Piston extension rod for syringe piston mounting

Abstract

The present invention relates to a piston extension rod (1) for mounting a piston in a syringe comprising a container having a longitudinal axis and an inner wall, and a piston (3) having elastomeric properties, the piston having a cavity (10) having an opening (22) and a base (20), and a deformable sealing element (11), the base (20) having an opening (22), the deformable sealing element abuts against the inner wall (13) of the cylinder and seals an annular gap between the piston and the inner wall of the cylinder, the total length of the piston extension rod being at least 5% greater than the total cavity length of the piston measured from the piston cavity base (20) to the piston cavity opening (22). The piston extension rod for positioning the piston accelerates towards the container outlet end and into the piston cavity (10), the piston extension rod striking surface 19 strikes the piston cavity base (20) during an accelerated movement of at least 25 mm / min such that during the strike between the piston extension rod and the piston, the piston extension rod strikes the piston cavity base (20). Impingement and continuous velocity in the direction of the outlet end of the container causes the piston to extend over the longitudinal axis of the container, thereby causing a constriction of the piston deformable sealing element (11) perpendicular to the longitudinal axis of the container, which eliminates contact of the sealing element with the inner wall of the container, thereby allowing air (14) bypass in the space between the piston and the liquid medicament (23), thereby preventing the liquid medicament (23) from flowing through the container. The narrowing stops at a final piston location, thereby reestablishing a seal of the piston against the inner wall of the container.

Description

Technical Field

[0001] The present invention relates to a piston installation method for a syringe, which enables the piston to be positioned in a gas-filled compartment of the syringe by mechanical interaction of the compartment with the piston. The piston installation method includes a novel piston extension rod according to the present invention and is also intended to achieve optimized installation of the piston in syringes, pre-filled syringes (PFS) and cartridges for delivering pharmaceutical compositions (such as vaccines or biologics). Background Art

[0002] Known syringes are in many cases constructed so that they can be filled and the piston can be installed by automatic filling and installation equipment. Piston installation involves methods including installing the piston, which are done by different methods depending on the type of syringe in question. By way of example, a conventional disposable syringe typically comprises a container, a piston and a piston rod, the piston being mounted on the piston rod, which is then inserted into the container together with the piston to reach the bottom portion of the container interior defined by the container outlet, or the piston can be installed in the container and the piston rod installed thereafter.

[0003] By way of another example, the piston for a prefilled syringe (PFS) is installed after filling of the container, which is accomplished by vacuum or mechanical mounting, both of which are designed to allow the piston to enter the PFS and be positioned close to the drug without physical resistance from the air present between the upper surface of the drug and the container opening, which would compress and prevent the piston from being properly installed, which is a challenge to overcome during the installation of the piston in a drug-filled PFS. The mechanical piston installation (also known as the vent tube method) was the first method introduced for the installation of the piston of the PFS, and is accomplished by significantly compressing the piston and then inserting it into a tube, through which the piston is forced into the correct position in the PFS. This method ensures that excess air within the PFS can be bypassed through the gap between the inner wall of the container and the outer wall of the tube, and the piston can be positioned so that the amount of residual air is typically on the order of 1 mm to 5 mm.

[0004] Vacuum piston mounting was developed as an alternative to the pressure snorkel method, in which the severe compression and forces involved often lead to damage to the piston sealing elements and damage to the polytetrafluoroethylene (PTFE) coating of higher grade pistons used for sensitive biological agents. In addition, the snorkel method has compatibility issues for silicone-free applications because the piston cannot be installed and accelerated through the snorkel without adding a lubricant (usually silicone) without significantly damaging the piston sealing elements due to excessive friction and significant temperature increases.

[0005] Vacuum piston installation is accomplished by automated equipment that includes a vacuum pump that creates a vacuum within the container, between the PFS finger flange and the upper surface of the drug, the space defining a volume of air that, when converted to a sufficient vacuum, draws the piston into the container and further into the desired position just above the upper surface of the drug. In contrast to the vent tube method, vacuum installation enables installation with less residual air and even so-called bubble-free filling, which is advantageous for certain oxygen-sensitive drug applications. For larger containers and special applications with a smaller volume relative to the container size, vacuum alone may not be sufficient to draw the piston to the desired position, and therefore auxiliary vacuum installation is utilized in such cases. Assisted vacuum installation combines vacuum installation with physical support for the push rod that holds the piston.

[0006] Auxiliary vacuum is also used in silicone-free PFS applications where the piston and container are not lubricated, resulting in a higher coefficient of friction than siliconized PFS.

[0007] Existing installation methods are well known and used in the pharmaceutical industry. However, there are a variety of scenarios and applications where the described plugging techniques are not sufficient.

[0008] When the fill volume is significantly lower than the total physical volume of the container in use, vacuum installation presents challenges. For example, to complete an injectable volume of ophthalmic medication between 0.05 and 0.165 ml from a 0.5 ml container body, and to leave a residual air volume of approximately 0.49 ml to 0.34 ml, this configuration requires a significant amount of vacuum to move the piston down the distance from the container opening to the surface of the ophthalmic medication. As the vacuum increases, there is a real risk that the medication is exposed to excessive temperatures or even boiling, thereby reducing or even impairing the efficacy of the medication. At the same time, ophthalmic medications must not be exposed to silicone, so the combination of small fill volumes and silicone-free applications requires an installation method that accommodates these two challenges.

[0009] US 5,411,489 discloses a pre-filled syringe and a pre-filled cartridge for administering various fluids to a patient. The goal of US 5,411,489 is to solve the problem of insufficient sliding characteristics in a pre-filled syringe stored for an extended period of time due to the need to obtain a good leak-proof seal. The syringe comprises a barrel, a cup-shaped plunger, a plunger actuating cylinder and a plunger rod. The plunger rod of US 5,411,489 has a top end with a convex surface at the distal end, a knob at the proximal end that is located outside the plunger actuating cylinder, and also has a flange at the proximal end. The plunger rod is configured to be inserted into the plunger actuating cylinder and push the inner wall of the cup-shaped plunger and deform the plunger. After the plunger is inserted into the syringe barrel, the syringe is filled with medicine from the conical top end, and a hypodermic needle can be installed at the conical top end.

[0010] WO 2019 / 199901 discloses a plunger and its use in a drug delivery device (such as a prefilled syringe, a cartridge or an automatic syringe). The drug delivery device has a plunger, which can be in an "expanded state" or a "storage mode", and can be changed to be in a "narrowed state" or a "dispensing mode". The plunger rod for a drug delivery device has an axial protrusion, which is inserted into a cavity in the plunger, and when sufficient distal forces are applied via the plunger rod, this causes the axial protrusion to apply force to the engaging surface in the cavity in the distal direction. The plunger then extends axially along the stretching zone, thereby causing the plunger to narrow slightly around the stretching zone, and the narrowing of the plunger reduces the radial compression on the sidewall of the medical barrel, thereby allowing the plunger to more easily move downward along the medical barrel, while maintaining a liquid-tight seal and container closure integrity.

[0011] WO 2019 / 185101 discloses a syringe having a stopper with a cavity, the position and design of the cavity providing the syringe with a reduced release force (BLF) compared to a syringe having a stopper without a cavity.

[0012] In the field of pre-filled syringes, there is a need for a simplified procedure for installing a piston in a syringe which would reduce the risk of damaging the liquid drug in the syringe. The present invention is intended to address this need. Summary of the invention

[0013] The present invention is achieved by providing a novel installation method for installing a piston in a pre-filled syringe (PFS). The method comprises the following steps:

[0014] providing a syringe comprising a barrel having a longitudinal axis and an inner wall, and a liquid drug defining an upper drug surface,

[0015] providing a piston having a cavity extending from a piston cavity opening to a piston cavity base to define a piston cavity total length and a deformable sealing element,

[0016] inserting the piston into the cylinder so that the deformable sealing element abuts against the inner wall of the cylinder and seals the annular gap between the piston and the inner wall of the cylinder,

[0017] providing a piston extension rod having an overall length at least 5% greater than an overall length of the cavity and having an impact surface,

[0018] inserting the piston extension rod into the piston cavity and striking the piston cavity base with the striking surface at a speed of at least 25 mm / min to extend the piston along the barrel longitudinal axis and cause constriction of the deformable sealing element, thereby causing air bypass in the space between the piston and the upper surface of the medicament, and

[0019] The piston extension rod velocity is maintained to move the piston to the final piston position.

[0020] For example, the present invention provides a method for installing a piston in a pre-filled syringe, the method comprising the steps of:

[0021] providing a syringe comprising a barrel having an inner wall and an inner diameter, and an outlet at an outlet end opposite the actuation end, the barrel containing a liquid drug defining an upper surface; and

[0022] A piston is provided, the piston having a piston body having an actuation surface opposite the outlet surface, an axial length between the actuation surface and the outlet surface, and a transverse diameter, the piston body defining a piston cavity opening having an entry diameter, the piston including a deformable sealing element surrounding the plug body at an axial position from the actuation surface, the deformable sealing element having an outer diameter greater than the transverse diameter, and

[0023] The piston includes a piston cavity extending from a piston cavity opening to a base of the piston cavity and defining an overall cavity length,

[0024] providing a piston extension rod having a diameter equal to or less than the entry diameter and a length at least 5% greater than the total length of the cavity, the piston extension rod having an impact surface at the end of the piston extension rod,

[0025] inserting the piston into the cylinder at the actuation end so that the deformable sealing element seals the annular gap between the stopper body and the inner wall of the cylinder,

[0026] Insert the piston extension rod into the piston cavity opening and allow the impact surface to impact with the base of the piston cavity at a speed of at least 25 mm / min,

[0027] moving the piston extension rod in a longitudinal direction from the actuation end of the barrel to the outlet end of the barrel to narrow the deformable sealing element and create an air bypass between the deformable sealing element and the inner wall of the barrel, and

[0028] The speed of the piston extension rod is maintained to move the piston to the final piston position. For example, moving the piston extension rod in the longitudinal direction from the actuation end of the barrel to the outlet end of the barrel will cause the piston to extend in the longitudinal direction, thereby narrowing the deformable sealing element and creating an air bypass between the deformable sealing element and the inner wall of the barrel.

[0029] In these methods, a piston is installed in a prefilled syringe. In this context, "installation" may also be referred to as "insertion", and the two terms may be used interchangeably. In addition, a "piston" may also be referred to as a "stopper", and the two terms may be used interchangeably. The piston cavity base is impacted by the impact surface of the piston extension rod at a speed of at least 25 mm / min. It should be understood that the piston extension rod is typically accelerated from zero speed to the impact speed, and therefore this speed may also be referred to as "accelerated movement", and the two terms may be used interchangeably in this context. The piston extension rod may also be abbreviated as PER, and the two terms may be used interchangeably in the context of this disclosure. The piston has a piston cavity opening. "Piston cavity opening" may also be referred to as "cavity inlet" or "piston cavity inlet", and these terms may be used interchangeably in the context of this disclosure. Typically, the piston cavity opening may have an entry diameter. Therefore, for example, the method may also be considered a method for inserting a piston into a cylinder, the method comprising the following steps:

[0030] providing a syringe comprising a barrel having an inner wall and an inner diameter, and an outlet at an outlet end, the outlet end being opposite to an actuation end, and

[0031] providing a plug having a plug body having an actuation surface opposite the outlet surface, an axial length between the actuation surface and the outlet surface, and a transverse diameter, the plug body defining a cavity entrance having an entry diameter,

[0032] The stopper includes a deformable sealing element surrounding the stopper body at an axial position from the actuation surface, the deformable sealing element having an outer diameter greater than the transverse diameter, and

[0033] The stopper includes a piston cavity extending from a cavity inlet to a base of the piston cavity and defining an overall cavity length,

[0034] providing a piston extension rod having a diameter equal to or less than the entry diameter and a length at least 5% greater than the total length of the cavity, the piston extension rod having an impact surface at the end of the piston extension rod,

[0035] inserting the piston into the cylinder at the actuation end so that the deformable sealing element seals the annular gap between the stopper body and the inner wall of the cylinder,

[0036] Insert the piston extension rod into the cavity entrance and allow the impact surface to impact with the base of the piston cavity at an acceleration of at least 25 mm / min,

[0037] The piston extension rod is moved in a longitudinal direction from the actuation end of the barrel to the outlet end of the barrel to deform the deformable sealing element and create an air bypass between the deformable sealing element and the inner wall of the barrel. For example, the piston may be moved to a final piston position.

[0038] The step of inserting the piston into the barrel can employ a special tool. For example, the piston can be pre-inserted into an insertion tube before being inserted into the barrel. The inner diameter of the insertion tube can be the same as the inner diameter of the barrel, or slightly smaller or larger than the inner diameter of the barrel. For example, the inner diameter of the insertion tube can be in the range of 90% to 110% of the inner diameter of the barrel. The length of the insertion tube is typically in the range of 80% to 200% of the length of the piston, for example 100% to 150%. By using an insertion tube, the insertion of the piston into the barrel can be performed more quickly than when the insertion tube is not used, and thereby a faster process for installing the piston in a prefilled syringe is provided.

[0039] When the piston has been inserted into the cylinder, the piston extension rod is inserted into the cavity of the piston and the piston cavity base is impacted with the impact surface of the piston extension rod at a speed of at least 25 mm / min. This speed ensures that the piston extends along the longitudinal axis of the cylinder, and at the same time it causes a narrowing of the deformable sealing element, which in turn causes air bypass in the space between the piston and the upper surface of the drug. Thus, the piston can be moved closer to the upper surface of the drug, and air can be removed between the upper surface of the drug and the piston during the movement of the piston to the final piston position. In addition to the ability to bypass air from the PFS, the present invention introduces further significant advantages. The narrowing of the sealing element enables low friction to be achieved without the usual strains and stresses on the sealing elements known from existing piston mounting systems. The method makes the vacuum redundant, including the costs associated with investing in and operating the vacuum system.

[0040] Due to the low friction installation, the installation speed can be significantly increased, so that a greater annual output per time unit can be achieved. The speed can be, for example, in the range of 50mm / min to 120,000mm / min. Once the piston cavity base has been impacted by the impact surface, the speed does not need to be constant during the piston movement to the final piston position, and the speed can vary in the range of 25mm / min to 120,000mm / min, for example, the speed can be in the range of 50mm / min to 20,000mm / min, for example, 50mm / min to 10,000mm / min, 100mm / min to 5,000mm / min, 200mm / min to 2,000mm / min, or 400mm / min to 800mm / min. Compared with the vent pipe method and vacuum installation, the lower power consumption and higher output per time unit have a significant positive impact on the CO2 operating curve. An appropriate piston extension rod speed may be selected for each piston feature and PFS configuration, and may range from at least 50 mm / min up to the maximum speed of the automated filling and installation system in which the piston extension rod is installed.

[0041] The cylinder has an inner wall, and the cylinder can be further defined by an inner diameter. However, in this context, the term "diameter" does not mean that the corresponding element must have a circular cross-section, and any desired cross-sectional shape can be used for the corresponding element. For example, the cross-section of the cylinder can be polygonal, such as a triangle, square, pentagon, hexagon, etc., and in this case, the term "diameter" refers to the cross-sectional size, such as the maximum cross-sectional size of the corresponding cross-sectional shape. Correspondingly, the cavity opening and the piston extension rod are not limited to rounding, but can have any shape as required, for example, the piston extension rod and the cavity opening can have a polygonal cross-section, such as a triangle, square, pentagon, hexagon, etc., and the term "diameter" in this case will refer to the cross-sectional size, such as the maximum cross-sectional size of the corresponding cross-sectional shape. The polygonal cross-section is not limited to a polygon with equal angles and equal sides, i.e. a regular polygon, and the cross-section can also be elliptical. The piston extension rod size can also be asymmetric on its longitudinal axis, suitable for interacting with the piston cavity.

[0042] The piston can be defined as having a piston body. Generally, the piston body does not interact with the inner wall of the cylinder, and the cross-sectional shape of the piston body can be freely selected, regardless of the cross-sectional shape of the deformable sealing element. The piston body generally has a transverse diameter, which is smaller than the inner diameter of the cylinder. The piston has a deformable sealing element. The deformable sealing element is configured to abut the inner wall of the cylinder and seal the annular gap between the inner wall of the piston and the cylinder. Therefore, the deformable sealing element generally surrounds the stopper body and has an outer diameter, which is larger than the inner diameter of the cylinder. For example, the outer diameter of the deformable sealing element can be 1.5% to 10% larger than the inner diameter of the cylinder, for example, 2% to 5% larger. When the outer diameter of the deformable sealing element is at least 1.5% larger than the inner diameter of the cylinder, especially when the deformable sealing element has a Shore A hardness in the range of 40 to 75, the container closure integrity (CCI) is ensured.

[0043] The piston extension rod may be mounted on the connector. In particular, the piston extension rod may extend from the connector. The connector has a size that allows it to be inserted into the barrel during installation of the piston in the syringe, for example, the connector has a diameter that is smaller than the inner diameter of the barrel. The connector may suitably have any length. For example, the combined length of the connector and the piston extension rod may be sufficient to move the piston to a final piston position in which the outlet surface of the piston contacts the liquid drug in the barrel, for example at the drug upper surface of the liquid drug.

[0044] The piston has a piston cavity opening. The piston can be described as having an actuation surface opposite to the outlet surface, wherein the piston cavity opening is located in the actuation surface. The actuation surface and the outlet surface are located at opposite ends of the piston body, i.e. opposite ends in the axial dimension. When inserted into the cylinder, the axial dimension of the piston body substantially coincides with the longitudinal axis of the cylinder. The actuation surface can also be considered as the actuation end of the piston body, and the outlet surface can also be considered as the outlet end of the piston body. When inserted into the cylinder of the syringe, the outlet end of the piston body faces the outlet of the syringe.

[0045] The outlet surface of the piston is the surface facing the liquid drug in the barrel of the syringe. In an example, in the final piston position, the outlet surface of the piston is in contact with the liquid drug in the barrel. Thus, the method allows for substantially no residual air between the piston and the liquid drug in a pre-filled syringe. This is particularly advantageous for ophthalmic drugs, where the injection volume is typically very small, for example between 0.05 ml and 0.165 ml in a barrel with a nominal dose of 0.5 ml.

[0046] The piston has a cavity. The cavity may also be referred to as a "piston cavity", and the two terms may be used interchangeably. The cavity is configured to receive a piston extension rod, but its shape is otherwise not limited. The cavity and the piston rod for use with the syringe may include engagement means and complementary engagement means, respectively, and the engagement means and complementary engagement means may be freely selected. For example, the piston rod for use with the syringe may include an external thread, such as a spiral external thread, and the cavity may correspondingly include a complementary internal thread, such as a spiral internal thread, which threads thus provide an engagement means and a complementary engagement means, respectively.

[0047] In an example, the cavity has a generally cylindrical shape. For example, the cavity can have a diameter substantially equal to the entry diameter. In another example, the cavity has a generally conical shape, wherein the diameter of the cavity narrows from the cavity opening toward the piston cavity base.

[0048] In a specific example, the piston has a cavity as defined in WO 2019 / 185101. Thus, for example, the piston may include a deformable sealing element at an axial position from the piston cavity opening (e.g., from the actuating surface), and a widened cavity segment at the axial position of the deformable sealing element, the axial extension of the widened cavity segment being in the range of 5% to 70% of the total length of the piston cavity, for example, in the range of 5% to 50% of the total length of the piston cavity, and the widened cavity segment, for example, has a lateral extension greater than the piston cavity opening (e.g., entry diameter) in its axial extension. This example with a widened cavity segment can also be referred to as a cavity with reduced BLF. In the example, the lateral extension of the widened cavity segment (e.g., in the axial extension of the widened cavity segment) is at least 50% of the outer diameter of the deformable sealing element and greater than the piston cavity opening (e.g., entry diameter). In examples of the present disclosure, the widened cavity section has a lateral extension of up to 90%, such as up to 80%, up to 70% or up to 60% of the outer diameter of the deformable sealing element. For example, the piston may have a piston body having an actuating surface opposite to the outlet surface, an axial length between the actuating surface and the outlet surface, and a transverse diameter, and the piston includes a deformable sealing element, for example made of a thermoplastic elastomer (TPE), at an axial position from the actuating surface, the deformable sealing element surrounding the piston body and having an outer diameter greater than the transverse diameter, for example, the axial extension of the deformable sealing element is in the range of 5% to 95% of the axial length of the piston body, and when the piston is inserted into the cylinder, the deformable sealing element seals the annular gap between the piston body and the inner wall of the cylinder, and the piston includes a widened cavity section at the axial position of the deformable sealing element, the axial extension of the widened cavity section is in the range of 5% to 50% of the total length of the piston cavity, and the widened cavity section (for example, in its axial extension) has a lateral extension, which is greater than the piston cavity opening (for example, the entry diameter) and is in the range of 50% to 90% of the outer diameter of the deformable sealing element.

[0049] The piston (e.g., piston body) may have a tubular section for accommodating a piston rod or for receiving a piston extension rod, which extends from the piston cavity opening (e.g., from the actuating surface of the piston) to the widened cavity section. When the piston includes a tubular section, the piston cavity opening may have an entry diameter. Specifically, when a syringe having a piston of this example is equipped with a piston rod, a cavity may be formed at the interface between the piston body and the piston rod and / or at the interface between the deformable sealing element and the piston rod when the syringe is ready for use. Typically, the widened cavity section has a lateral extension that is at least 50% of the outer diameter of the deformable sealing element and greater than the entry diameter. Specifically, the widened cavity section is greater than the entry diameter. When the piston comprises a widened cavity section at the axial position of the deformable sealing element as defined by the actuating surface, i.e. when there is an overlap in the axial position of the deformable sealing element and the cavity, and when the diameter of the cavity is larger than the entry diameter, in particular when the diameter of the cavity is in the range of 50% to 90%, for example 60% to 80%, of the outer diameter of the deformable sealing element, the formation of the air bypass is more easily obtained than when the piston comprises a cavity of smaller size. This is particularly relevant when the speed is relatively low, for example in the range of 25 mm / min to 800 mm / min. This effect is also particularly relevant when the deformable sealing element has a Shore A hardness in the range of 40 to 75, and even more relevant when the deformable sealing element is made of TPE, for example when the piston has been injection molded of TPE. Furthermore, when the syringe comprises a widened cavity section as defined above, i.e. when the cavity has a diameter greater than the entry diameter, in particular when the diameter of the cavity is in the range of 50% to 90%, for example 60% to 80%, of the outer diameter of the deformable sealing element, and when the axial extension of the cavity is in the range of 5% to 50% of the total length of the piston cavity, and when the tubular section for accommodating the piston rod or for receiving the piston extension rod has an entry diameter, a syringe equipped with a piston and an appropriate piston rod will have a reduced release force (BLF) compared to a syringe with a piston having a cavity portion comprising a widened or BLF-reduced cavity section.

[0050] In another aspect, the invention relates to a kit of parts, the kit of parts comprising: a syringe comprising a barrel having a longitudinal axis and an inner wall, such as a barrel having an inner diameter; a piston having a piston body having an actuation surface opposite to an outlet surface and a transverse diameter, the piston comprising a deformable sealing element surrounding the piston body at an axial position from the actuation surface, the deformable sealing element having an outer diameter greater than the transverse diameter, the piston having a cavity extending from a piston cavity opening (i.e., the piston cavity opening in the actuation surface) to a piston cavity base to define a total piston cavity length, the cavity having an entry diameter extending from the piston cavity opening (i.e., from the actuation surface) and having a substantially longitudinal axis; The invention relates to a method for manufacturing a piston according to the present invention, wherein the piston comprises a tubular section, a widened cavity section at the axial position of the deformable sealing element, the axial extension of the widened cavity section being in the range of 5% to 50% of the total length of the piston cavity, and the widened cavity section having, for example, a lateral extension in its axial extension, which is greater than the entry diameter, for example, at least 50% of the outer diameter of the deformable sealing element, and greater than the entry diameter, such as up to 90%, for example up to 80%, up to 70% or up to 60% of the outer diameter of the deformable sealing element; and a piston extension rod having a diameter equal to or less than the entry diameter and a length at least 5% greater than the total length of the cavity, for example, the piston extension rod extends from the connector. The piston may, for example, have an axial length between the actuation surface and the outlet surface. The deformable sealing element is generally configured to seal the annular gap between the piston body and the inner wall of the cylinder when the piston is inserted into the cylinder.

[0051] The kit of parts may include any additional elements, such as an actuator, a processor unit, etc., to perform the method of the present invention. In an example, the deformable sealing element has a Shore A hardness in the range of 40 to 75. For example, the deformable sealing element can be made of TPE, for example, the piston can be injection molded from TPE, for example as a single piece. In an example, the piston extension rod includes a stopper located at the end opposite to the impact surface. The stopper has a lateral size relative to the piston extension rod, which is larger than the piston cavity opening, such as an entry diameter. The lateral size of the stopper is smaller than the inner diameter of the barrel. Thus, the piston is prevented from being pushed too far into the barrel of the prefilled syringe. For example, the length of the piston extension rod can be in the range of 10% to 30% of the total length of the cavity.

[0052] It can be said that the tubular section is configured to receive the piston extension rod and that the tubular section generally extends from the piston cavity opening to the widened cavity section.

[0053] In an example, the piston extension rod has a diameter, and the entry diameter is in the range of 10% to 500% greater than the diameter of the piston extension rod. In addition, the length of the piston extension rod can be 5% to 80% longer than the total length of the piston cavity, for example 5% to 50% longer than the total length of the piston cavity.

[0054] The deformable sealing element can be made of any suitable elastomeric material. In the example, the deformable sealing element and optionally the piston body are made of TPE, for example, formed by injection molding of TPE. Any TPE can be used for the piston of the present invention, for example, for the deformable sealing element and the piston body. Suitable TPEs include SBCs, such as hydrogenated H-SBC-(SEBS-styrene ethylene butylene-styrene or the like) or non-hydrogenated (SBS-styrene-butadiene styrene) or alloys of these with other compatible polymers, such as COC elastomers, or styrene-butadiene (SB), styrene-isoprene-styrene (SIS), styrene-isoprene-butadiene-styrene (SIBS), styrene-ethylene-ethylene-propylene-styrene (SEEPS) or alloys of any of these compounds. Preferred SBCs are those known under the trademark Evoprene sold by AlphaGary Company (Lewster, Massachusetts, USA) and Mexichem Specialty Compounds Company. Evoprene is described in the brochure "EVOPRENE TM Thermoplastic Elastomer(TPE)Compounds-GENERAL INFORMATION”[EVOPRENE TM Thermoplastic Elastomer (TPE) Compounds - Basic Information] (published by AlphaGary in July 2007), and the preferred Evoprene TM The polymer is Evoprene TM Super G, Evoprene TM G. Evoprene TM GC and Evoprene TM HP, they are respectively in the brochure "EVOPRENE TM SUPER G Thermoplastic Elastomer(TPE)Compounds”[EVOPRENE TM SUPER G thermoplastic elastomer (TPE) compounds], "EVOPRENE TM GThermoplastic Elastomer(TPE)Compounds”[EVOPRENE TMG thermoplastic elastomer (TPE) compounds], "EVOPRENE TM GC Thermoplastic Elastomer(TPE)Compounds”[EVOPRENE TM GC thermoplastic elastomer (TPE) compounds] and “EVOPRENE TM HP Thermoplastic Elastomer(TPE)Compounds”[EVOPRENE TM HP thermoplastic elastomer (TPE) compounds] (published by AlphaGary in July 2007). The contents of all mentioned brochures of AlphaGary are incorporated herein by reference. Other related elastomers include COC elastomers, for example, Elastomer E-140. TPEs can be selected based on gas, such as oxygen, permeability, and generally, particularly for pistons for prefilled syringes, it is preferred that the gas permeability be as low as possible. The gas permeability of SIBS TPEs is generally very low, so these are suitable for pistons for prefilled syringes. Other related elastomeric materials include rubbers, such as natural rubber, synthetic rubbers (polyisoprene rubber, butyl rubber, halobutyl rubber), silicone rubber, and the like, and thermoplastic vulcanizates (TPVs).

[0055] Elastomeric materials can be defined by their hardness, such as the Shore durometer value, which indicates the elasticity of the elastomeric material and measures the hardness of the elastomeric material, wherein the higher the durometer value, the harder the compound. Materials having a Shore A hardness are preferred, and the Shore A hardness may be in the range of 40 to 75. The measurement of Shore A hardness is well known to the skilled person, and in particular, Shore A hardness is usually recorded according to the ISO 868 standard.

[0056] TPE can also be defined by its compression set value, which corresponds to the deformation remaining after the force applied to it is removed (and is usually expressed in %). Compression set values ​​are usually recorded over a specified time period (for example, in the range of 18 hours to 96 hours or 22 hours to 72 hours) and at a specified temperature, for example, according to ISO815 standard. In the context of the present invention, compression set is usually recorded at "ambient temperature", for example, in the range of 10°C to 40°C. However, the temperature range may also exceed ambient temperature, for example, 23°C to 100°C. Generally, the higher the temperature, the shorter the relevant time for recording compression set. Compression set should generally be as low as possible, but for the plug or part of the plug of the present invention, for example, at ambient temperature, the compression set can be in the range of 15% to 40%. At higher temperatures (for example 100°C), the compression set will generally be higher, for example up to 50%. However, it is preferred that the compression set at ambient temperature is in the range of 10% to 40%. Compression set values ​​are generally relevant for prefilled syringes, where the stopper will be inserted into the barrel and thus compressed when the prefilled syringe is stored for a long time. When the stopper, for example the stopper body and also the deformable sealing element, has a Shore A hardness in the range of 30 to 90, for example 50 to 90, and a compression set value of at least 25% (for example, in the range of 25% to 35%), the BLF of the prefilled syringe of the present invention will decrease after storage, for example, for at least 5 days, making the stopper of the present invention particularly advantageous for prefilled syringes.

[0057] The deformable sealing element is preferably convex. In this context, the term "convex" means that a straight line between any two points within the deformable sealing element does not cross the surface of the deformable sealing element. Any convex shape is contemplated, but the deformable sealing element preferably has a point, such as a point in the axial plane of the plug, which represents the maximum extent from the central axis of the plug.

[0058] In a specific example, the deformable sealing element is made of TPE, for example with a Shore A hardness in the range of 40 to 75. This allows the piston to be inserted into the cylinder and moved to the final piston position without external lubricants.

[0059] The present invention provides a piston extension rod for installing a piston in a syringe, the syringe comprising a barrel having a longitudinal axis and an inner wall, and a piston having elastomeric properties, the piston having a cavity and a deformable sealing element, the deformable sealing element abutting the inner wall of the barrel and sealing the annular gap between the piston and the inner wall of the barrel, the piston extension rod for piston positioning is accelerated toward the outlet end of the container and enters the piston cavity, the lowest surface of the piston extension rod hits the base of the piston cavity during the accelerated movement, so that during the piston extension rod, the piston extension rod causes the piston to extend on the longitudinal axis of the barrel, thereby causing the deformable sealing element of the piston to narrow, which eliminates the contact between the sealing element and the inner wall of the container, thereby allowing air to bypass in the space between the piston and the injectable liquid, and the narrowing stops at the final piston positioning, thereby re-establishing the seal of the piston against the inner wall of the container.

[0060] A piston installation method, the piston installation method includes a novel mounting component for piston installation, referred to as a piston extension rod, which enables accurate installation without vacuum or without using piston compression through a vent tube method. According to a preferred example, the piston extension rod can be cylindrical along its longitudinal axis parallel to the longitudinal axis of the container. In other examples, it can be oval, square or rectangular as required to cooperate with a specific piston cavity. In another example, the piston extension rod can have an outward protrusion or an inward groove to adapt to the interaction with the piston cavity, and the protrusion and or groove are established along the longitudinal axis of the piston extension rod. According to the present invention, the piston extension rod has a length along its longitudinal axis parallel to the longitudinal axis of the container, which exceeds the depth of the piston cavity along the longitudinal axis of the container by at least 5%. In particular, it is preferred that only the impact surface of the piston extension rod impacts the piston, that is, at the base of the piston cavity. For example, the piston extension rod may not have a portion or section (such as a stopper) that can impact the piston surface with a cavity entrance. However, the piston extension rod may also have a stopper that can control the maximum extension of the piston during installation. During the installation of the piston, the piston extension rod will accelerate and enter the piston cavity. During the acceleration of the piston extension rod and the downward movement when reaching the base of the piston cavity, the acceleration of the piston extension rod will extend the piston when it hits the base of the piston cavity and continue to position the piston close to the upper surface of the drug. The piston extension is caused by the acceleration of the piston extension rod and the impact with the stationary piston and its cavity base, as well as the elastomeric properties of the piston. At the same time, due to the extension, the piston extension will cause the piston to narrow perpendicular to the longitudinal axis of the container, thereby completely or partially releasing the contact between the piston sealing element and the inner wall of the container, and finally creating a necessary bypass for exhausting the excess air between the piston and the upper surface of the drug. The narrowing of the piston is a function of the piston extension and is a natural result of the piston being an elastomeric component, which will narrow when it is extended. When the narrowing is triggered by the impact of the piston extension rod entering the base of the piston cavity in the stationary position, the narrowing is maintained due to the combination of the speed of the piston extension rod during the final piston positioning and the reciprocating force friction caused by the compressed air, and the compressed air will accelerate through the bypass created between the narrowed sealing element and the inner wall of the container. The constriction will be maintained and only stop as the speed decreases and the piston extension decreases, but stops completely when the piston extension is 0, while the sealing ability between the piston sealing element and the inner wall of the container is restored and fully re-established at the final position of the piston.

[0061] In one aspect, the present invention provides a method of inserting a piston into a barrel (e.g., the barrel of a syringe), particularly a syringe for delivering a pharmaceutical composition comprising a liquid drug. The method comprises the following steps:

[0062] A syringe is provided, the syringe comprising a barrel having an inner wall and an inner diameter, and an outlet at an outlet end, the outlet end being opposite to an actuation end, and a stopper having a stopper body having an actuation surface opposite to the outlet surface,

[0063] an axial length between the actuation surface and the outlet surface, and a transverse diameter, the plug body defining a cavity entrance having an entry diameter, the plug including a deformable sealing element surrounding the plug body at an axial position from the actuation surface, the deformable sealing element having an outer diameter greater than the transverse diameter, and the plug including a piston cavity extending from the cavity entrance to a base of the piston cavity, the piston cavity defining a total cavity length; providing a piston extension rod having a diameter equal to or less than the entry diameter and a length at least 5% greater than the total cavity length, the piston extension rod having an impact surface at the end of the piston extension rod,

[0064] The piston is inserted into the cylinder at the actuation end so that the deformable sealing element seals the annular gap between the plug body and the inner wall of the cylinder, the piston extension rod is inserted into the cavity entrance and the impact surface is impacted with the base of the piston cavity at an accelerated movement of at least 25 mm / min, and the piston extension rod is moved in the longitudinal direction from the actuation end of the cylinder to the outlet end of the cylinder to deform the deformable sealing element and create an air bypass between the deformable sealing element and the inner wall of the cylinder. The piston extension rod is inserted into the cavity entrance and the impact surface is impacted with the base of the piston cavity at an accelerated movement of at least 25 mm / min. However, it should be understood that it is the accelerated movement of at least 25 mm / min that causes the deformation of the deformable sealing element and creates an air bypass between the deformable sealing element and the inner wall of the cylinder. Therefore, in the present invention, it is conceivable to insert the piston extension rod into the cavity entrance at a low speed, that is, at a movement of less than 25 mm / min, so that the impact surface impacts with the base of the piston cavity before increasing the speed to reach an accelerated movement of at least 25 mm / min. Accordingly, the movement of the piston extension rod can also be stopped after the piston extension rod is inserted into the cavity entrance. For example, the piston extension rod can be inserted into the cavity entrance at a high speed or a low speed, and then the movement can be stopped, for example regardless of how far the piston extension rod has been inserted into the cavity entrance. When the piston extension rod is inserted into the cavity entrance at a low speed, it is particularly relevant that the piston extension rod does not have a part or section (e.g., a stopper) that may hit the piston surface with the cavity entrance. For example, the piston extension rod can have a stopper located at a distance from the impact surface, which is at least 10% longer than the piston cavity length, for example, the distance from the impact surface to the stopper can be at least 20% longer than the piston cavity length or at least 30% longer than the piston cavity length. In an example, the piston extension rod does not have a stopper. In an example, the piston extension rod is inserted into the cavity entrance at a movement of less than 25 mm / min before increasing the movement to an accelerated movement of at least 50 mm / min, at least 100 mm / min, at least 200 mm / min, or at least 400 mm / min.

[0065] Thus, the piston extension rod (i.e., at the impact surface) pushes the piston (i.e., via the impact surface) and moves the piston. The piston movement performed using the piston extension rod causes the deformation of the deformable sealing element, thereby creating an air bypass between the deformable sealing element and the inner wall of the cylinder. In this context, accelerated movement can also be referred to as speed, and the two terms can be used interchangeably. In general, an accelerated movement of at least 25mm / min is enough to deform the deformable sealing element and create an air bypass between the deformable sealing element and the inner wall of the cylinder. However, the greater the accelerated movement, the greater the deformation, and the greater the air bypass. In other examples, the accelerated movement can be in the range of 50mm / min to 10,000mm / min, for example, 100mm / min to 5,000mm / min, 200mm / min to 2,000mm / min or 400mm / min to 800mm / min.

[0066] The entry diameter is equal to or greater than the diameter of the piston extension rod. In the present context, this means that the piston extension rod can be inserted into the piston via the cavity entrance. Therefore, it is also conceivable that the entry diameter is smaller than the diameter of the piston extension rod, for example the entry diameter can be 5% smaller than the diameter of the piston extension rod. However, it is preferred that the entry diameter is at least 5% larger than the diameter of the piston extension rod, but the exact ratio between the entry diameter and the diameter of the piston extension rod is not important. When the diameter of the piston extension rod is smaller than the entry diameter, the difference in diameter creates flexibility in the material of the piston, making it easier for the piston to extend in the longitudinal direction of the cylinder, thereby making it easier to create an air bypass between the deformable sealing element and the inner wall of the cylinder than when there is no space between the piston extension rod and the material of the piston (for example, when the entry diameter is equal to or smaller than the diameter of the piston extension rod). The entry diameter can be, for example, in the range of 10% greater than the diameter of the piston extension rod to 500% greater than the diameter of the piston extension rod, such as at least 10% greater than the diameter of the piston extension rod, or at least 20% greater, at least 30% greater, at least 50% greater, at least 100% greater, at least 200% greater, or at least 400% greater than the diameter of the piston extension rod.

[0067] The method is particularly useful when the syringe is a syringe for delivering a pharmaceutical composition comprising a liquid drug, such that the method allows the piston to be inserted into the syringe and simultaneously removes air between the piston and the surface of the liquid drug. This is particularly relevant for pre-filled syringes, particularly for pre-filled syringes intended to deliver small doses (e.g., ophthalmic drugs).

[0068] The method particularly allows the piston to be inserted into the syringe (i.e., the barrel of the syringe) without lubrication, such as silicone lubrication. The syringe without silicone lubrication can have a piston made of TPE, such as SEBS, SBS, etc. In a specific example, the stopper includes a cavity at the axial position of the deformable sealing element, and the cavity has a lateral extension greater than the entry diameter of the cavity entrance. Such stoppers are described in WO 2019 / 185101, the contents of which are incorporated herein by reference. The presence of a cavity (e.g., a cavity with a lateral extension greater than the entry diameter of the cavity entrance) at the axial position of the deformable sealing element allows even greater flexibility, thereby making it easier to create an air bypass. The piston can have a single deformable sealing element, and the impact between the piston extension rod and the impact surface with an accelerated movement of at least 25mm / min can create an air bypass. The piston can also have two or more deformable sealing elements. When the piston has two or more deformable sealing elements, each sealing element will abut the inner wall of the cylinder, and therefore, the deformation of the piston caused by the impact of the piston extension rod with the base of the piston cavity will be greater than the deformation when the piston has a single deformable sealing element. Therefore, when the piston has two or more deformable sealing elements, an accelerated movement of at least 25 mm / min is also sufficient to create an air bypass.

[0069] In addition to the ability to bypass air from the PFS, the present invention introduces further significant advantages. The narrowing of the sealing element enables low friction, and in some cases even zero friction, piston installation without the usual strains and stresses on the sealing elements known from existing piston installation systems. The present invention makes the vacuum redundant, including the costs associated with investing in and operating the vacuum system. Due to the low friction installation, the installation speed can be significantly increased, thereby enabling a greater annual output per time unit. Compared with the vent tube method and vacuum installation, the lower power consumption and higher output per time unit will have a significant positive impact on the CO2 operating curve. The appropriate piston extension rod speed can be selected for each piston feature and PFS configuration, and the piston extension rod speed range is at least 50mm / min up to the maximum speed of the automatic filling and installation system equipped with the piston extension rod.

[0070] The plunger extension rod can also be used for manual plunger installation, but is preferably used as an integrated component for an automated plunger installation system (e.g., a tabletop system or a larger plunger installation system for multiple syringe filling and plunger installation lines).

[0071] For automated installation, the piston extension rod can be incorporated as a new component into new or existing PFS mounting systems as a replacement for existing mounting components such as rods and pins for snorkel methods, and auxiliary vacuum mounting.

[0072] The existing filling and installation systems are relatively similar in order to comply with general standards including ISO11040, and the most common brands are Bausch & Bosch, Syntegon, Groninger, OptimaPackaging, and Colanar.

[0073] The piston extension rod may be manufactured from any material as desired, such as metal, preferably hardened steel, but may also be manufactured from a plastic compound deemed suitable for the purpose.

[0074] The piston extension rod is compatible with elastomeric pistons including cavities, however such pistons are generally within the Shore A hardness range for syringes. These pistons typically have Shore A values ​​ranging from 40 to 75. The axial dimensions of the piston extension rod may vary relative to the particular piston with which it cooperates. While its length will be at least 5% greater than the piston cavity measured along the longitudinal axis of the container from the base of the cavity interior to the cavity opening, the width of the piston extension rod will vary with the piston cavity diameter.

[0075] A reduced piston extension rod width at the lowest surface of the piston extension rod that impacts the base of the piston cavity will mean increased extension, while an increased width will reduce piston extension. The piston extension rod may include a stop to limit its travel, which may be implemented in a variety of ways, including a plate that interacts with the upper surface of the piston (acting as a physical brake), thereby limiting over-extension of the piston.

[0076] The piston extension rod can be modified for each individual syringe / piston configuration, with piston size, material hardness, thickness, coating, number of sealing elements, total sealing area and container material being factors that may have an impact on the size of the piston extension rod. The piston extension rod has the ability to achieve appropriate piston extension by changing the speed, but also by extending its length to more than 5% greater than the total length of the piston cavity.

[0077] The syringe piston is an elastomeric component having at least one deformable sealing element, but can be made of any suitable elastomeric material, such as natural rubber, TPE, styrene-butadiene block copolymer, polyisoprene, polybutadiene, ethylene propylene rubber, ethylene propylene diene rubber, silicone elastomers, fluoroelastomers, polyurethane elastomers, halogenated butyl rubber and nitrile rubber, and can further be coated with PTFE or similar coating types to reduce friction.

[0078] The piston installation is performed after filling the syringe, which is positioned vertically with the container outlet in a downward position and is filled with the injectable liquid from its container opening in an upward position.

[0079] For example, a 1 ml long standard glass PFS has a nominal volume that is less than the total container volume in order to accommodate the piston and the portion of the piston rod that fits into the piston after the piston is installed. The nominal volume represents approximately 32 mm of travel, while the remaining travel of approximately 21 mm represents the amount of air above the injectable liquid that must be bypassed in order to fit the piston closest to the upper surface of the drug.

[0080] It is further contemplated that the method of the present invention may also be used to install a vial stopper in a vial. Thus, in another aspect, the present invention relates to a method for installing a vial stopper in a vial. The vial stopper has a cavity generally as defined for a piston, and any features associated with installing the piston in the barrel of a syringe are also associated with installing the vial in the vial stopper.

[0081] Any embodiment of the invention may be used with any aspect of the invention, and any advantages of a particular embodiment also apply when the embodiment is used with a particular aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1a A piston extension rod for use in the method of the present invention is shown;

[0083] Figure 1b shows a top view of a piston extension rod used in the method of the present invention;

[0084] Figure 2 A syringe is shown with the plunger ready for installation in the method of the invention;

[0085] Figure 3 A syringe is shown with the plunger ready for installation in the method of the invention;

[0086] Figure 4 The syringe is shown with the plunger and plunger extension rod;

[0087] Figure 5 A syringe is shown in which a piston is being installed with a piston extension rod in accordance with the method of the present invention;

[0088] Figure 6 A syringe is shown in which a piston is mounted using a piston extension rod in the method of the present invention;

[0089] Figure 7 A piston for installation in accordance with the method of the present invention is shown;

[0090] Figure 8 A syringe is shown with the plunger ready for installation in the method of the invention;

[0091] Fig. 9A syringe is shown in which a piston is being installed in accordance with the method of the present invention;

[0092] Fig.10 The syringe is shown with the piston in its final position;

[0093] Fig.11 The steps of an example of the method of the present invention are shown;

[0094] Fig.12 An improved snorkel apparatus for use in the method of the present invention is shown;

[0095] Fig.13 Parameters for an example of the method of the present invention are shown.

[0096] The present invention is not limited to the one or more embodiments shown in the drawings. Therefore, it should be understood that when features mentioned in the appended claims are followed by reference numerals, such reference numerals are included only for the purpose of improving the intelligibility of the claims and in no way limit the scope of the claims.

[0097] As used in the specification and claims, the term "comprising" means "consisting at least in part of". When interpreting statements in the specification and claims containing the term "comprising", other features may be present in addition to the features preceded by the term in each statement. Related terms such as "comprising" and "including" should be interpreted in a similar manner. DETAILED DESCRIPTION

[0098] The installation process may vary for each application. Automated installation systems will typically perform a two-step installation, first pre-positioning to simply secure the piston within the uppermost portion of the container (this is typically installed by a separate tool), then the actual downward movement and final positioning of the piston by placement of a pin or rod. The piston extension rod is independent of the pre-positioning of the piston, as the piston extension rod functions during the downward movement and final positioning of the piston, and therefore functions appropriately regardless of the pre-positioning configuration, and any examples of pre-positioning do not affect the piston extension rod invention, but are merely provided as an explanation.

[0099] Figure 1a and Figure 1b A piston extension rod 1 is shown with a stopper 7 and a connector 21 for mounting on an automated machine, and with a rounded impact surface 19 for cooperating with a piston cavity base 20 during piston positioning. The impact surface may have a different geometry and instead of being rounded, may be flat or pointed instead of rounded, depending on the geometry of the piston cavity base 20. By reducing the width of the piston extension rod 1 relative to the piston cavity base 20, the extension will increase, while increasing the width relative to the piston cavity base 20 will cause the extension to decrease.

[0100] Figure 2 The piston 3 is shown after being pre-positioned inside the upper portion 5 of the drug filled container with air 14 between the piston outlet surface 15 and the liquid drug upper surface 16, and the cavity opening 22 and the piston cavity base 20 are shown with the liquid drug 23. The piston outlet surface 15 may also be referred to as the piston front surface 15.

[0101] Figure 3 An alternative piston 3 is shown which is pre-positioned outside the container opening 22, just above the container opening, and which is held in place by a special tool which is located in the container opening. Figure 3 The insertion tube 102 is shown in FIG. The insertion tube 102 has an inner wall 103 .

[0102] Therefore, Figures 1 and Figure 2 It is only an example of pre-positioning. The pre-positioning takes place before the piston extension rod 1 according to the present invention moves downward and is finally positioned.

[0103] Figure 4 A piston extension rod 1 is shown, which is configured for final positioning of a piston 3, which is a SEBS piston having a cavity 10 (as shown, a widened cavity 10), a Shore A hardness of 72, and two sealing elements 11. It can be seen that the piston extension rod 1 is positioned inside the pre-positioned piston 3 during acceleration just before or at the time of impact with the piston cavity base 20.

[0104] The length 4 of the piston extension rod 1 exceeds the piston cavity length 6 by approximately 30% and, in this embodiment, has a stop 7 which limits the longitudinal extension of the piston 3 .

[0105] Figure 5 The movement and extension of the piston 3 after the impact between the impact surface 19 of the piston extension rod 1 and the piston cavity base 20 is shown, and this extended piston configuration is maintained during the movement (e.g., continuous movement) of the piston extension rod 1 and the piston. The piston narrowing that occurs as the piston extends is also shown, wherein the piston sealing elements 11 are forced away from their seal with the container inner wall 13, thereby forming an open channel 12 between the sealing elements 11 and the container inner wall 13 for air to bypass.

[0106] Figure 6 The final position of the piston 3 is shown, in which the piston extension 1 and constriction have ceased and a complete seal of the piston sealing element 11 towards the inner wall 13 of the container has been reestablished.

[0107] Figure 7An example of a piston 3 for installation in the method of the invention is shown. The piston 3 has a piston body 31 with an actuation surface 151 comprising a cavity opening 22 and an outlet end 15, and the cavity 10 has a helical internal thread 221 .

[0108] Figures 8 to 10 A syringe 100 with a piston 3 is shown for demonstrating the method of the invention. Figures 8 to 10 The barrel 101 is shown, and the outlet end 17 of the barrel and the actuation end 18 of the barrel are shown. Figure 8 In the embodiment, the piston 3 has been inserted into the cylinder 101 and is ready to be installed using this method. Fig. 9 In the embodiment, the piston cavity base 20 has been struck by the impact surface 19 of the piston extension rod 1 to extend the piston 3 in the longitudinal dimension of the barrel 101, whereby the piston 3 is narrowed to create an open channel 12 between the deformable sealing element 11 and the inner wall 13 of the barrel 101, so that air 14 can leave the space between the piston 3 and the upper surface 16 of the liquid drug. Fig.10 In the embodiment, the piston 3 is in its final position so that the outlet surface 15 of the piston is in contact with the liquid drug in the barrel 101.

[0109] Examples

[0110] In an example, the method is performed in a suitably modified but otherwise conventional vent tube apparatus, wherein the vent tube is replaced with a simple clamp for holding the piston. Before the piston extension rod begins to deform, the piston is placed relatively high above the barrel opening. Specifically, the piston is placed in an insertion tube, in this case, the inner diameter of the insertion tube is slightly larger than the inner diameter of the syringe. Fig.11 The steps of this process are shown in FIG. 1 , where the reference numerals of item C are understood to be related to items A, B, and D to H. A shows the pre-filled cylinder 101 before the piston 3 is inserted, and B shows the piston 3 inserted into the insertion tube 102. C shows the piston extension rod 1 extending from the connector 21 and being inserted into the cavity of the piston 3 ( Fig.11 D shows the piston extension rod 1 moving at the expected speed to show the deformable sealing element ( Fig.11 1 and 2 ), wherein arrows indicate the movement direction and the narrowing direction of the piston extension rod 1, respectively. E shows that the piston 3 has moved to its final position before stopping the movement of the piston extension rod 1. F and G show the piston 3 in its final position, wherein the deformable sealing element abuts the inner wall 13 of the barrel, and the piston extension rod 1 is being removed. H shows the syringe 100 in its final pre-filled stage. Fig.12 In this setup, an installation speed of 300 mm / s is used, and a minimum of 10 mm / s is used.2 Accelerate and decelerate.

[0111] Reference in Table 1 Fig.13 Provides relevant parameters.

[0112] Table 1

[0113]

[0114] Thus, the method of the present invention is applied via high speed industrial machinery at rates up to 60,000 units / hour, but the method can also be performed using smaller tabletop equipment in an isolator for small batches or custom applications.

[0115] List of Reference Numerals

[0116] 1 Piston extension rod

[0117] 100 Syringes

[0118] 101 Cylinder

[0119] 102 Insertion tube

[0120] 103 Inner wall of the insertion tube

[0121] 10 Cavity

[0122] 11 Piston deformable sealing element

[0123] 12 Open Channel

[0124] 13 Inner wall of cylinder

[0125] 14 Air

[0126] 15 Piston outlet surface

[0127] 151 Actuating surface of piston

[0128] 16 Liquid medicine upper surface

[0129] 17 Exit end of cylinder

[0130] 18 Actuating end of cylinder

[0131] 19 Impact Surface

[0132] 20 Piston cavity base

[0133] 21 Connectors

[0134] 22 Cavity opening

[0135] 221 Helical internal thread

[0136] 23 Liquid medication

[0137] 3 Piston

[0138] 31 Piston body

[0139] 4 Length

[0140] 5 Upper part of the container

[0141] 6 Piston cavity length

[0142] 7 Stopper.

Claims

1. A method for installing a piston in a prefilled syringe, the method comprising the steps of: providing a syringe comprising a barrel having a longitudinal axis and an inner wall, and a liquid drug defining an upper drug surface, providing a piston having a cavity extending from a piston cavity opening to a piston cavity base to define a piston cavity total length and a deformable sealing element, inserting the piston into the cylinder so that the deformable sealing element abuts against the inner wall of the cylinder and seals the annular gap between the piston and the inner wall of the cylinder, providing a piston extension rod having an overall length at least 5% greater than an overall length of the cavity and having an impact surface, inserting the piston extension rod into the piston cavity and striking the piston cavity base with the striking surface at a speed of at least 25 mm / min to extend the piston along the barrel longitudinal axis and cause constriction of the deformable sealing element, thereby causing air bypass in the space between the piston and the upper surface of the medicament, and The piston extension rod velocity is maintained to move the piston to the final piston position.

2. A method for installing a piston in a prefilled syringe according to claim 1, wherein: The piston includes a deformable sealing element at an axial position away from the piston cavity opening, and a widened cavity section at the axial position of the deformable sealing element, the widened cavity section having an axial extension in the range of 5% to 70% of the total length of the piston cavity, and the widened cavity section having a lateral extension larger than the piston cavity opening.

3. A method for installing a piston in a prefilled syringe according to claim 2, wherein: The lateral extension of the widened cavity section is in the range of 50% to 90% of the outer diameter of the deformable sealing element.

4. A method for installing a piston in a prefilled syringe according to any one of claims 2 or 3, wherein: The piston has a tubular section for receiving the piston extension rod, the tubular section extending from the piston cavity opening to the widened cavity section.

5. A method for installing a piston in a prefilled syringe according to any one of claims 1 to 4, wherein: The piston extension rod has a diameter, and the cavity opening has a diameter that is 10% to 500% greater than the diameter of the piston extension rod.

6. A method for installing a piston in a prefilled syringe according to any one of claims 1 to 5, wherein: The cylinder has an inner diameter and an outlet at an outlet end, which is opposite to the actuation end, and the piston has a piston body having a transverse diameter smaller than the inner diameter of the cylinder, and the deformable sealing element surrounds the plug body and has an outer diameter 1.5% to 10% larger than the inner diameter of the cylinder.

7. A method for installing a piston in a prefilled syringe according to any one of claims 1 to 6, wherein: The piston has an actuation surface opposite the outlet surface, and wherein, in the final piston position, the outlet surface of the piston is in contact with the liquid drug in the barrel.

8. A method for installing a piston in a prefilled syringe according to any one of claims 1 to 7, wherein: The length of the piston extension rod is 5% to 50% longer than the total length of the piston cavity.

9. A method for installing a piston in a prefilled syringe according to any one of claims 1 to 8, wherein: The speed is in the range of 50 mm / min to 120,000 mm / min.

10. A method for installing a piston in a pre-filled syringe according to any one of claims 1 to 9, wherein: The piston extension rod has an outward protrusion and / or a groove on its longitudinal axis, which is suitable for interacting with the piston cavity.

11. A method for installing a piston in a pre-filled syringe according to any one of claims 1 to 10, wherein: At least one of the deformable sealing element, the piston and the deformable sealing element has a Shore A hardness in the range of 40-75.

12. A method for installing a piston in a pre-filled syringe according to any one of claims 1 to 11, wherein: At least one of the deformable sealing element, the piston and the deformable sealing element is made of a thermoplastic elastomer.

13. A kit of parts comprising: a syringe comprising a barrel having a longitudinal axis and an inner wall; a piston having a piston body having an actuation surface opposite the outlet surface and a transverse diameter, the piston including a deformable sealing element surrounding the piston body at an axial position from the actuation surface, the deformable sealing element having an outer diameter greater than the transverse diameter, the piston having a cavity extending from a piston cavity opening to a piston cavity base to define a total piston cavity length, the cavity including a tubular section extending from the piston cavity opening and having an entry diameter, and a widened cavity section at the axial position of the deformable sealing element, the axial extension of the widened cavity section being within the range of 5% and 50% of the total piston cavity length, and the widened cavity section having a lateral extension greater than the entry diameter; as well as A piston extension rod has a diameter equal to or less than the entry diameter and a length at least 5% greater than the total length of the cavity.

14. The kit of parts according to claim 13, wherein: The lateral extension of the widened cavity section is in the range of 50% to 90% of the outer diameter of the deformable sealing element.

15. A kit of parts according to any one of claims 13 or 14, wherein: The tubular section extends from the piston cavity opening to the widened cavity section.

16. A kit of parts according to any one of claims 13 to 15, wherein: The piston extension rod has a diameter, and the entry diameter is in the range of 10% to 500% greater than the diameter of the piston extension rod.

17. A kit of parts according to any one of claims 13 to 16, wherein: The length of the piston extension rod is 5% to 50% longer than the total length of the piston cavity.

18. A kit of parts according to any one of claims 13 to 17, wherein: The piston extension rod has an outward protrusion and / or a groove on its longitudinal axis, which is suitable for interacting with the piston cavity.

19. A kit of parts according to any one of claims 13 to 18, wherein: The deformable sealing element, or the piston and the deformable sealing element, has a Shore A hardness in the range of 40-75.

20. A kit of parts according to any one of claims 13 to 19, wherein: At least one of the deformable sealing element, the piston and the deformable sealing element is made of a thermoplastic elastomer.

21. A kit of parts according to any one of claims 13 to 20, wherein: The piston extension rod extends from the connector.

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