Injector device stopper with an activatable layer - Patent Application 20070122997

Abstract

A stopper for use with an injector device, the stopper having an exterior configured to engage an inner lumen of a barrel of the injector device, includes an elastomeric body and a barrier coupled to the elastomeric body, the barrier having an inner surface facing toward the elastomeric body and an outer surface facing away from the elastomeric body, the barrier including a first layer of a first material and a second layer of a second material, the first layer configured to be activatable by an energy source and the second layer configured to be less activatable by an energy source than the first layer.

Description

[Technical Field]

[0001] Field Various inventive concepts featured herein relate to injector devices, such as syringes, autoinjectors and pens, that include a barrel and a stopper slidably received within the barrel, as well as related methods of making and using such devices. [Background technology]

[0002] background Injector devices (e.g., syringes, autoinjectors, and pens) typically include a barrel, a stopper disposed within the barrel, and a plunger rod or actuation mechanism for displacing the stopper. The stopper is typically air- and liquid-impermeable and forms an airtight and liquid-tight seal with the barrel while providing low-friction sliding properties. Air and liquid impermeability are important for preventing leakage of liquid within the barrel and preventing air from being trapped between the outer surface of the stopper and the inner wall of the barrel when filling or discharging liquid into or from the injector device. Low-friction sliding properties are important for facilitating filling and discharging of liquid within the injector device. In addition to these requirements, medical syringes, autoinjectors, or pens should not adversely affect pharmaceutical compositions, such as biopharmaceuticals, that come into contact with the syringe (e.g., a prefilled syringe, autoinjector, or pen containing a pharmaceutical composition).

[0003] Some examples of injector device components can be found in U.S. Patent Application Publication No. 2021 / 0030970, entitled "Medical Injector Device Having a Low-Lubricant Hydrophobic Syringe Barrel," by applicant W.L. Gore & Associates, Inc., which describes a medical injector device that includes a barrel having a hydrophobic inner surface. The medical injector device includes a barrel and a stopper that provide air and liquid impermeability while also providing one or more of low breakloose force, low average glide force, and low glide force variation.

[0004] Further examples of injector device components can be found in U.S. Pat. Nos. 8,722,178 and 9,597,458, and U.S. Patent Application Publication No. 2016 / 0022918, entitled "Syringe Stopper," "Fluoropolymer Barrier Material for Containers," and "Non-Fluoropolymer Barrier Material for Containers," respectively, by applicant WL Gore & Associates, Inc. (e.g., describing syringe stoppers suitable for use with syringes that do not use silicone oil or other liquid lubricants).

[0005] Further examples of injector device components can be found in U.S. Patent No. 10,751,473, entitled "Gasket and Medical Syringe," by applicant Sumitomo Rubber Industries, Ltd. It describes a gasket for use with a medical syringe, including a body made of an elastic material and an inert resin film applied to the surface of the body. The gasket has a cylindrical shape and includes an annular rib on its outer periphery, which has a sliding portion that maintains sliding contact with the inner periphery of the syringe barrel. The annular rib is disposed axially from the distal end to the rear end of the gasket. The sliding portion of the distal annular rib has a width that is 1 to 25% of the axial length of the cylindrical gasket. Summary of the Invention

[0006] Abstract Forming a durable seal can be difficult for stoppers that include a barrier or barrier layer and do not use silicone or other added lubricious materials (e.g., liquid lubricants) to fill imperfections in the barrier. These imperfections can occur due to wrinkles that form in the barrier due to compression of the stopper during insertion, scratches on the surface of the seal area that occur during stopper manufacturing or insertion, or other imperfections that result from the component manufacturing and assembly processes. It is believed that adding microfeatures to the seal area of ​​the stopper can have a dramatic effect in reducing or eliminating these seal imperfections by reducing wrinkles and / or concentrating the sealing force in a small area, helping to better seal leakage channels associated with such imperfections.

[0007] In many cases, defects do not occur or are not apparent until the stopper is inserted into the barrel. Therefore, it may not be possible to prevent, remove, or treat various defects prior to the process of inserting the stopper into the barrel. Various inventive concepts addressed in this description relate to treating such defects or improving seal geometry during or after the stopper undergoes the associated insertion process into the barrel.

[0008] According to some examples, a stopper for use with an injector device, the stopper having an exterior configured to engage with the lumen of a barrel of the injector device, includes an elastomeric body and a barrier coupled to the elastomeric body, the barrier having an inner surface facing the elastomeric body and an outer surface facing away from the elastomeric body. The barrier includes a first layer of a first material and a second layer of a second material, the first layer configured to be activatable by an energy source, and the second layer configured to be less activatable by the energy source than the first layer. The barrier optionally has at least one microfeature formed therein by activating the first layer with an energy source, the at least one microfeature including one or both of a microgroove and / or a microrib. The energy source optionally includes at least one of a vibrational energy source, such as a laser energy source, an RF energy source, an ultrasonic energy source, and a thermal energy source. The first layer can be positioned below the second layer. The barrier can have a thickness of 1 μm to 200 μm. In some examples, the first material and / or the second material comprises a fluoropolymer (e.g., polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE)). The first layer is optionally microporous and defines a first porosity, and the second layer has a lower porosity than the first layer. And, the second layer is optionally characterized by a higher melting temperature than the first layer. The second layer can be characterized by higher dimensional stability than the first layer. Where applicable, the microgrooves may have a depth of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and a width of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and / or the microribs may have a height of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and a width of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm.

[0009] In any of the aforementioned designs, the microgrooves and / or microribs can extend in a circumferential direction, including a helical direction. The microgrooves can have a bottom and two sides, one of the two sides defining a microrib. The material forming the microribs can optionally have a higher density than the material forming the bottom of the microgroove or a lower density than the material forming the bottom of the microgroove. In some examples, the first layer includes one or more materials configured to increase in volume when activated by an energy source, and further, the microribs correspond to portions of the first layer that increase in volume when activated by the energy source and / or include materials configured to be removed when activated by the energy source, and further, the microgrooves correspond to portions of the first layer that are removed when activated by the energy source.

[0010] If desired, the barrier can be bonded to the elastomeric body by activating the first layer with an energy source. Microgrooves and / or microribs can be formed after bonding the barrier to the elastomeric body. The porosity of the portions of the first layer corresponding to the microgrooves and / or microribs is optionally modified after bonding the barrier to the elastomeric body. In any of the foregoing designs, at least one of the first material of the first layer and the second material of the second layer comprises a thermoplastic material, and / or the first material of the first layer comprises a filler configured to increase the first material's absorption of light energy and / or radio frequency energy (e.g., the filler can comprise at least one of fluorinated ethylene propylene (FEP) and ethylene tetrafluoroethylene (ETFE)). For the avoidance of doubt, the microfeatures can be formed on the outer surface of the barrier and / or on the inner surface of the barrier.

[0011] In any of the above examples and designs, a method of forming the injector device stopper can include forming at least one of the microribs and / or microgrooves by activating the first layer with an energy source.

[0012] In some examples, a stopper for use with an injector device, the stopper having an exterior configured to engage a lumen of a barrel of the injector device, includes an elastomeric body and a multi-zone barrier coupled to the elastomeric body, the multi-zone barrier including a first zone having a first material property and a second zone having a second material property, the second zone configured to be activatable by an energy source, and the first zone having the two and optionally, the multi-zone barrier has at least one microfeature formed by activating the second zone with an energy source, the at least one microfeature comprising one or both of a microgroove and / or a microrib.

[0013] A method for manufacturing a stopper for use in an injector device, the stopper having a sealing surface configured to engage with a lumen of a barrel of the injector device, can include activating a first layer of a barrier of the stopper with an energy source to form at least one microfeature, the barrier having an inner surface and an outer surface. The microfeature can include one or both of microgrooves and / or microribs. The method also includes bonding the barrier to an elastomeric body. In this method, the barrier optionally includes a second layer disposed on the first layer, and the first layer is activated through the second layer. The energy source optionally includes at least one of a laser energy source, an RF energy source, and a thermal energy source. In some examples, the first layer includes FEP and the second layer includes PTFE. The barrier can be bonded to the elastomeric body during the formation of the at least one microfeature.

[0014] Forming the at least one microfeature can include cooling the barrier after activating the first layer, and the microgrooves and microribs can optionally be formed simultaneously by reflowing and re-solidifying the molten portion of the barrier. Activating the first layer of the barrier of the stopper with an energy source to form the at least one microfeature optionally includes inducing relative motion between the energy source and the stopper, where the motion optionally includes one or both of linear motion and rotational motion.

[0015] The at least one microfeature can be formed before bonding the barrier to the elastomeric body (in some cases, the microfeature is formed on the barrier in sheet form), or after bonding the barrier to the elastomeric body. In some instances, the microfeature is formed on the outer surface of the barrier and / or on the inner surface of the barrier.

[0016] Some examples of methods for manufacturing a stopper for use in an injector device, the stopper having a sealing surface configured to engage a lumen of a barrel of an injector device, include activating a first layer of a multi-zone barrier of the stopper with an energy source to form at least one microfeature in the multi-zone barrier, wherein the multi-zone barrier includes a first zone having a first material property and a second zone having a second material property, the second zone being configured to be activatable by the energy source, and the first zone having a second material property. two the multi-zone barrier is configured to be less susceptible to activation by an energy source than the other zone, and bonding the multi-zone barrier to an elastomeric body.

[0017] Some examples of stoppers for use with an injector device, the stopper having an exterior configured to engage with a barrel lumen, include an elastomeric body and a multilayer barrier bonded to the elastomeric body, the multilayer barrier including a first layer and a second layer, the second layer having one or more discontinuities, the first layer extending across the one or more discontinuities and the elastomeric body. The one or more discontinuities in the second layer are optionally defined by at least one microgroove, and the first layer optionally provides a continuous barrier between the elastomeric body and the at least one microgroove. The first layer can be exposed through the second layer to define at least a portion of the exterior of the stopper. The one or more discontinuities can make the second layer less tear-resistant than the first layer at the one or more discontinuities.

[0018] In any of the above designs, the first layer can be formed from a microporous layer having greater strength than the second layer, where the first layer extends across one or more discontinuities. For example, the first layer can include a densified fluoropolymer, a thermoplastic material, and / or an elastomeric material. The first layer can optionally include microribs and / or microgrooves. And the discontinuities in the second layer can optionally include microribs and / or microgrooves. The second layer can be non-porous and / or made from polytetrafluoroethylene, for example.

[0019] The foregoing examples are merely illustrative and should not be construed as limiting or narrowing the scope of the inventive concepts otherwise provided by this disclosure. While multiple examples are disclosed, still other embodiments will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative examples. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive. [Brief explanation of the drawings]

[0020] BRIEF DESCRIPTION OF THE DRAWINGS 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.

[0021] [Figure 1] FIG. 1 illustrates an injector device configured as a syringe, according to some embodiments.

[0022] [Figure 2] FIG. 2 illustrates an injector device configured as an autoinjector, according to some embodiments.

[0023] [Figure 3] FIG. 3 shows a stopper for the injector device of FIG. 1 or FIG. 2 according to some embodiments.

[0024] [Figure 4] FIG. 4 shows a stopper for the injector device of FIG. 1 or FIG. 2 according to some embodiments.

[0025] [Figure 5] FIG. 5 shows a portion of the stopper of FIG. 3 or FIG. 4 according to some embodiments.

[0026] [Figure 6] FIG. 6 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 7] FIG. 7 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 8] FIG. 8 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 9] FIG. 9 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 10] FIG. 10 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 11]FIG. 11 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 12] FIG. 12 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 13] FIG. 13 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments.

[0027] [Figure 14] FIG. 14 shows a portion of the stopper of FIG. 3 or 4 according to some embodiments.

[0028] [Figure 15] FIG. 15 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 16] FIG. 16 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments. [Figure 17] FIG. 17 depicts various microfeatures in the area of ​​FIG. 5, according to some embodiments. [Figure 18] FIG. 18 depicts various microfeatures in the area of ​​FIG. 5 according to some embodiments.

[0029] [Figure 19] FIG. 19 illustrates a system and method, according to some embodiments, that can be used to form stopper microfeatures such as those of FIGS. 6-13 and 15-18. [Figure 20] FIG. 20 illustrates a system and method, according to some embodiments, that can be used to form stopper microfeatures such as those of FIGS. 6-13 and 15-18. [Figure 21] FIG. 21 illustrates a system and method, according to some embodiments, that can be used to form stopper microfeatures such as those of FIGS. 6-13 and 15-18.

[0030] [Figure 22]FIG. 22 depicts a tool and method, according to some embodiments, that can be used to assemble and join the stoppers. [Figure 23] FIG. 23 depicts a tool and method, according to some embodiments, that can be used to assemble and join the stoppers.

[0031] [Figure 24] FIG. 24 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 25] FIG. 25 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 26] FIG. 26 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 27] FIG. 27 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 28] FIG. 28 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 29] FIG. 29 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 30] FIG. 30 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 31] FIG. 31 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 32] FIG. 32 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments. [Figure 33] FIG. 33 depicts the arrangement and configuration of microfeatures such as those of FIGS. 6-13 and 15-18, according to some embodiments.

[0032] [Figure 34]FIG. 34 shows a portion of the stopper of FIG. 3 or 4, according to some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description Definitions and Terminology This disclosure is not intended to be read in a restrictive manner, for example, the terms used in this application should be read broadly in the context of the meanings ascribed to such terms by experts in the field.

[0034] The use of headings is provided solely for ease of review of the description and is not intended to differentiate or to indicate that concepts under one heading are inapplicable to or unrelated to concepts under another heading. In fact, the opposite is intended; the description is intended to be read and interpreted as a whole, with various features and aspects of a particular embodiment being applicable across and to various other embodiments described herein.

[0035] With respect to the term imprecision, the terms "about" and "approximately" may be used interchangeably to refer to measurements that include the stated measurement, as well as any measurement that is reasonably close to the stated measurement. A measurement that is reasonably close to the stated measurement deviates from the stated measurement by a reasonably small amount, as understood and easily ascertained by one of ordinary skill in the relevant art. Such deviations may result from measurement error, differences in calibration of measuring and / or manufacturing equipment, human error in reading and / or setting measurements, fine-tuning made to optimize performance and / or structural parameters given differences in measurements associated with other components, specific implementation scenarios, imprecise adjustment and / or manipulation of objects by humans or machines, etc. If it is determined that the value of such a reasonably small difference would not be easily ascertainable by one of ordinary skill in the relevant art, the terms "about" and "approximately" may be understood to mean plus or minus 10% of the stated value.

[0036] As used herein, the term "activatable by an energy source" and the like refers to a change in the state of a material, such as a change in physical and / or chemical state. One example of activation by an energy source includes a noticeable (i.e., clearly evident) change from a solid form (or a more solid form) to a liquid form (or a more liquid form). Another example of activation by an energy source includes exhibiting a noticeable (i.e., clearly evident) change in crosslinking or molecular weight (e.g., by crosslinking or chain scission) upon exposure to the energy source. For reference, as used herein, "energy source" refers to any of various types of energy sources, including heat, laser, radio frequency (RF), microwave, ultraviolet light, radiation, ultrasound, etc.

[0037] As used herein, the terms "barrier," "barrier structure," and the like refer to a material that blocks or prevents interaction between one component (e.g., the stopper body) and another component (e.g., the barrel and / or the contents of the barrel).

[0038] As used herein, the terms "elastic" and "elastomeric" refer to a material property understood with reference to stoppers used in injector devices (e.g., in FDA approved applications) and relate to the tendency of a material to spontaneously return to or recover its undeformed shape after being dimensionally deformed (e.g., contracted, expanded, distorted, etc.).

[0039] As used herein, the term "injector device" is intended to include any of a variety of devices that include a stopper received within a barrel and an actuation mechanism configured to displace the stopper within the barrel to eject or deliver contents held within the barrel from within the barrel. Examples of injector devices include syringes, autoinjectors, pens, etc.

[0040] As used herein, the term "macrofeature" (e.g., "macrorib" or "macrogroove") is intended to refer to a stopper rib or groove feature whose outline is visible to the naked eye, or a stopper feature that exhibits a height greater than or equal to two times the thickness of the stopper barrier.

[0041] As used herein, the term "microfeatures" (e.g., microribs, microgrooves, or microvoids) is intended to refer to stop features (which may be surface features or subsurface features) where the outline of the stop feature is not visible to the naked eye (although the general presence of the feature can be appreciated). For example, microfeatures include stop microrib or microgroove features located on or within a macrorib or macrogroove.

[0042] As used herein, the term "multilayer barrier" refers to a barrier structure having multiple layers of materials, at least a portion of which are arranged overlapping one another (parallel arrangement), or in some instances adjacent one to the other (series arrangement). Multilayer structures may have thicknesses or layers of material with relatively sharp, well-defined boundaries, or may have mixed or more gradual transition boundaries between them.

[0043] As used herein, the term "multi-zone barrier" refers to a barrier structure having multiple zones or sections with different material properties. Multi-zone structures may have zones or sections separated by relatively sharp, distinct boundaries, or may have mixed or gradual boundaries. Some examples of multi-zone barriers include separate layers arranged in parallel or series, resulting in a multi-layer barrier defining the multi-zone barrier. Other examples may include a single layer modified to define multiple zones.

[0044] As used herein, terms such as "oscillate" (e.g., "oscillation") are intended to mean motion that alternates in direction with a frequency that can be constant or variable.

[0045] As used herein, the term "proximal" means closer to the operator end of the device (e.g., the plunger end), while the term distal means further from the operator than proximal (e.g., the piercing element end).

[0046] As used herein, terms such as "rotate" (e.g., "rotation") refer to circumferential movement.

[0047] As used herein, the term "sealing surface" is intended to refer to a feature that maintains a fluid-tight seal (eg, during storage and / or use).

[0048] As used herein, the terms "silicone" and "silicone oil" may be used interchangeably herein.

[0049] As used herein, the term "substantially free" is intended to mean that the specified substance (e.g., silicone, silicone oil, or other lubricant) is present in an unquantifiable or trace amount, or that no amount is intentionally added to the system (e.g., no silicone oil is intentionally added to an injector device such as a barrel or stopper).

[0050] As used herein, the term "vibrate" (e.g., "vibration") is intended to mean alternating motion with acceleration that changes in alternating direction at a frequency that can be constant or variable.

[0051] As used herein, the term "wiper" is intended to refer to an element that is movable (e.g., flexible or bendable) and configured to wipe a surface, and is sometimes referred to as a "wiper element."

[0052] Description of Various Embodiments Those skilled in the art will readily appreciate that the various aspects of the present disclosure may be implemented by any number of methods and apparatus configured to perform the intended functions. It should also be noted that the accompanying drawings referred to herein are not necessarily drawn to scale and may be exaggerated to illustrate various aspects of the present disclosure, and in that regard, the drawings should not be construed as limiting.

[0053] The present disclosure is directed to injector devices (e.g., syringes, autoinjectors, and pens) that include a stopper, a barrel, and a plunger rod or actuation mechanism for displacing the stopper within the barrel, the stopper being at least partially covered with a fluoropolymer or non-fluoropolymer film or a fluoropolymer or non-fluoropolymer laminate.

[0054] Various aspects of this description relate to a barrier of a stopper having at least one microfeature formed by activating the barrier with an energy source (e.g., a laser). For example, the barrier 242 may include multiple layers or may be a multi-layer barrier, where one layer (or layers) of the structure is configured to be more reactive to the energy source than another layer (or layers). Also, in various embodiments described below, one or more microfeatures may be formed before bonding the barrier to the body of the stopper, after bonding the barrier to the body but before inserting the stopper into the barrel, and / or after bonding the barrier to the body but before inserting the stopper into the barrel 20. Various benefits may be realized by utilizing such features, including more efficient and / or higher-yield manufacturing, reduced contamination and / or particle generation, enhanced sealing, etc.

[0055] Injector Device Concept In use, injector devices can be used to store (e.g., short-term or long-term) and deliver fluids, typically therapeutic agents or other substances delivered to patients in medical applications. In some embodiments, such injector devices may be prefilled with a therapeutic agent (e.g., as a prefilled syringe) prior to planned use of the injector device to deliver the therapeutic agent to a patient. The injector device can include a therapeutic agent to treat diseases such as, but not limited to, eye diseases (e.g., macular degeneration and glaucoma) or diabetes. Non-limiting examples of potential therapeutic agents are described below. Advantageously, in various embodiments, the stopper and barrel are free of silicone or silicone oil. For example, according to various embodiments, the barrels and stoppers of the injector devices described herein can be free or substantially free of silicone and silicone oil (or other liquid lubricants). In some examples, the stopper and barrel are free or substantially free of substantial amounts of other liquid lubricants (except, of course, for the therapeutic agent within the injector device, which is in liquid form and therefore lubricates itself to at least some extent).

[0056] 1 illustrates an injector device 10 in the form of a syringe, according to some embodiments. As shown, the injector device 10 includes a barrel 20, a piercing element 30, and a stopper 40 received within the barrel 20 and operably coupled to an actuation mechanism 50 (e.g., a plunger rod, as shown).

[0057] As shown, barrel 20 extends between a proximal end 120 and a distal end 122. Barrel 20 has an inner surface 124 and an outer surface 126, the inner surface forming a boundary of a receiving chamber 128 defined by barrel 20. As shown, proximal end 120 of barrel 20 can include a flange that can be used as a finger stop or handle to assist a user in pushing or pulling actuation mechanism 50.

[0058] The piercing element 30 may comprise a sharply pointed needle cannula or a blunt cannula such as those used in "needle-free" systems. For ease of illustration, the piercing element 30 is shown as a sharply pointed, elongated needle cannula having a sharply pointed distal end. As shown, the piercing element 30 is coupled to the distal end 122 of the barrel 20.

[0059] Stopper 40 is configured to be slidably received within barrel 20 and to seal with inner surface 124 of barrel 20. More specifically, stopper 40 is configured to be actuated within barrel 20 by actuation mechanism 50 to pressurize the contents of receiving chamber 128 and expel them from barrel 20 through piercing element 30.

[0060] The actuating mechanism 50 has a distal end 152 and a proximal end 154, and the distal end 152 is operably coupled to the stopper 40, e.g., fastened to the stopper 40, integrally formed with the stopper 40, or otherwise associated with the stopper 40, such that the actuating mechanism 50 is configured to displace the stopper 40 longitudinally (or in other directions) within the barrel 20.

[0061] FIG. 2 illustrates an injector device 100 in the form of an autoinjector according to some embodiments, in which the barrel 20, stopper 40, and actuation mechanism 50 (also described as an injection member in connection with the injector device 100) can be similarly configured and used. The actuation mechanism 50 of the injector device 100 can use or exhibit a variable actuation force applied to the stopper 40. For example, the actuation mechanism 50 can include one or more biasing members (e.g., springs) and other mechanisms for achieving such functionality. As will be understood by those skilled in the art, various other components of the injector device 100 are substantially similar to those of the injector device 10. For purposes of this description, the various features of the stopper 40 described herein are applicable regardless of whether they are utilized in the configuration of the injector device 10 or the injector device 100. More broadly, the concepts described herein with respect to the barrel 20 and stopper 40 can be implemented in any of a variety of injector device configurations.

[0062] The injector device 10, 100 can contain the material 60 within the receiving chamber 128 of the barrel 20. In some examples, the material 60 is inserted or otherwise placed within the chamber at a manufacturing site, a location away from the treatment site, or at the location where the injector device 10, 100 will be used by the end user (e.g., a clinical site). In such cases, the injector device 10, 100 may be referred to as "prefilled" (e.g., in the example of the injector device 10, a prefilled syringe). The material 60 can be a predetermined amount (e.g., one or more doses) of a pharmaceutical composition. Some examples of suitable pharmaceutical compositions are described below. However, it should be understood that the material 60 can be any type of liquid or material that can be expelled from a syringe, or the material 60 may not be entirely present in the receiving chamber, such as in an unfilled syringe. In such examples, the injector device 10, 100 can be filled (e.g., also described as "loading" the injector device) at or near the treatment site.

[0063] 3 and 4 are plan views or front views of example configurations of stopper 40, with the configuration in FIG. 3 showing a cross-sectional view of the right half of stopper 40 and the configuration in FIG. 4 showing a cross-sectional view of the left half of stopper 40.

[0064] 3 and 4 , the stopper 40 includes a body 240 made of a resilient material and a barrier 242, such as a barrier film, disposed on the body 240. The stopper 40 has an outer side 244, a longitudinal axis X, and a height along the longitudinal axis X. The stopper 40 extends between a front surface 246 and a rear surface 248. As shown, the barrier 242 may extend along portions (including the entirety) of the outer side 244 and / or the front surface 246. If desired, the barrier 242 may also extend along portions (including the entirety) of the rear surface 248.

[0065] In some embodiments, body 240 provides a desired degree of elastic compliance to stopper 40. For example, body 240 may be compressed upon insertion of stopper 40 into barrel 20 such that stopper 40 positively engages barrel 20. Suitable materials for body 240 are further described below.

[0066] In various examples, the barrier 242 disposed on the body 240 is configured to prevent migration of materials from (or into) the body 240 through the barrier 242, reduce slippage and / or stiction between the stopper 40 and the barrel 20, and enhance the seal between the stopper 40 and the barrel 20. These features are mentioned in an exemplary manner and are not intended to be an exhaustive list. The barrier 242 may be single-layered or multi-layered. The barrier 242 may be constructed of multiple layers each having unique properties, and / or the barrier may include multiple layers having similar properties fused or otherwise bonded to form a more homogeneous structure with more uniform properties between the layers. The barrier 242 may include composite materials (e.g., a matrix film material and a filler) that function as one or more layers of the barrier 242. Suitable materials for the barrier 242 are further described below.

[0067] 3 and 4, the stopper 40 has a short, cylindrical shape, with the forward surface 246 defined by a conical end of the stopper 40. As shown, the conical end may project from the longitudinal axis X to define an obtuse angle. In examples in which the actuation mechanism 50 is coupled to the stopper 40 using a threaded fastening arrangement, the stopper 40 may include an axial recess 250 in the rearward surface 248 that is internally threaded.

[0068] As shown, the exterior 244 of the stopper 40 may define one or more ribs 300, also referred to as macroribs, such as one or more circumferentially extending annular ribs 300, and / or one or more grooves 310, also referred to as macrogrooves, such as one or more circumferentially extending annular grooves 310. During operation, one or more of the ribs 300 are configured to slidingly engage the interior surface 124 ( FIGS. 1 and 2 ) of the barrel 20. The stopper 40 may be configured to achieve container closure integrity with a high level of gas (e.g., air) and liquid impermeability while maintaining one or more of an acceptably low breakloose force, a low average sliding force, and a low sliding force variation.

[0069] The ribs 300 can be constructed in any number of configurations. For example, only the distal-most or forward rib may have a sealing surface. It should be understood that the quality of the seal thus formed can be evaluated by any number of methods well known to those skilled in the art (e.g., a helium leak test). In some embodiments, multiple ribs 300 may have a sealing surface. In one or more embodiments, all of the ribs 300 having a sealing surface can have the same predetermined outer diameter (e.g., measured from the apex of each rib with the stopper 40 in an uncompressed state). In other embodiments, each rib 300 having a sealing surface can have its own predetermined outer diameter. For example, the distal or forward rib can have a predetermined outer diameter, and the proximal or rearward rib can have a predetermined outer diameter that is about 75% to about 99.9% of the predetermined outer diameter of the distal or forward rib. Other types of rib configurations, such as having three ribs having sealing surfaces, are contemplated without departing from the spirit and scope of the present disclosure.

[0070] Although three ribs 300 are shown in FIGS. 3 and 4, any number of ribs (e.g., 1, 2, 4, 10, etc.) is contemplated. As shown, the ribs 300 include a forward rib 300A having a sealing surface 320A (also referred to as a sliding portion 320A) configured to slidingly contact the inner surface 124 of the barrel 20. As shown in FIG. 3, one or more of the ribs 300 optionally have a flattened sealing surface (e.g., sealing surface 320A) with a width of 1% to 25% of the length of the outer side 244 of the stopper 40 (e.g., forward rib 300A). As shown in FIG. 4, one or more ribs 300 (e.g., forward rib 300A) optionally have an outwardly convex shape with a sealing surface (e.g., sealing surface 320A) having a relatively narrow profile. As shown in FIGS. 3 and 4, the ribs 300 also include a middle rib 300B and a rear rib 300C. As shown, the intermediate rib 300B and the rear rib 300C optionally have an outwardly convex shape when viewed in cross section. Each of the intermediate rib 300B and the rear rib 300C optionally has a sealing surface 320B, 320C, respectively, configured to slidingly engage the inner surface 124 of the barrel 20. When one or more ribs 300B have an outwardly convex shape, the corresponding sealing surface may have a relatively small width as measured along the longitudinal axis X of the stopper 40. Depending on the configuration, each of the sliding contact portions 320B, 320C can have a width greater than 0% and up to 15% of the length of the outer side 244 of the stopper 40.

[0071] As shown in FIGS. 3 and 4 , the exterior 244 of the stopper 40 can include one or more defects 900, such as wrinkles 362 and scratches 364. The various defects 900, such as wrinkles 362 and / or scratches 364, can be oriented longitudinally, circumferentially, or both (e.g., spirally). The defects 900 can be relatively straight, curvilinear, or both. The defects can be located anywhere on the stopper 40, but particularly on or along the ribs 300 and associated sealing or sliding surfaces 320, as well as one or more microfeatures 400, for example, as described below. These defects can form at any time during the manufacturing process, including when the stopper 40 is initially formed (e.g., when the barrier 242 is attached to the body 240) or during the process of installing the stopper 40 within the barrel 20. For example, the wrinkles 362 can form when the stopper is compressed diametrically. Additionally, scratches 364 may form, for example, when stopper 40 slides against barrel 20 or other tubular member used during the assembly process.

[0072] Micro-mechanism concept As shown in FIGS. 3 and 4 , the stopper 40 includes one or more microfeatures 400 located on one or more of the ribs 300, such as the sliding portion 320A of the forward rib 300A. In some examples, the one or more microfeatures 400 include one or more microgrooves and / or microribs. In some examples, the microfeatures 400 have a width and a depth, where the depth is the amount of protrusion in the case of a microrib or the amount of recession in the case of a microgroove. In some embodiments, one or both of the width and depth are, for example, 200 μm or less, 100 μm or less, 50 μm or less, 10 μm or less, or 5 μm or less, although various dimensions are contemplated. Note that the range of "less than" above includes values ​​greater than "0."

[0073] Figure 5 shows an enlarged cross-sectional view of one or more portions of stopper 40 (e.g., one of ribs 300) along the exterior 244 of stopper 40. Figures 6-9 depict various microfeatures (microgrooves / microvoids) contained within region "A" shown in Figure 5, which are formed in barrier 242. While body 240 and barrier 242 are shown with straight edges in Figures 5-9 for ease of illustration, it should be understood that they may exhibit some degree of curvature (e.g., convex inward or outward) if the illustrated region corresponds to a curved portion of stopper 40 (e.g., over one of ribs 300).

[0074] With the above in mind, Figure 5 illustrates a cross section of the body 240 and barrier 242 of stopper 40, according to some embodiments. As shown, barrier 242 includes multiple layers, or is a multi-layer barrier, including a first layer 402 of a first material and a second layer 404 of a second material. Barrier 242 can have any of a variety of thicknesses, such as between 1 μm and 200 μm.

[0075] As shown, the first layer 402 can be disposed below the second layer 404. While two layers are generally shown, it should be understood that any number of layers is contemplated. As shown, the first layer 402 has an inner surface 410 that faces the body 240 of the stopper 40 and an outer surface 412 that faces the second layer 404. Meanwhile, the second layer 404 includes an inner surface 420 that faces the first layer 402 and an outer surface 422 that faces away from the body 240. In various examples, the inner surface 410 of the first layer 402 is coupled (e.g., bonded, adhered, fastened, or otherwise coupled) to the body 240. In turn, the inner surface 420 of the second layer 404 is coupled (e.g., bonded, adhered, fastened, or otherwise coupled) to the first layer 402. In some embodiments, the first layer 402 may be referred to as the “inner layer” of the barrier 242 and the second layer 404 may be referred to as the “outer layer,” although either the first layer 402 and / or the second layer 404 may be an intermediate or buried layer located between one or more other layers of the barrier 242.

[0076] In various examples, one of the layers (e.g., first layer 402) can include a first material that is more likely to be activated by an energy source than a second material of another layer of the layers (e.g., second layer 404). In particular, as shown in Figures 6-13 and 15-18, this characteristic of some layers being more likely to be activated by an energy source than other layers can be utilized to preferentially form different microfeatures 400 at different locations on barrier 242.

[0077] A variety of materials are contemplated for each layer of the barrier 242, including those described separately. For example, the first material and / or the second material can include a fluoropolymer (e.g., polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE)). In some examples, the first layer 402 is microporous and defines a first porosity, and the second layer 404 has a lower porosity than the first layer, and optionally, the second layer 404 is characterized by a higher melting temperature than the first layer 402. If desired, the second layer 404 can be characterized by higher dimensional stability than the first layer 402. At least one of the first material of the first layer 402 and the second material of the second layer 404 can include a thermoplastic material. If desired, the first material of the first layer 402 can include a filler configured to increase the first material's absorption of light energy and / or radio frequency energy. The filler may also include, for example, at least one of fluorinated ethylene propylene (FEP) and ethylene tetrafluoroethylene (ETFE).

[0078] While Figures 6-13 each show a set of example microfeatures (e.g., three in the case of Figure 6), it should be understood that not all examples need be present together, and that any of the examples can be combined with various other example microfeatures shown and described in connection with other figures. An exemplary method for forming such features includes directing an energy source (see, e.g., Figures 19-21 and associated discussion) through one layer (e.g., second layer 404) to another layer (e.g., first layer 402) to activate (e.g., reflow, ablate, melt, or vaporize) portions of the other layer to form one or more microfeatures 400. For example, in the case of laser energy, second layer 404 is sufficiently transparent to the laser that the laser can pass through second layer 404 without activating it. Second, first layer 402 is relatively more absorptive of, and therefore more sensitive to, laser energy. The microfeatures 400 can be formed as discrete volumes extending around the stopper, continuous annular features, and / or a series or pattern of discrete volumes (see, eg, Figures 24-33 and associated discussion).

[0079] Following the formation of various microfeatures (e.g., microvoids, microgrooves, or microribs) at or near a particular microfeature 400, the barrier 242 in general, and more specifically the first layer 402 and / or second layer 404, may exhibit different physical properties relative to the surrounding portions of the barrier 242, such as one or more of: increased compliance in the case of microvoids or microgrooves; decreased compression resistance in the case of microvoids or channels; increased compression resistance in the case of microribs; decreased thickness in the case of microvoids or channels; increased thickness in the case of microribs; or decreased tensile strength in the case of microvoids or microgrooves. Such properties may be advantageous for reducing the effective sealing surface area of ​​the ribs 300 (e.g., optimizing the relationship between increased sealing force and reduced slip resistance), creating preferential failure lines in the barrier 242 (e.g., preselecting more desirable areas for tearing or failing the barrier to avoid contamination of the contents of the injector device 10 and / or failure of the seal), or other benefits in performance and reliability.

[0080] In view of the above, various aspects of the present disclosure relate to a stopper for an injector device 10 having an exterior 244 configured to engage an inner surface 124 of a barrel 20 of the injector device. The stopper 40 includes a body 240 and includes a barrier 242 formed, for example, from an elastomeric material and coupled to the body 240. The barrier 242 has an inner surface 410 oriented toward the body 240 and an outer surface 422 oriented away from the body 240. The barrier 242 includes a first layer 402 of a first material and a second layer 404 of a second material. The first layer 402 is configured to be activatable by an energy source (e.g., laser energy source, RF energy source, thermal energy source, ultrasonic energy source, microwave energy source, plasma energy source, or the like), and the second layer 404 is configured to be less activatable by the energy source than the first layer 402. The barrier 242 has one or more microfeatures 400 formed by activating the first layer with an energy source, the one or more microfeatures 400 including one or both of microgrooves extending at least partially along the outer side 244 of the stopper 40 and / or microribs extending at least partially along the outer side 244 of the stopper 40.

[0081] With the above in mind, FIG. 6 illustrates a first set of example potential microfeatures 400 that may be formed in a first layer 402 of a barrier 242 using an energy source, where the first layer 402 is more susceptible to activation by the energy source than the second layer.

[0082] 6 , the one or more microfeatures 400 can include embedded microgrooves 400A or microvoids 400A that extend from the inner surface 410 partially through the thickness of the first layer 402. To initiate activation toward the inner surface 410 of the first layer 402, an energy source can be focused (e.g., by directing two separately angled “beams” of the energy source) toward the inner surface 410 of the first layer 402. As another example, the microgrooves 400A can be formed by directing an energy source toward the inner surface 410 of the first layer 402 before bonding the barrier 242 to the body 240.

[0083] 6 shows another example of microfeatures 400 in the form of microchannels 400B or microvoids 400B that extend from the outer surface 412 of the first layer 402 partially through the thickness of the first layer 402. Again, energy can be directed through the second layer 404 into the first layer 402 to activate (e.g., reflow, ablate, melt, or vaporize) portions of the first layer 402 to form the microchannels 400B.

[0084] 6 shows yet another example of microfeatures 400 in the form of microchannels 400C or microvoids 400C that extend through the thickness of the first layer 402 from the inner surface 410 to the outer surface 412 of the first layer 402. As described above, energy can be directed through the second layer 404 into the first layer 402 to activate (e.g., reflow, ablate, melt, or vaporize) portions of the first layer 402 to form microchannels 400B, or microchannels 400A can be formed by directing an energy source toward the inner surface 410 of the first layer 402 prior to bonding the barrier 242 to the body 240.

[0085] FIG. 7 shows a second example set of latent microfeatures 400 formed in the second layer 404 of the barrier 242 using an energy source, where the second layer 404 is more susceptible to activation by the energy source than the second layer.

[0086] 7 , one or more microfeatures 400 can include embedded microgrooves 400D or microvoids 400D extending from the inner surface 420 partially through the thickness of the second layer 404. To initiate activation toward the inner surface 420 of the second layer 404, an energy source can be focused (e.g., by directing two separately angled “beams” of the energy source) toward the inner surface 420 of the second layer 404. As another example, the microgrooves 400D can be formed at the inner surface 410 of the first layer 402 by directing an energy source through the first layer 402 and into the second layer 404 prior to bonding the barrier 242 to the body 240.

[0087] 7 shows another example of microfeatures 400 in the form of microchannels 400E or microvoids 400E extending from the outer surface 422 of the second layer 404 partially through the thickness of the second layer 404. Again, energy can be directed to the second layer 402 or directed through the first layer 402 into the second layer 404 prior to attaching the barrier 242 to the body 240 to activate (e.g., reflow, ablate, melt, or vaporize) portions of the second layer 404 to form the microchannels 400E.

[0088] 7 shows yet another example of microfeatures 400 in the form of microchannels 400F or microvoids 400F that extend through the thickness of the second layer 404 from the inner surface 420 to the outer surface 422 of the second layer 404. As described above, energy can be directed at the second layer 404 or directed through the first layer 402 and into the second layer 404 to activate (e.g., reflow, ablate, melt, or vaporize) portions of the second layer 404 to form the microchannels 400F.

[0089] FIG. 8 shows a third set of examples of latent microfeatures 400 formed in the second layer 404 and / or the first layer 402 of the barrier 242 using an energy source, where one of the first layer 402 and the second layer 404 is more susceptible to activation by the energy source than the other.

[0090] 8 , the one or more microfeatures 400 can include embedded microgrooves 400G or microvoids 400G extending between an inner surface 420 and an outer surface 422 within the thickness of the second layer 404. To initiate activation within the second layer 404, an energy source can be focused (e.g., by directing two separately angled “beams” of the energy source) toward the inner surface 420 of the second layer 404, or can include a localized filler material (e.g., a pigment or other material that enhances energy absorption) that is more amenable to absorbing laser energy than surrounding portions of the second layer 404. For example, the barrier 242 can be a multi-zone barrier including a first zone 400Z1 having a first material property (e.g., activatability or responsiveness to an energy source) and an activatable zone 400Z2 having a second material property (e.g., increased activatability or responsiveness to an energy source compared to the first zone). For example, in the case of laser energy, the first zone 400Z1 can have lower light absorption characteristics (e.g., a lower amount of pigment, or a different pigment with higher transmittance) than the activatable zone 400Z2. As another example, the microgrooves 400G can additionally or alternatively be formed by directing an energy source at the inner surface 410 of the first layer 402 and through the first layer 402 into the second layer 404 prior to bonding the barrier 242 to the body 240.

[0091] 8 , the one or more microfeatures 400 can include embedded microgrooves 400H or microvoids 400H that extend between the inner surface 410 and the outer surface 412 within the thickness of the first layer 402. To initiate activation within the first layer 402, an energy source can be focused toward the inner surface 410 of the first layer 402 (e.g., by directing two separately angled “beams” of the energy source) or can include a localized filler material (e.g., a pigment or other material that enhances energy absorption) that is more likely to absorb laser energy than the surrounding portions of the first layer 402. As another example, the embedded microgrooves 400H can be formed by directing an energy source toward the inner surface 410 of the first layer 402 before bonding the barrier 242 to the body 240.

[0092] FIG. 9 shows a fourth set of example latent microfeatures 400 formed in the second layer 404 and / or the first layer 402 of the barrier 242 using an energy source, where one of the first layer 402 and the second layer 404 is more susceptible to activation by the energy source than the other.

[0093] 9, one or more microfeatures 400 may include embedded microchannels 400J or microvoids 400J that extend from the inner surface 410 of the first layer into the second layer 404 but terminate before reaching the outer surface 422 of the second layer. Such characteristics may arise when the first layer 402 is more susceptible to activation by an energy source than the second layer, resulting in the microchannels 400J forming only partially through the second layer 404. The microchannels 400J may be formed using methods as previously described.

[0094] Similarly, microchannels 400K or microvoids 400K can be formed in the first layer 402 from the outer surface 422 of the second layer 404, through the thickness of the second layer 404, partially through the outer surface 412 of the first layer, and terminate within the thickness of the first layer 402. Such a feature can occur when the first layer 402 is more easily activated by an energy source than the first layer, resulting in the microchannels 400K forming only partially through the first layer. The microchannels 400J can be formed using methods as previously described.

[0095] 10 and 11 show examples of how microfeatures 400 can be formed in one layer (e.g., a second layer 404) through the formation of microfeatures 400 in another layer (e.g., a first layer 402). For example, FIG. 10 illustrates how the formation of microvoids 400M or microchannels 400M in the first layer 402 (e.g., using any of the techniques described above) can result in the formation of microchannels 400N in the second layer 404. The first layer 402 is more activatable or responsive to an energy source than the second layer 404, and that energy source can be used to form the microchannels 400M in the first layer 402. This can then be used to form the microchannels 400N in the second layer 404. For example, the material of the first layer 402 can conform to or be forced into the microchannels 400M to form the microchannels 400N. The use of this feature can help ensure that the microgrooves 400N can be formed without compromising the integrity of the barrier 242, or, in other words, without compromising the integrity of the second layer 404 to provide a path from the outside 244 of the stopper 40 to the body 240 of the stopper 40.

[0096] 11 , microfeatures 400, specifically microribs 400P, can be formed by protrusions or increased thicknesses of portions of barrier 242 along opposite edges of other microfeatures 400, specifically microgrooves 400Q or microvoids 400Q, which occurs when microgrooves 400Q are formed by activating barrier 242 with an energy source (e.g., laser energy). For example, when a portion of barrier 242 (e.g., first layer 402) is evaporated or decomposed by an energy source (e.g., a laser beam) using any of the methods described above, the evaporated or decomposed portion can be partially redeposited along opposite edges of microgrooves 400Q to form microribs 400P. This can then form microribs 400R and microgrooves 400S in another layer (e.g., second layer 404) without having to directly modify the other layer (e.g., second layer 404) with an energy source. Such a feature can have various advantages, including avoiding the generation of loose particles, contaminants, or by-products of the energy activation process that could contaminate the exterior 244 of the stopper 40 and, therefore, the contents of the injector device 10.

[0097] 12 and 13 show another example of a potential microfeature 400 in the form of a microrib 400T (FIG. 13). As shown in FIG. 12, a first layer 402 includes a mass of material or activatable zone 400Z2 configured to expand or increase in volume through activation by an energy source (e.g., laser energy). As shown in FIG. 12, the activatable zone 400Z2 begins with a first size or volume and, after activation as shown in FIG. 13, assumes a second, larger size or volume. This expansion or volume change causes the barrier 242, particularly the second layer 404, and optionally the first layer 402, to flex, resulting in the formation of the microrib 400T as shown in FIG. 12. While the expandable material may be confined to the zone referred to as the activatable zone 400Z2, it is also contemplated that the entire layer may be formed from the activatable material and only a portion of the layer is activated to form the microrib 400T.

[0098] An example of an expandable, energy-activatable material can be found in U.S. Patent No. 5,571,592 to McGregor et al. The activatable zone 400Z2 can include expandable thermoplastic microspheres interspersed within the activatable zone 400Z2. The use of such expandable microspheres (1) allows for the introduction of unexpanded microspheres into the first layer 402 and (2) allows the microspheres within the first layer 402 to expand to larger diameters. In various examples, upon exposure to heat (e.g., thermal energy from application of a laser or other energy source) or similar activation energy, the microspheres dramatically expand to many times their original size and retain such size when the activation energy is removed. A process for producing such materials can be found, for example, in U.S. Patent No. 3,615,972 to Morehouse et al.

[0099] FIG. 14 shows an enlarged cross-sectional view of one or more portions of stopper 40 (e.g., one of ribs 300) along the exterior 244 of stopper 40. FIGS. 15-18 depict various microfeatures (microribs / microgrooves / microvoids) included in region "A" shown in FIG. 14. As shown in FIG. 14, barrier 242 optionally includes multiple layers (shown in dashed lines in FIG. 14), but may be monolithic or of single-layer construction. In various examples, barrier 242 is less susceptible to activation by an energy source than body 240 of stopper 40, and one or more microfeatures 400 are formed by activating body 240 of stopper 40. For the avoidance of doubt, body 240 may be considered a "layer" of stopper 40.

[0100] 15 and 16 show examples of how microfeatures 400 can be formed in one layer (e.g., body 240) of stopper 40 through the formation of microfeatures 400 in another layer (e.g., barrier 242). For example, FIG. 15 illustrates how microchannels 400V are formed in barrier 242 as a result of forming microvoids 400U or microchannels 400U in body 240 (e.g., using any of the techniques described above, including laser irradiation "through" barrier 242 without activating it). Body 240 is more activatable or responsive to an energy source than barrier 242, and the energy source can be used to form microchannels 400U in body 240. This can then be used to form microchannels 400V in barrier 242. This feature can be used to reliably form microchannels 400V without compromising the integrity of barrier 242 and without providing a path from outside 244 of stopper 40 to body 240 of stopper 40.

[0101] 16, microfeatures 400, specifically microribs 400W, can be formed by protrusions or increased thicknesses of portions of barrier 242 along the opposite edges of other microfeatures 400, specifically microgrooves 400X or microvoids 400X, which occurs when microgrooves 400X are formed by activating body 240 with an energy source (e.g., laser energy). For example, when a portion of a layer of stopper 40 (e.g., body 240) is evaporated or decomposed by an energy source (e.g., a laser beam) using any of the methods described above, the evaporated or decomposed portion can be partially redeposited along the opposite edges of microgrooves 400X to form microribs 400W. This allows microribs 400Y and microgrooves 400Z to be formed in another layer (e.g., barrier 242) without having to directly alter the other layer (e.g., barrier 242) with an energy source. Such a feature can have various advantages, including avoiding the generation of loose particles, contaminants, or by-products of the energy activation process that could contaminate the exterior 244 of the stopper 40 and, therefore, the contents of the injector device 10.

[0102] 17 and 18 show another example of a potential microfeature 400 in the form of microribs 400AB (FIG. 18). As shown in FIG. 17, the first layer of the stopper, body 240, includes a mass of material or activatable zone 400AZ that is configured to expand or increase in volume through activation by an energy source (e.g., laser energy). As shown in FIG. 17, activatable zone 400AZ begins with a first size or volume and, after activation as shown in FIG. 18, assumes a second, larger size or volume. This expansion, or change in volume, causes barrier 242 to deflect, resulting in the formation of microribs 400AB as shown in FIG. 18. While the expandable material may be limited to the zones referred to as activatable zones 400AZ, it is also contemplated that the entire layer could be formed of activatable material and only a portion of the layer activated to form microribs 400AB.

[0103] In view of the above, various examples include a barrier 242 defining a stopper 40, and more specifically, a microgroove (e.g., any of the microgrooves shown in Figures 6-16), where the barrier 242 in the microgroove is continuous and uninterrupted and is relatively thinner than the barrier 242 in the surrounding portion of the barrier 240.

[0104] The microgrooves can define a discontinuous, broken circumferential pattern, for example, as described in connection with FIG. 27 . In some examples, the barrier 242 is a multi-layer barrier (e.g., two or more layers) in which a first layer 402 has one or more discontinuous portions (e.g., continuous circumferential microgrooves or microgrooves having a discontinuous circumferential broken line pattern, as described in connection with FIG. 27 ). The second layer 404 overlies the one or more discontinuous portions, such as microgrooves. In this manner, the second layer 404 can provide a continuous barrier between the body 240 and the barrel 20 and its contents. In other words, the second layer 404 can extend across one or more discontinuous portions of the first layer 402.

[0105] The underlying first layer 402 can be formed of a relatively high strength material, while the overlying second layer 404 can be formed of a relatively more flexible and weaker material. In this manner, the barrier 242 can provide a high degree of flexibility on the exterior surface while exhibiting relatively high tear resistance due to the underlying first layer 402. This feature can also be combined with the ability to provide the microgrooves and / or microribs exhibited by the second layer 404 on the exterior 244 without directly (e.g., mechanically or energetically) forming the second layer 404, creating undesirable debris and particles (which could contaminate the barrel 20 and its contents), and / or unduly weakening the more flexible second layer 404 to the point that it would break during use.

[0106] Various examples include forming discontinuities in the underlying first layer 402, but in some examples, the second layer 404 can have one or more discontinuities, and the first layer 402 can extend across one or more discontinuities, providing a barrier between the exterior 244 and the body 240, similar to the elastomeric body 21 (e.g., microgroove 400F in FIG. 7 ). Again, the discontinuity can be defined by at least one microgroove. The first layer 402 can be exposed through the second layer 404 to define at least a portion of the exterior 244 of the stopper 40. The one or more discontinuities can cause the second layer 404 to be less tear-resistant than the first layer 402 at the one or more discontinuities.

[0107] This feature of forming microchannels in the second layer 404 while preserving the first layer 402 or inner layer 402 can be advantageous at least in the concept that the underlying first layer is still relatively stronger than the outer layer, preventing both layers from tearing and exposing the underlying body 242 to the barrel 20 and its contents. For example, the first layer 402 can be formed from a microporous layer having greater strength than the second layer 404, where the first layer 402 extends across one or more discontinuities. The first layer can include a densified fluoropolymer (e.g., having a relatively high tensile strength), a thermoplastic material, and / or an elastomeric material. The first layer 402 can additionally or alternatively include microribs and / or microgrooves.

[0108] The discontinuous portions of the second layer 404 can include microribs and / or microgrooves. In some examples, the second layer can be non-porous. For example, the second layer 404 can be polytetrafluoroethylene (e.g., skived PTFE).

[0109] FIG. 34 is yet another view of a portion of stopper 40 corresponding to region A shown in FIGS. 5 and 12, but with a different barrier 242 configuration than shown in those figures. As previously referenced, for the avoidance of doubt, FIG. 35 illustrates an example of a multi-layer barrier configuration including more than two layers (five total as shown). As shown, first layer 402 and / or second layer 404 can be located anywhere within the layers. Also, in various implementations, there can be more or fewer layers. First layer 402 can be, for example, an innermost layer or a buried layer. Second layer 404 can be, for example, an outermost layer or a buried layer. And, first layer 402 and second layer 404 can be in contact or separated by one or more other layers.

[0110] The various microfeatures 400 described above can have any of a variety of dimensions. In some examples, one or more microgrooves can have a depth of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and a width of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and / or one or more microribs can have a height of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and a width of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm. As described below, the microgrooves and / or microribs can have any of a variety of configurations, e.g., extending circumferentially, helically, or even longitudinally. As described above in connection with FIGS. 11 and 16, for example, one or more microgrooves can have a bottom and two sides, one or both of which define a microrib. In some embodiments, the material forming the microribs has a higher density than the material forming the bottom of the microgrooves, and in some embodiments, the material forming the microribs has a lower density than the material forming the bottom of the microgrooves.

[0111] Also, as described above, a portion of the stopper 40, such as the first layer 402, optionally includes a material configured to increase in volume when activated by an energy source, where the resulting microribs correspond to the portions of the first layer 402 that increase in volume when activated by the energy source. Also, in the case of microchannels or voids, a portion of the stopper 40, such as the first layer 402, includes a material configured to be removed when activated by an energy source, where the microgrooves correspond to the portions of the first layer 402 that are removed when activated by the energy source.

[0112] Means for applying energy to stopper components A method of fabricating stopper 40 includes activating a layer or zone (e.g., first layer 402) of barrier 242 with an energy source to form one or more microfeatures 400, where the one or more microfeatures 400 include one or both of microgrooves and microribs. Barrier 242 can be bonded to elastomeric body 240 before or after such formation, depending on the particular method. In some examples, barrier 242 can be bonded to body 240 during formation of the one or more microfeatures (e.g., by reflowing a material that aids in bonding between components).

[0113] As described above, one layer (e.g., first layer 402) can be activated by directing energy through another layer (e.g., second layer 404). For example, second layer 404 can be disposed over first layer 402, and first layer 402 can be activated through second layer 404. In some methods, forming at least one microfeature includes cooling barrier 242 after activating first layer 402. While microgrooves and microribs can be formed separately, some methods include simultaneously forming one or more microgrooves and microribs, optionally by reflowing and resolidifying a melted portion of barrier 242.

[0114] Activating the layer of the barrier 242 with energy can include inducing relative motion between an energy source from the forming module 1300 and the stopper 40, which motion can optionally include one or both of linear and / or rotational motion. The at least one microfeature 400 can be formed using a barrier in a sheet shape (e.g., a sheet preform) or a tubular shape (e.g., a tubular preform). The microfeature 400 can be formed on the outer surface 422 of the barrier 242 and / or the inner surface 410 of the barrier 242.

[0115] 19 and 20 illustrate a system 1000 and a method by which the system 1000 can be used to form one or more microfeatures 400 of a stopper 40. As illustrated, the system 1000 includes a control module 1100, a drive module 1200, a formation module 1300, and a processing module 1400. As previously referenced, the one or more microfeatures 400 can be formed after assembly of the stopper 40 or before assembly of the barrier 242 to the body 240 (e.g., by forming the microfeatures 400 on a barrier preform or a body preform). And, as shown in FIG. 20, in various embodiments, the one or more microfeatures can be formed in one or more stopper components after assembly of the injector device 10 (i.e., after the stopper 40 is inserted into the barrel 20, optionally with the contents of the barrel 20 already disposed in a prefilled assembly).

[0116] Control module 1100 is configured to control the operation of system 1000. In various examples, control module 1100 may include a power supply (not shown), one or more microprocessors, one or more user input devices (e.g., keyboards), one or more display devices (e.g., monitors), and other functionality for controlling the operation of system 1000.

[0117] The power source may provide power to the operating components of control module 1100 and / or other components of system 1000 and may be any type of power source suitable to provide the desired performance and / or life requirements of control module 1100 and / or system 1000. In various embodiments, the power source may include one or more batteries, which may be rechargeable (e.g., using an external energy source).

[0118] The control module 1100 may include or be included in one or more field programmable gate arrays (FPGAs), one or more programmable logic devices (PLDs), one or more complex PLDs (CPLDs), one or more custom application-specific integrated circuits (ASICs), one or more special-purpose processors (such as microprocessors), one or more central processing units (CPUs), software, hardware, firmware, or any combination of these and / or other components. The control module 1100 may include a processing unit configured to communicate with a memory and execute computer-executable instructions stored in the memory. Additionally or alternatively, the control module 1100 may be configured to store information (e.g., sensor data) in the memory and / or access information (e.g., sensor data) from the memory.

[0119] In some embodiments, memory includes computer-readable media in the form of volatile and / or non-volatile memory, and can be removable, non-removable, or a combination thereof. Examples of media include random access memory (RAM), read-only memory (ROM), electronically erasable programmable read-only memory (EEPROM), flash memory, optical or holographic media, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage, data transmission, and / or any other medium that can be used to store information and that can be accessed by a computing device, such as, for example, quantum state memory. In embodiments, memory stores computer-executable instructions that cause a processor to implement aspects of embodiments of the system components discussed herein and / or perform aspects of embodiments of the methods and procedures discussed herein.

[0120] Computer-executable instructions may include, for example, computer code, digital signal processing, machine-usable instructions, etc., such as program components that may be executed by one or more processors in conjunction with a computing device. The program components may be programmed using any number of different programming environments, including various languages, development kits, frameworks, etc. Some or all of the functionality contemplated herein may also or alternatively be implemented in hardware and / or firmware.

[0121] In some embodiments, the drive module 1200 is controlled by the control module 1100 to generate relative motion between the forming module 1300 and one or more stop components (e.g., body 240 and / or barrier 242) while the forming tool forms the microfeatures 400 in a desired configuration. For example, the drive module 1200 can cause rotation of one or more stop components (e.g., body 240 and / or barrier 242) relative to the forming module 1300 and / or circumferential motion of the forming module 1300 about the stop components. The drive module 1200 can additionally or alternatively cause axial motion of the stop components (e.g., body 240 and / or barrier 242). The drive module 1200 can include drive motors, sensors, control circuits, drive shafts, turntables, and / or various additional or alternative components to achieve the desired relative motion between the forming module (and possibly the processing module 1400) and the stop components. As shown in FIG. 20, the drive module 1200 can be configured to generate relative motion between the assembled injector device 10 (eg, barrel 20 and stopper 40 ) and the forming module 1300 .

[0122] In various embodiments, the forming module 1300, controlled by the control module 1100, includes a primary energy generator 1310 that generates and directs energy 1312 to one or more stopper components, such as the barrier 242 and / or the body 240, for example, as described above in connection with Figures 5-18. In some embodiments, the forming module 1300 includes a secondary energy generator 1320 that generates and directs energy 1322 to one or more stopper components, such as the barrier 242 and / or the body 240. For example, in embodiments in which a secondary energy generator 1320 is present, the secondary energy generator 1320 can direct the energy 1322 to the stopper components at an angle that is offset from the energy 1312 from the primary energy generator 1310. The beams or directionality of the two energies 1312 and 1322 can intersect at a desired location on or within the stopper component, such that, even though each of the energies 1312, 1322 alone is insufficient to activate the material of the stopper component, the cumulative energy from the energies 1312, 1322 is sufficient to activate the material of the stopper component. In this manner, the energy can be focused at a desired location (e.g., a desired depth) in the stopper component, for example, as described above in connection with one or more of Figures 5-18. While the forming module preferably includes a laser energy source, it is contemplated that any of a variety of energy sources can be implemented, including an electron beam energy source, an ultraviolet light energy source, a plasma energy source, an ultrasonic energy source, or other energy sources capable of activating one or more stopper components.

[0123] Examples of suitable laser generators include, for example, CO2 lasers. Some examples of suitable laser generators include those configured to activate materials within the barrier 242 and / or body 240 without adversely affecting the barrel 20. In such examples, the selection of the type and wavelength of the laser generator may depend on the barrel material and the stopper material. For example, for a barrel made of borosilicate glass, a suitable wavelength may range from 400 to 1700 nm. In one particular example, a 1070 nm laser beam has been shown to easily pass through a borosilicate barrel without heating it, while providing enough energy to change the shape of the stopper.

[0124] In some embodiments, forming module 1300 simultaneously forms microfeatures 400 around the stopper (e.g., barrier 242 and / or body 240). In some embodiments, drive module 1200 generates relative motion between forming module 1300 and one or more stopper components such that a beam or directionality of energy 1312 and / or energy 1322 is applied to the material of the components in a desired pattern (e.g., a continuous circumferential pattern, or any of the patterns described in connection with FIGS. 24-33 ). As shown in FIG. 20 , in some embodiments, forming module 1300 is configured to direct energy through barrel 20 to stopper 40 to form microfeatures 400. For example, barrel 20 may be formed from an optically transparent material (e.g., borosilicate glass), and forming module 1300 may include a laser (e.g., a CO laser) configured to transmit energy in the form of a laser beam through barrel 20 to stopper 40.

[0125] In some embodiments, a processing module 1400, which may be controlled by the control module 1100, applies a processing material 1410 to the stopper 40, such as a rinse solution to remove debris generated during the formation of the microfeatures, a coolant (e.g., a gas such as nitrogen gas, or a fluid such as a refrigerant) to help avoid overheating and / or promote re-solidification of the stopper constituent material after heating, or for other purposes. As shown in FIG. 20 , the processing module 1400 can apply the processing material 1410 to the barrel 20 during or after the formation of one or more microfeatures 400 (e.g., to cool the barrel 20, the stopper 40, and / or the contents of the barrel 20 (e.g., a therapeutic substance)).

[0126] 21 illustrates another example of a system 1000 and method by which the system 1000 can be used to form one or more microfeatures 400 of the stopper 40 into preforms of one or more stopper components (e.g., the body 240 or the barrier 242). For example, as described in connection with FIGS. 22 and 23, one or more components of the stopper 40 can be provided as sheet-shaped preforms 2000 that are then molded or otherwise assembled to form the stopper 40. The system 1000 has substantially the same components and can operate substantially similarly to the example of FIG. 19, except that the drive module 1200 is configured to handle the preforms 2000.

[0127] Stopper assembly and coupling mechanism Various ways of assembling the stopper, and particularly various ways of placing the barrier 242 and body 240 together, are contemplated.

[0128] For example, Figure 22 includes the use of a tool 3000 similar to that described in connection with Figure 23, which includes a forming apparatus such as a mold 3002 and a mandrel 3004. The mold 3002 includes a cavity 3006 defined by an interior wall 3008. The cavity 3006 is shaped and sized to produce a stopper 40 having a desired shape and size. As shown, the tool 3000 is configured to produce the stopper 40 from a preform 2000a of barrier material and a preform 2000b of body material, each of which is initially in a sheet or relatively planar shape.

[0129] Preforms 2000a, 2000b are optionally aligned and forced (e.g., simultaneously) into cavity 3006 of mold 3002 as shown, whereby body 240 is formed from preform 2000b, onto which barrier 242 is co-molded or laminated from preform 2000a, forming the illustrated stopper 40. In the illustrated embodiment, mandrel 304 is actuated to force preforms 2000a, 2000b into mold 3002. In some embodiments, mandrel 3004 can be configured to define structure in body 240 during formation (e.g., axial recess 250 in female-threaded rear surface 248).

[0130] Injection molding, compression molding, vacuum pressing, co-molding, or other known or conventional processes and equipment may also be used to manufacture stopper 40 using preforms 2000a, 2000b.

[0131] As another example, Figure 23 illustrates some embodiments showing how a cylindrical barrier 242 material preform 2000c can be combined with a sheet-shaped body 240 material preform 2000b to assemble stopper 40. As shown in Figure 23, this process involves the use of a tool 3000 that includes a forming device such as a mold 3002 and a mandrel 3004. Mold 3002 includes a cavity 3006 defined by an interior wall 3008. Cavity 3006 is shaped and sized to produce stopper 40.

[0132] The tool 3000 is configured to fabricate the stopper 40 from a barrier material preform 2000c and a mass of body material defining the preform 2000b. As shown, the barrier material preform 2000c is placed within a cavity 3006 of a mold 3002. The body material preform 2000b is then applied to an interior void region within the barrier material preform 2000c. As shown, the mandrel 3004 is actuated to force the preform 2000b, which can be in solid or semi-solid form, through an open proximal end portion of the preform 2000c and into the preform 2000c. The mandrel 3004 can be configured to define structure within the preform 2000b (e.g., an axial recess 250 in the rear face 248 with internal threads).

[0133] While mandrel 3004 is optionally utilized, in other embodiments, the body material is deposited into barrier material preform 2000c by other approaches, such as in a flowable form by application of pressure or other fluid form. Preform 2000c can be used to manufacture stopper 40 using injection molding, compression molding, vacuum pressing, co-molding, or other known or other conventional processes and equipment.

[0134] Various modifications to the foregoing can be applied to enhance or achieve bonding of the components. In some instances, the barrier 242 can be bonded (or further bonded) to the body 240 during the formation of one or more microfeatures 400 or by activating the first layer 402 with an energy source. Additional use of adhesives, elastomeric bonding materials, surface treatments, and other methods are also contemplated.

[0135] Micromechanism layout and configuration The one or more microfeatures 400 may be arranged in any of a variety of continuous (e.g., circumferential) and discontinuous (e.g., dashed circumferential) patterns. In other words, each of the one or more microfeatures 400 may have any of a wide variety of configurations. The following various configurations and functions may provide various benefits and advantages. For example, the microfeatures 400 may be arranged to, among other things, enhance the sealing and / or sliding function of the stopper 40, reduce wrinkling of the barrier 242 (e.g., as part of compression and insertion into the barrel 20), and / or reduce the incidence of delamination or separation of the barrier 242 from the body 240.

[0136] FIG. 24 , for example, illustrates an embodiment of microfeatures 400 that are continuous and extend circumferentially in a substantially linear path around the entire exterior 244 of the stopper 40. In the embodiment illustrated in FIG. 24 , the microfeatures 400 are parallel to one another and do not intersect, and the plane defined by each microgroove is substantially perpendicular to the longitudinal axis X of the stopper 40. FIG. 25 illustrates an embodiment of a stopper 40 having one or more microfeatures 400 (two shown by way of example) that lie in a plane oblique to the longitudinal axis X of the stopper 40 (FIGS. 1 and 2 ), but is otherwise similar in configuration to the microfeatures 400 described in connection with FIG. 24 . FIG. 26 illustrates an embodiment of a stopper 40 having microfeatures 400 that define a plurality of different inclined planes relative to the longitudinal axis X of the stopper 40 (four such microfeatures 400 are shown by way of example). In the embodiment illustrated in FIG. 26 , the planes and microfeatures 400 intersect one another. In other embodiments (not shown), one or more microfeatures 400 lie in a plane oblique to, and possibly parallel to, the longitudinal axis of the stopper 40, which does not intersect with a plane defined by one or more other microfeatures 400.

[0137] The addition of the above-described microfeatures to the sealing surface of stopper 40 can have the advantage of enhancing the seal without increasing the sliding force required for operation of the injector device. This enhanced functionality can be achieved by reducing wrinkles formed during the assembly process (e.g., insertion of stopper 40 into barrel 20) and / or by modifying the sealing interface by increasing the sealing pressure with raised microribs and / or reducing the sliding surface area with the addition of microgrooves.

[0138] Figures 27-29 illustrate embodiments of stopper 40 that include one or more discontinuous or broken microfeatures 400. For example, microfeatures 400 can include one or more sections that are approximately zero depth. While two discontinuous microfeatures 400 are shown in Figures 27-29 for example purposes, other embodiments may have more or fewer discontinuous microfeatures 400. The embodiments shown in Figures 27-29 that include microfeatures 400 can otherwise be similar to those described in connection with Figures 24-26, respectively.

[0139] The various dashed or discontinuous configurations and features described above in connection with Figures 27-29 can provide various benefits and advantages. The addition of discontinuous grooves or ribs can be beneficial in reducing wrinkles (e.g., microwrinkles) that may tend to form during the insertion process when the stopper 40 is introduced into the barrel 20. For example, by arranging the microfeatures 400 in discontinuous lines or patterns, the stopper 40, and particularly the barrier 242, can be less likely to wrinkle or deform when the stopper 40 is compressed for insertion into the barrel 20. For example, the pattern of microfeatures 400 can create strain relief or similar functionality that allows for compression without (or with reduced) associated wrinkles or other undesirable deformations.

[0140] 30 and 31 show an embodiment of a stopper 40 that includes multiple microfeatures 400 that include nonlinear portions. Other embodiments include more or fewer microfeatures 400 that include nonlinear portions as shown in FIGS. 30 and 31. While the nonlinear portions of the microfeatures 400 in the embodiments shown in FIGS. 30 and 31 are generally in the form of repeating patterns, in other embodiments, the nonlinear portions include or consist of nonrepeating pattern portions. In the embodiment shown in FIGS. 30 and 31, the microfeatures 400 include nonlinear portions that extend completely around the periphery of the stopper 40 (i.e., the microfeatures 400 consist of nonlinear portions). In other embodiments, one or more microfeatures 400 include linear and nonlinear portions.

[0141] 30 and 31 can achieve various benefits and advantages. For example, by arranging the microfeatures 400 in a nonlinear configuration, the stopper 40, and particularly the barrier 242, may be less likely to wrinkle or deform when the stopper 40 is compressed for insertion into the barrel 20. The wavy or circumferentially overlapping pattern of the microfeatures 400 can create strain relief, gaps in the material of the barrier 242, or other effects that allow compression of the stopper 40 without (or with reduced) associated wrinkles or other undesirable deformations.

[0142] FIG. 32 illustrates an embodiment of a stopper 40 including microfeatures 400 that extend in a circuitous, non-linear path circumferentially around one or more ribs 300. FIG. 33 illustrates an embodiment of a stopper 40 including microfeatures 400 in the form of a grid or cellular structure pattern. While diamond-shaped cells are shown in FIG. 33, other embodiments include cells having other shapes. The various diamond and cross patterns discussed above can also achieve various benefits and advantages. Again, with such a configuration, the barrier 242 may be less likely to wrinkle or deform when the stopper 40 is compressed for insertion into the barrel 20.

[0143] Various configurations are contemplated, and embodiments of stopper 40 may include one or more microfeatures 400 each including one or more of the microgroove characteristics or attributes described above in connection with any one or more of Figures 24-33, for example.

[0144] Exemplary Material Set The barrel 20 can be formed from a substantially rigid or hard material, such as a glass material (e.g., borosilicate glass), a ceramic material, one or more polymeric materials (e.g., polypropylene, polyethylene, and their copolymers), a metal material, or a plastic material (e.g., cyclic olefin polymer (COC) and cyclic olefin copolymer (COP)), and combinations thereof. It should be understood that a barrel formed from a material that is not inherently hydrophobic (e.g., a glass barrel) can be coated or otherwise treated to impart hydrophobic properties. In some embodiments, the barrel 20 has a hydrophobic inner wall characterized by the absence of lubricants, such as, but not limited to, silicone or silicone oil. As used herein, the term "hydrophobic inner wall" refers to the inner surface of a barrel that is free or substantially free of silicone oil (i.e., has an unquantifiable or trace amount of silicone oil). Furthermore, the hydrophobic surface of the barrel 20 has a contact angle of deionized water greater than 90° on a flat surface of the material, indicating that the surface is hydrophobic. In some embodiments, the water contact angle is from about 90° to about 180°, or from about 96° to about 180°, from about 96° to about 130°, or from about 96° to about 120°.

[0145] In some embodiments, the body 240 of the stopper 40 is formed from a suitable elastomer, such as a rubber material. Examples of suitable rubber materials include synthetic rubber, thermoplastic elastomers, and materials prepared by blending synthetic rubber and thermoplastic elastomers. The material can be rubber composed of butyl, bromobutyl, or chlorobutyl, halogenated butyl rubber, styrene butadiene rubber, butadiene rubber, epichlorohydrin rubber, neoprene rubber, ethylene propylene rubber, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomer, thermoplastic elastomer (TPE), thermoplastic vulcanizate (TPV), materials sold under the trade name VITON®, and combinations and blends thereof. In some embodiments, the body 240 can have an initial modulus (small strain) of about 2.5 MPa to about 5 MPa, or about 3 MPa to about 4 MPa. In some embodiments, the initial modulus is about 3.5 MPa, although various values ​​are contemplated.

[0146] As previously mentioned, portions (e.g., layers or zones) of the barrier 242 can be configured to be more activatable or reactive to an energy source than other layers or zones of the barrier 242. For example, in the case of laser or other light energy sources, the reactivity or activatability can be tailored by modifying the material thickness, pigmentation, density / open space / air content, chemical / material composition, etc. In the case of radio frequency (RF), electrical, and electromagnetic energy sources, the barrier 242 can be tailored to include pigments or other fillers, such as metals (e.g., iron, platinum, etc.), that are more reactive to such energy. In the case of microwave energy sources, metals, water, or other materials can be implemented. Also, in the case of ultraviolet (UV) energy, crosslinkers (acrylates that crosslink to increase density / rigidity) or other materials that absorb UV energy can be incorporated.

[0147] Examples of suitable materials for one or more layers of the stopper's barrier 242 include films of ultra-high molecular weight polyethylene and fluoropolymers. The barrier 242 can include a fluoropolymer film, such as a polytetrafluoroethylene (PTFE) film or a densified expanded polytetrafluoroethylene (ePTFE) film. Films and film composites including PTFE or ePTFE can help provide a thin, strong barrier layer against leachables and extractables that may be present in the underlying elastomer and contaminate the therapeutic fluid within the barrel.

[0148] Some specific examples of suitable materials for the barrier 242 include, but are not limited to, (1) PTFE (polytetrafluoroethylene) homopolymer film produced by skiving (e.g., VALFLON (trade name) available from Nippon Valqua Industries Co., Ltd.), (2) modified PTFE (a copolymer of tetrafluoroethylene monomer and a few percent of perfluoroalkoxide monomer) film produced by skiving (e.g., NEW VALFLON (trade name) available from Nippon Valqua Industries Co., Ltd.), and (3) ultra-high molecular weight polyethylene film produced by skiving (e.g., NEW LIGHT NL-W (trade name) available from Saxin Corporation).

[0149] As shown, barrier 242 may be a composite or laminate material or may include a multi-component (e.g., multi-layer) barrier. Other suitable fluoropolymers for use in or as barrier 242 include, but are not limited to, fluorinated ethylene propylene (FEP), polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymers, tetrafluoroethylene (TFE), Parylene AF-4, Parylene VT-4, and copolymers and combinations thereof. Non-fluoropolymers, such as, but not limited to, polyethylene, polypropylene, Parylene C, and Parylene N, may also or alternatively be used to form barrier 242.

[0150] Densified ePTFE films for barrier 242 can be prepared by the methods described in U.S. Patent No. 7,521,010 to Kennedy et al., U.S. Patent No. 6,030,694 to Dolan et al., U.S. Patent No. 5,792,525 to Fuhr et al., or U.S. Patent No. 5,374,473 to Knox et al. Expanded copolymers of PTFE, such as those described in U.S. Patent No. 5,708,044 to Branca, U.S. Patent No. 6,541,589 to Baillie, U.S. Patent No. 7,531,611 to Sabol et al., U.S. Patent No. 8,637,144 to Ford, and U.S. Patent No. 9,139,669 to Xu et al., can also be used for barrier 242, especially when they are densified.

[0151] In one or more embodiments, the barrier 242 can include or be formed from one or more of the following materials: ultra-high molecular weight polyethylene, as taught in U.S. Pat. No. 9,926,416 to Sbriglia; polyparaxylylene, as taught in U.S. Patent Application Publication No. 2016 / 0032069 to Sbriglia; polylactic acid, as taught in U.S. Pat. No. 9,732,184 to Sbriglia et al.; and / or VDF-co-(TFE or TrFE) polymer, as taught in U.S. Pat. No. 9,441,088 to Sbriglia et al.

[0152] The barrier 242 can also comprise an expanded (expanded, swollen, stretched, or foamed) polymer material comprising a functionalized tetrafluoroethylene (TFE) copolymer material having a microstructure characterized by nodes interconnected by fibrils, where the functionalized TFE copolymer material includes a functionalized copolymer of TFE and PSVE (perfluorosulfonyl vinyl ether), or a functionalized copolymer of TFE and another suitable functional monomer, such as, but not limited to, vinylidene fluoride (VDF), vinyl acetate, or vinyl alcohol. The functionalized TFE copolymer material can be prepared, for example, according to the methods described in U.S. Pat. No. 9,139,669 to Xu et al. or U.S. Pat. No. 8,658,707 to Xu et al.

[0153] In some embodiments, the barrier 242 can be formed from a composite fluoropolymer or non-fluoropolymer material having a barrier layer and a tie layer, such as described in U.S. Patent Application Publication No. 2016 / 0022918 to Gunzel. Note that as used herein, the term "tie layer" can include fluoropolymer and / or non-fluoropolymer materials. The tie layer can include or be formed from expanded polytetrafluoroethylene or other porous expanded fluoropolymers (e.g., ePTFE as taught in U.S. Patent No. 6,541,589 to Baille). Alternatively, the tie layer can be formed from or include a non-fluoropolymer material. Non-limiting examples of non-fluoropolymer materials suitable for use in or as tie layers include non-fluoropolymer membranes, non-fluoropolymer microporous membranes, nonwoven materials (e.g., spunbond, meltblown fiber materials, electrospun nanofibers), polyvinylidene difluoride (PVDF), nanofibers, polysulfone, polyethersulfone, polyarylsulfone, polyetheretherketone (PEEK), polyethylene, polypropylene, and polyimide.

[0154] In some embodiments, the barrier 242 can be fabricated by forming a thin densified composite including a porous ePTFE layer and a thermoplastic barrier layer. In this embodiment, a thermoplastic with a low coefficient of friction surface is preferred. Therefore, fluoropolymer-based thermoplastics such as fluorinated ethylene propylene (FEP), perfluoroalkoxy (PFA), tetrafluoroethylene, hexafluoropropylene, and polymers of vinylidene fluoride (THV) are applicable. The barrier according to this embodiment can be an FEP / ePTFE laminate obtained according to the process taught in WO 94 / 13469 to Bacino. The barrier can be formed at a process temperature above the softening temperature, or even above the melting temperature, of the FEP film in the female cavity mold.

[0155] In some embodiments, the barrier 242 can comprise a composite of a densified ePTFE film and a thin layer of porous ePTFE bonded to a barrier layer film. The densified ePTFE film can be obtained as described in U.S. Patent No. 7,521,010 to Kennedy et al. The ePTFE / densified ePTFE composite can be combined in the manner described in U.S. Patent No. 6,030,694 to Dolan et al. In this embodiment, the composite comprises a layer of densified ePTFE film and a layer of porous ePTFE.

[0156] In some embodiments, the barrier 242 comprises a composite material having at least three layers: a densified expanded fluoropolymer layer, a barrier melt fluoropolymer layer, and a porous layer. The densified expanded fluoropolymer layer can include or be formed from densified ePTFE. The barrier melt fluoropolymer layer can include fluoropolymers such as densified expanded fluoropolymer, polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), densified expanded polytetrafluoroethylene, fluorinated ethylene propylene (FEP), polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymers, and copolymers and combinations thereof. Non-limiting examples of non-fluoropolymers that can be utilized in the barrier melt layer include polyethylene and polypropylene. The porous layer can include or be formed from ePTFE or other porous expanded fluoropolymers. The laminate layer having a densified expanded fluoropolymer layer, a barrier melt fluoropolymer layer, and a porous layer 180 can be constructed by coating or depositing the densified expanded fluoropolymer onto the porous layer to create a composite material. In one non-limiting embodiment, the laminate layer 130 is formed from a densified fluoropolymer (e.g., densified ePTFE), a thermoplastic adhesive (e.g., FEP), and a porous fluoropolymer (e.g., ePTFE).

[0157] It should be understood that stopper 40 can have various degrees of penetration, either from the material of body 240 to the material of barrier 242, or vice versa, including those described in U.S. Pat. No. 8,722,178 to Ashmead et al., U.S. Pat. No. 9,597,458 to Ashmead et al., and U.S. Patent Publication No. 2016 / 0022918 to Gunzel. It should also be understood that there are many variations of the processes described herein that can be utilized to form stopper 40 without departing from the scope and / or spirit of the present invention.

[0158] Examples of therapeutic substances The syringes, tip caps, and other embodiments of the present disclosure can be used in combination with a variety of therapeutic compounds, including, but not limited to, drugs and biologics such as clotting factors, cytokines, epigenetic protein families, growth factors, hormones, peptides, signaling molecules, and variants thereof, as well as amino acids, vaccines, and / or combinations thereof. Therapeutic compounds further include antibodies, antisense, RNA interference directed against the above biologics and their target receptors, and variants thereof. Additional therapeutic compounds include gene therapy, primary stem cells, and embryonic stem cells. Therapeutic compounds include antibodies, antisense, RNA interference against protein kinases, esterases, phosphatases, ion channels, proteases, structural proteins, membrane transport proteins, nuclear hormone receptors, and / or combinations thereof. Furthermore, it should be understood that at least one of the therapeutic compounds identified herein, as well as two or more of the therapeutic compounds listed in this application, used in the present disclosure, is considered within the scope of the present disclosure.

[0159] Examples of clotting factors include, but are not limited to, fibrinogen, prothrombin, Factor I, Factor V, Factor X, Factor VII, Factor VIII, Factor XI, Factor XIII, protein C, platelets, thromboplastin, and co-clotting factor VIIa.

[0160] Examples of cytokines include, but are not limited to, lymphokines, interleukins, chemokines, monokines, interferons, and colony-stimulating factors.

[0161] Examples of epigenetic protein families include, but are not limited to, ATPase family AAA domain-containing protein 2 (ATAD2A), ATPase family-AAA domain-containing 2B (ATAD2B), ATPase family-AAA domain-containing-2B (ATAD2B), bromodomain adjacent to zinc finger domain-1A (BAZ1A), bromodomain adjacent to zinc finger domain-1B (BAZ1B), bromodomain adjacent to zinc finger domain-2A (BAZ2A), bromodomain adjacent to zinc finger domain-2A (BAZ2A), bromodomain adjacent to zinc finger domain-2B (BAZ2B), bromodomain-containing protein 1 (BRD1), bromodomain-containing protein 2-1st bromodomain (BRD2), Bromodomain-containing protein 2 - first and second bromodomains (BRD2), Bromodomain-containing protein 2 isoform 1 - bromodomain 2 (BRD2(2)), Bromodomain-containing protein 3 - bromodomain 1 (BRD3(1)), Bromodomain-containing protein 3 - first bromodomain (BRD3), Bromodomain-containing protein 3 - first and second bromodomains (BRD3), Bromodomain-containing protein 3 - bromodomain 2 (BRD3(2)), Bromodomain-containing protein 4 - first bromodomain (BRD4), Bromodomain-containing protein 4 isoform length - bromodomains 1 and 2 (BRD4(1-2)), Bromodomain-containing protein 4 isoform long-bromodomain 2 (BRD4(2)), bromodomain-containing protein 4 isoform short (BRD4(full-length-short-iso)), bromodomain-containing protein 7 (BRD7), bromodomain-containing 8-bromodomain 1 (BRD8(1)), bromodomain-containing 8-bromodomain 2 (BRD8(2)), bromodomain-containing protein 9 isoform 1 (BRD9), bromodomain-containing testis-specific-1 bromodomain (BRDT), bromodomain-containing testis-specific-1 and 2 bromodomain (BRDT), bromodomain testis-specific protein isoform b-bromodomain 2 (BRDT(2)), bromodomain and PHD finger-containing-1 (BRPF1),Bromodomain and PHD finger-containing-3 (BRPF3), bromodomain and PHD finger-containing-3 (BRPF3), bromodomain and WD repeat-containing 3-second bromodomain (BRWD3(2)), cat eye syndrome critical region protein 2 (CECR2), CREB binding protein (CREBBP), E1A binding protein p300 (EP300), EP300 (EP300), nucleosome remodeling factor subunit BPTF isoform 1 (FALZ), nucleosome remodeling factor subunit BPT (FALZ), euchromatin histone-lysine N-methyltransferase 2 (EHMT2), histone acetyltransferase-KAT2A (GCN5L2), euchromatin histone-lysine N-methyltransferase 1 (EHMT1), histone-lysine N-methyltransferase MLL (MLL), polybromo1-first bromodomain (PB1(1)), polybromo1- 2nd bromodomain (PB1(2)), polybromo l-bromodomain 2 (PBRM1(2)), polybromo l-bromodomain 5 (PBRM1(5)), histone acetyltransferase KAT2B (PCAF), PH interacting protein-1st bromodomain (PHIP(1)), PH interacting protein-2nd bromodomain (PHIP(2))), protein kinase C binding protein 1 (PRKCBP1), protein arginine N-methyltransferase SWI / SNF-related matrix-associated actin-dependent regulator of chromatin subfamily a member 2 (SMARCA2), SWI / SNF-related matrix-associated actin-dependent regulator of chromatin subfamily a member 4 (SMARCA4), nuclear body protein SP110 (SP110), nuclear body protein SP140 (SP140), transcription initiation factor TFIID subunit 1 (TAF1(1-2))), TAF1 RNA polymerase II TATA box-binding protein (TBP)-associated factor 250 kDa bromodomain 2 (TAF1(2)), transcription initiation factor TFIID subunit 1-like bromodomain 1 (TAF1L(1)), transcription initiation factor TFIID subunit 1-like bromodomain 2 (TAF1L(2)),These include tripartite motif-containing 24 (TRIM24(Bromo.)), tripartite motif-containing 24 (TRIM24(PHD-Bromo.)), E3 ubiquitin-protein ligase TRIM33 (TRIM33), tripartite motif-containing 33 (TRIM33(PHD-Bromo.)), WD repeat 9-first bromodomain (WDR9(1)), and WD repeat 9-second bromodomain (WDR9(2)).

[0162] Examples of growth factors include, but are not limited to, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), c-fos-induced growth factor (FIGF), platelet-activating factor (PAF), transforming growth factor beta (TGF-β), bone morphogenetic proteins (BMP), activin, inhibin, fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), glial cell line-derived neurotrophic factor (GDNF), growth differentiation factor-9 (GDF9), epidermal growth factor (EGF), transforming growth factor-α (TGF-α), growth factor (KGF), migration-stimulating factor (MSF), hepatocyte growth factor-like protein (HGFLP), hepatocyte growth factor (HGF), hepatoma-derived growth factor (HDGF), and insulin-like growth factor.

[0163] Examples of hormones include, but are not limited to, amino acid derived (such as melatonin and thyroxine), thyrotropin-releasing hormone, vasopressin, insulin, growth hormone, glycoprotein hormones, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, eicosanoids, arachidonic acid, lipoxins, prostaglandins, steroids, estrogens, testosterone, cortisol, and progestogens.

[0164] Examples of proteins and peptides and signaling molecules include, but are not limited to, ataxia telangiectasia variabile, tumor protein p53, checkpoint kinase 2, breast cancer susceptibility protein, double-strand break repair protein, DNA repair protein RAD50, nibrin, p53-binding protein, DNA damage checkpoint protein mediator, H2A histone family member X, microcephalin, C-terminal binding protein 1, chromosome integrity protein 1A, cell division cycle 25 homolog A (CDC25A), forkhead box O3, and B-cell inhibitor kappa kinase. These include nuclear factor of light polypeptide gene enhancer, alpha (NFKBIA), nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), natriuretic peptide receptor A (NPR1), tumor necrosis factor receptor superfamily, member 11a (TNFRSF11A), v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA), sterol regulatory element-binding transcription factor 2 (SREBF2), CREB-regulated transcriptional coactivator 1 (CRTC1), CREB-regulated transcriptional coactivator 2 (CRTC2), X-box binding protein 1 (XBP1), and catenin beta 1 (cadherin-associated protein or CTNNB1).

[0165] Examples of G protein-coupled receptors (GPCRs) include, but are not limited to, the adenosine receptor family, the adrenergic receptor family, the angiotensin II receptor, the apelin receptor, the vasopressin receptor family, the brain-specific angiogenesis inhibitor family, the bradykinin receptor family, the bombesin receptor family, the complement component 3a receptor 1, the complement component 5a receptor 1, the calcitonin receptor family, the calcitonin receptor-like family, the calcium-sensing receptor, the cholecystokinin A receptor (CCK1), the cholecystokinin B receptor (CCK2), the chemokine (CC motif) receptor family, the sphingosine 1-phosphate receptor family, the succinate receptor, and the choline receptor. Agonist receptor family, chemokine-like receptor family, cannabinoid receptor family, corticotropin-releasing hormone receptor family, prostaglandin D2 receptor, chemokine C-X3-C receptor family, chemokine (CXC motif) receptor family, Burkitt's lymphoma receptor, chemokine (CXC motif) receptor family, cysteinyl leukotriene receptor 2 (CYSLT2), chemokine receptor (FY), dopamine receptor family, G protein-coupled receptor 183 (GPR183), lysophosphatidic acid receptor family, endothelin receptor family, coagulation factor II (thrombin) receptor family, free fatty acid receptor family , formyl peptide receptor family, follicle-stimulating hormone receptor (FSHR), gamma-aminobutyric acid (GABA) B receptor, galanin receptor family, glucagon receptor, growth hormone-releasing hormone receptor (GHRH), ghrelin receptor (ghrelin), growth hormone secretagogue receptor 1b (GHSR1b), gastric inhibitory polypeptide receptor (GIP), glucagon-like peptide receptor family, gonadotropin-releasing hormone receptor (GnRH), pyroglutamylated RFamide peptide receptor (QRFPR), G protein-coupled bile acid receptor 1 (GPBA), hydroxycarboxylic acid receptor family, lysophosphatidic acid receptor 4 (LPA4), lysophosphatidic acid receptor 5 (GPR92), G protein-coupled receptor 79 pseudogene (GPR79), hydroxycarboxylic acid receptor 1 (HCA1), G protein-coupled receptor (C5L2, FFA4,FFA4, FFA4, GPER, GPR1, GPR101, GPR107, GPR119, GPR12, GPR123, GPR132, GPR135, GPR139, GPR141, GPR142, GPR143, GPR146, GPR148, GPR149, GPR15, GPR150, GPR151, GPR152, GPR157, GPR161, GPR162, GPR17, GPR171, GPR173, GPR176, GPR18, GPR182, GPR20, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR35, GPR37L1, GPR39, GPR4, GPR45, GPR50, GPR52, GPR55, GPR6, GPR61, GPR65, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR97,TM7SF1), metabotropic glutamate receptor family, gastrin-releasing peptide receptor (BB2), orexin receptor family, histamine receptor family, 5-hydroxytryptamine receptor family, KISS1-derived peptide receptor (kisspeptin), leucine-rich repeat-containing G protein-coupled receptor family, gonadotropin receptor (LH), leukotriene B4 receptor (BLT1), adenylate cyclase-activating polypeptide 1 receptor 1 (mPAC1), motilin receptor, melanocortin receptor family, melanin-concentrating hormone receptor 1 (MCH1), neuropeptide Y1 receptor (Y1), neuropeptide Y2 receptor (NPY2R), opioid receptor family, oxytocin receptor (OT), P2Y purinoceptor 12 (mP2Y12), P2Y purinoceptor 6 (P2Y6), pancreatic polypeptide receptor receptor family, platelet-activating factor receptor family, prostaglandin E receptor family, prostanoid IP1 receptor (IP1), MAS-related GPR, member family, rhodopsin (rhodopsin), relaxin family peptide receptor family, somatostatin receptor family, tachykinin receptor family, melatonin receptor family, urotensin receptor family, vasoactive intestinal peptide receptor 1 (mVPAC1), neuromedin B receptor (BB1), neuromedin U receptor 1 (NMU1), neuropeptide B / W receptor family, neuropeptide FF receptor 1 (NPFF1), neuropeptide S receptor 1 (NPS receptor), neuropeptide Y receptor family, neurotensin receptor 1 (NTS1), opsin 5 (OPN5), opioid receptor-like receptor (NOP), oxoeicosanoid(OXE) receptor 1 (OXE), oxoglutarate (α-ketoglutarate) receptor 1 (OXGR1), purinergic receptor family, pyrimidinergic receptor family, prolactin-releasing hormone receptor (PRRP), prokineticin receptor family, platelet-activating receptor (PAF), prostaglandin F receptor family, prostaglandin 12 (prostacyclin) receptor family, parathyroid hormone receptor family, muscarinic acetylcholine receptor (such as rM4), prostanoid DP2 receptor (rGPR44), prokineticin receptor family, relaxin family peptide receptor family, secretin receptor (secretin), Frizzled class receptor (Smoothened), trace amine-associated receptor family, tachykinin family, thromboxane A2 receptor (TP), thyrotropin-releasing hormone receptor (TRH1), and thyroid-stimulating hormone receptor (TSH).

[0166] Examples of nuclear hormone receptors include, but are not limited to, androgen receptor (AR), estrogen-related receptor alpha (ESRRA), estrogen receptor 1 (ESR1), nuclear receptor subfamily 1 - group H - member 4 (NR1H4), nuclear receptor subfamily 3 - group C - member 1 (glucocorticoid receptor) (NR3C1), nuclear receptor subfamily 1 - group H - member 3 (liver X receptor alpha) (NR1H3), nuclear receptor subfamily 1 - group H - member 2 (liver X receptor beta) (NR1H2), nuclear receptor subfamily 1 - group H - member 2 (liver X receptor beta) (NR1H2), nuclear receptor subfamily 3 - group C - member 2 (mineralocorticoid receptor). (NR3C2), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor gamma (PPARG), peroxisome proliferator-activated receptor delta (PPARD), progesterone receptor alpha (PGR), progesterone receptor beta (PGR), retinoic acid receptor alpha (RARA), retinoic acid receptor beta (RARB), retinoid X receptor alpha (RXRA), retinoid X receptor gamma (RXRG), thyroid hormone receptor alpha (THRA), thyroid hormone receptor beta (THRB), retinoic acid-related orphan receptor, liver X receptor, farnesoid X receptor, vitamin D receptor, pregnane X receptor, constitutive androstane receptor, hepatocyte nuclear factor 4, estrogen receptor, estrogen-related receptor, glucocorticoid receptor, and nerve growth factor-inducible receptor B, germline nuclear factor.

[0167] Examples of membrane transport proteins include, but are not limited to, the ATP-binding cassette (ABC) superfamily, solute carrier (SLC) superfamily, multidrug resistance protein 1 (P-glycoprotein), organic anion transporter 1, and proteins such as EAAT3, EAAC1, EAAT1, GLUT1, GLUT2, GLUT9, GLUT10, rBAT, AE1, NBC1, KNBC, CHED2, BTR1, NABC1, CDPD, SGLT1, SGLT2, NIS, CHT1, NET, DAT, GLYT2, CRTR, BOAT1, SIT1, XT3, y+LAT1, BAT1, NHERF1, NHE6, ASBT, DMT1, DCT1, NRAMP2, NKCC2, NCC, KCC3, NACT, MCT1, MCT8, MCT12, SLD, VGLUT3, THTR1, THTR2, PIT2, GLVR2, OCTN2, URAT1, NCKX1, NCKX5, CIC, PiC, ANTI, ORNT1, AGC1, ARALAR, Citrin, STLN2, aralar2, TPC, MUP1, MCPHA, CACT, GC1, PHC, DTD, CLD, DRA, PDS, Prestin, TAT1, FATP4, ENT3, ZnT2, ZnT10, AT1, NPT2A, N Examples of genes encoding the PT2B, HHRH, CST, CDG2F, UGAT, UGTL, UGALT, UGT1, UGT2, FUCT1, CDG2C, NST, PAT2, G6PT1, SPX4, ZIP4, LIV4, ZIP13, LZT-Hs9, FPN1, MTP1, IREG1, RHAG, AIM1, PCFT, FLVCR1, FLVCR2, RFT1, RFT2, RFT3, OATP1B1, OATP1B3, and OATP2A1.

[0168] Examples of structural proteins include, but are not limited to, tubulin, heat shock proteins, microtubule stabilizing proteins, tumor protein 18, stathmin, kinesin-8 and kinesin-14 families, Kip3 and Kif18A.

[0169] Examples of proteases include, but are not limited to, the ADAM (a disintegrin and metalloprotease) family.

[0170] Examples of protein kinases include, but are not limited to, AP2-related kinases, human ABL proto-oncogene 1-non-receptor tyrosine protein kinase family, c-abl oncogene 1 receptor tyrosine kinase family, v-abl Abelson murine leukemia viral oncogene homolog 2, activin A receptor family, ABC1 activity of chaperone-bc1 complex homolog (S. pombe) (ADCK3), aarF domain-containing kinase 4 (ADCK4), v-akt murine thymoma viral oncogene homolog family, anaplastic lymphoma receptor tyrosine kinase family, protein kinase A family, protein kinase B family, ankyrin repeat and kinase domain-containing 1 (ANKK1), NUAK family-SNF1-like kinase, mitogen-activated protein kinase kinase kinase family, Aurora kinase A (AURKA), Aurora kinase B (AURKB), aurora kinase C (AURKC), AXL receptor tyrosine kinase (AXL), BMP2-inducible kinase (BIKE), B lymphoid tyrosine kinase (BLK), bone morphogenetic protein receptor family, BMX non-receptor tyrosine kinase (BMX), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), protein tyrosine kinase 6 (BRK), BR serine / threonine kinase family, Bruton's agammaglobulinemia tyrosine kinase (BTK), calcium / calmodulin-dependent protein kinase family, cyclin-dependent kinase family, cyclin-dependent kinase-like family, CHK1 checkpoint homolog (S. pombe) (CHEK1), CHK2 checkpoint homolog (S. pombe) (CHEK2), insulin receptor, isoform A (INSR), insulin receptor, isoform B (INSR), rho-interacting serine / threonine kinase (CIT), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), CDC-like kinase family - hepatocyte growth factor receptor (MET), proto-oncogene tyrosine protein kinase receptor, colony-stimulating factor family receptor, c-src tyrosine kinase (CSK), casein kinase family,Megakaryocyte-associated tyrosine kinase (CTK), death-associated protein kinase family, doublecortin-like kinase family, discoidin domain receptor tyrosine kinase, dystrophy myotonic protein kinase (DMPK), dual specificity tyrosine-(Y)-phosphorylation-regulated kinase family, epidermal growth factor receptor family, eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1), EPH receptor family, ephrin type A receptor family, ephrin type B receptor family, v-erb-b2 erythroblastic leukemia viral oncogene homolog Milli, mitogen-activated protein kinase family, endoplasmic reticulum nuclear signaling 1 (ERN1), PTK2 protein tyrosine kinase 2 (FAK), fer (fps / fes-related) tyrosine kinase (FER), feline sarcoma oncogene (FES), fibroblast growth factor receptor family, Gardner-Rashid feline sarcoma virus (v-fgr) oncogene homolog (FGR), fms-related tyrosine kinase family, Fms-related tyrosine kinase family, fyn-related kinase (FRK), SRC-related FYN oncogene, cyclin G-associated kinase (GAK) , eukaryotic translation initiation factor 2 alpha kinase, growth hormone receptor, G protein-coupled receptor kinase 1 (GRK1), G protein-coupled receptor kinase family, glycogen synthase kinase family, germ cell-associated 2 (haspin) (HASPIN), hematopoietic cell kinase (HCK), homeodomain-interacting protein kinase family, mitogen-activated protein kinase kinase kinase kinase family, hormone-upregulated Neu-related kinase (HUNK), enterocyte (MAK-like) kinase (ICK), insulin-like growth factor 1 receptor (IGF1R), conserved helix-loop-helix ubiquitous kinase (IKK-α), inhibitor of kappa ray polypeptide gene enhancer in B-cell kinase beta family, insulin receptor (INSR), insulin receptor-related receptor (INSRR), interleukin-1 receptor-related kinase family, IL2-inducible T-cell kinase (ITK), Janus kinase family, kinase insert domain receptor, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog,Lymphocyte-specific protein tyrosine kinase (LCK), LIM domain kinase family, serine / threonine kinase family, leucine-rich repeat kinase family, v-yes-1 Yamaguchi sarcoma virus-associated oncogene homolog (LYN), male germ cell-associated kinase (MAK), MAP / microtubule affinity-regulating kinase family, e.g., microtubule-associated serine / threonine kinase family, maternal-fetal leucine zipper kinase, c-mer proto-oncogene tyrosine kinase (MERTK), met proto-oncogene (hepatocyte growth factor receptor), MAP kinase-interacting serine / threonine kinase family, myosin light chain kinase family, mixed lineage kinase domain-like protein isoform, CDC42-binding protein kinase family, serine / threonine kinase family, macrophage-stimulating receptor 1 receptor (c-met-related tyrosine kinase) (MST1R), mechanistic target of rapamycin (serine / threonine kinase family) threonine kinase) (MTOR), musculoskeletal receptor tyrosine kinase (MUSK), myosin light chain kinase family, NIMA (never in mitosis gene a)-related kinase family, serine / threonine protein kinase NIM1 (NIM1), nemo-like kinase (NLK), oxidative stress responsive 1 (OSR1), p21 (Cdc42 / Rac)-activated kinase family, PAS domain-containing serine / threonine kinase, platelet-derived growth factor receptor family, 3-phosphoinositide-dependent protein kinase-1 (PDPK1), calcium-dependent protein kinase 1, phosphorylase kinase gamma family, phosphatidylinositol 4,5-bisphosphate 3-kinase, phosphoinositide-3-kinase family, phosphatidylinositol 4-kinase family, phosphoinositide kinase, FYVE finger-containing, Pim-1 oncogene (PIM1), pim-2 oncogene (PIM2), pim-3 oncogene (PIM3), phosphatidylinositol-4-phosphate 5-kinase family, phosphatidylinositol-5-phosphate 4-kinase family protein kinase, membrane-associated tyrosine / threonine 1 (PKMYT1), protein kinase N family, polo-like kinase family, protein kinase C family,Protein kinase D family, cGMP-dependent protein kinase family, eukaryotic translation initiation factor 2-alpha kinase 2 (PRKR), X-linked protein kinase (PRKX), prolactin receptor (PRLR), PRP4 pre-mRNA processing factor 4 homolog B (yeast) (PRP4), PTK2B protein tyrosine kinase 2 beta (PTK2B), SIK family kinase 3 (QSK), v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1), neurotrophic tyrosine kinase receptor type family, receptor (TNFRSF)-interacting serine-threonine kinase family, dual serine / threonine and tyrosine protein kinase (RIPK5), Rho-associated coiled-coil-containing protein kinase family, c-ros oncogene 1, receptor tyrosine kinase (ROS1), ribosomal protein S6 kinase family, SH3-binding domain kinase 1 (SBK1), serum / glucocorticoid-regulated kinase tyrosine kinase family, putative uncharacterized serine / threonine protein kinase (Sugen kinase 110) (SgK110), salt-inducible kinase family, SNF-related kinase (SNRK), src-related kinase, SFRS protein kinase family, spleen tyrosine kinase (SYK), e.g., TAO kinase family, TANK-binding kinase 1 (TBK1), e.g., TEC protein tyrosine kinase (TEC), testis-specific kinase 1 (TESK1), transforming growth factor, beta receptor family, immunoglobulin-like and EGF-like domain 1-containing tyrosine kinase (TIE1), TEK tyrosine kinase, endothelial (TIE2), angiopoietin-1 receptor (Tie2), Tusle-like kinase family, TRAF2 and NCK-interacting kinase (TN IK), non-receptor tyrosine kinase family, TNNI3-interacting kinase (TNNI3K), transient receptor potential cation channel, testis-specific serine kinase family, TTK protein kinase (TTK), TXK tyrosine kinase (TXK), tyrosine kinase 2 (TYK2), TYRO3 protein tyrosine kinase (TYRO3), unc-51-like kinase family, phosphatidylinositol 3-kinase,These include vaccinia-related kinase 2 (VRK2), the WEE1 homolog family, the WNK lysine-deficient protein kinase family, the v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES), the sterile alpha motif and leucine zipper-containing kinase AZK (ZAK), and the zeta chain (TCR)-associated protein kinase 70 kDa (ZAP70).

[0171] Cell therapy primarily uses cells derived from endoderm such as exocrine secretory epithelial cells and hormone-secreting cells, keratinized epithelial cells, moist stratified barrier epithelial cells, sensory transduction cells, autonomic nerve cells, sensory organ and peripheral nerve supporting cells, central nervous system neurons and glial cells, ectoderm such as lens cells, metabolic and storage cells, barrier function cells (lung, intestine, exocrine glands and urogenital tract), mesoderm such as extracellular matrix cells, contractile cells, blood and immune system cells, germ cells, nurse cells, interstitial cells, and combinations thereof. Additionally, cells that have been genetically, chemically or physically altered or otherwise modified are also within the scope of the present invention.

[0172] Examples of exocrine secretory epithelial cells include, but are not limited to, salivary gland mucous cells, salivary gland number 1, von Ebner's gland cells of the tongue, mammary gland cells, lacrimal gland cells, ceruminous gland cells of the ear, eccrine sweat gland dark cells, eccrine sweat gland clear cells, apocrine sweat gland cells, Mohr's gland cells of the eyelid, sebaceous gland cells, Bowman's gland cells of the nose, Brunner's gland cells of the duodenum, seminal vesicle cells, prostate cells, bulbourethral gland cells, Bartholin's gland cells, Littré gland cells, endometrial cells of the uterus, isolated goblet cells of the respiratory and digestive tract, gastric mucosal cells, gastric gland zymogen cells, gastric gland oxidative cells, pancreatic acinar cells, Paneth cells of the small intestine, type II pneumocytes of the lung, and and Clara cells of the lung, hormone-secreting cells, such as, but not limited to, anterior pituitary cells, intermediate pituitary cells, magnocellular neurosecretory cells, cells of the intestinal and respiratory tracts, thyroid cells, parathyroid cells, adrenal gland cells, Leydig cells of the testes that secrete testosterone, theca cells of the ovarian follicle that secrete estrogen, luteal cells of ruptured follicles that secrete progesterone, juxtaglomerular cells, macula densa cells of the kidney, peripolar cells of the kidney, mesangial cells of the kidney, and pancreatic islets, keratinizing epithelial cells, such as, but not limited to, epidermal keratinocytes, epidermal basal cells, keratinocytes of the fingernails and toenails, nail bed Basal cells, medullary hair stem cells, cortical hair stem cells, epidermal hair stem cells, epidermal root sheath cells, root sheath cells of Huxley's layer, root sheath cells of Henle's layer, outer root sheath cells and hair matrix cells, moist stratified barrier epithelial cells, including but not limited to, surface epithelial cells of stratified squamous epithelium and basal cells of the epithelium of the cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, and urothelial cells, sensory transduction cells, including but not limited to, auditory inner hair cells of the organ of Corti, auditory outer hair cells of the organ of Corti, basal cells of the olfactory epithelium, cold-sensitive primary sensory neurons, heat-sensitive primary sensory neurons, Merkel cells of the epidermis , olfactory receptor neurons, pain-sensitive primary sensory neurons, photoreceptor cells in the retina of the eye, proprioceptive primary sensory neurons, touch-sensitive primary sensory neurons, type I carotid body cells, type II carotid body cells, type I hair cells of the vestibular system of the ear, type II hair cells and type I taste bud cells of the vestibular system of the ear, autonomic nerve cells, including but not limited to cholinergic neurons, adrenergic neurons and peptidergic neurons, sensory organ and peripheral neuron supporting cells, including but not limited to inner column cells of the organ of Corti, outer column cells of the organ of Corti, inner phalangeal cells of the organ of Corti,Ectophalangeal cells of the organ of Corti, border cells of the organ, Hensen's cells of the organ of Corti, vestibular organ supporting cells, taste bud supporting cells, olfactory epithelial supporting cells, Schwann cells, satellite glial cells and enteric glial cells, central nervous system neurons and glial cells, including but not limited to astrocytes, neuronal cells, oligodendrocytes and spindle neurons, lens cells, including but not limited to anterior lens epithelial cells and crystallin-containing lens fiber cells, metabolic and storage cells, including but not limited to adipocytes and hepatic adipocytes, barrier function cells, including but not limited to cells, including but not limited to kidney parietal cells, kidney glomerular podocytes, kidney proximal tubule brush border cells, loop of Henle's slice cells, kidney distal tubule cells, kidney collecting duct cells, chief cells, intercalated cells, type I pneumocytes, pancreatic duct cells, non-striated duct cells, chief cells, intercalated cells, duct cells, intestinal brush border cells, exocrine gland striated duct cells, gallbladder epithelial cells, efferent duct non-ciliated cells, epididymal chief cells and epididymal basal cells, extracellular matrix cells, including but not limited to ameloblast epithelial cells, meniscal epithelial cells of the vestibular system of the ear, organ of Corti interdental epithelial cells, loose connective tissue fibroblasts, corneal fibroblasts, tendon fibroblasts, Bone marrow reticular fibroblasts, other non-epithelial fibroblasts, pericytes, nucleus pulposus cells of the intervertebral disc, cementoblasts / cementocytes, odontoblasts / odontoblasts, hyaline cartilage chondrocytes, fibrocartilage chondrocytes, elastic cartilage chondrocytes, osteoblasts / osteocytes, osteoprogenitor cells, vitreous cells of the vitreous body of the eye, stellate cells of the perilymphatic space of the ear, hepatic stellate cells and pancreatic stellate cells, contractile cells, including but not limited to skeletal muscle cells, satellite cells, cardiac myocytes, smooth muscle cells, myoepithelial cells of the iris and myoepithelial cells of exocrine glands, blood cells and immune system cells, including but not limited to erythrocytes, megakaryocytes, monocytes, connective tissue cells, tissue macrophages, epidermal Langerhans cells, osteoclasts, dendritic cells, microglial cells, neutrophil granulocytes, eosinophil granulocytes, basophil granulocytes, hybridoma cells, mast cells, helper T cells, suppressor T cells, cytotoxic T cells, natural killer T cells, B cells, natural killer cells, reticulocytes, stem cells and progenitor cells of the blood and immune system, germ cells, including but not limited to oogonia, oocytes, spermatocytes, spermatocytes, spermatogonia and sperm, nurse cells, including but not limited to ovarian follicle cells and Sertoli cells, thymic epithelial cells,Stromal cells, including but not limited to interstitial renal cells, and any combination of the foregoing.

[0173] Non-limiting examples of other known biologics include, but are not limited to, Avosinagis, Abeglin, Actemra, AFP-Cyde, Antova, Alzera, Aurexis, Avastin, Benlysta, Vexar, Brontres, Bosatria, Campath, CEA-Cyde, CEA-Scan, Cimzia, Siramza, Ectomab, Erbitux, Fibricint, Gadiva, Herceptin, hPAM4-Cyde, HumaSPECT, HuMax-CD4, HuMax-EGFr, Humira, HuZAF, Hybri-Ceaker, Ilaris, Indimasys-125, Kadcyla, Lemtrada, Leucarest, Leukoscan, Lucentis, and Lin. These include Fomun, Lymphoscan, Lymphostat-B, MabThera, Mycograb, Mylotarg, Myosint, Neutrospec, Pneumax, Nuvion, Omnitarg, Opdivo, Orthochron OKT3, Ovalex, Panorex, Prolia, Prostasint, Raptiva, Remicade, Rimovab, Lencarex, LeoPro, Lexomun, Rituxan, Roactemra, Syntimun, Simponi, Simulect, Soliris, Stelara, Synagis, Taxless, Serasim, Theladgin, Thelalock, Tysabri, Vectibix, Verluma, Xolair, Yervoy, Zenapax and Zevalin, and combinations thereof.

[0174] Non-limiting examples of known monoclonal antibodies include, but are not limited to, 3F8, 8H9, abagovomab, abciximab, abituzumab, abrilumab, actotuzumab, adalimumab, adecatumumab, aducanumab, afacevicumab, afelimomab, afutuzumab, alacizumab pegol, ALD518, ALD403, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, AMG334, and anatumomab. Mafenatox, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, arcitumomab, ascribvacumab, acelizumab, atezolizumab, atinumab, atlizumab, atolimu-mab, avelumab, bapineuzumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezloxumab, biciromab, bimagrumab, bimekizumab, bivatuzumab mertansine, bleselumab, blinatumab, brontuzumab, brosozumab, bococizumab, brazikumab, blu- Lentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontuzumab, burosumab, cabilalizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, carotuximab, catumaxomab, cBR96-doxorubicin immunoconjugate, cedelizumab, sergituzumab amnaleukin, certolizumab pegol, cetuximab, sitatuzumab bogatox, cixutuzumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine, conatumumab, concizumab, CR6261, crenezumab, clotezumab, dacetuzumab, daclizumab, darotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, delrotuximab biotin, detumomab, zina Tuximab, dilidabumab, domaglotumab, dorlimomab-alitonox, drozitumab, durigotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elocinib, Limab, emactuzumab, emibetuzumab, emicizumab, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faretuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fivatuzumab, ficlatuzumab, figitumumab, filibumab, framvotumab, fretikumab, fontolizumab, foralumab, foravirumab, fresolimumab, furanumab, futuximab, galcanezumab, galiximab, ganitumab, gantenerumab, gavilimab, gemtuzumab ozogamicin, gevokizumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiusetan, icrucumab, idarucizumab, igovomab, IMA-638, IMAB362, imalumab, imciromab, imgatuzumab, incl. Mab, indatuximab ravtansine, indusatumab vedotin, inebilizumab, infliximab, inolimab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, isatuximab, itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, LBR-101 / PF0442g7429, lebrikizumab, remaresomab, lendali Ibuprofen, lentilumab, lerdelimumab, lexatumumab, ribivirumab, rifatuzumab vedotin, ligelizumab, rilotumab satetraxetan, lintuzumab, lirilumab, roderucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, lumiliximab, lumletuzumab, LY2951742, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretum Mab, mirvetuximab sorafutansine, mitumomab, mogamulizumab, monalizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab butafenatox, namirumab, naptumomab estafenatox, naratuximab emtansine, narunatumab, natalizumab, nabicixizumab, nabibumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesbacumab, nimotuzumab, nivolumab, nofetumomabMerpentan, obilutoxiaximab, obinutuzumab, occaratuzumab, ocrelizumab, odulimab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otreltuzumab, oxelumab, ozonazumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pasco Lisumab, pasotuximab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placuramab, prosalizumab, pogalizumab, polatuzumab vedotin, ponezumab, prezalizumab, priliximab, pritoximab, pritumumab, PRO140, kilimumab, racotumomab, radletumab, rafivirumab, ralpanizumab, ramucirumab, ranibizumab, raxibax Mab, refanezumab, regavirumab, reslizumab, rilotumab, rinukumab, risankizumab, rituximab, rivavazumab pegol, lobatumumab, loredumab, romosozumab, lontalizumab, rovalpituzumab tesirin, rovelizumab, ruplizumab, sacituzumab govitecan, samalizumab, sapelizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, cetoxiaximab, sevirumab, SGN-CD19A, SGN-CD33A, sibrotuzumab, sifalimumab , siltuximab, simtuzumab, siplizumab, sirukumab, sofituzumab vedotin, solanezumab, solitomab, soneptizumab, sontuzumab, stamulumab, sulesomab, suvismab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tamtubetomab, tanezumab, taplitumomab paptox, talexuzumab, tefibazumab, terimomab alitox, tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, ticilimumab, tigatuzumab, tildrakizumab, timolumab, tisotumab vedotin, TNX-650, tocilizumab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocuprumab, urelumab, urtoxazumab, ustequitin These include numab, utomilumab, vadastaximab butarilin, bundletuzumab vedotin, vanticizumab, vanucizumab, bapaliximab, valilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, borsetuzumab mafodotin, votumumab, zentuzumab, zalutumumab, zanolimumab, zatuximab, diralimumab, and zolimomab alitox, and combinations thereof.

[0175] Examples of vaccines developed for viral diseases include, but are not limited to, hepatitis A vaccine, hepatitis B vaccine, hepatitis E vaccine, HPV vaccine, influenza vaccine, Japanese encephalitis vaccine, MMR vaccine, MMRV vaccine, polio vaccine, rabies vaccine, rotavirus, chickenpox vaccine, shingles vaccine, smallpox vaccine, yellow fever vaccine, adenovirus vaccine, coxsackie B virus vaccine, cytomegalovirus vaccine, human dengue fever vaccine, human eastern equine encephalitis virus vaccine, Ebola hemorrhagic fever vaccine, enterovirus 71 vaccine, Epstein-Barr vaccine, hepatitis C vaccine, HIV vaccine, and human HTLV-1 vaccine. Examples of vaccines for bacterial diseases include, but are not limited to, T lymphocytic leukemia vaccines, Marburg virus disease vaccines, norovirus vaccines, human respiratory syncytial virus vaccines, severe acute respiratory syndrome (SARS) vaccines, and human West Nile virus vaccines; examples of vaccines for bacterial diseases include, but are not limited to, anthrax vaccines, DPT vaccines, Q fever vaccines, Hib vaccines, tuberculosis (BCG) vaccines, meningococcal vaccines, typhoid vaccines, pneumococcal conjugate vaccines, pneumococcal polysaccharide vaccines, cholera vaccines, dental caries vaccines, ehrlichiosis vaccines, leprosy vaccines, Lyme disease vaccines, Staphylococcus aureus vaccines, Streptococcus pyogenes vaccines, syphilis vaccines, tularemia vaccines, and plague vaccines. Examples of parasitic disease vaccines include, but are not limited to, malaria vaccine, schistosomiasis vaccine, Chagas disease vaccine, hookworm vaccine, human onchocerciasis / river blindness vaccine, trypanosomiasis vaccine, and visceral leishmaniasis vaccine. Examples of non-infectious diseases include, but are not limited to, Alzheimer's disease amyloid protein vaccine, breast cancer vaccine, ovarian cancer vaccine, prostate cancer vaccine, and talimogene laherparepvec (T-VEC), including, but not limited to, vaccines under the following trade names: ACAM2000, ActHIB, Adacel, AFLURIA.QUADRIVALENT, AgriFlu, BCG vaccine, BEXSERO, Vislax, Boostrix, Cervarix, Comvax, DAPTACEL, DECAVAC, Engerix-B, FLUAD, Fluarix, Fluarix tetravalent, Flubloc, Flucervax, Flucervax tetravalent, Flulaval, Flumist, Flumist tetravalent, Fluvirin, Fluzone tetravalent, Fluzone, Fluzone high dose and Fluzone intradermal, Gardasil, Gardasil 9, Havrix, Hivex, Imovax, Infanrix, IPOL, Ixiaro, JE-Vax, KINRIX, Menactra, Menhybrix, Menomne-A / C / Y / W-135, Menoveo, MMR II, MM-Vax, Pediarix, Pedovax HIB, Pentacel, Pneumovax 23, Poliovax, Prevnar, Prevnar 13, ProQuad, Quadracel, Quadrivalent, RabAvert, RecombiVax HB, ROTARIX, RotaTeq, TENIVAC, TICE BCG, Tripedia, TRUMENBA, Twinrix, TYPHIM Vi, VAQTA, Varivax, Vaccola, Vivotif, YF-Vax, Zostavax and combinations thereof.

[0176] Examples of injectable drugs include, but are not limited to, Abravar (gadofosveset trisodium injection), Abarelix depot, abobotulinum toxin A injection (Dysport), ABT-263, ABT-869, ABX-EFG, Acretropine (somatropin injection), Acetadot (acetylcysteine ​​injection), Acetazolamide injection, Acetadot, Actemra (tocilizumab injection), Axrel (corticorelin ovine triflate for injection), Actamune, Activase, injectable acyclovir (Zovirax injection), Adacel, adalimumab, and Adenoscaine. Adenosine (adenosine injection), adenosine injection (Adenoscan), AdrenaClick, Adrevue (intravenous iobenguane 1123 injection), Afluria, Ak-Fluor (fluorescein injection), Aldurazyme (laronidase), alglucerase injection (Ceredase), Alkeran injection (melphalan HCl injection), allopurinol sodium for injection (Aloprim), Alloprim (allopurinol sodium for injection), alprostadil, Arsuma (sumatriptan injection), ALTU-238, amino acid injection, Aminosine, Apidra, Apremilast, injectable alprostadil dual chamber system (Caverject) Impulse), AMG 009, AMG 076, AMG 102, AMG 108, AMG 114, AMG 162, AMG 220, AMG 221, AMG 222, AMG 223, AMG 317, AMG 379, AMG 386, AMG 403, AMG 477, AMG 479, AMG 517, AMG 531, AMG 557, AMG 623, AMG 655, AMG 706, AMG 714, AMG 745, AMG 785, AMG 811, AMG 827, AMG 837, AMG 853, AMG 951, Amiodarone Hydrochloride Injection (Amiodarone Hydrochloride Injection), Amobarbital Sodium Injection (Amytal Sodium), Amytal Sodium (Amobarbital Sodium Injection), Anakinra, Anti-Aβ, Anti-β7, Anti-β20, Anti-CD4, Anti-CD20, Anti-CD40, Anti-IFNα, Anti-IL13, Anti-OX40L, Anti-oxLDS, Anti-NGF, Anti-NRP1,Arixtra, Amphadase (hyaluronidase injection), Ammonur (sodium phenylacetate and sodium benzoate injection), Anaprox, Anzemet injection (dolasetron mesylate injection), Apidra (insulin glulisine [rDNA-derived] injection), Apomab, Aranesp (darbepoetin alfa), Argatroban (argatroban injection), Arginine hydrochloride injection (R-Gene 10, Aristocort, Aristospan, arsenic trioxide injection (Trisenox), Altican hydrochloride and epinephrine injection (Septocain), Alzera (ofatumumab injection), Asclera (polidocanol injection), ataluren, ataluren-DMD, atenolol injection (Tenormin intravenous infusion), atracurium besilate injection (atracurium besilate injection), Avastin, Azactam injection (aztreonam injection), azithromycin (Zithromax) Injection), Aztreonam Injection (Azactam Injection), Baclofen Injection (Lioresal Intrathecal), Bacteriostatic Water (Bacteriostatic Water for Injection), Baclofen Injection (Lioresal Intrathecal), Valuin Oil Ampoule (Dimercarprol Injection), BayHepB, BayTet, Benadryl, Bendamustine Hydrochloride Injection (Trenda), Benztropine Mesylate Injection (Cogentin), Betamethasone Injectable Suspension (Celeston Solspan), Bexar, Bisilin CR 900 / 300 (Penicillin G Benzathine and Penicillin G Progain Injection), Blenoxan (Bleomycin Sulfate Injection), Bleomycin Sulfate Injection (Blenoxan), Boniva Injection (Ibandronate Sodium Injection), Botox Cosmetic (Onabotulinum Toxin A for Injection), BR3-FC, Bravere (Urofollitropin Injection), Bretylium (Bretylium Tosylate Injection), Brevital Sodium (Methohexital Sodium for Injection), Bretin, Briobercept, BTT-1023, Bupivacaine Hydrochloride, Byetta, Ca-DTPA (Calcium Pentetate Trisodium Injection), Cabazitaxel Injection (Jevtana), Caffeine Alkaloids (Caffeine and Sodium Benzoate Injection), Calcigex Injection (Calcitrol), Calcitrol (Calcigex Injection),Calcium chloride (Calcium chloride injection 10%), versenate calcium disodium (edetate calcium disodium injection), Campas (artemtuzumab), Camptosar injection (irinotecan hydrochloride), canakinumab injection (Ilaris), Capastatin sulfate (capreomycin for injection), Capreomycin for injection (capastatin sulfate), Cardiolite (preparation kit for technetium Tc99 sestamibi for injection), Carticel, Casflo, cefazolin and dextrose for injection (cefazolin injection), cefepime hydrochloride, cefotaxime, cefepime Futriaxone, Cerezyme, Carnitor Injection, Caverject, Celeston Solspan, Celsior, Cerebix (fosphenytoin sodium injection), Ceredase (alglucerase injection), Seretec (technetium Tc99m exametazyme injection), certolizumab, CF-101, chloramphenicol sodium succinate (chloramphenicol sodium succinate injection), chloramphenicol sodium succinate injection (chloramphenicol sodium succinate), Cholestagel (colesevelam HCl), Coligona Dotropin alfa injection (Ovidrel), Cimzia, Cisplatin (Cisplatin injection), Chlor (Clofarabine injection), Clomiphine citrate, Clonidine injection (Duraclone), Cogentin (Ventropine mesylate injection), Colistimeth injection (Colimycin M), Colistimeth M (Colistimeth injection), Compass, Conivaptan hydrochloride injection (Baprisol), Injectable conjugated estrogens (Premarin injection), Copaxone, Injectable corticorelin ovine triflate (Axrel), Colbert (Ibutilide fumarate) sodium chloride injection), Cubicin (daptomycin injection), CF-101, Cyanokit (hydroxocobalamin for injection), cytarabine liposome injection (DepoCyt), cyanocobalamin, Cytoven (ganciclovir), DHE45, dacetuzumab, Dacogen (decitabine injection), dalteparin, Dantrium IV (dantrolene sodium for injection), dantrolene sodium for injection (Dantrium IV), daptomycin injection (Cubicin), darbepoetin alfa, DDAVP injection (desmopressin acetate injection), Decabax,Decitabine Injection (Dacogen), Dehydrated Alcohol (Dehydrated Alcohol Injection), Denosumab Injection (Prolia), Delatestril, Delestrogen, Delteparin Sodium, Depacon (Sodium Valproate Injection), DepoMedrol (Methylprednisolone Acetate Injection Suspension), DepoCyte (Cytarabine Liposomal Injection), Depodur (Morphine XR Liposomal Injection), Desmopressin Acetate Injection (DDAVP Injection), Depoestradiol, DepoProvera 104mg / ml, DepoProvera 150mg / ml, DepoTestosterone, Dexrazoxane for Injection, Intravenous Infusion Only (Totect), Glucose / Electrolytes, Glucose and Sodium Chloride Injection (5% Glucose in 0.9% Sodium Chloride), Glucose, Diazepam Injection (Diazepam Injection), Digoxin Injection (Lanoxin Injection), Dilaudid HP (Hydromorphone Hydrochloride Injection), Dimer Carprol Injection (in oil inval ampoules), Diphenhydramine Injection (Benadryl Injection), Dipyridamole Injection (Dipyridamole Injection), DMOAD, Injectable Docetaxel (Taxotere), Dolasetron Mesylate Injection (Anzemet Injection), Dorivax (Injectable Doripenem), Injectable Doripenem (Drivax), Doxercalciferol Injection (Hectol Injection), Doxil (Doxorubicin Hcl Liposomal Injection), Doxorubicin Hcl Liposomal Injection (Doxil), Duramorph (Morphine Injection), Dysport (Abobotulinum Toxin A Injection), Ecallantide Injection ( Carbitol), EC-Naprosyn (naproxen), edetate calcium disodium injection (versenate calcium disodium), Edex (injectable alprostadil), Engelix, edrophonium injection (Enron), eliglustat tartrate, Eloxatin (oxaliplatin injection), Emend injection (fosaprepitant dimeglumine injection), enalaprilat injection (enalaprilat injection), Enron (edrophonium injection), enoxaparin sodium injection (Lavenox), Eovist (gadoxetate disodium injection), Enbrel (etanercept), enoxaparin, Epicel, epinepherine, Epipen, Epipen Junior, epratuzumab,Erbitux, Ertapenem Injection (Invanz), Erythropoietin, Essential Amino Acid Injection (Nephramin), Estradiol Cypionate, Estradiol Valerate, Etanercept, Exenatide Injection (Byetta), Ebrotra, Fabrazyme (Adalusidase β), Famotidine Injection, FDG (Fludeoxyglucose F18 Injection), Ferahem (Ferumoxytol Injection), Feridex IV (Ferumoxide Injection), Fertinex, Ferumoxide Injection (Feridex IV), Ferumoxytol Injection (Ferahem), Flagyl Injection (Metronidazole Injection), Fluarix, Fludara (Fludarabine Phosphate), Fludeoxyglucose F18 Injection (FDG), Fluorescein Injection (Ak-Fluor), Follitropin AQ Cartridge (Follitropin beta injection), follitropin alfa injection (Gonal-f RFF), follitropin beta injection (Follistim AQ cartridge), Folotin (pralatrexate intravenous solution), fondaparinux, Forteo (teriparatide (rDNA-derived) injection), fostamatinib, fosaprepitant dimeglumine injection (Emend injection), foscarnet sodium injection (Foscavir), Foscavir (foscarnet sodium injection), fosphenytoin sodium injection (Cerebyx), fosproporpol disodium injection (Lucedra), Fragmin, Fuzeon (enfuvirtide), GA101, gadobenat dimeglumine injection (Multihance), gadofosbecet trisodium injection (Ablavar), gadoteridol injection (ProHance), gadoversetamide injection (OptiMARK), gadoxetate disodium injection (Eovist), ganirelix (ganirelix acetate injection), Gardasil, GC1008, GDFD, gemtuzumab ozogamicin ion injection (Mylotarg), Genotropin, gentamicin injection, GENZ-112638, golimumab injection (Simponi injection), Gonal-f RFF (follitropin alfa injection), granisetron hydrochloride (Kytril injection), gentamicin sulfate, glatiramer acetate, Glucagen, glucagon, HAE1, Haldol (haloperidol injection),Havlix, Hector injection (doxercalciferol injection), hedgehog pathway inhibitor, heparin, Herceptin, hG-CSF, Humalog, human growth hormone, Humatrope, HuMax, Humegon, Humira, Humulin, ibandronate sodium injection (Boniva injection), ibuprofen lysine injection (Neoprofen), ibutilide fumarate injection (Corvert), idamycin PFS (idarubicin hydrochloride) Injection), idarubicin hydrochloride injection (idamycin PFS), Ilaris (canakinumab injection), injectable imipenem and cilastatin (Primaxin IV), Imitrex, incobotulinumtoxinA injection (Xeomin), Increx (mecasermin [rDNA-derived] injection), Indocin IV (indomethacin injection), indomethacin injection (Indocin IV), Infanrix, Innohept, insulin, insulin aspart [r, [rDNA-derived] Injection (NovoLog), Insulin glargine [rDNA-derived] Injection (Lantus), Insulin glulisine [rDNA-derived] Injection (Apidra), Interferon α-2b, Recombinant for Injection (Intron A), Intron A (Interferon α-2b, Recombinant for Injection), Invanz (Ertapenem Injection), Invega Sustena (Paliperidone Palmitate Extended-Release Injectable Suspension), Invirase (Saquinavir Mesilate), Lobenguan 1123 Intravenous Injection (AdreView), Iopromide Injection (Ultravist), Ioversol Injection (Optiray Injection), Iprex (Mecasermin Linfabate [rDNA-derived] Injection), Iprivasc, Irinotecan Hydrochloride (Camptosar Injection), Iron Sucrose Injection (Venofer), Istodax (Injection) Romidepsin for injection), Itraconazole injection (Sporanox injection), Jevtana (Cabazitaxel injection), Jonexa, Carbitol (Ecallantide injection), KCL in D5NS (Potassium chloride and sodium chloride injection in 5% dextrose), KCL in D5W, KCL in NS, Kenalog 10 injection (Triamcinolone acetonide injectable suspension), Kepivance (Palifermin), Kepu La injection (levetiracetam), Keratinocyte, KFG, kinase inhibitors, Kineret (anakinra), Kinlytic (urokinase injection), Kinrix, Klonopin (clonazepam), Kytril injection (granisetron hydrochloride), lacosamide tablets and injection (Vinpat), Ringer's lactate, Lanoxin injection (digoxin injection), injectable lansoprazole (Prevacid IV), Lantus , Leucovorin calcium (leucovorin calcium injection), Lente (L), leptin, Levemir, leukinsargramostim, leuprolide acetate, levothyroxine, levetiracetam (Kepra injection), Labenox, levocarnitine injection (Carnitol injection), Rexcan (Regadenoson injection), Lioresal intrathecal (baclofen injection), liraglutide [rDNA] injection (Victoza), Labenox (enoxaparin sodium injection), Lucentis (ranibizumab injection), Lumizyme, Lupron (leuprolide acetate injection), Lucedra (fospropofol disodium injection), Machi,Magnesium sulfate (magnesium sulfate injection), mannitol injection (mannitol IV), Marcaine (bupivacaine hydrochloride and epinephrine injection), Maxipim (cefepime hydrochloride for injection), MDP multi-dose kit of technetium injection (technetium Tc99m medronate injection), mecasermin [rDNA-derived] injection (Inclelex), mecasermin rinfabate [rDNA-derived] injection (Iplex), melphalan hydrochloride injection (Alkeran injection), methotrexate, Menactra, Menopur (menotropin injection) ), Injectable Menotropin (Repronex), Injectable Methohexital Sodium (Brevital Sodium), Methyldoped Hydrochloride Injection, Liquid (Methyldoped Acid Hcl), Methylene Blue (Methylene Blue Injection), Methylprednisolone Acetate Injectable Suspension (Depo-Medrol), MetMab, Metoclopramide Injection (Reglan Injection), Metrodin (Urofollitropin Injection), Metronidazole Injection (Flagyl Injection), Miacalcin, Midazolam (Midazolam Injection), Minpara (Sinakare), Minocin Injection (Minocycline) Injection), Minocycline Injection (Minocin Injection), Mipomersen, Mitoxantrone Injectable Concentrate (Novantrone), Morphine Injection (Duramorph), Morphine Sulfate XR Liposomal Injection (Depodur), Sodium Morphate (Sodium Morphate Injection), Motesanib, Mozobil (Plerixafor Injection), Multihans (Gadobenate Dimeglumine Injection), Multiple Electrolytes and Dextrose Injection, Multiple Electrolytes Injection, Mylotarg (Gemtuzumab Ozogamicin for Injection), Myozyme (Alglucosidase Alfa), Nafcillin Injection (Nafcillin Sodium), Nafcillin Sodium (Nafcillin Injection), Naltrexone XR Injection (Vivitrol), Naprosyn (Naproxen), Neoprofen (Ibuprofen Lysine Injection), Nandrol Decanoate, Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection), NEO-GAA, Neotect (Technetium Tc99m Depreotide Injection), Nephlamin (Essential Amino Acid Injection), Neulasta (Pegfilgrastim), Neupogen (Filgrastim), Novolin, Novolog, Neolicormon,Nutrexin (Trimetrexate Glucuronate Injection), NPH(N), Nexsteron (Amiodarone Hydrochloride Injection), Norditropin (Somatropin Injection), Saline (Sodium Chloride Injection), Novantrone (Mitoxantrone Injection Concentrate), Novolin 70 / 30 Innolet (70% NPH, Human Insulin Isophane Suspension and 30% Regular Human Insulin Injection), Novolog (Insulin Aspart [rDNA-derived] Injection), Nplate (Romiplostim), Nutropin (Somatropin for Injection (rDNA-derived)), Nutropin AQ, Nutropin Depot (Somatropin for Injection (rDNA-derived)), Octreotide Acetate Injection (Sandostatin LAR), Ocrelizumab, Ofatumumab Injection (Arzerra), Olanzapine Sustained-Release Injectable Suspension (Zyprexa Relprevv), Omnitarg, Omnitrope (somatropin [rDNA-derived]) injection), ondansetron hydrochloride injection (Zofran injection), OptiMARK (gadoversetamide injection), Optiray injection (iobersol injection), Orencia, osmitrol injection in Aviva (mannitol injection in Aviva 250 plastic container), osmitrol injection in Viaflex (mannitol injection in Viaflex 250 plastic container), osteoprotegrin, Ovidrel (chorionic gonadotropin alfa injection), oxacillin (oxacillin for injection), oxaliplatin injection (Eloxatin), oxytocin injection (Pitocin), paliperidone palmitate sustained-release injectable suspension (Invegasus Tena), Pamidronate Disodium Injection (Pamidrone Disodium Injection), Intravenous Panitumumab Injection (Vectibix), Papaverine Hydrochloride Injection (Papaverine Injection), Papaverine Injection (Papaverine Hydrochloride Injection), Parathyroid Hormone, Paricalcitol Injectable Flip-Top Vial (Zemplar Injection), PARP Inhibitors, Pedialix, PEG Instron, Pegininterferon, Pegfilgrastim, Penicillin G Benzathine and Penicillin G Procaine, Calcium Pentetate Trisodium Injection (Ca-DTPA), Zinc Pentetate Trisodium Injection (Zn-DTPA), Pepcid Injection (Famotidine Injection),Pergonal, pertuzumab, phentolamine mesylate (phentolamine mesylate for injection), physostigmine salicylate (physostigmine salicylate (injection)), physostigmine salicylate (physostigmine salicylate (injection)), piperacillin and tazobactam injection (Zosyn), Pitocin (oxytocin injection), Plasma-Lite 148 (multiple electrolytes injection), Plasma-Lite 56 and dextrose (multiple electrolytes and glucose injection in a Viaflex 250 plastic container), Plasma-Lite, plerixafor injection (Mozobil), polidocanol injection (Asclera), potassium chloride, pralatrexate solution for intravenous use (Folotyn), pramlintide acetate injection (Symlin), Premarin injection (injectable conjugated estrogens), technetium Tc99 injection sestamibi preparation kit (Cardiolite), Prevacid IV (lansoprazole for injection), Primaxin IV (Imipenem and Cilastatin for injection), Prochimar, Procrit, Progesterone, Prohans (Gadoteridol injection), Prolia (Denosumab injection), Promethazine Hydrochloride Injection (Promethazine Hydrochloride Injection), Propranolol Hydrochloride Injection (Propranolol Hydrochloride Injection), Quinidine Gluconate Injection (Quinidine Injection), Quinidine Injection (Quinidine Gluconate Injection), R-Gene 10 (Arginine Hydrochloride Injection), Ranibizumab Injection (Lucentis), Ranitidine Hydrochloride Injection (Zantac Injection), Raptiva, Reclus (Zoledronic acid injection), Recombivarix HB, Regadenoson Injection (Rexiscan), Reglan Injection (metoclopramide injection), Remicade, Renagel, Renbella (sevelamer carbonate), Repronex (injectable menotropin), Retrovir IV (zidovudine injection), rhApo2L / TRAIL, Ringer's and 5% dextrose injection (Ringer's in dextrose), Ringer's injection (Ringer's injection), Rituxan, rituximab, Rocephin (ceftriaxone), rocuronium bromide injection (Zemron), Roferon-A (interferon alpha-2a), Romazicon (flumazenil), romidepsin for injection (Istodax), Saizen (somatropin injection), Sandostatin LAR (octreotide acetate injection),Sclerostin Ab, Sensipar (Cinacalcet), Sensakyne (Bupivacaine Hydrochloride Injection), Septokyne (Altican Hydrochloride and Epinephrine Injection), Serostim LQ (Somatropin (rDNA-derived) Injection), Simponi Injection (Golimumab Injection), Sodium Acetate (Sodium Acetate Injection), Sodium Bicarbonate (Sodium Bicarbonate 5% Injection), Sodium Lactate (Sodium Lactate Injection in AVIVA), Sodium Phenylactate and and sodium benzoate injection (Ammonul), injectable somatropin (rDNA-derived) (Nutropin), Sporanox injection (itraconazole injection), Stelara injection (ustekinumab), Stemgen, Sufenta (sufentanil citrate injection), sufentanil citrate injection (Sufenta), Smavel, sumatriptan injection (Arsma), Symlin, Symlin Pen, systemic hedgehog antagonist, Symviskwan (Hylan GF 20 single-agent intra-articular injection), Tarceva, Taxotere (docetaxel for injection), technetium Tc99m, injectable telavancin (Vibativ), temsirolimus injection (Toricel), Tenormin IV Injection (atenolol injection), teriparatide (rDNA-derived) injection (Forteo), testosterone cypionate, testosterone enanthate, testosterone propionate, tebutropin (somatropin, rDNA-derived, for injection), tgAAC94, thallium chloride, theophylline, thiotepa (thiotepa injection), thymoglobulin (antithymocyte globulin (rabbit)), thyrogen (thyrotropin alpha for injection), ticarcillin disodium and clavulanate potassium Galaxy (Timentin injection), Taigan injection (trimethobenz Amino acid (injection)), Trianda (bendamustine hydrochloride injection), Trelstar (triptorelin pamoate injection suspension), triamcinolone acetonide, triamcinolone diacetate,Triamcinolone hexacetonide injectable suspension (Aristospan Injection 20 mg), Trilicense (triamcinolone acetonide injectable suspension), trimethobenzamide hydrochloride injection (Tygan Injection), trimetrexate glucuronate injection (Nutrexin), triptorelin pamoate for injectable suspension (Trelstar), Twinject, Trivaris (triamcinolone acetonide injectable suspension), Trisenox (arsenic trioxide injection), Twinrix, Typhoid Vi, Ultravist (iopromide injection), urofollitropin for injection (Metrozine), urokinase injection (Kinriti, ck), ustekinumab (Stelara injection), Ultralente (U), Valium (diazepam), sodium valproate injection (Depacone), valtropin (somatropin injection), vancomycin hydrochloride (vancomycin hydrochloride injection), vancomycin hydrochloride injection (vancomycin hydrochloride), Baprizol (conivaptan hydrochloride injection), VAQTA, Vasovist (gadofosbecet trisodium intravenous injection), Vectibix (intravenous panitumumab injection), Venofer (sucrose Iron Injection), Verteporfin Injection (Visudyne), Vibativ (Telavancin Injection), Victoza (Liraglutide "rDNA" Injection), Vimpat (Lacosamide Tablets and Injection), Vinblastine Sulfate (Vinblastine Sulfate Injection), Vincasar PFS (Vincristine Sulfate Injection), Victoza, Vincristine Sulfate (Vincristine Sulfate Injection), Visudyne (Verteporfin Injection), Vitamin B-12, Vivitrol (Naltrexone XR Injection), Voluven (Hydroxyethyl Starch Injection in Sodium Chloride), Xeloda, Xenical (Orlistat), Xeomin (IncobotulinumtoxinA Injection), Xolair, Zantac Injection (ranitidine hydrochloride injection), Zemplar injection (paricalcitol injectable flip-top vial), Zemlon (rocuronium bromide injection), Zenapax (daclizumab), Zevalin, zidovudine injection (retrovir IV), Zithromax injection (azithromycin), Zn-DTPA (zinc pentetate trisodium injection), Zofran injection (ondansetron hydrochloride injection), Zingo, zoledronic acid for injection (Zometa), zoledronic acid injection (Reclus), Zometa (zoledronic acid for injection), Zosyn (piperacillin and tazobactam injection), Zyprexarelprev (olanzapine extended-release injectable suspension), and combinations thereof.

[0177] Announcement The invention of this application has been described above both generically and with reference to specific embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments without departing from the scope of the present disclosure. Therefore, it is intended that the embodiments cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. (Aspect) (Aspect 1) 1. A stopper for use with an injector device, the stopper having an exterior configured to engage an inner lumen of a barrel of an injector device, the stopper comprising: an elastomeric body; and a barrier coupled to the elastomeric body; Including, the barrier has an inner surface facing the elastomeric body and an outer surface facing away from the elastomeric body, the barrier including a first layer of a first material and a second layer of a second material, the first layer configured to be activatable by an energy source and the second layer configured to be less activatable by an energy source than the first layer; Depending on the situation, The barrier has at least one microfeature formed therein by activating the first layer with an energy source, the at least one microfeature comprising one or both of a microgroove and / or a microrib. (Aspect 2) 2. The stopper of embodiment 1, wherein the energy source comprises at least one of a laser energy source, an RF energy source, a vibrational energy source, and a thermal energy source. (Aspect 3) 3. The stopper of claim 1 or 2, wherein the first layer is located below the second layer. (Aspect 4) The stopper according to any one of embodiments 1 to 3, wherein the barrier has a thickness of 1 μm to 200 μm. (Aspect 5) Aspect 5. The stopper of any one of aspects 1 to 4, wherein the first material and / or the second material comprises a fluoropolymer (eg, polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE)). (Aspect 6) The stopper of any one of embodiments 1-5, wherein the first layer is microporous and defines a first porosity, and the second layer has a lower porosity than the first layer. (Aspect 7) 7. The stopper of any one of aspects 1 to 6, wherein the second layer is characterized by a higher melting temperature than the first layer. (Aspect 8) 8. The stopper of any one of aspects 1 to 7, wherein the second layer is characterized by greater dimensional stability than the first layer. (Aspect 9) the microgrooves have a depth of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and a width of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm; and / or The stopper according to any one of aspects 1 to 8, wherein the microribs have a height of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm, and a width of 0.25 μm to 50 μm, optionally 0.25 μm to 0.5 μm. (Aspect 10) 10. The stopper according to any one of aspects 1 to 9, wherein the microgrooves and / or the microribs extend in a circumferential direction. (Aspect 11) 11. The stopper according to any one of aspects 1 to 10, wherein the microgrooves and / or microribs extend in a spiral direction. (Aspect 12) 12. The stopper of any one of embodiments 1 to 11, wherein the microgroove has a bottom and two sides, and further wherein one of the two sides defines the microrib. (Aspect 13) 13. The stopper of embodiment 12, wherein a material forming the microribs has a higher density than a material forming the bottom of the microgrooves. (Aspect 14) 13. The stopper of embodiment 12, wherein a material forming the microribs has a lower density than a material forming the bottom of the microgrooves. (Aspect 15) 12. The stopper of any one of embodiments 1-11, wherein the first layer comprises a material configured to increase in volume upon activation by an energy source, and further wherein the microribs correspond to portions of the first layer that increase in volume upon activation by the energy source. (Aspect 16) 12. The stopper of any one of embodiments 1 to 11, wherein the first layer comprises a material configured to be removed upon activation by an energy source, and further wherein the microgrooves correspond to portions of the first layer that are removed upon activation by the energy source. (Aspect 17) 17. The stopper of any one of aspects 1 to 16, wherein the barrier is bonded to the elastomeric body by activating the first layer with the energy source. (Aspect 18) Aspect 18. The stopper of any one of aspects 1 to 17, wherein the microgrooves and / or microribs are formed after bonding the barrier to the elastomeric body. (Aspect 19) 19. The stopper of any one of the preceding aspects, wherein the porosity of the portions of the first layer corresponding to the microgrooves and / or microribs is altered after bonding of the barrier to the elastomeric body. (Aspect 20) 20. The stopper of any one of aspects 1 to 19, wherein at least one of the first material of the first layer and the second material of the second layer comprises a thermoplastic material. (Aspect 21) 21. The stopper of any one of aspects 1 to 20, wherein the first material of the first layer comprises a filler configured to increase absorption of optical energy and / or radio frequency energy of the first material. (Aspect 22) 22. The stopper of embodiment 21, wherein the filler comprises at least one of fluorinated ethylene propylene (FEP) and ethylene tetrafluoroethylene (ETFE). (Aspect 23) 23. The stopper according to any one of aspects 1 to 22, wherein the microfeatures are formed on an outer surface of the barrier. (Aspect 24) 24. The stopper according to any one of aspects 1 to 23, wherein the microfeatures are formed on an inner surface of the barrier. (Aspect 25) 25. A method of forming an injector device stopper according to any one of aspects 1 to 24, comprising forming at least one of the microribs and / or microgrooves by activating the first layer with the energy source. (Aspect 26) 1. A stopper for use with an injector device, the stopper having an exterior configured to engage an inner lumen of a barrel of an injector device, the stopper comprising: an elastomeric body; and a multi-zone barrier bonded to said elastomeric body; Including, the multi-zone barrier includes a first zone having first material properties and a second zone having second material properties, the second zone being configured to be activatable by an energy source, and the first zone being configured to be less activatable by the energy source than the second zone; Depending on the situation, The multi-zone barrier has at least one microfeature formed by activating the second zone with the energy source, the at least one microfeature including one or both of a microgroove and / or a microrib. (Aspect 27) 1. A method of manufacturing a stopper for use in an injector device, the stopper having a sealing surface configured to engage a lumen of a barrel of the injector device, the method comprising: activating the first layer of the barrier of the stopper with an energy source to form at least one microfeature; and bonding the barrier to an elastomeric body; Including, The method, wherein the barrier has an inner surface and an outer surface, and the microfeatures include one or both of microgrooves and / or microribs. (Aspect 28) 28. The method of embodiment 27, wherein the barrier comprises a second layer overlying the first layer, and further wherein the first layer is activated through the second layer. (Aspect 29) 29. The method of embodiment 27 or 28, wherein the energy source comprises at least one of a laser energy source, an RF energy source, a vibrational energy source, and a thermal energy source. (Aspect 30) 30. The method of any one of embodiments 27-29, wherein the first layer comprises FEP and the second layer comprises PTFE. (Aspect 31)

[0039] Aspect 31. The method of any one of aspects 27-30, wherein the barrier is bonded to the elastomeric body during formation of the at least one microfeature. (Aspect 32)

[0039] Embodiment 32. The method of any one of embodiments 27-31, wherein forming the at least one microfeature comprises cooling the barrier after activating the first layer. (Aspect 33) 33. The method of any one of embodiments 27-32, further comprising optionally allowing a molten portion of the barrier to reflow and resolidify, thereby simultaneously forming the microgrooves and the microribs. (Aspect 34)

[0039] Aspect 34. The method of any one of aspects 27-33, wherein activating the first layer of the barrier of the stopper with the energy source to form at least one microfeature comprises inducing relative motion between the energy source and the stopper, the motion optionally comprising one or both of linear motion or rotational motion. (Aspect 35)

[0037] Aspect 35. The method of any one of aspects 27-34, wherein the at least one microfeature is formed prior to bonding the barrier to the elastomeric body. (Aspect 36)

[0039] Embodiment 36. The method of any one of embodiments 27 to 35, wherein the at least one microfeature is formed using the barrier in a sheet form. (Aspect 37)

[0033] Aspect 35. The method of any one of aspects 27 to 34, wherein the at least one microfeature is formed after bonding the barrier to the elastomeric body. (Aspect 38) 38. The method of any one of embodiments 25 or 27-37, wherein the microfeatures are formed on an exterior surface of the barrier. (Aspect 39) 27. The stopper of any one of aspects 1 to 24 or 26, wherein the microfeatures are formed on an interior surface of the barrier. (Aspect 40) 1. A method of manufacturing a stopper for use in an injector device, the stopper having a sealing surface configured to engage a lumen of a barrel of an injector device, the method comprising: activating a first layer of a multi-zone barrier of the stopper with an energy source to form at least one microfeature in the multi-zone barrier; and bonding the multi-zone barrier to an elastomeric body; Including, The multi-zone barrier includes a first zone having first material properties and a second zone having second material properties, the second zone being configured to be activatable by an energy source, and the first zone being configured to be less activatable by the energy source than the second zone. (Aspect 41) 1. A stopper for use in an injector device, the stopper having an exterior configured to engage a lumen of a barrel, the stopper comprising: an elastomeric body; and a multi-layer barrier bonded to the elastomeric body; Including, The multilayer barrier includes a first layer and a second layer, the second layer having one or more discontinuous portions, and the first layer extending across the one or more discontinuous portions and the elastomeric body. (Aspect 42) A stopper as described in embodiment 41, wherein the one or more discontinuous portions of the second layer are defined by at least one microgroove, and the first layer provides a continuous barrier between the elastomeric body and the at least one microgroove. (Aspect 43) 42. The stopper of embodiment 41, wherein the first layer is exposed through the second layer and defines at least a portion of an exterior of the stopper. (Aspect 44) 44. The stopper of any one of aspects 41 to 43, wherein the one or more discontinuous portions cause the second layer to have a lower resistance to tearing than the first layer at the one or more discontinuous portions. (Aspect 45) 45. The stopper of any one of embodiments 41 to 44, wherein the first layer is formed from a microporous layer having greater strength than the second layer extending across the one or more discontinuities. (Aspect 46) 46. ​​The stopper of any one of embodiments 41 to 45, wherein the first layer comprises a densified fluoropolymer. (Aspect 47) 47. The stopper of any one of embodiments 41 to 46, wherein the first layer comprises a thermoplastic material. (Aspect 48) 48. The stopper of any one of embodiments 41 to 47, wherein the first layer comprises an elastomeric material. (Aspect 49) Aspect 49. The stopper of any one of aspects 41 to 48, wherein the first layer comprises microribs and / or microgrooves. (Aspect 50) Aspect 50. The stopper of any one of aspects 41 to 49, wherein the discontinuous portions of the second layer comprise microribs and / or microgrooves. (Aspect 51) The stopper of any one of embodiments 41 to 50, wherein the second layer is non-porous. (Aspect 52) 52. The stopper of any one of embodiments 41 to 51, wherein the second layer is polytetrafluoroethylene.

Claims

1. 1. A method of manufacturing a stopper for use in an injector device, the stopper having a sealing surface configured to engage a lumen of a barrel of the injector device, the method comprising: activating the first layer of the barrier of the stopper with an energy source to form at least one microfeature; and bonding the barrier to an elastomeric body; Including, the barrier has an inner surface and an outer surface, and the microfeatures include one or both of microgrooves and / or microribs; The method, wherein the barrier includes a second layer overlying the first layer, and the first layer is activated through the second layer.

2. The method of claim 1 , wherein the energy source comprises at least one of a laser energy source, an RF energy source, a vibrational energy source, and a thermal energy source.

3. The method of any one of claims 1 to 2, wherein the first layer comprises FEP and the second layer comprises PTFE.

4. The method of any one of claims 1 to 3, wherein the barrier is bonded to the elastomeric body during formation of the at least one microfeature.

5. The method of any one of claims 1 to 4, wherein forming the at least one microfeature comprises cooling the barrier after activating the first layer.

6. simultaneously forming the microgrooves and the microribs; or simultaneously forming the microgrooves and the microribs by reflowing and resolidifying the molten portion of the barrier; The method of any one of claims 1 to 5, further comprising:

7. activating the first layer of the barrier of the stopper with the energy source to form at least one microfeature includes inducing relative motion between the energy source and the stopper. or 7. The method of claim 1, wherein activating a first layer of a barrier of the stopper with an energy source to form at least one microfeature comprises inducing relative motion between the energy source and the stopper, the motion comprising one or both of linear motion and rotational motion.

8. The method of any one of claims 1 to 7, wherein the at least one microfeature is formed prior to bonding the barrier to the elastomeric body.

9. The method of any one of claims 1 to 8, wherein the at least one microfeature is formed using the barrier in a sheet form.

10. The method of any one of claims 1 to 7, wherein the at least one microfeature is formed after bonding the barrier to the elastomeric body.

11. The method of any one of claims 1 to 10, wherein the microfeatures are formed on an outer surface of the barrier.

12. The method of any one of claims 1 to 11, wherein the microfeatures are formed on an inner surface of the barrier.

13. 1. A method of manufacturing a stopper for use in an injector device, the stopper having a sealing surface configured to engage a lumen of a barrel of an injector device, the method comprising: activating a first layer of the multi-zone barrier of the stopper with an energy source to form at least one microfeature in the multi-zone barrier; and bonding the multi-zone barrier to an elastomeric body; Including, the multi-zone barrier includes a first zone having first material properties and a second zone having second material properties, the second zone being configured to be activatable by an energy source, and the first zone being configured to be less activatable by the energy source than the second zone; the multi-zone barrier includes a second layer overlying the first layer; the first layer, or both the first layer and the second layer, comprises the second zone; the first layer is configured to be activatable by an energy source and the second layer is configured to be less activatable by an energy source than the first layer; The method wherein the second zone in the first layer is activated through the second layer.

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