Surface modification of injector device component

Abstract

A method for manufacturing an injector device, comprising: placing a stopper of an injector device within a tubular member such that the exterior of the stopper engages with an inner surface of the tubular member; and modifying the exterior of the stopper by causing relative motion between the stopper and the tubular member, the relative motion comprising one or both of rotational motion and vibrational motion.

Description

Technical Field

[0001] Field The various inventive concepts addressed herein relate to injector devices, such as syringes, autoinjectors, and pens, that include a barrel and a stopper slidably received within the barrel, and related methods of manufacturing and using such devices.

Background Art

[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 actuating mechanism for displacing the stopper. The stopper is typically air and liquid impermeable while having low friction slidability. Air impermeability and liquid impermeability are important to eliminate leakage of liquid within the injector device and the entrainment of air between the outer surface of the stopper and the inner wall of the barrel when filling or discharging liquid into the injector device. Low friction slidability is important to facilitate 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 contact the syringe (e.g., prefilled syringes, autoinjectors, or pens containing a pharmaceutical composition).

[0003] Examples of some of the components of injector devices can be found in U.S. Patent Application Publication No. 2021 / 0030970, titled "Medical Injector Device Having a Low Lubricant Hydrophobic Syringe Barrel," by applicant W.L.Gore & Associates, Inc., which describes a medical injector device. The medical injector device includes a barrel and a stopper that provide air and liquid impermeability while being capable of having one or more of a low breakaway force, a low average glide force, and a low glide force variation.

[0004] An example of the components of an injector device can be found in U.S. Patent No. 10,751,473, entitled “Gaskets and Medical Syringes,” by applicant Sumitomo Rubber Industries, Ltd. It describes a gasket used in a medical syringe, comprising a body made of an elastic material and an inert resin film provided on the surface of the body. The gasket has a cylindrical shape and includes an annular rib on its outer circumferential surface, having a sliding portion that maintains sliding contact with the inner circumferential surface of the syringe barrel. The annular rib is axially positioned from the distal end to the rear end of the gasket. The sliding portion of the distal annular rib has a width of 1 to 25% of the axial length of the cylindrical gasket. [Overview of the project]

[0005] Abstract Forming a durable seal can be challenging for stoppers that include a barrier or barrier layer and do not use silicone or other additional lubricating materials (e.g., liquid lubricants) to fill defects in the barrier. These defects may result from wrinkles formed in the barrier by the compression of the stopper during insertion, scratches on the surface of the sealing area occurring during the manufacture or insertion of the stopper, or other defects resulting from the manufacturing and assembly processes of the components. 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, eliminate, or address various defects before the stopper insertion process into the barrel. The various inventive concepts discussed in this description relate to addressing such defects or improving sealing performance during or after the stopper undergoes the relevant insertion process into the barrel.

[0006] In some examples, a method for manufacturing an injector device includes positioning a stopper of the injector device within a tubular member such that the outside of the stopper engages with the inner surface of the tubular member, and modifying the outside of the stopper by causing relative motion between the stopper and the tubular member, the relative motion including either or both rotational motion and / or vibrational motion. The tubular member may be the barrel of the injector device, a vent tube configured to be inserted into the barrel of the injector device and configured to deliver the stopper into the barrel of the injector device, or another tubular member. The outside of the stopper may optionally define ribs, which are locally heated at the ribs by the relative motion between the stopper and the tubular member. In some examples, the relative motion reduces the roughness of the outside of the stopper. The outside of the stopper may contain wrinkles, which can be reduced by the relative motion. The outside of the stopper may have longitudinal and circumferential roughness, and the relative motion can cause a reduction in longitudinal and / or circumferential roughness. Relative motion can transfer material from the outside of the stopper to the inner surface of the tubular member. The outside of the stopper may optionally include a polymer material, and the relative motion induces polymer motion of the polymer material. The stopper may include a barrier formed from a first material and a body formed from a second material, the barrier being bonded to the body. The outside of the stopper may also include a fluoropolymer material. In some examples, the relative motion between the stopper and the tubular member includes a longitudinal component.

[0007] According to some examples, a method for manufacturing an injector device includes: positioning a stopper of the injector device within a vent tube; inserting the vent tube into the barrel of the injector device; delivering the stopper from the vent tube into the barrel of the injector device such that the outside of the stopper engages with the inner surface of the barrel to define a sealing interface between the outside of the stopper and the inner surface of the barrel; and inducing relative motion between the stopper and the barrel to reinforce the sealing interface between the outside of the stopper and the inner surface of the barrel. The relative motion between the stopper and the tubular member may include a rotational component. In some cases, the relative motion between the stopper and the tubular member may include a longitudinal component. The outside of the stopper may include a polymer material, and reinforcing the sealing interface between the outside of the stopper and the inner surface of the barrel includes inducing polymer motion of the polymer material at the sealing interface. Furthermore, as another optional step, after the stopper has been delivered from the vent tube into the barrel of the injector device, the outside of the stopper may form wrinkles at the seal interface, and further strengthening the seal interface between the outside of the stopper and the inner surface of the barrel may include reducing the wrinkles at the seal interface. The stopper may include a body and a barrier bonded to the body, the barrier being formed from a fluoropolymer material, and strengthening the seal interface between the outside of the stopper and the inner surface of the barrel may include causing localized heating at the seal interface. And strengthening the seal interface between the outside of the stopper and the inner surface of the barrel may include transferring material from the outside of the stopper to the inside of the barrel. In various examples, the outside of the stopper may define ribs, and the seal interface may include the ribs of the stopper.

[0008] In yet another example, the injector device includes a stopper having an outer casing and comprising a body and a barrier formed from a different material from the body, wherein the barrier is coupled to the body and the barrier defines at least a portion of the outer casing of the stopper, and a barrel having an inner surface that engages with the outer casing of the stopper to define a seal interface, the inner surface of the barrel containing a deposit material corresponding to the material of the barrier at the seal interface, so that the seal interface is defined by the deposit material and the material of the barrier, and the deposit material has directional orientation. The directional orientation may include a circumferential component. The directional orientation of the deposit material may be defined by rows of PTFE chains aligned in a common direction. The outer casing of the stopper may optionally include at least one of microribs and macroribs at the seal interface, and the barrier may optionally contain a fluoropolymer material. In some examples, the deposit material fills one or more defects on the inner surface of the barrel. The deposit material may optionally be located only at the seal interface. The sealing interface can correspond to one or more circumferential bands on the outside of the stopper that engage with the inner surface of the barrel. The deposited material may also define one or more circumferential bands on the inside of the barrel.

[0009] The examples described herein are merely embodiments and should not be construed as limiting or narrowing the scope of the concepts of the present invention provided elsewhere in this disclosure. While several examples are disclosed, further embodiments will become apparent to those skilled in the art from the following detailed description, which illustrates and explains exemplary examples. Therefore, the drawings and detailed description should be considered illustrative and not restrictive in nature. [Brief explanation of the drawing]

[0010] Brief explanation of the drawing The accompanying drawings are included to provide a further understanding of this disclosure, are incorporated herein and constitute part thereof, illustrate embodiments, and help to explain the principles of this disclosure together with the description.

[0011] [Figure 1]Figure 1 shows an injector device configured as a syringe according to some embodiments.

[0012] [Figure 2] Figure 2 shows an injector device configured as an auto-injector according to some embodiments.

[0013] [Figure 3] Figure 3 shows a stopper of the injector device of Figure 1 or 2 according to some embodiments.

[0014] [Figure 4] Figure 4 shows a stopper of the injector device of Figure 1 or 2 according to some embodiments.

[0015] [Figure 5] Figure 5 shows a part of the stopper of Figure 3 or 4 according to some embodiments.

[0016] [Figure 6-7] Figures 6 and 7 represent various micro-mechanisms in region A of Figure 5 according to some embodiments.

[0017] [Figure 8-9] Figures 8 and 9 represent a tool and method, and the tool can be used for assembling and coupling the stopper according to some embodiments.

[0018] [Figure 10-14] Figures 10 - 14 show some methods of assembling the injector device of Figure 1 or 2 according to some embodiments.

[0019] [Figure 15] Figures 15A and 15B show a system and method for changing a stopper according to some embodiments.

[0020] [Figure 16-19]Figures 16A to 19B show the changes of the stopper for removing defects according to some embodiments.

Mode for Carrying Out the Invention

[0021] Detailed Description Definitions and Terms This disclosure is not intended to be read in a limiting sense. For example, the terms used in this application should be read broadly in the context of the meaning that an expert in the field would ascribe to such terms.

[0022] The use of headings is provided only to facilitate the consideration of the description, and is not intended to differentiate or indicate that the concepts under one heading cannot be applied to the concepts under another heading or are unrelated to the concepts under another heading. In fact, the opposite is intended, and this description is intended to be read and interpreted as a whole, such that the various features and aspects of a particular embodiment are applicable across the various other embodiments described herein and vice versa.

[0023] Regarding the term of inaccuracy, the terms "about" and "approximately" can be used interchangeably to refer to a measured value that includes the stated measured value and any measured value that is reasonably close to the stated measured value. A measured value that is reasonably close to the stated measured value deviates from the stated measured value by a reasonably small amount, as would be understood and readily confirmed by one of ordinary skill in the relevant art. Such deviations can be due to measurement errors, differences in calibration of measurement and / or manufacturing equipment, human error in reading and / or setting of measured values, fine adjustments made to optimize performance and / or structural parameters considering differences in measured values related to other components, specific implementation scenarios, inaccurate adjustment and / or operation of an object by a person or machine, etc. When it is determined that one of ordinary skill in the relevant art cannot readily confirm such values of reasonably small differences, the terms "about" and "approximately" can be understood to mean plus or minus 10% of the stated value.

[0024] As used herein, the terms “activatable by an energy source” and similar terms refer to a change in the state of a material, such as a change in physical and / or chemical state. An example of activation by an energy source is a significant (i.e., clearly apparent) change from a solid (or more solid) state to a liquid (or more liquid) state. Another example of activation by an energy source is a significant (i.e., clearly apparent) change in crosslinking or molecular weight (e.g., by crosslinking or chain breaking) upon exposure to an energy source. For reference, as used herein, “energy source” refers to any of the various types of energy sources, including heat, lasers, radio frequency (RF), microwaves, ultraviolet light, radiation, and ultrasound.

[0025] As used herein, the terms “barrier,” “barrier structure,” etc., refer to a material that blocks or interferes with the interaction between one component (e.g., a stopper body) and another component (e.g., a barrel and / or the contents of the barrel).

[0026] As used herein, the terms “elastic” and “elastomer” refer to material properties understood in reference to stoppers used in injector devices (e.g., FDA-approved applications) relating to the tendency of a material to spontaneously return to or recover its original shape after dimensional deformation (e.g., shrinkage, expansion, distortion, etc.).

[0027] As used herein, the term “injector device” is intended to include any of a variety of devices comprising a stopper that is received in a barrel and an actuation mechanism configured to displace the stopper within the barrel in order to discharge or deliver the contents held in the barrel. Examples of injector devices include syringes, autoinjectors, pens, and the like.

[0028] As used herein, the term “macromechanism” (e.g., “macrorib” or “macrogroove”) is intended to refer to a stopper rib or groove mechanism whose contour is visible to the naked eye, or a stopper mechanism having a height of at least twice the thickness of the stopper barrier.

[0029] As used herein, the term “micromechanism” (e.g., microribs, microgrooves, or microvoids) is intended to refer to a stopper mechanism (which may be a surface mechanism or a subsurface mechanism) whose contour is not visible to the naked eye (however, the general existence of the mechanism itself can be appreciated). For example, a micromechanism includes a microrib or microgroove mechanism of a stopper located on or within a macrorib or macrogroove.

[0030] As used herein, the term “multilayer barrier” refers to a barrier structure having multiple material layers, at least some of which are arranged to overlap each other (parallel arrangement), or, in some examples, one adjacent to the other (series arrangement). The multilayer structure may have material thicknesses or layers with relatively sharp and distinct boundaries, or it may have mixed boundaries or more gradual transition boundaries between them.

[0031] As used herein, the term “multizone barrier” refers to a barrier structure having multiple zones or sections having different material properties. A multizone structure may have zones or sections separated by relatively sharp and clear boundaries, or it may have mixed or loose boundaries. Some examples of multizone barriers include separate layers arranged in parallel or in series, resulting in a multilayer barrier defining a multizone barrier. Other examples include a single layer modified to define multiple zones.

[0032] As used herein, terms such as “oscillate” (e.g., “oscillation”) are intended to mean motion that alternates in direction at a frequency that may be constant or variable.

[0033] 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 the proximal end (e.g., the puncture element end).

[0034] As used herein, terms such as "rotate" (e.g., "rotation") refer to motion in the circumferential direction.

[0035] As used herein, the term “sealing surface” is intended to indicate a characteristic that maintains a liquid-tight seal (for example, during storage and / or use).

[0036] As used herein, the terms “silicone” and “silicone oil” may be used interchangeably herein.

[0037] As used herein, the term “substantially absent” is intended to mean that the identified substance (e.g., silicone, silicone oil, or other lubricant) is not quantifiable or present in trace amounts, or that no amount is intentionally added (e.g., silicone oil is not intentionally added to injector devices such as barrels or stoppers).

[0038] As used herein, the term “vibrate” (e.g., “vibration”) is intended to mean alternating motion having an acceleration that alternates in direction at a frequency that may be constant or variable.

[0039] Description of various embodiments Those skilled in the art will readily understand that various aspects of this disclosure can be realized by any number of methods and apparatus configured to perform the intended functions. It should also be noted that the accompanying drawings referenced herein are not necessarily drawn to a fixed scale and may be exaggerated to illustrate various aspects of this disclosure; in this respect, the drawings should not be construed as limiting.

[0040] This disclosure relates to injector devices (e.g., syringes, autoinjectors, and pens) that include a stopper, barrel, plunger rod or actuation mechanism for displacing the stopper within the barrel, at least partially covered with a fluoropolymer or non-fluoropolymer film, or a fluoropolymer or non-fluoropolymer laminate.

[0041] The various embodiments described herein relate to mechanical modifications of a stopper while it is located within a barrel of an injector device or a tubular member such as a vent tube that is operable to insert the stopper into the barrel of the injector device. The stopper may have a barrier, and may or may not have at least one micromechanism (e.g., formed by the barrier). Such a barrier may consist of multiple layers or may be a multilayer barrier. Certain defects, such as wrinkles, scratches, and fragments, may be present in the assembled form of the stopper and / or may be generated or otherwise present when the stopper is assembled into the barrel of the injector device. To mitigate the effects of such defects and imperfections, mechanical modifications of the stopper may be performed during the manufacturing process (e.g., before or after the stopper is inserted into the barrel). Additionally or alternatively, the mechanical modifications may transfer material from the stopper to the barrel to mitigate the effects of imperfections on the barrel surface and / or help to create a sliding interface containing the same material. For example, a PTFE-to-PTFE (or ePTFE-to-ePTFE interface) formed by a transfer material on the barrel and a barrier material on the stopper can improve sealing and / or sliding performance. Such an interface is thought to reduce the likelihood of leakage based on the surface energy between the two similar materials.

[0042] These various features can then help achieve better and / or more reproducible results in sealing and / or sliding performance. By utilizing these features, various additional or alternative benefits can be realized, including more efficient and / or higher yield production, reduced contamination and / or particle generation, and enhanced sealing.

[0043] Concept of an injector device When in use, the injector device may be used to store (e.g., short-term or long-term) and deliver fluids, which are typically therapeutic agents or other substances delivered to a patient in a medical application. In some embodiments, such an injector device may be pre-filled with the therapeutic agent (e.g., as a pre-filled syringe) prior to the planned use of the injector device for delivering the therapeutic agent to a patient. The injector device may contain, but is not limited to, therapeutic agents for treating eye diseases (e.g., macular degeneration and glaucoma) or diseases such as diabetes. Non-limiting examples of potential therapeutic agents are described below. Advantageously, in various embodiments, the stopper and barrel are silicone-free or silicone oil-free. For example, according to various embodiments, the barrel and stopper of the injector device described herein may be silicone-free and substantially silicone oil-free (or other liquid lubricants). In some examples, the stopper and barrel may be substantially free of other liquid lubricants (excluding, of course, the therapeutic substance in the injector device, which is in liquid form and therefore lubricates itself to at least some extent).

[0044] Figure 1 shows an injector device 10 in the form of a syringe according to several embodiments. As shown, the injector device 10 includes a barrel 20, a puncture element 30, and a stopper 40 that is received within the barrel 20 and operably coupled to an operating mechanism 50 (e.g., a plunger rod shown).

[0045] As shown, the barrel 20 has a wall 118 extending between a proximal end 120 and a distal end 122. The barrel 20 has an inner surface 124 and an outer surface 126, respectively defined by the wall 118 of the barrel 20, the inner surface forming the boundary of the receiving chamber 128 defined by the barrel 20. As shown, the proximal end 120 of the barrel 20 may also include a flange that can be used as a finger stopper or handle to assist the user in pushing or pulling the actuation mechanism 50.

[0046] The puncture element 30 may include a sharply pointed needle cannula or a blunt-ended cannula, such as those used in a "needle-free" system. For ease of explanation, the puncture element 30 is shown as a sharply pointed elongated needle cannula with a sharply pointed distal end. As shown in the illustration, the puncture element 30 is coupled to the distal end 122 of the barrel 20.

[0047] The stopper 40 is configured to be slidably received within the barrel 20 and to seal together with the inner surface 124 of the barrel 20. More specifically, the stopper 40 is configured to be actuated within the barrel 20 by an actuation mechanism 50 to pressurize the contents of the receiving chamber 128 and discharge them from the barrel 20 through the puncture element 30.

[0048] The actuation mechanism 50 has a distal end 152 and a proximal end 154, the distal end 152 being operably coupled to the stopper 40, for example, fastened to the stopper 40, integrally formed with the stopper 40, or otherwise coupled with the stopper 40, so that the actuation mechanism 50 displaces the stopper 40 longitudinally (or in other directions) within the barrel 20.

[0049] Figure 2 shows injector devices 100 in the form of auto-injectors according to several embodiments, in which the barrel 20, stopper 40, and actuation mechanism 50 (also described as an injection member in relation to injector device 100) can be similarly configured and used. The actuation mechanism 50 of injector device 100 may use or demonstrate a variable actuation force applied to the stopper 40. For example, the actuation mechanism 50 may include one or more biasing members (e.g., springs) and other mechanisms to achieve such a function. As will be understood by those skilled in the art, various other components of injector device 100 are substantially similar to those of injector device 10. For the purposes of this description, various features of the stopper 40 described herein are applicable whether they are used in the configuration of injector device 10 or in the configuration of injector device 100. In a broader sense, the concepts described herein with respect to the barrel 20 and stopper 40 can be implemented in any of the various injector device configurations.

[0050] The injector devices 10, 100 may contain material 60 within the receiving chamber 128 of the barrel 20. In some examples, the material 60 is inserted or otherwise placed into the chamber at the manufacturing site, a location away from the treatment site, or where the injector devices 10, 100 are used by the end user (e.g., in a clinical setting). In such cases, the injector devices 10, 100 may be referred to as “pre-filled” (e.g., pre-filled syringe in the example of injector device 10). The material 60 may 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 may be any type of liquid or material that can be dispensed from the syringe, or that the material 60 does not have to be completely present in the receiving chamber, as in an unfilled syringe. In such examples, the injector devices 10, 100 may be filled at or near the treatment site (e.g., also referred to as “loading” the injector device).

[0051] Figures 3 and 4 are plan views or front views of example configurations of the stopper 40. In the configuration shown in Figure 3, the right half of the stopper 40 is shown in a cross-sectional view, while in the configuration shown in Figure 4, the left half of the stopper 40 is shown in a cross-sectional view.

[0052] As shown in the configurations of Figures 3 and 4, the stopper 40 includes a body 240 made of an elastic material and a barrier 242, such as a barrier film, provided on the body 240. The stopper 40 has an outer surface 244, a longitudinal axis X, and a height along the longitudinal axis X. The stopper 40 extends between the front surface 246 and the rear surface 248. As shown, the barrier 242 may extend along the outer surface 244 and / or the portion (including the whole) of the front surface 246. If desired, the barrier 242 may also extend along the portion (including the whole) of the rear surface 248.

[0053] In some embodiments, the body 240 provides the stopper 40 with a desired degree of elastic compliance. For example, the body 240 may be compressed when the stopper 40 is inserted into the barrel 20 so that the stopper 40 actively engages with the barrel 20. Suitable materials for the body 240 will be described further below.

[0054] In various examples, the barrier 242 provided on the body 240 is configured to prevent the movement of material from (or to) the body 240 through the barrier 242, reduce slip and / or static friction between the stopper 40 and the barrel 20, and enhance the seal between the stopper 40 and the barrel 20. Such features are mentioned in an illustrative sense and are not intended to be an exclusive list. The barrier 242 may be a single layer or a multilayer. The barrier 242 may be constructed of multiple layers having properties distinct from each other, and / or the barrier may include multiple layers having similar properties that are fused or otherwise joined to form a more homogeneous structure with more homogeneous properties between the layers. The barrier 242 may include composite materials (e.g., matrix film material and filler) that function as one or more layers of the barrier 242. Suitable materials for the barrier 242 are described further below.

[0055] As shown in the configurations of Figures 3 and 4, the stopper 40 has a short cylindrical shape, and its front surface 246 is defined by a conical end of the stopper 40. As shown, the conical end can protrude from the longitudinal axis X and define an obtuse angle. In an example where the actuation mechanism 50 is coupled to the stopper 40 using a screw fastening structure, the stopper 40 may include an axial recess 250 in its rear surface 248, which has a female thread.

[0056] As shown in the figures, the outer surface 244 of the stopper 40 may define one or more ribs 300, also called macroribs, such as one or more circumferentially extending annular ribs 300, and / or one or more grooves 310, also called macrogrooves 310, such as one or more circumferentially extending annular grooves 310. During operation, one or more of the ribs 300 are configured to slide and engage with the inner surface 124 of the barrel 20 (Figures 1 and 2). The stopper 40 may be configured to achieve a container closure integrity with a high level of gas (e.g., air) and liquid impermeability while maintaining one or more of the following: an acceptable low brake run force, a low mean run force, and low run force variation.

[0057] The ribs 300 can be constructed in any number configuration. For example, only the distal or forward ribs 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., helium leak tests). In some embodiments, multiple ribs 300 may have sealing surfaces. In one or more embodiments, all ribs 300 having sealing surfaces may have the same predetermined outer diameter (e.g., measured from the apex of each rib in an uncompressed stopper 40). In other embodiments, each rib 300 having a sealing surface may have its own predetermined outer diameter. For example, the distal or forward rib may have a predetermined outer diameter, and the proximal or rear rib may have a predetermined outer diameter of about 75% to about 99.9% of the predetermined outer diameter of the distal or forward rib. Without departing from the spirit and scope of this disclosure, other types of rib configurations are conceivable, such as having three ribs having sealing surfaces.

[0058] Figures 3 and 4 show three ribs 300, but any number of ribs (e.g., 1, 2, 4, 10, etc.) is possible. As shown, the ribs 300 include a forward rib 300A having a sealing surface 320A (also called a sliding portion 320A) configured to slide against the inner surface 124 of the barrel 20. As shown in Figure 3, one or more of the ribs 300 may have a somewhat flattened sealing surface (e.g., sealing surface 320A) and a flat profile (e.g., forward rib 300A) having a width of 1% to 25% of the length of the outer surface 244 of the stopper 40. As shown in Figure 4, one or more ribs 300 (e.g., forward rib 300A) may have an outwardly convex shape and a relatively narrow profile of the sealing surface (e.g., sealing surface 320A). As shown in Figures 3 and 4, the ribs 300 also include intermediate ribs 300B and rear ribs 300C. As shown in the diagram, the intermediate rib 300B and the rear rib 300C may have an outwardly convex shape when viewed in cross-section. Each of the intermediate rib 300B and the rear rib 300C has a sealing surface 320B, 320C, respectively, which may be configured to slide against the inner surface 124 of the barrel 20. When one or more ribs 300 have an outwardly convex shape, the corresponding sealing surface may have a relatively small width when measured along the longitudinal axis X of the stopper 40. Depending on the configuration, each of the sealing surfaces 320B, 320C (also called the sliding contact portions 320B, 320C) may have a width greater than 0% of the length of the outer surface 244 of the stopper 40 and up to 15%.

[0059] As shown in Figures 3 and 4, the outer surface 244 of the stopper 40 may have one or more defects 900, such as wrinkles 362 and scratches 364 (examples of defects 900 in the form of fragments can be found and described in relation to Figure 16A). Various defects 900, such as wrinkles 362 and / or scratches 364, may be oriented longitudinally, circumferentially, or both (e.g., helically). The defects 900 may be relatively linear, curved, or both. The defects may be located anywhere on the stopper 40, but may be particularly prominent on the ribs 300 and associated sealing surfaces 320, as well as on or along one or more micro-mechanisms 400, as described later. These defects may be formed at any point in the manufacturing process, including when the stopper 40 is first formed (e.g., when the barrier 242 is attached to the body 240) or during the process of attaching the stopper 40 to the barrel 20. For example, wrinkles 362 may be formed when the stopper is compressed in the diametrical direction. Also, scratches 364 may be formed, for example, when the stopper 40 slides against the barrel 20 or other tubular members during the assembly process.

[0060] As shown in Figures 3 and 4, the outer surface 244 of the stopper 40 may contain one or more defects 900, such as wrinkles 362 and scratches 364 (examples of defects 900 in the form of fragments can be found and described in relation to Figure 16A). Various defects 900, such as wrinkles 362 and / or scratches 364, may be oriented longitudinally, circumferentially, or both (e.g., helically). The defects 900 may be relatively linear, curved, or both. The defects may be located anywhere on the stopper 40, but are particularly present on or along the ribs 300 and associated sealing surfaces 320, or one or more micro-mechanisms 400 as described below. These defects may be formed at any point in the manufacturing process, including when the stopper 40 is first formed (e.g., when the barrier 242 is attached to the body 240) or during the process of installing the stopper 40 in the barrel 20. For example, wrinkles 362 may be formed when the stopper is compressed in the diametrical direction. Scratches 364 may also be formed, for example, when the stopper 40 slides against the barrel 20 or another tubular member used during the assembly process.

[0061] Concept of Micromechanisms As shown in Figures 3 and 4, the stopper 40 includes one or more micro-mechanisms 400 located on one or more ribs 300, such as the sliding contact portion 320A of the forward rib 300A. In some examples, one or more micro-mechanisms 400 include one or more micro-grooves and / or micro-ribs. In some examples, the micro-mechanisms 400 have a width and a depth, where the depth is the amount of protrusion in the case of a micro-rib and the amount of recess in the case of a micro-groove. In some embodiments, one or both of the width and / or 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, but a variety of dimensions are possible. Note that the above "or less" range includes values ​​greater than "0".

[0062] Figure 5 shows an enlarged cross-sectional view of one or more portions of the stopper 40 along the outer surface 244 of the stopper 40 (for example, one of the ribs 300, such as the first rib 300A). Although Figure 5 shows the first rib 300A, the same concepts described in relation to the first rib 300A can be applied to any of the ribs 300. Figures 6 and 7 represent various micromechanisms that may be included in the region "A" shown in Figure 5. Micromechanisms can be formed by the barrier 242 and / or the body 240.

[0063] With the above in mind, Figure 5 shows cross-sectional views of the body 240 of the stopper 40 and the barrier 242 along the barrel 20 according to several embodiments (for example, the position where the outer surface 244 of the stopper 40 engages with the inner surface 124 of the barrel 20). As shown, the barrier 242 may optionally consist of multiple layers or be a multilayer barrier consisting of a first layer 402 of the first material and a second layer 404 of the second material. The barrier 242 can have any of various thicknesses, such as 1 μm to 200 μm.

[0064] As shown in the figure, the first layer 402 may be placed below the second layer 404 if present. Although two layers are generally shown, it should be understood that any number of layers, including a single layer, are possible. As shown in the figure, the first layer 402 has an inner surface 410 facing the body 240 of the stopper 40 and an outer surface 412 facing the second layer 404. On the other hand, the second layer 404 includes an inner surface 420 facing the first layer 402 and an outer surface 422 facing away from the body 240. In various examples, the inner surface 410 of the first layer 402 is bonded to the body 240 (e.g., bonded, glued, fastened or otherwise). Then, the inner surface 420 of the second layer 404 is bonded to the first layer 402 (e.g., bonded, glued, fastened or otherwise). In some embodiments, the first layer 402 may be called the “inner layer” of the barrier 242 and the second layer 404 may be called the “outer layer,” but either the first layer 402 and / or the second layer 404 may be an intermediate or embedding layer located between one or more other layers of the barrier 242.

[0065] In various examples, one of the layers (e.g., the first layer 402) may contain a first material that is more readily activated by the energy source than a second material in another layer (e.g., the second layer 404). In particular, this characteristic of one layer being more readily activated by the energy source than another can be used to preferentially form various micromechanisms 400 at various locations in the barrier 242.

[0066] Various materials are possible for the barrier 242, including those described separately. For example, the barrier (e.g., the first material and / or the second material) may include fluoropolymers (e.g., polytetrafluoroethylene (PTFE) or stretched PTFE (ePTFE)). In some examples, the first layer 402 is microporous and defines the first porosity, 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 may 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 may include a thermoplastic material. If desired, the first material of the first layer 402 may include a filler configured to increase the absorption of light energy and / or high-frequency energy of the first material. Furthermore, the filler may include, for example, at least one of fluorinated ethylene propylene (FEP) and ethylene tetrafluoroethylene (ETFE).

[0067] Figures 6 and 7 show examples of micromechanisms. Figure 6 shows an example of a potential micromechanism 400 in the form of microribs 400A, and Figure 7 shows a potential micromechanism in the form of microgrooves 400B or microvoids 400B. While Figures 6 and 7 show examples of micromechanisms, it should be understood that any number of micromechanisms may exist, or any combination of stoppers 40 may form micromechanisms. Exemplary methods for forming such micromechanisms include directing an energy source to the barrier 242 to form such mechanisms, pre-molding or molding such mechanisms, or various other formation methods.

[0068] Following the formation of various micromechanisms (e.g., microvoids, microgrooves, or microribs) in or near a specific micromechanism 400, the barrier 242, more specifically the first layer 402 and / or the second layer 404, may exhibit physical properties that differ relatively from the surrounding portion of the barrier 242, such as increased compliance in the case of microvoids or microgrooves, decreased compressive resistance in the case of microvoids or microgrooves, increased compressive resistance in the case of microribs, decreased thickness in the case of microvoids or microgrooves, increased thickness in the case of microribs, or decreased tensile strength in the case of microvoids or microgrooves. Such characteristics may be advantageous in reducing the effective sealing surface area of ​​the rib 300 (e.g., optimizing the relationship between increased sealing force and decreased sliding resistance of the macrorib), creating a preferred failure line of the barrier 242 (e.g., pre-selecting a more desirable area to tear or break the barrier to avoid contamination of the contents of the injector device 10 and / or failure of the seal), filling one or more voids or defects between the barrel 20 and the stopper 40, or other advantages in performance and reliability.

[0069] As described above, to avoid ambiguity, various multilayer barrier configurations may include more than two layers (e.g., five layers in total). The first layer 402 and / or the second layer 404 are as described in relation to the previous example and can be located at any position within the layers. Also, various implementations may have more or fewer layers. The first layer 402 may be, for example, the innermost layer or the embedding layer. The second layer 404 may be, for example, the outermost layer or the embedding layer. The first layer 402 and the second layer 404 may be in contact or separated by one or more other layers. Also, a single layer may be consistently present in various embodiments.

[0070] The various micro-mechanisms 400 described above can have any of the following dimensions. In some examples, one or more micro-grooves 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 one or more micro-ribs 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. As will be described later, the micro-grooves and / or micro-ribs can have any of the following configurations, for example, extending in the circumferential, helical, or even longitudinal direction.

[0071] Stopper assembly and coupling mechanism Various methods can be considered for assembling the stopper, particularly various methods for arranging the barrier 242 and the main body 240 together.

[0072] For example, Figure 8 includes the use of tool 3000, which includes molding equipment such as mold 3002 and mandrel 3004. Mold 3002 includes a cavity 3006 defined by an inner wall 3008. The cavity 3006 is shaped and sized to produce a stopper 40 having a desired shape and size. As shown, 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 sheet or relatively planar form.

[0073] The preforms 2000a and 2000b are optionally aligned and pressed (for example, simultaneously) into the cavity 3006 of the mold 3002 as shown. This forms the body 240 from the preform 2000b, and the barrier 242 is simultaneously molded or laminated on top of it from the preform 2000a to form the stopper 40 shown. In the illustrated embodiment, the mandrel 304 is operated to press the preforms 2000a and 2000b into the mold 3002. In some embodiments, the mandrel 3004 may be configured to define a structure within the body 240 during formation (for example, an axial recess 250 on the rear surface 248 with a female thread).

[0074] Injection molding, compression molding, vacuum press molding, co-forming, or other known or conventional processes and equipment can also be used to manufacture the stopper 40 using preforms 2000a and 2000b.

[0075] As another example, Figure 9 shows several embodiments illustrating how a stopper 40 can be assembled by combining a preform 2000c of material for a cylindrical barrier 242 with a preform 2000b of material for a sheet-shaped body 240. As shown in Figure 9, this process involves the use of a tool 3000, which includes molding equipment such as a mold 3002 and a mandrel 3004. The mold 3002 includes a cavity 3006 defined by an inner wall 3008. The cavity 3006 is shaped and sized to manufacture the stopper 40.

[0076] Tool 3000 is configured to manufacture a stopper 40 from a barrier material preform 2000c and a body material defining the preform 2000b. As shown in the figure, the barrier material preform 2000c is placed in the cavity 3006 of the mold 3002. The body material preform 2000b is then applied to the internal void region within the barrier material preform 2000c. As shown in the figure, the mandrel 3004 is operated to push the preform 2000b, which may be in solid or semi-solid form, into the preform 2000c through the open proximal end portion of the preform 2000c. The mandrel 3004 may be configured to define a structure within the preform 2000b (e.g., an axial recess 250 on the rear surface 248 with a female thread).

[0077] Mandrel 3004 may be used, but in other embodiments, the main material is deposited within the preform 2000c of the barrier material by other approaches, such as a fluid form by the application of pressure or other fluid forms. The stopper 40 can be manufactured using the preform 2000c by injection molding, compression molding, vacuum press molding, co-forming or other known or other conventional processes and apparatus.

[0078] Various modifications to those described above can be applied to strengthen or achieve bonding of the components. In some examples, the barrier 242 can be bonded (or further bonded) to the body 240 during the formation of one or more micromechanisms 400, or by activating the first layer 402 with an energy source. The additional use of adhesives, elastomer bonding materials, surface treatments, and other methods is also conceivable.

[0079] The concept of stopper insertion Figures 10-14 are schematic diagrams of a series of steps by which an insertion device 4260 can be used to insert a stopper 40 into a barrel 20 that can be pre-filled or later filled with any of the various contents described herein, such as any therapeutic substance. As shown, the insertion device 4260 includes an insertion pin 4262 and a vent tube 4264. The vent tube 4264 includes an elongated tubular member 4266 having an outer diameter smaller than the inner diameter of the barrel 20 and an inner diameter 4267 that is large enough to accommodate the stopper 40. As best shown in Figure 11, the tubular member 4266 of the vent tube 4264 is inserted into the barrel 20 through its proximal end. In some embodiments, the distal end portion 4268 of the vent tube 4264 is positioned in the barrel 20 of the assembled injector device 10, 100 to correspond to a desired position of the stopper 40. For example, as shown in Figures 11 and 12, when the tubular member 4266 is placed inside the barrel 20, the distal end portion 4268 of the vent tube 4264 is positioned adjacent to the surface of the syringe contents, such as a therapeutic substance.

[0080] The insertion pin 4262 has an outer diameter smaller than the inner diameter of the vent pipe 4264 and a distal end portion 4263. In an embodiment, the inner diameter of the vent pipe 4264 is smaller than the outer diameter of the stopper 40. The proximal end portion 4270 of the vent pipe 4264 has a tapered internal guide surface 4272. Perhaps best shown in Figures 11 and 12, while the vent pipe 4264 is positioned in the barrel 20, the insertion pin 4262 is actuated or moved to engage its distal end portion 4263 with the stopper 40, pushing or otherwise driving or moving the stopper 40 into the proximal end portion 4270 of the vent pipe 4264 and into the distal portion 4268 of the vent pipe 4264 through the tubular member 4266. This movement of the insertion pin 4262 compresses the stopper 40 diametrically (for example, as the stopper 40 moves through the tapered guide surface 4272) and positions it in a desired position within the barrel of the assembled injector devices 10, 100, along the length of the barrel 20 (for example, adjacent to the therapeutic material in the barrel 20).

[0081] As is probably best shown in Figure 13, the vent tube 4264 is withdrawn from the proximal end of the barrel 20 while the relative positions of the insertion pin 4262 and the barrel 20 remain fixed. During the removal of the vent tube 4264, the insertion pin 4262 holds the stopper 40 in the desired position within the barrel 20, and the stopper 40 is pushed out from the distal end portion 4268 of the vent tube 4264. After exiting the vent tube 4264, the stopper 40 expands diametrically to engage with the barrel 20 (for example, the outer surface 244 of the stopper 40 engages with the inner surface 124 of the barrel 20 at one or more sealing interfaces). This positions the stopper 40 in the desired position within the barrel 20. The insertion pin 4262 and the vent tube 4264 can then be withdrawn from the barrel 20, for example, as shown in Figure 14.

[0082] The stopper insertion process described above in relation to Figures 10-14 may result in wrinkles or surface defects, as will be explained later. In particular, irregular shapes and elongated ridges may occur adjacent to the grooves 310 and / or ribs 300. These irregular shapes and elongated structures may be referred to herein as wrinkles or surface defects 900 (Figures 3, 16A, 18A, and 19A) and may have substantial components at the seal interface 702 (Figure 15B) in a direction substantially parallel, perpendicular, or at any angle to the longitudinal axis X after the stopper 40 has been inserted into the barrel 20. Wrinkles or surface defects 900 (Figure 3) may impair or adversely affect the sealing properties of the seal interface. For example, they may function as channels that allow undesirable gases and / or liquids to enter and exit through the stopper 40.

[0083] As described above, modifying the stopper 40 within the barrel 20 can facilitate a reduction in such wrinkles or surface defects 900 (Figure 3) and / or generally strengthen the seal between the stopper 40 and the barrel 20.

[0084] Concepts of change systems and methods Figure 15A is a schematic diagram of a modification system 5230 that can be used to manufacture an injector device 10 including a stopper 14 according to an embodiment. The modification system 5230 can be used to perform processing on the stopper 40 and / or barrel 20 (e.g., before the stopper 40 is inserted into the barrel 20, while the stopper 40 is inserted into the barrel 20, and / or after the stopper 40 is inserted into the barrel 20). Various examples relate to a method for manufacturing injector devices 10, 100, which includes arranging the stopper 40 of the injector device 10, 100 within a tubular member (e.g., barrel 20 or vent tube 4264) such that the outer surface 244 of the stopper 40 engages with the inner surface 5310 (e.g., inner surface 124 of the barrel 20 or inner surface 4267 of the vent tube 4264). The stopper 40 can engage with the inner surface 124 of the barrel 20 in any of many ways, including the use of a vent tube 4264. Furthermore, the stopper 40 can engage with the inner surface 4267 of the vent pipe 4264 in any of many ways, including the method described in relation to Figures 10-14.

[0085] In various examples, modifying the outer surface 244 of the stopper 40 involves creating relative motion between the stopper 40 and the inner surface 5310 of the tubular member 5300, where relative motion includes either or both rotational motion and linear motion. Such rotational motion can be a rotation of any angle, such as 5 degrees or more, 10 degrees or more, 20 degrees or more, 40 degrees or more, 100 degrees or more, 180 degrees or more, 360 degrees or more, greater than 360 degrees, 720 degrees or more, or any value or range between the aforementioned values. Relative motion may be inherently amplitudeful (oscillating) (e.g., vibrational), or continuous or discontinuous. Relative amplitudeful (oscillating) motion may occur at frequencies of 0.5 Hz or more, 1 Hz or more, 5 Hz or more, 10 Hz or more, 20 Hz or more, 50 Hz or more, 100 Hz or more, or any other desired value or range. The modification system 5230 may be configured to provide such relative motion. Relative motion can cause localized heating at the interface between the stopper and the tubular member (e.g., syringe barrel 20 or vent tube), or more generally, generate energy.

[0086] In various embodiments, the modification system 5230, which provides relative motion between the barrel 20 and the stopper 40, enhances the properties of the injector device 10, such as the sealing ability of the stopper 40. These enhanced properties can be produced, for example, by polishing or smoothing the outer surface 244 of the stopper 40 that will eventually contact the inner surface 124 of the barrel 20, and / or by transferring and depositing the material of the outer surface 244 of the stopper onto the inner surface 124 of the barrel 20 (for example, if the tubular member 5300 to which the stopper 40 is modified is the barrel 20). In various embodiments, the processing provided by the modification system 5230 can be performed after the injector device 10 has been filled (for example, with the contents as described above).

[0087] As described above, the modification system 5230 can be used for barrel processing of the stopper 20, and / or the modification system 5230 can be used to perform processing of the stopper 40 while the stopper 40 is inside the vent pipe 4264 when inserting the stopper 40 into the barrel 20, as described in relation to Figures 1-14. In these embodiments, the reduction of the surface roughness of the stopper 40 is provided by the relative motion of the stopper 40 with respect to the vent pipe 4264.

[0088] As shown, the modification system 5230 includes a drive module 5234 and a control module 5236 that can operate to process the outer surface 40 of the stopper 40 and / or the inner surface 5310 of the tubular member 5300. In the illustrated embodiment, the drive module 5234 (which may be an actuation mechanism 50 (Figures 1 and 2)) including a shaft 5237 coupled to the stopper 40 is controlled by the control module 5236 to generate relative motion between the tubular member 5300 and the stopper 40. For example, the drive module 5234 can cause rotation 5240 of the stopper 40 relative to the tubular member 5300 in a direction substantially perpendicular to the longitudinal axis X of the stopper 40 (for example, by rotating the shaft 5237) (Figures 3 and 4). Alternatively or additionally, the drive module 5234 can cause linear motion 5242 of the stopper 40 relative to the tubular member 5300 in a direction parallel to the longitudinal axis X of the stopper 40 (for example, by moving the shaft 5237 relative to the tubular member 5300). The rotation 5240 and / or linear motion 5242 can be in a first direction or a second opposite direction, or reciprocating motion. In various embodiments, the rotation 5240 and / or linear motion 5242 can be reciprocating motion in a first direction and a second opposite direction, and can be periodic.

[0089] Alternatively or additionally, the drive module 5234 may cause rotation 5244 of the tubular member 5300 relative to the stopper 40 by rotating the tubular member 5300 in a direction substantially perpendicular to the longitudinal axis X of the stopper 40. Alternatively or additionally, the drive module 234 may cause linear motion 5246 of the tubular member 5300 relative to the stopper 40 by moving the tubular member 5300 in a direction parallel to the longitudinal axis X of the stopper 40. For example, the changing system 5230 may include an actuation assembly 5238 (e.g., a roller, stage, or other actuated member) fixed to the tubular member 5300 and configured to move the tubular member 5300. The rotation 5244 and / or linear motion 5246 of the tubular member 5300 may be in a first direction or a second opposite direction, or reciprocating / amplifying motion. In various embodiments, the rotation 5244 and / or linear motion 5246 of the barrel 20 is reciprocating motion in a first direction and a second opposite direction and can be periodic. The rotations 5240, 5244 and / or linear motions 5242, 5246 between the tubular member 5300 and the stopper 40 can be oscillating motion.

[0090] In some embodiments, the modification system 5230 can produce relative rotations 5240 and / or 5244 and / or relative linear motions 5242 and / or 5246 of the tubular member 5300 with respect to the stopper 40 in any of various combinations, speeds, directions and / or frequencies. In some embodiments, the relative motions produced by the modification system 5230 have a larger amount of rotation 5240 and / or 5244 than the linear motions 5242 and / or 5246. The distance that the inner surface 244 of the tubular member 5300 moves relative to the outer surface 244 of the stopper 40 during this relative motion can be greater in the circumferential direction of the rotations 5240 and / or 5244 than in the direction parallel to the linear motions 5242 and / or 5246. In some embodiments, the rotations 5240 and / or rotations 5244 are substantially greater than the linear motions 5242 and / or 5246 produced by the modification system 5230 during the processing / modification of the stopper. In some embodiments, the stopper 40 may be rotated relative to the tubular member 5300 while it is moving into the tubular member 5300 along a path parallel to the longitudinal axis X (e.g., without reciprocating motion). (For example, to change the surface of the stopper 40 and / or the inner surface of the vent pipe 4264 and / or barrel 20, the stopper 40 may be rotated while it is longitudinally inserted into the vent pipe 4264 and / or barrel 20.)

[0091] This surface modification, or treatment on the tubular member 5300 (and optionally the vent pipe 4264 and / or barrel 20), can help reduce the roughness of the outer surface 244 of the stopper 40 that ultimately engages with the barrel 20. The roughness may be reduced in the circumferential and / or longitudinal directions. In some examples, the surface roughness is reduced perpendicular to the direction of relative motion (for example, longitudinal surface roughness may be reduced in the case of rotation 5240 and / or 5244, and circumferential surface roughness may be reduced in the case of linear motion 5242 and / or 5246).

[0092] In some embodiments, the processing of the stopper 40 using the change system 5230 is performed at ambient temperature (e.g., without heating or cooling by an external source), but a change temperature (e.g., a high temperature) may be present during the processing of the stopper 40 in the change system 5230. The relative motion between the tubular member 5300 and the stopper 40 provided by the change system 5230 may cause heating of the tubular member 5300 and / or the stopper 40, and such heating may reduce the roughness of the outside 244 of the stopper 40, as described above.

[0093] The control module 5236 is configured to control the operation of system 1000. In various examples, the control module 5236 includes 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 functional units for controlling the operation of system 5230.

[0094] The power supply may be of any type suitable for providing the desired performance and / or lifespan requirements of the control module 5236 and / or the system 5230, and can supply power to the operating components of the control module 5236 and / or other components of the system 5230. In various embodiments, the power supply may include one or more batteries that can be rechargeable (e.g., using an external energy source).

[0095] The control module 5236 may include, or may contain, 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 dedicated processors (such as microprocessors), one or more central processing units (CPUs), software, hardware, firmware, or any combination thereof and / or other components. The control module 5236 may include processing units configured to communicate with memory and execute computer executable instructions stored in memory. Additionally or alternatively, the control module 5236 may be configured to store information (e.g., sensing data) in memory and / or access information (e.g., sensing data) from memory.

[0096] In some embodiments, the memory includes a computer-readable medium in the form of volatile and / or non-volatile memory, which may 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 tapes, magnetic disk storage devices or other magnetic storage devices, and any other medium that can be used for data transmission and / or information storage and is accessible by a computing device, such as quantum state memory. In embodiments, the memory stores computer-executable instructions for causing a processor to implement embodiments of the system components discussed herein and / or perform embodiments of the methods and procedures discussed herein.

[0097] Computer executable instructions may include, for example, computer code, digital signal processing, machine-usable instructions, and program components that can be executed by one or more processors working in conjunction with a computing device. Program components can be programmed using any number of different programming environments, including various languages, development kits, and frameworks. Some or all of the functions conceivable herein may also be implemented in hardware and / or firmware, or may be implemented in hardware and / or firmware instead.

[0098] In some embodiments, the drive module 5234 is controlled by the control module 5236 to generate relative motion between the stopper components (e.g., the body 240 and / or barrier 242) and the tubular member 5300 during surface changes. As referenced, the drive module 5234 can cause rotation of one or more stopper components (e.g., the body 240 and / or barrier 242) and / or the tubular member 5300. The drive module 5234 can also, additionally or alternatively, generate axial motion of the stopper components (e.g., the body 240 and / or barrier 242) and / or the tubular member 5300. The drive module 5234 may include a drive motor, sensors, control circuits, drive shafts, turntables, and / or various additional or alternative components to achieve the desired relative motion.

[0099] The heating generated during processing by the modification system 5230 raises the temperature of the material of the stopper 40 (e.g., on the outside 244) sufficiently to promote polymer motion on the outside 244, reducing the possibility of wrinkles, scratches, fragments or other undesirable surface defects that may contribute to surface roughness, and / or sealing defects at the interface between the stopper 40 and the barrel 20. The temperature rise induced by relative motion can be below the melting temperature, above the melting temperature, or otherwise a desired temperature at which surface defects / roughness are reduced as desired when combined with mechanical engagement / operation by relative motion. In various examples, relative motion between the stopper 40 and the tubular member 5300 results in localized heating of one or more ribs 300.

[0100] While a stopper 40 is commonly shown, the modification may be applied only to the rib 300 or micro-rib 400, rather than to the entire outer 244. In fact, the surface modification may be applied to only one rib 300 or even just one micro-rib 400. The amount or extent of the modification may be influenced by the initial shape of the stopper 40. For example, a rib 300 with a larger interference fit with the barrel 20 will inevitably cause a higher degree of friction and energy. In some examples, a second or third rib 300 may be configured to engage with the barrel 20 in a manner that facilitates the surface modification. Facilitating the modification at one or more intermediate ribs rather than the forward rib can help avoid problems of unwanted particle generation and deposition in the barrel contents.

[0101] The stopper 40 processed within the tubular member 5300 may also attempt to reduce the roughness of the outer surface 244 without generating a substantial amount of undesirable particles / contaminants. Particles formed as part of surface modification or otherwise may aggregate or encapsulate to become part of the deformed or molten material of the stopper 40.

[0102] During in-barrel processing using the modification system 5230, it is also conceivable that surface defects of the barrel 20 can be reduced to improve sealing and / or sliding performance. For example, the relative motion between the barrel 20 and the stopper 40 can induce rubbing or transfer of material from the outer surface 244 of the stopper 40 to the inner surface 124 of the barrel 20. Such material transfer can form a seal line (in the form of friction welding) or simply fill in surface irregularities (e.g., scratches) of the barrel 20 to promote a more reliable seal with the stopper 40. Such material transfer from the stopper 40 to the barrel 20 helps to mitigate the effects of defects on the barrel surface (inner surface 124) and / or helps to generate a configuration of the seal interface 702 that contains the same or similar material. For example, a PTFE-to-PTFE (or ePTFE-to-eTPFE interface) formed by the transfer material on the barrel 20 can have enhanced sealing and / or sliding performance. Such a configuration of the seal interface 702 is thought to be able to reduce the possibility of leakage based on the surface energy between the two similar materials.

[0103] Various aspects of this disclosure relate to methods for manufacturing injector devices 10, 100, which include modifying a stopper 40 by relative motion or motion. In various examples, modifying the stopper 40 includes modifying the outer surface 244 of the stopper 40 by melting a portion of the stopper 40 or by inducing polymer motion, thereby ultimately improving the seal integrity of the stopper 40 to the barrel 20. The seal integrity may be improved by, for example, reducing the surface roughness of the outer surface of the stopper 40, reducing wrinkles on the outer surface 244 of the stopper 40, forming a seal line between the outer surface 244 of the stopper 40 and the inner surface 124 of the barrel 20, and / or reducing one or more leak paths between the stopper 40 and the barrel 20. In some examples, modifying the stopper includes modifying the activatable layer of the stopper 40 by directing energy to the activatable layer through the wall 118 of the barrel 20.

[0104] Figures 16A–19B are schematic diagrams illustrating the potential advantages of such manufacturing techniques at the seal interface 702 corresponding to region "A" of the stopper 40 shown in Figure 5. Figures 16A–18B show potential defects 700 in the form of surface irregularities of the barrel 20 when the inner surface 124 of the barrel 20 is not perfectly smooth. Such defects 700 can be scratches, unevenness, voids or pores, or other mechanisms. In various embodiments after surface modification of the stopper 40 by inducing relative motion between the barrel 20 and the stopper 40, as shown in Figure 16A, the barrier 242 of the stopper 40 may be able to fit more closely to the barrel 20 by accommodating defects 700 (e.g., locations where the stopper 40 engages with the barrel 20, such as the vicinity of macro and / or micromechanisms 400) or by better filling within those defects. Figure 16B is intended to illustrate this concept, showing that the defect 700 is at least partially filled with material from the outside 244 of the stopper 40, specifically from the barrier 242 of the stopper 40.

[0105] As described above, the outer surface 244 of the stopper 40 may include a polymer material (e.g., FEP, ePTFE, PTFE, and / or other polymer materials described herein) that forms a sealing interface 702 with the barrel 20, and modifying the stopper 40 involves inducing polymer motion of the polymer material at the sealing interface 702 through the relative motion of the components. As shown in Figure 16A, before the defect 700 is thus filled or accommodated, a space 710 or potential leak path 710 may exist between the stopper 40 (barrier 242) and the barrel 20. After the surface modification, the space 710 or potential leak path 710 is more effectively sealed or closed at the sealing interface 702. As a result, a relatively firm or stable seal can be obtained at the sealing interface 702 (e.g., near the macro mechanism 300 or micro mechanism 400).

[0106] Furthermore, as shown in Figure 16A, the seal interface 702 between the outer surface 244 of the stopper 40 and the barrel 20 may contain particles 800 (e.g., fragments) introduced into the seal interface 702. Such particles may include broken or loosened parts of the stopper 40 or barrel 20, or other foreign matter, during manufacturing. As shown in Figure 16B, during in-barrel processing, such particles may reflow or aggregate within the seal interface 702. Clearly, a reduction in such particles is desirable, especially in pharmaceutical applications where contamination of the barrel contents is particularly undesirable.

[0107] Furthermore, as shown in Figure 16A, and as described above with respect to Figures 3 and 4, the surface of the stopper 40, and in particular the barrier 242, may contain one or more wrinkles or surface defects 900. Such surface defects 900 may be generated during manufacturing, such as when inserting the stopper 40 into the barrel 20. Modifying the syringe stopper 40 by inducing relative motion between the stopper and the tubular member 5300 (for example, the barrel 20 as shown in Figures 16A and 16B) results in polymer movement of the material of the barrier 242, thereby smoothing out surface defects or wrinkles. This, in turn, can help to better fit the outer surface 244 of the stopper 40 with the inner surface 124 of the barrel 20 (either after the stopper 40 is assembled into the barrel 20 or after the stopper 40 is assembled into the barrel 20). This, in turn, can be said to reduce the roughness of the outer surface 244 of the stopper 40. As mentioned above, surface modification can be applied to the stopper in a circumferential pattern (e.g., by continuous, amplitude, or other relative rotation) to help improve seal integrity.

[0108] Figures 17A and 17B show similar effects, where energy (e.g., frictional energy) is used to reflow or fluidize the surface of the barrier 242 to fill defects (e.g., scratches or grooves) on the inner surface 124 of the barrel 20. As shown in Figure 17A, a space or potential leak path 710 exists between the barrel 20 and the stopper 40. By inducing relative motion and mobilizing the surface of the barrier 242, the potential leak path 710 is filled, and the overall seal integrity is enhanced. Then, as in Figures 16A and 16B, the relative motion can be applied in a desired pattern (e.g., circumferential and / or longitudinal) to produce the desired effect.

[0109] Figures 18A and 18B illustrate the application of energy to the stopper 40 to cause surface modification of the stopper 40, similar to the principle shown in Figures 16A-17B. Figures 18A and 18B are cross-sectional views of the injector device 10. Figures 18A and 18B can represent cross-sectional views of the injector device 10 including, for example, the region "A" designated in Figure 5 at the seal interface 702 between the stopper 40 and the barrel 20. Figure 18A is a longitudinal view of defects 700 in the form of surface irregularities (e.g., scratches) around the inner surface 124 of the barrel 20. Wrinkles or surface defects 900 on the outer surface 244 around the stopper 40 are also shown.

[0110] Figure 18B shows the expected effect on the seal interface 702 after surface modification. As shown, the induced polymer movement of the stopper 40 (e.g., barrier 242) fills in defects 700 in the barrel 20, smooths out wrinkles or surface defects in the stopper 40, strengthens the seal interface 702, and, for example, can create a circumferential seal line corresponding to the seal interface 702.

[0111] Considering the above, various methods for manufacturing the injector devices 10, 100 include in-barrel processing of the stopper 40. Exemplary methods may include placing the stopper 40 in a vent tube 4264, inserting the vent tube 4264 into the barrel 20, delivering the stopper 40 from the vent tube 4264 into the barrel 20 such that the outer 244 engages with the inner surface 124 of the barrel 20 to define a seal interface 702 between the outer 244 of the stopper 40 and the inner surface 124 of the barrel 20, and inducing relative motion between the stopper 40 and the barrel 20 to reinforce the seal interface 702 between the outer 244 of the stopper 40 and the inner surface 124 of the barrel 20. As discussed, the relative motion may include a rotational component, a longitudinal component, or a combination thereof. As described above, after the stopper 40 is delivered from the vent pipe 4264 into the barrel 20, the outer surface 244 of the stopper 40 includes wrinkle formation at the seal interface 702, and reinforcing the seal interface between the outer surface 244 of the stopper 40 and the inner surface 124 of the barrel 20 includes reducing wrinkle formation at the seal interface 702. Reinforcing the seal interface 702 between the outer surface 244 of the stopper 40 and the inner surface 124 of the barrel 20 includes transferring material from the outer surface 244 of the stopper 40 to the inner surface 124 of the barrel 20. One or more ribs 300 can define the seal interface 702.

[0112] As previously mentioned, the transfer of material from the stopper 40 to the barrel 20 is carried out to help mitigate the effects of imperfections on the barrel surface (inner surface 124) and / or to create a configuration of a seal interface 702, where the seal interface 702 contains the same or similar material. For example, a PTFE-to-PTFE (or ePTFE-to-eTPFE interface) formed by the transfer material on the barrel 20 and the barrier material 242 on the stopper 40 can have enhanced sealing and / or sliding performance. Such a configuration of the seal interface 702 is thought to reduce the likelihood of leakage based on the surface energy between the two similar materials.

[0113] U.S. Patent No. 5,772,755 by applicant WL Gore & Associates, Inc. provides evidence of the feasibility of this transfer mechanism between barrier 242 and barrel 20 (e.g., made of borosilicate glass). For example, the patent describes a coating of a glass plate for producing oriented PTFE. Specifically, a glass plate was placed on a platform and heated to a temperature of 200°C by radiant heat. A PTFE tape was produced by lubricating (paste) extruding solidified dispersion PTFE, evaporating the lubricant, and stretching the extruded tape in a 2:1 ratio to make the tape conformable. This tape was wrapped around a heatable bar about 14 inches long. The wrapped bar was then heated to about 300°C and then dragged on a glass substrate with an adjustable force. Multiple passes were performed to ensure complete coverage of the glass surface. By dragging the PTFE bar, the PTFE was deposited on the glass surface as aligned rows of PTFE chains.

[0114] Similar to the mechanism described above, the relative motion between the barrier 242 and the barrel 20 may result in some heating and the transfer of a material (e.g., PTFE or ePTFE) having an orientation corresponding to the direction of the relative motion (e.g., circumferential, longitudinal, or a combination thereof, depending on the specific implementation).

[0115] Therefore, in various examples, the injector devices 10, 100 include a barrel and a stopper defining a seal interface, the barrel having a deposited material corresponding to the barrier material, and the deposited material having directional orientation. The directional orientation of the material can be defined, for example, by rows of PTFE chains aligned in a common direction. The common direction can be circumferential, longitudinal, or a combination thereof. Figures 19A and 19B show a similar principle to Figures 18 and 18, but relate to a more general tubular member 5300, which may be a vent tube 4264 or other tubular member. As previously stated, the outer surface 244 of the stopper 40 may include a polymer material (e.g., FEP, ePTFE, PTFE, and / or other polymer materials described herein). Modifying the stopper 40 involves inducing polymer motion of the polymer material at the interface between the stopper 40 and the tubular member 5300. The surface of the stopper 40, in particular the barrier 242, is thought to include one or more wrinkles or surface defects 900. Here again, such surface defects 900 may be generated during manufacturing or by other means. Modifying the syringe stopper 40 by inducing relative motion between the stopper and the tubular member 5300 results in polymer motion of the barrier material 242, thereby smoothing out surface defects or wrinkles. This, in turn, can help to better fit the outer surface 244 of the stopper 40 with the inner surface 124 of the barrel 20 (either after the stopper 40 is assembled to the barrel 20 or after the stopper 40 is assembled to the barrel 20). This, in turn, can result in a reduction in the roughness of the outer surface 244 of the stopper 40. As previously mentioned, surface modifications can be applied to the stopper in a circumferential pattern (e.g., by continuous, amplitude, or other relative rotation) and can help to enhance the seal integrity.

[0116] Exemplary material set The barrel 20 may be formed from substantially rigid or hard materials such as glass materials (e.g., borosilicate glass), ceramic materials, one or more polymer materials (e.g., polypropylene, polyethylene and their copolymers), metallic materials, or plastic materials (e.g., cyclic olefin polymers (COC) and cyclic olefin copolymers (COP)) and combinations thereof. It should be understood that barrels formed from materials that are not inherently hydrophobic (e.g., glass barrels) may be coated or otherwise treated to impart hydrophobicity. In some embodiments, the barrel 20 has a hydrophobic inner wall characterized by the absence of lubricants such as silicone or silicone oil, though not limited to these embodiments. As used herein, the term “hydrophobic inner wall” refers to the inner surface of a barrel that is free from 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 is indicated by a contact angle of deionized water with a flat surface of the material that exceeds 90°, indicating that the surface is hydrophobic. In some embodiments, the water contact angle is approximately 90° to approximately 180°, or approximately 96° to approximately 180°, approximately 96° to approximately 130°, or approximately 96° to approximately 120°.

[0117] 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 may 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, fluoroelastomers, thermoplastic elastomers (TPEs), thermoplastic vulcanized rubber (TPVs), materials sold under the trade name VITON®, and combinations and blends thereof. In some embodiments, the body 240 may have an initial modulus of elasticity (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 of elasticity is about 3.5 MPa, but various values ​​are possible.

[0118] As described above, a portion of the barrier 242 (e.g., a layer or zone) may 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 lasers or other optical energy sources, the reactivity or activation capability can be adjusted by changing the thickness of the material, pigment formation, density / open space / air content, chemical / material composition, etc. In the case of radio frequency (RF), electrical, and electromagnetic energy sources, the barrier 242 may be adjusted to include pigments or other fillers such as metals (e.g., iron, platinum, etc.) that are more reactive to such energies. In the case of microwave energy sources, metals, water, or other materials may be implemented. In the case of ultraviolet (UV) energy, a crosslinking agent (acrylate that crosslinks to increase density / rigidity) or other materials that absorb UV energy may be incorporated.

[0119] Examples of materials suitable for one or more layers of the stopper barrier 242 include ultra-high molecular weight polyethylene and fluoropolymer films. The barrier 242 may include fluoropolymer films such as polytetrafluoroethylene (PTFE) films or densified stretched polytetrafluoroethylene (ePTFE) films. Films and film composites containing PTFE or ePTFE can help provide a thin, strong barrier layer against leachates and extracts present in the underlying elastomer that may contaminate the therapeutic substance in the barrel.

[0120] Some specific examples of suitable materials for Barrier 242 include, but are not limited to, (1) PTFE (polytetrafluoroethylene) homopolymer films manufactured by the skiving method (e.g., VALFLON (trade name) available from Nippon Valqua Industries Ltd.), (2) modified PTFE (polymer of tetrafluoroethylene monomer and several percent of perfluoroalkoxide monomer) films manufactured by the skiving method (e.g., NEW VALFLON (trade name) available from Nippon Valqua Industries Ltd.), and (3) ultra-high molecular weight polyethylene films manufactured by the skiving method (e.g., NEW LIGHT NL-W (trade name) available from Succine).

[0121] As shown, the barrier 242 may be a composite material or a laminate material, or it may include a multi-component (e.g., multilayer) barrier. Other suitable fluoropolymers for use in or as part of the 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 polyethylene, polypropylene, parylene C and parylene N may also be used, or may be used instead, to form the barrier 242, but are not limited to.

[0122] Densified ePTFE films for Barrier 242 may be prepared by the methods described in U.S. Patent No. 7,521,010 by Kennedy et al., U.S. Patent No. 6,030,694 by Dolan et al., U.S. Patent No. 5,792,525 by Fuhr et al., or U.S. Patent No. 5,374,473 by Knox et al. Stretched PTFE copolymers, such as those described in U.S. Patent No. 5,708,044 by Branca, U.S. Patent No. 6,541,589 by Baillie, U.S. Patent No. 7,531,611 by Sabol et al., U.S. Patent No. 8,637,144 by Ford, and U.S. Patent No. 9,139,669 by Xu et al., can also be used for Barrier 242, especially if they are densified.

[0123] In one or more embodiments, the barrier 242 may comprise or be formed from one or more materials, including ultra-high molecular weight polyethylene as taught in Sbriglia's U.S. Patent No. 9,926,416, polyparaxylylene as taught in Sbriglia's U.S. Patent Application Publication No. 2016 / 0032069, polylactic acid as taught in Sbriglia et al.'s U.S. Patent No. 9,732,184, and / or VDF-co-(TFE or TrFE) polymer materials as taught in Sbriglia et al.'s U.S. Patent No. 9,441,088.

[0124] Barrier 242 may also include an expandable polymer material comprising a functional tetrafluoroethylene (TFE) copolymer material having a microstructure characterized by nodes interconnected by fibrils, wherein the functional TFE copolymer material includes functional copolymers of TFE and PSVE (perfluorosulfonyl vinyl ether), or functional copolymers of TFE and another suitable functional monomer, such as, but not limited to, vinylidene fluoride (VDF), vinyl acetate, or vinyl alcohol. Functional TFE copolymer materials can be prepared, for example, according to the methods described in U.S. Patent No. 9,139,669 or U.S. Patent No. 8,658,707 by Xu et al.

[0125] In some embodiments, the barrier 242 may be formed from a composite fluoropolymer or non-fluoropolymer material having a barrier layer and a binder layer, as described in Gunzel's U.S. Patent Application Publication No. 2016 / 0022918. Note that, as used herein, the term “binder layer” may include fluoropolymer materials and / or non-fluoropolymer materials. The binder layer may include or be formed from stretched polytetrafluoroethylene or other porous expanded fluoropolymers (e.g., ePTFE, as taught in Baille's U.S. Patent No. 6,541,589). Alternatively, the binder layer may be formed from or include non-fluoropolymer materials. Non-exclusive examples of non-fluoropolymer materials suitable for use in or as a binding layer include non-fluoropolymer films, non-fluoropolymer microporous films, nonwoven materials (e.g., spunbond, meltblown fiber materials, electrospun nanofibers), polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarylsulfones, polyetheretherketones (PEEK), polyethylene, polypropylene, and polyimide.

[0126] In some embodiments, the barrier 242 can be fabricated by forming a thin densified composite comprising a porous ePTFE layer and a thermoplastic barrier layer. In this embodiment, thermoplastics having a surface with a low coefficient of friction are preferred. Therefore, fluoropolymer thermoplastics such as fluorinated ethylene propylene (FEP), perfluoroalkoxy (PFA), tetrafluoroethylene, hexafluoropropylene, and polyvinylidene fluoride (THV) are applicable. The barrier according to this embodiment can be an FEP / ePTFE laminate obtained according to the process taught in Bacino's WO94 / 13469. The barrier can be formed at a process temperature exceeding the softening temperature of the FEP film in the female cavity mold, or even exceeding the melting temperature.

[0127] In some embodiments, the barrier 242 may include a composite material of a densified ePTFE film and a thin layer of porous ePTFE bonded to the barrier layer film. The densified ePTFE film can be obtained as described in U.S. Patent No. 7,521,010 by Kennedy et al. The ePTFE / densified ePTFE composite material can be combined in the manner described in U.S. Patent No. 6,030,694 by Dolan et al. In this embodiment, the composite material includes a layer of densified ePTFE film and a porous ePTFE layer.

[0128] In some embodiments, the barrier 242 comprises a composite material having at least three layers, namely a densified expanded fluoropolymer layer, a barrier melt fluoropolymer layer, and a porous layer. The densified expanded fluoropolymer layer may contain or be formed from densified ePTFE. The barrier melt fluoropolymer layer may include fluoropolymers such as densified expanded fluoropolymers, polytetrafluoroethylene (PTFE), stretched polytetrafluoroethylene (ePTFE), densified stretched 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 used in the barrier melt layer include polyethylene and polypropylene. The porous layer may contain or be formed from ePTFE or other porous expanded fluoropolymers. A laminate layer having a densified expanded fluoropolymer layer, a barrier melt fluoropolymer layer, and a porous layer can be constructed by coating or depositing the densified expanded fluoropolymer onto the porous layer to produce a composite material. In one non-limiting embodiment, the laminate layer is formed from a densified fluoropolymer (e.g., densified ePTFE), a thermoplastic adhesive (e.g., FEP), and a porous fluoropolymer (e.g., ePTFE).

[0129] It should be understood that the stopper 40 can have various degrees of penetration from the material of the body 240 to the material of the barrier 242, or vice versa, including those described in U.S. Patent No. 8,722,178 by Ashmead et al., U.S. Patent No. 9,597,458 by Ashmead et al., and U.S. Patent Publication No. 2016 / 0022918 by Gunzel. It should also be understood that there are many variations of the processes described herein that can be used to form the stopper 40 without departing from the scope and / or spirit of the invention.

[0130] Examples of therapeutic substances The syringes, tip caps, and other embodiments of this disclosure, without limitation, include drugs and biologics such as coagulation factors, cytokines, epigenetic protein families, growth factors, hormones, peptides, signaling molecules, and their variants, and can be used in combination with a variety of therapeutic compounds, including amino acids, vaccines, and / or combinations thereof. Therapeutic compounds further include antibodies, antisenses, RNA interference against the biologics and their target receptors, and their variants. Additional therapeutic compounds include gene therapies, primary stem cells, and embryonic stem cells. Therapeutic compounds include antibodies, antisenses, 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 specified herein used in this disclosure, and two or more therapeutic compounds enumerated in this application, are also considered to be within the scope of this disclosure.

[0131] Examples of coagulation factors, though not limited to them, include fibrinogen, prothrombin, factor I, factor V, factor X, factor VII, factor VIII, factor XI, factor XIII, protein C, platelets, thromboplastin, and cocoagulation factors VIIa.

[0132] Examples of cytokines, though not limited to them, include lymphokines, interleukins, chemokines, monokines, interferons, and colony-stimulating factors.

[0133] Examples of epigenetic protein families, though not limited to them, include: ATPase family AAA domain-containing protein 2 (ATAD2A), ATPase family-AAA domain-containing 2B (ATAD2B), ATPase family-AAA domain-containing-2B (ATAD2B), bromodomain-1A (BAZ1A), bromodomain-1B (BAZ1B), bromodomain-2A (BAZ2A), bromodomain-2A (BAZ2A), bromodomain-2B (BAZ2B), bromodomain-containing protein 1 (BRD1), and 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 isoforms 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 1st bromodomain (BRDT), bromodomain-containing testis-specific 1st and 2nd bromodomains (BRDT), bromodomain testis-specific protein isoform b-bromodomain 2 (BRDT(2)), bromodomain and PHD finger-containing-1 (BRPF1),Bromodomain and PHD finger-3 (BRPF3), Bromodomain and PHD finger-3 (BRPF3), Bromodomain and WD repeat-2nd 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 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), polybromo 1 - first bromo domain (PB1(1)), polybromo 1- Second bromodomain (PB1(2)), polybromo-1-bromodomain 2 (PBRM1(2)), polybromo-1-bromodomain 5 (PBRM1(5)), histone acetyltransferase KAT2B (PCAF), pH-interacting protein-first bromodomain (PHIP(1)), pH-interacting protein-second bromodomain (PHIP(2)), protein kinase C-binding protein 1 (PRKCBP1), protein arginine N-methyltransfer Lase 3 (PRMT3), SWI / SNF-related - matrix-related - actin-dependent regulator of chromatin - subfamily a - member 2 (SMARCA2), SWI / SNF-related - matrix-related - actin-dependent regulator of chromatin - subfamily a - member 4 (SMARCA4), nuclear protein - SP110 (SP110), nuclear protein - SP140 (SP140), transcription initiation factor TFIID subunit 1 (TAF1(1-2)), TAF1 RNA polymerase II - TATA box-binding protein (TBP) related factor - 250kDa - bromodomain 2 (TAF1(2)), transcription initiation factor TFIID subunit 1-like - first bromodomain (TAF1L(1)), transcription initiation factor TFIID subunit 1-like - second bromodomain (TAF1L(2)),Examples 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)).

[0134] Examples of growth factors, though not limited to them, include 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 protein (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), hepatocellular carcinoma-derived growth factor (HDGF), and insulin-like growth factor.

[0135] Examples of hormones, though not limited to them, include amino acid-derived hormones (such as melatonin and thyroxine), thyroid-stimulating hormone-releasing hormone, vasopressin, insulin, growth hormone, glycoprotein hormone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, eicosanoids, arachidonic acid, lipoxin, prostaglandins, steroids, estrogen, testosterone, cortisol, and progestogens.

[0136] Examples of proteins, peptides, and signaling molecules include, but are not limited to, ataxia telangiectasia variant, oncoprotein p53, checkpoint kinase 2, breast cancer-sensitive proteins, double-strand break repair proteins, DNA repair protein RAD50, nibrin, p53-binding proteins, DNA damage checkpoint protein mediators, H2A histone family member X, microcephalin, C-terminal binding protein 1, chromosome structure maintenance protein 1A, cell division cycle 25 homolog A (CDC25A), forkheadbox O3, and κ in B cell inhibitors. Examples include photopolypeptide gene enhancers: nuclear factor alpha (NFKBIA), nuclear factor (erythrocyte-derived 2)-like 2 (NFE2L2), natriuretic peptide receptor A (NPR1), tumor necrosis factor receptor superfamily member 11a (TNFRSF11A), v-rel reticuloendotheliopathy virus oncogene homolog A (avian) (RELA), sterol regulatory element binding transcription factor 2 (SREBF2), CREB regulatory transcriptional coactivator 1 (CRTC1), CREB regulatory transcriptional coactivator 2 (CRTC2), X-box binding protein 1 (XBP1), and catenin beta 1 (cadherin-related protein or CTNNB1).

[0137] Examples of G protein-coupled receptors (GPCRs), though not limited to them, include the adenosine receptor family, adrenergic receptor family, angiotensin II receptor, apelin receptor, vasopressin receptor family, brain-specific angiogenesis inhibitor family, bradykinin receptor family, bombesin receptor family, complement 3a receptor 1, complement 5a receptor 1, calcitonin receptor family, calcitonin receptor-like family, calcium-sensitive receptors, cholecystokinin A receptor (CCK1), cholecystokinin B receptor (CCK2), chemokine (CC motif) receptor family, sphingosine 1-phosphate receptor family, succinate receptor, and 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 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 suppressor polypeptide receptor (GIP), glucagon-like peptide receptor family, gonadotropin-releasing hormone receptor (GnRH), pyroglutamylated RF amide 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, horiogonadotropin receptor (LH), leukotriene B4 receptor (BLT1), adenylyl cyclase-activated 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 prenoceptor 12 (mP2Y12), P2Y prenoceptor 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, 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), oxoeicosanoidsExamples include (OXE) receptor 1 (OXE), oxoglutaric acid (α-ketoglutaric acid) receptor 1 (OXGR1), purinergic receptor family, pyrimidineergic receptor family, prolactin-releasing hormone receptor (PRRP), prokinethicin receptor family, platelet-activating receptor (PAF), prostaglandin F receptor family, prostaglandin 12 (prostacyclin) receptor family, parathyroid hormone receptor family, muscarinic acetylcholine receptor (rM4, etc.), prostanoid DP2 receptor (rGPR44), prokinethicin receptor family, relaxin family peptide receptor family, secretin receptor (secretin), Frizzled class receptor (Smoothened), trace amine-related receptor family, tachykinin family, thromboxane A2 receptor (TP), thyroid-stimulating hormone-releasing hormone receptor (TRH1), and thyroid-stimulating hormone receptor (TSH).

[0138] Examples of nuclear hormone receptors, though not limited to them, include 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 α) (NR1H3), nuclear receptor subfamily 1-group H-member 2 (liver X receptor β) (NR1H2), nuclear receptor subfamily 1-group H-member 2 (liver X receptor β) (NR1H2), and nuclear receptor subfamily 3-group C-member 2 (mineralicorticoid receptor). Examples include (NR3C2), peroxisome proliferator-activated receptor α (PPARA), peroxisome proliferator-activated receptor γ (PPARG), peroxisome proliferator-activated receptor δ (PPARD), progesterone receptor α (PGR), progesterone receptor β (PGR), retinoic acid receptor α (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 receptors, liver X receptor, farnesoid X receptor, vitamin D receptor, pregnane X receptor, constitutive androstan receptor, hepatocyte nuclear factor 4, estrogen receptor, estrogen-related receptor, glucocorthioate receptor, and nerve growth factor-inducible B, and germ cell nuclear factor.

[0139] Examples of membrane transport proteins, though not limited to them, include 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, Citrine, STLN2, aralar2, TPC, MUP1, MCPHA, CACT, GC1, PHC, DTD, CLD, DRA, PDS, Prestin, TAT1, FATP4, ENT3, ZnT2, ZnT10, AT1, NPT2A, N Examples include 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.

[0140] Examples of structural proteins, though not limited to them, include tubulin, heat shock proteins, microtubule stabilizing proteins, tumor protein 18, stasmin, the kinesin-8 and kinesin-14 families, Kip3, and Kif18A.

[0141] Examples of proteases, though not limited to them, include the ADAM (disintegrin and metalloprotease) family.

[0142] Examples of protein kinases, though not limited to them, include AP2-related kinases, human ABL oncogene 1 non-receptor tyrosine protein kinase family, c-abl oncogene 1 receptor tyrosine kinase family, v-abl Abelson mouse leukemia virus 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 mouse thymoma virus 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 mouse sarcoma virus 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 virus 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), bispecific tyrosine-(Y)-phosphorylation-regulated kinase family, epidermal growth factor receptor family, eukaryotic translation initiation factor 2-α kinase 1 (EIF2AK1), EPH receptor family, ephrin type A receptor family, ephrin type B receptor family, v-erb-b2 erythroblastic leukemia virus oncogene homologue Millie, 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-related kinase (GAK) Eukaryotic translation initiation factor 2α kinase, growth hormone receptor, G protein-coupled receptor kinase 1 (GRK1), G protein-coupled receptor kinase family, glycogen synthase kinase family, germ cell-related 2 (HASPIN) (HASPIN), hematopoietic cell kinase (HCK), homeodomain-interacting protein kinase family, mitogen-activated protein kinase kinase kinase kinase family, hormone upregulate Neu-related kinase (HUNK), intestinal (MAK-like) kinase (ICK), insulin-like growth factor 1 receptor (IGF1R), conserved helix-loop-helix ubiquitous kinase (IKK-α), inhibitors of kappa ray polypeptide gene enhancers in the 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 virus oncogene homolog,Lymphocyte-specific protein tyrosine kinase (LCK), LIM domain kinase family, serine / threonine kinase family, leucine-rich repeat kinase family, v-yes-1 Yamaguchi sarcoma virus-associated oncogene homolog (LYN), male germ cell-associated kinase (MAK), MAP / microtubule affinity-regulated kinase family, e.g., microtubule-associated serine / threonine kinase family, maternal-fetal leucine zipper kinase, c-mer oncogene tyrosine kinase (MERTK), met oncogene (hepatocyte growth factor receptor), MAP kinase-interacting serine / threonine kinase family, myosin light chain kinase family, mixed-lineage kinase domain-like protein isoforms, CDC42-binding protein kinase family, serine / threonine kinase family, macrophage-stimulating receptor 1 (c-met-associated tyrosine kinase) (MST1R), mechanistic target of rapamycin (serine / Threonine kinase (MTOR), musculoskeletal receptor tyrosine kinase (MUSK), myosin light chain kinase family, NIMA (Never-in mitotic gene a) related kinase family, serine / threonine protein kinase NIM1 (NIM1), nemo-like kinase (NLK), oxidative stress-responsive kinase 1 (OSR1), p21 protein (Cdc42 / Rac) activating 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 kinases, 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-α kinase 2 (PRKR), X-binding 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 mouse leukemia virus 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-related 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 regulatory kinase -se 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 factors, 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 interaction kinase (TN IK), non-receptor tyrosine kinase family, TNNI3 interaction kinase (TNNI3K), transient receptor latent cation channels, 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,Examples include vaccinia-related kinase 2 (VRK2), the WEE1 homolog family, the WNK lysine-deficient protein kinase family, v-yes-1 Yamaguchi sarcoma virus oncogene homolog 1 (YES), sterile alpha motif and leucine zipper-containing kinase AZK (ZAK), and zeta chain (TCR)-related protein kinase 70 kDa (ZAP70).

[0143] Cell therapies primarily using cells derived from the following: endoderm such as exocrine epithelial cells and hormone-secreting cells; ectoderm such as keratinized epithelial cells, moist stratified barrier epithelial cells, sensory signaling cells, autonomic nerve cells, sensory organ and peripheral nerve supporting cells, central nervous system neurons and glial cells, lens cells; metabolic and storage cells; barrier function cells (lung, intestine, exocrine gland and urogenital tract); extracellular matrix cells; contractile cells; blood and immune system cells; germ cells; nurse cells; stromal cells; and combinations thereof. Furthermore, genetically, chemically, or physically modified or otherwise modified cells are also included in the scope of this invention.

[0144] Examples of exocrine epithelial cells, though not limited to them, include salivary gland mucus cells, salivary gland number 1, von Ebner gland cells of the tongue, mammary gland cells, lacrimal gland cells, earwax gland cells, eccrine sweat gland dark cells, eccrine sweat gland clear cells, apocrine sweat gland cells, Mohr gland cells of the eyelids, sebaceous gland cells, Bowman gland cells of the nose, Brunner gland cells of the duodenum, seminal vesicle cells, prostate cells, bulbourethral gland cells, Bartholin's gland cells, Littre's gland cells, endometrial cells of the uterus, isolated goblet cells of the respiratory and digestive tract, gastric mucosal cells, gastric gland enzyme progenitor cells, gastric gland oxidizing cells, pancreatic acinar cells, Paneth's cells of the small intestine, type II lung cells of the lung, and Clara cells of the lungs, hormone-secreting cells, including, but not limited to, anterior pituitary cells, middle pituitary cells, macrocellular neurosecretory cells, cells of the intestines and airways, thyroid cells, parathyroid cells, adrenal cells, Leydig cells of the testis that secrete testosterone, inner membrane cells of follicular cells that secrete estrogen, corpus luteum cells of ruptured follicular cells that secrete progesterone, progesterone-secreting cells near the glomerulus, macula densa cells of the kidney, circumpolar cells of the kidney, mesangial cells of the kidney, and islets of the pancreas, keratinized epithelial cells, including, but not limited to, epidermal keratinocytes, epidermal basal cells, keratinocytes of the fingernails and toenails, and nail beds. Basal cells, medullary hair stem cells, cortical hair stem cells, epidermal hair stem cells, epidermal root sheath cells, root sheath cells of the Huxley layer, root sheath cells of the Henle layer, outer root sheath cells and hair matrix cells, moist stratified barrier epithelial cells, for example, 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 transmission cells, for example, but not limited to, intraauditory hair cells of the organ of Corti, extraauditory hair cells of the organ of Corti, basal cells of the olfactory epithelium, cold-sensitive primary sensory neurons, heat-sensitive primary sensory neurons, and Merkel cells of the epidermis , olfactory receptor neurons, pain-sensitive primary sensory neurons, photoreceptor cells of the retina of the eye, proprioceptor primary sensory neurons, touch-sensitive primary sensory neurons, type I carotid bodies, type II carotid bodies, 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, for example, but not limited to, cholinergic nerve cells, adrenergic nerve cells and peptide-glutinating nerve cells, sensory organ and peripheral neuron supporting cells, for example, but not limited to, endocosal cells of the organ of Corti, endocosal cells of the organ of Corti,External digitolar cells of the organ of Corti, organ boundary cells, Hensen cells of the organ of Corti, vestibular organ supporting cells, taste bud supporting cells, olfactory epithelial supporting cells, Schwann cells, satellite glial cells and intestinal glial cells, central nervous system neurons and glial cells, for example, but not limited to astrocytes, neuronal cells, oligodendrocytes and spindle neurons, lens cells, for example, but not limited to pre-lens epithelial cells and crystallin-containing lens fiber cells, metabolic and storage cells, for example, but not limited to adipocytes and hepatic adipocytes, barrier function cells, for example, but limited to While not limited to these, renal parietal cells, renal glomerulopoda cells, renal proximal tubular brush border cells, loop of Henle's tubular cells, renal distal tubular cells, renal collecting duct cells, chief cells, insertion cells, type I lung cells, pancreatic duct cells, non-striated duct cells, chief cells, insertion cells, tubular cells, intestinal brush border cells, exocrine gland striated duct cells, gallbladder epithelial cells, lobular non-cilia cells, epididymal chief cells and epididymal basal cells, extracellular matrix cells, for example, 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 tissue fibroblasts, other non-epithelial fibroblasts, pericytes, nucleus pulposus cells of intervertebral discs, cementoblasts / cementocytes, odontoblasts / odontocytes, hyaline chondrocytes, fibrochondrocytes, elastochondrocytes, osteoblasts / osteocytes, bone progenitor cells, vitreous cells of the eye, stellate cells of the perilymphatic space of the ear, hepatic stellate cells and pancreatic stellate cells, contractile cells, for example, but not limited to skeletal muscle cells, satellite cells, cardiomyocytes, smooth muscle cells, myoepithelial cells of the iris and myoepithelial cells of exocrine glands, blood cells and immune system cells, for example, but not limited to erythrocytes, megakaryocytes, monocytes, conjugate cells Macrophages, epidermal Langerhans cells, osteoclasts, dendritic cells, microglia, 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, for example, but not limited to oogonia, oocytes, spermatocytes, spermatocytes, spermatogonia, spermatogonia and sperm, nurse cells, for example, but not limited to ovarian follicular cells and Sertoli cells, thymic epithelial cells,Examples include interstitial cells, such as interstitial kidney cells (though not limited to these), and any combination of the aforementioned types.

[0145] Other known biologics, though not limited to them, include, but are: Abosinagis, Abegurin, Actemra, AFP-Side, Antova, Arzera, Aurexis, Avastin, Benlysta, Vexar, Brontres, Bosatria, Campas, CEA-Side, CEA-Scan, Cimzia, Silamza, Ectomab, Erbitux, Fibricint, Gaziva, Herceptin, hPAM4-Side, HumaSPECT, HuMax-CD4, HuMax-EGFr, Fumira, HuZAF, Hybri-ceaker, Ilaris, Indimasis-125, Kadcyla, Remtrada, Leucoresto, Leucoscan, Lucentis, and Lin Examples include Fomun, Lymphoscan, Lymphostat-B, Mabusera, Mycograb, Mylotarg, Myosinto, Nutrospec, Pneumax, Nuvion, Omnitarg, Opdivo, Orthoclon OKT3, Ovalex, Panorex, Prolia, Prostacinto, Raptiva, Remicade, Rimovab, Lencarex, Leopro, Lexomun, Rituxan, Roactemra, Syntimun, Simponi, Simulect, Soliris, Stellara, Synagis, Tactless, Cerasim, Cerasin, Ceralock, Tysabri, Vectibix, Verluma, Xolair, Yervoy, Xenapax, and Zevalin, as well as combinations thereof.

[0146] Non-exclusive examples of known monoclonal antibodies include, but are not limited to, 3F8, 8H9, avagovomab, absiximab, abituzumab, abrilumab, actotsumab, adalimumab, adekatumumab, aducanumab, afasebicumab, aferimomab, aftuzumab, aracizumab pegol, ALD518, ALD403, alemtuzumab, alirocumab, pentetate artumomab, amatsuximab, AMG334, and anatumomab. Mafenatox, Anetumab-Luvtansine, Aniflorumab, Anlukinzumab, Apolizumab, Alcitumomab, Ascrimbacumab, Aselizumab, Atezolizumab, Atinumab, Atolizumab, Atrolimumab, Avelumab, Bapineozumab, Basiliximab, Bavituximab, Vectumomab, Begeromab, Belimumab, Benralizumab, Vertilimumab, Besilesomab, Bevacizumab, Bezloxumab, Bisilomab, Bimaglumab, Bimekizumab, Vibatuzumab-Meltansine, Breserumab, Blinatumab, Brosozumab, Brosozumab, Vococizumab, Brazicumab, B Lentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontuzumab, brosumab, kabilizumab, canakinumab, cantuzumab meltansine, cantuzumab bravtansine, caplacizumab, capromab pendetide, carrumab, carotuximab, catumakisomab, cBR96-doxorubicin immune complex, sedelizumab, cergutuzumab amnaloykin, certolizumab pegol, cetuximab, sitatuzumab bogatox, cyclosumab, crazakizumab, clenoliximab, cribatuzumab tetraxetan, codolituzumab, coltuximab bravtansineConatumumab, Concizumab, CR6261, Crenezumab, Clotezumab, Dasetuzumab, Dacrizumab, Darotuzumab, Dapirolizumab Pegol, Daratumumab, Dectrecumab, Demcizumab, Denintuzumab Mahodotin, Denosumab, Depatuxizumab Mahodotin, Delrotuximab Biotin, Detumomab, Dina Tuximab, diridabumab, domaglozumab, dorimomab aritox, dorodizumab, durigotumab, dupilumab, durvalumab, dusigitumab, eclomeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efungumab, erderumab, ergemzumab, elotuzumab, ersi Limab, Emuctuzumab, Emibetuzumab, Emicizumab, Enabatuzumab, Enfortuzumab Vedotin, Enrimomab Pegol, Enobrituzumab, Enokizumab, Enoticumab, Encituximab, Epitumomab Citucetan, Epratuzumab, Erenumab, Erlizumab, Erzumaxomab, Etalacizumab, Etrolizumab, Evinacumab, Evolocumab, Exvivirumab, Fanoresomab, Faralimomab, Faretuzumab, Facinumab, FBTA05, Felbizumab, Fezakinumab, Fivatuzumab, Ficlatuzumab, Figitumumab, Frivumab, Flambotumab, Fleticumab, Fontrizumab, Foralumab, folavirumab, fresolimmab, fluranumab, futuximab, galcanezumab, galiximab, ganitumab, gantenerumab, gabirimab, gemtuzumab ozogamicin, gevokizumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiusetan, iclucumab, idarucizumab, igobomab, IMA-638, IMA-362, imarumab, imusilomab, imugatuzumab, incrak Mab, indatuximab lavtansine, indusatumab vedotin, innebilizumab, infliximab, inorimab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, isatuximab, itorizumab, ixekizumab, keriximab, lavetuzumab, lambrolizumab, lamparizumab, lanadelmab, landgrozumab, laprituximab emtansine, LBR-101 / PF0442g7429, lebrikizumab, remaresomab, lendali Zumab, lentilumab, reldelimumab, lexatumumab, rivivirumab, rifatuzumab vedotin, rigerizumab, rilotomab satetraxetan, lintuzumab, lirirumab, rodelcizumab, lokivetomab, rorbotuzumab meltansine, lucatumumab, rulizumab pegol, lumiliximab, lumuretuzumab, LY2951742, mapatuzumab, margetuximab, masurimomab, matsuzumab, mapurilimumab, mepolizumab, metelimunomab, milatuzumab, minretsumo Mab, milbetuximab sorafutansine, mitumomab, mogamulizumab, monalizumab, morolimumab, motabizumab, moxetumomab pasdotox, muromonab-CD3, nacolomab butafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, nalnatumumab, natalizumab, nabicilizumab, navibumab, nevacumab, necitumumab, nemolizumab, nererimomab, nesbacumab, nimotuzumab, nivolumab, nofetumomabMerpentan, obiltoxiaximab, obinutuzumab, okalatuzumab, ocrelizumab, odulimab, ofatumumab, oraratuzumab, orokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, olegobomab, orticumab, otelixizumab, otreltuzumab, oxerumab, ozanezumab, ozoralizumab, pagibactimab, palivizumab, pamrebulumab, panitumumab, pancomab, panobacumab, pulsatuzumab, Pasco Lizumab, pasotukizumab, pateclizumab, patrizumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, prakmab, prozarizumab, pogalizumab, polatuzumab vedotin, ponezumab, prezarizumab, priliximab, pritokiaximab, pritumumab, PRO140, kirizumab, lacotsumomab, radrezumab, rafivirumab, ralpanchizumab, ramucirumab, ranibizumab, laxibac Mab, refanezumab, regavirumab, reslizumab, rilotumab, linucumab, risankizumab, rituximab, ribabazumab pegol, lobatumumab, loredumab, romosozumab, lontalizumab, lovalpituzumab tesirin, loberizumab, luprizumab, sacituzumab govitecan, samarizumab, sapelizumab, sarilumab, sacimomab pendetide, secukinumab, cerivantuzumab, cetokiaximab, sevilumab, SGN-CD19A, SGN-CD33A, sibrotuzumab, cifalimumab siltuximab, simtuzumab, cilizumab, silutuzumab, sofituzumab vedotin, solanezumab, solitomab, soneptizumab, sontuzumab, stamlumab, thresomab, subisumab, tabarmab, takatuzumab tetraxetan, tadocizumab, talizumab, tamtuvetomab, tanezumab, tapritumomab paptox, tarextumab, tefivazumab, terimomab aritox, tenatumomab, teneriximab, teprizumab, teprotumumab, tesidorumab, tetulomab, tezeperumabTGN1412, tisilimuab, tigatuzumab, tildrakizumab, timorumab, tisotuzumab vedotin, TNX-650, tocilizumab, tralizumab, tosatoxumab, tositumomab, tobetuzumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotsuzumab cermoloukin, tubilumab, ublituximab, urocuplumab, urerumab, urtoxazumab, usuteki Examples include numab, utomirumab, vadastaximab tariline, bundutuzumab vedotin, vantictumab, vanucizumab, bapariximab, valirumab, baterizumab, vedolizumab, bertuzumab, bepalimomab, besenkumab, bicilizumab, bovalilizumab, borosiximab, borsetuzumab mahodotin, botumumab, zentuzumab, zaltumumab, zanorimumab, zatuximab, diralimumab, and zolimomab aritox, as well as combinations thereof.

[0147] 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 vaccine, varicella vaccine, shingles vaccine, smallpox vaccine, yellow fever vaccine, adenovirus vaccine, coxsackie B virus vaccine, cytomegalovirus vaccine, human dengue fever vaccine, human Eastern equine encephalitis virus vaccine, Ebola 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 T lymphocytic leukemia vaccine, Marburg virus disease vaccine, norovirus vaccine, human respiratory syncytial virus (RSV) vaccine, severe acute respiratory syndrome (SARS) vaccine, and human West Nile virus vaccine. Examples of bacterial diseases, though not limited to these, include anthrax vaccine, DPT vaccine, Q fever vaccine, Hib vaccine, tuberculosis (BCG) vaccine, meningococcal vaccine, typhoid vaccine, pneumococcal complex vaccine, pneumococcal polysaccharide vaccine, cholera vaccine, dental caries vaccine, ehrlichiosis vaccine, leprosy vaccine, Lyme disease vaccine, Staphylococcus aureus vaccine, Streptococcus pyogenes vaccine, syphilis vaccine, tularemia vaccine, and plague. Examples of bacterial 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 tarimodine-rherparepvec (T-VEC). Examples of vaccines that include, but are not limited to, the following brand names: ACAM2000, ActHIB, Adacel, Afluria, AFLURIAQUADRIVALENT, Agriful, BCG vaccine, BEXSERO, Visrax, Boostrix, Cervarix, Comvax, DAPTACEL, DECAVAC, Engerix-B, FLUAD, Fluarix, Fluarix tetravalent, Flublock, Flucellvax, Flucellvax tetravalent, Fluraval, Flumist, Flumist tetravalent, Fluvirine, Fluzon tetravalent, Fluzon, Fluzon high dose and Fluzon intradermal, Gardasil, Gardasil 9, Habrix, Hyberix, Imovax, Infanrix, IPOL, Ixialo, JE-Vax, KINRIX, Menactra, Menhybrix, Menomne-A / C / Y / W-135, Menobeo, MMR II, MM-Vax, Pedialix, Pedbax HIB, Pentacell, Pneumovax 23, PolioVax, Prevner, Prevner 13, Proquad, Quadracell, Quadrivalent, RabAvert, RecombiVax HB, ROTARIX, RotaTeq, TENIVAC, TICE BCG, Tripedia, TRUMENBA, Twinrix, TYPHIM Vi, VAQTA, Varivax, Vacuola, Vivotif, YF-Vax, Zostavax and combinations thereof.

[0148] Examples of injectable drugs, though not limited to them, include Abrabar (gadfosvecet trisodium injection), Avalerix Depot, Avobotulinum toxin A injection (Dysport), ABT-263, ABT-869, ABX-EFG, Acretropin (somatropin injection), Acetadot (acetylcysteine ​​injection), Acetazolamide injection (acetazolamide injection), Acetazolamide injection (acetadot), Actemra (tocilizumab injection), Axrel (corticolin sheep trifluate for injection), Actamune, Activase, Acyclovir for injection (Zovirax injection), Adacel, Adalimumab, and Adenoscan. Adenosine injection (adenosine), adenosine injection (adenoscan), Adrenaclik, Adreview (intravenous iobenguan 1123 injection), Afluria, Ak-Fluor (fluorescein injection), Aldurazyme (laronidase), alglucerase injection (seredase), Alkeran injection (melphalan HCl injection), allopurinol sodium for injection (alloprim), alloprim (alopurinol sodium for injection), alprostadil, Arsuma (sumatriptan injection), ALTU-238, amino acid injection, aminocin, Apidra, Apremilast, alprostadil dual chamber system for injection (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, Anfadase (hyaluronidase injection), Ammonul (sodium phenylacetate and sodium benzoate injection), Anaprox, Anzemet injection (drasetron mesylate injection), Apidra (insulin glulysine [rDNA-derived] injection), Apomab, Aranesp (darbepoetin alfa), Argatroban (argatroban injection), Arginine hydrochloride injection (R-Gene 10. Aristocort, Aristospan, Arsenic Oxide Injection (Trisenox), Artican Hydrochloride and Epinephrine Injection (Septkaine), Alzera (Ofatumumab Injection), Asclera (Polidocanol Injection), Atalen, Atalen-DMD, Atenolol Injection (Tenormin Intravenous Infusion), Atracurium Besylate Injection (Atracurium Besylate Injection), Avastin, Azactam Injection (Aztreonam Injection), Azithromycin (Zithromax) Injectable preparations), Aztreonam injection (azactam injection), Baclofen injection (Lioresal subarachnoid space), Bacteriostatic water (bacteriostatic water for injection), Baclofen injection (Lioresal intra-subarachnoid space), Bal-in-oil ampoule (Dimercarprole injection), BayHepB, BayTet, Benadryl, Bendamustine hydrochloride injection (Torenda), Benztropine mesylate injection (Cogentin), Betamethasone suspension for injection (Celeston Solspan), Vexar, Bicillin CR 900 / 300 (Penicillin G Benzatine and Penicillin G Progain Injection), Blenoxan (Bleomycin Sulfate Injection), Bleomycin Sulfate Injection (Blenoxan), Boniva Injection (Ibandronate Sodium Injection), Botox Cosmetic (Onabotrinium Toxin A for Injection), BR3-FC, Bravere (Urofolitropin Injection), Bretilium (Bretillium Tosylate Injection), Brevital Sodium (Methhexital Sodium for Injection), Bretin, Briovacept, BTT-1023, Bupivacaine Hydrochloride, Byetta, Ca-DTPA (Calcium Trisodium Pentetate Injection), Cabazitaxel Injection (Jevtana), Caffeine Alkaloids (Caffeine and Sodium Benzoate Injection), Calcijex Injection (Calcitrol), Calcijex Injection,Calcium chloride (10% calcium chloride injection), disodium calcium versenate (disodium calcium edetate injection), Campas (artemtuzumab), Camptosar injection (irinotecan hydrochloride), canakinumab injection (iraris), capasta sulfate (capreomycin for injection), capreomycin for injection (capasta sulfate), cardiolite (technetium Tc99 cestamivi preparation kit for injection), carticel, casfloxacin, cefazolin and glucose for injection (cefazolin injection), cefepime hydrochloride, cefotaxime, ce Phthriaxone, Cerezyme, Carnitor Injection, Cabelject, Celeston Solspan, Celcio, Cerevix (fosphenytoin sodium injection), Seredase (alglucerase injection), Celetec (technetium Tc99m examethazyme injection), Certolizumab, CF-101, chloramphenicol sodium succinate (chloramphenicol sodium succinate injection), chloramphenicol sodium succinate injection (chloramphenicol sodium succinate), Cholestagel (Coleceveram HCl), Corigona Dotropin alpha injection (Ovidrel), Cimzia, cisplatin (cisplatin injection), chlorar (clofarabine injection), clomifine citrate, clonidine injection (Duracron), cogentin (ventropine mesylate injection), colistimate injection (Colimycin M), Colimycin M (colistimate injection), Compass, conivaptan hydrochloride injection (vaprizol), conjugated estrogen for injection (Premarin injection), copaxone, corticolin sheep trifluate for injection (Axrel), Colbert (ibutilidofumarol) (Salt acid injection), Cubicin (daptomycin injection), CF-101, Cyanokit (hydroxocobalamin injection), Cytarabine liposomal injection (DepoCyt), cyanocobalamin, Cytoben (ganciclovir), DHE45, dasetuzumab, Dacogen (decitabine injection), dalteparin, Dantrium IV (dantrolene sodium injection), dantrolene sodium injection (Danttrium 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), deposite (cytarabine liposome injection), depodure (morphine sulfate XR liposome injection), desmopressin acetate injection (DDAVP injection), depoestradiol, depopropera 104 mg / ml, depopropera 150 mg / 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), Dimercalprole injection (in oil-in-valve ampoule), Diphenhydramine injection (Benadryl injection), Dipyridamole injection (Dipyridamole injection), DMOAD, Docetaxel for injection (Taxotele), Dracetron mesylate injection (Anzemet injection), Doribax (Doripenem for injection), Doripenem for injection (Doribax), Doxelcalciferol injection (Hector injection), Doxil (Doxorubicin HCl liposome injection), Doxorubicin HCl liposome injection (Doxil), Duramorph (Clonidine injection), Duramorph (Morphine injection), Dysport (Avobotulinum toxin A injection), Ecalantide injection ( Carbitol), EC-Naprosin (Naproxen), Calcium Disodium Edetate Injection (Calcium Disodium Verseneate), Edex (Alprostadil for Injection), Engerix, Edrophonium Injection (Enron), Eliglustat Tartrate, Eloxatin (Oxaliplatin Injection), Emend Injection (Fosaprepitant Dimeglumine Injection), Enalaprirat Injection (Enalaprirat Injection), Enron (Edrophonium Injection), Enoxaparin Sodium Injection (Ravenox), Eovist (Gadoxetate Disodium Injection), Enbrel (Etanercept), Enoxaparin, Epicel, Epinephelin, EpiPen, EpiPen Junior, Epratuzumab,Erbitux, Ertapenem Injection (Invanz), Erythropoiethene, Essential Amino Acid Injection (Neflamin), Estradiol Cypionate, Estradiol Valerate, Etanercept, Exenatide Injection (Byetta), Ebrotra, Fabrazyme (Adalusidase β), Famotidine Injection, FDG (Fludeoxyglucose F18 Injection), Ferhem (Fermoxytol Injection), Feridex IV (Fermoxide Injection), Fertinex, Fermoxide Injection (Feridex IV), Fermoxytol 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 alpha injection (Gonal-f RFF), follitropin beta injection (Follistim AQ cartridge), Forotin (pralatrexate intravenous solution), fondaparinax, Forteo (teriparatide (rDNA-derived) injection), fostamatinib, fosaprepitant dimeglumine injection (Emend injection), foscarnet sodium injection (foscavir), foscavir (foscarnet sodium injection), fosphenytoin sodium injection (Cerebyx), fosproporol disodium injection (Lucedra), Fragmin, Fuzeon (enfvirtide), GA101, Gadobenato dimeglumine injection (Multihance), Gadfosbeceto trisodium injection (Ablavar), Gadoteridol injection (ProHance), Gadovercetamide injection (OptiMARK), Gadoxetate disodium injection (Eovist), Ganirelix (Ganirelix acetate injection), Gardasil, GC1008, GDFD, Gemtuzumab ozogamicin ion for injection (Mylotarg), Genotropin, Gentamicin injection, GENZ-112638, Golimumab injection (Simponi injection), Gonal-f RFF (Follitropin alpha injection), Granisetron hydrochloride (Kitril injection), Gentamicin sulfate, Glatiramer acetate, Glucagen, Glucagon, HAE1, Haldol (Haloperidol injection),Habrix, Hector injection (doxelcalciferol injection), Hedgehog pathway inhibitors, heparin, Herceptin, hG-CSF, Humalog, human growth hormone, Humatrope, HuMax, Humegon, Humira, Humurin, ibandronate sodium injection (Boniva injection), ibuprofenlysine injection (neoprofen), ibutilide fumarate injection (Corvert), Idamycin PFS (idarubicin hydrochloride injection) ), Idarubicin hydrochloride injection (Idamycin PFS), Ilaris (canakinumab injection), Imipenem and cilastatin for injection (Primaxin IV), Imitrex, Incobotulinum toxin A for injection (Xeomin), Increx (Mecasermin [rDNA-derived] injection), Indomethacin IV (Indomethacin injection), Indomethacin injection (Indomethacin IV), Infanrix, Inohep, Insulin, Insulin aspart [rDNA-derived] injection, Injectable agents (NovoLog), insulin glargine [rDNA derived] injection (Lantus), insulin glulisin [rDNA derived] injection (Apidra), interferon α-2b, recombinant for injection (Intron A), Intron A (interferon α-2b, recombinant for injection), Inbanz (ertapenem injection), Invega Sustena (paliperidone palmitate sustained-release injection suspension), Invirase (saquinavir mesylate), Lobenguan 1123 intravenous injection (AdreView), iobromide injection (Ultravis), iobersol injection (Optiray injection), Iplex (mecasermin linfabate [rDNA derived] injection), Iprivasc, irinotecan hydrochloride (Camptosar injection), sucrose iron injection (Benofar), Istodax (for injection) Midepsin, itraconazole injection (Sporanox injection), Jevtana (cabazitaxel injection), Jonexa, Carbitol (ecalantide injection), KCl in D5NS (potassium chloride and sodium chloride injection in 5% glucose), KCl in D5W, KCl in NS, Kenalog 10 injection (triamcinolone acetonide injection suspension), Kepivans (palifermin), Kepra injection (levetiracetam), keratinocyte, KFG, kinase inhibitors, Kineret (anakinra), Kinritic (urokinase injection), Kinrix, Clonopin (clonazepam), Kitril injection (granisetron hydrochloride), lacosamide tablets and injection (Vinpat), Ringer's lactate, Lanoxin injection (digoxin injection), lansoprazole for injection (Prevacid IV), Lantus , leucovorin calcium (leucovorin calcium injection), Lente (L), leptin, levemir, leukinsal grammostim, leuprolide acetate, levothyroxine, levetiracetam (keppra injection), Ravenox, levocarnitine injection (carnitine injection), Lexcan (legadenoson injection), lioresal subarachnoid (baclofen injection), liraglutide [rDNA] injection (Victoza), Ravenox (enoxaparin sodium injection), Lucentis (ranibizumab injection), Lumizyme, Leupron (leuprolide acetate injection), Lucedra (fospropofol disodium injection), Mati,Magnesium sulfate (magnesium sulfate injection), mannitol injection (mannitol IV), Marcain (bupivacaine hydrochloride and epinephrine injection), Maxipime (cefepime hydrochloride for injection), Technetium injection MDP multidose kit (technetium Tc99m medrone injection), Mecasermin [rDNA derived] injection (Increx), Mecasermin rhinfabate [rDNA derived] injection (Iplex), Melphalan hydrochloride injection (Alkeran injection), Methotrexate, Menactra, Menopool (menotropin injection) ), menotropin for injection (Repronex), methhexital sodium for injection (Brevital sodium), methyl dope hydrochloride injection, solution (methyl dope HCl), methylene blue (methylene blue injection), methylprednisolone acetate suspension for injection (Depo-Medrol), MetMab, metoclopramide injection (Regran injection), Metrodin (urofolitropin for injection), metronidazole injection (Flagyl injection), miacalcin, midazolam (midazolam injection), minpara (Cinnacare), minosin injection (minocycline injection) Minocycline injection (Minosin injection), mipomersen, mitoxantrone concentrate for injection (Novantrone), morphine injection (Duramorph), morphine sulfate XR liposome injection (Depodure), sodium morphate (sodium morphate injection), motesanib, mozovir (Prelixafor injection), Multihans (gadbenate dimeglumine injection), multiple electrolytes and glucose injections, multiple electrolyte injections, Mylotarg (gemtuzumab ozogamicin for injection), myozyme (alglucosidase alfa), naphicillin Injectable preparations (nafcillin sodium), nafcillin sodium (nafcillin injection), naltrexone XR injection (vivitrol), naprosin (naproxen), neoprofen (ibuprofenlysine injection), nandrol decanoate, neostigmine methylsulfate (neostigmine methylsulfate injection), NEO-GAA, Neotect (technetium Tc99m depreotide injection), neflamin (essential amino acid injection), Neulasta (pegfilgrastim), Newpogen (filgrastim), Novolin, Novolog, Neolicolmon,Nutrexin (trimethrexate glucuronide injection), NPH(N), Nexterone (amiodarone hydrochloride injection), Norditropin (somatropin injection), physiological 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 injection suspension (Zyprexa Relprevv), Omnitarg, Omnitrope (somatropin [rDNA-derived] injection), Ondansetron hydrochloride injection (Zofran injection), OptiMARK (gadvercetamide injection), Optiray injection (iobersol injection), Orencia, Osmitrol injection in Aviva (mannitol injection in Aviva plastic container 250), Osmitrol injection in Viaflex (mannitol injection in Viaflex plastic container 250), Osteoprotegrin, Ovidrel (human chorionic gonadotropin alpha injection), Oxacillin (oxacillin for injection), Oxaliplatin injection (eloxatin), Oxytocin injection (pitosin), Paliperidone palmitate sustained-release suspension for injection (Invegasas Tena), Pamidronate disodium injection (Pamidronate disodium injection), Panitumumab injection for intravenous injection (Vectibix), Papaverine hydrochloride injection (Papaverine injection), Papaverine injection (Papaverine hydrochloride injection), Parathyroid hormone, Paricalcitol injection flip-top vial (Zempler injection), PARP inhibitors, Pedialix, PEG Instron, Peggin interferon, Pegfilgrastim, Penicillin G benzathine and Penicillin G procaine, Calcium trisodium pentetate injection (Ca-DTPA), Zinc trisodium pentetate injection (Zn-DTPA), Pepsid injection (Famotidine injection),Pergonal, pertuzumab, phentolamine mesylate (phentolamine mesylate for injection), physostigmine salicylate (physostigmine salicylate (injection)), physostigmine salicylate (injection) (physostigmine salicylate), piperacillin and tazobactam injection (Zosyn), pitosin (oxytocin injection), Plasma-Lite 148 (multiple electrolyte injections), Plasma-Lite 56 and glucose (multiple electrolytes and glucose injections in Viaflex plastic container 250), Plasma-Lite, Prelixafor injection (Mozobil), polidocanol injection (Asclera), potassium chloride, pralatrexate solution for intravenous injection (Folotyn), Pramulintide acetate injection (Symlin), Premarin injection (conjugated estrogen for injection), Technetium Tc99 cesamivi preparation kit for injection (cardiolite), Prevacid IV (lansoprazole for injection), Primaxin IV (Imipenem and cilastatin for injection), Prokymar, 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), Laptiva, Leclast (Zoledronic acid injection), Recomvivarix HB, Rigadenoson injection (Lexiscan), Regran injection (metoclopramide injection), Remicade, Renagel, Lembella (sevelamer carbonate), Repronex (menotropin for injection), Retrovir IV (zidovudine injection), rhApo2L / TRAIL, Ringer's solution and 5% glucose injection (Ringer's solution in glucose), Ringer's solution (Ringer's solution for injection), Rituxan, Rituximab, Rocephin (ceftriaxone), Rocuronium bromide injection (Zemlon), Loferon-A (interferon α-2a), Romagicon (flumazenil), Romidepsin for injection (istodax), Saizen (somatropin injection), Sandostatin LAR (octreotide acetate injection),Sclerostin Ab, Sensiper (Cinacalcet), Sensakine (Bupivacaine Hydrochloride Injection), Septkaine (Artican Hydrochloride and Epinephrine Injection), Cerostim LQ (Somatropin (rDNA-derived) Injection), Simponi Injection (Golimumab Injection), Sodium Acetate (Sodium Acetate Injection), Sodium Bicarbonate (5% Sodium Bicarbonate Injection), Sodium Lactate (Sodium Lactate Injection in AVIVA), Sodium Phenylacetate and Sodium benzoate injection (Ammonul), somatropin injection (rDNA-derived) (Neutropin), Sporanox injection (itraconazole injection), Stelara injection (ustekinumab), Stemgen, Sufenta (sufentanyl citrate injection), Sufentanyl citrate injection (Sufenta), Smavel, Sumatriptan injection (Arsma), Simurin, Simurinpen, systemic hedgehog antagonist, Cymbisquan (Hylan GF 20 monotherapy intra-articular injection), Tarceva, Taxotere (docetaxel injection), Technetium Tc99m, Teravancin injection (Vivative), Temsirolimus injection (Tricel), Tenormin IV Injectable preparations (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 alfa for injection), ticarcillin disodium and clavulanate potassium Galaxy (thimentine injection), tigan injection (trimethobenz (Amido hydrochloride injection), timentin injection (ticalcillin disodium and clavulanate potassium galaxy), TNKase, tobramycin injection (tobramycin injection), tocilizumab injection (Actemra), Tricel (temsirolimus injection), Totect (dexrazoxane for injection, intravenous infusion only), trastuzumab-DM1, travazole (amino acid (injection)), trianda (bendamustine hydrochloride injection), Torelstar (triptorelin pamoate injection suspension), triamcinolone acetonide, triamcinolone diacetate,Triamcinolone hexacetonide injection suspension (Aristospan injection 20 mg), Triaïs (triamcinolone acetonide injection suspension), Trimethobenzamide hydrochloride injection (Tygan injection), Trimethrexate glucuronide injection (Nutrexin), Triptorelin pamoate for injection suspension (Torelstar), Twinject, Trivaris (triamcinolone acetonide injection suspension), Trisenox (arsenic trioxide injection), Twinrix, Typhoid Vi, Ultravist (iopromide injection), Urofolitropin for injection (Metrozine), Urokinase injection (Quinlitic), Ustekinumab (, Stellara injection, Ultralente (U), Barium (diazepam), sodium valproate injection (Depakon), Bartropin (somatropin injection), vancomycin hydrochloride (vancomycin hydrochloride injection), vancomycin hydrochloride injection (vancomycin hydrochloride), baprizole (conivaptan hydrochloride injection), VAQTA, Vasovist (gadofosbeceto trisodium for intravenous injection), Vectibix (panitumumab injection for intravenous injection), Venofar (ferric sucrose injection), Verteporfin injection (Visudyne), Vibativ (Teravancin for injection), Victoza (Liraglutide "rDNA" injection), Vimpat (Lacosamide tablets and injection), Vinblastine sulfate (Vinblastine sulfate injection), Vincasar PFS (Vincristine sulfate injection), Victoza, Vincristine sulfate (Vincristine sulfate injection), Visudyne (Verteporfin injection), Vitamin B-12, Vivitrol (Naltrexone XR injection), Voluben (Hydroxyethyl starch in sodium chloride injection), Xeloda, Xenical (Orlistat), Xeomin (Incobotulinum toxin A for injection), Xolair, Zantac injection Examples include ranitidine hydrochloride injection, Zempla injection (palicalcitol flip-top vial for injection), Zemlon (rocuronium bromide injection), Zenapax (daclizumab), Zevalin, zidovudine injection (Retrovir IV), azithromycin injection, Zn-DTPA (zinc trisodium pentetate injection), Zofran injection (ondansetron hydrochloride injection), Zingo, zoledronic acid for injection (Zometa), zoledronic acid injection (Lecrust), Zometa (zoledronic acid for injection), Zosyn (piperacillin and tazobactam injection), zyprexalelprev (olanzapine sustained-release injection suspension), and combinations thereof.

[0149] Announcement The invention of this application has been described above, both in general and with respect 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 this disclosure. Accordingly, the embodiments are intended to cover modifications and variations of the invention, insofar as they fall within the scope of the appended claims and their equivalents. (Aspect) (Aspect 1) A method for manufacturing an injector device, The stopper of the injector device is positioned inside the tubular member such that the outside of the stopper engages with the inner surface of the tubular member, and By causing relative motion between the stopper and the tubular member, the outside of the stopper is altered. A method comprising, wherein the relative motion includes either or both rotational motion and vibrational motion. (Aspect 2) The method according to embodiment 1, wherein the tubular member is the barrel of the injector device. (Aspect 3) The method according to embodiment 1, wherein the tubular member is a vent pipe configured to be inserted into the barrel of the injector device, and the vent pipe is configured to deliver the stopper into the barrel of the injector device. (Aspect 4) The method according to any one of embodiments 1 to 3, wherein the outside of the stopper is defined by a rib, and the rib is locally heated by the relative motion between the stopper and the tubular member. (Aspect 5) The method according to any one of embodiments 1 to 4, wherein the relative motion reduces the roughness of the outer surface of the stopper. (Aspect 6) The method according to any one of embodiments 1 to 5, wherein the stopper has wrinkles on its outer surface, and the wrinkles are reduced by the relative movement. (Aspect 7) The method according to any one of embodiments 1 to 6, wherein the outer surface of the stopper has defined roughness in the longitudinal and circumferential directions, and further, the relative motion reduces the roughness in the longitudinal and / or circumferential directions. (Pattern 8) The method according to any one of embodiments 1 to 7, wherein the material is transferred from the outside of the stopper to the inner surface of the tubular member by the relative motion. (Aspect 9) The method according to any one of embodiments 1 to 8, wherein the outer surface of the stopper comprises a polymer material, and the relative motion induces polymer motion of the polymer material. (Aspect 10) The method according to any one of embodiments 1 to 9, wherein the stopper comprises a barrier formed from a first material and a body formed from a second material, and the barrier is coupled to the body. (Aspect 11) The method according to any one of embodiments 1 to 10, wherein the outer surface of the stopper comprises a fluoropolymer material. (Aspect 12) The method according to any one of embodiments 1 to 11, wherein the relative motion between the stopper and the tubular member includes a longitudinal component. (Aspect 13) A method for manufacturing an injector device, The stopper for the injector device is placed inside the vent pipe. Inserting the vent pipe into the barrel of the injector device, The stopper is delivered from the vent tube into the barrel of the injector device such that the outer surface of the stopper engages with the inner surface of the barrel, defining a sealing interface between the outer surface of the stopper and the inner surface of the barrel, and To induce relative motion between the stopper and the barrel, thereby strengthening the sealing interface between the outer surface of the stopper and the inner surface of the barrel. Methods that include... (Aspect 14) The method according to embodiment 13, wherein the relative motion between the stopper and the tubular member includes a rotational component. (Aspect 15) The method according to embodiment 13 or 14, wherein the relative motion between the stopper and the tubular member includes a longitudinal component. (Aspect 16) The method according to any one of embodiments 13 to 15, wherein the outer surface of the stopper comprises a polymer material, and reinforcing the seal interface between the outer surface of the stopper and the inner surface of the barrel includes inducing polymer motion of the polymer material at the seal interface. (Aspect 17) The method according to any one of embodiments 13 to 16, wherein after the stopper is delivered from the vent pipe into the barrel of the injector device, the outside of the stopper forms wrinkles at the sealing interface, and further strengthening the sealing interface between the outside of the stopper and the inner surface of the barrel includes reducing wrinkles at the sealing interface. (Aspect 18) The method according to any one of embodiments 13 to 17, wherein the stopper comprises a body and a barrier bonded to the body, the barrier being formed from a fluoropolymer material, and further comprising reinforcing the seal interface between the outside of the stopper and the inside of the barrel, thereby causing localized heating at the seal interface. (Aspect 19) The method according to any one of embodiments 13 to 18, wherein strengthening the seal interface between the outside of the stopper and the inside of the barrel includes transferring a material from the outside of the stopper to the inside of the barrel. (Aspect 20) The method according to any one of embodiments 13 to 19, wherein the outer surface of the stopper is defined by a rib, and the sealing interface includes the rib of the stopper. (Aspect 21) A stopper having an outer casing, comprising a body and a barrier formed from a material different from the body, wherein the barrier is coupled to the body and the barrier defines at least a portion of the outer casing of the stopper, and A barrel having an inner surface that engages with the outer surface of the stopper to define a seal interface, wherein the inner surface of the barrel contains a deposit material corresponding to the barrier material at the seal interface, and as a result the seal interface is defined by the deposit material and the barrier material, and the deposit material is directionally oriented. Injector devices, including... (Aspect 22) The injector device according to embodiment 21, wherein the directional orientation includes a circumferential component. (Aspect 23) The injector device according to embodiment 21 or 22, wherein the directional orientation of the deposited material is defined by rows of PTFE chains aligned in a common direction. (Aspect 24) The injector device according to any one of embodiments 21 to 23, wherein the outside of the stopper includes at least one of microribs and macroribs at the sealing interface. (Aspect 25) The injector device according to any one of embodiments 21 to 24, wherein the barrier comprises a fluoropolymer material. (Aspect 26) The injector device according to any one of embodiments 21 to 25, wherein the deposited material fills one or more defects on the inner surface of the barrel. (Aspect 27) The injector device according to any one of embodiments 21 to 26, wherein the deposited material is disposed only at the seal interface. (Aspect 28) The injector device according to any one of embodiments 21 to 27, wherein the sealing interface corresponds to one or more circumferential bands on the outside of the stopper that engage with the inner surface of the barrel. (Aspect 29) The injector device according to any one of embodiments 21 to 28, wherein the deposited material defines one or more circumferential bands on the inside of the barrel.

Claims

1. A method for manufacturing an injector device, The stopper of the injector device is positioned inside the tubular member such that the outside of the stopper engages with the inner surface of the tubular member, and To change the outer surface of the stopper through the relative motion between the stopper and the tubular member, Includes, The aforementioned relative motion includes either or both rotational motion and vibrational motion. The outer surface of the stopper is defined by a rib, and the relative motion between the stopper and the tubular member causes local heating at the rib, and A method wherein, by the aforementioned relative motion, the material is transferred from the outside of the stopper to the inner surface of the tubular member.

2. The method according to claim 1, wherein the tubular member is the barrel of the injector device.

3. The method according to claim 1, wherein the tubular member is a vent pipe configured to be inserted into the barrel of the injector device, and the vent pipe is configured to deliver the stopper into the barrel of the injector device.

4. The method according to any one of claims 1 to 3, wherein the relative motion reduces the roughness of the outer surface of the stopper.

5. The method according to any one of claims 1 to 4, wherein the stopper has wrinkles on its outer surface, and the wrinkles are reduced by the relative movement.

6. The method according to any one of claims 1 to 5, wherein the outer surface of the stopper has defined roughness in the longitudinal and circumferential directions, and further, the relative motion reduces the roughness in the longitudinal and / or circumferential directions.

7. The method according to any one of claims 1 to 6, wherein the outer surface of the stopper includes a polymer material, and the relative motion induces the movement of the polymer material.

8. The method according to any one of claims 1 to 7, wherein the stopper comprises a barrier formed from a first material and a body formed from a second material, and the barrier is coupled to the body.

9. The method according to any one of claims 1 to 8, wherein the outer surface of the stopper includes a fluoropolymer material.

10. The method according to any one of claims 1 to 9, wherein the relative motion between the stopper and the tubular member includes a longitudinal component.

11. A method for manufacturing an injector device, The stopper for the injector device is placed inside the vent pipe. Inserting the vent pipe into the barrel of the injector device, The stopper is delivered from the vent tube into the barrel of the injector device such that the outer surface of the stopper engages with the inner surface of the barrel, defining a sealing interface between the outer surface of the stopper and the inner surface of the barrel, and To induce relative motion between the stopper and the barrel, and for this relative motion to strengthen the sealing interface between the outer surface of the stopper and the inner surface of the barrel, Methods that include...

12. The method according to claim 11, wherein the relative motion between the stopper and the barrel includes a rotational component.

13. The method according to claim 11 or 12, wherein the relative motion between the stopper and the barrel includes a longitudinal component.

14. The method according to any one of claims 11 to 13, wherein the outer surface of the stopper includes a polymer material, and reinforcing the seal interface between the outer surface of the stopper and the inner surface of the barrel includes inducing motion of the polymer material at the seal interface.

15. The method according to any one of claims 11 to 14, wherein after the stopper is delivered from the vent pipe into the barrel of the injector device, the outside of the stopper forms wrinkles at the sealing interface, and further strengthening the sealing interface between the outside of the stopper and the inner surface of the barrel includes reducing wrinkles at the sealing interface.

16. The method according to any one of claims 11 to 15, wherein the stopper comprises a body and a barrier bonded to the body, the barrier being formed from a fluoropolymer material, and further comprising reinforcing the seal interface between the outside of the stopper and the inside of the barrel, thereby causing localized heating at the seal interface.

17. The method according to any one of claims 11 to 16, wherein strengthening the seal interface between the outside of the stopper and the inside of the barrel includes transferring a material from the outside of the stopper to the inside of the barrel.

18. The method according to any one of claims 11 to 17, wherein the outer surface of the stopper is defined by a rib, and the sealing interface includes the rib of the stopper.

19. A stopper having an outer casing, comprising a body and a barrier formed from a material different from the body, wherein the barrier is coupled to the body and the barrier defines at least a portion of the outer casing of the stopper, and A barrel having an inner surface that engages with the outer surface of the stopper to define a seal interface, wherein the inner surface of the barrel contains a deposit material corresponding to the barrier material at the seal interface, and as a result the seal interface is defined by the deposit material and the barrier material, and the deposit material is directionally oriented. Injector devices, including...

20. The injector device according to claim 19, wherein the directional orientation includes a circumferential component.

21. The injector device according to claim 19 or 20, wherein the directional orientation of the deposited material is defined by rows of PTFE chains aligned in a common direction.

22. The injector device according to any one of claims 19 to 21, wherein the outside of the stopper includes at least one of microribs and macroribs at the sealing interface.

23. The injector device according to any one of claims 19 to 22, wherein the barrier comprises a fluoropolymer material.

24. The injector device according to any one of claims 19 to 23, wherein the deposited material fills one or more defects on the inner surface of the barrel.

25. The injector device according to any one of claims 19 to 24, wherein the deposited material is disposed only at the seal interface.

26. The injector device according to any one of claims 19 to 25, wherein the sealing interface corresponds to one or more circumferential bands on the outside of the stopper that engage with the inner surface of the barrel.

27. The injector device according to any one of claims 19 to 26, wherein the deposited material defines one or more circumferential bands on the inside of the barrel.

Images