Injector and method for testing airtightness

Abstract

To provide a method for testing an airtightness between a stopper and a plunger of an injector.SOLUTION: An injector includes: a barrel; a stopper; and a plunger. The barrel includes a hollow inside, an orifice, and an opening on the side opposite to the orifice. The stopper is provided in the hollow inside of the barrel and thus defines a chamber sealed inside the barrel. The stopper is displaceable inside the barrel and thus changes a capacity of the chamber. The plunger extends into the hollow inside of the barrel through the opening (22) of the barrel. The plunger includes a distal end on an outer side of the barrel, and a proximal end on an inner side of the hollow inside of the barrel. The stopper includes: a distal face directed to the plunger; a proximal face directed to the chamber; and an inside cavity that opens on the distal face. The injector includes a sealing structure for sealing the cavity of the stopper such that the cavity of the stopper is sealed in a microbiological manner.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to syringes, and more particularly to a method for testing the airtightness between the stopper and plunger of a syringe.

[0002] Such a syringe includes (i) a barrel having a hollow interior, an orifice, and an opening opposite the orifice, (ii) a stopper disposed within the hollow interior of the barrel, thereby defining a sealed chamber within the barrel, the stopper being displaceable within the barrel, thereby varying the volume of the chamber, and (iii) a plunger extending through the opening in the barrel into the hollow interior of the barrel and which can be used to deliver the drug substance to a patient. Particularly when the syringe is embodied as a pre-filled syringe, the syringe can enable convenient administration of a pre-defined dose of the drug substance to a patient. [Background technology]

[0003] Many pharmaceuticals and active pharmaceutical ingredients are administered in liquid form. For efficient administration and efficacy, liquid active pharmaceutical ingredients are often delivered parenterally via injection. Therefore, especially for subcutaneous, intramuscular, intradermal, or intravitreal injections, active pharmaceutical ingredients are often provided in prefilled syringes (PFS). Such PFS may have a crimped needle or be capable of accepting a separate connecting needle. In a PFS, the active pharmaceutical ingredient is provided in a solution, suspension, or other liquid form inside the syringe barrel, ready for administration. A PFS may have the advantage that users receive a (semi-)ready-to-inject syringe without the need for preparation, such as loading the active pharmaceutical ingredient into the syringe from a vial. This can reduce the risk of contamination of the active pharmaceutical ingredient with particles or microorganisms, injury, and / or improper or inconvenient handling during use. A PFS may also enable self-administration by patients.

[0004] Typically, a PFS comprises a barrel having an open end and a tip with an orifice essentially opposite the open end, a rubber stopper, a plunger, and a needle or needle adapter over the orifice of the barrel. For example, a specific ophthalmic PFS is described in WO 2014 / 005728 A1.

[0005] Although PFS can be beneficial for use or administration compared to conventional formulations, it is usually more difficult to manufacture drug substances in PFS than in other containers such as vials. One aspect that can be of great importance, especially in ophthalmic applications, is the external sterilization of the syringe after complete assembly, composition, and / or packaging.

[0006] In such external sterilization, the exterior of the syringe is typically sterilized using gaseous chemical sterilization. It can be important to prevent the sterilant from entering the sealed interior of the syringe barrel to prevent the active pharmaceutical ingredient (API) from being affected. In particular, sterilant intrusion must be below limits provided by health authorities or the International Organization for Standardization (ISO) or must not impair the quality of the drug product until the end of its shelf life. For example, when ethylene oxide (EO) is used as the sterilant, the European Medicines Agency (EMEA) specifies limits of 1 μg / mL for EO and 50 μg / mL for ethylene chlorihydrin (ECH) in its EMEA / CVMP / 271 / 01 guidance. Alternatively, ISO 10993-7 specifies limits of 0.5 μg EO / IOL / 24 hr and 1.25 μg EO / IOL, which are interpreted as 0.5 μg EO / eye / 24 hr and 1.25 μg EO / eye, and 2.0 μg ECH / IOL / 24 hr and 5.0 μg EO / IOL, which are interpreted as 2.0 μg EO / eye / 24 hr and 5.0 μg EO / eye.

[0007] A problem encountered with external sterilization of such syringes can be the inability of the sterilant to adequately reach all parts and portions of the syringe other than the active pharmaceutical ingredient in the barrel. Access to the space and area within the region of the plunger coupled to or adjacent to the stopper is typically difficult. Particularly when extensive stoppers with internal cavities are used, the cavities themselves may be difficult to reach by the sterilant. More specifically, the plunger is often provided within or adjacent to the cavity of the stopper, which may prevent the sterilant from entering the cavity. This may allow contaminants, such as live organisms, to reside within the cavity and escape from the syringe at a later stage, reducing safety during use. Solid stoppers without cavities may be impractical for certain applications due to machinability challenges and / or the lack of availability as a commercial solution. A further problem is the limited assembly force of the plunger to the stopper to avoid stopper movement during or after plunger assembly and / or compression of the syringe's fluid contents.

[0008] Therefore, there is a need for a system or syringe that can reduce the risk of contamination during use or application. Summary of the Invention

[0009] According to the present invention, this need is solved by a syringe as defined by the features of independent claim 1 and by a method as defined by the features of independent claim 12. Preferred embodiments are the subject matter of the dependent claims.

[0010] In one aspect, the present invention provides a syringe comprising a barrel, a stopper, and a plunger. The barrel has a hollow interior, an orifice, and an opening opposite the orifice. The stopper is disposed within the hollow interior of the barrel, thereby defining a sealed chamber within the barrel. The stopper is displaceable within the barrel, thereby changing the volume of the chamber. During use, the plunger extends through the opening of the barrel into the hollow interior of the barrel. When the stopper is moved toward the orifice by the plunger to reduce the volume of the chamber, it can expel liquid from the barrel through the orifice. The plunger has a distal end outside the barrel and a proximal end inside the hollow interior of the barrel. The stopper has a distal surface facing the plunger, a proximal surface facing the chamber, and an internal cavity opening to the distal surface. The syringe includes a sealing structure that seals the cavity of the stopper so that the cavity is microbiologically sealed.

[0011] In the context of the present invention, the term "syringe" relates to all kinds of syringes in the literal sense, such as single-chamber syringes, double-chamber syringes or multi-chamber syringes. Syringes can be pre-filled, partially filled or emptied. They can also be provided with crimped needles or adapters to which needles or similar administration ducts can be coupled. In addition to syringes in the literal sense, the term "syringe" as used herein also encompasses similar devices or storage containers, such as in particular cartridges.

[0012] As used herein, the term "proximal" refers to the portion, tip, or component that is located closest to or toward the medicament or drug delivery site when the syringe is in use. Thus, the proximal direction can be the direction toward the body or person to which the syringe is intended to be applied. For example, in an embodiment of a syringe having a needle intended to be inserted into a body or person and a plunger that is pressed to deliver a medicament through the needle, the proximal end of the syringe is formed by the tip of the needle. The proximal direction can be the direction toward the end of the barrel orifice or the location on the patient's skin that the needle penetrates to deliver a medicament or drug substance to the patient.

[0013] Conversely, the term "distal" is used to refer to the portion, tip, or component located furthest from, or facing away from, the medication delivery site when the syringe is in use. Thus, the distal direction can be the direction facing away from the body or person to which the syringe is applied. For example, during use, the distal end of a syringe can be the end of the plunger where the operator's thumb rests to advance the plunger to deliver the medication. Typically, proximal and distal are opposite directions.

[0014] The term "tight" as used in connection with stoppers and plungers may particularly relate to being airtight, or more specifically, tight against contamination such as deposits of organic matter (e.g., microorganisms or endotoxins). Advantageously, the airtightness is sufficient to prevent potential microorganisms and / or endotoxins from escaping from the stopper cavity.

[0015] Preferably, a liquid is disposed in the chamber of the barrel. Thus, the syringe may be a pre-filled syringe. In a particularly advantageous embodiment, the syringe is an ophthalmic pre-filled syringe and the active pharmaceutical ingredient is an ophthalmic active pharmaceutical ingredient.

[0016] The syringe barrel may have an essentially cylindrical main portion. In particular, the main portion may have the shape of a hollow cylinder. The barrel may be made of any suitable material, including suitable hard plastic materials or, for most pharmaceutical applications, inert materials that can be sterilized, such as glass. Glass barrels may be advantageous for reasons of manufacturing, sterility, inertness, and stability. The barrel opening may span the entire diameter of the barrel's interior. The orifice may be embodied in a tip or spout formed at the end of the barrel opposite the opening. In particular, the orifice may have a channel at the tip that is reduced in diameter compared to the diameter of the barrel's interior. The orifice may be sized to allow liquid to be expelled when the volume of the chamber in the barrel is reduced by advancing the stopper through the plunger.

[0017] The term "drug" as used herein relates to a therapeutically active agent, also commonly referred to as an active pharmaceutical ingredient (API), and to combinations or pluralities of such therapeutically active substances. The term also encompasses diagnostic or imaging agents that must be administered to a patient in liquid form, such as, for example, contrast agents, such as MRI contrast agents, tracers, such as PET tracers, and hormones.

[0018] The term "drug substance" as used herein refers to a drug as defined above that has been formulated or reconstituted in a form suitable for administration to a patient. For example, in addition to the drug, the drug substance may further comprise excipients and / or other auxiliary ingredients. A particularly preferred drug substance in the context of the present invention is a drug solution, particularly a drug solution for injection.

[0019] Typically, the liquid in the chamber of the syringe barrel is a drug substance. In the case of a double-chamber prefilled syringe, one chamber may contain a drug substance that must be reconstituted for drug administration with a diluent contained in the second chamber. Alternatively, the first and second chambers may contain two different drug substances that must be mixed prior to drug administration. In particular, the syringe may contain a specific dose of drug substance to be administered when injected.

[0020] The term "pharmaceutical product" as used herein relates to a final product that includes a drug substance or drug substances. In particular, a pharmaceutical product can be a ready-to-use product having a drug substance in an appropriate dosage and / or in an appropriate form for administration. For example, a pharmaceutical product can include an administration device such as a syringe in the form of a pre-filled syringe or the like.

[0021] As used herein, the term "sterilant" refers to any liquid, gas, or vaporized substance capable of externally sterilizing or externally sterilizing a PFS surface. For example, the sterilant can be or include ethylene oxide (EO), hydrogen peroxide (HO), steam, vaporized hydrogen peroxide (VHP), vaporized peracetic acid (VPA), or nitrogen dioxide.

[0022] The term "sterilize" thereby relates to rendering a structure or element, such as a PFS, sterile. As used herein, the term "sterility" relates to the maximum contamination rate that allows the PFS or another element to be used in its intended application. For example, it can relate to the state of the PFS being in compliance with the American National Standards Institute (ANSI) and the Association for the Advancement of Medical Instrumentation (AAMI) standard ST67, i.e., the requirements and guidance pursuant to ANSI / AAMI ST67. More specifically, the term "sterility" refers to the state of the PFS being in compliance with the requirements and guidance pursuant to ANSI / AAMI ST67. -6A sterility assurance level (SAL) value of 0.05% may be used for products labeled as sterile, as specified in ANSI / AAMI ST67.

[0023] Thus, a state free of viable organisms can be achieved by sterilization or sterilization. In particular, sterilization can refer to a validated process used to render a product essentially free of viable organisms. In such a sterilization process, the increase in microbiological death can be described as an exponential function. Therefore, the number of microorganisms that survive the sterilization process can be expressed as a probability.

[0024] The stopper may be made of an inert, resilient, and deformable material, such as rubber or silicone. In particular, the stopper may be configured to seal a chamber inside a barrel containing a fluid or a solid and a fluid. The stopper further has a distal surface that can face the liquid in the chamber and a distal surface that faces the plunger. The outer periphery of the stopper may correspond to the inner periphery of the barrel when mounted. A cavity may be centrally located to receive the proximal portion of the plunger.

[0025] A syringe may have a central axis along which the barrel, stopper, and plunger extend. A syringe or part thereof, such as a barrel, may be rotationally symmetric about the central axis.

[0026] The sealing structure can close and seal the cavity of the stopper, thereby preventing contaminants such as viable organisms from escaping from the cavity of the stopper when the syringe is in use. Therefore, even if external sterilization cannot achieve complete sterilization of the cavity of the stopper, safety of the syringe can be provided, because contaminants ultimately present in the cavity of the stopper cannot escape due to the sealing structure that tightly closes the cavity microbiologically. In this way, the syringe can reduce or even eliminate the risk of contaminants escaping from the cavity of the stopper after terminal sterilization or during use of the syringe.

[0027] The proximal end of the plunger may form a stopper contact portion that allows for an appropriate force transmission from the plunger to the stopper, for example, such transmission may be intended to be more or less uniform in order to prevent differential deformation of the stopper when transferring the stopper to expel the liquid.

[0028] Thus, after coupling the plunger with the stopper, the component design and materials embodied may ensure constant pressing of the plunger rod region against the corresponding stopper region, thus creating a microbiologically sealed interface.

[0029] In a first preferred embodiment, the proximal end of the plunger has an abutment surface and barbs extending proximally from the abutment surface, and the cavity in the stopper and the barbs on the proximal end of the plunger are shaped to snap fit together such that the abutment surface on the proximal end of the plunger abuts the distal face of the stopper, securing the stopper to the plunger.

[0030] The term "secured" in this context relates to a connection between the stopper and plunger that is strong enough to prevent the stopper and plunger from being detached from each other during use of the syringe, thereby allowing the stopper and plunger to move together or in conjunction as a unit. In particular, by providing a snap-fit ​​formation embodied by the barbs and cavities, an efficient mechanical coupling can be achieved that allows a form-fit connection to be established.

[0031] Thus, in a first embodiment of the syringe, the barbs at the proximal end of the plunger preferably have a (distal) neck portion and a (proximal) head portion, the cavity of the stopper has a (distal) channel portion and a (proximal) internal chamber portion, and the cavity of the stopper and the barbs at the proximal end of the plunger are snap-fitted together by the channel portion of the cavity of the stopper that receives the neck portion of the barbs at the proximal end of the plunger and the internal chamber portion of the cavity of the stopper that receives the head portion of the barbs at the proximal end of the plunger. Such an arrangement, when snap-fitted together, effectively provides a form-fitting connection between the plunger and stopper, allowing the plunger to be pressed against the stopper.

[0032] Preferably, the neck portion of the barbs at the proximal end of the plunger has a first axial length extending between the proximal surface of the plunger and the head portion of the barbs at the proximal end of the plunger, and the channel portion of the cavity of the stopper has a second axial length extending between the distal surface of the stopper and the internal chamber portion of the cavity of the stopper, the first length of the neck portion of the barbs at the proximal end of the plunger being smaller than the second length of the channel portion of the cavity of the stopper when the stopper is not snap-fitted to the plunger. More specifically, the difference in length is specifically set before the stopper is connected to the plunger. By sizing the first and second lengths in this manner, a sealing structure can be realized, such that when the plunger is attached to the stopper, the stopper is compressed and the cavity is sealed by the plunger, achieving a microbiologically tight and typically airtight connection between the plunger and the stopper. In particular, the distal surface of the stopper can be pressed against the proximal end of the plunger so that the stopper is compressed and tightly connected to the plunger. This allows for an efficient sealing of the cavity, whereby the first length of the neck portion of the barb at the proximal end of the plunger is preferably at least 0.3 millimeters (mm) or about 0.5 mm less than the second length of the channel portion of the cavity in the stopper. In particular, when 1 ml or 0.5 ml pre-filled syringes are involved, such a difference has proven appropriate to ensure, on the one hand, the tightness of the closure of the cavity and, on the other hand, to allow an efficient connection or assembly of the plunger and the stopper.

[0033] Preferably, the neck portion of the barbs at the proximal end of the plunger has a first compressed portion and the channel portion of the cavity of the stopper has a second compressed portion, the first compressed portion of the neck portion of the barbs at the proximal end on the plunger being more tapered compared to the second compressed portion of the channel portion of the cavity of the stopper.

[0034] The term "more tapered" in reference to the constriction portions refers to a first constriction portion of the neck portion being thinner or having a smaller diameter than a second constriction portion of the channel portion along the same length, such that an angle between a shoulder of the first constriction portion and the axis of the barb may be greater than an angle between a shoulder of the second constriction portion and the axis of the channel portion.

[0035] This difference in taper between the cavity and the barbs allows for an efficient implementation of a sealing structure, compressing the stopper between the inside and outside of the cavity, e.g., at the beginning of the cavity, thus providing a tight connection between the plunger and the stopper and effectively sealing the cavity.

[0036] Thereby, a first compression portion of the neck portion of the barb at the proximal end of the plunger preferably tapers toward a head portion of the barb at the proximal end of the plunger. The first compression portion may be conical. Additionally or alternatively, a second compression portion of the channel portion of the cavity of the stopper preferably tapers toward an inner chamber portion of the cavity of the stopper. The second compression portion may also be conical. In particular, if both portions are conical, improved compression and airtightness are achieved when the stopper is snap-fitted onto the plunger.

[0037] Preferably, the syringe or its sealing structure includes a gasket or a physically or chemically attached elastomeric member, such as an overmolded or co-molded sealing feature made of a thermoplastic elastomer or similar resilient material, disposed around the barbs at the proximal end of the plunger, the gasket or member being compressed between the adjacent surface of the proximal end of the plunger and the distal surface of the stopper. Such a gasket or member can provide additional or alternative sealing between the plunger and the stopper, allowing for greater variability in material hardness and dimensional tolerances, and lower plunger assembly forces, reducing the risk of stopper movement induced by relatively high assembly forces.

[0038] Preferably, the distal surface of the stopper has a bulge extending circumferentially around the cavity of the stopper opening at the distal surface, such a bulge may allow for greater sealing capability for a given assembly force.

[0039] In another aspect, the invention is a method for testing the airtightness between a stopper and a plunger in a syringe. The stopper has a distal face, a proximal face, and an interior cavity opening to the distal face, and the syringe has a barrel with a hollow interior, an orifice, and an opening opposite the orifice. The method includes (i) opening the cavity in the stopper to the proximal face, for example, by piercing the front face of the stopper with a needle or cannula or by cutting the tip of the stopper without affecting the sealing properties of the stopper, (ii) placing the stopper in the hollow interior of the barrel through the opening of the barrel so that the distal face of the stopper faces toward the plunger, (iii) coupling a gas detector to the opening of the syringe barrel, and (iv) supplying gas through the orifice in the barrel.

[0040] The steps of the method according to the invention do not necessarily have to be performed in the listed order, i.e., in the order (i) to (iv). Rather, other orders of the listed steps are possible. A suitable gas that is also reliably detectable could be, for example, helium.

[0041] This method effectively tests the airtightness between the plunger and the stopper. More specifically, when gas is supplied through the orifice, it enters the cavity through the open proximal face so that the gas is disposed inside the cavity. If the gas cannot exit the cavity from the distal side of the stopper, as confirmed by a gas detector, the connection between the stopper and the plunger is microbiologically airtight. Additionally, the airtightness can be evaluated by evaluating the amount of gas and / or the gas flow rate detected distal to the stopper.

[0042] Preferably, the method further includes the step of operating a gas detector to detect gas distal to the stopper. Such an arrangement allows for efficient evaluation of the tightness of the connection between the stopper and the plunger. The gas detector thereby preferably measures the concentration of gas distal to the stopper. Measuring the concentration allows for evaluation of the level of tightness. For example, this allows for comparison of various sealing structures and selection of the most appropriate one.

[0043] Preferably, the method includes generating a vacuum distal to the stopper, which may be in the sub-millibar pressure range, such that gas can be attempted to pass through the stopper, thus effectively testing its airtightness.

[0044] The syringe according to the invention and the leak-tightness testing method according to the invention are described in more detail herein below by way of exemplary embodiments and with reference to the accompanying drawings, in which: FIG. [Brief explanation of the drawings]

[0045] [Figure 1] 1 is a schematic cross-sectional side view of a first embodiment of a syringe according to the present invention. FIG. [Figure 2] FIG. 2 is a diagram showing detail A of FIG. [Figure 3] FIG. 2 is a schematic cross-sectional side view of a second embodiment of a syringe according to the present invention. [Figure 4] FIG. 4 is a diagram showing detail B of FIG. 3. [Figure 5] FIG. 10 is a schematic cross-sectional side view of a third embodiment of a syringe according to the present invention. [Figure 6] FIG. 6 is a diagram showing detail C of FIG. 5. DETAILED DESCRIPTION OF THE INVENTION

[0046] In the following description, certain terminology is used for convenience only and is not intended to limit the invention. The terms "right," "left," "up," "down," "under," and "above" refer to directions within the figures. The terminology consists of explicitly mentioned terms, their derivatives, and terms of similar meaning. Also, as shown in the figures, spatially relative terms such as "beneath," "below," "lower," "above," "upper," "proximal," "distal," etc. may be used to describe the relationship of one element or feature to another element or feature. These spatially relative terms are intended to encompass various positions and orientations of the device during use or operation in addition to the positions and orientations shown in the figures. For example, if a device in the figures is turned upside down, elements described as "below" or "beneath" other elements or features would then be "above" or "over" the other elements or features. Thus, the exemplary term "below" can encompass both above and below positions and orientations. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, descriptions of movement along and about various axes include various particular device positions and orientations.

[0047] To avoid repetition of illustrations and descriptions of various aspects and exemplary embodiments, it should be understood that many features are common to many aspects and embodiments. The omission of an aspect from a description or illustration does not imply that the aspect is absent from an embodiment incorporating that aspect. Instead, the aspect may be omitted for clarity and to avoid redundant description. In this context, the following applies to the remainder of this description: For clarity of the drawings, if a figure contains a reference sign that is not described in the directly relevant part of the description, please refer to the preceding or following part of the description. Furthermore, for clarity, if not all features of a part are marked with a reference sign in a drawing, please refer to other drawings showing the same part. Like numerals in two or more figures represent the same or similar elements.

[0048] FIG. 1 shows an ophthalmic prefilled syringe (PFS) 1 as a first embodiment of a syringe according to the present invention in an upright position. The PFS 1 includes a barrel 2, a stopper 3, and a plunger 4. The barrel 2 is essentially cylindrical and includes a hollow interior, an orifice 21, and an opening 22 opposite the orifice 21. The stopper 3 is disposed within the hollow interior of the barrel 2 and defines a sealed chamber 5 within the barrel 2. More specifically, the stopper 3 has an upper distal surface 31 and a lower proximal surface 32, and the chamber 5 is disposed between the proximal surface 32 and the orifice 21 of the barrel 2. The orifice 21 has a spout with an internal channel tightly closed by a closure cap 8. The PFS 1 is equipped with a Luer lock adapter 9 around the orifice 21.

[0049] A liquid ophthalmic drug substance 6 is disposed within chamber 5. Stopper 3 is displaceable within barrel 2, thereby changing the volume of chamber 5. More specifically, by moving stopper 3 downward or proximally toward orifice 21, the volume of chamber 5 decreases, allowing drug substance 6 to be expelled from orifice 21 after removal of cap 8.

[0050] The stopper 2 is further designed with an internal cavity 33. The cavity 33 opens upwards to the distal face 31.

[0051] The plunger 4 has a vertical cylindrical rod portion 43 that extends through the opening 22 of the barrel 2 into its hollow interior. The vertical cylindrical rod portion 43 has an upper distal end 41 and a lower proximal end 42. The distal end 41 includes a ribbed upper finger pressure surface. The lower end 42 includes an essentially horizontal abutment surface 421 and a barb 422 extending proximally downward from the abutment surface 421. As described in more detail below, the barb 422 is disposed inside the cavity 33 of the stopper 3.

[0052] The PFS 1 further has an extended finger flange 7 clipped to the barrel 2 around its opening 22. The finger flange 7 allows for convenient manipulation of the PFS 1.

[0053] 2, the portion of the PFS1 around the stopper 3 is shown in more detail. This shows that the cavity 33 of the stopper 3 has a lower or proximal interior chamber portion 332 and an upper or distal channel portion 331 that extends from the proximal face 31 to the interior chamber portion 332. The spines 422 have a proximal or lower head portion 4221 that essentially corresponds to the interior chamber portion 332 of the cavity 33, and a distal or upper neck portion 4222 that essentially corresponds to the channel portion 331 of the cavity 33. The stopper 3 snaps onto the spines 422 of the plunger 4 such that a form-fit connection is established.

[0054] The neck portion 4222 of the barb 422 of the proximal end 42 of the plunger 4 has a conical first compressed portion 4223, and the channel portion 331 of the cavity 33 of the stopper 3 has a straight or cylindrical second compressed portion disposed around the first compressed portion 4223. Thus, the first compressed portion 4223 of the neck portion 4222 is more tapered in a downward or proximal direction compared to the second compressed portion of the channel portion 331, such that the stopper material is compressed around the first compressed portion 4223.

[0055] In this way, the first compressed portion 4223 of the neck 4222 of the barb 422 together with the second compressed portion of the channel 331 of the cavity 33 establish a sealing structure that seals the cavity 33 of the stopper 3 so that it is microbiologically sealed.

[0056] To verify the effectiveness of the sealing structure of the PFS1, it can be tested by an embodiment of a method for testing the airtightness between the stopper and plunger in a syringe according to the present invention. This method is applied to an unassembled PFS1 and includes the following steps: opening the cavity 33 of the stopper 3 relative to the proximal face 32, for example, by drilling a hole in the proximal face 32 or by cutting a portion of the proximal face 32; installing the stopper 3 in the hollow interior of the barrel 2 through the opening 22 of the barrel 2 so that the distal face 31 of the stopper 3 faces the plunger 4; coupling a helium detector to the opening 22 of the barrel 2; and supplying helium through the orifice 21 of the barrel 2 at an overpressure of approximately 5 mbar. The helium detector measures the helium concentration distal to the stopper 3. Therefore, if the helium detector does not detect helium, the sealing structure of the PFS1 hermetically closes the cavity 33. Otherwise, the airtightness of the closure is evaluated by the measured helium concentration.

[0057] Figures 3 and 4 show another ophthalmic PFS 10 as a second embodiment of a syringe according to the present invention in an upright position. PFS 10 is embodied substantially similarly to PFS 1 of Figures 1 and 2. In particular, PFS 10 similarly includes barrel 20 with orifice 210 and opening 220, stopper 30 with distal face 310, proximal face 320, and cavity 330 having interior chamber portion 3320 and cylindrical channel portion 3310, chamber 50, active pharmaceutical ingredient 60, extended finger flange 70, cap 80, and Luer lock adapter 90.

[0058] Plunger 40 has a vertical cylindrical rod portion 430 that extends through opening 220 in barrel 20 into its hollow interior. Vertical cylindrical rod portion 430 has an upper distal end 410 and a lower proximal end 420. Proximal end 420 includes an essentially horizontal abutment surface 4210 and a barb 4220 extending proximally downward from abutment surface 4210.

[0059] As best seen in FIG. 4 , the barbs 4220 have a lower or proximal head portion 42210 and an upper or distal essentially cylindrical neck portion 42220. The neck portion 42220 has a first axial length 42230 extending between the proximal surface 4210 and the head portion 42210. The first axial length 42230 is less than a second axial length of the channel portion 3310 of the cavity 330 of the stopper 30, which extends between the distal surface 310 of the stopper 30 and the interior chamber portion 3320 of the cavity 330. These different first and second lengths cause the stopper 30 to be compressed toward the proximal surface 4210 of the plunger 40 when the stopper 30 is snapped onto the barbs 4220 of the plunger 40.

[0060] In this manner, the shorter first axial length 42230 of the neck portion 42220 of the barb 4220 establishes a sealing structure with the second axial length of the channel portion 3310 of the cavity 330 of the stopper 30. In particular, this structure compresses the distal surface 310 of the stopper 30 against the adjacent surface 4210 of the plunger 40 such that the cavity 330 of the stopper 30 is microbiologically sealed.

[0061] Figures 5 and 6 show yet another ophthalmic PFS 19 as a third embodiment of a syringe according to the present invention in an upright position. PFS 19 is embodied in substantially the same manner as PFS 1 of Figures 1 and 2 and PFS 10 of Figures 3 and 4. In particular, PFS 19 similarly includes a barrel 29 with an orifice 219 and an opening 229, a stopper 39 with a distal face 319, a proximal face 329, and a cavity 339 having an internal chamber portion 3329 and a cylindrical channel portion 3319, a chamber 59, a drug substance 69, an extended finger flange 79, a cap 89, and a Luer lock adapter 99.

[0062] Plunger 49 has a vertical cylindrical rod portion 439 that extends through opening 229 in barrel 29 into its hollow interior. Vertical cylindrical rod portion 439 has an upper distal end 419 and a lower proximal end 429. Proximal end 429 includes an essentially horizontal abutment surface 4219 and a barb 4229 extending proximally downward from abutment surface 4219.

[0063] 6, the barbs 4229 have a lower or proximal head portion 42219 and an upper or distal essentially cylindrical neck portion 42229. The barbs 4229 of the plunger 49 are snapped into the cavity 339 of the stopper 39 such that a form-fit connection is established between the plunger 49 and the stopper 39. The neck portion 42229 of the barbs 4229 is thereby disposed in the channel portion 3319 of the cavity 339, and the head portion 42219 of the barbs 4229 is disposed in the interior chamber portion 3329 of the cavity 339.

[0064] A gasket 42239 is disposed between the proximal surface 4219 of the proximal end 429 of the plunger 49 and the distal surface 319 of the stopper 30. The gasket 42239 is ring-shaped and extends around the neck portion 42229 of the spines 4229. The spines 4229 are sized and shaped so that the gasket 42239 is compressed. In this manner, the gasket 42239 and the spines 4229 establish a sealing structure that clamps the distal surface 310 of the stopper 30 against the proximal end 429 of the plunger 49 such that the cavity 330 of the stopper 30 is microbiologically sealed.

[0065] This description and the accompanying drawings describing aspects and embodiments of the present invention should not be construed as limiting the scope of the claims defining the protected invention. In other words, while the present invention has been illustrated and described in detail in the drawings and the foregoing description, such illustration and description should be considered exemplary or exemplary and not limiting. Various mechanical, compositional, structural, electrical, and operational changes can be made without departing from the spirit and scope of this description and claims. In some instances, well-known circuits, structures, and techniques have not been shown in detail so as not to obscure the invention. It will therefore be understood that changes and modifications can be made by those skilled in the art within the scope and spirit of the following claims. In particular, the present invention covers further embodiments having any combination of features from the different embodiments described above and below. For example, the present invention can be defined as The sealing structure of PFS1 in Figures 1 and 2 is combined with the sealing structure of PFS10 in Figures 3 and 4, It is possible to operate the embodiment such that the sealing structure of the PFS1 of FIGS. 1 and 2 is combined with the sealing structure of the PFS19 of FIGS.

[0066] The present disclosure also covers all additional features individually shown in the drawings, which may not be described in the preceding or following description. Also, single alternatives of the embodiments and features described in the drawings and description may be omitted from the subject matter of the present invention or disclosed subject matter. The present disclosure includes subject matter consisting of features defined in the claims or exemplary embodiments, as well as subject matter including said features.

[0067] Furthermore, in the claims, the word "comprise" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. A single unit or step may fulfill the functions of several features recited in a claim. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be advantageously used. Terms such as "essentially," "about," and "approximately" in connection with an attribute or value specifically also define the exact attribute or exact value, respectively. The term "about" in the context of a given numerical value or range refers, for example, to a value or range that is within 20%, 10%, 5%, or 2% of the given value or range. Components described as coupled or connected may be directly coupled electrically or mechanically, or indirectly coupled via one or more intermediate components. Reference signs in the claims should not be construed as limiting the scope.

Claims

1. A syringe (1, 10, 19) comprising: a barrel (2, 20, 29) having a hollow interior, an orifice (21, 210, 219), and an opening (22, 220, 229) opposite the orifice (21, 210, 219); a stopper (3, 30, 39) disposed in the hollow interior of the barrel (2, 20, 29), thereby defining a sealed chamber (5, 50, 59) within the interior of the barrel (2, 20, 29), the stopper (3, 30, 39) being displaceable within the interior of the barrel (2, 20, 29), thereby varying the volume of the chamber (5, 50, 59); a plunger (4, 40, 49) extending through the opening (22, 220, 229) of the barrel (2, 20, 29) into the hollow interior of the barrel (2, 20, 29); Equipped with the plunger (4, 40, 49) has a distal end (41, 410, 419) outside the barrel (2, 20, 29) and a proximal end (42, 420, 429) inside the hollow interior of the barrel (2, 20, 29); the stopper (3, 30, 39) has a distal surface (31, 310, 319) facing the plunger (4, 40, 49), a proximal surface (32, 320, 329) facing the chamber (5, 50, 59), and an internal cavity (33, 330, 339) opening to the distal surface (31, 310, 319); the syringe (1, 10, 19) is provided with a sealing structure (4223, 42230, 42239) that seals the cavity (33, 330, 339) of the stopper (3, 30, 39) so that the cavity (33, 330, 339) of the stopper (3, 30, 39) is microbiologically sealed; Syringes (1, 10, 19).

2. the proximal end (42, 420, 429) of the plunger (4, 40, 49) has an abutment surface (421, 4210, 4219) and barbs (422, 4220, 4229) extending proximally from the abutment surface (421, 4210, 4219); the cavity (33, 330, 339) of the stopper (3, 30, 39) and the barbs (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) have a snap-fit ​​shape such that the adjacent surface (421, 4210, 4219) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) is adjacent to the distal surface (31, 310, 319) of the stopper (3, 30, 39) and the stopper (3, 30, 39) is fixed to the plunger (4, 40, 49); A syringe (1, 10, 19) according to claim 1.

3. the barbs (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) having a neck portion (4222, 42220, 42229) and a head portion (4221, 42210, 42219); the cavity (33, 330, 339) of the stopper (3, 30, 39) has a channel portion (331, 3310, 3319) and an internal chamber portion (332, 3320, 3329); The cavity (33, 330, 339) of the stopper (3, 30, 39) and the barbs (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) are such that the cavity (33, 330, 339) of the stopper (3, 30, 39) receives the neck portion (4222, 42220, 42229) of the barbs (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49). a channel portion (331, 3310, 3319) of the stopper (3, 30, 39) and an internal chamber portion (332, 3320, 3329) of the cavity (33, 330, 339) of the stopper (3, 30, 39) that receives the head portion (4221, 42210, 42219) of the barb (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49); A syringe (1, 10, 19) according to claim 2.

4. the neck portion (4222, 42220, 42229) of the spines (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) has a first axial length (42230) extending between the adjacent surface (421, 4210, 4219) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) and the head portion (4221, 42210, 42219) of the spines (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49); the channel portion (331, 3310, 3319) of the cavity (33, 330, 339) of the stopper (3, 30, 39) has a second axial length extending between the distal surface (31, 310, 319) of the stopper (3, 30, 39) and the internal chamber portion (332, 3320, 3329) of the cavity (33, 330, 339) of the stopper (3, 30, 39); when the stopper (3, 30, 39) is not snap-fitted to the plunger (4, 40, 49), the first length (42230) of the neck portion (4222, 42220, 42229) of the barb (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) is less than the second length of the channel portion (331, 3310, 3319) of the cavity (33, 330, 339) of the stopper (3, 30, 39); A syringe (1, 10, 19) according to claim 3.

5. 5. The syringe (1, 10, 19) of claim 4, wherein the first length (42230) of the neck portion (4222, 42220, 42229) of the barb (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) is at least 0.3 millimeters or about 0.5 millimeters smaller than the second length of the channel portion (331, 3310, 3319) of the cavity (33, 330, 339) of the stopper (3, 30, 39).

6. the neck portion (4222, 42220, 42229) of the barb (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) has a first compression portion (4223); the channel portion (331, 3310, 3319) of the cavity (33, 330, 339) of the stopper (3, 30, 39) has a second compression portion (331); the first compressed portion (4223) of the neck portion (4222, 42220, 42229) of the barb (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) is more tapered than the second compressed portion (331) of the channel portion (331, 3310, 3319) of the cavity (33, 330, 339) of the stopper (3, 30, 39); A syringe (1, 10, 19) according to any one of claims 3 to 5.

7. 7. The syringe (1, 10, 19) of claim 6, wherein the first compressed portion (4223) of the neck portion (4222, 42220, 42229) of the spines (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) tapers toward the head portion (4221, 42210, 42219) of the spines (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49).

8. 8. The syringe (1, 10, 19) of claim 6 or 7, wherein the second compressed portion (331) of the channel portion (331, 3310, 3319) of the cavity (33, 330, 339) of the stopper (3, 30, 39) tapers toward the internal chamber portion (332, 3320, 3329) of the cavity (33, 330, 339) of the stopper (3, 30, 39).

9. 9. A syringe (1, 10, 19) according to any one of claims 2 to 8, comprising a gasket (42239) arranged around the spines (422, 4220, 4229) of the proximal end (42, 420, 429) of the plunger (4, 40, 49), the gasket (42239) contacting the adjacent surface (421, 4210, 4219) of the proximal end (42, 420, 429) of the plunger (4, 40, 49) and the distal surface (31, 310, 319) of the stopper (3, 30, 39).

10. 10. A syringe (1, 10, 19) according to any one of claims 1 to 9, wherein the distal surface (31, 310, 319) of the stopper (3, 30, 39) has a bulge extending circumferentially around the cavity (33, 330, 339) of the stopper (3, 30, 39) that opens at the distal surface (31, 310, 319).

11. 11. The syringe (1, 10, 19) according to any one of claims 1 to 10, wherein a liquid (6, 60, 69) is disposed in the chamber (5, 50, 59) of the barrel (2, 20, 29).

12. A method for testing the airtightness between a stopper (3, 30, 39) and a plunger (4, 40, 49) of a syringe (1, 10, 19), wherein the stopper (3, 30, 39) has a distal surface (31, 310, 319), a proximal surface (32, 320, 329), and an internal cavity (33, 330, 339) opening to the distal surface (31, 310, 319), and the syringe (1, 10, 19) has a barrel (2, 20, 29) with a hollow interior, an orifice (21, 210, 219), and an opening (22, 220, 229) opposite the orifice (21, 210, 219), the method comprising: opening the cavity (33, 330, 339) of the stopper (3, 30, 39) to the proximal face (32, 320, 329); placing the stopper (3, 30, 39) into the hollow interior of the barrel (2, 20, 29) through the opening (22, 220, 229) of the barrel (2, 20, 29) so that the distal surface (31, 310, 319) of the stopper (3, 30, 39) faces the plunger (4, 40, 49); coupling a gas detector to the opening (22, 220, 229) of the syringe barrel (2, 20, 29); supplying gas from the orifices (21, 210, 219) of the barrels (2, 20, 29); A method comprising:

13. 13. The method of claim 12, further comprising operating the gas detector to detect gas distal to the stopper (3, 30, 39).

14. 14. The method of claim 13, wherein the gas detector measures the concentration of the gas distal to the stopper (3, 30, 39).

15. 15. The method of any one of claims 12 to 14, comprising creating a vacuum distal to the stopper (3, 30, 39).

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