Improved Syringe and Gasket System

Abstract

A process for manufacturing an improved gasket for use in matched syringe and plunger systems, preferably pre-filled plastic syringe systems. In particular, a process for creating and inspecting non-continuous channels in or through a gasket film by laser processing. The gasket is useful in matched syringe and plunger systems to provide high and consistent container closure integrity (CCI), as well as consistent release and sliding forces over time, and sealability.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 316,611, filed March 4, 2022, the disclosure of which is incorporated by reference in its entirety herein.

[0002] introduction The present disclosure relates to an improved process for making and inspecting matched syringe and plunger systems, particularly gaskets used in syringes, and laser cuts in the gaskets. This application incorporates by reference in its entirety PCT International Application No. PCT / US2019 / 065099, filed December 6, 2019, and U.S. Patent No. 7,985,188 B2, issued July 26, 2011. This application more specifically incorporates by reference U.S. Patent No. 7,985,188 B2 for its disclosure of a syringe barrel or the like lubricated by applying a PECVD coating of SiOxCy or SiOxCyHz, and methods of making, testing, and using such a syringe barrel.

[0003] Pre-filled parenteral containers, such as syringes or cartridges, and plunger systems have been developed to facilitate rapid and accurate administration of sterile products (e.g., saline, injectable dyes, medicamentously active preparations, etc.), minimize administration errors, reduce the risk of biological contamination, enhance convenience and ease of use, prevent overfilling of products, etc. (e.g., Yoshino et al., J Pharm Sci. 2014;103(5):1520-8). Pre-filled parenteral containers are typically sealed with a rubber gasket secured to the plunger at the distal end, which provides closure integrity over the shelf life of the container's contents. To use a pre-filled syringe, the packaging and cap are removed, and optionally, a hypodermic needle or another delivery conduit is attached to the distal end of the barrel, the delivery conduit or hypodermic needle is moved to a use position (e.g., inserted into the target tissue or into a device that is rinsed with the contents of the syringe), and the plunger is advanced within the barrel to inject the barrel's contents to the point of application.

[0004] The seal provided by the rubber gasket in the barrel of the syringe is usually achieved by the rubber of the gasket being pressed against the barrel. Typically, the maximum diameter of the rubber gasket is greater in diameter than the minimum inner diameter of the barrel. Thus, this pushing force of the rubber gasket must be overcome in order to displace the rubber gasket and its attached plunger when the injection product is dispensed from the syringe. Moreover, this pushing force provided by the rubber seal typically not only needs to be overcome when the gasket fixed to the plunger is initially moved, but also needs to continue to be overcome as the rubber gasket is displaced along the barrel during the dispensing of the injection product. A relatively high force is required to advance the gasket and plunger in the syringe, which can make it more difficult for the user to administer the injection product from the syringe. This is particularly problematic for automatic injection systems, where the syringe is disposed in an automatic injection device and the gasket is advanced by a fixed spring. Thus, the primary considerations regarding the use of gaskets secured to plungers in prefilled parenteral containers include (1) container closure integrity ("CCI", defined below) and liquid / air tightness, and (2) the plunger force (defined below) required to dispense the syringe contents.

[0005] In practice, maintaining CCI / fluid-tightness or air-tightness and providing a desired plunger force tend to be conflicting considerations. In other words, the tighter the fit between the gasket and the interior surface of the container to maintain adequate CCI / fluid-tightness or air-tightness, the greater the force required to advance the gasket during use, barring other factors. In the field of syringes, it is important to ensure that the gasket secured to the plunger can move at a substantially constant speed and with a substantially constant, relatively low force as it advances within the barrel. Furthermore, the force required to initiate and then continue plunger advancement should be low enough to allow comfortable administration by the user and prevent rocking or unnecessarily high pushing forces that may cause discomfort to the patient.

[0006] To reduce friction and therefore improve plunger force, lubricants are traditionally applied to the barrel contact mating surface of the gasket secured to the plunger, the interior surface of the barrel, or both. Liquid or gel-like mobile lubricants such as silicone-free oils (e.g., polydimethylsiloxane or "PDMS") can provide the desired level of lubrication between the plunger and barrel to optimize plunger force. In fact, PDMS is a standard mobile lubricant used in the industry. However, it is not desirable to use a mobile lubricant between the gasket and the barrel. One reason is that the mobile lubricant can mix and interact with the pharmaceutical agent in the syringe, degrading the drug or otherwise affecting its efficacy and / or safety. For example, silicone oil, when used as a lubricant, can cause droplets, which can potentially result in aggregation of sensitive biopharmaceuticals or clouding of the solution (Bee JS et al., PDA J Pharm Sci Technol. 2014;68(5):494-503), or cause increased drug interactions and particle formation (Yamashita A et al., Adv Drug Deliv Rev. 2013;65(1):139-47). Monoclonal antibodies, conjugate vaccines, and protein formulations are particularly vulnerable to silicone-induced protein aggregation and particle formation. (Majumdar et al., J Pharm Sci. 2011 July;100(7):2563-73). Furthermore, over time, silicone migration can alter the release and gliding forces (BLGF) and injection times, thus affecting the consistency of delivery (Thornton JD et al., 2015, ON drug Delivery SIP, No. 61 (October 2015), pp10-15). Sub-visible particles caused by migration of silicone oil into drug formulations can pose several product quality concerns.For example, exceeding the USP limit for particles in parenteral containers, structural instability of proteins caused by adsorption, and / or immunogenic responses caused by injection of silicone oil-induced protein aggregates or silicone oil / protein complexes, can reduce the efficacy of the drug and / or cause potentially dangerous reactions in patients, making the product unsuitable for use (Thornton JD et al., 2015, ON drug Delivery Magazine, Issue 61 (October 2015), pp 10-15). Thus, lubricants can be problematic when injected into patients with pharmaceutical drugs.

[0007] Furthermore, when used in pre-filled syringes, mobile lubricants can migrate away from the gasket over time, resulting in spots with little or no lubrication between the gasket and the interior surface of the container. This can cause a phenomenon known as "stiction," which is the industry term for adhesion between the gasket and barrel that must be overcome to allow the plunger and gasket to begin moving in order to exit. For these reasons, there is an industry need for an "oil-free" solution, i.e., a gasket that does not contain a mobile lubricant between the gasket and barrel, where such a mobile lubricant is not present in the pharmaceutical product stream.

[0008] As an alternative (or in addition) to mobile lubricants, gaskets are developed from materials with lubricating properties or to include friction-reducing coatings or films on their exterior surfaces. In some embodiments, such fluoropolymer films can provide a barrier to minimize interactions between the formulation and the plunger while maintaining the seal of the gasket (Christa Jansen-Otten 2019, blog, Westpharma). For example, "i-coating by TERUMO" referred to in Canadian Patent No. 1,324,545, incorporated herein by reference in its entirety, "WLGore expanded PTFE film on rubber stopper" disclosed in EP2493534B1, incorporated herein by reference in its entirety, and "CZ plunger" by WEST. However, such gaskets have been subject to CCI failures due to film wrinkling, film defects, and / or film peeling from the rubber gasket may have poor gas barrier properties. Thus, conventional fluoropolymer film laminate gaskets alone may not be a viable solution for pre-filled syringes containing certain gas sensitive products, and furthermore, the CCI of such syringe and gasket systems is poor.

[0009] Additionally, in these prefilled syringe systems, the gasket comes into contact with the enclosed sterile product during administration and during drug storage. Interactions between the sterile product and its packaging can significantly impact the purity and degradation of the drug product, as well as the safety of patients administered the product (Christa Jansen-Otten 2019, blog, Westpharma). Thus, the selection of appropriate gaskets for syringe systems, especially prefilled syringe systems, is an important consideration for the pharmaceutical and biopharmaceutical industries.

[0010] US Patent Application No. 15 / 445,108, which is incorporated herein by reference in its entirety, refers to a laminated gasket for use in a medical syringe. Such a gasket includes a body made of an elastic material and a film provided on the surface of the body. In a syringe system, the syringe typically includes a syringe barrel and a plunger that is reciprocally movable within the syringe barrel. A gasket is attached to the distal end of the plunger. In this application, the gasket is further subjected to a laser machining process by applying a laser beam to a circumferential surface portion of the gasket at an angle to the circumferential surface portion while rotating the circumferential surface portion of the gasket about the central axis of the gasket, thereby forming annular grooves in the circumferential direction on at least the surface portion of the film on the gasket. Such laser cut grooves or channels improve the sliding and sealing of the laminated gasket in the syringe while maintaining the elasticity of the gasket and minimizing liquid leakage from a pre-filled syringe. In addition, the laser cut grooves form a moat-like structure on the ribs of the gasket with the microprojections elevated on the film surface, improving the sliding and sealing of the laminated gasket in the syringe. However, this method of laser processing has some drawbacks because the laser cut grooves in the gasket increase the risk of defects formed in the gasket, which can cause defects in the microprojections and lead to gasket failure, which in some embodiments can result in failure of the container closure integrity.

[0011] In the gaskets disclosed in U.S. Patent Application Serial No. 15 / 445,108, the laser cut grooves or channels of the gasket are formed throughout the circumferential surface portion of the film of the gasket such that the grooves are continuous. However, such continuous grooves in the gasket have experienced failure in CCI due to circularity. The circularity can affect the uniformity of the microprojections, for example, while rotating the gasket during the laser process, the depth of the projections can vary based on the position of the gasket. As the gasket rotates, without being perfectly centered, this method of laser processing can result in elliptical cutouts with deeper grooves at one point and shallower grooves at another point along the circumference of the gasket, resulting in poor gas barrier properties. Thus, conventional laser cut gaskets alone are not a viable solution for pre-filled syringes containing certain gas sensitive products. Furthermore, such syringe and gasket systems have poor CCI.

[0012] Additionally, certain lasers used to form the grooves can lead to cutting the grooves unevenly based on the laser beam profile. For example, a laser beam with a Gaussian laser beam profile provides a spatial intensity distribution in a bell-shaped intensity profile, which leads to energy waste in the "tails" of the beam profile when the intensity is below the ablation threshold and sufficient to melt / heat the material (Hoang et al., Micromachines, February 2020, 11(221)).

[0013] In the process mentioned in US Patent Application No. 15 / 445,108, the internal cavity of the gasket (or plunger) is rotated during the laser cutting process. However, this method of fixing the gasket (plunger) during the laser process has some drawbacks because the walls of the gasket (plunger) may deform or loosen while the gasket (plunger) is rotating to create the laser cut grooves. This results in less consistent laser cuts or grooves on the gasket (plunger) film. Syringe systems incorporating gaskets (plungers) manufactured by the process of US Patent Application No. 15 / 445,108 are also more prone to liquid or gas leakage and have poorer CCI. Summary of the Invention

[0014] There is a need for a process for generating two or more non-continuous channels on the surface of a gasket (or plunger) with a film on its outer surface, as well as an improved gasket for use in a syringe gasket system for delivery of, for example, pharmaceutical products to a subject in need thereof. The resulting gasket improves the prevention of liquid or gas leakage and has excellent CCI when used in a matched syringe and plunger system. Syringes assembled with the improved gasket of the present disclosure improve the protection of the product contained therein and are characterized by improved product shelf life.

[0015] In some embodiments, the present application provides a process for creating two or more non-continuous channels in or through a film present on the outer surface of a gasket that extends into the gasket itself, in some embodiments, for use in a matched syringe and plunger gasket system, thereby providing excellent container closure integrity and sealability and minimal liquid / gas leakage.

[0016] In some embodiments, the present disclosure provides a gasket with non-continuous channels for use in a matched syringe-plunger system. The non-continuous channels may be included in or, in some embodiments, through a film present on at least a portion of the circumferential outer surface portion of the gasket. The non-continuous channels of some of the embodiments also include non-channel portions disposed around the circumferential outer surface portion of the gasket. The non-continuous channels may be generally parallel to each other, and each of these channels includes non-channel portions that are, in some embodiments, not aligned with each other. The silicone oil-free syringe and gasket system, preferably the pre-filled plastic syringe system, of some embodiments of the present disclosure has excellent container closure integrity (CCI), avoids high opening forces and liquid / gas leakage, provides consistent delivery performance over time, provides protection for sealed products, minimizes gasket-product interactions, maintains efficacy and sterility during the product's shelf life, and has improved product shelf life. The syringe and gasket system of some embodiments can provide particle reduction that is not visible to the naked eye and protect complexes or sensitive biologics contained within the syringe from silicone oil induced aggregation and particle formation. The present disclosure in some embodiments provides a process for making non-continuous channels in the gasket and film reside on their outer surface by laser cutting.

[0017] In some embodiments, the present disclosure also provides a process for manufacturing a silicone oil-free syringe and gasket system having less than 300 particles of 2 micron size or greater as measured using light obscuration (LO) or microflow imaging (MFI). Additionally, in some embodiments, the syringe system of the present disclosure incorporates a process that improves the seal provided by a built-in lubricating film on the gasket that eliminates the need to use a lubricated syringe barrel. In some embodiments, the present disclosure incorporates state-of-the-art manufacturing process controls and substantially 100% inspection systems that provide tight dimensional control of the gasket and corresponding syringe and channel, allowing for highly consistent compression of the assembled syringe and gasket system optimized for container closure integrity and plunger force.

[0018] In some embodiments, the present disclosure is directed to a process for forming a plurality of non-continuous channels in or through a film present on at least a portion of a circumferential outer surface of a gasket, the gasket including a body and an internal cavity, the internal cavity being defined by an inner surface of the gasket and including an open end, the process comprising: (a) inserting one end of a mandrel into an open end of a cavity; (b) positioning the mandrel and gasket relative to a laser; (c) applying a laser beam emitted from the laser to a plurality of locations on a surface of the film while rotating the mandrel and gasket along a longitudinal axis of the mandrel to form a plurality of non-contiguous channels; Each non-contiguous channel is generally parallel to the other non-contiguous channels, and each non-contiguous channel of the plurality of non-contiguous channels extends partially around a circumferential outer surface of the gasket, hi some embodiments, a non-channel portion interrupts each non-contiguous channel and is positioned along a circumferential outer surface portion of the gasket such that it is not aligned with another non-channel portion of an adjacent non-contiguous channel or channels.

[0019] In some embodiments, the process includes monitoring a plurality of selected locations using a laser micrometer by monitoring the exact location where the laser beam is applied, and adjusting the laser beam based on the monitoring.

[0020] In some embodiments, the thickness of the film present on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

[0021] In some embodiments, the film is configured to slide along the tube of a syringe and is chemically stable.

[0022] In some embodiments, the film can prevent migration of components from the elastic material of the gasket.

[0023] In some embodiments, the process includes securing the gasket to the mandrel, for example, in some embodiments, the gasket is secured to the mandrel by a press-fit assembly.

[0024] In some embodiments, the diameter of at least a portion of the mandrel that is inserted into the internal cavity of the gasket is greater than the inner diameter of the internal cavity prior to insertion of the mandrel.

[0025] In some embodiments, the plurality of non-contiguous channels comprises two non-contiguous channels axially spaced apart from one another. In some embodiments, each non-contiguous channel of the plurality of non-contiguous channels comprises axially opposed first and second sidewalls and a floor. In some embodiments, each non-contiguous channel of the plurality of non-contiguous channels comprises an axial width between sidewalls selected from 1-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns. In some embodiments, each non-contiguous channel of the plurality of non-contiguous channels comprises a radial depth selected from 0-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns. In some embodiments, each non-contiguous channel of the plurality of non-contiguous channels comprises a laser cut depth selected from 20-80 microns, 30-60 microns, 40-50 microns, 50-60 microns, 40-45 microns, 45-50 microns, 50-55 microns, and 55-60 microns.

[0026] In some embodiments, one or more of the plurality of non-contiguous channels extend through the film into the circumferential outer surface of the gasket.

[0027] In some embodiments, each of the plurality of non-contiguous channels includes a radial depth greater than a thickness of the film on the surface of the gasket.

[0028] In some embodiments, the plurality of non-contiguous channels includes a first circumferentially extending lip located adjacent a first sidewall of the channel and extending radially of the film.

[0029] In some embodiments, the plurality of non-contiguous channels further comprises a second circumferentially extending lip located adjacent the second sidewall and extending radially of the film, in some embodiments, the first lip comprises a first peak height selected from 10-100 microns, 15-60 microns, 20-50 microns, or 30-40 microns, and the second lip comprises a second peak height selected from 10-100 microns, 15-60 microns, 20-50 microns, or 30-40 microns.

[0030] In some embodiments, a first lip of each non-contiguous channel of the plurality of non-contiguous channels comprises a first peak width selected from 200-1,000 microns, 275-550 microns, 300-400 microns, or 450-500 microns, and a second lip of each non-contiguous channel of the plurality of non-contiguous channels comprises a second peak width selected from 200-1,000 microns, 275-550 microns, 300-400 microns, or 450-500 microns.

[0031] In some embodiments, each lip comprises a film material that is displaced from the channel by the laser beam as the channel is formed.

[0032] In some embodiments, a gasket can be positioned within the tubular syringe barrel to form a seal between an inner surface of the barrel and the at least one lip.

[0033] In some embodiments, the position of the laser relative to the mandrel and gasket is controlled by a servo motor.

[0034] In some embodiments, the film comprises a fluoropolymer film. In some embodiments, the fluoropolymer film comprises polytetrafluoroethylene (PTFE). In some embodiments, the elastic material comprises bromobutyl rubber.

[0035] In some embodiments, the process includes treating the inner surface of the film prior to application to the outer surface of the gasket to promote adhesion to the outer surface, for example, in some embodiments, the inner surface of the film is corona treated or chemically treated.

[0036] In some embodiments, the dimensional tolerance of the gasket is selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns.

[0037] In some embodiments, the gasket has less than 300 particles 2 microns or larger in size as measured using light obscuration (LO) or microflow imaging (MFI).

[0038] In some embodiments, the present disclosure is directed to a matched syringe and plunger system including: (a) a tubular barrel; (b) a plunger located inside the tubular barrel and longitudinally movable within the barrel; (c) a gasket coupled to an end of the plunger, the gasket including a body made of a resilient material having a circumferential surface portion, a film on at least a portion of the circumferential outer surface portion of the gasket, and an internal cavity defined by an inner surface portion of the gasket and including an open end; (d) a plurality of non-continuous channels in or through the film, each non-continuous channel being generally parallel to the other non-continuous channels, each non-continuous channel of the plurality of non-continuous channels extending around a circumferential outer surface of the gasket and having a non-channel portion interrupting the non-continuous channel; The non-channel portions of each non-contiguous channel are positioned along the circumferential outer surface portion of the gasket such that they are not aligned with the non-channel portions of the immediately adjacent non-contiguous channel or channels. In some embodiments, the matched syringe and plunger system features improved longer shelf life.

[0039] In some embodiments, the thickness of the film present on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

[0040] In some embodiments, the film has one or more of good sliding properties and chemical stability, hi some embodiments, the film is configured to slide along the tube of the syringe and is chemically stable.

[0041] In some embodiments, the film can prevent migration of components from the elastic material of the gasket.

[0042] In some embodiments, the gasket is attached to the plunger by a press-fit assembly.

[0043] In some embodiments, the tubular barrel contains an injectable fluid that contacts the gasket.

[0044] In some embodiments, the syringe and plunger system is capable of maintaining a container closure integrity (CCI) over a two-year shelf life as measured by one or both of a liquid migration test method and a helium leak detection test method, hi some embodiments, the syringe and plunger system comprises a container closure integrity (CCI) with a failure rate of 6 sigma or less.

[0045] In some embodiments, the plunger and gasket comprise a release force of between 4 and 20 Newtons (N).

[0046] In some embodiments, the plunger and gasket comprise a sliding force of 4 to 20 Newtons (N).

[0047] In some embodiments, the release force or gliding force changes by less than about 10-30% over a two year shelf life at 2°C-8°C.

[0048] In some embodiments, the release force or gliding force changes by less than about 20-40% over a two year shelf life at 20°C-25°C.

[0049] In some embodiments, the tubular barrel comprises a wall having an inner surface coated with a lubricating layer having an atomic ratio of 1 atom of Si:0.5-2.4 atoms of O:0.6-3 atoms of C as measured by X-ray photoelectron spectroscopy (XPS).

[0050] In some embodiments, the tubular barrel comprises a wall having an interior surface characterized by a tri-layer coating, the tri-layer comprising a tie coating, a barrier coating, and a pH protective coating; (a) the tie coating comprises SiOxCy or SiNxCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, the tie coating having an outer surface facing the inner surface of the wall, and the tie coating having an inner surface facing the lumen of the tubular barrel; (b) the barrier coating comprises SiOx, x being 1.5 to 2.9, the barrier coating having a thickness of 2 to 1000 nm, the barrier coating having an outer surface facing the inner surface of the tie coating, and the barrier coating having an inner surface facing the lumen of the syringe barrel; (c) the pH protective coating comprises SiOxCy or SiNxCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, the pH protective coating having an exterior surface facing the interior surface of the barrier coating and an interior surface facing the lumen of the tubular barrel.

[0051] In some embodiments, the tubular barrel includes a lubricious layer, the lubricious layer having an outer surface facing the inner surface of the pH protective coating and an inner surface facing the lumen of the tubular barrel. In some embodiments, for example, the lubricious layer can reduce one or both of the static and sliding friction of a gasket within the barrel compared to one or both of the static and sliding friction of a gasket within the tubular barrel without the lubricious layer.

[0052] In some embodiments, the film comprises a fluoropolymer film. In some embodiments, the fluoropolymer film comprises polytetrafluoroethylene (PTFE).

[0053] In some embodiments, the multiple non-contiguous channels improve the container closure integrity (CCI) of the system when assembled to form a pre-filled syringe, as compared to an otherwise substantially similar pre-filled syringe that does not include the multiple non-contiguous channels produced by the aforementioned process. In some embodiments, the improvement in CCI is measured by a vacuum decay leak detection method. In some embodiments, the improvement is measured by a liquid CCI test method.

[0054] In some embodiments, the tubular barrel includes a wall including an inner surface defining a generally cylindrical lumen, the barrel has an inner diameter, the gasket includes a leading surface, a side surface, a trailing portion, and an outer diameter, the gasket is configured to be received within the tubular syringe barrel with the gasket outer diameter disposed within and movable relative to the barrel inner diameter, and the tubular barrel and gasket of the system, when assembled, are each sized to provide a spacing between a minimum barrel inner diameter and a maximum gasket outer diameter that deviates from the nominal spacing by no more than ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±2 microns.

[0055] In some embodiments, the present disclosure is directed to a gasket comprising: (a) a body comprising a resilient material and having a circumferential surface portion and an interior cavity, the cavity being defined by an inner surface portion of a gasket, one end of the cavity being open; (b) a film over at least a portion of a circumferential outer portion of the gasket; and (c) a plurality of non-continuous channels extending in or through the film and about a circumferential outer surface portion of the gasket, the non-continuous channels having respective non-channel portions interrupting each respective non-continuous channel; Each non-channel portion of each non-contiguous channel is positioned along the circumferential outer surface portion of the gasket such that the respective non-channel portion is not aligned with an adjacent non-channel portion.

[0056] In some embodiments, the gasket exhibits one or more of the following characteristics: (i) Maintaining container closure integrity (CCI) over a two-year shelf life as measured by one or more of the following test methods: liquid migration and helium leak detection; (ii) Container Closure Integrity (CCI) having a defect rate of 6 sigma or less when assembled into a matched syringe and plunger system; (iii) when assembled into a matched syringe and plunger system, a release force of 4 to 20 Newtons (N), alternatively 4 to 10 Newtons (N), alternatively 4 to 8 Newtons (N); (iv) a gliding force of 4 to 20 Newtons (N), alternatively 4 to 10 Newtons (N), alternatively 4 to 8 Newtons (N) when assembled in a matched syringe and plunger system; and The release or gliding force changes by less than about 10-30% over a two-year shelf life. [Brief description of the drawings]

[0057] The present disclosure, according to one or more various embodiments, will be described in detail with reference to the following figures. The drawings are provided for illustrative purposes only and merely depict typical or exemplary embodiments. These drawings are provided to facilitate understanding of the concepts disclosed herein and should not be considered as limiting the breadth, scope, or applicability of these concepts. It should be noted that for clarity and ease of illustration, these drawings are not necessarily made to scale. [Figure 1] FIG. 1 shows a cross-sectional view of a syringe 10 including a syringe barrel 12 assembled with a gasket 14 attached to a plunger 26 according to some embodiments of the present disclosure. [Diagram 2] FIG. 2 shows a fragmentary detailed view of the syringe of FIG. 1 according to some embodiments of the present disclosure. [Figure 3A] FIG. 3A shows a schematic cross-sectional view along section line 3A-3A of FIG. 2, illustrating the gasket core 18 in the internal cavity (IC), the film 16, and a first non-continuous channel 20 in the surface of the film (in some embodiments, the channel 20 extends through the film to the outer surface of the gasket (not shown)), and a second non-continuous channel 21 in the surface of the film (in some embodiments, the channel 21 extends through the film to the outer surface of the gasket and is generally parallel to the first non-continuous channel 20 (not shown)). [Figure 3B] FIG. 3B shows a fragmentary detailed view of the structure of FIG. 3A , illustrating one embodiment of first non-continuous channel 20 and first non-continuous channel 21 extending around the circumferential outer surface of gasket core 18 and generally parallel to first non-continuous channel 20, and lips 22 and 24 on each side of channel 20. [Figure 3C]3C shows a top view of the gasket 14 and also shows the general geometric distribution of first non-continuous channels 20 extending around the circumferential outer surface of the gasket core 18 and the general geometric distribution of second non-continuous channels 21 extending around the circumferential outer surface of the gasket core 18. The non-continuous layers each include a non-channel portion (21a, 20a) associated with the non-continuous layer. The non-channel portions (21a, 20a) are not aligned with one another on the circumferential outer surface portion of the gasket. [Figure 3D] 3D shows a top view of the gasket 14 and the approximate geometric distribution of the three non-continuous channels 20, 21, 23 extending around the circumferential outer surface of the gasket core 18. The three non-continuous channels 20, 21, 23 are axially spaced from one another and are positioned such that the non-continuous channel 20 is closer to the top of the plunger than the other two non-continuous channels 21 and 23, the non-continuous channel 21 is adjacent to the non-continuous channel 20 and is distal to the top of the plunger compared to the non-continuous channel 20, and the non-continuous channel 23 is adjacent to the non-continuous channel 21 and is distal to the top of the plunger compared to the non-continuous channel 21. The non-continuous channels 20, 21, 23 each include a non-channel portion (20a, 21a, 23a) associated with the non-continuous channels 20, 21, 23. The non-channel portions (20a, 21a, 23a) are positioned such that they are not aligned with the non-channel portions of adjacent non-contiguous channels along the circumferential outer surface portion of the gasket. [Figure 4A] 4A shows the assembly of gasket 14 with mandrel 28 inserted into the interior cavity of the gasket. This figure also shows how the mandrel 28 and gasket 14 are rotated along the longitudinal axis of the mandrel while a laser beam is applied at an angle to an outer portion of film 16 on a circumferential outer surface portion of gasket 14 secured to mandrel 28 to form non-continuous channels 20 in film 16 on the circumferential outer portion of gasket 14. [Figure 4B]4B shows a schematic cross-sectional view of one embodiment of a gasket along section line 4B-4B of FIG. 4A, illustrating a mandrel 28 secured to an interior cavity of the gasket, film 16, and first and second non-continuous channels 20 and 21 in the outer surface of film 16 at a circumferential outer surface portion of gasket 20, in accordance with some embodiments of the present disclosure. In other embodiments, first and second non-continuous channels 20 and 21 extend through the film to the outer surface of the gasket. [Figure 5A] FIG. 5A shows a gasket 14 having a film 16 with first non-continuous channels 20 within the film 16 according to some embodiments of the present disclosure. [Figure 5B] 5B shows a fragmentary detailed view of the structure of FIG. 5A according to some embodiments of the present disclosure. An embodiment of a first non-continuous channel 20 on a surface of a film is shown with lips 22 and 24 on either side of the first non-continuous channel 20, and various dimensions (peak width, axial width, laser cut depth, and radial depth) of the first non-continuous channel 20 and lips 22 and 24 are shown. In other more preferred embodiments, the first non-continuous channel 20 extends to the outer surface of a gasket (not shown). [Figure 6] FIG. 6 shows an image of one example of a gasket (sample 40110) having non-continuous channels 20 extending around the circumferential outer surface of the gasket core, according to some embodiments of the present disclosure. [Figure 7] FIG. 7 shows an image of one example of a gasket (sample 40125) having non-continuous channels 20 extending around the circumferential outer surface of the gasket core, according to some embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] The following reference characters are used in the drawings of any embodiment: 10 Syringe 12 Syringe Barrel 14 Gasket 16 Film 18 Gasket core 20 First non-contiguous channel 20a First non-channel portion 21 Second non-contiguous channel 21a Second non-channel portion 22 First Lip of Channel 23 Third non-contiguous channel 23a Third non-channel part 24 Second Lip of Channel 25 Plunger 28 Mandrel

[0059] In the context of this disclosure, the following definitions and abbreviations are used:

[0060] The word "comprises" in any embodiment does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality, unless otherwise specified. Whenever a parameter range is given, it is intended to disclose the parameter value given as the limit of the range, and all values ​​of the parameter that fall within that range. With reference to "about", a value or parameter herein includes embodiments that are directed to (and describe) the value or parameter itself. For example, a description that refers to "about X" includes a description of "X". Numerical ranges include the numerical values ​​that define the range. As used herein, the term "about" allows for a variation of ±10% within significant orders of magnitude.

[0061] When an aspect or embodiment is described in terms of a Markush group or other group of alternatives, the present application encompasses not only the entire group listed as a whole, but each member of the group individually, and all possible subgroups of the main group, and the main group where one or more of the group members are absent. The application also envisions the explicit exclusion of one or more of the group members in the present disclosure.

[0062] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0063] In order to make the present disclosure easier to understand, certain terms are first defined. These definitions should be read in light of the remaining parts of the present disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the meanings that are commonly understood by those skilled in the art. Additional definitions are described throughout the detailed description.

[0064] As used herein, the term "syringe" is broadly defined to include cartridges, injection pens, and other types of barrels or reservoirs adapted to be assembled with one or more other components to provide a functional syringe. "Syringe" is also broadly defined to include related articles such as autoinjectors that provide a mechanism for dispensing the contents. Preferably, "syringe" includes pre-filled syringes. As used herein, "syringe" may also apply to vaccine dispensing syringes that include a product space that contains a vaccine or immunization antigen with a composition of the product. As used herein, "syringe" may also have applications in diagnostics, e.g., sampling devices including medical barrels pre-filled with diagnostic agents (e.g., contrast dyes) or the like. In general, as used herein, "syringe" is any medical barrel that functions as a container / dispenser of a fluent product when assembled with one or more other components (e.g., gaskets and plungers). For example, syringes having lumens with void volumes of 0.5-50 mL, optionally 1-10 mL, optionally 0.5-5 mL, optionally 1-3 mL are contemplated, although the present invention is not necessarily limited to syringes of any particular volume. The syringe of the present disclosure includes a hollow cylindrical syringe barrel 12, a plunger 26 coupled to and reciprocally movable within the syringe barrel 12, and a gasket 14 attached to a distal end of the plunger 26. See FIG. 1.

[0065] As used herein, the term "gasket" in the context of the present disclosure is a molded piece or ring made of an elastomeric material that can be used to mechanically seal the space between two opposing inner surfaces of a syringe barrel. The gasket is also called a plunger. The gasket is preferably cylindrical with a short axis. The gasket has a circumferential surface portion that is held in substantially air-tight and liquid-tight contact with the inner peripheral surface of the syringe barrel. The gasket of the present disclosure may be a gasket that includes a body made of an elastic material and a film that is present on at least the circumferential surface of the body, the gasket having a circumferential surface portion and an internal cavity (IC) at its center, the cavity being defined by the inner surface of the gasket and one end of the cavity being open. See Figures 2 and 3A. In a preferred embodiment, the internal cavity of the gasket is not provided with threads.

[0066] The "elastic material" may be a rubber or elastomer. Specifically, preferred types of rubber include butyl rubber, chlorinated butyl rubber, and brominated butyl rubber. Other types of elastic materials may include thermoset rubbers and dynamically crosslinkable thermoplastic elastomers that have crosslinking sites that make them heat resistant. These polymeric components of such elastomers include ethylene-propylene-diene rubber and butadiene rubber.

[0067] As used herein, the term "film" refers to a material present on at least a circumferential outer surface portion of the body of the gasket. Preferably, the film coats or is present on substantially all of the outer surface of the gasket. The film may have an optional thickness of less than about 100 micrometers (μm or microns), optionally about 10-30 microns, about 15-35 microns, or about 20-50 microns. Most preferably, the thickness of the film is about 20 microns. A variety of different materials may be used for the film, such as, for example, fluorinated ethylene propylene (FEP), ethylene tetrafluoroethylene (ETFE), polytetrafluoroethylene (PTFE), ethylene perfluoroethylene propylene (EFEP), ethylene chlorotrifluoroethylene (ECTFE), polychlorotrifluoroethene (PCTFE), perfluoroalkoxy (PFA), among other coatings. Preferably, the film is an ultra-high molecular weight polyethylene film (UHMWPE) or a fluoropolymer film. Fluoropolymer films such as polytetrafluoroethylene (PTFE) are preferred due to their excellent sliding properties and chemical stability. The type of film provided on the surface of the gasket body is not particularly limited, as long as the film can prevent the migration of materials from the crosslinked rubber (body) and has a sliding property, i.e., a smaller coefficient of friction, compared to the gasket body.

[0068] Optionally, the film may include a CPT fluoropolymer. CPT is a modified perfluoroalkoxy (PFA) that generally involves the addition of PCTFE side chains to a PFA backbone during polymerization.

[0069] Optionally, additives may be added to the film material for the film, such as additives that may improve the adhesion of the film to the underlying portion of the gasket to create a liquid-tight section and / or reduce friction between that section and the sidewall of the syringe barrel. In addition, according to certain embodiments, adhesion-promoting coatings or processes, such as corona treatment or chemical treatment, may be used. Corona treatment or air plasma is a surface modification technique that uses low-temperature corona discharge plasma to impart changes to the properties of a surface. Corona plasma is created by the application of high voltage to an electrode with a sharp tip. For some applications, it may be desirable to co-extrude different materials to form a film. For example, a co-extruded film combination may include cyclic olefin copolymer (COC) with Aclar, polyethylene (PE) with Aclar, and FEP with PE, among other combinations.

[0070] As used herein, the term "mandrel" refers to a device or tool that may be attached at its distal end to a base that keeps the body of the mandrel stable and fixed but allows the mandrel to rotate along its longitudinal axis. The proximal portion of the mandrel has a shape similar to the male portion of a two-part mold that can be inserted and fixed into the internal cavity of the gasket (the corresponding female portion). In some embodiments, the mandrel is in the form of a metal or steel bar, such as a cylindrical rod. The proximal end of the mandrel may be continuous with the body of the mandrel or may have a smaller or larger circumferential portion than the distal section of the mandrel. In a preferred embodiment, the proximal end of the mandrel is secured to the gasket using a "press fit assembly" in which the gasket is secured to the mandrel by friction rather than any other fastening means (such as threading) after the parts are pressed together. In some embodiments, the diameter of at least a portion of the mandrel portion that is inserted into the internal cavity of the gasket is larger than the inner diameter of the cavity. "Fixing the gasket" to the mandrel refers to ensuring that the gasket is fixed or fastened to the proximal end of the mandrel so that it does not give way, loosen, or move independently of the mandrel. The gasket fixed on the mandrel maintains the shape of its inner and outer walls and does not collapse or deform during the laser cutting process. "Positioning" the mandrel and fixed gasket in proximity to the laser refers to fixing the base of the mandrel in a desired position relative to the laser beam so that the base of the mandrel is in a fixed, non-moving position during the laser beam process of the present disclosure. However, the mandrel still has the ability to rotate along its longitudinal axis. See FIG. 4A.

[0071] As used herein, the term "channel" refers to a cut into the film on the surface of the gasket by laser cutting. The term channel may be used interchangeably with the term "cut". In this disclosure, the term "cut" may also refer to a process using one or more laser beams to create a cut or separation in the film present on at least the circumferential outer surface portion of the gasket. In some embodiments, the channel is a cut in the surface portion of the film. In a more preferred embodiment, the channel extends through the film into the outer surface of the gasket. One or more such channels can be created, each surrounding a portion of the gasket. Each channel has a non-channel portion where no channel / cut is formed. For example, the channel can surround 350 degrees of the gasket and the non-channel portion can surround the remaining 10 degrees of the 360 ​​degree circle on the gasket. When two or more channels are present, they are preferably axially spaced from each other. The non-channel portions of two or more channels are not aligned on the gasket. For example, a non-channel portion can be located on one side of the gasket and a second non-channel portion can be located on the other side. Each channel has two lips. The term "lip" refers to the structure created by the build-up of film material along both sides of the channel created by laser beam cutting. Channel lips 22 and 24 are shown in Figures 3B and 5B. The lips are each a raised rib positioned to seal against the inside surface of the barrel. Thus, each channel has two lips that include two sealing ribs or peaks. In this disclosure, the terms "lip," "rib," "peak," and "microprojection" are interchangeable.

[0072] The laser cuts and the resulting channels are characterized by various dimensions including laser cut depth, radial depth, peak width, axial width, and peak height. The "laser cut depth" is measured from the surface of the uncut gasket film to the lowest point in the trough of the channel. See FIG. 5B. The laser cut depth of the channel or channels may be independently selected from the ranges of 30-60 microns, 40-50 microns, 50-60 microns, 40-45 microns, 45-50 microns, 50-55 microns, and 55-60 microns. The "radial depth" is measured from the uncut outer surface of the gasket to the lowest trough in the channel. See FIG. 5B. The radial depth of the channel or channels may be independently selected from the ranges of 0-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns. The "peak width" is the distance between the two peaks of the two lips on either side of the channel. The peak width is measured from the top of the peak. See FIG. 5B. The peak width may be one of the ranges of 200 to 1,000 microns, 275 to 550 microns, 300 to 400 microns, and 450 to 500 microns.

[0073] The circumferentially non-continuous channels of the present disclosure have axially opposed "first and second sidewalls" and a "floor". The floor of the channel can be either the film surface or, more preferably, the gasket surface, depending on the thickness of the film and the depth of the cut. The "axial width" is measured from the first sidewall to the second sidewall of the channel across the width of the channel floor. In other words, the "axial width" is measured across its width from one end of the channel to the other end of the channel at the baseline level, i.e., at the non-laser cut outer surface level of the film or gasket. The channel or channels independently have an axial width between sidewalls in one of the ranges of 1-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns.

[0074] "Peak height" is measured from the surface of the uncut gasket film to the highest peak of the lip created by the laser beam along the central axis of the peak, i.e., perpendicular to the surface of the film. The peak height of one or more of the lips of the channels is independently selected from one of the following ranges: 10-100 microns, 15-60 microns, 20-50 microns, and 30-40 microns.

[0075] As used herein, the term "container closure integrity" or "CCI" refers to the ability of a container closure system, e.g., a plunger attached to a gasket disposed within a syringe barrel, preferably a pre-filled syringe barrel, to provide protection and maintain efficacy and sterility during the shelf life of a sterile product contained within the container. In some embodiments, container closure integrity is related to the sealability of the syringe system of the present disclosure. The laser-created channel or channels in the film are intended to enhance the CCI of the plunger attached to the gasket when assembled into a pre-filled syringe by providing a physical break in the film that prevents film defects (such as peels, tears, or wrinkles) from adversely affecting the seal integrity between the gasket and the syringe. Container closure integrity (CCI) should be substantially maintained throughout the shelf life of the syringe of the present disclosure. CCI is an important feature of pre-filled syringes for parenteral pharmaceutical products contained within the syringe. One important element of CCI is maintaining a sterile barrier. The improved process of the present disclosure for creating one or more channels on a film reduces the likelihood of CCI failure (sterility breach) and / or facilitates a longer shelf life.

[0076] As used herein, the term "release force" refers to the force required to initiate movement of a plunger attached to a gasket in a syringe, e.g., a pre-filled syringe. This is the maximum force required to break the static friction of the gasket attached to the plunger. Release force is synonymous with "plunger force," "plunger breakthrough force," "breakthrough force," "initiation force," and "Fi" in the context of this disclosure.

[0077] As used herein, the term "gliding force" refers to the force required to maintain plunger movement (when the plunger is attached to a gasket of the present disclosure) within a syringe barrel when static friction is overcome, for example, during aspiration or dispensing. Gliding force is synonymous with "pushing force," "plunger sliding force," "maintenance force," and "Fm" in the context of this disclosure.

[0078] As used herein, the terms "release force", "gliding force" are collectively referred to as "BLGF force", i.e., the various forces of the plunger and attached gasket of the present disclosure. BLGF force can be measured using any test known in the art, such as ISO7886-1:1993. For example, BLGF force can be tested by filling a syringe of the present disclosure with 1 ml of liquid (such as water) and then vacuum loading the stopper. Plunger force can be tested with a plastic threaded (or non-threaded) rod at 300 mm / min. In the present disclosure, an improved process of creating channels on the surface of the gasket prevents the degradation of plunger force (i.e., increase in release force over time). The matched syringe-plunger system of the present disclosure maintains a release force and gliding force of 4-20 Newtons (N), optionally about 4-10 Newtons (N) or about 4-8 Newtons (N). Most preferably, the gliding force is about 4-8 Newtons (N) and varies less than about 10%-30% over a two year shelf life. The process of the present disclosure provides consistent release and gliding forces by incorporating manufacturing process controls and 100% inspection systems.

[0079] As used herein, the term "static friction" refers to the phenomenon that must be overcome to allow the plunger attached to the barrel to escape and begin to move, which is the industry term for adhesion between the plunger (attached to the gasket) and the syringe barrel. The term "sliding friction" or "kinetic friction" refers to the resistance generated by two objects sliding against each other. Sliding friction is intended to prevent the objects from moving. In the present disclosure, the lubricating layer in the syringe barrel can reduce one or both of the static friction and sliding friction of the gasket in the barrel as needed or appropriate, compared to one or both of the static friction and sliding friction of the gasket in the barrel in the absence of the lubricating layer.

[0080] As used herein, the terms "dimensional tolerance", "dimensional accuracy", or "dimensional consistency" are the degree of control over the dimensions of a part (Quality Management for the Technology Sector (2000) 142-158). Dimensional tolerances are the allowable limits of variation in the physical dimensions of various parts of the present disclosure, such as gaskets and syringe barrels. "Tolerance" is the acceptable variation for any given size of a gasket or syringe barrel of the present disclosure that allows for proper functioning of the syringe system. In other words, dimensional tolerances are the acceptable variation for the dimensions of a syringe or gasket of the present disclosure that does not impair one or more of the following properties: container closure integrity, BLGF force, sealing, leakage characteristics, slidability, etc. Dimensional tolerances between gaskets that can be used in the process of the present disclosure are selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns. The term "nominal spacing" in the presently disclosed syringe system relates to dimensional tolerances, where the barrels and gaskets of the disclosed system are sized to provide spacing between the smallest barrel inner diameter and largest gasket outer diameter, respectively, that deviates by no more than ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±2 microns from the nominal spacing when assembled.

[0081] The present disclosure in some embodiments will be described in more detail with reference to the accompanying drawings. However, the present disclosure may be embodied in many different forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments are examples having a full scope indicated by the language of the claims. Like reference numerals refer to like or corresponding elements throughout.

[0082] Exemplary Syringe and Plunger System Embodiments In FIG. 1, one exemplary embodiment of a matched syringe and plunger system of the present disclosure is shown, including a gasket 14 and a plunger 26 constructed according to one aspect of the disclosure. The terms "distal" and "proximal" generally refer to a spatial or positional relationship relative to a given reference point, where "proximal" is a position at or relatively close to that reference point, and "distal" is a position further away from that reference point. When applied herein to plunger 26, for example, the relevant reference point is the bottom end of plunger 26, the distal end that is attached to gasket 14. When applied herein to syringe barrel 12, for example, the relevant reference point is the bottom end of barrel 12, the distal end that is attached to a delivery conduit or hypodermic needle.

[0083] Syringe 10 is generally of conventional construction and materials, preferably plastic, and includes a hollow barrel 12 having a central longitudinal axis A. The barrel has an interior surface 14 and is configured to hold an injectable liquid therein. A hypodermic needle or delivery conduit is located at the distal end of the barrel and in fluid communication therewith. The plunger 26 is also generally of conventional construction and materials. The gasket 14 of the present invention is attached to the distal end of the plunger.

[0084] 2 shows a fragmentary detailed view of the syringe of FIG. 1, illustrating that the inside diameter (ID) of barrel 12 and the outside diameter (OD) of gasket 14 are adjusted to within a predetermined tolerance, and also shows film 16 on the outer surface of gasket core 18, a first non-continuous channel 20 that extends around the circumferential outer surface of gasket core 18, and a second non-continuous channel 21 that extends around the circumferential outer surface of gasket core 18 and is generally parallel to first non-continuous channel 20. The channel has lips 22 and 24, as shown in FIG. 3B.

[0085] Exemplary Laser Process Embodiments FIG. 4A is a diagram of a laser processing process of one embodiment of the present disclosure. Referring to FIG. 4A, a laser beam is applied to a circumferential surface portion of a gasket 14 fixed to a mandrel 28 at a desired angle. The angle at which the laser beam is applied can be 5 degrees to 90 degrees from the surface portion of the gasket. For the formation of channels in at least a portion of the circumferential surface portion of the gasket, a laser beam source is fixed relative to the circumferential surface portion of the gasket 14 having a film 16 present on the outer surface of the gasket, and a laser beam is applied to the circumferential surface portion while the gasket 14 fixed to the mandrel 28 rotates about its longitudinal axis. Thus, the laser beam can be applied to any angular position of the circumferential surface portion with a predetermined incidence angle α (e.g., 5° to 90°), thereby forming channels uniformly.

[0086] With the laser beam applied obliquely to the circumferential surface portion, the gasket is rotated in a direction that moves the circumferential surface portion away from the laser beam application location where the laser beam is applied (in FIG. 4A, the gasket is rotated clockwise).

[0087] FIG. 3C shows a top view of a gasket 14 having a first non-continuous channel 20 and a second non-continuous channel 21. This top view is intended to be illustrative of the location of the non-channel portion of each of the multiple non-continuous channels. In some embodiments, for one or more non-channel portions within a single channel, referring to FIG. 3C, the non-channel portion of the first non-continuous channel is not aligned with the non-channel portion of the second non-continuous channel. Although FIG. 3C shows the non-channel portion of the first non-continuous channel positioned 180 degrees from the non-channel portion of the adjacent non-continuous channel around the circumference of the gasket, the non-channel portion may be positioned around the circumference of the gasket as long as the adjacent non-channel portions are not aligned, for example, the non-channel portion of the first non-continuous channel may be positioned within a range of 90-270 degrees from the adjacent non-channel portion around the circumference of the gasket with the adjacent non-channel portions not aligned. In a preferred embodiment, the non-channel portion of the first non-continuous channel may be positioned approximately 180 degrees from the adjacent non-channel portion around the circumference of the gasket.

[0088] In another embodiment, each non-contiguous channel may include multiple non-channel portions arranged around the periphery such that the non-contiguous channel may be a "dashed" line of channel and non-channel portions. Adjacent non-contiguous channels may be "dashed" channels of channel and non-channel portions. The channel and non-channel portions of adjacent non-contiguous channels may be positioned around the periphery of the gasket as long as the adjacent non-channel portions are not aligned. For example, the non-channel portions may be out of phase with the adjacent non-channel portions.

[0089] 3D shows a top view of a gasket 14 having a first non-continuous channel 20, a second non-continuous channel 21, and a third non-continuous channel 23. This top view is intended to be an illustration of the location of the non-channel portion of each of the plurality of non-continuous channels 20, 21, 23. The channels each extend around the circumferential surface of the gasket, and each has a portion that does not include a channel. The three non-continuous channels 20, 21, 23 are axially spaced apart from one another and are positioned such that the non-continuous channel 20 is closer to the top of the plunger than the other two non-continuous channels 21 and 23, the non-continuous channel 21 is adjacent to the non-continuous channel 20 and is distal to the top of the plunger compared to the non-continuous channel 20, and the non-continuous channel 23 is adjacent to the non-continuous channel 21 and is distal to the top of the plunger compared to the non-continuous channel 21. 3D, the non-channel portions (20a, 21a, 23a) are positioned such that they are not aligned with the non-channel portions of adjacent non-contiguous channels along the circumferential outer surface portion of the gasket, in some embodiments, the non-channel portion of one non-contiguous channel may be aligned with the non-channel portion of a non-adjacent non-contiguous channel.

[0090] In some embodiments, the laser beam is applied through a beam expander via multiple rotating mirrors, and then the laser beam profile is transformed from a Gaussian spatial intensity distribution to a top-hat spatial intensity distribution via a shaping optics. In the top-hat spatial intensity distribution, the uniform spatial intensity can improve the processing conditions at the laser spot, generally resulting in higher geometric precision and repeatability, lower surface roughness, and higher laser microstructure quality. The camera is used for fine positioning and monitoring of the process.

[0091] Thus, by performing the laser machining process of this embodiment of the invention, channels are formed substantially uniformly in the film, and more preferably extend to the circumferential surface portion of the gasket, as well as forming outer edges 22 and 24 (FIG. 5B).

[0092] Exemplary Gasket Manufacturing and Laser Cutting Process In some embodiments of the present disclosure, the gasket comprises two materials: a bromobutyl rubber base gasket and a film, preferably a PTFE film, present on the exterior surface. Examples of bromobutyl rubber include Sumitomo LAG 5010-50 and West 4023. The PTFE film in a preferred embodiment substantially covers the exterior surface of the gasket. Gasket manufacture includes the following process, which is relevant to some embodiments of the present disclosure: (a) Molding: The PTFE film is treated to promote adhesion with the bromobutyl rubber of the gasket. A typical treatment is corona treatment. In some embodiments, chemical treatments may also be used. The PTFE film is placed into a multi-cavity gasket mold. Bromobutyl rubber is poured / injected into the multi-cavity mold. The mold is closed and the PTFE film and bromobutyl rubber are formed into the gasket. The mold is opened and the gasket is removed from the mold. The gasket thus produced has a substantially uniform wall thickness and comprises rubber and PTFE. The gasket is cut out by die cutting to remove excess material. In some embodiments, the multi-cavity mold produces a gasket that is not threaded into an internal cavity. (b) Laser cutting of PTFE or other film: The disclosed process includes (1) inserting a portion of one end of a mandrel into the open end of the gasket cavity of the gasket produced in step (a), (2) positioning the mandrel and gasket in close proximity to a laser, and (3) rotating the mandrel and gasket along the longitudinal axis of the mandrel while applying a laser beam emitted from a precision laser to one or more selected locations on a surface portion of the film that is on the circumferential outer surface portion of the gasket to form a plurality of non-continuous channels in the film that extend partially around the circumferential outer surface of the gasket. This process creates a plurality of non-continuous channels in the circumferential direction in the PTFE or other film on the outer surface of the gasket. The accuracy of the channels created by the laser beam is directly related to the fixation of the gasket on the mandrel, the position of the laser beam, and the dimensional tolerances of the gasket used in the process.

[0093] The resulting channel creates a physical separation in the PTFE or other film on the gasket. Specifically, without being bound by theory, it is believed that the laser process melts the PTFE or other film, forcing the PTFE material to either side of the channel. During the laser process, the PTFE or other film material is "piled" on either side of the channel, creating two sealing ribs or peaks (microprotrusions). The PTFE or other film sealing ribs on either side of the channel can maintain the CCI, which is both a liquid barrier and a sterility barrier. Assuming that the PTFE film is uniform in thickness and "defect free," the height and angle of the sealing ribs depend on the alignment and position control of the laser beam (relative to the rotating gasket on the mandrel). The largest sources of variation in the sealing ribs are due to the PTFE or other film, namely (1) film thickness variations, and (2) film defects (e.g., blockages).

[0094] Furthermore, fluoropolymer films are generally stretched during manufacturing when the initial film is formed. This stretching process creates microchannels or micropores (the terms "microchannel" or "micropore" are used interchangeably herein) in the film, which vary in size and dimensions depending on the specific manufacturing conditions. It is believed that these microchannels or micropores, at least in some instances, provide a path along the fluoropolymer or other film from the rear of the gasket of the pre-filled syringe, outside the sealed portion of the syringe, into the lumen of the syringe that contains the material to fill the syringe. This reduces the CCI and shelf life of the matched syringe-plunger system.

[0095] Although cutting multiple non-contiguous channels in or through a film may mitigate some of the degradation of container closure integrity and shortened shelf life caused by these microchannels, the process of creating the channels itself may cause other problems that degrade CCI and shelf life. For example, without wishing to be bound by theory, unless the gasket is properly secured during the laser cutting process, it may sag on its outer surface or otherwise deform to accommodate channel mismatch and deformation. Also, unless the gasket and channels are carefully and individually inspected after fabrication, the failure rate of the gasket when used in a syringe plunger system is unacceptable.

[0096] The improved process, gasket and syringe plunger system, and gasket of the present disclosure overcome these problems. Additionally, the rigorous inspection process of the present disclosure ensures that the gasket has a low failure rate when used with a syringe plunger system.

[0097] Improved Gasket Inspection System: Inspection of gasket properties after gasket manufacture, and in some embodiments, after the laser treatment process of the present disclosure, includes, but is not limited to, (1) dimensional check of the overall height and outer diameter of the gasket, (2) camera inspection of the shape of the sealing ribs, (3) camera inspection of the laser cut, such as verifying peak dimensions and laser cut dimensions (peak height, peak width, axial width, laser cut depth, and radial depth (if present)), and (4) camera inspection of the PTFE film for evidence of wrinkles, tears, or delamination (lack of adhesion) to the rubber. Further tests to inspect the properties of the syringe and gasket system of the present disclosure are performed, such as container closure integrity test (CCIT), plunger release and sliding force test, sterility assurance, and particle test sub-visible to the naked eye.

[0098] Gasket inspection (die cut and micro projection): A vision system is used to inspect the plungers in-line (100% inspection). An example of a high speed inspection system for plungers is manufactured by Simac (Netherlands). The camera inspection system has the following attributes: (1) 13 plungers / second, (2) supports a wide range of plunger colors, (3) performs top-bottom, exterior, and interior surface inspection, (4) inspects microprojections, (5) inspects stamping and form defects, (6) has 100% quality control with a minimum defect detection of 100 μm. Rejected parts are sorted into separate containers and statistically tracked. Good parts are accurately counted and automatically packed.

[0099] Dimensional Measurements Using a Laser Micrometer: Each finished gasket of the present disclosure is measured for dimensional consistency. This is preferably an in-line system. In a preferred embodiment, a scanning laser micrometer is used to perform these measurements. An example of a scanning laser micrometer is the LS-3000 series manufactured by Keyence. A scanning laser micrometer uses rotating optics to reflect or refract a laser beam through the measurement area and across the path of the object being measured. The part blocks the laser light, creating a shadow that lasts for a time proportional to the size of the part. Receiver optics collect the unblocked laser light and focus it onto a photocell. The output of the photocell is analyzed by electronic circuitry to detect the exact time the laser crosses each part edge. Software converts the timing data into meaningful measurements.

[0100] Sorting: Using dimensional measurements, the gaskets of the present disclosure may be sorted to ensure that each gasket has a particular dimensional tolerance. The tolerance may be ±100 microns, more specifically ±50 microns, more specifically ±35 microns, more specifically ±25 microns, more specifically ±20 microns, more specifically ±15 microns, more specifically ±10 microns, more specifically ±5 microns, more specifically ±3 microns.

[0101] The dimensions of the pre-filled syringe barrels are measured in a similar manner to ensure that a precise and consistent fit between the syringe and gasket is achieved. This allows for precise control of gasket compression within the assembled syringe. Quality attributes of the assembled syringes include, but are not limited to, (1) vessel closure integrity measurement by dye intrusion, (2) vessel closure integrity measurement by vacuum decay method, and (3) consistency of plunger force profile (Fi / Fm) (aging and lot-to-lot variability).

[0102] In some embodiments, the gaskets of the present disclosure maintain container closure integrity with a defect failure rate of at least 6 sigma.System elements may include 100% inspection of molded plungers, 100% inspection of plunger fluoropolymer laser cuts or channels, 100% inspection of plunger diameter, 100% measurement of syringe barrel ID, and low draft syringe barrels.

[0103] In some embodiments, in the context of the improved laser process of the present disclosure, (a) the perimeter depth of the gasket fixed onto a stainless steel mandrel, (b) the shape of the film edge formed by the laser cut or channel is 100% inspected using a servo motor to control the laser movement. In some embodiments, the adhesion of the film to the rubber gasket is optimized using plasma and / or chemical treatment.

[0104] Testing for container closure integrity (CCI) may be performed using a vacuum decay leak detection method, where a vacuum is maintained inside the test volume and a pressure rise is measured over time. A sufficiently large pressure rise indicates that there is flow into the system, which is evidence of a leak. 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 of time. If a gross leak is detected, a relatively weak vacuum is pulled in the first cycle, since a large pressure difference is not required to detect a large pressure rise. The use of the first cycle described helps to reduce the total test time if a gross leak is present. If no leak is detected in the first cycle, a second cycle is performed that conforms to the ASTM F2338-09 Standard Test Method for Non-Destructive Detection of Leaks in Packages by Vacuum Decay Method. The second cycle begins with an evaluation of the system to reduce the signal-to-noise ratio of the pressure rise measurement. A relatively strong vacuum is pulled for a longer period of time in the second cycle to increase the likelihood of detecting a pressure rise in the system. EXAMPLES

[0105] Example: Liquid CCI test method In an illustrative example, in some embodiments, the syringe and gasket system of the present disclosure are filled with water and the stopper is vacuum filled. The syringes are stored at 4°C with the luer end or needle end up. Each syringe is removed at specific time points (e.g., 0 days, 1 day, 4 days, 7 days, 1 month, and 3 months), allowed to reach room temperature, and then visually inspected for signs of water getting into the space between the ribs of the stopper. A text description of each failure is recorded and a photograph of each failure is taken. The leakage characteristics of the syringes of the present disclosure are compared to the leakage characteristics of other syringes with gasket films (such as laminated films). The syringes of the present disclosure have superior CCI over time compared to syringes not produced by the improved laser and inspection process of the present disclosure.

[0106] See below in Table 1 for preliminary liquid CCI data collected for two variations of the gasket (samples 40110 and 40125) and the uncut gasket. This data does not indicate liquid CCI failure, but data was collected for time points up to one month. Additional liquid CCI test data will be collected over longer periods to demonstrate superior performance of the syringe and gasket system. [Table 1]

[0107] As shown in Figures 6-7, the non-continuous channels formed in the #40125 stopper (Figure 7) are wider and shallower than those in the #40110 stopper (Figure 6). This difference is due to the rotational speed of the mandrel during laser processing. The channels are formed in the #40125 at 30 deg / sec, while the channels are formed in the #40110 at 60 deg / sec. In both processes, the laser beam was Gaussian and at normal incidence.

[0108] The foregoing is merely illustrative of the principles of the present disclosure, and various modifications may be made by those skilled in the art without departing from the scope of the present disclosure. The above-described embodiments are presented for purposes of illustration and not limitation. The present disclosure can also take many forms other than those described herein. It is therefore emphasized that the present disclosure is not limited to the methods, systems, and apparatus expressly disclosed, but is intended to include any variations and modifications thereof that are within the spirit and scope of the following claims.

Claims

1. 1. A process for forming a plurality of non-contiguous channels in or through a film present on at least a portion of a circumferential outer surface of a gasket, the gasket comprising a body and an internal cavity, the internal cavity being defined by an inner surface of the gasket and including an open end, the process comprising: (a) inserting one end of a mandrel into the open end of the internal cavity; (b) positioning a mandrel and the gasket relative to a laser; (c) rotating the mandrel and the gasket along a longitudinal axis of the mandrel while applying a laser beam emitted from the laser to a plurality of locations on a surface of the film to form the plurality of non-contiguous channels; each non-contiguous channel is substantially parallel to the other non-contiguous channels; wherein each non-contiguous channel of the plurality of non-contiguous channels extends partially around the circumferential outer surface of the gasket.

2. 2. The process of claim 1, wherein non-channel portions interrupt each non-continuous channel and are positioned along the circumferential outer surface of the gasket such that they are not aligned with other non-channel portions of an adjacent non-continuous channel or channels.

3. monitoring a plurality of the selected locations using a laser micrometer by monitoring locations at which the laser beam is applied; The process of claim 1 , further comprising: adjusting the laser beam based on the monitoring.

4. 10. The process of claim 1, wherein the thickness of the film on at least a portion of the circumferential outer surface portion of the gasket is about 10 to 30 microns, about 15 to 35 microns, about 20 to 50 microns, or about 20 microns.

5. 3. The process of claim 1, wherein the film is configured to slide along a syringe tube and is chemically stable.

6. The process of any one of claims 1 to 5, wherein the gasket comprises an elastic material and the film is capable of preventing migration of components from the elastic material of the gasket.

7. The process of any one of claims 1 to 6, wherein the process further comprises securing the gasket to the mandrel.

8. The process of claim 7 , wherein the gasket comprises a resilient material, and wherein the gasket is secured to the mandrel by a press-fit assembly.

9. 9. The process of claim 8, wherein a diameter of at least a portion of the mandrel inserted into the internal cavity of the gasket is greater than an inner diameter of the internal cavity prior to insertion of the mandrel.

10. The process of any one of claims 1 to 9, wherein the plurality of non-contiguous channels comprises two non-contiguous channels axially spaced apart from each other.

11. The process of any one of claims 1 to 10, wherein each non-contiguous channel of the plurality of non-contiguous channels comprises axially opposed first and second sidewalls and a floor.

12. 12. The process of claim 11, wherein each non-contiguous channel of the plurality of non-contiguous channels comprises an axial width between the sidewalls selected from 1 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns.

13. 13. The process of any one of claims 1 to 12, wherein each non-contiguous channel of the plurality of non-contiguous channels comprises a radial depth selected from 0 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns.

14. 14. The process of any one of claims 1 to 13, wherein each non-contiguous channel of the plurality of non-contiguous channels comprises a laser cut depth selected from 20 to 80 microns, 30 to 60 microns, 40 to 50 microns, 50 to 60 microns, 40 to 45 microns, 45 to 50 microns, 50 to 55 microns, and 55 to 60 microns.

15. The process of any one of claims 1 to 14, wherein one or more of the plurality of non-contiguous channels extend through the film into the circumferential outer surface of the gasket.

16. 16. The process of claim 15, wherein the plurality of non-contiguous channels each include a radial depth greater than a thickness of the film on the surface of the gasket.

17. 13. The process of any one of claims 1 to 12, wherein the plurality of non-contiguous channels includes a first circumferentially extending lip located adjacent the first sidewall of the channel and extending radially above the film.

18. 20. The process of any one of claims 17 to 29, wherein the plurality of non-contiguous channels further comprises a second circumferentially extending lip located adjacent the second sidewall and extending radially above the film.

19. 19. The process of any one of claims 18, wherein the first lip comprises a first peak height selected from 10 to 100 microns, 15 to 60 microns, 20 to 50 microns, or 30 to 40 microns, and the second lip comprises a second peak height selected from 10 to 100 microns, 15 to 60 microns, 20 to 50 microns, or 30 to 40 microns.

20. 20. The process of any one of claims 17-19, wherein the first lip of each non-contiguous channel of the plurality of non-contiguous channels comprises a first peak width selected from 200 to 1,000 microns, 275 to 550 microns, 300 to 400 microns, or 450 to 500 microns, and the second lip of each non-contiguous channel of the plurality of non-contiguous channels comprises a second peak width selected from 200 to 1,000 microns, 275 to 550 microns, 300 to 400 microns, or 450 to 500 microns.

21. A process according to any one of claims 17 to 20, wherein each lip comprises a film material that is displaced from the channel by the laser beam as the channel is formed.

22. The process of any one of claims 17 to 21, wherein the gasket is positionable within a tubular syringe barrel so as to form a seal between an inner surface of the barrel and at least one lip.

23. The process of any one of claims 1 to 22, wherein the position of the laser relative to the mandrel and gasket is controlled by a servomotor.

24. The process of any one of claims 1 to 23, wherein the film comprises a fluoropolymer film.

25. 25. The process of claim 24, wherein the fluoropolymer film comprises polytetrafluoroethylene (PTFE).

26. The process of any one of claims 1 to 25, wherein the elastic material comprises bromobutyl rubber.

27. The process of any one of claims 1 to 26, further comprising treating an inner surface of the film prior to application to the outer surface of the gasket to promote adhesion to the outer surface.

28. 30. The process of claim 27, wherein the inner surface of the film is corona treated or chemically treated.

29. 29. The process of any one of claims 1 to 28, wherein the gasket has dimensional tolerances selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns.

30. 28. The process of any one of claims 1 to 27, wherein the gasket has less than 300 particles 2 microns or larger in size as measured using light obscuration (LO) or microflow imaging (MFI).

31. (a) a tubular barrel; (b) a plunger located inside the tubular barrel and longitudinally movable within the barrel; (c) a gasket coupled to an end of the plunger, the gasket including a body made of a resilient material having a circumferential surface portion, a film on at least a portion of a circumferential outer surface of the gasket, and an internal cavity defined by an inner surface of the gasket and including an open end; (d) a plurality of non-contiguous channels in or through the film, each non-contiguous channel being generally parallel to the other non-contiguous channels, each non-contiguous channel of the plurality of non-contiguous channels extending around the circumferential outer surface of the gasket and having a non-channel portion interrupting the non-contiguous channel; A matched syringe and plunger system positioned along the circumferential outer surface portion of the gasket such that the non-channel portion of each non-contiguous channel is not aligned with the non-channel portion of one or more immediately adjacent non-contiguous channels.

32. 32. The matched syringe and plunger system of claim 31, wherein the thickness of the film present on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

33. 33. The matched syringe and plunger system of claim 32, wherein the film is configured to slide along the tube of the syringe and is chemically stable.

34. 34. The matched syringe and plunger system of any one of claims 31 to 33, wherein the film is capable of preventing migration of components from the elastic material of the gasket.

35. 32. The matched syringe and plunger system of claim 31, wherein the gasket is attached to the plunger by a press-fit assembly.

36. 32. The matched syringe and plunger system of claim 31, wherein the tubular barrel contains an injectable fluid in contact with the gasket.

37. 37. The matched syringe and plunger system of any one of claims 31-36, capable of maintaining a container closure integrity (CCI) over a two-year shelf life as measured by one or both of a liquid migration test method and a helium leak detection test method.

38. 37. The matched syringe and plunger system of any one of claims 31 to 36, comprising a container closure integrity (CCI) having a failure rate of 6 sigma or less.

39. 37. The matched syringe and plunger system of any one of claims 31 to 36, wherein the plunger and gasket comprise a release force of between 4 and 20 Newtons (N).

40. 37. The matched syringe and plunger system of any one of claims 31 to 36, wherein the plunger and gasket comprise a sliding force of 4 to 20 Newtons (N).

41. 34. The matched syringe and plunger system of claim 32 or 33, wherein the release force or gliding force varies by less than about 10-30% over a two year shelf life at 2°C to 8°C.

42. 35. The matched syringe and plunger system of claim 33 or 34, wherein the release force or gliding force varies by less than about 20-40% over a two year shelf life at 20°C to 25°C.

43. 43. The matched syringe and plunger system of any one of claims 31 to 42, wherein the tubular barrel comprises a wall having an inner surface coated with a lubricating layer having an atomic ratio of 1 atom Si:0.5-2.4 atoms O:0.6-3 atoms C as measured by X-ray photoelectron spectroscopy (XPS).

44. the tubular barrel comprises a wall having an interior surface characterized by a three-layer coating, the three layers comprising a tie coating, a barrier coating, and a pH protective coating; (a) the tie coating comprises SiOxCy or SiNxCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, the tie coating having an outer surface facing the inner surface of the wall, and the tie coating having an inner surface facing the lumen of the tubular barrel; (b) the barrier coating comprises SiOx, x is 1.5 to 2.9, the barrier coating is 2 to 1000 nm thick, the barrier coating has an outer surface facing the inner surface of the tie coating, and the barrier coating has an inner surface facing the lumen of the tubular barrel; 43. The matched syringe and plunger system of any one of claims 31-42, wherein (c) the pH protective coating comprises SiOxCy or SiNxCy, where x is from about 0.5 to about 2.4, and y is from about 0.6 to about 3, and the pH protective coating has an outer surface facing the inner surface of the barrier coating and an inner surface facing the lumen of the tubular barrel.

45. 45. The matched syringe and plunger system of claim 44, wherein the tubular barrel further comprises a lubricious layer, the lubricious layer having an outer surface facing the inner surface of the pH protective coating and an inner surface facing the lumen of the tubular barrel.

46. 45. The matched syringe and plunger system of claim 43 or 44, wherein the lubricating layer is capable of reducing one or both of the static and sliding friction of the gasket within the tubular barrel compared to one or both of the static and sliding friction of the gasket within the barrel without the lubricating layer.

47. 47. The matched syringe and plunger system of any one of claims 31 to 46, wherein the film comprises a fluoropolymer film.

48. 48. The matched syringe and plunger system of any one of claims 31 to 47, wherein the fluoropolymer film comprises polytetrafluoroethylene (PTFE).

49. 49. The matched syringe and plunger system of any one of claims 31-48, wherein the plurality of non-contiguous channels, when assembled to form a pre-filled syringe, improves the container closure integrity (CCI) of the system compared to an otherwise substantially similar pre-filled syringe that does not include the plurality of non-contiguous channels produced by the process.

50. 50. The matched syringe and plunger system of any one of claims 31 to 49, characterized by an improved longer shelf life.

51. 51. The matched syringe and plunger system of claim 49 or 50, wherein the improvement in the CCI is measured by a vacuum decay leak detection method.

52. 51. The matched syringe and plunger system of claim 49 or 50, wherein the improvement is measured by a Liquid CCI test method.

53. the tubular barrel includes a wall including an inner surface defining a generally cylindrical lumen, the barrel having an inner diameter; the gasket includes a leading surface, a side surface, a trailing portion, and an outer diameter; the gasket is configured to be received within the tubular syringe barrel with the gasket outer diameter positioned within and movable relative to the barrel inner diameter; 53. The matched syringe and plunger system of any one of claims 31-52, wherein the tubular barrel and gasket of the system, when assembled, are each sized to provide a spacing between a minimum barrel inner diameter and a maximum gasket outer diameter that deviates from the nominal spacing by no more than ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±2 microns.

54. A gasket comprising: (a) a body comprising a resilient material and having a circumferential surface portion and an interior cavity, the cavity being defined by an inner surface portion of the gasket and having an open end; (b) a film over at least a portion of a circumferential outer portion of the gasket; and (c) a plurality of non-contiguous channels in or through the film extending about the circumferential outer surface portion of the gasket and having respective non-channel portions interrupting each respective non-contiguous channel; the gasket being positioned along the circumferential outer surface portion of the gasket such that the respective non-channel portions of each non-contiguous channel are not aligned with adjacent non-channel portions.

55. The gasket is (i) maintaining container closure integrity (CCI) over a two-year shelf life as measured by one or more of the following test methods: liquid migration and helium leak detection; (ii) Container Closure Integrity (CCI) having a failure rate of 6 sigma or less when assembled into a matched syringe and plunger system; (iii) when assembled into a matched syringe and plunger system, a release force of 4 to 20 Newtons (N), alternatively 4 to 10 Newtons (N), alternatively 4 to 8 Newtons (N); (iv) a gliding force of 4 to 20 Newtons (N), alternatively 4 to 10 Newtons (N), alternatively 4 to 8 Newtons (N) when assembled in a matched syringe and plunger system; and 55. The gasket of claim 54, exhibiting one or more of the following characteristics: said release force or said sliding force changes by less than about 10-30% over a two year shelf life.

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