringe), however, it is also envisioned that in other applications, the contents 12 can also be drawn into the syringe 20 after the syringe 10 is assembled. The inner diameter of the syringe barrel 20 can be any of a variety of values, such as from about 3 mm to about 20 mm, or from about 5 mm to about 20 mm, although a variety of sizes are contemplated. In one example, the syringe 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 a variety of sizes are contemplated. In another example, the syringe 20 corresponds to a 20 mL syringe and has a diameter of 19.05 mm ± 0.2 mm, although a variety of sizes are contemplated.

[0081] The plunger rod 22 of the syringe 10 can be moved within the barrel 20 to expel the contents 12 by moving the stopper 24 toward the distal end 30 of the barrel 20. Figure 12. It is shown in a pre-filled state, but it is contemplated that in other applications, the syringe 20 may be filled or primed by pulling the stopper 24 in a proximal direction. Figure 2 The syringe 10 is shown in a partially assembled state, and Figure 1 The syringe 10 is shown in a fully assembled state. Some assembly methods include placing a stopper 24 in the barrel 20 with the contents 12 received therein, such as Figure 2 Then, the plunger rod 22 can be assembled to the stopper by applying an axial insertion force Fi on the plunger rod 22. Figure 2 As shown, the plunger rod 22 includes a proximal end 42, a distal end 44, a head 46 at the distal end 44, a rear portion 48 at the proximal end 42, and a rod portion 50 extending between the head 46 and the rear portion 48. For reference, the head 46 is represented by a box and an "X" because several different configurations of the head 46 are contemplated and will be described in greater detail later. Generally speaking, the head 46 is configured to couple the plunger rod 22 to the stopper 24.

[0082] like Figure 2 As shown, the stopper 24 is positioned in the receiving chamber 38 such that the stopper 24 is in slidable and sealing engagement with 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 operation). The stopper 24 has a body 60 having a front end 62, a rear end 64, and an outer surface 66 extending between the front end 62 and the rear end 64, the outer surface 66 being operable to sealingly and slidably engage the barrel 20 of the syringe 10. The body 60 also has an inner surface 68 and a recess 70 having a first end 72 and a second end 74, the recess 70 being defined by the inner surface 68. The body 60 has an opening 76 leading to the second end 74 of the recess 70, which is formed in the rear end 64 of the body 60. Similar to the head 46 of the plunger rod 22, the recess 70 is shown in generalized form with a box and an "X" because several different configurations of the recess 70 are contemplated and will be described in more detail below. The outer surface 66 of the stopper 24 optionally defines one or more ridges (also known as ribs), valleys (also known as recesses), or other features to assist in sealingly and slidably engaging the stopper 24 with the inner surface 36 of the barrel 20 .

[0083] The body 60 of the stopper 24 is made of an elastomeric material. The stopper 24 may also include a thin film cover made of a polymer material, such as a fluoropolymer material, including PTFE, ePTFE, and variations thereof. Examples of suitable stopper and thin film cover materials can be found in U.S. Patent 10,471,211 to W.L. Gore & Associates, Inc. In some examples, the thin film cover can be used as a solid lubricant. In addition to or in lieu of a lubricant (e.g., silicone oil) provided in the syringe 20, a thin film cover may also be provided on the stopper 24. The stopper 24 should generally have low air and liquid permeability to minimize and prevent the introduction of air between the stopper 24 and the inner surface 68 of the syringe 20 and the leakage of liquid within the syringe 20 when filling and / or expelling the therapeutic agent 12 of the syringe 10. The overall diameter of stopper 24 can be any of a variety of values, but in some examples, the outer diameter of a 0.5 mL syringe is from 5.2 mm to 5.5 mm + / - 0.1 mm, while the outer diameter of a 20 mL syringe is from 19.9 mm to 21 mm + / - 0.15 mm, although various sizes 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 applied directly to 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 certain amount of thin film lubricant. The thin film lubricant may also be baked or cross-linked to the solid lubricant of the stopper 24. Applying the thin film lubricant directly to the solid lubricant of the stopper 24 may help prevent the thin film lubricant from diffusing into the therapeutic agent 150. As further described herein, the thin film lubricant may also be applied to the solid lubricant (e.g., ePTFE) of the stopper 200 through a vent (ventilator) or insertion tube (not shown) or through the syringe 20. In some embodiments, the thin film lubricant may be applied directly to the syringe 20. In addition, the thin film lubricant may be applied to a limited number of portions of the syringe 20 to reduce the total amount of thin film lubricant in the system.

[0085] The thin-film lubricant can be any solid or liquid lubricant. In some embodiments, the thin-film lubricant is silicone oil. In other embodiments, the thin-film lubricant can be another lubricant such as polysorbate. Furthermore, the thin-film lubricant can be chemically or physically altered to improve its affinity for the solid lubricant, thereby reducing the amount of thin-film lubricant that is removed from the stopper 24. In some embodiments, the thin-film lubricant is configured to have a greater affinity for the solid lubricant than for the syringe 20 and / or the therapeutic agent.

[0086] The amount of thin film lubricant applied to the stopper 24 can vary. In at least one embodiment, the thin film lubricant is applied at a "low" level, which can be from about 0.3 pg (picograms) to about 100 pg per stopper 24. The amount of thin film lubricant applied to the 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, from about 10 pg to about 100 pg. From about 5 pg to about 60 pg, from about 0.3 pg to about 50 pg, from about 5 pg to about 50 pg, from about 0.3 pg to about 40 pg, from about 5 pg to about 40 pg, from about 0.3 pg to about 30 pg, from about 5 pg to about 30 pg, from about 0.3 pg to about 20 pg, from about 5 pg to about 20 pg, from about 0.3 pg to about 10 pg, from about 5 pg to about 10 pg. In terms of surface density, for a surface area of 2 cm 2 The amount of thin film lubricant present on the stopper 24 may be from about 0.15 pg / cm 2 (picograms / square centimeter) to about 50 pg / cm 2 , from about 2.5pg / cm 2 to about 50 pg / cm 2 , from about 0.15pg / cm 2 to about 45 pg / cm 2 , from about 2.5pg / cm 2 to about 45 pg / cm 2 , from about 0.15pg / cm 2 to about 40 pg / cm 2 , from about 2.5pg / cm 2 to about 40 pg / cm 2 , from about 0.15pg / cm 2 to about 35 pg / cm 2 , from about 2.5pg / cm 2 to about 35 pg / cm2, from about 0.15 pg / cm 2 to about 30 pg / cm 2 , from about 2.5pg / cm 2 to about 30 pg / cm 2 , from about 0.15pg / cm 2 to about 25 pg / cm 2 , from about 2.5pg / cm 2 to about 25 pg / cm 2 , from about 0.15pg / cm 2to about 20 pg / cm 2 , from about 2.5pg / cm 2 to about 20 pg / cm 2 , from about 0.15pg / cm 2 to about 15 pg / cm 2 , from about 2.5pg / cm 2 to about 15 pg / cm 2 , from about 0.15pg / cm 2 to about 10 pg / cm 2 , from about 2.5pg / cm 2 to about 10 pg / cm 2 , from about 0.15pg / cm 2 to about 5 pg / cm 2 , from about 2.5pg / cm 2 to about 5 pg / cm 2 Of course, the surface density may vary depending on the size of the stopper 24 .

[0087] like Figure 1 As shown, the stopper 24 contacts the inner surface 36 of the syringe 20 via one or more sealing ribs, but any number of sealing ribs and / or non-sealing ribs may be present on the stopper 24. Typically, a certain breakaway force needs to be applied in order to initiate the movement of the stopper 24 within the syringe 20. The breakaway force is typically measured as a "wet" or "dry" value (i.e., filled with liquid contents such as saline or water compared to an empty one). Typically, such measurements are made for pre-filled syringes ("wet") rather than empty syringes ("dry"). The breakaway force of a pre-filled syringe is typically 20N or less. In various examples, the breakaway force is less than 15N. In some pre-filled syringes, the breakaway force is less than about 11N or less than 9N, less than 7N, less than 5N, or between about 2N and 5N. In some examples, for a 0.5mL syringe, the target breakaway force (pre-filled or "wet") is approximately 4N, with an average range of between 2N and 8N. The break-away force or the break-away force can be assessed using a method similar to that described in Section 6 of ISO 11040-8. Reference may also be made to the sliding force measurement technique in Annex E of ISO 11040-4, which can be used to assess the break-away force. The break-away force can be measured while the stopper is moving within the syringe 20 at a travel speed of 250 mm / min (millimeters per minute). U.S. Patent No. 10,369,292 to W.L. Gore and Associates, Inc. describes various break-away forces that are expected to be encountered in pre-filled syringes. U.S. Patent No. 9,220,631 to Juergen et al. also describes various break-away forces that are expected to be encountered in pre-filled 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 "needle-less" and / or not coupled to the barrel 20 if desired (e.g., as in an automatic injection device). If 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 show the plunger rod 22 ( Figure 1 ) and a prior art stopper design 24P of the head 46 of the syringe 10. The views of Figures 3A and 3B are longitudinal cross-sectional views of the stopper 24P. The head 46P is configured to be inserted axially into the recess 70P of the stopper 24P, thereby coupling the head 46P to the stopper 24P. Figure 3A shows the head 46P in the recess 70P without the stopper 24P in a compressed state, as the stopper 24P would otherwise be placed in the syringe barrel 20. In other words, Figure 3A shows the stopper 24P in a relaxed state. Figure 3B shows the shape and interface between the stopper 24P and the recess 70P when the stopper 24P is received in the barrel 20 of the syringe 10 in a compressed state. Therefore, Figure 3B is more representative than Figure 3A of the actual interaction between the head 46P and the stopper 24P when the syringe 10 is assembled.

[0090] As shown, pocket 70P includes a capture portion 80P having an expanded diameter and a coupling portion 84P having a reduced diameter relative to the expanded diameter coupling portion 84P. As shown, capture portion 80P has a constant diameter and is cylindrical, then tapers distally or conically. Capture portion 80P extends the remainder of pocket 70P and has a constant diameter and is cylindrical.

[0091] The head 46P in turn has a tapered crown 90P having a first diameter and an enlarged section 94P defining a retention feature 96P, wherein the diameter of the enlarged section 94P decreases to a reduced section 98P having a smaller diameter than the enlarged section 94P. Figure 3E An enlarged view of the head 46P is shown. Figure 3EAs shown, in one embodiment, the head 46P defines an OD (outer diameter) diameter of approximately 2.1 mm (e.g., 2.06 mm) at the retention feature 96P, and a coupling length C of, for example, approximately 5.1 mm, wherein the combined length Lte of the tapered crown 90 and the enlarged feature 96P is, for example, approximately 1.6 mm, although a variety of sizes are contemplated. As shown in FIG3B , the enlarged section 94P engages the capture portion 80P, the retention feature 96P engages the coupling portion 84P, and the reduced section 98P also engages the coupling portion 84P. These various engagements couple the stopper 24 to the head 46P, but require a substantial axial insertion force Fi in order to insert the head 46 into the recess 70P. It is expected that the insertion force Fi in the prior art design represented by FIG3B will exceed the breakaway force associated with the stopper 24.

[0092] With respect to the interaction between the prior art recess 70P and the head 46P, it has been observed that during insertion, the stopper 24P may move or become displaced within the syringe 10 due to the axial insertion force Fi on the plunger rod 22 required to insert the head 46P into the recess 70P exceeding the breakaway force between the stopper 24P and the barrel 20. Once the breakaway force has been exceeded, the prior art stopper design 24P moves distally within the barrel 20, thereby risking ejection of the contents 12 and / or other undesirable effects (e.g., seal failure).

[0093] Figure 3C and 3D Shown Figure 1 The stopper design of the illustrated syringe is shown in a more generalized form for ease of reference. Figure 3C and 3D In FIG, the stopper is shown without a sealing rib, but such a feature is clearly envisioned. Figure 3C and 3D Modified stopper designs are shown that may be used with heads similar to head 46P, or alternative head designs, that facilitate assembly without requiring a high axial insertion force Fi (e.g., an insertion force Fi that is lower than a break-out force associated with the design of stopper 24 and the design of syringe 10 more generally). Figure 3C The stopper designs in FIG. 1 typically show coupling protrusions or ridges (also described as "ribs") for coupling, whereas Figure 3D A coupling recess or valley for coupling to the stopper rod 22 is generally shown.

[0094] like Figure 3C and 3D As shown in the design of FIG, the stopper 24 is provided with a recess 70 to facilitate a lower 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 syringe 20). Figure 1 The various features of the stopper 24 described may be applied as desired. Figure 3C and 3D As shown, the recess 70 includes a capture portion 80 having a first diameter D1, a release portion 82 having a second diameter D2, and a coupling portion 84 having a third diameter D3 located between the capture portion 80 and the release portion 82. Figure 3C In the case of , the diameter D3 is generally measured to correspond to the smallest diameter of the pocket 70 at the capture portion 80, which diameter is defined by the coupling protrusion 88. Figure 3C In the case of , the third diameter is smaller than the first diameter and the second diameter. Figure 3D In the case of , the diameter D3 is generally measured to correspond to the maximum diameter of the pocket at the capture portion 80 defined by the coupling recess 88. And, as shown, the third diameter is greater than the first and second diameters. Specifically, in Figure 3C In the case of the body 60 having an inner surface 68, the inner surface includes one or more coupling protrusions 88 corresponding to the coupling portion 84 of the recess 70. Figure 3D In this case, the body 60 has an inner surface 60 including one or more coupling recesses 88 corresponding to the coupling portions 84 of the pockets 70 .

[0095] As shown, the first diameter is substantially the same as the second diameter. Figure 3C In some embodiments of the illustrated designs, the third diameter (including the coupling protrusion 88) 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% smaller than the first and / or second diameters, or any value or range therebetween. In one non-limiting example, prior to compression within the barrel 20, the inner diameters of the first and second diameters are approximately 2.4 mm, and the inner diameter of the third diameter is 2.05 mm. In some other examples, one or more coupling protrusions protrude approximately 0.175 mm relative to the surrounding portion of the stopper 24 (on each side). Thus, in some embodiments involving coupling protrusions, the third diameter differs from the first diameter and / or the second diameter by approximately 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 sizes are contemplated.

[0096] exist Figure 3DIn some embodiments of the illustrated designs, the third diameter (including the coupling recess 88) 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% greater than the first and / or second diameters, or any value or range therebetween. Thus, in some embodiments involving the coupling recess, the third diameter differs from the first and / or second diameters by approximately 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 sizes are contemplated.

[0097] like Figure 3C As shown, one or more coupling projections 88 include a circumferential ridge (also referred to as a "rib"). As shown, a second coupling projection (designated 89 for ease of reference) having a diameter greater than that of coupling projection 88 may be included. The circumferential ridge may optionally extend continuously around the perimeter of pocket 70. One or more coupling projections 88 may also additionally or alternatively include a longitudinal ridge (not shown), such as one of the longitudinal ridges described herein in connection with other pocket designs. Figure 3C As shown, the coupling protrusion 88 has a leading edge 100 and a trailing edge 102. In some embodiments, at least the leading edge 100 is at least one of beveled and rounded. Figure 3C As shown, the leading edge 100 and the trailing edge 102 are both rounded (radii). The rounding (radii treatment) or chamfering of the leading edge 100 can help reduce the axial insertion force Fi required to insert the plunger rod 22 into the stopper 24.

[0098] like Figure 3D As shown, one or more coupling recesses 88 include circumferential valleys. Figure 3D As shown, there is a second coupling recess (designated 89 for ease of reference) having a smaller diameter than coupling recess 88. The circumferential valley optionally extends continuously around the periphery of pocket 70. One or more coupling recesses 88 may additionally or alternatively include a longitudinal recess or valley (not shown), such as one of those coupling recesses described herein in association with other pocket designs. For reference, diameter D3 generally corresponds to the maximum diameter measurement of pocket 70 at the capture portion 80 that is protected by coupling recess 88. As shown Figure 3D As shown, the coupling recess 88 has a leading edge 100 and a trailing edge 102. In some embodiments, at least the leading edge 100 is at least one of chamfered and rounded. Figure 3D As shown, both the leading edge 100 and the trailing edge 102 are rounded. The rounding or chamfering 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] In general, the effectiveness of the coupling portion 84 can be characterized in terms of the total length or axial dimension of the largest coupling protrusion or recess, as applicable, for each of the subsequent examples. Figure 3C In FIG, a smaller second coupling protrusion (i.e., less protruding inwards) is shown in dashed lines, and in FIG. Figure 3D In the figure, the smaller second coupling recess (ie, the one protruding less outwards) is shown in dashed lines, and these two coupling protrusions or recesses do not participate in the calculation of the corresponding maximum coupling length ratio described below.

[0100] like Figure 3C and 3D As shown, each recess 70 can have a substantially smooth or featureless surface, except for the coupling protrusion(s) 88, 89 or coupling recess 88, 89. In other words, except for the coupling protrusion / recess, the wall of the recess 70 can be substantially cylindrical (e.g., a straight cylindrical or non-tapered cylindrical shape, including a slight taper of, for example, 1-5 degrees for ease of molding, or a conical or relatively more tapered cylindrical shape as desired). This smooth or featureless recess (except for variations introduced by coupling features) can be applied to each of the designs described below.

[0101] For circumferential ridges (also called "ribs") or valleys (also called "valleys"), the performance of the coupling protrusion 88 or coupling valley 88 can be evaluated as the ratio of the axial length of the largest ridge or valley to the overall valley length. Figure 3C As shown, the largest coupling protrusion 88 (e.g., the protrusion that defines the smallest overall diameter in the pocket) has a linear axial distance or protrusion length Lp that corresponds to the total height of the largest coupling protrusion 88. In the event that multiple coupling protrusions 88 have the same diameter, the coupling protrusion with the longest or largest axial protrusion length Lp is used to determine Lp. For reference, Lp is measured from the proximal transition and distal transition between the maximum diameters of the pocket 70 adjacent to the coupling protrusion 88. In other words, the edge at which the coupling protrusion 88 begins to protrude inwardly into the pocket 70. In turn, the stopper pocket defines the total linear axial distance or height L. The ratio of Lp to L, mathematically expressed as "Lp / L" and referred to as the "maximum coupling length ratio," directly affects the insertion force Fi. For reference, FIG. 3A illustrates the protrusion length Lp corresponding to the narrow region of the stopper 24P and the pocket length L for the stopper 24P.

[0102] Similarly, if Figure 3DAs shown, the largest coupling recess 88 has a linear axial distance or recess length Lr, which corresponds to the overall height of the largest coupling recess 88. Likewise, in the case of multiple recesses having the same diameter, Lr is selected for the coupling recess 88 with the longest axial length. Lr is measured from the proximal transition to the distal transition between the smallest diameters of the recesses 70 adjacent to the coupling recess 88. In other words, it is the edge where the coupling protrusion 88 begins to protrude outward from the surrounding recess 70. In turn, the stopper recess 70 defines the overall linear axial distance or height L. The ratio of Lr to L, mathematically described as "Lr / L" and also described as the "maximum coupling length ratio", directly affects the insertion force Fi.

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

[0104] Examples 1 and 2 discussed below include various values for the maximum coupling length ratio for the various coupling protrusion designs shown and described in the respective figures.

[0105] The stopper 24 may include an elastomeric body having an outer surface optionally having one or more ribs and an inner surface defining an inner cavity. The elastomeric body may be made from a variety of elastomeric materials, such as, but not limited to, butyl, bromobutyl, chlorobutyl, silicone, nitrile, styrene butadiene, chloroprene, EPDM, fluoroelastomer, thermoplastic elastomer (TPE), thermoplastic vulcanizate (TPV), silicone, and other materials.

[0014] Rubbers comprised of materials sold under the trademarks PTFE and combinations and blends thereof. Exemplary elastomeric materials include, but are not limited to, butyl rubber, bromobutyl rubber, chlorobutyl rubber, silicone rubber, nitrile rubber, styrene butadiene rubber, chloroprene rubber, EPDM rubber, fluoroelastomers, and combinations thereof.

[0106] In some embodiments, the stopper 24 may include an outer layer of material or coating to reduce friction as the stopper slides within the syringe barrel. Suitable materials that may be used as the outer layer include, but are not limited to, polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), dense 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 may also include a composite fluoropolymer (thin) membrane having a barrier layer and a porous layer. For example, the porous layer may be made of ePTFE or other porous expanded and fiberized fluoropolymers (e.g., ePTFE as taught in U.S. Patent No. 6,541,589 to Baille). The ePTFE layer may be filled with organic or inorganic materials to provide color, lubricity, or other functions.

[0108] As described above, in some embodiments, the outer layer may comprise a dense expanded fluoropolymer, such as, but not limited to, dense expanded polytetrafluoroethylene (ePTFE). The dense ePTFE (thin) film may be prepared as 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 copolymers of PTFE such as those described in U.S. Pat. No. 5,708,044 to Branca, 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. No. 12 / 410,050 to Xu et al., and U.S. Pat. Publication No. 2010 / 0248324 to Xu et al. can be utilized if they are densified.

[0109] In some embodiments, the outer layer may further comprise an expanded polymeric material comprising a functional tetrafluoroethylene (TFE) copolymer material having a microstructure characterized by nodes interconnected by fibrils, wherein the functional TFE copolymer material comprises a functional copolymer of TFE and PSVE (perfluorosulfonyl vinyl ether), or TFE and another suitable functional monomer, such as, but not limited to, vinylidene fluoride (VDF), vinyl acetate, or vinyl alcohol. The functional TFE copolymer material may 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] Figure 4A to 1 5 shows some modified stop designs that can be used with heads similar to head 46P, or alternative head designs that facilitate assembly without the high axial insertion forces Fi used in other prior art designs for rod coupling. In other words, Figure 4A to 1 The various stopper recess designs provided in 5C facilitate insertion of the rod to couple the stopper rod 22 to the stopper 24 without excessive breakaway forces between the stopper 24 and the syringe 20.

[0111] Figure 4A and 4C It shows Figure 1 and 2 Longitudinal section through the stop 24, which is provided with a recess 70A which promotes a lower insertion force Fi. Figure 4A The stopper 24 is shown in a relaxed or uncompressed state. Figure 4C The stopper 24 is shown in a compressed state (as it would normally appear within the barrel 20) with its head 46P inserted into the recess 70A. Figure 1 The various features of the stopper 24 described are applicable to Figure 4A and 4C 70A, and thus are not described in detail. For reference, additional examples of recess designs are provided, and similar reference numerals are used in the subsequent description and / or drawings to indicate similar features. For example, recess 70B is also described and illustrated, and similar features to recess 70A are indicated in the description and / or drawings using the same reference numerals as recess 70A plus a "B" to indicate the presence of similar features having similar properties to those described above.

[0112] like Figure 4AAs shown, the recess 70A includes a capture portion 80A having a first diameter, a release portion 82A having a second diameter, and a coupling portion 84A between the capture portion 80A and the release portion 82A, the coupling portion 84A having a third diameter that is smaller than the first and second diameters. The inner surface 68A of the body 60 includes one or more coupling protrusions 88A corresponding to the coupling portion 84A of the recess 70A.

[0113] As shown, the first diameter is substantially 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, prior to compression within the syringe 20, the first and second diameters have an inner diameter of approximately 2.4 mm, and the third diameter has an inner diameter of 2.05 mm. In some other examples, the one or more coupling protrusions protrude approximately 0.175 mm relative to the surrounding portion of the stopper 24 (on each side).

[0114] like Figure 4A As shown, one or more coupling protrusions 88A include circumferential ridges (also referred to as "ribs"). The circumferential ridges optionally extend continuously around the perimeter of the recess 70A. One or more coupling recesses 88A may additionally or alternatively include longitudinal ridges (not shown), such as those described herein in connection with other recess designs. Figure 4A As shown, the coupling protrusion 88A has a leading edge 100A and a trailing edge 102A. In some embodiments, at least the leading edge 100A is at least one of chamfered and rounded. Figure 4A As shown, both the leading edge 100A and the trailing edge 102A are rounded. The rounding or chamfering of the leading edge 100 can help reduce the axial insertion force Fi required to insert the plunger rod 22 into the stopper 24.

[0115] Figure 4B is an enlarged view close to the coupling protrusion 88A. As shown, the largest (and only shown) coupling protrusion 88A has a linear axial distance or protrusion length Lp, which corresponds to the total height of the coupling protrusion 88A. Lp is measured from the proximal transition portion and the distal transition portion between the maximum diameters of the recess 70 adjacent to the coupling protrusion 88. In other words, it is the edge at which the coupling protrusion 88 begins to protrude inwardly into the recess 70 (which edge roughly corresponds to the starting point of the leading edge 100A and the trailing edge 102A). In turn, the stopper recess defines the total linear axial distance or height L. As described above, the ratio of Lp to L, mathematically described as "Lp / L" and referred to as the "maximum coupling length ratio", directly affects the insertion force Fi.

[0116] Figure 4CThe stopper 24 is shown compressed, and thus the recess 70A, such as it would typically assume when interacting with the head 46 of the plunger rod 22 according to the design of the head 46P. As shown, the retaining feature 96P engages the coupling portion 84A of the recess 70A to couple the plunger rod 22 to the stopper 24, with the head 46P received in the capture portion 80A of the stopper 24.

[0117] During insertion into the recess 70A, the tapered crown 90P slidably engages the coupling protrusion 88A of the coupling portion 84A during insertion of the head 46P into the recess 70A of the stopper 24. The stopper 24, including the recess 70A, is configured such that the head 46P can be axially inserted into the stopper 24 with an insertion force Fi that is less than a break-away force (e.g., a break-away force of 2N to 20N), wherein the stopper 24 is received in the barrel 20 ( Figure 1 ). After insertion, the head 46P is captured in the capture portion 80A of the recess 70A.

[0118] In order to disengage the head 46P from the recess 70A, a non-zero separation force must be applied in the longitudinal direction between the stop 24 and the plunger rod 22 so that the components can be separated by withdrawing the retaining feature 96P from the coupling portion 84A of the recess 70A. As shown, the smooth surface of the tapered crown helps to insert the retaining feature 96P over the coupling protrusion 88A, reducing the required axial insertion force, while at the same time, once the head 46P is seated in the capture portion 80A, the relatively hard or chamfered edge of the retaining feature 96P is inhibited from retracting over the coupling protrusion 88A. 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 significantly different from the rotational or torsional insertion force required for threaded engagement. The embodiments described herein are configured for axial insertion assembly, rather than threaded, screw-in assembly methods.

[0119] In various examples, the rod-stop assembly described herein can be relatively rotated without causing relative axial movement between the two components. In addition, in various examples, the rod-stop assembly described herein can be freely rotated relative to each other after assembly (i.e., according to some examples, due to the lack of threads, free rotation between the rod and the stop is allowed). In other embodiments, the interaction between the assembled plunger rod 22 and the stop 24 prevents relative rotation after the plunger rod 22 is inserted into the stop 24 to couple the two components.

[0120] For reference, the embodiments described herein can be used with devices for coupling the plunger rod to the stopper that include a twisting / threading motion (the barrel 20 and stopper 24 are rotated onto the plunger rod 22 with accompanying axial motion). Furthermore, such twisting motion may be present even in "push-on" plunger rods similar to those described herein. Regardless, in various examples, the plunger rod 22, and more specifically the head 46, is pushed axially through one or more coupling projections of the stopper 24, rather than being threaded through these coupling projections.

[0121] Figures 5 to 10A , are longitudinal cross-sectional views showing several design variations of the recess 70 configured to achieve a similar result, namely an axial insertion force Fi that is lower than the associated breakaway force of the stop 24 .

[0122] Figure 5 It shows Figure 1 and 2 24, which is provided with a recess 70B which also promotes a lower insertion force Fi than the recess 70P. Figure 5 One or more coupling protrusions 88B are shown, which include coupling protrusions 88A ( Figure 4A ) is a circumferential ridge (also referred to as a "rib") that is smaller (narrower) than the circumferential ridge of the recess 70A. The ridge defines an inner diameter that is substantially the same as the ridge of the recess 70A. It should be understood from this (and from the additional examples that follow) that various sizes of coupling projections are contemplated. Similar to coupling projection 88A, the circumferential ridge extends continuously around the periphery of recess 70B. In other respects, recess 70B operates similarly to recess 70A, but due to the smaller profile of coupling projection 88A, it is expected that the average axial insertion force Fi of recess 70B will be lower than that of recess 70A, and the associated separation force will also be lower than that of recess 70A.

[0123] Figure 6 It shows Figure 1 and 2 24, which is provided with a recess 70C which causes a lower insertion force Fi than the recess 70P. Figure 6 One or more coupling protrusions 88C are shown, which include coupling protrusions 88A ( Figure 4A ) and the coupling protrusion 88B ( Figure 4B) is a circumferential ridge (also referred to as a "rib") that is larger (wider) than the circumferential ridges of coupling protrusions 88A and 88B. Similar to coupling protrusions 88A and 88B, the circumferential ridge extends continuously around the periphery of pocket 70C. In other respects, pocket 70C operates similarly to pockets 70A and 70B, but due to the larger (wider) profile of coupling protrusion 88A, it is expected that the average axial insertion force Fi of pocket 70C will be higher than that of pockets 70A and 70B, and the associated separation force will also be higher than that of pockets 70A and 70B.

[0124] Figure 7 It shows Figure 1 and 2 2 is a longitudinal sectional view of a stopper 24 provided with a recess 70D which facilitates a lower insertion force Fi than the recess 70P. Figure 7 Intended to illustrate one or more coupling protrusions 88D, these coupling protrusions include coupling protrusions 88A ( Figure 4A )、Connecting protrusion 88B( Figure 5 ) and the coupling protrusion 88C ( Figure 6 ) circumferential ridges (also referred to as "ribs") that are larger (wider) than the circumferential ridges of coupling protrusions 88A, 88B, and 88C. Similar to coupling protrusions 88A, 88B, and 88C, the circumferential ridges extend continuously around the perimeter 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. This effect can be achieved by flattening the design of coupling protrusion 88D. Notably, the same flattening can be applied to the narrower peak or apex of coupling protrusion 88A.

[0125] Flattening one or more coupling protrusions 88 can increase the stiffness of the coupling protrusions, thereby reducing insertion force, and / or helping to increase separation force. With respect to other variations, thickening and / or lengthening the coupling protrusions can aid in the manufacturing process, strength, or robustness of the coupling protrusions, and / or increase the separation force between the stopper 24 and the plunger rod 22. In some examples, features with larger radii exhibit greater stiffness than features with relatively smaller radii, which are more susceptible to tearing during molding, during coupling to the plunger rod 22, or during decoupling from the plunger rod 22.

[0126] Figure 8 It shows Figure 1 and 2 24, which is provided with a recess 70E which promotes a lower insertion force Fi than the recess 70P. Figure 7One or more coupling projections 88E are intended to be illustrated and include circumferential ridges (also referred to as "ribs") having various sizes or configurations (narrower, wider, less pronounced, more pronounced, rounded peaks, flat peaks, etc.). However, as shown, coupling projection 88E is positioned more proximally than coupling projections 88A, 88B, 88C, and 88D. Similar to the aforementioned coupling projections, circumferential ridge 88E (also referred to as "ribs") extends continuously around the periphery of pocket 70E. Pocket 70E operates similarly to the aforementioned pockets, except that the capture portion 80E is significantly longer than in other embodiments, thereby providing the capture portion 80E with greater proximal-distal play, or potential displacement space, to the head 46P (not shown) when the head 46P is fully inserted into the capture portion 80E, relative to other embodiments that include coupling projections that directly engage with the retention feature 96P (not shown). This feature can promote a desired amount of proximal sliding or displacement before the retaining feature 96P engages the coupling protrusion 88E, thereby gradually preventing any further movement between the components. In this way, the stopper 24 and the plunger rod 22 can remain coupled and can only be separated upon application of a separation force similar to that described above, while also allowing some relative axial displacement between the two components.

[0127] Figure 9 It shows Figure 1 and 2 24 , which is provided with a recess 70F which, during coupling of the stopper 24 with the plunger rod 22 , facilitates a lower insertion force Fi than the recess 70P. Figure 9 A plurality of coupling projections 88F are shown, comprising a plurality of circumferential ridges (also referred to as "ribs") having any of the aforementioned dimensions or configurations (narrower, wider, less pronounced or more pronounced, rounded peaks, flat peaks, or other variations). As shown, the plurality of coupling projections 88F include one ridge (also referred to as "rib") positioned more proximally and a second ridge (also referred to as "rib") positioned more distally (e.g., in a similar position to coupling projections 88A, 88B, 88C, 88D). In at least this manner, when the head 46P (not shown) is fully inserted into the capture portion 80F, at least one coupling projection 88F directly engages the retention feature 96P (not shown). This feature can facilitate a higher degree of engagement (e.g., a higher separation force) without significantly increasing the accompanying axial insertion force Fi required to insert the head 46P to couple the stopper 24 and the plunger rod 22.

[0128] Figure 10A It shows Figure 1 and 23B . FIG. 2 is a longitudinal cross-sectional view of the stopper 24 provided with a recess 70G which, during coupling of the stopper 24 with the plunger rod 22, causes a lower insertion force Fi than the recess 70P of FIG. 3B . Figure 10B is an end view of the recess 70G, different from Figure 10A The perspective view of the recess 70 shows its features. As shown, the recess 70G includes one or more coupling projections 88G, which include multiple longitudinal ridges (also referred to as "ribs") having any of the aforementioned sizes or configurations (narrower, wider, less obvious or more obvious, rounded peaks, flat peaks or other modifications). As shown, multiple coupling projections 88G include multiple longitudinal ridges (also referred to as "ribs") that are circumferentially spaced apart from each other. In other words, the longitudinal ridges are discontinuously spaced apart across the periphery of the recess 70. As shown, each ridge is equidistant from each other and each has a similar configuration (size and shape), and it should be understood that these configuration variables can be modified as desired, including the number of ridges (e.g., six are shown).

[0129] Each ridge has a leading edge 100G and a trailing edge 102G. As previously described, the leading edge 100G can be at least one of chamfered and rounded. As shown, the leading edge 100G and the trailing edge 102G of each ridge are rounded. The rounding or chamfering of the leading edge 100G 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 with the retaining feature 96P (not shown) when the head 46P (not shown) is fully inserted into the capture portion 80G to couple the stopper 24 and the plunger rod 22.

[0130] Figures 11A to 13B Additional examples of coupling protrusion designs or configurations according to some embodiments are provided.

[0131] For example, Figure 11A It shows Figure 1 and 2 A longitudinal sectional view of a stopper 24 having a stopper relative to Figure 10A and 10B The number of coupling protrusions 70G is modified, wherein Figure 11A The recess 70G also makes the insertion force Fi lower than Figure 10A and 10B The insertion force is also lower than the insertion force exhibited by the recess 70P during the connection between the stop member 24 and the head 70P. Figure 11B is an end view of the recess 70G, different from Figure 11A The viewing angle shows its characteristics. Figure 11A and Figure 11BAs shown, the pocket 70G includes one or more coupling projections 88G that include a plurality of longitudinal ridges (also referred to as "ribs") having any of the aforementioned sizes or configurations (narrower, wider, less pronounced or more pronounced, rounded peaks, flat peaks, etc.). Figure 11A and Figure 11B In the example of FIG. 8 , one or more coupling protrusions 88G include longitudinal ridges (also referred to as “ribs”) configured to engage with the Figure 10A and 10B Those described are similar, but include fewer ridges (three as shown). Generally, the number and configuration of longitudinal ridges or grooves can be modified to help reduce the axial force of insertion while providing the desired separation force performance. Such longitudinal ridges or grooves can also assist in combined torsional and axial installation (although such installation is still in contrast to threaded installation). In other aspects, Figure 11A and 11B The recess 70G may optionally be connected to Figure 10A and 10B The pocket 70G operates substantially similarly, having similar features and functions.

[0132] Since the number of coupling protrusions 70G included is greater than Figure 10A and 10B As shown, there are fewer (e.g., three equally spaced coupling protrusions), so according to Figure 11A and 11B The modified recess 70G may have a Figure 10A and 10B The structure has lower axial insertion force Fi and lower separation force. Figure 11A and 11B In the example of Figure 10A As shown, the spacing is greater. For example, in Figure 10A In the embodiment, each coupling protrusion 88G may be spaced apart by a width that is between 0.5 times and 1.5 times the width of the coupling protrusion 88G. Figure 11A and 11B As shown, each coupling projection 88G may be circumferentially spaced apart by a width that is greater than 2 times the width of the coupling projection 88G.

[0133] Figure 12A It shows Figure 1 and 2 4. A longitudinal cross-sectional view of a stopper 24 provided with a recess 70H which facilitates a lower insertion force Fi than the recess 70P during coupling of the stopper 24 with the head 46P. Figure 12B is an end view of the recess 70H, different from Figure 12AAs shown, the recess 70H includes one or more coupling protrusions 88H (e.g., three equally spaced protrusions) that include a plurality of circumferentially extending ridges (also referred to as ribs) having any of the aforementioned sizes or configurations (narrower, wider, less pronounced or more pronounced, rounded peaks, flat peaks, etc.) that are circumferentially aligned and spaced apart from one another. The circumferential ridges are substantially similar to the recess 70D ( Figure 7 ) (which also includes a wider, flatter circumferential ridge profile) operates, thereby having similar features and similar functions.

[0134] Figure 13A It shows Figure 1 and 2 Another example of a longitudinal cross-sectional view of a stopper 24 provided with a recess 70J which facilitates a lower insertion force Fi than the recess 70P during coupling of the stopper 24 with the head 70P. Figure 13B is an end view of (looking into) recess 70J, different from Figure 13A As shown, the recess 70J includes one or more coupling protrusions 88J, similar to Figure 12A and Figure 12B The connecting protrusion 70J in Figure 12A and Figure 12B In contrast, the coupling projections 88J are more segmented (and therefore the number of coupling projections 70J is greater, such as six in total). The coupling projections 70J are circumferentially aligned and spaced a desired distance apart from one another. In addition to being relatively short in longitudinal length and having a wider, flatter profile than a slotted or longitudinally extending ridge design, Figure 13A and 13B The ridges (also referred to as "ribs") shown operate substantially similarly to the previous examples, having similar features and similar functions.

[0135] In terms of design, Figures 10A to 13B Examples of all include circumferentially discontinuous and / or circumferentially spaced longitudinally extending coupling projections. By spacing the coupling projections around the circumference, the coupling projections undergo a certain degree of radial expansion or deformation (or the gaps between the coupling projections close) during insertion of the plunger rod 22, which helps reduce the required axial insertion force. In other words, these slotted designs (spaced longitudinally oriented coupling projections) or discontinuous circumferential designs (spaced circumferentially oriented coupling projections) facilitate greater deformation of the stopper 24 at the coupling projections, thereby reducing the expected insertion force.

[0136] Figures 14 to 15B Alternative designs are shown that include coupling recesses as opposed to coupling protrusions for engaging with the head 46P or other heads as desired.

[0137] Figure 14 It shows Figure 1 and 2 4. A longitudinal cross-sectional view of a stopper 24 provided with a recess 70K which, during coupling of the stopper 24 with the head 46P, promotes a lower insertion force Fi than the recess 70P.

[0138] like Figure 14 As shown, the pocket 70K includes a capture portion 80K having a first diameter, a release portion 82K having a second diameter, and a coupling portion 84K between the capture portion 80K and the release portion 82K, the coupling portion having a third diameter that is smaller than the first and second diameters at the one or more recesses associated with the coupling portion 84K. Specifically, the inner surface 68K of the body 60 includes one or more coupling recesses 88K corresponding to the coupling portion 84A of the 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 and / or second diameters. 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 and / or second diameters. In one example, when the stopper 24 is compressed in the syringe 20, the third diameter is approximately 2.8 mm. In such an example, the stopper 24 can be paired with a plunger rod head having a retention feature that defines 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, prior to compression in the syringe 20, the first and second diameters have an outer diameter of approximately 2.05 mm, and the third diameter has an outer diameter of 2.4 mm. In some other examples, one or more coupling protrusions are recessed relative to surrounding portions of the stopper 24 by approximately 0.175 mm (on each side).

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

[0141] Figure 14 The uncompressed stopper 24 is shown, and thus the recess 70A is generally shown as it would normally appear prior to insertion into the syringe 20 and actual interaction with the head 46 of the plunger rod 22 .

[0142] During insertion into the recess 70K, the tapered crown 90P is slidably received within the one or more coupling recesses 88K of the coupling portion 84K during insertion of the head 46P into the recess 70K of the stopper 24. Specifically, the retaining feature 96P of the head 46P can be received in one of the one or more coupling recesses 88K. The stopper 24, including the recess 70K, is configured such that the head 46P can be axially inserted into the stopper 24 with an insertion force Fi that is less than a break-away force (e.g., in the case of a break-away force of 2N to 20N), wherein the stopper 24 is received in the barrel 20 ( Figure 1 ). After insertion, the head 46P can be captured in the capture portion 80K of the recess 70K.

[0143] In order to disengage the head 46P from the recess 70K, a non-zero separation force must be applied in the longitudinal direction between the stop 24 and the plunger rod 22 to separate the components by withdrawing the retaining feature 96P from the one or more coupling recesses 88K of the recess 70K. As shown, the smooth surface of the tapered crown facilitates insertion of the retaining feature 96P into the coupling portion 84K and the one or more coupling recesses 88K, thereby reducing the required axial insertion force, while the relatively hard or chamfered edge of the retaining feature 96P inhibits its withdrawal from the coupling portion 84K once the head 46P is seated (seated) in the capture portion 80A. As previously described, 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 significantly different from the rotational or torsional insertion force required for threaded engagement.

[0144] As previously mentioned, the embodiments described herein are configured for axial insertion assembly, rather than threaded, screw-in assembly methods. Similarly, the embodiments described herein can be used with devices for attaching the plunger rod to the stopper that include a twisting / threading motion (the syringe 20 and the stopper 24 are screwed onto the plunger rod 22 and move axially). Moreover, such twisting motion may also exist in "push-in" plunger rods similar to those described herein. In any case, in various examples, the plunger rod 22, and more specifically the head 46, is pushed axially through one or more coupling protrusions of the stopper 24, rather than being threaded through these coupling protrusions.

[0145] Figure 15A and 15B A longitudinal cross-section is shown of a longitudinally positioned or slotted recess design variant for the pocket 70 , which is also configured to achieve a similar result, namely an axial insertion force Fi that is lower than the associated breakaway force of the stop 24 .

[0146] Figure 15A It shows Figure 1 and 2 24, which is provided with a recess 70L which also promotes a lower insertion force Fi than the recess 70P. The features of the recess 70L are substantially similar to those of the recess 70K, except for the longitudinal orientation of the recess. Figure 15A One or more coupling recesses 88L are shown, which include one or more longitudinally extending coupling recesses (e.g., valley-shaped recesses). The plurality of longitudinal recesses have any of the sizes or configurations described above (narrower, wider, more pronounced or less pronounced, rounded peaks, flat peaks, or other modifications). As shown, the plurality of coupling recesses 88L include a plurality of longitudinal valley-shaped depressions, or recesses that are circumferentially spaced apart from one another. As shown, the recesses are equidistant from one another and are each similarly configured (size and shape), it being understood that these configuration variables can be modified as desired, including the number of recesses (e.g., Figure 15A There are four in the design). Figure 15B is a transverse section through one or more coupling recesses 88L, illustrating how the recesses are clocked 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 at least one of chamfered and rounded. As shown, both the leading edge 100L and the trailing edge 102L of each recess are rounded. In various examples, the leading edge 100L and / or the trailing edge 102L of each coupling recess 88L can be positioned so as to directly engage the plunger rod 22 when the plunger rod 22 is fully inserted into the capture portion 80L to couple the stopper 24 and the plunger rod 22.

[0148] Figures 16 to 18B An alternative head design for the plunger rod 22 is shown. Any of the aforementioned stopper designs may be used with Figure 16 to 1 8 is used together with the head design shown.

[0149] Figure 16 The plunger rod 22 ( Figure 1 ) is a longitudinal cross-sectional view of the head 46A, which facilitates reducing the insertion force Fi when the plunger rod 22 is coupled to the stopper 24. Figure 16 The surrounding recess 70F of the stopper 24 is shown in a compressed state (see Figure 9 In one example, the maximum outer diameter OD of the head 46A at the retention feature 96A is about 2.06 mm, 2.1 mm, 2.2 mm, or 2.3 mm, for example, depending on the desired engagement with the corresponding design for the stop 24, particularly the required axial insertion force Fi and separation force.

[0150] The head 46A is configured to be axially inserted into a recess (eg, recess 70F) of the stop 24P to couple the head 46A to the stop 24P. Figure 16 The head 46A is shown in the recess 70F with the stopper 24P in a compressed state, as the stopper 24P would otherwise be placed in the syringe barrel 20 .

[0151] The head 46A has a tapered crown 90A having a first diameter and terminating in a flat end and extending to a first enlarged section 94A having a diameter that sharply decreases to define a first retention feature 96A and a second tapered section having a diameter that increases proximally and sharply decreases at a proximal engagement section 98A to define a second retention feature 97A. The proximal engagement section 98A has a smaller diameter than the first enlarged section 94A and the second enlarged section 98A.

[0152] like Figure 16 As shown in FIG. 4 (where the stopper 24 is shown in a compressed state), the first and second retention features 96A, 97A are configured to engage with the plurality of coupling projections 88F of the recess 70F. These various engagements couple the stopper 24 to the head 46A, but require a relatively low axial insertion force Fi to insert the head 46A into the recess 70A (e.g., lower than the breakaway force between the stopper 24 and the syringe 20, as previously described), while still requiring a substantial, non-zero separation force to disengage the stopper 24 from the head 46A.

[0153] Figure 17 The plunger rod 22 ( Figure 1) is a side view of the head 46B, which is configured to cause the insertion force Fi to be less than the breakaway force between the stopper 24 and the syringe 20 when the plunger rod 22 is coupled to the stopper 24, as previously described.

[0154] The head 46B is configured to be axially inserted into a recess (e.g., recess 70K or a variation thereof) of the stop 24 to couple the head 46B to the stop 24. As shown, the head 46B has a tapered crown 90B having a first diameter and terminating in a flat end; an enlarged section 94B, wherein the diameter of the enlarged section 94B increases to a peak (peak) and then decreases in diameter to a proximal engagement section 98B having a smaller diameter than the enlarged section 94B.

[0155] and Figure 16 Unlike the designs shown that include one or more sharp transitions to define the retention feature, the expanded section 94B tapers, either increasing in width or diameter proximally to a peak and then tapering, or decreasing in width or diameter proximally to a proximal engagement section 98B. The expanded section 94B is configured to engage a coupling portion of a stopper, such as coupling portion 84K ( Figure 14 ) engage. For example, the enlarged section 94B can define a retaining feature 96B that engages one of the one or more coupling recesses 88K. Although a relatively sharp apex is shown defining the retaining feature 96B, a rounded (rounded) or squared-off apex, for example, can also be implemented. In addition, multiple similar retaining features can be positioned along the length of the head 46B that engage with the recess 70K ( Figure 14 ) to facilitate coupling the plunger rod 22 to the stopper 24. These various engagements couple the stopper 24 to the head 46B but require an axial insertion force Fi that is lower than the break-away force between the barrel 20 and the stopper 24 to insert the head 46B into the recess 70 (e.g., recess 70K), while still requiring a substantial, non-zero separation force to disengage the stopper 24 from the head 46A.

[0156] Figure 18A is a side view showing a head 46C for a plunger rod 22 that facilitates an insertion force Fi that is less than a breakaway force present between the stopper 24 and the syringe 20 when the plunger rod 22 is coupled to the stopper 24. As shown, the head 46C includes one or more (e.g., four) retention features 96C in the form of surface protrusions that define longitudinally extending ridges (also referred to as "ribs"). The one or more retention features 96C may be configured, or otherwise sized and shaped, to complement 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 may define a complementary fit with the one or more coupling recesses 88G.

[0157] The head 46C may be configured to be inserted axially into a recess (e.g., recess 70G, Figure 15A and 15B ) to connect the head 46C to the stopper 24. For example, Figure 18B is a longitudinal cross-sectional view showing the head 46C in the recess 70G, with the stopper 24 shown in a compressed state, as the stopper 24 would otherwise be positioned in the syringe barrel 20.

[0158] As shown, the head 46C terminates in a cylindrical section with a flat end and has an expanded section 94C, wherein the diameter of the expanded section 94C is increased via longitudinal surface protrusions defining one or more retaining features 96C. As shown, when the stopper 24 is compressed (e.g., as assembled in the pre-filled syringe example), when the plunger rod 22 is inserted into the stopper 24, the expanded section 94C engages with the capture portion 80G. This engagement couples the stopper 24 to the head 46C, but requires an axial insertion force Fi that is lower than the breakaway force between the stopper 24 and the syringe 20 in order to insert the head 46C into the recess 70G, while still requiring a considerable, non-zero separation force in order to disengage the stopper 24 from the head 46C.

[0159] It will be understood that the various head designs and features described above may be combined and / or used with any of the various recess designs described above.

[0160] With the foregoing description in mind, a method of assembling a plunger rod to a stopper can be described as follows.

[0161] A method for coupling a plunger rod to a stopper positioned in a syringe barrel includes axially inserting a head of the plunger rod into a recess of the stopper, wherein the insertion force is less than a breakaway force defined between the stopper and the syringe barrel. When the head of the plunger rod is axially inserted into a catch portion of the stopper, the plunger rod is coupled to the stopper.

[0162] Inserting the head into the recess may include sliding the tapered crown of the head of the plunger rod over one or more coupling protrusions corresponding to the coupling portion of the recess so as to couple the plunger rod to the stopper. The one or more coupling protrusions 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 coupling protrusions may have a leading edge and a trailing edge, wherein at least the leading edge is one of chamfered and rounded, and inserting the head into the recess includes sliding the head longitudinally over the leading edge and / or trailing edge of the one or more coupling protrusions. As previously described, the breakaway force may be, for example, from 2N to 20N. Once the plunger rod is inserted into the stopper, the stopper and the plunger rod also need to apply a separation force in the longitudinal direction to disengage the plunger rod from the stopper. In various examples, the separation force is greater than the breakaway force.

[0163] Inserting the head into the recess can also include sliding the enlarged section of the head of the plunger rod into one or more coupling recesses corresponding to the coupling portion of the recess so that the plunger rod is coupled to the stopper. The one or more coupling recesses can include one or more longitudinally extending recesses and / or one or more circumferentially extending recesses. Each of the one or more coupling recesses can have a leading edge and a trailing edge, wherein at least the leading edge is at least one of chamfered and rounded, and inserting the head into the recess includes sliding the head longitudinally over the leading edge of the one or more coupling recesses so that the enlarged section of the head (e.g., one or more retaining features) is placed into the one or more coupling recesses. Similarly, as referenced above, the breakaway force can be, for example, from 2N to 20N. Once the plunger rod is inserted into the stopper, the stopper and the plunger rod also need to apply a separation force in the longitudinal direction to disengage the plunger rod from the stopper. Again, in various examples, the separation force is greater than the breakaway force.

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

[0165] The syringe stopper is manufactured according to the teachings of U.S. Patent No. 8,722,178 (hereinafter referred to as the '178 patent), assigned to WL Gore & Associates, Inc. Typically, the sample is made according to Figure 4A 、 5 , 6 and 7 were prepared. The dimple dimensions selected for each design are shown in Table 1, and each of these values is measured in an uncompressed state. The dimensions of the samples were measured using a Mitutoyo TM-505 Toolmakers microscope. As previously described, each dimple includes a capture portion having a first diameter D1, a release portion having a second diameter D2, and a coupling portion having a third diameter located between the capture portion and the release portion. See Figure 3C and 3DSchematic view. For measurement purposes, the third diameter generally corresponds to the smallest diameter of the recess at the capture portion, which is defined by the coupling protrusion(s). Furthermore, since the first and second diameters of each sample were manufactured to be identical, only the second diameter was measured, and it was assumed that the first diameter was identical to the second diameter.

[0166] Each stopper sample was then manually vented into a non-siliconized glass barrel (ie, without silicone lubricant) having a nominal inner diameter of 4.65 mm according to ISO 11040-4 and filled with 200 uL (microliters) of water for injection (WFI).

[0167] The filled and stoppered syringes were stored at ambient conditions for 1 week with the luer end of the glass barrel oriented upwards prior to testing.

[0168] Purchase a commercially available plunger rod to displace the stopper in the syringe, the dimensions of which are reference Figure 3E During insertion of the plunger rod into the stopper, a visual assessment is made to determine whether insertion of the plunger rod causes longitudinal translation of the stopper. If a majority of the assessments are "no," the stopper did not longitudinally translate during insertion of the plunger rod, indicating that the plunger rod insertion force is less than the breakaway force.

[0169] After the plunger rod was inserted into the stopper, the plunger rod was longitudinally compressed (towards the end of the syringe) at a speed of 100 mm / min (millimeter / minute) using a TA XT Plus texture analyzer (Massachusetts, Hamilton, MA), so that the stopper was translated by about 10 mm. The plunger rod was then longitudinally retracted (towards the flange end of the syringe) at a speed of 10 mm / min on the texture analyzer, and a visual assessment was performed to assess the motion of the plunger towards the flange end of the syringe. In each case, there was a non-zero separating force between the plunger and the stopper sample. In other words, if there was no external force to separate them, the two would remain connected. In addition, if the majority of the evaluation results for each sample were "yes", the stopper did move towards the flange end of the syringe when the plunger rod was retracted, which indicates that the separating force was not only non-zero, but also that the separating force actually exceeded the force to break free.

[0170] Table 1: Example 1 test results

[0171] For reference, the prior art plunger depicted in FIG3A can be manufactured according to ISO 1140-5 without a release portion defining the second diameter D2. The third diameter (coupling portion) is 1.6-1.9 mm and the nominal first diameter (capturing portion) is 2.5 mm. The nominal value of L is 5.3 mm, and Lp is 3.15 mm, so the Lp / L ratio is 0.594. For reference, the design of FIG3A (e.g., with the above dimensions) is expected to have a plunger rod insertion force that exceeds its breakaway force.

[0172] In summary, it is assumed that Lp / L values less than 0.5, such as less than 0.3, or even less than 0.2, may be beneficial in reducing insertion force. Generally, it is envisioned that Lp / L values will be greater than 0 (e.g., 0.05) and less than or equal to 0.5, less than or equal to 0.3, or less than or equal to 0.2. For example, Lp / L values may range from 0.1 to 0.2.

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

[0174] Syringe stops were again manufactured according to the teachings of the '178 patent. Similar to Example 1, the cavity dimensions of each stopper sample were measured in the uncompressed state, as shown in Table 2. The sample dimensions were again measured using a Mitutoyo TM-505 Toolmakers microscope. Again, the first diameter corresponding to the capture portion was manufactured to be the same as the second diameter corresponding to the release portion, so only the second diameter was measured, assuming the first diameter was the same. Overall, both samples were measured according to Figure 6 The selected cavity sizes are shown in Table 2, and each value is measured in an uncompressed state.

[0175] Similar to Example 1, each stopper sample was then inserted into a non-siliconized glass syringe with a nominal inner diameter of 4.65 mm and a water contact angle of approximately 80 degrees using a vent tube according to ISO 11040-4, and 200 uL of water for injection (WFI) was added at a rate of 120 mm / s using an AST CCS container closure system (Tacoma, WA).

[0176] The filled and stoppered syringes were stored at ambient conditions for 1 week with the luer end of the glass barrel facing upwards prior to testing.

[0177] Purchase a commercially available plunger rod to displace the stopper in the syringe, the dimensions of which are reference Figure 3EThe 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. Using the same TA XT Plus Texture Analyzer (Hamilton, MA), the breakaway force of the stopper in the glass syringe was tested by displacing it toward the Luer end at a speed of approximately 100 mm / min. The maximum force was recorded in each case.

[0178] Table 2: Example 2 test results

[0179] As shown in the data above, for the above designs, the recorded insertion forces were much lower than the breakout forces, in every case below 75% of the breakout force, and even below 50% of the breakout force or lower. Examples of potential syringe barrel contents

[0180] The syringes disclosed herein can be used in combination with different therapeutic compounds, including but not limited to drugs and biological agents, such as coagulation factors, cytokines, epigenetic protein families, growth factors, hormones, peptides, signal transduction molecules and mutations thereof; also include amino acids, vaccines and / or combinations thereof. Therapeutic compounds also include RNA interference, antibodies, antisense nucleic acids and mutations thereof against the above-mentioned biological agents and their target receptors. Other therapeutic compounds include gene therapy, primary stem cells and embryonic stem cells. Therapeutic compounds also include antibodies, antisense nucleic acids, RNA interference and / or combinations thereof against protein kinases, esterases, phosphatases, ion channels, proteases, structural proteins, membrane transporters, nuclear hormone receptors. In addition, it should be understood that at least one therapeutic compound specified herein used in the present disclosure and two or more therapeutic compounds listed in this application are considered to be within the scope of the present disclosure.

[0181] Examples of coagulation 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 a cofactor for Vila.

[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 zinc finger domain-1A (BAZ1A), bromodomain-adjacent zinc finger domain-1B (BAZ1B), bromodomain-adjacent zinc finger domain-2A (BAZ2A), bromodomain-adjacent zinc finger domain-2A (BAZ2A), bromodomain-adjacent zinc finger domain-2B (BAZ2B), bromodomain-containing protein 1 (BRD1), bromodomain-containing protein 2-1 bromodomain domain (BRD2), bromodomain-containing protein 2-1st and 2nd bromodomains (BRD2), bromodomain-containing protein 2 homolog 1-bromodomain 2 (BRD2(2)), bromodomain-containing protein 3-bromodomain 1 (BRD3(1)), bromodomain-containing protein 3-1st bromodomain (BRD3), bromodomain-containing protein 3-1st and 2nd bromodomains (BRD3), bromodomain-containing protein 3-bromodomain 2 (BRD3(2)), bromodomain-containing protein 4-1st bromodomain (BRD4), bromodomain-containing protein 4 homolog long-bromodomain 1 and 2 (BRD4(1-2)), bromodomain-containing protein 4 homolog long-bromodomain 2 ( BRD4(2)), bromodomain-containing protein 4 isoform short (BRD4(full-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-bromodomain 1 (BRDT), bromodomain-containing testis-specific-bromodomains 1 and 2 (BRDT), bromodomain-containing testis-specific protein isoform b-bromodomain 2 (BRDT(2)), bromodomain-containing and PHD finger-1 (BRPF1), bromodomain-containing and PHD finger-3 (BRPF3), bromodomain-containing and PHD finger-3 (BRPF3), bromodomain-containing and WD repeat 3–2 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 homolog 1 (FALZ), nucleosome-remodeling factor subunit BPT (FALZ), euchromatic histone (Euchromatichistone)-lysine N-methyltransferase 2 (EHMT2), histone acetyltransferase-KAT2A (GCN5L2),Euchromatin histone-lysine N-methyltransferase 1 (EHMT1), histone-lysine N-methyltransferase MLL (MLL), polybrominated 1-1st bromodomain (PB1(1)), polybrominated 1-2nd bromodomain (PB1(2)), polybrominated 1-bromodomain 2 (PBRM1(2)), polybrominated 1-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 3 (PRMT3), SWI / SNF-related-matrix-associated-actin-dependent chromatin regulator-subfamily a-member 2 (SMARCA2), SWI / SNF-related-matrix-associated-actin-dependent chromatin regulator-subfamily a-member 4 (SMARCA 4), 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-250kDa-bromodomain 2 (TAF1(2)), transcription initiation factor TFIID subunit 1-like-1st bromodomain (TAF1L(1)), transcription initiation factor TFIID subunit 1 -like-2nd bromodomain (TAF1L(2)), three-domain protein family 24 (TRIM24(bromo)), three-domain protein family 24 (TRIM24(PHD-bromo)), E3 ubiquitin-protein ligase TRIM33 (TRIM33), three-domain protein family 33 (TRIM33(PHD-bromo)), WD repeat 9-1st bromodomain (WDR9(1)), and WD repeat 9-2nd 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-inducing growth factor (FIGF), platelet-activating factor (PAF), transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP), activins, inhibins, 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), liver cancer-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, estrogen, testosterone, cortisol, and progesterone.

[0186] Examples of proteins and peptides and signal transduction molecules include, but are not limited to, ataxia telangiectasia mutated, tumor protein p53, checkpoint kinase 2, breast cancer susceptibility protein, double-strand break repair protein, DNA repair protein RAD50, Nibrin, p53-binding protein, mediator of DNA damage checkpoint protein, H2A histone family member X, cerebellar phospholipids, C-terminal binding protein 1, chromosome structure maintenance protein 1A, cell division cycle 25 homolog A (CDC25A), forkhead box O3 (forkhead box O3), nuclear factor kappa light chain polypeptide gene enhancer in B cell inhibitors, The genes involved in the study were NFKBIA, NFKBIA-1, NFKBIA-2, NFE2L2, NPR1, TNFRSF11A, RELA, SREB2, CREB-regulated transcriptional coactivator 1 (CRTC1), CREB-regulated transcriptional coactivator 2 (CRTC2), X-box binding protein 1 (XBP1), and catenin beta 1 (cadherin-related protein or CTNNB1).

[0187] Examples of G protein-coupled receptors (GPCRs) include, but are not limited to, adenosine receptor family, adrenaline receptor family, angiotensin II receptor, apelin receptor, vasopressin receptor family, brain-specific angiogenesis inhibitor family, bradykinin receptor family, bombesin receptor family, complement component 3a receptor 1, complement component 5a receptor 1, calcitonin receptor family, calcitonin receptor-like family, calcium-sensing receptor, cholecystokinin A receptor (CCK1), cholecystokinin B receptor (CCK2), chemokine (CC motif) receptor family, sphingosine 1-phosphate receptor family, succinate receptor, and cholinergic 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 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), gastric growth hormone secretagogue receptor (ghrelin), growth hormone secretagogue receptor 1b (GHSR1b), gastric inhibitory polypeptide receptor (GIP), glucagon-like peptide receptor family, gonadotropin-releasing hormone receptor (GnRH), pyroglutaminylation (pyroglutaminylation) mylated) 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 receptors (C5L2, FFA4, FFA4, FFA4, GPER, GPR1, GPR101, GPR107, GPR119, GPR12, GPR123, GPR132, GPR135, G PR139, 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, serotonin receptor family, KISS1-derived peptide receptor (kisspeptin), leucine-rich repeat-containing G protein-coupled receptor family, chorionic gonadotropin receptor (LH), leukotriene B4 receptor (BLT1), adenosine Acid 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 purinergic receptor 12 (mP2Y12), P2Y purinergic receptor 6 (P2Y6), pancreatic polypeptide receptor family, platelet-activating factor receptor family, prostaglandin E receptor family, prostaglandin IP1 receptor (IP1), MAS-related GPR, member family, rhodopsin, relaxin family peptide receptor family, somatostatin receptor family, tachykinin Peptide receptor family, melatonin receptor family, caudal tensin receptor family, vasoactive intestinal peptide receptor 1 (mVPAC1), neuromodulatory peptide B receptor (BB1), neuromodulatory peptide 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), oxoeicosane (OXE) receptor 1 (OXE), oxoglutarate (α-ketoglutarate) receptor 1 (OXGR1), purinergic receptor family, pyrimidine receptor family, prolactin release hormone receptors (PRRP), prokineticin receptor family, platelet-activated receptor (PAF), prostaglandin F receptor family, prostaglandin I2 (prostacyclin) receptor family, parathyroid hormone receptor family, muscarinic acetylcholine receptors (such as rM4), prostaglandin DP2 receptor (rGPR44), prokineticin receptor family, relaxin family peptide receptor family, secretin receptor (secretin), frizzled receptor (Smoothened), trace amine-related 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-induced B, nuclear factor of germ cells.

[0189] Examples of membrane transporters include, but are not limited to, the ATP-binding cassette (ABC) superfamily, the 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, NCK X1, 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, NPT2B, HHRH, CS T, CDG2F, UGAT, UGTL, UGALT, UGT1, UGT2, FUCT1, CDG2C, NST, PAT2, G6PT1, SPX4, ZIP4, LIV4, ZIP13, LZT-H s9, 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, oncoprotein 18, microtubule-destabilizing proteins, kinesin 8 and kinesin 14 families, Kip3, and Kif18A.

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

[0192] Examples of protein kinases include, but are not limited to, AP2-related kinases, Homo sapiens 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 protein-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 kinases, filaments 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, cell cycle Protein-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-related off protein kinase family, doublecortin family, discoidin domain receptor tyrosine kinase, dystrophin-protein kinase (DMPK), dual specificity tyrosine-(γ)-phosphorylation regulated kinase family, epidermal growth factor receptor family, eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1), EPH receptor family, ephrin A type receptor family, ephrin B type receptor family, v-erb-b2 erythroblastic leukemia virus oncogene homolog family, mitogen-activated protein kinase family, endoplasmic reticulum to nuclear signaling 1 (ERN1), PTK2 protein tyrosine kinase 2 (FAK), FER (fps / fes-related) tyrosine kinase (FER), feline sarcoma gene (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), FYN oncogene related to SRC, cyclin G-related kinase (GAK), eukaryotic translation initiation factor 2α 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 (haploid germ cell-specific nuclear protein kinase) (HASPIN), hematopoietic cell kinase (HCK), homeodomain-interacting protein kinase family, mitogen-activated protein kinase kinase kinase kinase family, hormone-upregulated Neu-related kinase (HUNK), intestinal cell (MAK-like) kinase (ICK), insulin-like growth factor 1 receptor (IGF1R), conserved helix-loop-helix ubiquitous kinase (IKK-α), enhancer inhibitor of kappa light chain polypeptide gene in B cells. Agents - kinase beta family, insulin receptor (INSR), insulin receptor-related receptor (INSRR), interleukin-1 receptor-associated kinase family, IL2-inducible T-cell kinase (ITK), Janus kinase family, kinase insert domain receptor, v-kit Hardy-Zuckerman 4 feline sarcoma virus 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, such as microtubule-associated serine / threonine kinase family, maternal embryonic 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 homolog, CDC42 binding protein kinase family, serine / threonine kinase family, macrophage stimulating 1 receptor (c-met-related tyrosine kinase) (MST1R), rapamycin (serine / threonine kinase) (MTOR ) mechanistic target kinases, muscle-skeletal-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 response 1 (OSR1), p21 protein (Cdc42 / Rac)) activated kinase family, PAS domain-containing serine / threonine kinases, platelet-derived growth factor receptor family, 3-phosphoinositide-dependent protein kinase-1 (PDPK1), calcium-dependent protein kinase 1, phosphorylase kinase gamma family,Phosphoinositide 4,5-bisphosphate 3-kinase, phosphoinositide-3-kinase family, phosphoinositide 4-kinase family. Phosphoinositide kinase, containing FYVE finger, 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 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), such as TAO kinase family; TANK binding kinase 1 (TBK1), such as tec protein tyrosine kinase (TEC), testis-specific kinase 1 (TESK1), transforming growth factor, beta receptor family, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), TEK tyrosine kinase, endothelial cell (TIE2), angiopoietin-1 receptor (Tie2), disheveled-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, vaccinia-related kinase 2 (VRK2), WEE1 homolog family, WNK lysine-deficient protein kinase family, v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES),Kinase AZK (ZAK) and ζ-chain (TCR)-associated protein kinase 70 kDa (ZAP70) containing a sterile α motif and a leucine zipper.

[0193] The cells used in cell therapy are mainly derived from: endoderm, such as exocrine epithelial cells (Exocrinesecretory epithelial cell) and hormone-secreting cells; ectoderm, such as keratinized epithelial cells, wet stratified barrier epithelial cells, sensory transduction cells, autonomic nerve cells, sensory organs and peripheral neuron supporting cells, central nervous system neurons and glial cells, lens cells; mesoderm, such as metabolic and storage cells, barrier function cells (lungs, intestines, exocrine glands and urogenital tract), extracellular matrix cells, contractile cells, blood and immune system cells, germ cells, trophoblasts, interstitial cells and their combinations. In addition, cells that have been genetically, chemically, or physically changed or otherwise modified are within the scope of the present invention.

[0194] Examples of exocrine epithelial cells include, but are not limited to, salivary gland mucous cells, salivary gland number 1, von Heibonne gland cells in the tongue, mammary gland cells, lacrimal gland cells, cerumen gland cells in the ear, eccrine sweat gland dark cells, eccrine sweat gland light cells, apocrine sweat gland cells, Melanie's gland cells of the eyelids, sebaceous gland cells, Bowman's gland cells of the nose, Brunner's gland cells of the duodenum, seminal vesicle cells, prostate cells, urethral gland cells, Bartholin's gland cells, urethral gland cells, endometrial cells, solitary goblet cells of the respiratory and digestive tracts, gastric mucous cells, gastric gland enzyme-producing cells, gastric gland acid-secreting cells, pancreatic acinar cells, Paneth cells of the small intestine, lung type II pneumocytes, and lung Clara cells. hormone-secreting cells include but are not limited to: anterior pituitary cells, middle pituitary cells, magnocellular neurosecretory cells, intestinal and respiratory tract cells, thyroid cells, parathyroid cells, adrenal cells, testicular Leydig cells that secrete testosterone, follicular endometrial cells that secrete estrogen, corpus luteum cells of ruptured follicles that secrete progesterone, juxtaglomerular cells, renal macula densa cells, renal pericytes, renal glomerular mesangial cells, pancreatic islet cells; keratinized epithelial cells include but are not limited to: epidermal keratinocytes, epidermal basal cells, keratinocytes of fingernails and toenails, nail bed basal cells, medullary hair stem cells, cortical hair stem cells, epidermal hair stem cells, epidermal hair root sheath cells, hair root sheath cells of Huxley's layer, hair root sheath cells of Henle's layer Cells, outer hair root sheath cells, and hair matrix cells; wet stratified barrier epithelial cells include but are not limited to: surface epithelial cells and basal cells of the stratified squamous epithelium of the cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, and urothelial cells; sensory transduction cells include but are 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, epidermal Merkel cells, olfactory receptor neurons, pain-sensitive primary sensory neurons, retinal photoreceptor cells, 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, type I taste bud cells; autonomic nerve cells include but are not limited to: cholinergic nerve cells, adrenergic nerve cells, and peptidergic nerve cells; sensory organs and peripheral neuron supporting cells include but are not limited to: inner column cells of the organ of Corti (spiral organ), outer column cells of the organ of Corti, inner digitate cells of the organ of Corti, outer digitate cells of the organ of Corti, marginal cells of the organ of Corti, Hansen cells of the organ of Corti, vestibular organ supporting cells, taste bud supporting cells, olfactory epithelium supporting cells, Schwann cells, satellite glial cells, and enteric glial cells; central nervous system neurons and glial cells include but are not limited to: astrocytes, neurons, oligodendrocytes, and spindle neurons;Lens cells include but are not limited to: anterior lens epithelial cells and lens fiber cells containing crystallin; metabolic and storage cells include but are not limited to: adipocytes and liver adipocytes; barrier function cells include but are not limited to: renal parietal cells, glomerular podocytes, renal proximal tubule brush border cells, Henle's mantle cells, renal distal tubule cells, renal 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 include but are not limited to: ameloblast epithelial cells (Ameloblast epithelial cells cell), semimeniscus epithelial cells of the vestibular system of the ear, interdental epithelial cells of the organ of Corti, loose connective tissue fibroblasts, corneal fibroblasts, tendon fibroblasts, bone marrow reticular tissue fibroblasts, other non-epithelial fibroblasts, adventitial cells, intervertebral disc nucleus pulposus cells, cementoblasts / cementinocytes, odontoblasts / odontoblasts (odontocytes), hyaline cartilage cells, fibrocartilage cells, elastic cartilage cells, osteoblasts / osteocytes, osteoprogenitor cells, vitreous cells of the vitreous body of the eye, stellate cells of the extralymphatic space of the ear, hepatic stellate cells, and pancreatic stellate cells; contractile cells include but are not limited to: skeletal muscle cells, satellite cells, cardiac myocytes, smooth muscle cells, myoepithelial cells of the iris, and myoepithelial cells of the exocrine glands; blood Blood and immune system cells include, but are not limited to, erythrocytes, megakaryocytes, monocytes, connective tissue macrophages, epidermal Langerhans cells, osteoclasts, dendritic cells, microglia, neutrophils, eosinophils, basophils, hybridoma cells, mast cells, helper T cells, suppressor T cells, cytotoxic T cells, natural killer T cells, B cells, natural killer cells, reticular cells, stem cells and committed progenitor cells of the blood and immune systems; germ cells include, but are not limited to, oogonia / oocytes, spermatocytes, spermatocytes, spermatogonia, and sperm; trophoblast cells include, but are not limited to, ovarian follicle cells, testicular Sertoli cells, thymic epithelial cells; interstitial cells include, but are not limited to, interstitial renal cells, and any combination of the foregoing cells.

[0195] Non-limiting examples of other known biologics include, but are not limited to, Abbosynagis, Abegrin, Actemra, AFP-Cide, Antova, Arzerra, Aurexis, Avastin, Benlysta, Bexxar, Blontress, Bosatria, Campath, CEA-Cide, CEA-Scan, Cimzia, Cyramza, and Etoclax. Ektomab, Erbitux, FibriScint, Gazyva, Herceptin, hPAM4-Cide, HumaSPECT, HuMax-CD4, HuMax-EGFr, Humira, HuZAF, Hybri-ceaker, Ilaris, Indimacis-125, Kadcyla, Lemtrada, LeukArrest, LeukoScan, Lucentis tis), Lymphomun, LymphoScan, LymphoStat-B, MabThera, Mycograb, Mylotarg, Myoscint, NeutroSpec, Numax, Nuvion, Omnitarg, Opdivo, Orthoclone OKT3, OvaRex, Panorex, Prolia, Palo Prostascint, Retifax, Remicade, Removab, Rencarex, ReoPro, Rexomun, Rituxan, RoActemra, Scintimun, Simponi, Simulect, Soliris, Stelara, Synagis, Tactress, Theracim, Theragyn,Theraloc, 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, Abamomab, Abciximab, Abituzumab, Abrilumab, Actoxumab, Adalimumab, Adelimumab, Aducanumab, Afasevikumab, Afelimomab, Afutuzumab, Pehalizumab, ALD518, ALD403, Alemtuzumab, Alirocumab, Atumomab Pentetate, Amatuximab, AMG 334, Anatumomab Mafenatox, Anetumab ravtansine), Anifrolumab, Anrulizumab, Apolizumab, Acitumomab, Ascrinvacumab, Aseluzumab, Atezolizumab, Atinumab, Atezolizumab, Atumumab, Avelumab, Bapineumab, Basiliximab, Bavituximab, Betumumab Becumomab, Begelomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimekizumab, Bivatuzumab mertansine), Bleselumab, Blinatumomab, Blonatumomab, Blosozumab, Bococizumab, Brazikumab, Brentuximab, Bragilumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumabmertansine, Cantuzumab roftansravtansine), Caplacizumab, capromab pendetide, Carlumab, Carotuximab, Catumaxomab, cBR96-doxorubicin immunoconjugate, Cedelizumab, Cergutuzumab amunaleukin, Cetuximab pegol, Cetuximab, Citatuzumab bogatox, Cituximab, Clazakizumab, Clenoliximab, Tetanus, Codrituzumab, Coltuximab ravtansine), Conatumumab, Concizumab, CR6261, Crenezumab, Crotedumab, Daclizumab, Daclizumab, Dalotuzumab, Dapirolizumab pegol, Datoluzumab, Dectrekumab, Demcizumab, Denintuzumab mafodotin, Denosumab, Depatuxizumab mafodotin), Derlotuximabartiox, Detumomab, Dinutuximab, Diridavumab, Domagrozumab, Dorlimomabaritox), Drozitumab, Duligotumab, Dupilumab, Durvalumab, Dusigitumab, Ecomeximab, Eculizumab, Edobacomab, Edecolomab, Efalizumab, Efentuzumab, Eldelumab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab, Emibetuzumab, Emicizumab, Enavatuzumab, Enfortumab vedotin, Enlimomab pegol), Enoblituzumab, Enokizumab, Enoticumab, Ensituximab, Epitumomabcituxetan), Epratuzumab, Erenumab, Erlizumab, Ertumaxomab, Etaracizumab, Etrolizumab, Evinacumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Farletuzumab, Fasizumab, FBTA05, Felvizumab, Fezakinumab, Fibatuzumab, Ficlatuzumab, and Figitumumab. ab), Firivumab, Flanvotumab, Fletikumab, Fontolizumab, Foralumab, Foravirumab, Fresolimumab, Fulranumab, Futuximab, Galcanezumab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumab Ozomib, Gevokizumab, Girentuximab, Glembatumumab vedotin), Golimumab, Gomilizumab, Guselkumab, Ibalizumab, Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Igovomab, IMA-638, IMAB362, Imalumab, Imciromab, Imgatuzumab, Inclacumab, Indatuximabravtansine, Indusatumab vedotin, Inebilizumab, Infliximab, Inolimomab, Inotuzumabozogamicin), Intetumumab, Ipilimumab, Iratumumab, Isatuximab, Itolizumab, Ixekizumab, Criximab, Labetuzumab, Lambrolizumab, Lampalizumab, Lanadezumab anadelumab), Landogrozumab, Laprituximabemtansine, LBR-101 / PF0442g7429, Roche, Lemalesomab, Lendalizumab, Lenzilumab, Lerdelimumab, Lexalimumab, Levitra, Lifastuzumab vedotin), Ligelizumab, Lilotomab satetraxetan, Lintuzumab, Lirilumab, Lodelcizumab, Lokivetmab, Lorvotuzumab mertansin, Lucatumumab, Lulizumab pegol), Luximab, Lumretuzumab, LY2951742, Mapamumab, Margetuximab, Maslimomab, Matuzumab, Mavuzumab, Mepolizumab, Metelimumab, Milatuzumab, Minretumomab, Mirvetuximabsoravtansine, Mitumomab, Mogamulizumab, Monalizumab, Morolimumab, Movuzumab, Moxetumomab pasudotox, Morolimumab-CD3, Nacolomab tafenatox), Namilumab, Naptumomabestafenatox, Naratuximabemtansine), Narnatumab, Natalizumab, Navicixizumab, Navivumab, Nebacumab, Neximab, Nemolizumab, Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab merpentan), Obiltoxaximab, Atezolizumab, Ocalazizumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab, Opicinumab, Oportuzumab monatox), Ogovuzumab, Orticumab, Otelixizumab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagiximab, Palivizumab, Pamrevlumab, Panitumumab, Pankomab, Panobacumab, Pasatuzumab Parsatuzumab, Pasotuxizumab, Patelizumab, Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab, Plozalizumab, Pogalizumab, Polatuzumabvedotin), Ponezumab, Prezalizumab, Priliximab, Pritoxaximab, Pritumumab, PRO 140. Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranibizumab, Raxibacumab, Refanezumab, Regavirumab, Reslizumab, Ritutumumab, Rinucumab, Risankizumab, Rituximab, Rivabazumab pegol), Robatumumab, Roledumab, Romosozumab, Rontalizumab, Rovalpituzumab tesirine, Rovelizumab, Ruplizumab, Sacituzumab govitecan, Samalizumab, Sapelizumab, Sarilumab, satumomab pendecan pendetide), Secukinumab, Seribantumab, Setoxaximab, Sevirumab, SGN-CD19A, SGN-CD33A, Sibrotuzumab, Sifalimumab, Siltuximab, Simtuzumab, Siplizumab, Sirukumab, Sofituzumabvedotin), Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tamtuvetmab, Tanezumab, Taplitumomab paptox, Tarextumab, Tefibazumab, Telimomab aritox), Tenatumomab, Teneliximab, Tilizumab, Teprotumumab, Tesidolumab, Tetulomab, Tezepelumab, TGN1412, Ticilimumab, Tigatuzumab, Tildrakizumab, Timolumab, Tisotumab vedotin), TNX-650, Tocilizumab, Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, tralokinumab, Trastuzumab, Trastuzumab emtansine, TRBS07, Tregalizumab, Tremelimumab, Trevogrumab, Tucotuzumab celmoleukin), Tuvirumab, Ublituximab, Ulocuplumab, Urelumab, Urtoxazumab, Ustekinumab, Utomilumab, Vadastuximabtalirine), Vandortuzumab vedotin, Vantictumab, Vanucizumab, Vapaliximab, Varlilumab, Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Vobarilizumab, Volociximab, Vorsetuzumab mafodotin), Votumumab, Xentuzumab, Zanolimumab, Zalutumumab, Zalutumumab, Zatuximab, Ziralimumab, and Zolimomab aritox, 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, measles, mumps and rubella (MMR) vaccine, MMRV vaccine, polio vaccine, rabies vaccine, rotavirus vaccine, varicella 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 vaccine, enterovirus 71 vaccine, Epstein-Barr virus vaccine, hepatitis C vaccine, HIV vaccine, human HTLV-1 T-lymphocytic leukemia vaccine, Marburg virus disease vaccine, norovirus vaccine, human respiratory syncytial virus vaccine, severe acute respiratory syndrome (SARS) vaccine, and human West Nile virus vaccine. Examples of bacterial diseases include, but are not limited to, anthrax vaccine, DPT vaccine, Q fever vaccine, Hib vaccine, tuberculosis (BCG) vaccine, meningococcal vaccine, typhoid vaccine, pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine, cholera vaccine, dental caries vaccine, ehrlichiosis vaccine, leprosy vaccine, Lyme disease vaccine, Staphylococcus aureus vaccine, Streptococcus pyogenes vaccine, syphilis vaccine, tularemia vaccine, and Yersinia pestis vaccine; examples of parasitic diseases include, but are not limited to, malaria vaccine, schistosomiasis vaccine, Chagas disease vaccine, hookworm vaccine, human clonorchiasis vaccine, trypanosomiasis vaccine, and visceral leishmaniasis vaccine; examples of non-infectious diseases include, but are not limited to, Alzheimer's disease amyloid vaccine, breast cancer vaccine, ovarian cancer vaccine, prostate cancer vaccine, oncolytic virus agent (Talimogene) laherparepvec) (T-VEC); vaccines also include, but are not limited to, the following trade names: ACAM2000, ActHIB, Adacel, Afluria, AFLURIAQUADRIVALENT, Agriflu, BCG vaccine, BEXSERO, Biothrax, Boostrix, Cervarix, Comvax, DAPTACEL, DECAVAC , Engerix-B, FLUAD, Fluarix, Fluarix Quadrivalent, Flublok, Flucelvax, Flucelvax Quadrivalent, FluLaval, FluMist, FluMist Quadrivalent, Fluvirin, FluzoneQuadrivalent), Fluzone, Fluzone High-Dose and Fluzone Intradermal, Gardasil, Gardasil 9, Havrix, Hiberix, Imovax, Infanrix, IPOL, Ixiaro, JE-Vax, KINRIX, Menactra, MenHibrix, Menomune-A / C / Y / W-135, Menveo, MMR II, MM-Vax, Pediarix, Pedvax 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, Vaxchora, Vivotif, YF-Vax, Zostavax, and combinations thereof.

[0198] Examples of injectable drugs include, but are not limited to, Ablavar (Gadofosveset Trisodium Injection), Abarelix Depot (Abarelix Depot), Abobotulinumtoxin A Injection (Dysport), ABT-263, ABT-869, ABX-EFG, Accretropin (Somatropin Injection), Acetadote (Acetylcysteine Injection), Acetazolamide Injection, Acetadote, Tocilizumab Injection, Acthrel (Corticorelin Ovine Trifluoroacetate Injection), and Benzothin (Dapoxetine). Triflutate), Actummune, Alteplase, Acyclovir for injection (Zovirax injection), Adacel, Adalimumab, Adenoscan (adenosine injection), Adrenaclick, AdreView (iodine-1123 benzylguanidine for intravenous use), 1123) injection), Afluria, Ak-Fluor (fluorescein injection), Aldurazyme (Laronidase), Ceredase, Alkeran injection (melphalan hydrochloride injection), Allopurinol sodium injection (Aloprim), Aloprim (allopurinol sodium injection), Alprostadil, Alsuma (sumatriptan injection), ALTU-238, Amino Acid Injection, Aminosyn, Apidra, Apremilast, Alprostadil injection 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, AMG655, AMG 706, AMG 714, AMG 745, AMG 785, AMG 811, AMG 827, AMG 837, AMG 853, AMG 951, Amiodarone Hydrochloride Injection (Amiodarone HCl Injection), Amobarbital Sodium Injection (Amytal Sodium), Amytal Sodium (Amobarbital Sodium Injection), Anakinra, Aβ Antibody (Anti-Abeta), β7 Antibody (Anti-Beta7), β20 Antibody (Anti-Beta20), CD4 Antibody (Anti-CD4), CD20 Antibody (Anti-CD20), CD40 Antibody (Anti-CD40), IFNα Antibody (Anti-IFNalpha), IL13 Antibody (Anti-IL13), OX40L Antibody (Anti-OX40L), o xLDS antibody (Anti-oxLDS), NGF antibody (Anti-NGF), NRP1 antibody (Anti-NRP1), Arixtra (pentosan sodium), Amphadase (hyaluronidase injection), Ammonul (sodium phenylacetate and sodium benzoate injection), Anaprox, Anzemet injection (dolasetron mesylate injection), Apijul (insulin glulisine [rDNA source] injection), Apomab, Aranesp (darbepoetin alfa), Argatroban (argatroban injection), arginine hydrochloride injection (R-Gene 10. Aristocort, Aristospan, Trisenox, Articane HCl and Septocaine, Arzerra (ofatumumab injection), Asclera (polidocanol injection), Ataluren, Ataluren-DMD, Atenolol injection (Tenormin IV Injection), Atracurium besylate injection (Atracurium besylate injection), Avastin, Azactam injection (Aztreonam injection), Azithromycin (Zithromax injection), Azactam injection (Aztreonam injection), Baclofen injection (Lioresal intrathecal injection), and INTRATHECAL), Bacteriostatic Water (Bacteriostatic Water for Injection), Baclofen Injection (Shangli Aolaisu Intrathecal Injection), Bal in Oil Ampoule (Bal in Oil AmpouleOilAmpules (Dimercarprol Injection), BayHepB, BayTet, Benadryl, Bendamustine Hydrochloride Injection (Treanda), Benztropine Mesylate Injection (Cogentin), Betamethasone Injectable Suspension (Celestone Soluspan), Bexxar, Bicillin CR 900 / 300 (Penicillin G Benzathine Penicillin and Penicillin G Procaine Injection), Blenoxane (Bleomycin Sulfate Injection), Bleomycin Sulfate Injection (Blenoxane), Boniva Injection (Ibandronate Sodium Injection), Botox Cosmetic (OnabotulinumtoxinA for injection), BR3-FC, Bravelle (follicle-stimulating hormone injection), Bretylium (brembenzylium injection), Brevital Sodium (methohexital sodium for injection), Brethine, Briobacept, BTT-1023, Bupivacaine Hydrochloride, Byetta, Ca-DTPA (pentetate calcium sodium injection), Cabazitaxel injection (Jevtana), Caffeine alkaloids ( Alkaloid (Caffeine and Sodium Benzoate Injection), Calcitriol Injection (Calcitrol), Calcitriol (Calcitriol Injection), Calcium Chloride (Calcium Chloride Injection 10%), EDTA Calcium Disodium Edetate (EDTA Calcium Disodium Edetate Injection), Campath (Alemtuzumab), Camptosar Injection (Irinotecan Hydrochloride), Canakinumab Injection (Ilaris), Capastat Sulfate (Capreomycin for Injection), Capreomycin for Injection (Capreomycin Sulfate), Cardiolite (Prep kit for Technetium Tc99 Injection),Tc99Sestamibi), Carticel, Cathflo, Cefazolin and Dextrose for Injection (Cefazolin Injection), Cefepime Hydrochloride, Cefotaxime Sodium, Ceftriaxone, Cerezyme, Carnitor Injection, Caverject, Betamethasone Sodium Phosphate, Celsior, Cerebyx (Fosphenytoin Sodium) Sodium Injection), Ceredase (alglucosidase injection), Ceretec (technetium Tc99m exametazime injection), Certolizumab pegol, CF-101, chloramphenicol sodium succinate (chloramphenicol sodium succinate injection), chloramphenicol sodium succinate injection (chloramphenicol sodium succinate), Cholestagel (colesevelam hydrochloride), choriogonadotropin alfa injection (Ovidrel), Cimzia, Cisplatin (cisplatin injection), Clolar (clofarabine injection), clomiphene citrate, clonidine injection (Duraclon), Cogentin (benztropine mesylate injection), colistimethate injection (Coly-Mycin M), Coly-Mycin M (colistin injection), Compath, conivaptan hydrochloride injection (Vaprisol), conjugated estrogens for injection (Premarin injection), Copaxone, ovine cortisol trifluoroacetate injection (Acthrel), Corvert (ibutilide fumarate injection), Cubicin (daptomycin injection), CF-101, Cyanokit (hydroxycobalamin injection), cytarabine liposomal (CytarabineLiposome Injection (DepoCyt), Cyanocobalamin, Cytovene (ganciclovir), DHE45, Dacilizumab, Dacogen (Decitabine Injection), Dalteparin, Dantrolene IV (Dantrolene Sodium Injection), Dantrolene Sodium Injection (Dantrolene IV), Daptomycin Injection (Cubicin), Darbepoietin alfa, DDAVP Injection (Desmopressin Acetate Injection), Decavax, Decitabine Injection (Dacogen), Anhydrous Ethanol (Anhydrous Ethanol Injection), Denizumab Injection (Prolia), Delatestryl, Delestrogen, Delteparin Sodium Sodium), Depacon (sodium valproate injection), DepoMedre (methylprednisolone acetate injectable suspension), DepoCyt (cytarabine liposome injection), DepoDur (Morphine Sulfate XR Liposome injection), Desmopressin Acetate Injection (DDAVP injection), Depo-estradiol, Provera 104mg / ml, Provera 150mg / ml, Depo-testosterone, Dilazocol for injection, Totect for IV infusion only, Dextrose / Electrolytes, Dextrose and Sodium Chloride Injection (dextrose 5% in 0.9% sodium chloride), Dextrose, Diazepam Injection Injection), digoxin injection (Lanoxin injection), dihydromorphine (Dilaudid)-HP (dihydromorphone hydrochloride injection), dimercaprol injection (Bal in oil ampoule), diphenhydramine injection (Benadryl injection), dipyridamole injection (Dipyridamole injection), DMOAD, docetaxel injection (Taxotere), dolasetron mesylate injection (Anzemet injection), Doribax (Doripenem injection), doripenem injection (Doribax), doxercalciferol injection (Hectorol injection), Doxil (Doxorubicin HCl liposomalLiposome injection), doxorubicin hydrochloride liposome injection (Doxil), Duraclon (Clottin injection), Duramorph (morphine injection), Dysport (Abo botulinum toxin type A injection), ecallantide injection (Kalbitor), EC-naproxen (naproxen), EDTA calcium disodium injection (edetate calcium disodium), Edex (alprostadil for injection), Engerix, Enlonium injection (edrophonium chloride), Eliglustat tartrate Tartate), Eloxatin (oxaliplatin injection), Emend injection (Fosaprepitant Dimeglumine injection), Enalapril injection (Enalaprilat injection), Edrophonium injection, Enoxaparin sodium injection (Lovenox), Eovist (Gadoxetate disodium Disodium injection), Enbrel (etanercept), Enoxaparin, Epicel, Epinepherine, Epipen, Epipen Jr., Epratuzumab, Erbitux, Ertapenem injection (Invanz), Erythropoieten, Nephramine, Estradiol Cypionate, Estradiol Valerate Valerate), etanercept, exenatide injection (Byetta), Evlotra, Fabrazyme (Adalsidase beta), famotidine injection, FDG (fluorodeoxyglucose F18 injection), Feraheme (Ferumoxytol injection), Feridex IVIV) (Ferumoxides Injectable Solution), Fertinex, Iron Oxide Nanoparticle Injectable Solution (Ferumoxide IV), Nano-Iron Oxide Injection (Flahemo), Flagyl Injection (Metronidazole Injection), Fluarix, Fludara (Fludarabine Phosphate), Fluodeoxyglucose F18 Injection (FDG), Fluorescein Injection (Ak-Fluor), Follistim AQ Cartridge (Follitropin Beta Injection), Follicle-Stimulating Hormone Alpha Injection (Gonal-Fluor), RFF), follitropin beta injection (Follitropin AQ cartridge), Folotyn (pralatrexate solution for intravenous injection), Fondaparinux, Forteo (teriparatide (rDNA origin) injection), Fostamatinib, Fosaprepitant Dimeglumine injection (Emend injection), Foscarnet sodium injection (Foscavir), Foscarnet sodium injection (Foscarnet), Cerebyx sodium injection, Luusedra sodium injection, Fragmin, Fuzeon (enfuvirtide), GA101, Multihance gadobenate dimeglumine injection, Ablavar trisodium injection, ProHance gadoteridol injection solution, OptiMARK gadoversetamide injection, and Gadoxetate disodium injection. Disodium injection (Eovist), Ganirelix (Ganirelix acetate injection), Gardasil, GC1008, GDFD, Gemtuzumab Ozogamicin injection (Mylotarg), recombinant human growth hormone (Genotropin), gentamicin injection, GENZ-112638, golimumab injection (Simponi injection), Gonal-fRFF (follicle-stimulating hormone alpha injection), granisetron hydrochloride (Kytril injection), gentamicin sulfate, glatiramer acetate, glucagon (Glucagen), glucagon, HAE1, Haldol (haloperidol injection), Havrix, Hectorol injection (doxercalciferol injection), Hedgehog Pathway inhibitors Inhibitor), heparin, Herceptin, hG-CSF, Humalog, human growth hormone, Humatrope, HuMax, Humegon, Humira, Humulin, ibandronate sodium injection (Boniva injection), ibuprofen lysine injection (NeoProfen), ibuprofen lysine injection (Corvert), Idamycin PFS (Idarubicin Hydrochloride Injection), Idarubicin Hydrochloride Injection (Idamycin PFS), Ilaris (canakinumab injection), Imipenem and cilastatin injection (Primaxin IV), Imitrex, Incobotulinumtoxin Type A for Injection (Xeomin), Increlex (Mecasermin [rDNA Origin] Injection), Indocin IV (Indomethacin Injection), Indomethacin Injection (Indomethacin IV), Infanrix, Innohep, Insulin, Insulin Aspart [rDNA Origin] Injection (NovoLog), Insulin Glargine [rDNA Origin] Injection (Lantus), Insulin Glulisine [rDNA Origin] Injection (Apizuela), Interferon Alpha-2b Recombinant Injection (Intron A), Intron A (Interferon Alpha-2b Recombinant Injection), Invanz (Ertapenem Injection), Invega Sustenna (Paliperidone Palmitate Extended ReleaseExtended-Release Injectable Suspension), Invirase (saquinavir mesylate), iobenzylguanidine 1123 injection for intravenous infusion (AdreView), iopromide injection (Ultravist), ioversol injection (Optiray injection), Iplex (mecasermin linfilpep [rDNA origin] injection), Iprivask, irinotecan hydrochloride (Camptosar injection), iron sucrose injection (Venofer), Istodax (romidepsin for injection), itraconazole injection (Sporanox injection), Jevtana (cabazitaxel injection), Jonexa (Jonexa), Kalbitor (ecallantide injection), KCL in D5NS (potassium chloride injection in 5% dextrose and sodium chloride), KCL in D5W, KCL in NS, Kenalog 10 injection (triamcinolone acetate) for oral administration Acetonide injectable suspension), Kepivance (palifermin), Keppra (levetiracetam) injection, Keratinocyte, KFG, kinase inhibitors, Kineret (anakinra), Kinlytic (urokinase injection), Kinrix, Klonopin (clonazem), Kytril (granisetron hydrochloride) injection, Lacosamide tablets and injection (Vimpat), Lactated Ringer's solution, Lanosin injection (digoxin injection), Lansoprazole injection (Protopin IV), Lantus, leucovorin (leucovorin calcium injection), Lente (L), Leptin, Levemir, LeukineSargramostim), leuprorelin acetate, levothyroxine, levetiracetam (Keppra injection), enoxaparin (Lovenox), L-carnitine injection (Carnitine injection), Lexiscan (Regadenoson injection), Sanlior intrathecal injection (baclofen injection), liraglutide [rDNA] injection (Vocalis), enoxaparin (Lovenox) (enoxaparin sodium injection), Lucentis (ranibizumab injection), Lumizyme, Lupron (leuprorelin acetate injection), Luusedra (fospropofol sodium injection), Maci, magnesium sulfate (magnesium sulfate injection) injection), mannitol injection (mannitol IV), marcaine (bupivacaine hydrochloride and epinephrine injection), Maxipime (cefepime hydrochloride injection), MDP multi-dose kit for technetium injection (technetium Tc99m oxametaoxime injection), mecasermin [rDNA source] injection (Increlex), mecasermin linfilpep [rDNA source] injection (Iplex), melphalan hydrochloride injection (Alkeran injection), methotrexate, Menactra, Menopur (fertility stimulant injection), fertility stimulant injection (Repronex), methohexital sodium injection (Brevital sodium) Sodium), methyldopa ethyl hydrochloride injectable solution (methyldopa ethyl hydrochloride), methylene blue (methylene blue injection), methylprednisolone acetate injectable suspension (DepoMedrol), MetMab, metoclopramide injection (Reglan injection), metoclopramide (Follitropin for Injection), metronidazole injection (Flagyl injection), metronidazole, midazolam (Midazolam injection), Mimpara (Cinacalet), minocycline injection (minocycline injection), minocycline injection (minocycline injection), Cyclocycline Injection), Mipomersen, Mitoxantrone Concentrate for Injection (Norvantron), Morphine Injection (Morphine Sulfate), Morphine Sulfate XR Liposomal Injection (DepoDur), Sodium Morrhuate (Sodium Morrhuate Injection), Motesanib, Mozobil (Plerixa Injection), Multihance (Gadobenate Diglucamide Injection), Multiple Electrolytes and Dextrose Injection, Multiple Electrolytes Injection, Mylotarg (Gemtuzumab Ozomicin Injection), Myozyme (Alglucosidasealfa), nafcillin injection (nafcillin sodium), nafcillin sodium (nafcillin injection), naltrexone XR injection (Vivitrol), naproxen (naproxen), NeoProfen (ibuprofen lysinate injection), nandrolone decanoate (Nandrol Decanoate), neostigmine methylsulfate (neostigmine methylsulfate injection), NEO-GAA, NeoTect (technetium Tc 99m depo-opeptide injection), Nephramine (essential amino acid injection), Neulasta (pegfilgrastim), Neupogen (filgrastim), Novolin, Novara, NeoRecormon, Neutrexin (trimetrexate glucuronate injection), NPH(N), Nexterone (amiodarone hydrochloride injection), Norditropin (somatropin injection), Normal saline (sodium chloride injection), Novantrone (mitoxantrone concentrate for injection), Novolin 70 / 30-Innolet (70% NPH, neutral hypoprotamine zinc human insulin suspension and 30% regular human insulin injection), Novara (insulin aspart [rDNA source] injection), Nplate (romiplostim), Nutropin (somatropin injection (rDNA source)), Nutropin AQ, Nutropin Depot (growth hormone (rDNA source) for injection), octreotide acetate injection (Sandotide LAR), occlizumab, ofatumumab injection (Arzerra), olanzapine extended-release injectable suspension (Zyprexa Relprevv), Omitrac, Omnitrope (growth hormone [rDNA source] injection), ondansetron hydrochloride injection (Zofran injection), OptiMARK (gadofrostamide injection), Ampelin injection (ioversol injection), Orencia, Osmitrol injection in Aviva (mannitol injection in Aviva plastic container 250), Osmitrol injection in Viaflex (mannitol injection in Viaflex plastic container 250), bone protection Osteoprotegrin, Ovidrel (chorionic gonadotropin alfa injection), oxacillin (oxacillin for injection), oxaliplatin injection (Eloxatin), oxytocin injection (pyridoxine), paliperidone palmitate extended-release injectable suspension (Susta), pamidronate disodium injection (pamidronate sodium injection), panitumumab injection for intravenous infusion (Vectibix), papaverine hydrochloride injection (papaveline injection), papaverine injection (papaveline hydrochloride injection), parathyroid hormone, paricalcitol injection trigger bottle (FliptopVial (Zemplar injection), PARP inhibitors, Pediarix, PEGlntron, Peginterferon, pegfilgrastim, benzathine penicillin G and procaine penicillin G, Pentetate calcium sodium injection (Ca-DTPA), pentetate zinc sodium injection (Zn-DTPA), Pepcid injection (famotidine injection), Pergonal, pertuzumab, phentolamine mesylate (phentolamine mesylate injection), physostigmine salicylate (physostigmine injection), physostigmine salicylate (physostigmine injection), piperacillin and tazobactam injection (Zosyn), Pyridoxine (oxytocin injection), Plasma-Lyte 148 (multiple electrolytes injection), Plasma-Lyte 56 and dextrose (multiple electrolytes and dextrose injection in Vivox plastic container 250), PlasmaLyte, (Plerixa for injection) (Mozobil), Polidocanol injection (Asclera), potassium chloride, pralatrexate solution for IV injection (Folotyn), pramlintide acetate injection (Symlin), Premarin injection (conjugated estrogens for injection), Technetium Tc-99 Sitabiprole preparation kit for injection (Cardiolite), Protopin IV (lansoprazole for injection), Primaxin IV (imipenem and cilastatin for injection), Prochymal, Procrit, progesterone, ProHance (gadoteridol injection solution), Prolia (denimab injection), Promethazine Hydrochloride Injection (promethazine hydrochloride injection), Propranolol Hydrochloride Injection (propranolol hydrochloride injection), Quinidine Gluconate Injection (quinidine injection), Quinidine Injection (quinidine gluconate injection), R-Gene10 (arginine hydrochloride injection), Lucentis, Zantac, Raptiva, Reclast (zoledronic acid injection), Recombivarix HB, Regadesone injection (Lexikan), Metoclopramide injection (metoclopramide injection), Remicade, Renagel, Renvela (sevelamer carbonate), Repronex (fertility enhancer for injection), Retrovir IV (zidovudine injection), rhApo2L / TRAIL, Ringer's, and 5% dextrose injection (dextrose). Ringer's injection (Ringer's), Rituxan, Rituximab, Rocephin (ceftriaxone), Rocuronium injection (Zemuron), Interferon-A (interferon alpha-2a), Romazicon (flumazenil), Romidepsin injection (Istodax), Saizen (growth hormone injection), Sandostatin LAR (octreotide acetate injection), Sclerostin Ab, Sensipar (Cinacalcet), Sensorcaine (bupivacaine hydrochloride injection), Septocaine (articaine hydrochloride and epinephrine injection), Serostim LQ (growth hormone (rDNA origin) injection), Simponi injection (golimumab injection), sodium acetate (sodium acetate injection), sodium bicarbonate (sodium bicarbonate 5% injection), sodium lactate (sodium lactate injection in AVIVA), sodium phenylacetate and sodium benzoate injection (Ammonul), growth hormone (rDNA origin) injection (Nutropin), Sporanox injection (itraconazole injection), Stelara injection (ustekinumab), Stemgen, sufentanil (sufentanil citrate injection), sufentanil citrate injection (Sufentanil), Sumavel, sumatriptan injection (Alsuma), Semeline, Semeline pen, systemic Hedgehog antagonist, Synvisc-One (Hilan GF injection), 20 single intra-articular injection), erlotinib (Tarceva), Taxotere (docetaxel for injection), technetium Tc99m, telavancin for injection (Vibativ), temsirolimus injection (Torisel), Tiannomin IV injection (atenolol injection), teriparatide (rDNA-derived) injection (Forteo), testosterone cypionate, testosterone enanthate, testosterone enanthate, Tev-Tropin (growth hormone, rDNA-derived, for injection), tgAAC94, thallium chloride, theophylline, thiotepa (thiotepa injection), Thymoglobulin (antithymocyte globulin (rabbit)), Shizhejin (thyroid-stimulating hormone alfa for injection), ticarcillin sodium, and clavulanate potassium Galaxy (Tamantine Injection), Digen Injection (Injectable Trimethoprim Hydrochloride), Tamantine Injection (Ticacillin Sodium and Clavulanate Potassium), Tenecteplase (TNKase), Tobramycin Injection (Tobramycin Injection), Tocilizumab Injection (Antinele), Torisel (temsirolimus Injection), Totect (Dexazolidinone for Injection, IV infusion only), Trastuzumab-DM1, Travasol (Amino Acid (Injection)), Treanda (Bendamustine Hydrochloride Injection), Trelstar (Triptorelin Hydrochloride Injectable Suspension), Pamoate for Injectable Suspension), triamcinolone acetonide acetate, triamcinolone diacetate, triamcinolone acetonide injectable suspension (Aristospan injection 20 mg), Triesence (triamcinolone acetonide acetate injectable suspension), injectable trimethoxazole hydrochloride (Tigan injection), trimetrexate glucuronate injection (Neutrexin), triptorelin hydroxynaphate injectable suspension (Trelstar), Twinject, Trivaris (triamcinolone acetonide acetate injectable suspension), Trisenox (arsenic trioxide injection), Twinrix, Typhoid Vi vaccine (TyphoidVi), Uvisen (iopromide injection), urofollicle-stimulating hormone for injection (Mei Chuding), urokinase injection (Kinlytic), Stelara injection, Ultralente (U), Valium (diazepam), sodium valproate injection (Dipaken), Valtropin (growth hormone injection), vancomycin hydrochloride (vancomycin hydrochloride injection), vancomycin hydrochloride injection (vancomycin hydrochloride), Vaprisol (Conivas hydrochloride) Injection), VAQTA, Vasovist (gadofosvesic trisodium injection for intravenous infusion), Vectibix (panitumumab injection for intravenous infusion), Venofer (iron sucrose injection), verteporfin injection (Visudyne), Vibativ (telavancin injection), Victoza (liraglutide [rDNA] injection), Vimpat (lacosamide tablets and injection), Vinblastine sulfate (vinblastine sulfate injection), Vincasar (vinblastine sulfate injection). PFS (vincristine sulfate injection), Victoza, Vincristine sulfate (vincristine sulfate injection), Visudyne (verteporfin injection), vitamin B-12, Vivitrol (naltrexone XR injection), Voluven (hydroxyethyl starch in sodium chloride injection), Xeloda, Xenical (orlistat), Xeomin (incobotulinum toxin type A injection), Xolair, Zantac injection (ranitidine hydrochloride injection), Zemplar injection (paricalcitol injection trigger bottle), Zemuron (

[00155] The present invention relates to a novel anti-cancer drug that is indicated for the treatment of idiopathic encephalopathy (IDS) and / or idiopathic encephalopathy (IDS). The invention also includes, but is not limited to, rocuronium bromide injection, Zenapax (daclizumab), Zevalin, zidovudine injection (Retovi IV), Zithromax injection (azithromycin), Zn-DTPA (sodium zinc pentetate injection), Zofran injection (ondansetron hydrochloride injection), Zingo, zoledronic acid for injection (Zometa), zoledronic acid injection (Reclast), Zometa (zoledronic acid for injection), Zosyn (piperacillin and tazobactam injection), Zyprexa Relprevv (olanzapine extended-release injectable suspension), and combinations thereof. Notice

[0199] The invention of the present application has been described above generally and with reference to specific embodiments. It will be apparent to those skilled in the art that various modifications and variations may be made to the embodiments without departing from the scope of the present disclosure. Therefore, the embodiments are intended to cover modifications and variations of the present invention as fall within the scope of the appended claims and their equivalents.

Claims

1. A stopper for a syringe, comprising: 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 a syringe; wherein the body of the stopper has an inner surface and a recess having a first end and a second end, the recess being defined by the inner surface, and the body further has an opening leading to the second end of the recess, the opening being formed in a rear end of the body; wherein the pocket comprises a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion between the capture portion and the release portion, the coupling portion having a third diameter that is smaller than the first diameter and the second diameter; Wherein, the inner surface of the body includes one or more coupling protrusions corresponding to the coupling portion of the recess.

2. The stopper according to claim 1, wherein: The one or more coupling protrusions include a circumferential ridge.

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

4. The stopper according to any one of claims 1 to 3, characterized in that The one or more coupling protrusions include a longitudinal ridge.

5. The stopper according to any one of claims 1 to 4, characterized in that The one or more coupling protrusions have a leading edge and a trailing edge, and further wherein at least the leading edge is at least one of chamfered and rounded.

6. The stopper according to any one of claims 1 to 5, characterized in that The first diameter is substantially the same as the second diameter.

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

8. The stopper according to any one of claims 1 to 7, characterized in that The first diameter and the third diameter differ by about 0.3 mm.

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

10. The stopper according to any one of claims 1 to 9, characterized in that The stopper is configured to exhibit an insertion force of less than 75% of the break-away force of the stopper when received in the syringe barrel, and optionally, an insertion force of less than 50% or less of the break-away force when received in the syringe barrel.

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

2.

12. A syringe comprising: a syringe having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper positioned in the receiving chamber so as to slidably and sealingly engage the inner surface of the barrel, the stopper having a recess, the recess including a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion located between the capture portion and the release 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 recess; as well as a plunger rod having a head, a rear portion, and a stem portion extending between the head and the rear portion, the head having a tapered crown and defining a retaining feature that engages the coupling portion of the recess to couple the plunger rod to the stopper, wherein the head is received in the capture portion of the stopper.

13. The syringe according to claim 12, wherein The tapered crown has a smooth surface for slidably engaging one or more coupling protrusions of the coupling portion during insertion of the plunger rod head into the recess of the stopper.

14. The syringe according to claim 12 or 13, characterized in that The stopper and the barrel define a break-away force, and the stopper and the plunger rod are configured such that the plunger rod head can be axially inserted into the stopper, wherein the stopper is received in the barrel with an insertion force less than the break-away force.

15. The syringe according to claim 14, wherein The break-away force is 2N to 20N.

16. The stopper according to claim 14 or 15, characterized in that The stop is configured to exhibit an insertion force that is less than 75% of the break-away force of the stop, and optionally, an insertion force that is less than 50% of the break-away force or less.

17. The syringe according to any one of claims 12 to 16, characterized in that The plunger rod and the stopper require a separating force to be applied in a longitudinal direction to disengage the plunger rod from the stopper.

18. A syringe according to claim 14, when dependent on any one of claims 14 to 17, characterised in that The separation force is greater than the break-away force.

19. The stopper according to any one of claims 12 to 18, characterized in that The stopper is characterized by an Lp / L value that is greater than 0, optionally 0.05, and 0.5 or less, or optionally 0.3 or less, or optionally 0.2 or less, or optionally from 0.1 to 0.

2.

20. A method of coupling a plunger rod to a stopper positioned within a barrel of a syringe, the method comprising axially inserting a head of the plunger rod into a recess of the stopper using an insertion force, wherein the insertion force is less than a breakaway force defined between the stopper and the barrel of the syringe, wherein The plunger rod is coupled to the stopper upon axially inserting the head of the plunger rod into the capture portion of the stopper.

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

22. The method according to 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. The method according to any one of claims 20 to 22, characterized in that Inserting the head into the recess comprises sliding the head 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 chamfered and rounded, and further wherein inserting the head into the recess comprises sliding the head longitudinally over the leading edge of the one or more coupling protrusions.

24. The method according to claim 23, wherein The break-away force is 2N to 20N.

25. The method according to any one of claims 20 to 24, characterized in that The plunger rod and the stopper require a separating force to be applied in a longitudinal direction to disengage the plunger rod from the stopper.

26. The method of claim 25, wherein: The separation force is greater than the break-away force.

27. The method according to any one of claims 20 to 26, characterized in that The stop is configured to exhibit an insertion force of less than 75% of the break-away force, and optionally an insertion force of less than 50% of the break-away force or less.

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

2.

29. A stopper for a syringe, the stopper comprising: 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 a syringe; wherein the body of the stopper has an inner surface and a recess having a first end and a second end, the recess being defined by the inner surface, and the body further has an opening leading to the second end of the recess, the opening being formed in a rear end of the body; wherein the pocket comprises a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion between the capture portion and the release portion, the coupling portion having a third diameter that is smaller than the first diameter and the second diameter; Wherein, the inner surface of the body includes one or more coupling recesses corresponding to the coupling portion of the recess.

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

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

32. The stopper according to any one of claims 29 to 30, characterized in that The one or more coupling recesses include a longitudinal recess.

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

34. The stopper according to any one of claims 29 to 33, characterized in that The first diameter is substantially the same as the second diameter.

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

36. The stopper according to any one of claims 29 to 35, characterized in that The first diameter and the third diameter differ by about 0.3 mm.

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

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

2.

39. A method of coupling a plunger rod to a stopper positioned within a barrel of a syringe, the method comprising axially inserting a head of the plunger rod into a recess of the stopper using an insertion force, wherein the insertion force is less than a breakaway force defined between the stopper and the barrel of the syringe, wherein The plunger rod is coupled to the stopper upon axially inserting the head of the plunger rod into the capture portion of the stopper.

40. The method of claim 39, wherein Inserting the head into the recess further includes sliding the enlarged section of the head of the plunger rod into one or more coupling recesses corresponding to coupling portions of the recess to couple the plunger rod to the stopper.

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. The method of claim 41, wherein Each of the one or more coupling recesses has a leading edge and a trailing edge, and wherein at least the leading edge is at least one of chamfered and rounded, and inserting the head into the recess comprises sliding the head longitudinally over the leading edge of the one or more coupling recesses so that the enlarged section of the head is seated in the one or more coupling recesses.

43. The method according to any one of claims 39 to 42, wherein The break-away force is 2N to 20N, and once the plunger rod is inserted into the stopper, the stopper and the plunger rod require a separation force applied in a longitudinal direction to disengage the plunger rod from the stopper.

44. The method of claim 43, wherein: The separation force is greater than the break-away force.

45. The method according to claim 43 or 44, wherein The stopper is configured to exhibit an insertion force of less than 75% of the break-away force of the stopper when received in the syringe barrel, and optionally, an insertion force of less than 50% or less of the break-away force when received in the syringe barrel.

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

2.

47. A syringe comprising: a syringe having an outer surface, an inner surface, and a receiving chamber, the inner surface defining the receiving chamber; a stopper positioned in the receiving chamber so that the stopper is slidably and sealingly engaged with the inner surface of the barrel, the stopper having a recess, the recess including a capture portion having a first diameter, a release portion having a second diameter, and a coupling portion located between the capture portion and the release portion, the coupling portion having a third diameter greater than the first diameter and the second diameter, the stopper including one or more coupling recesses corresponding to the coupling portion of the recess; as well as a plunger rod having a head, a rear portion, and a stem portion extending between the head and the rear portion, the head defining a retaining feature that engages the coupling recess of the pocket to couple the plunger rod to the stopper, wherein the retaining feature is received in the one or more coupling recesses of the stopper.

48. The syringe of claim 47, wherein The stopper and the barrel define a break-away force, and the stopper and the plunger rod are configured such that the plunger rod head can be axially inserted into the stopper, wherein the stopper is received in the barrel with an insertion force less than the break-away force.

49. The syringe according to claim 48, wherein The break-away force is 2N to 20N.

50. The syringe according to any one of claims 47 to 49, characterized in that The plunger rod and the stopper require a separating force to be applied in a longitudinal direction to disengage the plunger rod from the stopper.

51. A syringe as claimed in claim 50, when dependent on claim 48 or 49, characterised in that The separation force is greater than the break-away force.

52. The syringe according to claim 48 or 49, wherein The stopper is configured to exhibit an insertion force of less than 75% of the break-away force of the stopper when received in the syringe barrel, and optionally, an insertion force of less than 50% or less of the break-away force of the stopper when received in the syringe barrel.

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

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