Extendable plunger assembly

Abstract

A plunger assembly is disclosed that includes a plunger sleeve, a plunger rod, and an axial protrusion disposed within the lumen of the plunger sleeve. A distal force applied to the plunger by the plunger rod causes the axial protrusion to contact and apply pressure to an engagement surface in the lumen. The engagement surface is configured to receive the distal force from the end of the axial protrusion. This extends the plunger and slightly retracts it, thereby reducing the release force and facilitating the transition of the plunger from a storage mode to a dispensing mode.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 654,663 filed 9 April 2018, No. 62 / 666,450 filed 3 May 2018, and No. 62 / 672,934 filed 17 May 2018, all of which are incorporated herein by reference in their entirety.

[0002] The concepts of this disclosure relate to plungers and their use in drug delivery devices, such as syringes, cartridges, or autoinjectors (pre-filled, pre-filled, or empty). More specifically, the concepts of this disclosure relate, among other things, to retractable plungers that provide and maintain the integrity of the container closure in storage mode during the storage period of pre-filled syringes. These plungers are switchable to a dispensing mode by operating the plunger to extend it, which helps to easily generate a smooth, weak plunger force when dispensing the contents of the syringe. [Background technology]

[0003] This disclosure primarily describes the use of plungers and plunger assemblies according to the concepts of this disclosure, in relation to pre-filled syringes. However, the present invention is not limited to pre-filled syringes and may also include other drug delivery devices, such as syringes (pre-filled, filled before use, or empty), cartridges, and autoinjectors.

[0004] Pre-filled parenteral containers, such as syringes or cartridges, are generally sold ready so that the patient or caregiver does not need to fill the syringe before use. Syringes, more specifically syringe barrels, can be pre-filled with a variety of different injectable preparations, including, among several items, saline solutions, injectable dyes, or pharmaceutically active formulations. This is especially true for syringes used to administer very small and precise amounts of injectable products, such as in ophthalmic applications.

[0005] Pre-filled parenteral containers are generally sealed with a rubber plunger, ensuring the integrity of the closure throughout the storage period of the container's contents. To use a pre-filled syringe, remove the packaging and cap, optionally attach a subcutaneous needle or another delivery tube to the dispensing end of the syringe, move the delivery tube or syringe to the point of use (for example, by inserting it into the patient's blood vessel or into an instrument to be rinsed with the syringe contents), and advance the plunger axially within the syringe to inject the contents of the syringe into the application point.

[0006] The seal, i.e., hermetic seal, provided to the barrel by the rubber plunger generally involves pressing the rubber of the plunger against the barrel. In general, the diameter of the rubber plunger is smaller than the inner diameter of the barrel. Therefore, in order to displace the rubber plunger when administering an injection from the syringe, it is necessary to overcome this pressing force of the rubber plunger. Furthermore, not only is it generally necessary to overcome this pressing force provided by the rubber seal when initially moving the plunger, but it is also necessary to continue to overcome this pressing force during administration of the injection, as the rubber plunger is displaced along the barrel. The need for a slightly greater force to advance the plunger within the syringe can increase the difficulty for a user when administering an injection product from the syringe. Such a high force can also interfere with the user's ability to administer a small and precise amount, such as during a priming step using an ophthalmic syringe. Such a high force can prove problematic, particularly for auto-injection systems in which the syringe is arranged in an auto-injection device and the plunger is advanced by a fixed spring. Accordingly, the primary considerations regarding the use of plungers in prefilled parenteral containers include: (1) the adequacy of the seal provided by the plunger within the container during storage and use, for example whether the plunger provides container closure integrity ("CCI", defined below); and (2) the plunger force (defined below) required to administer the contents of the syringe.

[0007] In practice, CCI and plunger force tend to be conflicting considerations. In other words, in the absence of other factors, the tighter the fit between the plunger and the inner surface of the container for maintaining proper CCI, the greater the force required to advance the plunger during use. In the field of medical syringes, it is important to ensure that the plunger can move at a substantially constant speed and with a substantially constant force when being advanced within the barrel. Furthermore, the force required to initiate the movement of the plunger and then keep the plunger advancing needs to be sufficiently low to allow accurate administration by the user and be comfortable for the patient.

[0008] Plunger force is essentially a function of the coefficient of friction of each of the contacting surfaces (i.e., the surface of the plunger and the inner wall surface of the syringe) and the normal force exerted by the plunger against the inner wall of the syringe. The greater each coefficient of friction and the greater the normal force, the greater the force required to advance the plunger. Accordingly, efforts to improve plunger force should be directed to reducing friction and lowering the normal force between the contacting surfaces. However, such efforts should be moderated by the need to maintain an adequate seal, for example CCI, as described above.

[0009] To reduce friction and therefore improve plunger force, the plunger, the internal surface of the container, or both may be lubricated. A fluid lubricant, such as a liquid or gel, e.g., free silicone oil (e.g., polydimethylsiloxane, or "PDMS"), can provide the desired level of lubrication and optimize the plunger force. When used with a pre-filled syringe, a fluid lubricant may migrate from the plunger over time, potentially creating spots with little or no lubrication between the plunger and the internal surface of the container. This can result in a phenomenon known in the industry as "sticktion," which relates to the adhesion between the plunger and the cylinder, and this sticktion must be overcome in order for the plunger to break out and begin to move. [Overview of the project] [Problems that the invention aims to solve]

[0010] There is a need to optimize the plunger force in parenteral containers while maintaining appropriate CCI (Cellular Compression Intake), thereby preventing drug leakage, protecting the drug product, and achieving a sufficient product shelf life. For example, there is a need to achieve these goals with plungers that cannot be pulled backward while inside an ophthalmic syringe. [Means for solving the problem]

[0011] Accordingly, in one optional embodiment, a plunger assembly for use in a medical tube is provided. The plunger assembly includes a plunger rod, an axial projection, and a plunger. The plunger rod has a distal end and a proximal end. The axial projection is fixed to, extends from, or abuts against the distal end of the plunger rod. The plunger includes a plunger sleeve having an outer surface and an inner surface surrounding a lumen. The outer surface includes a distal nose cone and an annular outer wall extending proximal from the nose cone to an opening at the proximal end of the plunger sleeve. The opening receives the axial projection so that it extends into the lumen and contacts an engaging surface on the inner surface. The engaging surface is configured to receive a distal force applied by the axial projection so that when the plunger rod is moved distally, the plunger assembly moves distally. The distal end of the plunger rod does not initially contact the proximal end of the plunger sleeve when the plunger is in its unextended state. Even if sufficient axial force is applied to the proximal end of the plunger rod to move it a predetermined distance in the axial direction, the plunger will not move in the axial direction.

[0012] In another optional embodiment, the concept of the present disclosure relates to a plunger rod and an axial projection provided as a single piece of a unitary structure. Alternatively, the plunger rod and axial projection are provided as a multi-piece assembly, where a first part of the multi-piece assembly can be manually pulled apart from a second part of the assembly to at least a predetermined distance.

[0013] In another optional embodiment, the concept of the present disclosure is a pre-filled syringe in which the plunger of the plunger assembly described above is positioned within a medical tube containing an injectable product. The plunger is configured to provide sufficient CCI and an airtight seal over a desired storage period when the plunger is in storage mode. The plunger is converted to drug delivery mode by axially elongating the plunger, which axially elongates the annular outer wall of the plunger, thereby slightly contracting the plunger's radial pressure against the inner wall of the tube. This facilitates advancing the plunger within the tube while still maintaining at least a liquid-tight seal.

[0014] Optionally, in any embodiment, the internal surface of the axial projection and / or plunger comprises a fluid lubricant, such as silicone oil. Optionally, in any embodiment, the internal surface of the axial projection and / or plunger comprises a lubricating coating, which optionally is a coating deposited using plasma-accelerated chemical vapor deposition ("PECVD") having one of the following atomic ratios: SiwOxCy or SiwNxCy (where w is 1, x is approximately 0.5 to 2.4, and y is approximately 0.6 to 3). Such lubricity may, if desired, help facilitate the movement of the axial projection from the plunger.

[0015] Optionally, in any embodiment, the plunger is optionally made from a thermoplastic elastomer or rubber, optionally bromobutyl rubber, having a durometer of optionally 30 to 70, preferably 40 to 60. Optionally, in any embodiment, the annular outer wall of the plunger includes at least one annular rib, optionally at least two annular ribs, or optionally at least three annular ribs.

[0016] Optionally, in any embodiment, the concept of the present disclosure relates to a syringe comprising a medical tube in which a plunger is disposed, wherein the plunger is a component of any embodiment of the plunger assembly described herein. Such a syringe is optionally a pre-filled syringe in which an injectable product is stored in a product-holding area. In any embodiment, the plunger includes an elongation zone adapted to elongate along the central axis of the plunger when a distal force is applied to the engaging surface of the lumen of the plunger by an axial projection. Such elongation reduces the outer contour of the annular outer wall along the elongation zone. Optionally, the elongation of the plunger is less than 1.5 mm.

[0017] In any of the syringe embodiments, the plunger rod is initially not in contact with the plunger sleeve when the plunger is in its unextended state. Once the plunger is moved into dispensing mode, it extends and moves within the cylinder, and in some embodiments, the plunger does not contact the plunger sleeve, but in other embodiments, it does.

[0018] In one embodiment, the extension of the plunger causes the annular outer wall to contract along the extension zone, thereby reducing the radial pressure of the annular outer wall against the inner wall of the medical tube.

[0019] In any of the embodiments, the engaging surface is provided on the distal section of the inner surface of the lumen of the plunger, and the distal portion of the axial projection, or optionally only the distal portion of the axial projection, contacts the engaging section.

[0020] Optionally, in either embodiment, the plunger is configured to be translated only in the distal direction by the plunger rod.

[0021] Optionally, in any embodiment of the pre-filled syringe, when in storage mode, the plunger applies outward radial pressure to the inner wall of the medical tube, forming a liquid-tight, CCI, and airtight interface with it. After the plunger is converted to dispensing mode, the liquid-tight interface is maintained, and optionally, the CCI and airtight interface are maintained when the plunger is advanced within the tube to dispense the injectable product.

[0022] Optionally, in any embodiment of the pre-filled syringe, a fluid lubricant, such as silicone oil, is coated on the sidewall of the syringe and / or the annular outer wall of the plunger. Optionally, in an alternative embodiment, no fluid lubricant is provided between the plunger and the syringe sidewall.

[0023] Optionally, in any embodiment of the prefilled syringe, the plunger break loose force is less than 10N, optionally less than 9N, optionally less than 8N, optionally less than 7N, optionally less than 6N, optionally between 4 and 8N, or optionally between 4 and 6N. Optionally, this break loose force is achieved even without a fluid lubricant between the plunger and the syringe sidewall. Optionally, in any embodiment of the prefilled syringe, the difference between the break loose force and the glide force is less than 6N, optionally less than 4N, optionally less than 3N, optionally less than 2N, optionally less than 1.5N, optionally less than 1.0N, optionally less than 0.5N, optionally less than 0.25N, or optionally between 0.5N and 4N.

[0024] Optionally, in any embodiment, the plunger has a fluoropolymer film coating deposited on its outer surface. This coating includes the drug contact surface and may optionally extend along at least a portion of the annular outer wall of the plunger to provide lubrication to the plunger and reduce the plunger force.

[0025] The present invention will be described in conjunction with the following drawings, in which the same reference numerals indicate the same elements. [Brief explanation of the drawing]

[0026] [Figure 1] This is an isometric view of an exemplary pre-filled syringe assembly in which the concepts of this disclosure may be implemented. [Figure 2] This is an isometric view of an exemplary one-piece plunger rod and axial projection assembly according to a first optional embodiment of the concept of the present disclosure. [Figure 3A] Herein is an isometric view of an exemplary multi-piece plunger rod and axial projection assembly, according to a second optional embodiment of the concept of the present disclosure, shown in a collapsed position, configured to advance the syringe plunger downward within the syringe barrel. [Figure 3B] Here, we see an isometric view of the multi-piece plunger rod in Figure 3B, shown in a partially extended position. [Figure 4] This is an isolated longitudinal cross-sectional view of an exemplary plunger, which may be used in accordance with any embodiment of the concept of the present disclosure. [Figure 5] Figure 2 is a longitudinal cross-sectional view of a partial syringe assembly, including a one-piece plunger rod, in which the axial projection is inserted into the plunger within the syringe barrel. [Figure 5A] Figure 5 is an enlarged cross-sectional view of the inner surface of the syringe of the first alternative embodiment, where the three-layer coating set is arranged. [Figure 5B] Figure 5 is an enlarged cross-sectional view of the inner surface of a second alternative embodiment of the syringe, where the four-layer coating set is arranged. [Figure 5C] Figure 5 is an enlarged cross-sectional view of the inner surface of a third alternative embodiment of the syringe, where the organosiloxane coating is located. [Figure 6] Figure 5 is a longitudinal cross-sectional view of a partial syringe assembly, showing the axial projection and plunger rod extended from the plunger. [Figure 7] Figures 3A and 3B show a partial syringe assembly, including the multi-piece plunger rod and axial projection assembly, in a partially extended position, in a longitudinal cross-sectional view. [Figure 8] Figure 7 is a longitudinal cross-sectional view showing a partial syringe assembly in a retracted position, comprising a multi-piece plunger rod and an axial projection assembly. [Figure 9] A partial syringe assembly, including an exemplary two-piece plunger rod and axial projection assembly, according to a third optional embodiment of the concept of the present disclosure, is shown here in a longitudinal cross-sectional view in an extended position, where the rod is separated from the rod extension located within the plunger. [Figure 10] Figure 9 is a longitudinal cross-sectional view showing a partial syringe assembly in its assembled position, comprising a two-piece plunger rod and an axial projection, with the distal end of the rod abutting against the proximal end of a rod extension positioned within the plunger. [Figure 11A-11C] Figure 5 is a partial longitudinal section of a partial syringe assembly showing the extension of the plunger to transition from storage mode to dispensing mode. [Figure 12A-12C] Figure 8 is a partial longitudinal section of a partial syringe assembly showing the extension of the plunger to transition from storage mode to dispensing mode. [Figure 13A-13C] This is an enlarged cross-sectional view of an alternative embodiment of a plunger assembly according to an optional aspect of the concept of the present disclosure. [Figure 14] This graph shows data regarding the effect of the presence and length of axial projections extending from the plunger rod on the release force (Fi). [Figure 15] This graph shows data regarding the effect of the presence and length of the axial projection of the plunger rod on the release force (Fi) after changes over time at specific time intervals. [Modes for carrying out the invention]

[0027] The disclosed concepts will be further described below with reference to the accompanying drawings illustrating several embodiments. However, the present invention may be provided in many different forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments are examples of the present invention having the entire scope as indicated by the language of the claims. Similar reference numerals refer to similar elements throughout. Unless otherwise indicated, the features characterizing the embodiments and aspects described below may be combined with each other, and the resulting combinations are also embodiments of the present invention.

[0028] definition As used in this disclosure, “organosilicon precursor” is a compound: [ka] A compound having at least one of the following, the tetravalent silicon atom is linked to an oxygen atom or a nitrogen atom and an organic carbon atom (an organic carbon atom is a carbon atom bonded to at least one hydrogen atom). A volatile organosilicon precursor, defined as a precursor that can be supplied as vapor in a plasma-accelerated chemical vapor deposition (PECVD) apparatus, is an optional organosilicon precursor. Optionally, the organosilicon precursor is selected from the group consisting of linear siloxanes, monocyclic siloxanes, polycyclic siloxanes, polysilsesquioxanes, alkyl trimethoxysilanes, linear silazanes, monocyclic silazanes, polycyclic silazanes, polysilsesquiazanes, and combinations of two or more of these precursors. Preferably, the organosilicon precursor is octamethylcyclotetrasiloxane (OMCTS). The values ​​of w, x, y, and z are defined throughout this specification as the experimental composition Si w O x C y H zis applicable. It is understood that the values of w, x, y, and z used throughout this specification are not limitations on the number or type of atoms in the molecule, but are ratios or empirical formulas (for example, for coatings or layers). For example, the molecular composition Si4O4C8H 24 Octamethylcyclotetrasiloxane having the following empirical formula can be described, and the greatest common factor: Si1O1C2H6 can be achieved by dividing each of w, x, y, and z in the molecular formula by 4. The values of w, x, y, and z are also not limited to integers. For example, (acyclic) octamethyltrisiloxane, molecular composition Si3O2C8H 24 can be reduced to Si1O 0.67 C 2.67 H8. Also, SiO x C y H z is described as equivalent to SiO x C y , but it is not necessary to indicate the presence of hydrogen at any ratio to indicate the presence of SiO x C y .

[0029] "Container Closure Integrity" or "CCI" refers to the ability of a container closure system, for example a plunger disposed in a prefilled syringe, to protect and maintain the efficacy and sterility of the sterile product contained in the container over its shelf life.

[0030] In the context of the present invention, "plunger sliding force" (synonymous with "glide force", "maintenance force", or F as also used in this description) m is the force required to maintain the movement of the plunger tip of the syringe, for example during aspiration or administration. It may be advantageous to be determined using the test of ISO7886-1:1993 known in the art. Synonyms for "plunger sliding force" that are often used in the art are "plunger force" or "pushing force".

[0031] In relation to the present invention, "plunger breakout force" (similarly used in this description as "breakout force," "release force (break loose force)," "initiation force," F) i (Synonymous with) is the initial force required to initiate the action of the plunger in a syringe, such as a pre-filled syringe.

[0032] The term “syringe” is broadly understood to include cartridges, “pen” type injectors, and other types of tubes or reservoirs adapted to be assembled with one or more other components to provide a functional syringe. “Syringe” also includes related articles such as autoinjectors that provide a mechanism for dispensing contents. Optionally, “syringe” may include pre-filled syringes. In this specification, “syringe” may also apply to vaccine dispensing syringes that include a product space for holding vaccines. In this specification, “syringe” may also apply to sampling equipment that includes a medical tube pre-filled with, for example, a diagnostic agent (e.g., a contrast agent).

[0033] "PECVD" refers to plasma-accelerated chemical deposition.

[0034] Optional syringe materials Optionally, syringes according to any embodiment of the present invention may be made from one or more injection-molded thermoplastic materials, including, but not limited to, olefin polymers; polypropylene (PP); polyethylene (PE); cyclic olefin copolymers (COC); cyclic olefin polymers (COP); polymethylpentene; polyester; polyethylene terephthalate; polyethylene naphthalate; polybutylene terephthalate (PBT); PVdC (polyvinylidene chloride); polyvinyl chloride (PVC); polycarbonate; polymethyl methacrylate; polylactic acid; polystyrene; hydrogenated polystyrene; poly(cyclohexylethylene) (PCHE); nylon; polyurethane polyacrylonitrile; polyacrylonitrile (PAN); ionomer resins; and Surlyn® ionomer resins. For applications where a transparent, glass-like polymer is desired (e.g., for syringes and vials), cyclic olefin polymers (COP), cyclic olefin copolymers (COC), or polycarbonate may be preferred. Such materials can be manufactured, for example, by injection molding or injection-stretch blow molding to very tight and precise tolerances (generally far tighter than those achievable with glass). Alternatively, the syringe according to the embodiment of the present invention may be made from glass.

[0035] Components and embodiments of syringe and plunger assembly As stated above, the concepts of this disclosure generally relate to a plunger that is switchable to a drug delivery mode by operating the plunger to extend the plunger, thereby helping to easily generate a smooth, weak plunger force when dispensing the contents of a syringe. Applicant SiO2 Medical Products, Inc. has developed other convertible plungers, which are described in several of its published international patent applications, International Publication No. 2015 / 054282 published on 16 April 2015, International Publication No. 2016 / 039816 published on 17 March 2016, International Publication No. 2017 / 011599 published on 19 January 2017, and International Publication No. 2017 / 209800 published on 7 December 2017. Each of these published applications is incorporated herein by reference in its entirety.

[0036] Referring to Figure 1, an exemplary embodiment of a syringe assembly 10 (e.g., a pre-filled syringe assembly) according to an optional aspect of the concept of the present disclosure is shown. The syringe assembly includes a medical tube 12 and a plunger assembly disposed inside it, a portion of which of the plunger rods 22 is shown in Figure 1. The syringe assembly 10 may include accessories that are generally included with a pre-filled syringe, such as an end cap, a Luer fitting from which the injection needle can be optionally secured during use, etc. Alternatively, the syringe may be a staked needle syringe.

[0037] In any embodiment, as shown, for example, in Figures 5-10, the syringe assembly 10 includes a hollow medical tube 12 having a central longitudinal axis A. The medical tube 12 has an inner wall 14 and is configured to hold an injectable liquid 16, optionally a drug product, inside. The injectable liquid 16 is preferably prefilled to provide a prefilled syringe. In an alternative embodiment, the syringe is not prefilled. A needle (not shown) is provided at the distal end of the medical tube 12 to dispense the injectable liquid 16.

[0038] The terms “distal” and “proximal” are used throughout this specification. Generally, the terms “distal” and “proximal” refer to a spatial or positional relationship with respect to a given reference point, where “proximal” is located at or relatively close to that reference point, and “distal” is located far from that reference point. Referring to Figure 5, as applied to a medical tube as used herein, the reference point in question is at the rear end of the tube, for example, at the flange 21 at the top of the tube 12. The distal end is at the bottom of the tube 12 or the dispensing end 13 where the needle may be attached. This same convention applies to other components described herein, such as the plunger and plunger assembly. “Proximal” and “distal” may also be used to refer to the force vector and direction of movement. For example, the pushing force for dispensing the contents of a syringe is applied “distally” or “distally,” i.e., the force pushing the plunger advances the plunger downward toward the dispensing end or distal end of the medical tube. In contrast, the tensile force applied to the plunger rod in such a way that it pulls away from the dispensing end of the cylinder is a force applied "proximally" or "proximally".

[0039] In any embodiment of the syringe assembly, or as an embodiment of the concept of the present disclosure itself, plunger assemblies 20, 120, 220 are provided and shown in Figures 5-10. The plunger assemblies 20, 120, 220 include plunger rods 22, 122, 222, axial projections 30, 130, 230 fixed to, extending from or abutting against, the distal ends 27, 127, 227 of the plunger rods 22, 122, 222, and plungers 24 in which the axial projections 30, 130, 230 are located. These assemblies are described in more detail below.

[0040] An exemplary plunger 24 that can be used in accordance with an aspect of the concept of the present disclosure is shown in Figure 4. The plunger 24 includes a plunger sleeve 34 having an outer surface 36 and an inner surface 38 surrounding a lumen 40. The outer surface 36 includes a distal nose cone 42 and an annular outer wall 44 extending proximal therefrom. The annular outer wall 44 may include one or more ribs 52 and extends to an opening 46 at the proximal end 48 of the plunger sleeve 34. The opening 46 is configured to receive the axial projections 30, 130, 230 as described above, so that the axial projections 30, 130, 230 extend into the lumen 40 and contact an engaging surface 50 of the inner surface 38. The engaging surface 50 is configured to receive a force applied distally by the plunger rods 22, 122, 222 to move the plunger assemblies 20, 120, 220 distally. The lumen 40 optionally includes a distal compartment 40a having a wider internal morphology than the portion of the lumen 40 that extends to the distal compartment 40a.

[0041] When assembled with the plunger assemblies 20, 120, and 220 and placed inside the medical cylinder 12, the plunger 24 is configured to exert sufficient compressive force against the inner wall 14 of the pre-filled syringe or cartridge cylinder, effectively sealing it and preserving the shelf life of the cylinder's contents during storage. When the plunger 24 provides adequate container closure integrity (CCI) and airtight seal (e.g., providing barriers to oxygen, moisture, and / or optionally additional gases) for effectively sealing the cylinder and preserving the shelf life of the cylinder's contents during storage, the plunger (or at least a portion of its outer surface) may instead be characterized as being in an "expanded state" or "storage mode." The expanded state or storage mode may be, for example, the product of the widened outer diameter or profile of at least a portion of the plunger's syringe contact surface and / or the normal force exerted by the plunger against the inner wall of the syringe in which the plunger is placed. The plunger 24 (or at least a portion of its outer surface) can be retracted to a degree that may alternatively be characterized as a “contracted state” or “drug dispensing mode,” where the compressive force against the side wall of the tube is reduced or partially eliminated, allowing the user to more easily advance the plunger within the tube and thus dispense the contents of the syringe or cartridge. As will be described in more detail below, the conversion from storage mode to drug dispensing mode is brought about by the extension of the plunger 24. Before extension, the plunger 24 may be said to be in its natural state or “pre-extension state.” When the plunger is placed within a medical tube, the pre-extension state is synonymous with the extended state or storage mode.

[0042] According to the concept of this disclosure, the plunger rod and axial projection may optionally be provided as a single piece in a unitary structure, for example, as shown in Figures 2, 5, and 6. According to an alternative embodiment of the concept of this disclosure, the plunger rod and axial projection may be provided as multi-piece assemblies 123, 223, for example, as shown in Figures 3A, 3B, and 7-10, where the first parts 123a, 223a of the multi-piece assemblies 123, 223 can be manually separated from the second parts 123b, 223b of the assemblies to at least a predetermined distance. Although the illustrated multi-piece assemblies 123, 223 are two-piece assemblies, it should be understood that assemblies of three or more pieces may be within the scope of the concept of this disclosure. The alternative embodiments described above are detailed below.

[0043] Figures 2, 5, and 6 show embodiments in which the plunger rod 22 and the axial projection 30 are unitary. “Unitary structure” can mean a single manufactured piece or an assembly in which assembled components (e.g., the plunger rod and projection) are firmly fixed to each other so that they move together in any direction as a unitary part. The plunger rod 22 is an elongated member having a proximal end 25 and a distal end 27. The plunger rod 22 optionally includes a disc-shaped thumb rest 28 at the proximal end 25. The axial projection 30 is fixed to (and, in this case, integral to) the distal end 27 of the plunger rod 22 and extends from there. As described below, the axial projection may be provided in an alternative shape. However, in this embodiment, it is preferable that the axial projection 30 is cylindrical overall and has a substantially uniform cross-section along substantially its entire length, for example, at least 90% of its entire length, for example, optionally to its rounded tip. Optionally, the plunger rod 22 may include one or more radial stabilizing members 32 that loosely engage with the inner wall of the medical tube during use to stabilize the plunger rod 22 when the plunger assembly 20 is advanced forward (for example, by preventing wobbling).

[0044] Referring to Figures 3A, 3B, 7, and 8, an embodiment is shown in which the plunger rod 122 and the axial projection 130 are provided as a multi-piece assembly 123. In this embodiment, the first part 123a includes a proximal plunger rod piece 122a. The second part 123b of the assembly 123 includes a distal plunger rod piece 122b, and the axial projection 130 is fixed to (and, in this case, integral with) the distal end 127 of the plunger rod 122 and extends therefrom. The axial projection 130 optionally includes a head 130a at its distal end, having a wider cross-sectional width or diameter than that of the section of the axial projection 130 leading to the head 130a. It should be understood that the specific geometric shape of the head 130a shown in the illustration is illustrative only, and the head may be provided in other shapes, such as spherical or cylindrical. The plunger rod 122 optionally includes a disc-shaped thumb rest 128 at its proximal end 125. Optionally, as described above with respect to the embodiment in Figure 2, the plunger rod 122 includes one or more radial stabilizing members 132.

[0045] The first part 123a and the second part 123b of the multi-piece assembly 123 are assembled together in a nested configuration. The first and second parts 123a and 123b can be pulled axially apart to a predetermined distance and collapsed until the parts can no longer be pushed together. In the illustrated exemplary embodiment, the first part includes a hub 143 having a central hollow section 142 configured to receive the proximal shaft 140 of the second part 123b. The central hollow section 142 includes an upward-facing wall 154 and an opposing downward-facing wall 152. The first part 123a includes a distal contact surface 144, and the second part 123b includes a proximal contact surface 146. These two contact surfaces (144 and 146) are configured to contact each other when the first part 123a and the second part 123b are completely collapsed together. When these parts are compressed together in this manner, a sufficient distal force is applied to the thumb rest 128, causing the multi-piece assembly 123 to move distally as a whole. In an optional alternative embodiment (not shown), the configuration is reversed so that the hub and hollow section are part of the second part, and the shaft that can be housed inside is part of the first part.

[0046] The proximal shaft 140 is movable along axis A from a fully retracted state of assembly 123, as shown in Figures 3A and 8, to a fully extended state. A partially extended state is shown in Figures 3B and 7. The proximal end of the proximal shaft 140 includes a prong 148 having a radial contact portion 150. The radial contact portion 150 is configured to contact an upward wall 154 when assembly 123 is in the fully extended position, preventing the first portion 123a and the second portion 123b from being pulled further apart from each other in the fully extended state. Optionally, the upper end of the prong 148 contacts a downward wall 152 when assembly 123 is fully retracted.

[0047] An alternative multi-piece assembly 223 is shown in Figures 9 and 10. The assembly includes a first part 223a containing a plunger rod 222 and a second part 223b containing an axial projection 230. The first part 223a and the second part 223b are not fixed to each other. The distal end 227 of the plunger rod 222 is configured to abut the proximal end of the axial projection 230 so that the plunger rod 222 can move the axial projection 230 distally by applying a distal force to the plunger rod 222 (optionally via a thumb rest 228). Applying a proximal force to the plunger rod 222 acts to completely separate the plunger rod 222, i.e., the first part 223a of the assembly 223, from the axial projection 230, i.e., the second part 223b of the assembly 223.

[0048] As described above, the plunger 24 is configured to be positioned within the medical barrel 12 of the syringe, preferably a pre-filled syringe, as part of the plunger assemblies 20, 120, and 220. In this position, when sufficient distal force is applied to the plunger assemblies 20, 120, and 220, the plunger 24 advances the medical barrel 12 so as to dispense an injectable liquid 16 from the dispensing end 13 of the medical barrel 12, for example, through a needle. When this advancement occurs, the plunger 24 is converted from storage mode to dispensing mode. In storage mode, the plunger 24 provides a tight seal, as described above. This tight seal can apply a certain level of radial compression against the inner wall 14 of the medical barrel 12, thereby making it difficult for the plunger to advance in the barrel. When the user first applies sufficient distal force to the plunger assemblies 20, 120, and 220, the plunger 24 begins to extend axially, slightly contracting at least a portion of the annular outer wall 44 of the plunger sleeve 34 while still providing a liquid seal, thereby reducing radial pressure against the inner wall 14 and thus providing a more desirable sliding force than that which could be achieved without extending the plunger sleeve 34.

[0049] Referring here to Figures 11A-11C, the conversion of the plunger 24 of the plunger assembly 20 (Figure 5) from storage mode to dispensing mode is shown. Figure 11A shows the plunger 24 in its unextended state or storage mode. In this position, the axial projection 30 applies little to no distal force to the engagement surface 50 of the inner surface 38 of the plunger sleeve 34. As such, the plunger is in its "thickest" state, resulting in its maximum radial compression against the inner wall 14 of the medical tube 12, resulting in, for example, CCI over the storage period of the product 12. The diameter or cross-sectional width of the axial projection 30 preferably provides radial support to reinforce the seal provided by the plunger 24. However, in this embodiment, it is preferable that the axial projection 30 is relatively loosely fitted into the lumen 40 of the plunger sleeve 34 without using a compression fit. In this way, the axial projection 30 can be relatively easily withdrawn from the plunger 24 when a proximal force is applied to the plunger rod 22. Therefore, even if sufficient axial force is applied to the proximal end of the plunger rod 22 to move the plunger rod proximal in the axial direction, the plunger 24 will not move proximal in the axial direction. This is also true for the plunger assembly 220 in Figure 10. The only difference is that by pulling back the plunger rod 222 of the plunger assembly 220, the axial projection 230 is completely separated from the plunger rod 222, so that the axial projection 230 remains within the plunger sleeve 34, while the plunger rod 222 is moved proximal from there. Conversely, since both the plunger rod 22 and the axial projection 30 move axially as a single unit, pulling back the plunger rod 22 of the plunger assembly 20 in Figure 5 pulls the axial projection 30 out of the plunger sleeve 34, as shown in Figure 6. Optionally, a lubricant is provided in the lumen 40 of the plunger sleeve 34 so that the axial projection 30 can be easily removed from there when the plunger rod 22 is pulled backward.

[0050] Figures 11B and 11C illustrate the transition of the plunger 24 to the drug delivery mode. When the user applies sufficient initial distal force to the plunger rod 22, this causes the axial projection 30 to apply distal force to the engagement surface 50. Optionally, a portion of the plunger sleeve 34 may initially adhere to the inner wall by "sticktion". When this occurs, the plunger 24 extends axially along the stretch zone Z, causing the plunger 24 to contract slightly around the stretch zone Z. The contraction of the plunger 24 converts the plunger 24 to drug delivery mode by reducing radial pressure against the side wall 14 of the medical tube 12. Thus, the plunger 24 can advance the medical tube 12 more easily while maintaining a liquid-tight seal and optionally CCI.

[0051] Referring here to Figures 12A-12C, the conversion of the plunger 24 of the plunger assembly 120 (Figures 7 and 8) from storage mode to dispensing mode is shown. Figure 12A shows the plunger 24 in its unextended state or in storage mode. In this position, the shaft of the axial projection 130 applies little to no distal force to the engagement surface 50 of the inner surface 38 of the plunger sleeve 34. However, the head 130a of the axial projection 130, which is positioned in the distal compartment chamber 40a within the lumen 40, has a diameter or cross-sectional width such that it abuts against an adjacent section of the inner surface 38. Preferably, this configuration causes the distal portion of the annular outer wall 44 of the plunger sleeve 34, optionally the rib 52 closest to the nose cone 42, to exert additional radial compression against the inner wall 14 of the medical tube 12 (i.e., greater radial compression than would be present if the head 130a were not present).

[0052] The plunger sleeve 34 preferably includes a narrower section of the lumen 40 proximal to the distal compartment 40a. When the head 130a occupies the distal compartment 40a of the lumen 40, the axial projection 130 cannot be easily manually pulled out from the plunger 24 because the head 130a has a larger diameter or cross-sectional width than the narrower section of the lumen 40. Nevertheless, the retraction of the plunger rod 122 does not move the plunger 24 proximal. As described above, the nested arrangement of the multi-piece assembly 123 is configured such that the axial projection 130 or the plunger 24 is not pulled proximal even by applying sufficient axial force to the proximal end of the plunger rod 122 to move the proximal plunger rod piece 122a axially in the proximal direction.

[0053] As shown in Figure 12A, the plunger 24 is in storage mode or pre-extension mode. In this position, the plunger 24 is in its "thickest" state, resulting in its maximum radial compression against the inner wall 14 of the medical tube 12, providing, for example, CCI over the storage period of the injectable drug 16. Figures 12B and 12C show the transition of the plunger 24 to the dosing mode. When the user applies sufficient initial distal force to the plunger rod 122, this causes the axial projection 30 to apply distal force to the engagement surface 50. Optionally, a portion of the plunger sleeve 34 may initially adhere to the inner wall by "sticktion". When this occurs, the plunger 24 extends axially along the extension zone Z, and the plunger 24 contracts slightly around the extension zone Z. The contraction of the plunger 24 converts the plunger 24 to dosing mode by reducing the radial compression against the side wall 14 of the medical tube 12. Therefore, the plunger 24 can more easily advance the medical tube 12 while maintaining a liquid-tight seal and optionally CCI.

[0054] Referring to Figures 13A-13C, alternative embodiments of parts of the plunger assemblies 20a, 20b, and 20c are shown according to optional aspects of the concept of the present disclosure. Each of the plunger assemblies 20a, 20b, and 20c, such as plunger assemblies 20, 120, and 220, includes plungers 24a, 24b, and 24c and plunger rods 22a, 22b, and 22c. Each plunger rod 22a, 22b, and 22c has a uniquely shaped axial projection 30a, 30b, and 30c extending therefrom. Each of the axial projections 30a, 30b, and 30c extends into the lumen 40 of the plunger sleeve 34 and interfaces with a portion of the inner surface of the plunger sleeve 34.

[0055] Figures 13A and 13C show embodiments of axial projections 30a and 30c that are tapered inward distally. In this manner, each axial projection 30a and 30c contacts the inner surface of the plunger sleeve 34, and when pushed distally, it is conceivable that force vectors are applied to it in both the axial (distal) and radial directions. As described above, the axial force vector causes the plungers 24a and 24c to stretch axially along the stretch zone. The radial force vector causes the plunger sleeves 34a and 34c to expand radially and / or reinforce the plungers themselves to prevent them from collapsing when the plungers 24a and 24c transition from storage mode to dispensing mode, which may be desirable in some applications.

[0056] Figure 13B shows an embodiment of the axial projection 30b having a thicker proximal portion. However, the axial projection 30b does not have any tapered sides. As such, the thicker portion reinforces the plunger 24b so that it does not collapse on its own. However, this configuration would only apply an axial (distal) force vector into the lumen to axially extend the plunger without actively expanding the plunger as the cylinder is advanced.

[0057] In any of the optional embodiments, the axial projections 30, 130, and 230 are provided within the lumen 40 of the plunger sleeve 34, as the sole components located therein. The axial projections 30, 130, and 230 are not fixed to the plunger 24 or to an insert within the plunger by screw engagement.

[0058] Optionally, in any embodiment, when the plunger 24 is in the storage position, the distal ends 27, 127, 227 of the plunger rods 22, 122, 222 do not contact the proximal end 48 of the plunger 24. Optionally, in some embodiments (for example, as shown in Figures 7, 8, and 12A-12C, and optionally, other embodiments described herein), when the plunger 24 is in the dispensing position, the distal end 127 of the plunger rod 122 does not contact the proximal end 48 of the plunger 24. In other words, optionally, a space may be provided between the proximal end 48 of the plunger 24 and the distal end of the plunger rod in both the storage position (before extension) and the dispensing position (after extension).

[0059] Preferably, in any embodiment, the plunger rod cannot pull the plunger backward at any point after the syringe has been filled and the plunger has been loaded. This feature is necessary in some applications (e.g., ophthalmology), but until our invention, a switchable plunger assembly had not been provided.

[0060] Preferably, in any embodiment, after the syringe is filled and the plunger is loaded, the pressure in the filled portion of the syringe increases at any point, so the plunger cannot move more than 2 mm backward.

[0061] In any embodiment where the axial projection has the same diameter substantially along its entire length (e.g., to its distal end), the axial projection has a diameter of 1.8 mm or less, and optionally 1.6 mm or less. In any such embodiment, optionally 1.45 mm to 1.8 mm, and optionally 1.45 mm to 1.6 mm. If the axial projections 30, 230 have the same diameter substantially along their entire length (e.g., to their distal end), the diameter is such that they contact the lumen 40 of the plunger sleeve 34 to reinforce the plunger's ability to provide a seal rather than engaging with the lumen in an interlocking fit. As such, the plunger is not pulled backward by pulling the axial projection backward while the plunger is inside the cylinder.

[0062] Optionally, in any embodiment, the syringe is a 0.5 mL syringe, as the term is understood in the art.

[0063] PECVD coating layer In another embodiment, the present invention optionally includes the use of any embodiment (or combination of embodiments) of a plunger according to the concept of the present disclosure in a syringe having a PECVD coating or a set of PECVD coatings. The syringe may be made of, for example, glass or plastic. Optionally, the syringe according to any embodiment may be made of an injection-molded plastic material as defined above, in particular a material that is transparent and glass-like in the final form, such as a cyclic olefin polymer (COP), a cyclic olefin copolymer (COC), or polycarbonate. Such materials can be manufactured, for example, by injection molding with very tight and precise accuracy (generally far tighter than that achievable with glass). This is advantageous when balancing the conflicting considerations of seal tightness and weak plunger force in plunger design.

[0064] This section of the present disclosure focuses primarily on pre-filled syringes as preferred implementations of optional embodiments of the present invention. However, it should be understood here as well that the present invention may include any parenteral container utilizing a plunger, such as empty syringes, cartridges, autoinjectors, pre-filled syringes, or pre-filled cartridges.

[0065] In some applications, it may be desirable to provide one or more coatings or layers on the inner wall of a parenteral container to modify the properties of the container. For example, one or more coatings or layers may be added to a parenteral container to enhance the barrier properties or impediments of the container and prevent interaction between the container wall (or underlying coating) and the drug product held within the container. Such coatings or layers may be constructed in accordance with the teachings of PCT application PCT / US2014 / 023813, filed March 11, 2014, which are incorporated herein by reference in their entirety.

[0066] For example, as shown in Figure 5A, an alternative first embodiment of the enlarged cross-sectional view of the medical tube 12 of the syringe assembly 10 in Figure 5, the inner surface 14 of the medical tube 12 may include a coating set 400 comprising one or more coatings or layers. The medical tube 12 may include at least one tie coating or layer 402, at least one barrier coating or layer 404, and at least one organosiloxane coating or layer 406. The organosiloxane coating or layer 406 preferably has pH-protective properties. Herein, this embodiment of the coating set 400 is referred to as a “three-layer coating set,” where the barrier coating or layer 404 is protected from the contents by being sandwiched between the pH-protective organosiloxane coating or layer 406 and the tie coating or layer 402, otherwise the contents have a pH high enough to remove the barrier coating. The thickness (nanometers) of each layer to be considered (preferred range in parentheses) is given in the following table of three layer thicknesses:

[0067] [Table 1]

[0068] The characteristics and composition of each coating that make up the three-layer coating set are described below.

[0069] The bonding coating or layer 402 has at least two functions. One function of the bonding coating or layer 402 is to enhance the adhesion of the barrier coating or layer 404 to the substrate (e.g., the inner surface 14 of the cylinder 12), particularly to a thermoplastic substrate, while the bonding layer may be used to enhance adhesion to a glass substrate or another coating or layer. For example, the bonding coating or layer, also referred to as the adhesive layer or coating, is applied to the substrate, and the barrier layer may be applied to the adhesive layer to enhance the adhesion of the barrier layer or coating to the substrate.

[0070] Another function of the binding coating or layer 402 has been discovered: the binding coating or layer 402 applied beneath the barrier coating or layer 404 may enhance the function of the pH-protective organosiloxane coating or layer 406 applied above the barrier coating or layer 404.

[0071] The bonding coating or layer 402 is SiO x C y (where x is 0.5 to 2.4 and y is 0.6 to 3) can be composed of, contain, or essentially consist of. Alternatively, the atomic ratio of formula Si w O x C y It can be expressed as follows: The atomic ratios of Si, O, and C in the bonding coating or layer 402 are as follows: Si 100:O 50~150:C 90~200 (i.e., w=1, x=0.5~1.5, y=0.9~2); Si 100:O 70~130:C 90~200 (i.e., w=1, x=0.7~1.3, y=0.9~2) Si 100:O 80~120:C 90~150 (i.e., w=1, x=0.8~1.2, y=0.9~1.5) Si 100:O 90~120:C 90~140 (i.e., w=1, x=0.9~1.2, y=0.9~1.4), or Si 100:O 92~107:C 116~133 (i.e., w=1, x=0.92~1.07, y=1.16~1.33) That is the case.

[0072] The atomic ratio can be determined by XPS. Therefore, considering the H atoms that are not measured by XPS, the bonding coating or layer 402 is, in one embodiment, of the formula Si w O x C y H z (or equivalent SiO x C y ) has, for example, here w is 1, x is about 0.5 to about 2.4, y is about 0.6 to about 3, and z is about 2 to about 9. Thus, generally, the bonding coating or layer 402 contains 36% to 41% carbon, standardized with the total number of atoms of the elements carbon, oxygen and silicon as 100%.

[0073] The barrier coating or layer 404 for any embodiment defined herein (unless otherwise specified in particular) is optionally a coating or layer applied by PECVD as described in U.S. Patent No. 7,985,188. The barrier coating is preferably SiO x Characterized as a coating (where x, the ratio of oxygen to silicon atoms, is approximately 1.5 to 2.9). SiO x The thickness of the barrier coating or layer may be measured, for example, by a transmission electron microscope (TEM), and its composition may be measured by X-ray photoelectron spectroscopy (XPS). The barrier layer is effective in preventing oxygen, carbon dioxide, water vapor, or other gases (e.g., residual monomers of the polymer from which the container wall is made) from entering the container and / or preventing pharmaceutical materials from seeping into or through the container wall.

[0074] A preferred method for applying the barrier layer 404 and the bonding layer 402 to the inner surface 14 of the cylinder 12 is by plasma-accelerated chemical vapor deposition (PECVD), as described, for example, in U.S. Patent Application Publication No. 20130291632 (which is incorporated herein by reference in its entirety).

[0075] The applicant is SiO x It has been found that the barrier layer or coating can be corroded or dissolved by certain fluids, such as aqueous compositions with a pH above approximately 5. Because coatings applied by chemical vapor deposition can be very thin—tens to hundreds of nanometers thick—even a relatively slow corrosion rate can render the barrier layer ineffective or reduce its effectiveness in a shorter time than the desired shelf life of the product package. This is particularly problematic with respect to liquid pharmaceutical compositions, as many of them have a pH of approximately 7, or more broadly, in the range of 5 to 9, similar to the pH of blood and other human or animal bodily fluids. The higher the pH of the pharmaceutical, the more SiO2. x This causes the coating to corrode or dissolve more rapidly. Optionally, this problem can be addressed by protecting a barrier coating or layer, or other pH-sensitive material, with a pH-protective organosiloxane coating or layer.

[0076] Optionally, the pH protective coating or layer 406 is Si w O x C y H z (or equivalent SiO x C y ) or Si w N x C y H z (or its equivalent SiN) x C y) may consist of, may contain or essentially consist of. The atomic ratio of Si:O:C or Si:N:C can be determined by XPS (X-ray photoelectron spectroscopy). Therefore, considering the H atom, in one embodiment, the pH protective coating or layer is of the formula Si w O x C y H z , or equivalent SiO x C y (For example, in the formula, w is 1, x is approximately 0.5 to approximately 2.4, y is approximately 0.6 to approximately 3, and z is approximately 2 to approximately 9.)

[0077] In general, formula Si w O x C y As expressed as, the atomic ratios of Si, O, and C are as follows: Si 100:O 50~150:C 90~200 (i.e., w=1, x=0.5~1.5, y=0.9~2); Si 100:O 70~130:C 90~200 (i.e., w=1, x=0.7~1.3, y=0.9~2) Si 100:O 80~120:C 90~150 (i.e., w=1, x=0.8~1.2, y=0.9~1.5) Si 100:O 90~120:C 90~140 (i.e., w=1, x=0.9~1.2, y=0.9~1.4) Si 100:O 92~107:C 116~133 (i.e., w=1, x=0.92~1.07, y=1.16~1.33), or Si 100:O 80~130:C 90~150 That is the case.

[0078] Alternatively, the organosiloxane coating or layer may have atomic concentrations of less than 50% carbon and more than 25% silicon, as determined by X-ray photoelectron spectroscopy (XPS), with the total number of atoms of the elements carbon, oxygen, and silicon being 100%. Alternatively, the atomic concentrations are 25-45% carbon, 25-65% silicon, and 10-35% oxygen. Alternatively, the atomic concentrations are 30-40% carbon, 32-52% silicon, and 20-27% oxygen. Alternatively, the atomic concentrations are 33-37% carbon, 37-47% silicon, and 22-26% oxygen.

[0079] Optionally, the atomic concentration of carbon in the pH protective coating or layer 406, normalized to 100% of the total number of atoms of the elements carbon, oxygen, and silicon as determined by X-ray photoelectron spectroscopy (XPS), may exceed the atomic concentration of carbon in the atomic formula of the organosilicon precursor. For example, embodiments are considered in which the atomic concentration of carbon increases by only 1 to 80 atomic percent, or 10 to 70 atomic percent, or 20 to 60 atomic percent, or 30 to 50 atomic percent, or 35 to 45 atomic percent, or 37 to 41 atomic percent.

[0080] Optionally, the carbon-to-oxygen atomic ratio in the pH protective coating or layer 406 may be higher and / or the oxygen-to-silicon atomic ratio may be lower compared to the organosilicon precursor.

[0081] Exemplary experimental compositions of pH-protective coatings according to optional embodiments include SiO 1.3 C 0.8 H 3.6 That is the case.

[0082] Optionally, in any embodiment, the pH protective coating or layer 406 comprises, or consists of, a coating to which PECVD has been applied.

[0083] Optionally, in any embodiment, the pH protective coating or layer 406 is applied by using a precursor containing, essentially consisting of, or comprising a silane. Optionally, in any embodiment, the silane precursor contains, essentially consists of, or comprises one or more acyclic or cyclic silanes, and optionally contains, essentially consists of, or comprises one or more of silanes, trimethylsilane, tetramethylsilane, Si2-Si4 silane, triethylsilane, tetraethylsilane, tetrapropylsilane, tetrabutylsilane, or octamethylcyclotetrasilane, or tetramethylcyclotetrasilane.

[0084] Optionally, in any embodiment, the pH protective coating or layer 406 comprises, essentially, amorphous or diamond-like carbon to which PECVD has been applied. Optionally, in any embodiment, the amorphous or diamond-like carbon is applied using a hydrocarbon precursor. Optionally, in any embodiment, the hydrocarbon precursor comprises, essentially, linear, branched, or cyclic alkanes, alkenes, alkadienes, or alkynes, such as saturated or unsaturated acetylene, methane, ethane, ethylene, propane, propylene, n-butane, i-butane, butane, propyne, butyne, cyclopropane, cyclobutane, cyclohexane, cyclohexene, cyclopentadiene, or any combination of two or more of these. Optionally, in any embodiment, the hydrogen atom percentage of the amorphous or diamond-like carbon coating is 0.1% to 40%, or 0.5% to 10%, or 1% to 2%, or 1.1% to 1.8%.

[0085] Optionally, in any embodiment, the pH protective coating or layer 406 comprises, essentially, PECVD-treated SiN. Optionally, in any embodiment, the PECVD-treated SiN is applied using silane and nitrogen-containing compounds as precursors. Optionally, in any embodiment, the silane is acyclic or cyclic silane and optionally comprises, essentially, silane, trimethylsilane, tetramethylsilane, Si2-Si4 silane, triethylsilane, tetraethylsilane, tetrapropylsilane, tetrabutylsilane, octamethylcyclotetrasilane, or any combination of two or more of these. Optionally, in any embodiment, the nitrogen-containing compound comprises, essentially, one or more of nitrogen gas, nitrous oxide, ammonia, or silazane. Optionally, in any embodiment, the silazane essentially consists of, or comprises, a linear silazane, e.g., hexamethylene disilazane (HMDZ), a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, or a combination of two or more thereof.

[0086] Optionally, in any embodiment, the PECVD for the pH protective coating or layer 406 is carried out in a substantially or completely absent state of oxidizing gases. Optionally, in any embodiment, the PECVD for the pH protective coating or layer 406 is carried out in a substantially or completely absent state of carrier gases.

[0087] Optionally, the FTIR absorbance spectrum of the pH protective coating or layer 406, SiOxCyHz, has a ratio of the maximum amplitude of the Si-O-Si symmetrical stretch peak, typically between approximately 1000 and 1040 cm⁻¹, to the maximum amplitude of the Si-O-Si asymmetric stretch peak, typically between approximately 1060 and 1100 cm⁻¹, greater than 0.75. Alternatively, in any embodiment, this ratio may be at least 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or at least 1.2. Alternatively, in any embodiment, this ratio may be at most 1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at most 1.3. As an alternative embodiment, any of the minimum ratios described herein may be combined with any of the maximum ratios described herein.

[0088] Optionally, in any embodiment, the pH protective coating or layer 406 has an oil-free appearance in the absence of liquid fillers. This appearance is observed, in some cases, to distinguish the effective pH protective coating or layer 406 from a lubricating layer (such as, for example, described in U.S. Patent No. 7,985,188) which may have an oily (i.e., glossy) appearance.

[0089] The pH protective coating or layer may be applied by plasma-assisted chemical vapor deposition (PECVD) of a precursor feed comprising, optionally, acyclic siloxanes, monocyclic siloxanes, polycyclic siloxanes, polysilsesquioxanes, monocyclic silazanes, polycyclic silazanes, polysilsesquiazanes, silatrane, silquasilatrane, silproatrane, azasilatrane, azasilquasiatrane, azasilproatrane, or any combination of two or more of these precursors. Some specific non-limiting precursors considered for such use include octamethylcyclotetrasiloxane (OMCTS).

[0090] Other precursors and methods can be used to apply a pH-protective coating or layer 406 or passivation treatment. For example, hexamethylene disilazane (HMDZ) can be used as a precursor. HMDZ has the advantage of not containing oxygen in its molecular structure. This passivation treatment is considered to be a surface treatment of the SiOx barrier layer with HMDZ. The coating needs to be passivated in order to reduce and / or stop the rate of decomposition of the silicon dioxide coating at the silanol binding sites. Passivation of the surface with HMDZ (and optionally, the application of several monolayers of HMDZ-derived coatings) is considered to strengthen the surface against dissolution and reduce decomposition. It is considered that HMDZ reacts with the -OH sites present in the silicon dioxide coating to generate NH3 and bond S-(CH3)3 to silicon (it is considered that a hydrogen atom is generated and combines with nitrogen from HMDZ to produce NH3).

[0091] Another method for applying a pH protective coating or layer includes applying an amorphous carbon or fluorocarbon coating, or a combination of the two, as the pH protective coating or layer.

[0092] Amorphous carbon coatings can be formed by PECVD using saturated hydrocarbons (e.g., methane or propane) or unsaturated hydrocarbons (e.g., ethylene, acetylene) as precursors for plasma polymerization. Fluorocarbon coatings can be derived from fluorocarbons (e.g., hexafluoroethylene or tetrafluoroethylene). Either type of coating, or a combination thereof, can be deposited by vacuum PECVD or atmospheric pressure PECVD. Because amorphous carbon and / or fluorocarbon coatings do not contain silanol bonds, it is considered that amorphous carbon and / or fluorocarbon coatings result in better passivation of the SiOx barrier layer than siloxane coatings.

[0093] Furthermore, it is conceivable to use a fluorosilicon precursor to cover the upper side of the SiOx barrier layer to provide a pH-protective coating or layer. This can be carried out by using a fluorinated silane precursor, such as hexafluorosilane, as the precursor and employing a PECVD process. The resulting coating is also expected to be a non-wetting coating.

[0094] Another coating modality that can be considered for protecting or passivating the SiOx barrier layer is to coat the barrier layer with a polyamidoamine epichlorohydrin resin. For example, the barrier coating portion may be immersed in a molten, solution, or dispersion of a fluid polyamidoamine epichlorohydrin resin and cured by autoclaving or other heating at a temperature of 60–100°C. It is considered that polyamidoamine epichlorohydrin resin coatings may be preferentially used in aqueous environments with a pH of 5–8, because such resins are known to provide high wet strength in paper within that pH range. Since wet strength is the ability of paper to maintain its mechanical strength when completely immersed in water for a long period of time, it is considered that a polyamidoamine epichlorohydrin resin coating on the SiOx barrier layer will also be resistant to dissolution in an aqueous medium. Furthermore, polyamidoamine epichlorohydrin resins may also be considered to provide lubricity in the form of a coating on thermoplastic surfaces made of, for example, COC or COP, in order to improve the lubricity of paper.

[0095] Another method for protecting the SiOx layer is to apply a liquid application coating of polyfluoroalkyl ether as a pH protective coating or layer, followed by atmospheric plasma curing of the pH protective coating or layer. For example, it is conceivable that a pH protective coating or layer 406 providing similar lubricity could be provided using a process carried out under the trademark TriboGlide®.

[0096] Therefore, a pH protective coating for thermoplastic syringe walls according to an aspect of the present invention is given by the formula: SiOxCyHz (wherein x is 0 to 0.5, or 0 to 0.49, or 0 to 0.25 as measured by X-ray photoelectron spectroscopy (XPS), y is about 0.5 to about 1.5, or about 0.8 to about 1.2, or about 1 as measured by XPS, and z is measured by Rutherford Backscattering Spectrometry (RBS) or Hydrogen Forward Scattering Spectrometry) A plasma-accelerated chemical vapor deposition (PECVD) coated material having a Hz of 0 to 2 as measured by spectrometry (HFS); or a PECVD-treated amorphous or diamond-like carbon, CHz (wherein z is 0 to 0.7, or 0.005 to 0.1, or 0.01 to 0.02); or a PECVD-treated SiNb (wherein b is about 0.5 to about 2.1, or about 0.9 to about 1.6, or about 1.2 to about 1.4 as measured by XPS), which may essentially consist of or may consist of any one of these.

[0097] PECVD apparatus suitable for applying any of the PECVD coatings or layers described herein, including bonding coatings or layers, barrier coatings or layers, or organosiloxane coatings or layers, is shown and described in U.S. Patent No. 7,985,188 and U.S. Patent Application Publication No. 20130291632. This apparatus optionally includes a vessel holder, an inner electrode, an outer electrode, and a power supply. A vessel mounted on the vessel holder defines a plasma reaction chamber and optionally functions as its own vacuum chamber. Optionally, a vacuum source, a reaction gas source, a gas feeder, or a combination of two or more of these may be supplied. Optionally, a gas drain, not necessarily including a vacuum source, is provided to deliver gas into or from the interior of a vessel mounted on a port to define a closed chamber.

[0098] Syringes having a plunger contact surface may be provided substantially without the presence of a fluid lubricant. In this specification, “substantially absent fluid lubricant” means that no fluid lubricant (e.g., PDMS) is provided to the syringe in an amount that contributes to the lubricity of the plunger-syringe system. Since it may be customary to use a fluid lubricant when handling the plunger before assembling it into the syringe, “substantially absent fluid lubricant” may, in some cases, consider the presence of trace amounts of such lubricant as a result of such handling custom.

[0099] Accordingly, in an optional embodiment, the present invention may include an organosiloxane coating on the inner surface of a parenteral container that provides lubrication leading to acceptable plunger operation. The organosiloxane coating may be, for example, any embodiment of the pH protective coating described above. The organosiloxane coating may be applied directly to the inner wall of the container or as the top layer on a multilayer coating set, for example, the three-layer coating set described above.

[0100] Organo-siloxane coatings can optionally provide multiple functions: (1) a pH-tolerant layer that protects the underlying layer or underlying polymer substrate from drug products with a pH of 4-10, optionally 5-9; (2) a drug contact surface that minimizes aggregation, extraction, and leaching; (3) a reduction in protein binding on the container surface in the case of protein-based drugs; and (4) a lubricating layer that facilitates the advancement of the plunger when dispensing contents from a syringe, for example.

[0101] The use of organosiloxane coatings on polymer-based containers as contact surfaces for plungers offers clear advantages. Plastic syringes and cartridges can be injection-molded to tighter tolerances than their glass counterparts. The dimensional accuracy achievable by injection molding allows for optimization of the syringe's inner diameter, while ensuring sufficient compression of the plunger for CCI and airtightness, without overcompressing the plunger to provide the desired plunger force during drug product administration. Optimally, this eliminates or dramatically reduces the need to lubricate the syringe or cartridge with a fluid lubricant.

[0102] For example, a lubricating coating made according to the method disclosed in U.S. Patent No. 7,985,188 (which is incorporated herein by reference in its entirety) is particularly well suited to providing a desired level of lubrication to the plunger of a parenteral container. Such a lubricating coating is preferably applied using plasma-accelerated chemical vapor deposition ("PECVD") and may have one of the following atomic ratios, SiwOxCy or SiwNxCy (where w is 1, x is about 0.5 to 2.4, and y is about 0.6 to about 3). The thickness of such a lubricating coating may be 10 to 500 nm. Advantages of such a plasma-coated lubricating layer may include lower mobility into the drug product or patient than liquid, spray, or micron-coated silicone. The use of such a lubricating coating to reduce plunger force is considered to be within the broad scope of the present invention. Optionally, as shown in Figure 5B, the PECVD lubricating coating 408 may be placed on top of a three-layer coating set to form a four-layer coating set.

[0103] PECVD coating apparatus and processes are generally described in the PECVD protocols of U.S. Patent No. 7,985,188 or PCT / U.S. Patent Application No. 16 / 47622. The entire text and drawings of U.S. Patent No. 7,985,188 and PCT / U.S. Patent Application No. 16 / 47622 are incorporated herein by reference.

[0104] In one embodiment, a tie- or adhesive coating or layer, a barrier coating or layer, and optionally a pH protective layer are deposited in the same apparatus without vacuum breaking between the deposition of the adhesive coating or layer and the barrier coating or layer, or optionally between the deposition of the barrier coating or layer and the pH protective coating or layer. During the process, the lumen is partially vacuumed. While maintaining the partial vacuum in the lumen without breaking it, the SiOxCy tie-coating or layer is applied by a tie-PECVD coating process. The tie-PECVD coating process is carried out by supplying a gas suitable for forming the coating and applying sufficient power to generate plasma in the lumen. The supplied gas includes a linear siloxane precursor, optionally oxygen, and optionally a diluted inert gas. The values ​​of x and y are determined by X-ray photoelectron spectroscopy (XPS). Therefore, while maintaining the partial vacuum in the lumen without breaking it, the plasma is extinguished. As a result, a bonded coating or layer of SiOxCy is formed on the inner surface, where x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3.

[0105] Subsequently, a barrier coating or layer is deposited by a barrier PECVD coating process while maintaining a partial vacuum within the lumen without disrupting it during the process. The barrier PECVD coating process is carried out by applying sufficient power to generate plasma within the lumen while supplying a gas. The supplied gas contains a linear siloxane precursor and oxygen. As a result, a barrier coating or layer of SiOx with x = 1.5 to 2.9, as determined by XPS, is formed between the bonding coating or layer and the lumen.

[0106] Therefore, the plasma disappears while selectively maintaining a partial vacuum within the lumen without destroying it.

[0107] Later, as a further option, a pH-protective coating or layer of SiOxCy may be deposited. In this equation, x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3, as determined by XPS, respectively. The pH-protective coating or layer is optionally deposited between the barrier coating or layer and the lumen by a pH-protective PECVD coating process. This process involves supplying a gas containing a linear siloxane precursor, optionally oxygen, and optionally a diluted inert gas, while applying sufficient power to generate a plasma in the lumen.

[0108] Therefore, the plasma disappears while selectively maintaining a partial vacuum within the lumen without destroying it.

[0109] Later, as a further option, a SiOxCy lubricating coating or layer may be deposited. In this equation, as determined by XPS, x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3. The lubricating coating or layer is optionally deposited on the top surface of the pH protective coating by a lubricating PECVD coating process. This process involves supplying a gas containing an organosiloxane precursor, optionally oxygen, and optionally a diluted inert gas, while applying sufficient power to generate a plasma in the lumen.

[0110] In any of the optional embodiments, a PECVD process for depositing a bonding coating or layer, a barrier coating or layer, and / or a pH-protective coating or layer, and / or a lubricating coating, or any combination of two or more thereof, is carried out by applying pulsed power (or, the same concept, referred to herein as “energy”) to generate plasma in a lumen.

[0111] Alternatively, a bonding PECVD coating process, a barrier PECVD coating process, or a pH-protected PECVD coating process, or any combination of two or more of these, can be carried out by applying continuous power to generate plasma within the lumen.

[0112] 3-layer coating process protocol (all layers are coated within the same instrument) The three-layer coating described in this embodiment is formed by adjusting the flow of a single organosilicon monomer (HMDSO) and oxygen, and also by changing the PECVD generation power between each layer (without breaking the vacuum between any two layers).

[0113] A vessel (e.g., a COC syringe) is placed in a vessel holder, sealed, and a vacuum is drawn into the vessel. After the vacuum is drawn, a supply of precursor, oxygen, and argon gases is introduced, and then, at the end of the "plasma delay," a continuous (i.e., not pulsed) 13.56 MHz RF power is turned on to form a bonded coating or layer. The power is then turned off, the gas flow is adjusted, and after the plasma delay, the power is turned on for a second layer—a SiOx barrier coating or layer. This is then repeated for a third layer before the gas is shut off, the vacuum seal is broken, and the vessel is removed from the vessel holder. The layers are placed in the order of bonded layer, barrier layer, and then pH protection layer. An exemplary process setup is shown in the table below:

[0114] [Table 2]

[0115] Further alternatives include using pulsed power for some steps and continuous power for others. For example, when creating a three-layer coating or layer consisting of a bonding coating or layer, a barrier coating or layer, and a pH-protective coating or layer, the options specifically considered for the bonding PECVD coating process and the pH-protective PECVD coating process are pulsed power, while the option considered for the corresponding barrier layer is to use continuous power to generate plasma within the lumen.

[0116] Optional injectable product composition Optionally, in any embodiment, the syringe according to the concept of the present disclosure is pre-filled with an injectable drug product.

[0117] Optionally, in any embodiment, the injectable drug product may be an ophthalmic drug suitable for intravitreous injection. Optionally, in any embodiment, the ophthalmic drug comprises a VEGF antagonist, optionally an anti-VEGF antibody, or an antigen-binding fragment of such an antibody. Optionally, in any embodiment, the VEGF antagonist comprises ranibizumab, aflibercept, or a combination thereof.

[0118] In any of the optional embodiments, the concentration of the eye drop solution suitable for intravitreal injection is 1 to 100 mg (mg / ml), or 2 to 75 mg / ml, or 3 to 50 mg / ml, or 5 to 30 mg / ml, and / or 6 or 10 mg / ml of the drug active agent per 1 ml of solution 40.

[0119] In either embodiment, the eye drop solution suitable for intravitreal injection comprises 6 mg / ml or 10 mg / ml of ranibizumab.

[0120] Optionally, in any embodiment, an eye drop suitable for intravitreal injection further comprises: an amount of buffer effective to bring the pH of the solution 40 in the range of about 5 to about 7; a nonionic surfactant in mg / mL in the range of 0.005 to 0.02% of the total solution, or in the range of 0.007 to 0.018% of the total solution, or in the range of 0.008 to 0.015% of the total solution, or in the range of 0.009 to 0.012% of the total solution, or in the range of 0.009 to 0.011% of the total solution, or in the range of 0.01% of the total solution; and water for injection.

[0121] In any of the optional embodiments, an eye drop suitable for intravitreal injection comprises, in water for injection, 6 mg / mL or 0 mg / mL ranibizumab; 100 mg / mL α,α-trehalose dihydrate; 1.98 mg / mL L-histidine; and 0.1 mg / mL polysorbate 20.

[0122] Industry standards for testing plunger characteristics Testing of the compression setting characteristics of a plunger assembly can be carried out using methods known in the art, for example, ASTM D395.

[0123] Tests of the adhesive properties or bond strength between a film (e.g., a fluoropolymer) and a plunger may be carried out using methods known in the art, for example, in accordance with ASTM D1995-92(2011) or D1876-08.

[0124] The plunger sliding force is the force required to maintain the movement of the plunger within the syringe or cartridge barrel, for example, during aspiration or drug delivery. It may be convenient to determine this force using, for example, the ISO 7886-1:1993 test, known in the art, or a publicly available test method currently under review, which is intended to be incorporated into ISO 11040-4. The plunger breakout force, which can be tested using the same method as the plunger sliding force test, is the force required to initiate steady-state movement of the plunger within the syringe or cartridge barrel. A useful machine for testing the plunger sliding and breakout forces is, for example, an Instron machine using a 50N transducer.

[0125] Testing the amount of extractable material, i.e., the amount of material transferred from the plunger into the liquid in the syringe or cartridge, can be performed, for example, using the method described in Ph. Eur. 2.9.17 Test for Extractable Volume of Parenteral Preparations.

[0126] The integrity of the container closure (CCI) test can be performed using a vacuum decay leak detection method, where a vacuum is maintained within the test volume and the pressure rise is measured over time. A sufficiently large pressure rise indicates the presence of inflow into the system, which is evidence of leakage. Optionally, the vacuum decay test is performed over two separate cycles. The first cycle is dedicated to detecting large leaks over a very short period. For the first cycle, a relatively weak vacuum is drawn because, if a gross leak is detected, a large pressure difference is not necessary to detect a large pressure rise. Using the first cycle as described helps to shorten the total test time if a gross leak is present. If no leak is detected in the first cycle, a second cycle is performed according to ASTM F2338-09 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method. The second cycle begins with a system evaluation to reduce the signal-to-noise ratio in the pressure rise measurement. In the second cycle, a relatively strong vacuum is maintained for an extended period, increasing the opportunities to detect pressure increases in the system.

[0127] Tests for air leakage beyond the syringe piston during aspiration can be performed using methods known in the art, for example, ISO 7886-1:1993.

[0128] Tests for fluid leakage in a syringe piston under compression can be performed using methods known in the art, for example, by applying an axial force to the plunger stopper by the plunger rod of the finished product, thereby blocking the fluid path, and using ISO 7886-1:2015, Annex B, for fluid leakage.

[0129] In an exemplary method of applying this standard, a 0.5 mL syringe may be filled with 0.165 mL of MILLI-Q high-purity water. A plunger, optionally a West FLUROTEC plunger, is vacuum-loaded into the filled syringe. The plunger assembly with axial projections is positioned within the plunger as described herein to place the plunger into storage mode. The crosshead is compressed at a rate of 10 mm / min until a maximum force of 5.43 N is reached, corresponding to a pressure of 300 kPa in the syringe (or a force matching the maximum force generated during use). The crosshead is made small adjustments to hold the maximum force for 30 seconds. In this embodiment, the ISO 7886-1 test is considered to have failed if any water flows back out of the syringe over any of the plunger's ribs.

[0130] Various aspects of the present invention will be described in more detail with reference to the following examples, but it should be understood that the present invention is not limited thereto. [Examples]

[0131] Example 1 F after changes over time i Influence of the axial length of the projection on the In this embodiment, three groups of syringes A, B, and C manufactured by COP were used in an experiment to determine the effect of axial projection length on the release force (Fi) over time. Each group consisted of five syringes. Group A had no axial projection on the plunger rod (therefore, the plunger was pushed at the proximal end of the plunger instead of within the lumen of the plunger sleeve). Group B had an axial projection with an axial length of 5.71 mm, as shown in Figures 5 and 6. Group C had an axial projection with an axial length of 9.1 mm, as shown in Figures 5 and 6. The only difference between the three configurations was the axial length (L) of the projection. The plungers were identical for all three groups of syringes. The axial length of the lumen of each plunger was 5.3 mm. This measurement represents the length from the proximal end of the plunger sleeve to the most distal section (engaging surface) of the inner surface when the plunger is in its natural state (i.e., not compressed or stretched radially or axially).

[0132] All syringe barrels were coated with a three-layer coating set, on which an OMCTS lubricating coating was placed, thereby providing a four-layer coating set as disclosed herein (see Figure 5B). These syringes were filled with a buffer solution (10 mM histidine HCl, 10% α,α-trehalose dehydrate, 0.01% polysorbate, pH 5.5 aqueous solution). The filled syringes were stored at 4°C. After 9 months of storage, these syringes were tested for their release force without a needle at 190 mm / min. Release force data dependent on the length of the axial projection is shown in Figure 14.

[0133] When these syringes were tested for release force, the plunger rod moved axially from the proximal to the distal end within the barrel. In syringes of group A, the absence of a projection during testing meant that moving the plunger rod distally applied a full axial compressive force to the proximal end of the plunger. In syringes of group B, an axial projection slightly longer than the axial length of the lumen applied an axial compressive force to the proximal end of the plunger, but the plunger was stretched from the inside by the projection at its distal end. In syringes of group C, an axial projection considerably longer than the axial length of the lumen created a significant gap between the proximal end of the plunger and the distal end of the plunger rod when the plunger was moved from its resting position. Therefore, in group C, the plunger was stretched from the inside at its distal end by the projection, without any compressive force being applied to the proximal end of the plunger. The data shows that syringe C provided the lowest release force, syringe A provided the highest release force, and syringe B was somewhere in between.

[0134] Example 2 Effect of axial length of protrusion on Fi after time changes In this embodiment, the syringes were coated with PECVD in a four-layer coating set on the inner wall of the barrel by the process described herein and shown in Figure 5B. The syringes were filled with 1.165 mL of high-purity water and vacuum-loaded by a plunger. The plungers were part of a plunger assembly separated into the following groups: A1, B1, C1, and D1. Each plunger (West 4023 / 50) was made of bromobutyl rubber with a durometer of 50, and the drug contact surfaces, such as the nose cone area, were covered with a fluoropolymer (e.g., ETFE) film. These syringes and plunger assemblies were tested for their release force (F) after 1 day, 7 days, and 28 days of storage, respectively. i The following was tested regarding the plunger assembly corresponding to the four syringes: A1: No protrusion (length = 0.0 mm); B1: Protrusion (length = 4.7 mm); C1: Protrusion (length = 5.2 mm); D1: Protrusion (length = 5.7 mm).

[0135] In groups B1, C1, and D1, the axial projections were similar to the design in Figure 5, except for their respective lengths. The test results are shown in Table 1 and Figure 15 below. The data shows that syringes with projections longer than the plunger lumen (i.e., D1) had the lowest breakout force F i This demonstrates that it provides the best breakout force F. The protruding syringe (A1) has no plunger extension at all and is compressed from behind, resulting in the best breakout force F. i Syringes with projections shorter than the lumen of the plunger (i.e., B1 and C1) provide results between A1 and D1. The table below describes the results of this test, and the numbers represent the mean release force (N).

[0136] [Table 3]

[0137] These data indicate that a plunger assembly with axial projections reduced the release force by an average of approximately 20% to 25% compared to a plunger rod without axial projections at a given time point.

[0138] Example 3 Burst test using the axial projection of the plunger rod The burst test is used to determine the maximum force required on the extension of the plunger rod to break through the rubber plunger (hereinafter referred to as "burst").

[0139] The plunger assembly 20 shown in Figure 5 was used for the burst test. The axial projection was made of polypropylene and had a length of 9.1 mm and a diameter of 1.4 mm. A group of syringes were filled with 0.165 mL of water for injection (WFI) and fitted with stoppers (i.e., the plunger was inserted into the barrel). The filled syringes were stored at 4°C for 15 days. The syringes were removed from the refrigerator and allowed to warm to room temperature for 1 hour before the test.

[0140] The syringe is loaded into the Instron instrument, and the plunger rod is assembled with the plunger sleeve as described in this disclosure.

[0141] The measuring instrument pushes the plunger rod at a constant speed of 190 mm / min. The force required to push the plunger is measured. The force begins to increase as the plunger rod contacts the underside of the plunger. The data shows that the extension of the plunger rod stretches the rubber plunger by approximately 1.5 mm before bursting. The amount of force required to burst is approximately 25 N. This test demonstrates that when using preferred plunger and plunger rod materials in preferred dimensions, it is desirable to limit the length of the rod extension so that the rubber plunger does not become longer than 1.5 mm. This helps to ensure that the plunger rod does not burst.

[0142] Example 4 Leakage testing of a plunger assembly with an axial projection on the head. In this embodiment, leak testing was performed using a plunger assembly having an axial projection 130 including a head 130a, as described above and as shown in Figures 3A, 3B, 7, 8 and 12A-12C. Leak testing was performed in accordance with ISO 7886-1:2015, Annex B for liquid leaks, with the fluid path as described herein blocked. Heads of various shapes and dimensions (e.g., 130a) were tested. A total of 20 syringes were tested using each axial projection head configuration at different temperatures and time points. Testing was performed at storage temperatures of 4°C, 25°C, and 40°C at 1 day, 3 days, 7 days, 1 month, 3 months, 6 months, and 9 months, respectively, except that testing was not performed at 6 months and 9 months at 40°C. In other words, a total of 380 tests were performed for each axial projection head configuration and dimension.

[0143] The axial projection 130 having a head 130a, as precisely shown in Figures 3A, 3B, 7, 8, and 12A-12C, was found to exhibit superior performance compared to other configurations tested. Furthermore, a head 130a with a larger diameter (2.25 mm compared to 2.10 mm and 2.00 mm in this case) yielded superior results. This test demonstrated that in this configuration, the thicker head 130a (2.25 mm in diameter) resulted in greater radial pressure against the cylinder wall, which made the difference. This embodiment produced only one failure in 380 tests, and that failure occurred at 25°C, i.e., an overall failure rate of 0.26%. At a more typical refrigerated storage temperature of 4°C, this embodiment had zero failures in 140 tests, i.e., a failure rate of 0% at that temperature. The next best result was a head 130a of the same shape but with a diameter of 2.10 mm. The embodiment produced 26 failures in 380 tests, resulting in an overall failure rate of 6.8%, and 5 failures in 140 tests at 4°C, resulting in a failure rate of 3.6% at that temperature. Another embodiment with the same shape but a diameter of 2.00 mm yielded similar results to that of the same shape but with a diameter of 2.10 mm.

[0144] In contrast, embodiments with a bullet shape of 2.00 mm in diameter that did not properly match the internal shape of the lumen performed far worse. The "bullet-shaped" embodiments resulted in 67 failures out of 380 tests, i.e., an overall failure rate of 17.6%. These embodiments also resulted in 23 failures out of 140 tests at 4°C, i.e., a failure rate of 16.4% at that temperature.

[0145] This experiment demonstrated that, in axial projections with heads, the shape and dimensions of the head can dramatically affect the effectiveness of the fluid seal provided by the plunger. It appears that the geometric shape of the head substantially matching the corresponding geometric shape and dimensions of the distal compartment chamber of the lumen of the plunger sleeve enhances seal integrity.

[0146] Example 5 Testing of a plunger assembly with an axial projection and head i In this embodiment, the release force over the test was performed by a plunger assembly having an axial projection 130 including a head 130a, as described above and shown in Figures 3A, 3B, 7, 8 and 12A-12C. Heads of various shapes and dimensions (e.g., 130a) were tested. The tests were performed at different time points and temperatures, using heads of different shapes / dimensions. In particular, for a total of eight time points (1 day, 3 days, 7 days, 1 month, 3 months, and 9 months), five syringes per time point were tested at three different temperatures (4°C, 25°C, and 40°C). In other words, a total of 40 syringes were tested at each temperature. The cylinders were coated with silicone oil for lubrication.

[0147] The syringe was filled with 0.165 mL of MILLI-Q high-purity water. The plunger was loaded using a vacuum loader to a vacuum pressure of 28 in Hg (absolute pressure of 65 mbar). This filling process produced bubbles approximately 0.3 mm in height. The size of the bubbles was F i or maximum F mIt did not affect the results. Before the test, the syringes, which had been stored at each temperature, were returned to room temperature.

[0148] The control group consisted of plunger rods without axial projections, i.e., plunger rods with a distal end that directly contacts the proximal end of the plunger sleeve from storage mode through drug delivery mode. The data showed that, on average, regardless of the specific head shape and morphology, the control group was F i In this study, it was shown that the control group tended to be approximately 2N larger than the control group at a given time. For example, at 9 months, the control group was F i The average was approximately 8N, but at the same time, the plunger assembly in the test group was F i The average was less than 6N.

[0149] This experiment shows that the shape and dimensions of the embodiment are F i It demonstrated that this design had the lowest leakage test failure rate measured in the test population compared to other subgroups. In other words, its shape and dimensions appear to strike a good balance between seal integrity and plunger force. This experiment further demonstrated that the release force can be reduced without significantly sacrificing seal integrity by using axial projections to extend the plunger.

[0150] Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

Claims

1. It is a pre-filled syringe, The aforementioned pre-filled syringe is A medical tube comprising an inner wall and a region for holding a product, wherein the region for holding a product is configured to contain an injectable product, and the medical tube comprises a distal dispensing end for dispensing the injectable product and an open proximal end configured to receive a plunger assembly; and A plunger assembly for use in the aforementioned medical tube, comprising: A plunger rod having a distal end and a proximal end; An axial projection extending from the distal end of the plunger rod; and A plunger comprising a plunger sleeve having an outer surface and an inner surface surrounding a lumen, wherein the outer surface includes a distal nose cone and an annular outer wall extending proximal from the distal nose cone to an opening at the proximal end of the plunger sleeve, the opening receiving the axial projection so that the axial projection extends into the lumen and contacts an engaging surface of the inner surface, the engaging surface receiving a force applied distally by the axial projection, and is configured to move the plunger assembly distally when the plunger rod is moved distally; Plunger assembly Includes, The plunger rod and axial projection are provided as a single piece in a unitary structure. The plunger is positioned inside the medical tube so that the distal nose cone faces the injectable product. When the plunger is in its unextended state before operation, the plunger is configured to apply a compressive force to the inner wall of the medical tube, thereby sealing it and maintaining the shelf life of the injectable product, and the distal end of the plunger rod is not initially in contact with the proximal end of the plunger sleeve. When the axial projection first applies force in the distal direction, the plunger is converted from its pre-extension state to a drug-delivery mode, in which the plunger extends axially, contracting at least a portion of the annular outer wall of the plunger sleeve, thereby reducing radial pressure on the inner wall, and resulting in a gliding force lower than that which can be achieved without extending the plunger. The plunger advances the medical tube distally in the drug dispensing mode, and Even if sufficient axial force is applied to the proximal end of the plunger rod to move the axial projection axially out of the plunger sleeve, the plunger will not move in the proximal axial direction. A pre-filled syringe wherein the axial projection is cylindrical and has a uniform diameter along its entire length except for its tapered tip, and the cylindrical outer surface of the axial projection loosely contacts the inner surface of the plunger sleeve, so that the axial projection can be manually pulled out of the plunger sleeve when the plunger sleeve is placed inside a medical tube.

2. The pre-filled syringe according to claim 1, wherein in the drug dispensing mode, the plunger assembly is moved distally in the medical tube by applying sufficient force distally to the plunger rod.

3. The pre-filled syringe according to claim 1 or 2, wherein the plunger includes an extension zone, the extension zone is adapted to extend along the central axis of the plunger when a force is applied distally to the engagement surface by the axial projection, and the extension reduces the outer contour of the annular outer wall along the extension zone.

4. The pre-filled syringe according to claim 3, wherein the plunger rod and axial projection are configured such that the plunger rod does not come into contact with the proximal end of the plunger sleeve when the plunger assembly advances the medical tube distally, thereby preventing the plunger from being compressed axially during operation.

5. The pre-filled syringe according to any one of claims 1 to 4, wherein the pre-filled syringe is a 0.5 mL syringe.

6. The pre-filled syringe according to any one of claims 1 to 5, wherein the medical tube is injection-molded from a transparent polymer, optionally COP, or COC.

7. The pre-filled syringe according to any one of claims 1 to 6, wherein the inner wall of the medical tube comprises a plasma-accelerated chemical vapor deposition (PECVD) coating or a coating set.

8. The PECVD coating or coating set is: A two-layer coating set comprising, optionally, a bonding layer and a SiOx barrier layer disposed on the bonding layer; A three-layer coating set comprising, optionally, a bonding layer, a SiOx barrier layer disposed on the bonding layer, and an organosiloxane layer disposed on the SiOx barrier layer; and A four-layer coating set comprising, optionally, a bonding layer, a SiOx barrier layer disposed on the bonding layer, an organo-siloxane layer disposed on the SiOx barrier layer, and a lubricating layer disposed on the organo-siloxane layer. A pre-filled syringe according to claim 7, selected from the group consisting of the following.

9. A pre-filled syringe according to any one of claims 1 to 8, wherein a coating of a fluid lubricant, optionally silicone oil, is provided between the plunger and the medical tube.

10. The pre-filled syringe according to any one of claims 1 to 9, wherein the pre-filled syringe is a 0.5 mL syringe, and the injectable product is optionally a liquid ophthalmic formulation present in an amount of 165 μL.

11. The liquid ophthalmic formulation is suitable for intravitreal injection and comprises a VEGF antagonist, optionally comprising an anti-VEGF antibody or an antigen-binding fragment of such an antibody, according to claim 10.

12. The liquid ophthalmic formulation comprises ranibizumab and / or aflibercept, as described in claim 10 or 11.

13. The pre-filled syringe according to any one of claims 1 to 12, wherein the plunger rod is provided with one or more radial stabilizing members that stabilize the plunger rod by preventing wobbling as the plunger assembly moves forward within the medical tube.

Images