Prefilled syringes and methods for sterilizing prefilled syringes

Abstract

The prefilled syringe (1) includes a barrel (2) having a hollow interior, an orifice, and an opening opposite the orifice; a stopper (4) disposed within the hollow interior of the barrel (2) to define a sealed chamber (21) within the barrel (2), the stopper (4) being displaceable within the barrel (2) to change the volume of the chamber (21); a liquid filled within the chamber (21) of the barrel (2); and a plunger (3) extending through the opening of the barrel (2). When the stopper (4) is advanced toward the orifice by the plunger (3) so as to reduce the volume of the chamber (21), the stopper (4) expels the liquid from the barrel (2) through the orifice. The plunger (3) includes a proximal portion, a distal portion (33), and a rod portion (32) extending between the proximal and distal portions (33). The plunger (3) is shaped to form a passage (8) between the opening of the barrel (2) and the segment where the proximal portion (31) of the plunger (3) is adjacent to the stopper (4), so that the sterilant can be supplied through the opening of the barrel (2) to the segment where the proximal portion (31) of the plunger (3) is adjacent to the stopper (4). [Selected Figure] Figure 1

Description

Technical Field

[0001] The present invention relates to prefilled syringes, and more particularly to a method for sterilizing such syringes.

[0002] (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 changing the volume of the chamber; (iii) a liquid within the chamber of the barrel; and (iv) a plunger extending through the opening of the barrel. Such a prefilled syringe can be used to provide a pharmaceutical to a patient. In particular, such a prefilled syringe can enable the convenient administration of a predetermined dose of a pharmaceutical to a patient.

Background Art

[0003] A number of pharmaceutical products or pharmaceuticals are administered in liquid form. For efficient administration and effectiveness, liquid pharmaceuticals are often delivered parenterally by injection. Thereby, particularly in the case of subcutaneous, intramuscular, intradermal, or intravitreal injection, the pharmaceutical is often provided in a prefilled syringe (PFS). Such a PFS may have a fixed needle or may be capable of receiving a separate connecting needle. In a PFS, the pharmaceutical is provided within the interior of the barrel of the syringe in solution, suspension, or other liquid form ready for administration. The PFS has the advantage of providing the user with a (quasi) immediately injectable syringe that does not require preparation such as filling the syringe with the pharmaceutical, for example, by transfer from a vial. Thereby, it is possible to reduce contamination of the pharmaceutical, for example, by particles and microorganisms, injury, and / or inappropriate or cumbersome handling during application. Also, the PFS may enable self-administration by the patient.

[0004] Typically, a PFS comprises a barrel having an open end and a tip having an orifice substantially opposite this open end, a rubber stopper, a plunger, and a needle or needle adapter on the orifice of the barrel. For example, a special ophthalmic PFS is described in WO2014 / 005728A1.

[0005] Compared to conventional drug preparation, PFS may be beneficial for use or administration, but generally, preparing the active pharmaceutical ingredient (API) in a PFS is more difficult than preparing the API in other containers such as vials. For example, preparing the API in a PFS may involve the following steps:

[0006] (i) Assemble the needle or needle adapter on the tip of the barrel so that a rubber element tightly seals the orifice at the tip of the barrel in order to prevent loss of the active pharmaceutical ingredient and maintain sterility.

[0007] (ii) Sterilize the syringe barrel and needle or needle adapter assembly. This exposes the assembly to a sterilizing agent under clearly defined conditions, such as concentration, temperature, duration, relative humidity, and / or pressure, allowing for complete sterilization of the assembly, even between the rubber elements and the tip of the syringe barrel. Ethylene oxide (EO) is frequently used as the sterilizing agent.

[0008] (iii) Following this first sterilization, the sterile active pharmaceutical ingredient (API) is aseptically filled into the barrel through the opening of the barrel. Such aseptic filling is generally carried out in a cleanroom to maintain sterility. Cleanrooms are often classified by standards defined, for example, as “manufacturing of sterile pharmaceuticals by aseptic techniques” or “manufacturing of sterile pharmaceuticals” by the Good Manufacturing Practice (GMP) standards for the manufacture and quality control of active pharmaceutical ingredients (APIs) issued by the International Conference on Harmonisation of Regulations (USA-EU). For many parenteral APIs, such as ophthalmic APIs for intravitreal injection, the cleanroom must comply with the provisions for Class A of the GMP standard.

[0009] (iv) After the active pharmaceutical ingredient has been aseptically filled, the inside of the syringe barrel is sealed by placing a sterile stopper through the open end of the barrel. This step is generally also performed aseptically in a cleanroom.

[0010] (v) The sealed assembly is then typically moved out of the cleanroom and assembled with the plunger. The plunger is then often advanced through the open end of the barrel and may or may not be coupled to a stopper. If coupled, the stopper may be equipped with a cavity into which the plunger is fitted or screwed. In the same step, the sealed assembly may also include further elements such as an extended finger flange.

[0011] (vi) In particular, in ophthalmic applications, the outer surface of the PFS is sterilized using gas chemical sterilization after it has been prepared and finally packaged. Therefore, it may be important to prevent the sterilizer from entering the sealed interior of the syringe barrel in order to prevent the drug inside the barrel from being affected. In particular, the entry of the sterilizer should be below the limits provided by the health authorities or the International Organization for Standardization (ISO), or should not impair the quality of the drug until the end of its shelf life. For example, when EO is used as a sterilizer, the European Medicines Agency (EMEA) specifies limits of 1 μg / mL EO and 50 μg / mL ethylene chloride (ECH) in its EMEA / CVMP / 271 / 01 guidance. Alternatively, ISO 10993-7 specifies limits of 0.5 μg EO / IOL / 24 hours and 1.25 μg EO / IOL, which is interpreted as 0.5 μg EO / eye / 24 hours and 1.25 μg EO / eye, as well as 2.0 μg ECH / IOL / 24 hours and 5.0 μg EO / IOL, which is interpreted as 2.0 μg EO / eye / 24 hours and 5.0 μg EO / eye.

[0012] A problem that arises in such external sterilization of PFS is that the sterilizing agent may not be able to adequately reach all parts and sections of the PFS other than the active pharmaceutical ingredient inside the barrel. In particular, accessing the spaces and areas within the plunger region when coupled to a stopper is generally difficult. This can lead to at least partially unsatisfactory sterilization of the ends or outer surfaces of the PFS.

[0013] Another problem in the external sterilization of PFS can be induced by the conditions applied during the sterilization process. Generally, during sterilization, pressure is changed, often by decreasing it, as well as other physical parameters such as temperature and humidity. Such changing conditions, especially changing pressure, can cause the plunger to move to some extent along with the stopper, as gases that may be present inside the PFS can change volume when the external pressure changes during sterilization. Such movement carries the risk of breaking the sterility inside the barrel, and thus can result in contamination of the active pharmaceutical ingredient inside the barrel of the PFS. [Overview of the project]

[0014] Therefore, a system or pre-filled syringe is needed that allows for efficient and safe external sterilization of the surface.

[0015] According to the present invention, this need is solved by a pre-filled syringe as defined by the features of independent claim 1, by a pre-filled syringe as defined by the features of independent claim 18, by a pre-filled syringe as defined by the features of independent claim 29, and by a method as defined by the features of independent claim 37. Preferred embodiments are the subject of the dependent claims.

[0016] In a first aspect, the present invention is a pre-filled syringe (PFS) comprising: (i) a barrel having a hollow interior, an orifice, and an opening opposite the orifice; (ii) a stopper positioned within the hollow interior of the barrel, thereby defining a sealed chamber within the barrel, the stopper being displaceable within the barrel, thereby changing the volume of the chamber; (iii) liquid in the chamber of the barrel; and (iv) a plunger extending through the opening of the barrel. The stopper discharges the liquid from the barrel through the orifice when it is moved toward the orifice by the plunger so as to reduce the volume of the chamber. The plunger comprises a proximal portion, a distal portion, and a rod portion extending between the proximal and distal portions. The plunger is shaped such that a path is formed between the opening of the barrel and the segment adjacent to the stopper, so that a sterilizing agent can be supplied through the opening of the barrel to the segment adjacent to the stopper, with the proximal portion of the plunger being adjacent to the stopper.

[0017] Preferably, the stopper has a cavity, and the plunger is coupled to the stopper such that the proximal portion of the plunger is provided into the cavity of the stopper so that the stopper fits onto the proximal portion of the plunger. Thereafter, the segment adjacent to the stopper by the proximal portion of the plunger preferably comprises the proximal portion of the plunger provided into the cavity of the stopper, and the pathway preferably extends between the opening of the barrel and the cavity of the stopper so that a sterilizer can be supplied into the cavity of the stopper through the opening of the barrel.

[0018] In relation to the coupling of a stopper and a plunger, the term “fitted” may refer to a tight fit or any other engaging connection such as clamping or screwing.

[0019] The barrel of the PFS may have a main portion that is substantially cylindrical. In particular, this main portion may have the shape of a hollow right-circular column. The barrel can be fabricated from any suitable material, suitable rigid plastic material or sterilizable inert material, such as glass in particular, for most pharmaceutical applications. The opening of the barrel may be an opening that extends to the full diameter inside the barrel. An orifice can be implemented in the tip, formed within the end of the barrel opposite the opening. Specifically, the orifice may be a channel in the tip having a diameter reduced compared to the diameter inside the barrel. The orifice may be sized to allow the liquid to be discharged when the volume of the chamber inside the barrel is reduced by advancing a stopper via a plunger.

[0020] In the context of this invention, the term “proximal” is used to refer to the portion, end, or component of the PFS that is closest to the drug or drug delivery site when the PFS is in use, or the direction directed toward the drug delivery site. Thus, the proximal direction can be the direction toward the body or human to which the PFS is intended to be applied. For example, in an embodiment of a pre-filled syringe having a needle intended to pierce a body or human and a plunger pushed to deliver a drug through this needle, the proximal end of the PFS is established by the tip of the needle. The proximal direction can be the direction toward the end of the needle or the location of the patient's skin that the needle penetrates upon delivery of the drug or active pharmaceutical ingredient to the patient.

[0021] Conversely, the term “distal” is used to refer to the part, end, or component that is furthest from the drug delivery site when the safety configuration is in use, or the direction facing away from the drug delivery site. Therefore, the distal direction can be the direction facing away from the body or person to which the prefilled syringe is applied. For example, in use, the distal end of the prefilled syringe may be the end of the plunger on which the operator’s thumb rests to advance the plunger in order to deliver the drug.

[0022] As used herein, the term “drug” refers to therapeutically effective substances, also commonly known as the active ingredient (API) of a pharmaceutical product, as well as combinations of multiple such therapeutically effective substances. The term also encompasses diagnostic or imaging agents, such as contrast agents (e.g., MRI contrast agents), tracers (e.g., PET tracers), and hormones, which are required to be administered to the patient in liquid form.

[0023] As used herein, the term “API” refers to the drug as defined above, formulated or reduced in a form suitable for administration to a patient. For example, the API may additionally contain excipients and / or other auxiliary components in addition to the drug. Particularly preferred APIs in the context of the present invention are drug solutions, in particular breast (dug) solutions for injection.

[0024] Generally, the liquid inside the chamber of a syringe barrel is the active pharmaceutical ingredient (API). In a double-chamber PFS, one chamber may contain the API, which must be reduced for drug administration by a diluent contained in the second chamber. Alternatively, the first and second chambers may contain two different APIs that must be mixed before drug administration. Specifically, the syringe may contain a specific dose of the API that will be administered when injected.

[0025] As used herein, the term “drug product” refers to a finished product comprising one or more active pharmaceutical ingredients (APIs). Specifically, a drug product may be a ready-to-use product having an API in an appropriate dosage and / or form suitable for administration. For example, a drug product may include an administration device such as a PFS.

[0026] As used herein, the term "sterilant" relates to any liquid, gaseous, or vaporized substance that can externally sterilize the PFS surface or is capable of being externally sterilized. For example, the sterilant can be or can include ethylene oxide (EO), hydrogen peroxide (H2O2), steam, vaporized hydrogen peroxide (VHP), vaporized peracetic acid (VPA), or nitrogen dioxide.

[0027] Thereby, the term "sterilize" relates to bringing a structure or element such as a PFS to a sterile state. As used herein, the term "sterilization" relates to the maximum contamination rate that enables a PFS or another element to be used in the intended application. For example, this term can relate to the state of a PFS that complies with the requirements and guidelines described in the standard ST67 of the American National Standards Institute (ANSI) and the Association for the Advancement of Medical Instrumentation (AAMI) of the United States, namely ANSI / AAMI ST67. More specifically, a sterility assurance level (SAL) value of 10 -6 is available for use in labeling a product as being sterilized as specified by ANSI / AAMI ST67.

[0028] Therefore, a sterile situation can be achieved by a sterilant or sterilization. In particular, sterilization can relate to a validated process used to make a product substantially free of live bacteria. In such a sterilization process, the increase in microbial death can be explained by an exponential function. Therefore, the number of surviving microorganisms in the sterilization process can be expressed from a probabilistic perspective.

[0029] ]The stopper or stopper combination may be made from an inert, elastically deformable material such as rubber or silicone. Specifically, the stopper or stopper combination can be used to seal a chamber inside a barrel containing a fluid or a solid and a fluid. Furthermore, the stopper or stopper combination may have a surface oriented toward the liquid in the chamber and a surface oriented toward the distal surface. The outer circumference of the stopper may correspond to the inner circumference of the barrel when fitted. The cavity or recess of the stopper may be centrally positioned to receive the proximal portion of the plunger in a concentrated manner.

[0030] The PFS may have a central axis along which the barrel, stopper, and plunger extend. Some of its components, such as the PFS or the barrel, may be rotationally symmetric with respect to the central axis.

[0031] By designing the plunger to form a pathway between the barrel opening and the segment adjacent to the stopper where the proximal portion of the plunger is located, or, in some cases, between the barrel opening and the stopper cavity, more complete external sterilization of the PFS, particularly within it, can be achieved. Specifically, such design allows the sterilizing agent to move through the barrel opening to the segment adjacent to the stopper where the proximal portion of the plunger is located, and further to the stopper cavity, if present, so that the portion between the stopper and the plunger can also be efficiently sterilized. In this way, efficient and safe external sterilization of the PFS can be provided.

[0032] Preferably, the plunger includes a stopper contact section between the proximal portion and the rod portion, and this stopper contact section is equipped with at least one opening. Such a stopper contact section allows for proper force transmission from the plunger to the stopper. For example, such transmission may be intended to be approximately uniform in order to prevent differential deformation of the stopper when advancing the stopper to discharge liquid. By providing an opening in the stopper contact section, on the one hand, equally uniform force transmission is achieved, and on the other hand, the area or zone between the stopper and the plunger, as well as the cavity of the stopper, can be made reachable by a sterilizing agent. This makes it possible to ensure efficient and safe external surface sterilization.

[0033] Thereafter, at least one opening in the plunger's stopper contact section preferably comprises a bore. Such a bore can be efficiently implemented and allows for the central supply of a sterilizer to or near the zone in which the stopper contacts the plunger. The bore of at least one opening in the plunger's stopper contact section preferably lies adjacent to the stopper's cavity. In this way, the sterilizer can be efficiently advanced into or into the cavity, which allows for equally complete external surface sterilization.

[0034] Alternatively or additionally, at least one opening in the stopper contact section of the plunger preferably comprises a periphery recess. Such a recess allows for the supply of sterilizing agent to the periphery behind the stopper contact section, particularly in the zone between the plunger and the stopper.

[0035] Preferably, the stopper contact section of the plunger has a circumference that substantially engages with the inside of the barrel. In this way, the plunger can be safely guided when moving axially, so that safe axial movement is achievable. It also allows the plunger to uniformly transmit force to the stopper when it is moving forward. Preferably, the stopper contact section of the plunger is substantially disc-shaped.

[0036] Specifically, the stopper contact section of the plunger preferably contacts the distal end of the stopper. Thereafter, the stopper contact section of the plunger preferably has a projection that contacts the stopper. Such a projection allows for uniform force transmission from the plunger to the stopper, while simultaneously reducing the effective contact area that is difficult to sterilize. Thus, effective and equally complete sterilization is achievable while still allowing proper and accurate dispensing. For the same purpose, the stopper preferably has a ridge, annular rib, or radial rib that contacts the stopper contact section of the plunger.

[0037] Preferably, the proximal portion of the plunger has a stem that terminates proximally within a snap-fit ​​section projecting radially from the stem. The stem and snap-fit ​​section may have a substantially T-shaped or arrow-shaped axial cross-section. Using such a proximal portion, the plunger can be efficiently coupled to a stopper. Specifically, the plunger can be coupled to a stopper by advancing the snap-fit ​​section into the stopper cavity until it is tightly fitted. Thereafter, the snap-fit ​​section of the proximal portion of the plunger is preferably tapered in the proximal direction. Such a tapered snap-fit ​​section allows for efficient introduction of the proximal portion into the stopper cavity.

[0038] Preferably, the rod portion of the plunger is provided with substantially axial recesses. Such recesses, or in particular multiple such recesses, can enable an efficient implementation configuration of the sterilizer pathway. Thereafter, at least one opening in the stopper contact section and the axial recesses of the rod portion are preferably fluidly connected. The recesses and openings thus connected can efficiently provide a suitable pathway that allows the sterilizer to move to the stopper, and possibly, within it as needed.

[0039] The axial recesses in the rod portion are preferably formed by the rod portion having a substantially cruciate cross-section. The legs of the cruciate cross-section can have the same dimensions. Thus, the plunger can be equipped with four recesses, each of which is part of the path.

[0040] In a second aspect, the present invention is a PFS comprising (i) a barrel having a hollow interior, an orifice, and an opening opposite the orifice; (ii) a stopper positioned within the hollow interior of the barrel, thereby defining a sealed chamber within the barrel, the stopper being displaceable within the barrel, thereby changing the volume of the chamber; (iii) a liquid in the chamber of the barrel; and (iv) a plunger extending through the opening of the barrel. The stopper discharges the liquid from the barrel through the orifice when it is moved toward the orifice by the plunger so as to reduce the volume of the chamber. The plunger comprises a proximal portion, a distal portion, and a rod portion extending along an axis between the proximal and distal portions. The barrel is equipped with a backstop structure. The rod portion of the plunger has a rigid axial section and a set of flexible arms protruding from this axial section. The arms of the set of flexible arms bend when positioned within the interior of the barrel. Each arm of the flexible arm set terminates at a different position relative to the axis of the plunger. The backstop structure is positioned to abut against the ends of the arms of the flexible arm set, or at least one of them, to prevent the plunger from moving along its axis distally.

[0041] As used herein, the term “position of the plunger relative to the axis” is also called the axial position. This allows the axis of the plunger to be identical to the central axis of the PFS.

[0042] Stepwise blocking of the plunger's backward or distal movement can be achieved by each arm of a set of flexible arms ending at different axial positions. In this way, blocking can be precisely performed in equally small steps or axial backward movements. In other words, the tolerance for blocking the plunger's backward or distal movement can be kept equally small.

[0043] The term “arm” as used in relation to the PFS of a second aspect of the present invention relates to an elongated structure formed within the rod portion of the plunger. In a non-inclined position, the arm can be substantially straight and rod-shaped or rib-shaped. The arm can have a certain degree of flexibility, i.e., elasticity or stretchability, so that it can deflect, bend, or curve toward the axial section when positioned within the barrel. The arm extends from the central axial section in a direction different from the axis of the PFS or the axis of the plunger. Thereafter, the angle between the longitudinal extension of the arm and the central axis of the PFS can be between about 10° and about 50°, between about 15° and about 45°, between about 20° and about 35°, or between about 25° and about 30°, or the angle can be about 27°.

[0044] By bending the arm and thereby pre-tensioning it, it is possible to ensure that the arm efficiently contacts and interacts with the backstop structure. Compared to known backstop structures, for example, those with teeth, the arm allows for improved reliability and strength of the backstop mechanism. Thus, backward or distal movement of the plunger can be efficiently prevented. In this way, the PFS of the second aspect of the present invention can be efficiently and safely externally sterilized. In particular, the arrangement of the arm and backstop structure can efficiently prevent excessive movement of the stopper when the air pressure is reduced during external sterilization. Such prevention can be especially important in PFS of similarly small volume, such as in ophthalmic syringes. Excessive movement can move the stopper within an area that has not yet been sufficiently sterilized, increasing the risk of damaging the inside of the barrel, and thus potentially resulting in contamination of the active pharmaceutical ingredient inside the barrel of the PFS.

[0045] Preferably, the set of flexible arms comprises a first group of at least one arm extending radially from the axial section in a first direction, and a second group of at least one arm extending radially from the axial section in a second direction different from the first direction. Such arrangement of different groups of arms makes it possible to provide equally long arms that end up with equally small axial distances from each other. Thus, beneficial resilience and, thereby, the safe prevention of backward or distal movement is achievable while allowing and taking into account variations in the stopper and plunger positions. The first direction is preferably opposite to the second direction.

[0046] Furthermore, the set of flexible arms preferably comprises a third group of at least one arm extending radially from the axial section in a third direction substantially perpendicular to the first direction, and a fourth group of at least one arm extending radially from the axial section in a fourth direction opposite to the third direction. Such groups of arms circumferentially distributed around the axis of the plunger allow for the provision of robust and fine, stepped obstruction of backward or distal movement. A circumferential array of several groups of arms may have the additional benefit that the plunger can be assembled into the syringe barrel without the need to orient the plunger around its central axis.

[0047] Preferably, the stopper of a PFS according to a second aspect of the present invention has a plurality of axially spaced sealing sections that are tightly connected to the barrel or pressed against the inner wall of the barrel, wherein the minimum distance between the ends of the arms of a set of flexible arms along the axis of the plunger is less than the axial distance between two adjacent sealing sections of the stopper, which is essential for maintaining the sterility of the liquid in the chamber of the barrel. The sealing sections of the stopper can be circumferential ribs or rings. For example, when the barrel of the PFS has a nominal filling volume of 1.0 ml or less, the stopper can be equipped with three ribs that can be spaced about 1.5 mm apart. Such a stopper having a plurality of sealing sections can define a sterile zone in which a specified axial distance between adjacent arm ends is smaller than the sterile zone in which the risk of loss of sterility of the syringe contents, e.g., liquid, can be reduced. The number and position of the sealing sections may be selected taking into account the total friction induced by the total number of these sections limiting the maximum distance that the stopper can potentially move.

[0048] Advantageously, the friction between the stopper and the inner wall of the syringe barrel should be low to minimize the force required by the user to expel the syringe contents. To reduce friction, the inside of the stopper and / or syringe barrel may be treated with a low-friction coating such as silicone oil and polytetrafluoroethylene (PTFE).

[0049] Preferably, the backstop structure is integrated with the barrel or pre-assembled onto the barrel. Thereafter, the backstop structure preferably includes a projection extending toward the plunger, for example, radially. Such a projection can efficiently interact with the arm. Such a projection may be formed as one or more teeth or keys in a keyway and may extend beyond the full internal circumference of the barrel. In this way, an efficient backstop mechanism can be implemented.

[0050] Alternatively or additionally, a PFS of a second aspect of the present invention preferably comprises a backstop element having a backstop structure, the backstop element being attached to the distal end of the barrel. Thereafter, the backstop structure of the backstop element preferably has a projection extending toward the plunger, for example, radially. Herein, such projection can efficiently interact with the arm. Such projection may be formed as one or more teeth or keys in a keyway and may extend beyond the full internal circumference of the barrel. Thus, an efficient backstop mechanism can be implemented that can be removed before drug product administration as needed.

[0051] The backstop element is preferably an elongated finger flange. The barrel preferably has a flange section at its opening, and the backstop element is preferably attached to the flange section of the barrel. In this way, the backstop element can be efficiently implemented or attached, and convenient handling of the PFS can be achieved.

[0052] In a third aspect, the present invention is a pre-filled syringe comprising (i) a barrel having a hollow interior, an orifice, and an opening opposite the orifice; (ii) a stopper positioned within the hollow interior of the barrel, thereby defining a sealed chamber within the barrel, the stopper being displaceable within the barrel, thereby changing the volume of the chamber; (iii) a liquid in the chamber of the barrel; and (iv) a plunger extending through the opening of the barrel. The stopper discharges the liquid from the barrel through the orifice when it is moved toward the orifice by the plunger so as to reduce the volume of the chamber. The plunger comprises a proximal portion, a distal portion, and a rod portion extending along an axis between the proximal and distal portions. The barrel is equipped with a backstop structure. The rod portion of the plunger has a rigid axial section and a set of flexible arms protruding from the axial section. The arms of the flexible arm set bend when positioned inside the barrel, and each arm of the flexible arm set terminates at a different position relative to the axis of the plunger, and the backstop structure is positioned to abut against the ends of the arms of the flexible arm set to prevent the plunger from moving distally along its axis. The plunger is shaped such that the barrel opening and the segment adjacent to the stopper form a path between the barrel opening and the segment adjacent to the stopper, so that the sterilizing agent can be supplied through the barrel opening to the segment adjacent to the stopper where the proximal portion of the plunger is located.

[0053] Accordingly, a third aspect of the PFS of the present invention combines the sterilizer access feature of the PFS of the first aspect of the present invention with the plunger backstop mechanism of the PFS of the second aspect of the present invention. Such a combination provides particularly advantageous external surface sterilization of the PFS, where equivalent complete sterilization is achieved, and prevents potential loss of sterility due to excessive movement of the stopper.

[0054] The PFS of the third aspect of the present invention can be combined with any additional features mentioned above in relation to the PFS of the first aspect and the PFS of the second aspect of the present invention. In this way, additional effects and benefits related to the preferred embodiments described above can be achieved.

[0055] The following preferred features can be implemented in any of the first, second, and third embodiments of the PFS of the present invention.

[0056] The distal portion of the plunger preferably includes an extended finger rest surface. Such a surface or finger pad at the rear end of the plunger allows for the convenient application of appropriate manual force to the plunger to advance the stopper and drain the liquid from the barrel orifice.

[0057] The barrel preferably has a nominal filling volume of about 2.25 milliliters (ml) or less, about 1.0 ml or less, or about 0.5 ml or less. In syringes of such equally small volumes, the effects achieved by the features of the present invention may be particularly advantageous.

[0058] The liquid preferably contains an active pharmaceutical ingredient. Specifically, the active pharmaceutical ingredient may be for ophthalmic applications, i.e., it may be an ophthalmic active pharmaceutical ingredient.

[0059] Preferably, the barrel is made from glass or a thermoplastic polymer such as cycloolefin copolymer (COC) or cycloolefin polymer (COP). Barrels made from such materials can guarantee the desired robustness, inertness, and low gas permeability. Therefore, the barrel may be preferable for many pharmaceutical or drug products, as it allows for convenient handling and long-term storage.

[0060] The plunger is preferably made from a thermoplastic polymer such as polypropylene. Such plungers can be efficiently manufactured, for example, by injection molding, and can provide suitable properties.

[0061] The stopper is preferably made from natural rubber material, synthetic rubber such as thermoplastic elastomer, or silicone.

[0062] The orifice of the syringe barrel is preferably equipped with a needle adapter. Such an adapter allows for the attachment of a suitable needle immediately before administration of PFS. In this way, handling of PFS can be equally convenient.

[0063] This allows a seal, for example made from rubber or the same material as the stopper, to be provided between the needle adapter and the barrel orifice. In this way, the orifice can be efficiently sealed, and contamination of the liquid through the orifice can be prevented.

[0064] In a fourth aspect, the present invention relates to a method for sterilizing a prefilled syringe. This method includes (i) obtaining any of the PFS described above, supplying a sterilizing agent to the prefilled syringe at a predetermined temperature and pressure, and supplying a cleaning agent to the prefilled syringe. The cleaning agent may be, for example, pure water, which allows for the removal of any residue of the sterilizing agent.

[0065] The method according to the present invention, along with different embodiments of PFS, enables the efficient achievement of the effects and benefits described above.

[0066] The pre-filled syringe (PFS) and the method according to the present invention will be described in more detail below with reference to the accompanying drawings, by exemplary embodiments. [Brief explanation of the drawing]

[0067] [Figure 1] This is a perspective view of one embodiment of the PFS according to the present invention. [Figure 2] Figure 1 is a perspective rear view of the plunger of the PFS. [Figure 3]Figure 1 is a perspective front view of the plunger of the PFS. [Figure 4] Figure 1 is a perspective view of the PFS stopper. [Figure 5] This is a cross-sectional view of a portion of the PFS shown in Figure 1, where the stopper is connected to the plunger. [Figure 6] Figure 1 is a bottom view of the stretched finger flange of the PFS. [Figure 7] Figure 1 is a side view of a portion of the PFS. [Figure 8] Figure 1 is a perspective view of a portion of the plunger and stopper of the PFS. [Modes for carrying out the invention]

[0068] In the following description, several terms are used for convenience but are not intended to limit the invention. The terms “right,” “left,” “up,” “down,” “below,” and “up” refer to directions in the figures. Terminology includes terms explicitly mentioned, as well as derivatives of these terms and terms with similar meanings. Additionally, spatially relative terms such as “beneath,” “below,” “lower part,” “above,” “upper part,” “proximal,” and “distal” may be used to describe the relationship of one element or feature shown in the figures to another element or feature. These spatially relative terms are intended to encompass different locations and orientations of the device in use or operation, in addition to the locations and orientations shown in the figures. For example, if the device in the figure were upside down, an element described as being “below” or “beneath” another element or feature would be “above” or “over” that other element or feature. Therefore, the exemplary term “below” can encompass both the “above” and “below” positions and orientations. The device may be oriented in other ways (rotated by 90 degrees or other orientations), and the spatially relative descriptors used herein shall be interpreted accordingly. Similarly, descriptions of movement along and around various axes include various specific device positions and orientations.

[0069] To avoid repetition of figures and descriptions in various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. The omission of an aspect from the description or figures does not imply that the aspect is absent from the embodiments that incorporate that aspect. Instead, aspects may be omitted for clarity and to avoid redundant descriptions. In this context, the following applies to the remainder of this specification: To clarify a figure, if a figure contains reference numerals not described in the directly associated part of the description, that figure is referred to a previous or subsequent description section. Furthermore, for reasons of obviousness, if not all features of a part in a figure are represented by reference numerals, that figure is referred to another drawing showing the same part. The same number in two or more figures represents the same or similar elements.

[0070] Figure 1 shows an embodiment of a pre-filled syringe (PFS) 1 according to a first, second, and third aspect of the present invention. The PFS 1 comprises a glass barrel 2 extending along a longitudinal axis 7 and having a hollow interior, a left-side or proximal orifice, and a right-side or distal opening. A stopper 4 is pushed through the opening of the barrel 2 so as to be positioned inside the barrel 2. The stopper 4 defines a sealed chamber 21 inside the barrel 2, which is formed between the proximal surface 44 of the stopper 4 and the orifice of the barrel 2. The stopper 4 is displaceable inside the barrel 2, thereby changing the volume of the chamber 21. The chamber 21 is filled with a liquid active pharmaceutical ingredient. As the stopper 4 is moved toward the orifice of the barrel 2, the volume of the chamber 21 is reduced, and from a certain point, the stopper 4 begins to discharge the drug from the orifice.

[0071] The stopper 4 is coupled to a plunger 3 that extends distally from the stopper 4 through an opening in the barrel 2. Around the distal end of the barrel 2 where the barrel opening is located, a finger flange 5 is mounted as a backstop element. The orifice of the barrel 2 is connected to a needle adapter 6. The needle adapter 6 has a coupling piece 62 that is formed as the male component of a so-called Luer lock connection system. The coupling piece 62 is covered by a cap 61 of the needle adapter 6.

[0072] As can be seen in Figure 2, the plunger 3 comprises a proximal portion 31, a distal portion 33, and a rod portion 32 extending between the proximal portion 31 and the distal portion 33. A stopper contact section 34 is positioned between the rod portion 32 and the proximal portion 31, connected to the rod portion 32 via a transition section 35.

[0073] The distal portion 33 of the plunger 3 forms an elongated finger rest surface 331 shaped to receive the fingers of the operator applying the PFS 1. The rod portion 32 of the plunger 3 comprises a rigid axial section 325 that extends entirely along the rod portion 32 and a pair of flexible arms 321 that protrude from this axial section 325.

[0074] The set of arms 321 includes a first group of arms 3211 extending from the axial section 325 in a first radial direction 3216, a second group of arms 3212 extending from the axial section 325 in a second radial direction 3217 opposite to the first direction 3216, a third group of arms 3213 extending from the axial section 325 in a third radial direction 3218 perpendicular to the first direction 3216, and a fourth group of arms extending from the axial section 325 in a fourth direction opposite to the third direction 3218. Each of the first to fourth groups of arms 3211, 3212, and 3213 has two axially spaced arms 321.

[0075] Each arm 321 has an elongated rib portion 3215 with an open end 3214 substantially facing the distal direction 72. Furthermore, the ends 3214 of all arms 321 are axially displaced relative to one another such that all ends 3214 are positioned at different axial positions on the rod portion 32 or at different positions relative to the axis 7 of the PFS1 or plunger 3.

[0076] The rod portion 32 further has longitudinal ribs 323 extending from the arm 321 in proximal and distal directions 72. Specifically, each longitudinal rib 323 is collinear with one of the arm groups 3211, 3212, 3213, and thus the longitudinal ribs 323 are in a first direction 3216, a second direction 3217, a third direction 3218, or a fourth direction from the axial section 325. Each pair of circumferentially adjacent longitudinal ribs 323 form a 90° angle, forming a longitudinal recess 324, and thus four recesses 324 are arranged around the rod portion 32 of the plunger 3. In cross-section, the four longitudinal ribs 323, together with the axial section 325, form a cross.

[0077] The stopper contact section 34 has a disc 342 that matches the inner circumference of the barrel 2. The disc 342 is connected to the rod portion 32 by two opposing side walls 352 of the transition section 35. Between the side walls 352, the transition section forms a stirrup-shaped opening 351.

[0078] The proximal portion 31 of the plunger 3 has an axial stem 311 that terminates proximal to the arrow head 312 as a snap-type section. Both the stem 311 and the arrow head 312 have an arrow shape. In the proximal direction 71, the arrow head 312 is tapered to form a tip.

[0079] Figure 3 shows the plunger 3 from the front or proximal end. There, the disc 342 of the stopper contact section 34 is seen to have two bores 341, which serve as openings connecting the proximal portion 31 to the stirrup-shaped opening 351 of the transition section 35. Furthermore, the disc 342 is equipped with four projections 343 extending in the proximal direction 71. More specifically, the four projections 343 are arranged as four legs of a cross, two of which are blocked by the bores 341.

[0080] Figure 4 shows the stopper 4 in more detail. The stopper 4 is made of rubber or a rubber-like material and has a substantially cylindrical shape that fits inside the barrel 2. Inside, the stopper 4 has a cavity 41 that opens toward the distal surface 42 of the stopper 4. The distal surface 42 is equipped with a semi-toroidal rib 421 or ridge extending distally 72. The circumference 43 of the plunger 4 is provided with three ring-shaped sealing sections 431 having an outer diameter larger than the rest of the circumference 43. The sealing sections 431 are separated from each other by an axial sealing distance d 431 They are separated only in the axial direction.

[0081] As best illustrated in Figure 5, the stopper 4 is coupled to the plunger 3 by advancing its proximal portion 31 into the cavity 41. The cavity 41 is molded to correspond to the proximal portion 31, and thus these two elements provide a tight fit. In this way, the stopper 4 is fixed to the plunger 3.

[0082] The sealed section 431 of the stopper 4 is pressed against the barrel 2 from the inside, and thus they are slightly compressed. This establishes a liquid-tight and a degree of airtight connection, which allows the active pharmaceutical ingredient to be fixed in the chamber 21 of the barrel 2.

[0083] Figure 6 shows a finger flange 5 extending from its proximal side 51, which has a substantially oval basic shape. From top to bottom, a recess 52 is provided in the finger flange 5. The recess 52 has a proximal barrel clip outer shape 521 and a distal rod guide outer shape 522. The barrel clip outer shape 521 is molded to correspond to the outer circumference of the barrel 2. Specifically, the barrel clip outer shape 521 has a portion molded as a circular section that is engageable around the barrel 2. Thereafter, the finger flange 5 can be retained on the barrel 2 such that its opening is positioned between the barrel clip outer shape 521 and the rod guide outer shape 522.

[0084] The rod guide outer shape 522 of the recess 52 is formed to fit the shape of the rod portion 32 of the plunger 3. Specifically, when the finger flange 5 is secured on the barrel 2, the rod portion 32 extends through the rod guide outer shape 522 and is held in place so as to prevent the plunger 3 from rotating around the shaft 7.

[0085] A contacting projection 53 is positioned between the rod guide outer diameter 522 and the barrel clip outer diameter 521 as a backstop structure. The contacting projection 53 has the shape of a ring section and is sized to contact the end 3214 of the arm 321 to prevent the plunger 3 from moving along its axis 7 in the distal direction 72.

[0086] Figure 7 shows a portion of the PFS1 in more detail. The arms 321 of the rod portion 32 of the plunger 3 are positioned inside the barrel 2. Thereafter, when positioned inside the barrel 2, the arms 321 bend, i.e., bend toward the axial section 325. In this way, the arms 321 are pretensioned. Each arm 321 ends at a different position relative to the axis 7. More specifically, first, the ends 3214 of the distal arms 321 of each group of arms 3211, 3212, 3213 are separated axially in stages, and then the ends 3214 of the proximal arms 321 of each group of arms 3211, 3212, 3213 are separated axially in stages. Thus, each end 3214 of the eight arms is positioned at a different position along the axis 7 so that eight axial steps are provided. The minimum distance between two ends 3214 of an arm 321 along the axis 7 is the sealing distance d 431 It is smaller than that.

[0087] The protruding portion 53 of the finger flange 5 contacts one of the ends 3214 of the arm 321, preventing the plunger 3 from moving distally 72. The minimum distance between the two ends 3214 of the arm 321 along axis 7 is the sealing distance d. 431 Because it is smaller than that, the maximum movement of the plunger is also smaller than the sealed distance d 431 It is smaller. In this way, it is possible to ensure that contaminants cannot reach behind the stopper 4 so that the active pharmaceutical ingredient inside the chamber 21 is protected.

[0088] Referring to Figure 8, it can be seen that the axial recess 324 of the rod portion 32 forms a path 8 from the recess through the stirrup-shaped opening 351 of the transition section 35 and the bore 343 of the stopper contact section 34 toward the cavity 41 of the stopper 4. This allows for the supply of sterilizer from the opening of the barrel 2 to the cavity 41, so that equivalently complete external surface sterilization of the PFS1 can be achieved.

[0089] This specification and accompanying drawings illustrating aspects and embodiments of the present invention should not be considered to limit the claims defining the protected invention. In other words, although the present invention has been illustrated in detail in the drawings and described in detail above, such illustrations and descriptions should be considered illustrative or exemplary and not restrictive. Various mechanical, compositional, structural, electrical, and operational modifications may be made without departing from the spirit and scope of this specification and the claims. In some examples, well-known structures and techniques are not shown in detail so as not to obscure the present invention. It will be understood that changes and modifications may be made by those skilled in the art within the following claims and spirit. Specifically, the present invention encompasses further embodiments having any combination of features from the different embodiments described above and below.

[0090] This disclosure also encompasses all further features shown individually in the figures, which are not described in the prior or subsequent descriptions. Furthermore, any single alternative form of the embodiments described in the figures and descriptions, and any single alternative form of their features, are negligible from the subject matter of the invention or the disclosure. This disclosure includes subject matter consisting of features defined in the claims or exemplary embodiments, and subject matter containing such features.

[0091] Furthermore, in the claims, the words “comprising” do not exclude other elements or steps, and the indefinite articles “a” or “an” do not exclude plurals. A single unit or step may perform the function of several features described in the claims. The mere fact that several strategies are described in mutually different dependent claims does not mean that combinations of these strategies cannot be used advantageously. Terms such as “substantially,” “about,” and “nearly” related to attributes or values ​​also define, in particular, the attribute or the value precisely, respectively. In the context of a given mathematical value or range, the term “about” refers to a value or range that is, for example, within 20%, 10%, 5%, or 2% of a given value or range. Components described as being joined or connected may be joined directly electrically or mechanically, or indirectly through one or more intermediate components. No reference numeral in the claims should be construed as limiting the range.

Claims

1. A barrel (2) having a hollow interior, an orifice, and an opening on the opposite side of the orifice, A stopper (4) is disposed within the hollow interior of the barrel (2), thereby defining a sealed chamber (21) within the barrel (2), and is displaceable within the barrel (2), thereby changing the volume of the chamber (21). The liquid in the chamber (21) of the barrel (2) and A plunger (3) extending through the opening of the barrel (2) and Equipped with, The stopper (4) is moved toward the orifice by the plunger (3) so as to reduce the volume of the chamber (21), and discharges the liquid from the barrel (2) through the orifice. The plunger (3) comprises a proximal portion (31), a distal portion (33), and a rod portion (32) extending between the proximal portion (31) and the distal portion (33). The plunger (3) is shaped such that a path (8) is formed between the opening of the barrel (2) and the segment adjacent to the stopper (4) by the proximal portion (31) of the plunger (3). The stopper (4) has a cavity (41), The plunger (3) includes a stopper contact section (34) between the proximal portion (31) and the rod portion (32), In order to reduce the effective contact area between the plunger (3) and the stopper (4), the stopper contact section (34) of the plunger (3) has a projection (343) that contacts the stopper (4), and / or the stopper (4) has a ridge (421) that contacts the stopper contact section (34) of the plunger (3), The stopper contact section (34) comprises at least one opening (341) configured to supply the sterilizer to the zone between the stopper (4) and the plunger (3) and to the cavity (41) of the stopper (4). Pre-filled syringe (1).

2. The prefilled syringe (1) according to claim 1, wherein the plunger (3) is coupled to the stopper (4) such that the stopper (4) is fitted onto the proximal portion (31) of the plunger (3) by the proximal portion (31) of the stopper (4) being provided within the cavity (41) of the stopper (4).

3. The pre-filled syringe (1) according to claim 1, wherein the segment in which the proximal portion (31) of the plunger (3) is adjacent to the stopper (4) includes the proximal portion (31) of the plunger (3) that is provided into the cavity (41) of the stopper (4), and the path (8) extends between the opening of the barrel (2) and the cavity (41) of the stopper (4) so ​​that the sterilizer can be supplied through the opening of the barrel (2) into the cavity (41) of the stopper (4).

4. The prefilled syringe (1) according to any one of claims 1 to 3, wherein the at least one opening (341) of the stopper contact section (34) of the plunger (3) includes a bore (341).

5. The pre-filled syringe (1) according to claim 4, wherein the bore of at least one opening (341) of the stopper contact section (34) of the plunger (3) is adjacent to the cavity (41) of the stopper (4).

6. The prefilled syringe (1) according to any one of claims 1 to 5, wherein the at least one opening (341) of the stopper contact section (34) of the plunger (3) is provided with a surrounding recess.

7. The prefilled syringe (1) according to any one of claims 1 to 6, wherein the stopper contact section (34) of the plunger (3) has a circumference that substantially engages with the interior of the barrel (2).

8. The pre-filled syringe (1) according to any one of claims 1 to 7, wherein the stopper contact section (34) of the plunger (3) is substantially disc-shaped.

9. The prefilled syringe (1) according to any one of claims 1 to 8, wherein the proximal portion (31) of the plunger (3) has the stem (311) which terminates proximally within a snap-type section (312) that protrudes radially from the stem (311).

10. The pre-filled syringe (1) according to claim 9, wherein the snap-type section (312) of the proximal portion (31) of the plunger (3) is tapered in the proximal direction (71).

11. The pre-filled syringe (1) according to any one of claims 1 to 10, wherein the rod portion (32) of the plunger (3) is substantially provided with an axial recess (324).

12. The pre-filled syringe (1) according to claim 11, wherein the at least one opening (341) of the stopper contact section (34) and the axial recess (324) of the rod portion (32) are fluidly connected.

13. The pre-filled syringe (1) according to claim 11 or 12, wherein the axial recess (324) of the rod portion (32) is formed by a substantially cross-shaped cross-section of the rod portion (32).

14. The pre-filled syringe (1) according to any one of claims 1 to 13, wherein the distal portion (33) of the plunger (3) is provided with an extended finger rest surface (331).

15. The pre-filled syringe (1) according to any one of claims 1 to 14, wherein the barrel (2) has a nominal filling volume of about 2.25 milliliters or less, about 1.0 milliliter or less, or about 0.5 milliliters or less.

16. A pre-filled syringe (1) according to any one of claims 1 to 15, wherein the liquid contains the active pharmaceutical ingredient.

17. The pre-filled syringe (1) according to any one of claims 1 to 16, wherein the barrel (2) is made of glass.

18. The pre-filled syringe (1) according to any one of claims 1 to 17, wherein the plunger (3) is made from a thermoplastic polymer such as polypropylene.

19. The pre-filled syringe (1) according to any one of claims 1 to 18, wherein the stopper (4) is made of rubber material or silicone.

20. A method for sterilizing a pre-filled syringe (1), To obtain a pre-filled syringe (1) according to any one of claims 1 to 19, The sterilizing agent is supplied to the pre-filled syringe (1) at a predetermined temperature and pressure, To supply a cleaning agent to the aforementioned pre-filled syringe and A method that includes this.

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