Infusion devices for drug delivery and packages for infusion devices

Abstract

To provide an injection device including: a syringe having a barrel and a flange; and a backstop configured to be coupled with the syringe adjacently to the flange.SOLUTION: The backstop includes an inner surface generally extending around at least a portion of the syringe. The inner surface includes at least one protrusion 150. The at least one protrusion 150 extends away from the inner surface and is configured to engage the flange and / or the barrel to permit or promote an airflow through a space between the inner surface and the syringe.SELECTED DRAWING: Figure 2B

Description

Technical Field

[0001] Cross - Reference to Related Applications Priority is claimed to U.S. Provisional Patent Application No. 62 / 895,456, filed on September 3, 2019, and U.S. Provisional Patent Application No. 63 / 018,141, filed on April 30, 2020, the entire contents of which are hereby incorporated by reference.

[0002] The present disclosure generally relates to an infusion device for drug delivery and a package for the infusion device. More specifically, the present disclosure generally relates to a backstop for an infusion device that improves the grip, usability, and / or ergonomic design of the infusion device and / or reduces or prevents an unexpected movement of a stopper component associated with a plunger rod and / or an infusion device or package for identifying, securing, and / or holding the infusion device.

Background Art

[0003] As is well known in the art, a syringe is a medical delivery device used to administer a drug to a patient. Syringes are often commercially available in either a pre - filled form in which a set dose of the drug is provided therein or in an empty state to be filled by the end - user from a vial or other drug source when drug administration is desired.

[0004] Syringes often include a barrel portion adapted to hold a drug. The distal end of the barrel is often configured to include and / or engage with conventional perforating elements, such as a pointed needle cannula or a cannula with a blunt end, for delivering the drug contained within the barrel. The perforating elements may be made of steel, plastic, or any other suitable material. A plunger rod may be inserted through the open proximal end of the syringe barrel, and the engagement of the plunger rod with an elastomer or rubber stopper element mounted substantially fluid-tight inside the barrel allows the user to apply manual force to the plunger and deliver the drug through the perforating element. A flange is often also provided around the open distal end of the syringe barrel in the form of a finger rest to facilitate the user's operation of the device. Syringes may also include a retaining element (also known as a “retainer”) coupled or connected to the flange to improve the grip, usability, and / or ergonomic design of the syringe. As a more specific example, the retainer may have a radial length longer than the flange length, thereby effectively extending the length of the grip surface. The retainer and / or plunger rod may similarly, or instead, reduce or prevent accidental movement of the plunger rod and / or stopper components. As a more specific example, the retainer and / or plunger rod may have components that engage with each other to define the maximum point in the retraction direction from which the plunger rod can move.

[0005] For both drug integrity and patient safety, it may be desirable to thoroughly sterilize the components of the syringe. Sterilization can be performed at several stages of the assembly process, including pre-filling (e.g., sterilization of empty barrels and / or plungers) and post-filling (e.g., external sterilization of assembled pre-filled syringes). External sterilization is typically performed after the pre-filled syringes have been filled, fully assembled, and placed in at least some of their final packaging. U.S. federal regulations may require external sterilization under specific conditions, parameters, and / or consequences for certain use applications, such as certain ophthalmic applications. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] External sterilization can present design challenges. For example, drugs may be sensitive to sterilization and / or conditions such as temperature, gas, and radiation. Furthermore, achieving the desired or required level of sterilization of the syringe and / or its components can be difficult, particularly in terms of drug sensitivity. More specifically, surface interactions between various components of the syringe and / or package may create or promote occlusions that may not be effectively and / or completely sterilized during the external sterilization process performed on the syringe. More specifically, surface interactions between the syringe and the stopper and / or between the syringe and the package may create or promote occlusions. If an occlusion prevents or obstructs an area from reaching an effective level of sterilization gas, that area may not be effectively sterilized. If an occlusion prevents or obstructs the purging of sterilization gas from an area, patients, such as those who are already visually immunocompromised before treatment, may develop more serious conditions such as superficial eye infections or endophthalmitis. Therefore, it is desirable to maintain the integrity of the drug while achieving an appropriate level of sterilization of all relevant parts and components of the syringe. [Means for solving the problem]

[0007] This disclosure describes an injection device that embodies a favorable alternative to existing injection devices and their packaging, which can address one or more of the challenges or needs described herein and provide other benefits and advantages.

[0008] An injection device is provided, comprising a syringe having a barrel and a flange, and a retainer configured to be coupled to the syringe adjacent to the flange. The retainer may have an inner surface that extends substantially around at least a portion of the syringe, the inner surface including at least one projection, the at least one projection extending away from the inner surface and engaging with the flange and / or barrel, to allow or facilitate airflow through the space between the inner surface and the syringe.

[0009] The injection device may include at least two projections, the at least two of which extend away from the inner surface and are configured to engage with the flange and / or barrel to allow or facilitate airflow through the space between the inner surface and the syringe. The injection device may also include another number of projections, such as three, four, five, six, seven or another appropriate number.

[0010] The injection device may include a collar portion defining an inner surface that extends roughly around at least a portion of the barrel. The injection device may also be configured to engage with the syringe in a snap-fit ​​relationship, either similarly or alternatively.

[0011] At least one projection may be a rib extending roughly parallel to the axis of the syringe.

[0012] The retaining element may define a cavity for receiving at least a portion of the flange. The cavity may include opposing surfaces defining the cavity, and at least one projection may extend away from at least one of the opposing surfaces. The at least one projection may include at least one projection on the upper opposing surface and at least one projection on the lower opposing surface. Furthermore or alternatively, the at least one projection may include at least two ribs on the upper opposing surface and at least two ribs on the lower opposing surface.

[0013] The infusion device may be a pre-filled syringe containing a drug such as a VEGF inhibitor. For example, the VEGF inhibitor may be a non-antibody VEGF inhibitor. Another example is a non-antibody VEGF inhibitor, which may be a VEGF trap. The VEGF trap may be aflibercept.

[0014] The injection device may also include a package configured to receive and / or support a syringe, comprising a cavity surface and at least one projection extending away from the cavity surface, the at least one projection configured to engage with the barrel of the syringe to allow or facilitate airflow through the space between the cavity surface and the syringe.

[0015] The injection device may also include a package configured to receive and / or support a syringe, the package comprising a hollow surface, the hollow surface defining at least one stop surface configured to engage with the barrel of the syringe and to prevent and / or limit the movement of the plunger rod.

[0016] This disclosure will be better understood by interpreting the following description in conjunction with the accompanying drawings. Some of the drawings are simplified by omitting selected elements in order to more clearly illustrate other elements. Such omissions of elements in some drawings do not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments, unless expressly described in the corresponding specification. Furthermore, none of the drawings are necessarily shown to exact scale. [Brief explanation of the drawing]

[0017] [Figure 1] This is a perspective view of an exemplary injection device having a syringe comprising a barrel (partially shown), a flange, a plunger rod (partially shown), and a retaining element, according to an aspect of the present disclosure. [Figure 2A] This is a perspective view of another exemplary injection device having a barrel, a flange, and a stopper according to an aspect of the present disclosure. [Figure 2B] Figure 2A is an exploded perspective view of the device shown, illustrating the retaining clip separated from the barrel and flange. [Figure 2C] This is a front view of the device shown in Figure 2A, showing the barrel (partial view) and stopper. [Figure 2D] Figure 2A is a bottom view of the stopper and syringe shown. [Figure 2E] Figure 2B is a perspective view of the stopper shown. [Figure 2F] Figure 2B is a front view of the stopper shown. [Figure 2G] Figure 2B is a top view of the stopper shown. [Figure 2H] Figure 2B is a bottom view of the stopper shown. [Figure 3A] This is a top perspective view of another exemplary stopper having a barrel, a flange, and a stopper according to an aspect of the present disclosure. [Figure 3B] Figure 3A is a perspective view of the stopper shown from below. [Figure 4A]Perspective view from above of another exemplary backstop having a barrel, a flange, and a backstop, according to an aspect of the present disclosure. [Figure 4B] Perspective view from below of the backstop shown in FIG. 4A. [Figure 5A] Perspective view of another exemplary injection device having a barrel (partially shown), a flange, and a backstop, according to an aspect of the present disclosure. [Figure 5B] Perspective view of the backstop shown in FIG. 5A. [Figure 5C] Front view of the backstop shown in FIG. 5A. [Figure 5D] Top view of the backstop shown in FIG. 5A. [Figure 5E] Bottom view of the backstop shown in FIG. 5A. [Figure 6A] Perspective view of another exemplary injection device having a barrel (partially shown), a flange, and a backstop, according to an aspect of the present disclosure. [Figure 6B] Perspective view of the backstop shown in FIG. 6A. [Figure 6C] Front view of the backstop shown in FIG. 6A. [Figure 6D] Top view of the backstop shown in FIG. 6A. [Figure 6E] Bottom view of the backstop shown in FIG. 6A. [Figure 7A] Perspective view of another exemplary injection device having a barrel (partially shown), a flange, and a backstop, according to an aspect of the present disclosure. [Figure 7B] Perspective view of the backstop shown in FIG. 7A. [Figure 7C] Front view of the backstop shown in FIG. 7A. [Figure 7D] Top view of the backstop shown in FIG. 7A. [Figure 7E] Bottom view of the backstop shown in FIG. 7A. [Figure 8A] Perspective view of another exemplary injection device having a barrel (partially shown), a flange, and a backstop, according to an aspect of the present disclosure. [Figure 8B] Figure 8A is a front view of the stopper shown. [Figure 8C] Figure 8A is a top view of the stopper shown. [Figure 9A] This is a perspective view of another exemplary injection device according to an aspect of the present disclosure. [Figure 9B] Figure 9A is a front view of the stopper shown. [Figure 9C] Figure 9A is a top view of the stopper shown. [Figure 9D] Figure 9A is a bottom view of the stopper shown. [Figure 10A] This is a perspective top view of an exemplary package that may be used, for example, to fix and / or hold an injection device during external sterilization of the injection device, according to an aspect of the present disclosure. [Figure 10B] Figure 10A is a perspective view of the bottom of the package shown. [Figure 10C] Figure 10 is a perspective top view of the package shown, which has an exemplary injection device. [Figure 11] This is a perspective top view of another exemplary package according to an aspect of the present disclosure, which may be used, for example, to fix and / or hold an injection device during external sterilization of the injection device. [Figure 12A] This is a top view of another exemplary package with the top protective cover removed, which may be used, for example, to fix and / or hold an injector device during external sterilization of the injector device, according to an aspect of the present disclosure. [Figure 12B] Figure 12A is a top view of an exemplary package with the top protective cover in place. [Figure 13A] Figure 1 shows various perspective views of the syringe, highlighting areas of the syringe that are particularly susceptible to gas blockage during and after the external sterilization process. [Figure 13B] Figure 1 shows various perspective views of the syringe, highlighting areas of the syringe that are particularly susceptible to gas blockage during and after the external sterilization process. [Figure 13C]Figure 1 shows various perspective views of the syringe, highlighting areas of the syringe that are particularly susceptible to gas blockage during and after the external sterilization process. [Modes for carrying out the invention]

[0018] This disclosure relates, in general, to an infusion device that can be operated safely and reliably for a user to administer a drug or for a patient to self-administer a drug when the user is the user. More specifically, this disclosure relates, in general, to an infusion device comprising a syringe and a stopper and / or package configured to receive and / or support the syringe. The infusion device may be a syringe, such as a pre-filled syringe containing a drug. These components may be suitable for external sterilization processes, whether separately or together. In a more specific example, using these components separately or together may allow a manufacturer or user to achieve a desired level of contaminating microbial kill while minimizing or avoiding undesirable effects on the drug.

[0019] As used herein, the term "approximately" means within + / - 10% of the minimum significant figures.

[0020] Due to the engagement between stoppers and syringes, as is well known in the art, sterilization gases may not be able to reach the occluded or partially occluded spaces between each stopper and the syringe, thereby failing to completely or adequately sterilize these surfaces. In addition, or instead, the sterilization gases may not be effectively purged from these occluded or partially occluded spaces, thereby exposing the drug to the sterilization gases beyond the specified sterilization steps in the chamber. Either and / or both of these situations may be undesirable. As a more specific example, Figures 13A–13C include various diagrams of the syringe barrel and flange, whose surfaces are particularly susceptible to occlusion, shown in dark shading and indicated by reference numerals 11c (proximal section of barrel 11) and 12c (proximal section of flange 12). For example, the upper flange surface 12c and the outer barrel surface 11c may be particularly susceptible to occlusion due to their engagement with stoppers, respectively, as is well known in the art.

[0021] Figure 1 is a perspective view of an injection device 10, such as a syringe 10, which generally has a barrel 11 having a proximal open end 11a, a distal end 11b (Figures 2A, 2B, 12A, and 12B), a cavity 13, a flange portion 12, a plunger rod 16, a stopper component 18 (Figures 12A and 12B), and a return stopper 20.

[0022] The distal end 11b of the syringe barrel includes and / or supports other suitable components to complete the fluid path to the needle or patient. For example, the distal end of the syringe barrel may include a Luer lock component 17 (Figures 2A and 2B) and / or a protective cap 19 (Figure 12A) covering the Luer lock component 17. Before use, the protective cap 19 may be removed so that the Luer lock component 17 can receive the needle. The proximal end 11a of the syringe barrel (see Figure 2A) may push a stopper component 18 distally 15 to receive a plunger rod 16 for discharging the drug from the syringe 10. For example, the stopper component 18 may form a fluid-tight relationship with the cavity 13, while also moving distally 15 along the cavity 13, pushing the drug out of the distal end of the syringe 10. The plunger rod 16 may include a plunger rod end 14 having a larger diameter than the main body of the plunger rod 16 in order to limit the distance the plunger rod 16 travels in the distal direction 15 and / or to make it easier for the user to push the plunger rod 16. The plunger rod 16 may be a unidirectional component, and since the plunger rod is not fixedly connected to the stopper, when the plunger rod 16 moves in the proximal direction (opposite to the distal direction 15), the stopper 18 does not move with the plunger rod 16.

[0023] Figures 12A and 12B show syringes 10 (collectively packaged syringes 8) placed in a package 9, such as a blister pack 9. The package 9 includes a base portion 9a and a cover 9b (Figure 12B), such as a Tyvek cover 9b, which extends substantially or completely across the base portion 9a and / or is sealed to the base portion 9a. The Tyvek cover 9b may extend outside the frame of the base portion 9a in at least one portion, such as one side, to facilitate removal of the Tyvek cover 9b. Furthermore or alternatively, the base portion 9a may include a tab portion 9c that is not sealed by the Tyvek cover 9b to facilitate easy removal.

[0024] The syringe barrel 11 may be made of plastic, glass, or any suitable material. More specifically, the syringe barrel may be made of a plastic material comprising at least one of the following materials: a specific grade of polypropylene (homopolymer and / or copolymer polypropylene), cycloolefin copolymer (COC), cycloolefin polymer (COP), or other suitable material. More specifically, the syringe barrel may be made of cycloolefin polymer (COP).

[0025] The retaining arm 20 may be coupled or connected to the syringe 10 to improve the grip, usability, and / or ergonomic design of the syringe. The flange 12 may have a diameter larger than the diameter of the syringe barrel 11 and may serve as a finger rest, allowing the user to manipulate the syringe 10 during use. For example, the user may rest two or more of their fingers on the flange 12 while pressing the plunger rod end 14 with their thumb. In a more specific example, the retaining arm 20 may be coupled to the flange portion 12 to effectively extend the flange portion and thereby increase the length of the grip surface. In an even more specific example, in certain applications of the syringe, particularly in ophthalmic applications, the user may desire a larger effective grip surface to improve the grip, usability, and / or ergonomic design of the syringe. However, due to space constraints during manufacturing and distribution, and the economies of scale of using a standard syringe / flange configuration, increasing the size of the flange portion 12 may not be desirable. Furthermore, syringes are commonly used in autoinjectors with external shapes that are incompatible with syringes having enlarged flange sizes. Therefore, it may be desirable to have additional components, such as return retaining elements, that can be attached to and / or coupled to the syringe at the time of the manufacturing process.

[0026] The retaining ring can be manufactured from any suitable material. For example, the retaining ring can be molded from polypropylene ("PP") or acrylonitrile butadiene styrene ("ABS"). ABS may have the advantage of being harder than PP and other materials, and the retaining ring may be lighter. As a more specific example, if the retaining ring is made of PP, it may have a minimum wall thickness of 1.5 mm, while if the retaining ring is made of ABS, it may have a minimum wall thickness of 1 mm.

[0027] The retaining element 20 may also be used to restrict, limit, reduce, or prevent the accidental movement of the stopper component 18 relative to the syringe 10. For example, the retaining element 20 may be fitted onto the flange 12 to reduce or prevent the accidental movement of the plunger rod 16. For example, as shown in Figure 1, the retaining element 20 may have a locking surface 34 that engages with the plunger rod 16 to restrict or prevent relative movement between these two components in the distal direction 15. In a more specific example, the plunger rod 16 may have a locking ring 16a, which has a larger diameter than the rest of the plunger rod 16 but a smaller diameter than the cavity, and the locking surface 34 of the retaining element 20 may have a smaller diameter than the locking ring 16a so that the locking ring 16a cannot move proximal beyond the retaining element 20. This configuration would function to restrict the proximal movement of the plunger rod 16.

[0028] For the reasons stated above, and possibly other reasons, users generally do not remove the stopper 20 before using syringe 10.

[0029] External sterilization of injection devices during the manufacturing and / or assembly process may be desirable and / or required by regulations. Furthermore, external sterilization is required for some applications of pre-filled syringes, such as certain ophthalmic applications. For example, 21 CFR 200.50 states that "ophthalmic formulations and dispensers should be sterile." In addition, ANSI / AAMI ST67:2011 / (R)2017, "Sterilization of healthcare products - Requirements and guidance for selecting the level of sterility assurance (SAL) for products labeled as 'sterile'," states in section 4.1.1 that "generally, SAL values ​​of 10 to 6 are used for final sterilization of healthcare products." Furthermore, Appendix A of ST67 and EN556-1:2006 states the following: "Sterilization of medical devices - Requirements for medical devices to be marked as "sterile" - Part 1: Requirements for medical devices to be final sterilized"... Section 4.1: "For a medical device to be final sterilized to be marked as "sterile," the theoretical probability of the presence of viable microorganisms on / inside the device is 1 × 10⁻⁶." -6 The following is required: Therefore, the number of contaminating microorganisms should be 1 × 10⁻⁶. -6 (For example, 1 × 10 -6 It is desirable and / or may be required that it be less than )

[0030] Accordingly, the embodiments disclosed herein are particularly advantageous in these types of applications. As used herein, the terms “external sterilization” and / or “to externally sterilize” refer to the sterilization process of an infusion device after it has been assembled. For example, the infusion device shown in the figure may be externally sterilized after the syringe 10 (containing the drug in the cavity 13), plunger rod 16, stopper 20, and protective cap (not shown) have all been assembled. During the external sterilization process, the infusion device is typically placed in a sterilization chamber and exposed to a sterilization gas such as ethylene oxide (EtO), nitrogen dioxide (NO2), evaporated hydrogen peroxide (VPHP), carbon dioxide (CO2), chlorine dioxide, or any other suitable gas for a predetermined time and under other specified conditions (such as temperature and pressure). After the sterilization cycle, the sterilization gas is purged from the chamber, and for another predetermined time and under other specified conditions (such as temperature and pressure), the infusion device remains in the chamber (substantially or completely free of the sterilization gas).

[0031] Figures 2A to 2H show another exemplary retaining arm 120 that may be used with a syringe 10 as shown in Figures 2A to 2C. The retaining arm 120 may generally include a collar portion 130 extending around at least a portion of the syringe 10, an external grip portion 140 for handling and / or gripping by the user, at least one projection such as a raised portion 150 that helps allow or facilitate airflow through the space between the retaining arm and the syringe, a cavity 160 for receiving at least a portion of the syringe flange 12, and an opening 170 that allows a plunger rod 16 to extend through the retaining arm 120.

[0032] The collar portion 130, as best shown in Figures 2D to 2H, defines an inner surface 132 extending around at least a portion of the syringe 10. In a more specific example, the inner surface 132 is a roughly annular surface extending around most of the circumference of the barrel 11 of the syringe 10. In an even more specific example, the inner surface 132 extends around most of the circumference of the distal portion 11c of the barrel 11, which is highlighted in Figures 13A to 13C. In some embodiments, the “portion” of the barrel 11 surrounded by the inner surface 132 may be a portion of the circumference of the area of ​​the barrel 11, the entire circumference of the area of ​​the barrel 11, or any other discrete region of the surface of the barrel 11. The inner surface 132 may have approximately the same curvature as the barrel 11 and may extend around the barrel 11 over the length of the inner surface 132. As shown in Figure 2D, the inner surface 132 may extend into the inner surface of the collar 130 in a generally circular / annular manner, except where the collar 130 and the inner surface 132 are interrupted across the opening 134 of the collar 130, allowing the retaining ring 120 to connect with the syringe 10. In a more specific example, the opening 134 allows the retaining ring 120 to accept the syringe 10 by sliding the syringe 10 toward (or toward) the retaining ring 120 until the syringe 10 makes contact with the retaining ring 120 in a snap-fit ​​configuration. In another example, the inner surface 132 extends over approximately 270 degrees around the circumference of the barrel 11. The axial length of the collar 130 (measured along the axis of the barrel 11) is approximately 5 millimeters, but may have other suitable lengths. As the axial length of the collar 130 increases, the connection between the syringe 10 and the retaining ring 120 may become more secure. Similarly, or alternatively, as the axial length of the collar 130 increases, the center of gravity can move further away from the midpoint of the axial length. This makes it easier to orient the stopper 120 during manufacturing. As a more specific example, it may be desirable to use a “shaker” or “feeder” receptacle, such as a pan or bowl, to automate the assembly of syringes and to simplify the manufacturing process by orienting multiple stopper components in a shaking tray.A feeder bowl may have, for example, a central receiving opening with a spiral track along the side wall of the receiving opening, the spiral track carrying the parts upward through the side wall toward the upper edge of the receiving opening (where the parts may be supplied to an assembly station). Often, a feeder bowl is more reliable and / or effective if the center of gravity of the components is at least a certain distance from the midpoint of the axial length of the components, thereby ensuring that all or substantially all components flip toward the "heavier side" of the components. The center of gravity of the retainer 120 is shown by reference numeral 136 in Figure 2F. Furthermore, a feeder is often more reliable if the parts have some asymmetrical features (along at least one or two axes), and the feeder has a track edge or pattern that can push improperly oriented parts back into the bowl. In this case, the track edge or pattern feature acts as a gate; that is, when the part is oriented correctly, the part does not interact with this feature, but when the part is oriented incorrectly, the part interacts with this feature and falls back into the bowl.

[0033] As described above, the retaining arm 120 provides the user with a larger gripping surface than the flange 12 of the syringe 10. As a more specific example, the flange portion 12 shown in Figures 2A and 2B has a generally elliptical or oblong shape, with a maximum width 12a of about 13 millimeters and a barrel diameter 11 of about 9.5 millimeters. Thus, the flange portion 12 has an effective gripping surface of about 2 millimeters on each side. In comparison, the retaining arm 120 has a maximum width 120a of about 34 millimeters and a collar width 130b (Figures 2D and 2H) of about 12 millimeters. Thus, the external grip portion 140 of the retaining arm 120 has an effective gripping surface of about 11 millimeters on each side of the collar 130.

[0034] The external grip portion 140 has an angle 142 (Figure 2C) of approximately minus 25 degrees with respect to the top surface 144 of the stopper 120. Therefore, the external grip portion 140 has an angle of 115 degrees with respect to the syringe axis 11d. The angle of the external grip portion 140 with respect to the syringe axis 11d may be closer to 90 degrees (i.e., 135 degrees or less) than 180 degrees in order to allow the user to have a sufficient grip on the external grip portion 140. It may be more desirable for the external grip portion 140 to have a smaller angle with respect to the syringe axis 11d, such as 125 degrees or less, or 120 degrees or less, or 115 degrees or less. The external grip portion 140 may also include anti-slip or grip-enhancing features such as ribs or materials with a relatively high coefficient of friction.

[0035] As described above, the retaining element 120 may also include at least one projection, such as at least one ridge 150, which engages with the syringe 10 so that the inner surface of the collar 132 moves away from the syringe 10. In a more specific example, the retaining element inner surface 132 may include at least one projection 150, which extends away from the inner surface 132 and is configured to engage with the flange 12 and / or barrel 11 to allow or facilitate airflow through the space 152 between the inner surface 132 and the syringe 10. In Figures 2A to 2H, the retaining element includes five ridges 150a, 150b, 150c, 150d and 150e, which are generally spaced apart from each other around the inner surface of the collar 132, and more preferably equally spaced to form a five-point engagement between the retaining element 120 and the syringe 10. However, any suitable protrusions, such as one, two, three, four, five, six, seven, eight, nine, or ten or more, may be used. The protrusions 150 may be integrally formed with the inner surface 132 of the collar of the retaining element 120, or the protrusions 150 may be separate components attached to the inner surface 132 of the collar. In either case, the protrusions 150 may work together to enable a relatively secure fit between the retaining element 120 and the syringe 10, while providing a space 152 between the inner surface 132 and the syringe 10. For example, the protrusions 150 may engage with the barrel 11 in a snap-fit ​​relationship. The protrusions 150a, 150b, 150c, 150d, and 150e shown in the figure are generally parallel to the syringe axis 11d, but they may have other configurations. The raised portions 150a, 150b, 150c, 150d, and 150e shown in the figure may extend along the entire height 138 of the collar 130 as shown in Figure 2E, or the raised portions 150a, 150b, 150c, 150d, and 150e may extend along only a portion of the height of the collar 130.

[0036] By allowing airflow through the space 152 (Figure 2D) between the inner surface 132 and the syringe 10, the retaining element 120 and the syringe 10 work together to minimize or eliminate any obstruction between the inner surface 132 of the collar and the barrel or flange. For example, in one embodiment, the raised portion 150 is present only where the inner surface 132 of the collar engages with the barrel 11.

[0037] Alternatively, the projections of the retaining arm 120 shown in Figures 2A to 2H may have any suitable configuration that allows airflow through the space 152 between the inner surface 132 and the syringe 10. For example, in one embodiment, the projections may be replaced with a generally circular mass, bump or other nonlinear projection. In a more specific example, the projections of the retaining arm 120 may have a shape and size similar to the mass shown in Figures 4A and 4B, but may be located on the collar 130 instead of within a cavity.

[0038] As described above, the retaining element 120 includes a cavity 160 for receiving at least a portion of the syringe flange 12. In a more specific example, the cavity is defined by opposing surfaces 162, 164 (Figures 2E and 2F). As shown in Figure 2C, the distance between opposing surfaces 162 and 164 can be greater than the axial height of the flange 12 such that a gap 166 exists between at least one of the opposing surfaces 162, 164 and the upper and lower surfaces of the flange 12. In a more specific example, the gap 166 shown in Figure 2C is between the lower opposing surface 162 and the lower surface of the flange 12, but in other configurations, a similar gap may exist between the upper opposing surface 164 and the top surface of the flange or on both sides (upper and lower) of the flange 12. The gap 166 and other similar gaps described herein may be advantageous for allowing or facilitating airflow and / or preventing or reducing blockage space.

[0039] The cavity 160 is preferably shaped and sized to accommodate the entire flange 12 to facilitate secure engagement between the collar 130 and the barrel 11. Alternatively, the cavity 160 may be shaped and sized to accommodate the flange 12 in any orientation to simplify and / or improve manufacturing. For example, the cavity 160 may be shaped and sized to accommodate the flange 12 at its maximum width in any orientation. More specifically, the minimum width of the cavity 160 can be at least slightly greater than the maximum width of the flange 12 so that the flange can be inserted in any orientation and / or the flange 12 can rotate freely within the retaining element 120.

[0040] As described above, the opening 170 allows the plunger rod 16 to extend through the retaining ring 120. The opening 170 may be sized to allow free movement of the plunger rod 16 except when the locking ring 16a abuts against or engages with the surface defining the opening 170. In a more specific example, the opening 170 may have a diameter or width at least slightly larger than the diameter or width of the portion of the plunger rod shown as reference numeral 16 in Figure 1 (i.e., the section of the plunger rod having a positive-shaped cross-section), but the diameter or width of the opening 170 may be at least slightly smaller than the diameter or width of the locking ring 16a, thereby preventing or limiting the plunger rod 16 from moving proximal beyond the point shown in Figure 1.

[0041] Figures 3A to 3B show another exemplary retainer 220 that may be used with any suitable drug delivery device, such as a syringe, for example, the syringe 10 shown in the preceding figures. The retainer 220 may generally include a collar portion 230 extending around at least a portion of the syringe 10, an external grip portion 240 for handling and / or grasping by the user, at least one projection such as a raised portion 250 that helps to allow or facilitate airflow through the space between the retainer and the syringe, a cavity 260 for receiving at least a portion of the syringe flange 12, and an opening 270 that allows a plunger rod 16 to extend through the retainer 220. The retainer 220 may include the features described in Figures 2A to 2H and the corresponding paragraphs describing them, or other suitable features. Furthermore, the retainer 220 may further include at least one projection 255 extending into the cavity 260. As a more specific example, the retaining arm 220 includes a plurality of protrusions 255a, 255b, 255c, and 255d, respectively, which engage with, abut against, and / or are positioned adjacent to various parts of the flange 12, in order to allow or facilitate airflow into the cavity 260. This configuration can avoid or minimize the space or gap between the upper and lower opposing surfaces that define the cavity 260. This provides a more secure connection between the syringe 10 and the retaining arm 220, while also minimizing or reducing the obstructed air space.

[0042] Figures 4A to 4B show another exemplary retainer 320 that may be used with any suitable drug delivery device, such as a syringe, for example, the syringe 10 shown in the preceding figures. The retainer 320 may generally include a collar portion 330 extending around at least a portion of the syringe 10, an external grip portion 340 for handling and / or grasping by the user, at least one projection such as a raised portion 350 that helps to allow or facilitate airflow through the space between the retainer and the syringe, a cavity 360 for receiving at least a portion of the syringe flange 12, and an opening 370 that allows a plunger rod 16 to extend through the retainer 320. The retainer 320 may include the features described in Figures 2A to 2H and the corresponding paragraphs describing them, or other suitable features. Furthermore, the retainer 320 may further include at least one projection 355 extending into the cavity 360. In a more specific example, the retainer 320 may include a plurality of blocks extending from the opposing surface of the cavity. As a more specific example, the retaining arm 320 shown in Figures 4A and 4B comprises a total of eight blocks, four pairs of which are indicated by reference numbers 355a, 355b, 355c, and 355d. Each pair of blocks engages with, abuts against, and / or is positioned adjacent to various parts of the flange 12 to allow or facilitate airflow into the cavity 360. This configuration can avoid or minimize the space or gap between the upper and lower opposing surfaces that define the cavity 360. This provides a more secure connection between the syringe 10 and the retaining arm 320, while also minimizing or reducing the obstructed air space.

[0043] Figures 5A to 5E show another exemplary retainer 420 that may be used with any suitable drug delivery device, such as a syringe, for example, the syringe 10 shown in the preceding figures. The retainer 420 may generally include a collar portion 430 extending around at least a portion of the syringe 10, an external grip portion 440 for handling and / or gripping by the user, at least one projection such as a raised portion 450 that helps allow or facilitate airflow through the space between the retainer and the syringe, a cavity 460 for receiving at least a portion of the syringe flange 12, and an opening 470 that allows a plunger rod 16 to extend through the retainer 420. The retainer 420 may include the features described in Figures 2A to 2H and the corresponding paragraphs describing them, or other suitable features. The collar 430 shown in Figure 5A has a height 438 (e.g., length along axis 11d) that is lower than the collar height 138 shown in Figures 2A to 2H. As described above, a higher collar height may have certain advantages, and a lower collar height may have other advantages, but both or either design may be preferable. The center of gravity of the retainer 420 is indicated by reference numeral 436 in Figure 5C. Similarly or alternatively, a lower collar provides better access to the syringe barrel, so a lower collar height 138 may be advantageous for users who prefer to grip the barrel rather than gripping the retainer with their fingers. As a more specific example, a user may prefer to grip the syringe by the barrel such that the backs of their fingers engage with the external grip portion 440 rather than the fronts of their fingers engaging with the external grip portion 440.

[0044] Figures 6A–6E show another exemplary retainer 520 that may be used with any suitable drug delivery device, such as a syringe, for example, the syringe 10 shown in the preceding figures. The retainer 520 may generally include a collar portion 530 extending around at least a portion of the syringe 10, an external grip portion 540 for handling and / or grasping by the user, at least one projection such as a raised portion 550 that helps allow or facilitate airflow through the space between the retainer and the syringe, a cavity 560 for receiving at least a portion of the syringe flange 12, and an opening 570 that allows the plunger rod 16 to extend through the retainer 520. The retainer 520 may include the features described in Figures 2A–2H and the corresponding paragraphs describing them, or other suitable features. The center of gravity of the retainer 520 is indicated by reference numeral 536 in Figure 6C. The external grip portion 540 has an angle 542 of approximately minus 15 degrees with respect to the horizontal line (i.e., a line perpendicular to the axis). Therefore, the external grip portion 540 has an angle of 105 degrees with respect to the syringe axis 11d. The angle of the external grip portion 540 with respect to the syringe axis 11d may be closer to 90 degrees (i.e., 135 degrees or less) than 180 degrees in order to allow the user to have a sufficient grip on the external grip portion 540. It may be more desirable for the external grip portion 540 to have a smaller angle with respect to the syringe axis 11d, such as 125 degrees or less, or 120 degrees or less, or 115 degrees, or 105 degrees or less. The external grip portion 540 may also include anti-slip or grip-enhancing features such as ribs or materials with a relatively high coefficient of friction. As shown in Figure 6E, the return retainer 520 has a cutout 580 to reduce material costs and part weight.

[0045] Figure 7A shows another exemplary retainer 620 that may be used with any suitable drug delivery device, for example, a syringe such as the syringe 10 shown in the preceding figure. The retainer 620 may generally include a collar portion 630 extending around at least a portion of the syringe 10, an external grip portion 640 for handling and / or gripping by the user, at least one projection such as a raised portion 650 that helps allow or facilitate airflow through the space between the retainer and the syringe, a cavity 660 for receiving at least a portion of the syringe flange 12, and an opening 670 that allows the plunger rod 16 to extend through the retainer 620. The retainer 620 may include the features described in Figures 2A to 2H and the corresponding paragraphs describing them, or other suitable features. The center of gravity of the retainer 620 is indicated by reference numeral 636 in Figure 7C. The external grip portion 640 has an angle 642 of about minus 15 degrees with respect to the horizontal line (i.e., a line perpendicular to the axis). Therefore, the external grip portion 640 has an angle of 105 degrees with respect to the syringe axis 11d. The angle of the external grip portion 640 with respect to the syringe axis 11d may be closer to 90 degrees (i.e., 135 degrees or less) than 180 degrees in order to allow the user to have a sufficient grip on the external grip portion 640. It may be more desirable for the external grip portion 640 to have a smaller angle, such as 125 degrees or less, 120 degrees or less, 115 degrees or less, or 105 degrees or less with respect to the syringe axis 11d. The external grip portion 640 may also include anti-slip or grip-enhancing features such as ribs or materials with a relatively high coefficient of friction. As shown in Figure 7E, the return retainer 620 has a cutout 680 to reduce material costs and part weight. The return retainer 620 may be similar to the return retainer 520 shown in Figures 6A to 6E, except that the top surface has a more tapered outer shape, as shown in the corner and as indicated by reference numeral 682. A more tapered shape may be advantageous from an ergonomic, aesthetic, material cost, and / or component weight perspective. As a more specific example, the tapered shape of the retaining arm 620 may provide the user with a greater sense of precision.

[0046] Figures 8A to 8C show another exemplary retaining arm 720 that can be used with any suitable drug delivery device, such as a syringe like the syringe 10 shown in the preceding figure. The retaining arm 720 may be similar to the retaining arm 120 shown in Figures 2A to 2H, except that the external grip portion 740 has a more horizontal shape with respect to the syringe axis. A more horizontal shape may be advantageous in terms of grip.

[0047] Figures 9A–9D show another exemplary retainer 1020 that may be used with any suitable drug delivery device, such as a syringe, for example, the syringe 10 shown in the preceding figures. The retainer 1020 may generally include a collar portion 1030 extending around at least a portion of the syringe 10, an external grip portion 1040 for handling and / or gripping by the user, at least one projection such as a raised portion 450 that helps allow or facilitate airflow through the space between the retainer and the syringe, a cavity 1060 for receiving at least a portion of the syringe flange 12, and an opening 1070 that allows a plunger rod 16 to extend through the retainer 1020. The retainer 1020 may include the features described in Figures 2A–2H and the corresponding paragraphs describing them, or other suitable features. The center of gravity of the retainer 1020 is indicated by reference numeral 1036 in Figure 9B.

[0048] Lethal testing was performed on at least some of the stoppers shown in the figure. For example, before the sterilization cycle, 1 × 10^6 to 6 × 10^6 CFU (e.g., 1,000,000 to 6,000,000 CFU) of Geobacillus stearothermophilus was "added" to the pre-filled syringe. As a more specific example, 1 to 6 × 10^6 CFU of Geobacillus stearothermophilus was added to the stopper and barrel of the pre-filled syringe. As used herein, the term "CFU" refers to a "colony-forming unit." A "colony-forming unit" is a unit used to estimate the number of viable bacterial or fungal cells in a sample ("viability" means the ability to grow by binary fission under controlled conditions). Geobacillus stearothermophilus (formerly Bacillus stearothermophilus) is a rod-shaped, Gram-positive bacterium belonging to the phylum Firmicutes. This bacterium is thermophilic and widely distributed in soil, hot springs, and marine sediments, and can cause food spoilage. Therefore, pre-filled syringes were sterilized using various sterilization parameters, the lethality of the sterilization process was measured, and the level of sterility assurance (SAL) was assessed. Biological indicators were added to or directly inoculated into the pre-filled syringes, as described in more detail below.

[0049] Herein, an exemplary method for assembling and externally sterilizing a drug delivery device according to one embodiment of the present disclosure is described. During the first step, at least some individual components of the drug delivery device are often sterilized before being received by the manufacturing facility. For example, the syringe barrel and plunger stopper and any other components that may come into direct contact with the drug product may be sterilized during this step. In this step, various known methods may be used to sterilize various unassembled components of the drug delivery device, including but not limited to the components shown in the figure. During the second step, the barrel is filled and the stopper (also known as the “plunger stopper”) is assembled with the barrel. The assembly step may also include adding at least some of the following: a plunger rod, a flange extender, a tip cap with a Luer lock, a needle, a rigid needle shield and / or a return stopper, such as those shown in the figure. At least some of these components may be pre-assembled with each other, but they may also be assembled on the filling line, for example, if the filling process is carried out aseptically. Furthermore, syringes typically do not have both components, but rather either a tip cap with a Luer lock tip or a detachable (e.g., fixed) needle.

[0050] Next, the external sterilization process is carried out. First, the syringe is prepared. In the process using nitrogen dioxide (NO2), the preparation may include at least some or all of the following steps: removing the sample from the storage chamber, allowing the syringe to reach equilibrium at room temperature for a desired amount of time (e.g., 30 minutes, 90 minutes, 2 hours, or any desired amount of time), and placing the syringe in the sterilization chamber. The preparation may be carried out inside or outside the chamber. When using ethylene oxide (EtO), the preparation steps may differ slightly from those described for NO2. For example, the syringe may be prepared inside the sterilization chamber (without gas injection) for 360 minutes (or another desired length of time). However, as with the process using NO2, the preparation steps using EtO may be carried out inside or outside the chamber.

[0051] Next, the sterilization chamber is closed, and all or substantially all of the air is expelled from the chamber. The sterilization chamber is then humidified to a desired setting, such as 75 or 80 (or any desired percentage of relative humidity).

[0052] Next, the desired sterile gas is injected and held in the chamber for a desired residence time. In recipes using NO2, gas injection may include some or all of the following steps: delivering a certain dose of NO2 by drawing a vacuum into the chamber for a desired amount of time (i.e., residence time) while injecting a desired amount of gas (dose concentration); purging the gas and releasing the vacuum; and then repeating these steps for a desired number of pulses. Once the desired number of pulses is complete, the gas is then finally purged and removed from the sterile chamber. Finally, the chamber is vented for a desired number of cycles (also known as "venting exchange") to ensure that all or substantially all of the sterile gas is flushed out of the syringe and package. The vacuum level may vary during these steps. For example, the vacuum during the residence time may be as low as approximately 590 Torr.

[0053] This method may include any appropriate parameters relating to the above process, such as the following: - The vacuum level may be approximately 100-500 Torr, approximately 150-400 Torr, approximately 150-300 Torr, or another appropriate vacuum level. - The dose concentration of NO2 may be approximately 2-20 milligrams per liter, approximately 2-10 milligrams per liter, approximately 2-7 milligrams per liter, or another appropriate dose concentration. - The chamber may have a relative humidity of approximately 70-90 percent or another suitable humidity. - The length of stay may be approximately 2-20 minutes, 2-12 minutes, 2-7 minutes, or another appropriate length of stay. - The number of pulses may be approximately 1-24, 1-12, 1-8, 1-4, 1-2, or another appropriate number of pulses. - The process of ventilating the sterile chamber may include ventilating the sterile chamber for approximately 12 to 35 cycles or another appropriate number of cycles.

[0054] As a more specific example, Table 1 shows different variables in 10 different exemplary recipes for sterilizing drug delivery devices using nitrogen dioxide (NO2).

[0055] [Table 1]

[0056] As another example, Table 2 shows different variables in six different exemplary recipes for sterilizing drug delivery devices using NO2.

[0057] [Table 2]

[0058] In Tables 1 and 2, the label in the "Vacuum Level (Torr)" column refers to the vacuum force applied to the external sterilization chamber during step 4 in Figure 1. As shown, the vacuum force varies from 20 Torr to 500 Torr, although different vacuum forces may be appropriate. The listed vacuum force numbers are inversely related to their strength; a force of 20 Torr is stronger than a force of 100 Torr, and a force of 100 Torr is stronger than a force of 500 Torr (atmospheric pressure is typically around 760 Torr). Stronger vacuum forces are more likely to result in the elimination of the desired number of contaminating microorganisms. However, if the vacuum force is too high, the process may have undesirable effects on the drug, such as causing the plunger to move undesirably (i.e., move across the sterile barrier, causing sterility to be compromised). The "NO2 Dose (mg / L)" column refers to the NO2 concentration (mg) per liter of air introduced into the external sterilization chamber. As shown, the doses in Tables 1 and 2 vary from 5 to 20 mg / L, but different doses may be appropriate. Higher doses of NO2 during this process result in faster and more complete sterilization of the drug delivery device. However, if the dose of sterilization gas is too high, the process may have undesirable effects on the drug, such as contamination of the inside of the drug barrel with sterilization gas (i.e., intrusion of sterilization gas and / or discoloration of syringe components). The "Relative Humidity (%RH)" column refers to the relative humidity inside the external sterilization chamber. As shown, the relative humidity in each column of Tables 1 and 2 varies from 75% to 80%, but different relative humidity values ​​may be appropriate. Increasing the relative humidity also increases the likelihood of killing the desired number of contaminating microorganisms. The "Dwell Time (minutes:seconds)" column refers to the amount of time the drug delivery device is in the sterilization chamber while sterilization gas is present. For Tables 1 and 2, "Total Dwell Time" is equal to the "Dwell Time" column multiplied by the "Number of Pulses" column. For example, for the first row in Table 1, the sample has a total stay time of 80 minutes. As shown, the stay times listed in Tables 1 and 2 vary from 5 to 20 minutes, but different stay times may be appropriate. Stay time also increases the likelihood of killing the target number of contaminating microorganisms.However, if the residence time is too high, the process may have undesirable effects on the drug, such as contaminating the inside of the drug barrel with sterile gas. The “Number of Pulses” column refers to the number of times gas is injected by drawing a vacuum during the NO2 process. As shown, the pulses in each row of Tables 1 and 2 vary from 1 to 24, but different values ​​may be appropriate. A higher number of pulses is more likely to indicate the killing of the desired number of contaminating microorganisms. However, if the number of pulses is too high, the process may have undesirable effects on the drug, such as contaminating the inside of the drug barrel with sterile gas. The column referring to “Number of Vents” refers to the number of times the chamber is vented after the gas has been purged from the chamber. An exemplary process may use 12, 24, 28, 70 vents or any desired number of vents. Up to a certain point, by increasing the number of vents, manufacturers can increase the likelihood that all or substantially all of the sterile gas is removed from the syringe and package (post-purge).

[0059] For each recipe (NO2) in Table 1 and Figure 2, each step in Box 1 of Figure 1 can be carried out at room temperature (25 degrees Celsius), although other suitable temperatures may be used. However, other temperatures such as approximately 2 to 8 degrees Celsius, or any other desirable temperature that does not have an undesirable effect on the chemicals, may be used.

[0060] Table 3 shows different variables for 10 different exemplary recipes for sterilizing drug delivery devices using NO2.

[0061] [Table 3]

[0062] When using ethylene oxide (EtO), the gas injection process is slightly different. For example, the gas injection process may include some or all of the following steps: delivering a certain dose of EtO by drawing a vacuum into the chamber for a desired amount (dose concentration) of gas while injecting it for a desired amount of time (i.e., residence time), and then purging the gas. In other words, when using EtO, it may be preferable to perform only one pulse rather than the preferred multiple pulses described above for NO2. Regarding the gas purging process, an exemplary process using EtO proceeds as described above for NO2.

[0063] In particular, lethal tests were conducted on different return stoppers, such as those disclosed herein. Table 4 shows the results of lethal tests evaluating the effectiveness of NO2-based sterilization on various pre-filled syringes with and without return stoppers.

[0064] [Table 4]

[0065] For each recipe number, five samples (or at least five test sites for one or more samples) were tested. Table 4 shows, in the "Added Rebound Agent" and "Added Barrel" columns, how many of the five samples for each recipe reached the target lethality. For example, the target lethality for this test was a sterility assurance level (SAL) of 10^6. In other words, the target lethality for this test was a 6-log reduction in the number of bacteria present (before sterilization vs. after sterilization). As a more specific example, for recipe number 1, one of the five samples tested in the rebound agent area (the row corresponding to recipe number 1 in the "Added Rebound Agent" column) reached this target lethality, while all five samples tested in the barrel area (the row corresponding to recipe number 1 in the "Added Barrel" column) reached this target lethality. Note that the test results for added stoppers in recipes 1-4 (using stoppers without protrusions) were obtained by direct inoculation, while the test results for added stoppers in recipes 5-14 (using stoppers 120 or 220 shown in Figures 3-4) were obtained by biological indicators. Also note that the "-" symbol indicates that data has not been reported for these parameters / samples. Regardless of the difference in testing methods, samples tested with stoppers having protrusions achieved the target lethality at a higher rate than samples tested with stoppers without protrusions. As mentioned above, the protrusions minimize and / or block the obstruction space, instead allowing the bactericide to reach various components of the prefilled syringe, particularly the stopper area and flange area, completely or substantially.

[0066] Intrusion studies were also conducted for different sterilization parameters. As mentioned above, it is desirable to achieve the target lethality during external sterilization, but it is also desirable to reduce, minimize, and / or substantially prevent the intrusion of sterilization gases into the drug product chamber. However, the two objectives (achieving lethality and minimizing intrusion) may be conflicting or canceling interests. For example, some sterilization parameters that can improve the likelihood of achieving a higher lethality rate may increase the likelihood of sterilization gas intrusion. Table 5 below shows the results of intrusion studies evaluating the effects of different NO2-based sterilization recipes on drug product chambers.

[0067] [Table 5]

[0068] The last four columns on the right (collectively labeled "NO2 Content in Product (PPM)") refer to the amount of NO2 that entered the drug product container, more specifically the amount of NO2 that entered the drug container, and more specifically the NO2 level measured as parts per million nitrates in the liquid. The first three columns within this group, labeled "Day 1," "Day 14," and "Day 30," refer to the entry rates measured at different times after the sterilization process. The last column within this group, labeled "Control," refers to the baseline levels of NO2 and nitrates (NO3), which are the product of the sample (water for injection). The "unexposed" control sample provides a fundamental difference between the exposed sample and the control when compared to the "exposed" sample, such as on Day 1. For example, for test number 5, the entry rate on Day 1 is 0.342, and the control is 0.336, so the difference between the exposed and unexposed samples may be 0.006 PPM. Another potentially relevant parameter is that the test method may have an error rate of + / - 0.1 PPM.

[0069] In general, it may be desirable to minimize or substantially or completely block penetration, but it may also be desirable to avoid exceeding penetration levels of 3 PPM, 1 PPM, or another appropriate limit. It may be desirable to use “raw” 30-day values, such as those listed in the columns of Table 5 above, or to use “adjusted” 30-day values ​​adjusted based on control values. As shown in Table 5 above, almost all penetration values ​​are below the 1 PPM threshold (the only exception being the 30-day measurement for sample 11). Also, as shown in Table 5 above, different vacuum forces, pulse rates, and aeration rates have different effects on penetration measurements. These parameters and trends can be used to determine sterilization parameters that achieve the target lethality while maintaining below the desired penetration level.

[0070] Figures 10A–10C show a package 800 for an infusion device according to another embodiment of the present disclosure. The package 800 includes a support wall 810 for receiving and supporting an infusion device, such as a syringe 10 shown in other figures. The package 800 may be used during various stages of the lifecycle of an infusion device, including between at least one of the following steps: external sterilization, transport to the user, storage before use by the user, preparation of the infusion device and injection site for use, and storage after injection. For example, in a manufacturing setting, a manufacturer may place an assembled pre-filled syringe (e.g., syringe barrel, stopper, plunger rod, drug and protective cap) into the package such that the assembled pre-filled syringe is supported by the package 800 by a snap-fit ​​connection between the support wall 810 and the syringe barrel. The manufacturer may perform an external sterilization step on the assembled pre-filled syringe while it is supported by the package 800. Subsequently, the manufacturer may apply a protective coating (not shown) to the top wall 812 of the package to form an airtight seal and define a chamber 814 within the package 800 that protects the assembled pre-filled syringe from external air and / or contaminants. The protective coating may be a transparent plastic layer bonded to the package 800 by any suitable means, such as an adhesive and / or heat-sealing process. During another stage of the infusion device's lifestyle, the user may peel off the protective coating to gain access to the pre-filled syringe.

[0071] The package 800 may include protrusions or spacers to limit surface area contact between the tray and the infusion device, thereby reducing or preventing the enclosed space between them. For example, the package 800 may include protrusions 820 that extend outward from the support wall 810 of the package 800, creating a gap between the infusion device and the package 800, thereby minimizing or preventing the enclosed space between the infusion device and the package 800. Thus, the protrusions or spacers enable an effective connection between the package and the infusion device while allowing sterilization gas to flow between each component during the external sterilization process. The protrusions or spacers may also improve the ventilation of sterilization gas after the external sterilization process (reducing time and / or improving effectiveness). The package 800 shown in Figures 10A to 10C includes two protrusions 820, but any appropriate number may be used. Also, the protrusions 820 shown in Figures 10A to 10C have a generally pyramidal shape, but may have any appropriate shape. As another example, the package 800 does not have to include a snap-fit ​​configuration with the syringe, but instead may allow the syringe to sit inside the package 800 and allow sterilization gas to flow between the components during an external sterilization process. In such a design, the gap between the support walls 810 is larger than the diameter of the syringe to provide space between the support walls 810 and the syringe. Also in such a design, it is preferable that the Tyvek cover prevents the syringe from coming out of the package.

[0072] The package 800 includes a hollow central section 840 (between two snap-fit ​​areas 810) that is wider than other known central sections. For example, the distance 844 shown in Figure 10C is preferably at least 1.5 centimeters to give the user space to grasp the syringe 10 when removing the syringe 10 from the package 800. More preferably, the distance 844 shown in Figure 10C is preferably at least 2.0 centimeters. Even more preferably, the distance 844 shown in Figure 10C is preferably at least 2.5 centimeters. Even more preferably, the distance 844 shown in Figure 10C is preferably at least 3.0 centimeters. Even more preferably, the distance 844 shown in Figure 10C is preferably at least 4.0 centimeters. Even more preferably, the distance 844 shown in Figure 10C is preferably at least 5.0 centimeters. Even more preferably, the distance 844 shown in Figure 10C is preferably at least 6.0 centimeters.

[0073] Figure 11 shows a package 900 of an injection device according to another embodiment of the present disclosure. For example, the package 900 includes a raised wall section 960. The raised wall section 960 is located near the portion of the package 900 that receives the plunger rod and secures the plunger rod of the injection device and / or prevents unintended movement of the plunger of the injection device. For example, the package 900 shown in Figure 11 includes a support wall 910 similar to those shown in Figures 10A–10C for receiving and supporting the barrel of the syringe 10. However, the package 900 shown in Figure 11 also includes a raised wall section 960, which has, for example, a side wall 960a for receiving and supporting the plunger rod 16 to receive the plunger rod end 14 and to prevent and / or limit distal movement of the plunger rod end 14 (and the entire plunger rod 16) until the syringe 10 is removed from the package 900, and another wall 960c extending substantially perpendicular to the support wall 910 and the side wall 960a.

[0074] Naturally, the devices and methods described herein may have one or more advantages over the prior art, and any one or more of these may exist in particular embodiments according to the features of the disclosure included in those embodiments. Other advantages not specifically mentioned herein may be understood in the same way.

[0075] Preferably, pre-filled syringes do not have an internal coating. Syringes may also have coatings on their external surfaces that come into contact with the environment, such as an oxygen barrier coating.

[0076] The syringe barrel may have a length of 45–85 mm, 60–65 mm, or another suitable length. The length of the syringe barrel is the distance from the rear end to the opening where the needle is attached (but not including the needle, if present).

[0077] Syringe barrels can have an inner diameter of 4 to 6.5 mm. If the syringe has a nominal maximum filling volume of 1 ml, the inner diameter of the syringe barrel may be 5.5 to 6.5 mm. If the syringe has a nominal maximum filling volume of 0.5 ml, the inner diameter of the syringe barrel may be 4 to 5 mm.

[0078] The walls of the syringe barrel may have a thickness of at least 1 mm, approximately 1–3 mm, approximately 1.5–3 mm, or approximately 2.4–2.8 mm. The wall thickness limits or prevents sterile gas from entering the inside of the syringe, thereby minimizing or preventing contact with the liquid formulation contained in the pre-filled syringe.

[0079] The above description refers to various devices, assemblies, components, subsystems, and methods of use related to drug delivery devices. Devices, assemblies, components, subsystems, methods, or drug delivery devices may further include, or be used with, drugs specified below, as well as their generic and biosimilar equivalents. As used herein, the term "drug" may be interchangeable with other similar terms and may refer to any type of drug or therapeutic material, including conventional and non-conventional pharmaceuticals, dietary supplements, supplements, biological preparations, biological activators and compositions, large molecules, biosimilars, bioequivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic drugs. Non-therapeutic injectable materials are also included. Drugs may be in liquid form, lyophilized form, or reconstituted from lyophilized form. The following list of exemplary drugs should not be considered exhaustive or restrictive.

[0080] The drug is contained in a reservoir. In some cases, the reservoir is a pre-filled syringe. The pre-filled syringe may have a maximum filling volume, i.e., the maximum volume that can be occupied by the syringe, of 0.3 ml to 1.5 ml, preferably 0.5 ml to 1.0 ml. The amount of liquid composition filled into the syringe may be about 0.05 ml to 1.0 ml, about 0.1 ml to 0.5 ml, about 0.14 ml to 0.3 ml, or about 0.15 ml to 0.2 ml. The syringe is usually filled with more than the amount actually administered to the patient to account for any dead space in the syringe and needle, as well as losses incurred by preparing the syringe for injection. Therefore, the amount actually administered to the patient may be 0.01 ml to 1 ml, 0.02 ml to 0.5 ml, 0.025 ml to 0.5 ml, 0.03 ml to 0.05 ml, or 0.05 ml.

[0081] In some embodiments, the reservoir of the pre-filled syringe contains a VEGF inhibitor. For example, the VEGF inhibitor may be a non-antibody VEGF inhibitor. The term "VEGF inhibitor" refers to a molecule that specifically interacts with VEGF and inhibits one or more of its biological activities, such as its mitogenic activity, angiogenesis, and / or vascular permeability activity. VEGF inhibitors are intended to include both anti-VEGF antibodies and their antigen-binding fragments, as well as non-antibody VEGF inhibitors. Non-antibody VEGF inhibitors include aflibercept, pegaptanib, and antibody mimetic drugs. A non-antibody VEGF inhibitor may be a VEGF trap. Preferably, the non-antibody VEGF inhibitor is aflibercept. Aflibercept, currently marketed under the name Eylea® and also known as a VEGF trap, is a recombinant human soluble VEGF receptor fusion protein in which a portion of the extracellular domains of human VEGF receptors 1 and 2 are fused to the Fc portion of human IgGl (Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99(17):11393-11398, International Publication No. 00 / 75319A1, U.S. Patent No. 7,070,959). Aflibercept contains the Ig domain 2 of VEGFR1 and the Ig domain 3 of VEGFR2 fused to the Fc domain of IgG1.

[0082] In some embodiments, the reservoir of the drug delivery device may be filled with a colony-stimulating factor such as granulocyte colony-stimulating factor (G-CSF), or the device may be used with a colony-stimulating factor such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF preparations include, but are not limited to, Neulasta® (pegfilgrastim, PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF) and Neupogen® (filgrastim, G-CSF, hu-MetG-CSF). In other embodiments, the drug delivery device may contain or be used with an erythropoiesis-stimulating preparation (ESA), which may be in liquid or lyophilized form. An ESA is any molecule that stimulates erythrocyte production. In some embodiments, the ESA is an erythropoiesis-stimulating protein. As used herein, “erythropoiesis-stimulating protein” means any protein that directly or indirectly causes activation of the erythropoietin receptor by, for example, binding to the receptor and causing receptor dimerization. Examples of erythropoiesis-stimulating proteins include erythropoietin and its variants, analogs, or derivatives that bind to and activate the erythropoietin receptor; antibodies that bind to and activate the erythropoietin receptor; or peptides that bind to and activate the erythropoietin receptor.Examples of erythrocyte production-stimulating proteins include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), and Binocrit® (epoetin a). Examples include, but are not limited to, epoetin alpha (alpha), epoetin alpha Hexal, Abseamed® (epoetin alpha), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alpha, epoetin beta, epoetin iota, epoetin omega, epoetin delta, epoetin zeta, epoetin theta, and epoetin delta, PEGylated erythropoietin, carbamylated erythropoietin, and their molecules, variants, or analogues.

[0083] Certain exemplary proteins, including their fusions, fragments, analogs, biosimilars, variants, or derivatives, are described below: OPGL-specific antibodies, peptide bodies, and related proteins, including fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies (also referred to as RANKL-specific antibodies, peptide bodies, etc.); myostatin-binding proteins, peptide bodies, and related proteins, including myostatin-specific peptide bodies; IL-4 receptor-specific antibodies, peptide bodies, and related proteins, particularly those that suppress IL-4 and / or IL-13 receptor-mediated activity; and inter - Leukin-1 receptor 1 ("IL1-R1") specific antibodies, peptide bodies, related proteins, etc.; Ang2 specific antibodies, peptide bodies, related proteins, etc.; NGF specific antibodies, peptide bodies, related proteins, etc.; CD22 specific antibodies, peptide bodies, related proteins, etc., especially dimers of human-mouse monoclonal hLL2γ chain disulfide bound to human-mouse monoclonal hLL2κ chain, for example, human CD22 of epratuzumab (CAS registry number 501423-23-0) Human CD22-specific IgG antibodies, including but not limited to human CD22-specific fully humanized antibodies such as 2-specific fully humanized antibodies; human CD22-specific antibodies, including but not limited to humanized and fully human monoclonal antibodies; IGF-1 receptor-specific antibodies, peptide bodies, and related proteins, including but not limited to anti-IGF-1R antibodies; B7RP-specific fully human monoclonal IgG2 antibodies, including but not limited to fully human IgG2 monoclonal antibodies that bind to the epitope of the first immunoglobulin-like domain of B7RP-1; B7-related protein 1-specific antibodies, peptide bodies, and related proteins, including but not limited to those that suppress the interaction between B7RP-1 and ICOS, the natural receptor for B7RP-1 on activated T cells (also referred to as "B7RP-1", B7H2, ICOSL, B7h, and CD275); for example, HuMax such as 146B7 This includes, but is not limited to, IL-15 antibodies and related proteins, particularly IL-15-specific antibodies such as humanized monoclonal antibodies, peptide bodies, related proteins, etc.; human IFNIFN γ-specific antibodies, peptide bodies, and related proteins, including but not limited to γ-specific antibodies, and fully human anti-IFN γ antibodies; TALL-1 specific antibodies, peptide bodies, and related proteins, as well as other TALL-specific binding proteins; parathyroid hormone ("PTH") specific antibodies, peptide bodies, and related proteins; thrombopotiene receptor ("TPO-R") specific antibodies, peptide bodies, and related proteins; and fully human monoclonal antibodies that neutralize hepatocyte growth factor / dispersion factor (HGF / SF) on the HGF / SF:cMet axis. Hepatocyte growth factor ("HGF")-specific antibodies, peptide bodies, and related proteins, including those targeting HGF / SF (c-Met); TRAIL-R2-specific antibodies, peptide bodies, and related proteins; Activin A-specific antibodies, peptide bodies, and related proteins; TGF-β-specific antibodies, peptide bodies, and related proteins; Amyloid-β protein-specific antibodies, peptide bodies, and related proteins; and tans that bind to c-Kit and / or other stem cell factor receptors. c-Kit-specific antibodies, peptide bodies, and related proteins, including but not limited to proteins; OX40L-specific antibodies, peptide bodies, and related proteins, including but not limited to proteins that bind to OX40L and / or other ligands of the OX40 receptor; Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa or erythropoietin), GLP-1, Avonex® (interferon β-1a), Bexxar® (tositumomab, anti-CD22 monoclonal antibody), Betaseron® (interferon-β), Campath® (aremtuzumab, anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-α4β7)mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), Vectibix® (panitumumab), Xgeva( (Registered Trademark) (Denosumab), Prolia (Registered Trademark) (Denosumab), Enbrel (Registered Trademark) (Etanercept, TNF receptor / Fc fusion protein, TNF blocker), Nplate (Registered Trademark) (Romiplostim), Rilotumumab, Ganitumumab, Conatumumab, Brodalumab, Insulin in Solution, Infergen (Registered Trademark) (Interferon alfacon-1), Natrecor (Registered Trademark) (Nesiritide, Recombinant Human Type B Natriuretic Peptide (hBNP)), Kineret (Registered Trademark) (Anakinra), Leukine (Registered Trademark) (Sargamostim, rhuGM-CSF), LymphoCide (Registered Trademark) (Epiratuzumab, Anti-CD22 mAb), Benlysta (trademark) (lymphostat B, belimumab, anti-BlyS mAb), Metalyse (registered trademark) (tenecteplase, t-PA analog), Mircera (registered trademark) (methoxypolyethylene glycol-epoetin beta), Mylotarg (registered trademark) (gemtuzumab ozogamicin), Raptiva (registered trademark) (efalizumab), Cimzia (registered trademark) (certolizumab pegol, CDP870), Soliris (trademark) (eculizumab), paxerizumab (anti-complement C5), Numax (registered trademark) (MEDI-524), Lucentis (registered trademark) (ranibizumab), Panorex (registered trademark) (17-1A, edrecolomab), Trabio (registered trademark) (reldelimumab), TheraCimhR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem (registered trademark) (IDM-1), OvaRex (registered trademark) (B43.13), Nuvion (registered trademark) (vizilizumab), cantuzumab meltansine (huC242-DM1), NeoRecormon (registered trademark) (epoetin beta), Neumega (registered trademark) (oprelbequin, human interleukin-11), Orthoclone OKT3 (registered trademark) (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit (registered trademark) (epoetin alfa), Remicade (registered trademark) (infliximab, anti-TNFα monoclonal antibody), Reopro (registered trademark) (absiximab, anti-GP) (Ib / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanorimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alfa-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax®, Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor co-protein)), VEGF trap (IgG1 VEGFR1 Ig domain fused with Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimabe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO148 (golimumab, anti-TNFα mAb), HGS-ETR1 (mapatuzumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (saltumumab), M200 (boroxiximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. Clostridium difficile toxin A and toxin BC mAbs MDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adecatumumab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF fibrogen for idiopathic pulmonary fibrosis stage 1 (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2 mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12 mAb (ABT-874), anti-IL12 / IL23 mAb (CNTO1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO95), anti-IP10 ulcerative colitis mAb (MDX-1100), BMS-66513, anti-mannose receptor / hCGβ mAb (MDX-1307), anti-mesothelin dsFv-PE38 conjugate (CAT-5001), anti-PD1 mAb (MDX-1106(ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβmAb(GC-1008), TRAIL-2 mAb (HGS-ETR2), TWEAK mAb, VEGFR / Flt-1 mAb, ZP3 mAb (HuMax-ZP3)

[0084] In some embodiments, the drug delivery device may contain a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use, such as LUCENTIS® (ranibizumab). The drug delivery device may contain a recombinant humanized monoclonal IgG1 antibody including a human framework region and a mouse complementarity-determining region, such as AVASTIN® (bevacizumab). The drug delivery device may contain a humanized monoclonal single-chain Fv (scFv) antibody fragment, such as BEOVU® (brolucizumab-dbll), or may be used with a sclerostin antibody, such as but not limited to romosozumab, brosozumab, or BPS 804 / setorusumab (Mereo), and in other embodiments, a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9). Examples of such PCSK9-specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alilokuma). In other embodiments, the drug delivery device may contain or be used with rilotumumab, bixalomer, trevananib, ganitumumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device may be filled with, but are not limited to, OncoVEXGALV / CD;OrienX010;G207, 1716;NV1020;NV12023;NV1034; and NV1042, IMLYGIC® (tarimodine raharpalepvek) or another oncolytic HSV for the treatment of melanoma or other cancers, or the device may be used with them. In some embodiments, the drug delivery device may contain or be used with endogenous tissue inhibitors (TIMPs) of metalloproteinases, such as TIMP-3, but not limited to those mentioned above. Antibodies of the human calcitonin gene-related peptide (CGRP) receptor, such as erenumab and bispecific antibody molecules targeting the CGRP receptor and other headache targets, but not limited to those mentioned above, may also be delivered using the drug delivery device of this disclosure.In addition, bispecific T cell induction (BiTE®) antibodies, such as but not limited to BLINCYTO® (blinatumomab), may be used in or with the drug delivery devices of the Disclosure. In some embodiments, the drug delivery device may contain or be used with APJ macromolecule agonists, such as but not limited to apelin or its analogues. In some embodiments, therapeutically effective amounts of anti-thymoid-interstitial lymphocyte generating factor (TSLP) or TSLP receptor antibodies may be used in or with the drug delivery devices of the Disclosure.

[0085] While drug delivery devices, assemblies, components, subsystems, and methods have been described in terms of exemplary embodiments, they are not limited to exemplary embodiments. The detailed descriptions should be interpreted merely as examples and do not describe all possible embodiments of the disclosure. Many alternative embodiments can be carried out using either the current art or art developed after the filing date of this patent, but such embodiments would still fall within the scope of the claims defining the invention disclosed herein.

[0086] Those skilled in the art will understand that various modifications, changes, and combinations of the above embodiments can be made without departing from the spirit and scope of the invention disclosed herein, and that such modifications, changes, and combinations should be interpreted as falling within the scope of the concept of the invention.

Claims

1. An injection device, A syringe having a barrel and a flange, A stopper configured to be coupled to the syringe adjacent to the flange, The retaining arm has an inner surface including a C-shaped portion extending over the entire length of the C-shaped portion around at least a portion of the syringe, the C-shaped portion of the inner surface being interrupted by an opening that allows the retaining arm to receive the flange and / or the barrel. The C-shaped portion on the inner surface includes at least one projection extending away from the C-shaped portion on the inner surface, An injection device wherein, when the syringe is coupled to the stopper, the at least one projection is configured to engage with the flange and / or the barrel to form a space between the flange and / or the barrel and the inner C-shaped portion, thereby allowing or facilitating airflow through the space.

2. The injection device according to claim 1, wherein the barrel of the syringe defines an axis, and the at least one projection is a rib extending substantially parallel to the axis.

3. The injection device according to claim 1, wherein the retaining element has a cavity for receiving at least a portion of the flange, and the cavity is defined by opposing surfaces to restrict the axial movement of the retaining element.

4. The injection device according to claim 3, wherein the inner surface of the retaining element includes the opposing surface, and the at least one projection extends away from at least one of the opposing surfaces.

5. The injection device according to claim 4, wherein the opposing surface includes an upper opposing surface and a lower opposing surface, the upper opposing surface includes at least one projection, and the lower opposing surface includes at least one projection.

6. The injection device according to claim 1, wherein the syringe is a pre-filled syringe for containing a drug.

7. The infusion device according to claim 6, wherein the drug comprises a VEGF inhibitor.

8. The injection device according to claim 7, wherein the VEGF inhibitor includes a non-antibody VEGF inhibitor.

9. The injection device according to claim 7, wherein the VEGF inhibitor includes a VEGF trap.

10. The injection device according to claim 9, wherein the VEGF trap comprises aflibercept.

11. The injection device according to claim 1, wherein the at least one projection includes at least two projections.

12. The injection device according to claim 11, wherein the at least two protrusions include at least three protrusions.

13. The injection device according to claim 12, wherein the at least three protrusions include at least four protrusions.

14. The injection device according to claim 13, wherein the at least four protrusions include at least five protrusions.

15. The injection device according to claim 14, wherein the at least five protrusions include at least seven protrusions.

16. The injection device according to claim 1, wherein the inner surface of the stopper extends around at least a portion of the barrel of the syringe, and the at least one projection engages with the barrel of the syringe.

17. The injection device according to claim 1, wherein the stopper has a collar portion defining the inner surface that extends generally around at least a portion of the barrel.

18. The injection device according to claim 17, wherein the collar portion is configured to engage with the syringe in a snap-fit ​​relationship.

19. The injection device according to claim 5, wherein the at least one projection on the upper opposing surface includes at least two ribs on the upper opposing surface, and the at least one projection on the lower opposing surface includes at least two ribs on the lower opposing surface.

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