Medical containers

Abstract

The present invention relates to a medical container (1) for storing liquid pharmaceuticals. The medical container is made by solidifying a thermoplastic elastomer (TPE) from a molten state, and the glass transition temperature (TPE) of the thermoplastic elastomer is g The invention also relates to a method for manufacturing a medical container.

Description

[Technical Field]

[0001] This invention relates to a medical container for storing liquid drugs. The medical container comprises a cylinder and a stopper inserted into the cylinder. The medical container allows for the storage of sensitive drugs at extreme temperatures while maintaining closure integrity. This invention also relates to a method for manufacturing the medical container. [Background technology]

[0002] In the pharmaceutical world, biological products are becoming increasingly complex and sensitive, and their characteristics necessitate certain precautions regarding the packaging of such parenteral formulations. Biological products consist of complex combinations of proteins, peptides, amino acids, nucleic acids, or sugars produced through various biotechnological processes. Cooling is generally required to maintain chemical stability, for example, the formation of potentially harmful protein aggregates, and bacterial contamination must always be avoided. In contrast, most small molecules can be stored at ambient temperature.

[0003] For many years, and even now, cold chain storage is regulated according to ICH guidelines, and in most cases, injectable drugs are stored at room temperature, or more commonly between 2 and 8°C, a temperature range used across a wide range of formulations.

[0004] Over the past decade, there has been an increase in the development of innovative biological products, particularly those sensitive to temperature, requiring use under cryogenic conditions. Such products fall into large molecular segments, namely biological drugs, especially mRNA preparations, cell therapies, and even gene therapies. For example, in response to the COVID-19 pandemic, mRNA-based vaccines became available and were used on a large scale, but due to the low stability of mRNA, they now require storage at extremely low temperatures, such as below -80°C.

[0005] Drugs and vaccines can be stored in vials from which injectable doses are prepared when needed, or in pre-filled syringes (PFS) provided in a ready-to-use form. Whether drugs or vaccines are stored in vials or PFS, the storage temperature requirements are the same. Both vials and PFS include a container and a stopper, the stopper typically made from an elastomer material intended to ensure the integrity of the container. The container may be made from glass or a rigid polymer.

[0006] Vial stoppers are made from elastomer materials, with rubber being widely used, but thermoplastic elastomers (TPEs) have also been proposed; see, for example, WO00 / 73163 and EP0174032. TPEs are also used for syringe stoppers; see, for example, WO2014 / 194918, WO2017 / 157396, and WO2019 / 185101.

[0007] The stoppers for vials or syringes, such as rubber or elastomers, are elastomeric at ambient temperature and generally have a temperature below the temperature at which the material becomes brittle. This temperature is called the glass transition temperature (T). g ) is called. The required freezing conditions are T of the elastomer filtration material used in vials and PFS. g This includes temperatures below -196°C, and in some cases, extreme temperatures below -196°C.

[0008] Furthermore, materials generally contract or expand in response to temperature, and the materials of the container and stopper can be described by their coefficient of thermal expansion (CTE). Therefore, upon cooling, both the container and stopper will contract according to their respective CTEs.

[0009] The combination of material shrinkage and the transition of stopper materials to a brittle phase presents challenges to storing drugs and vaccines at extremely low temperatures, which can, among other things, translate into an increased risk of microbial contamination into the container. Therefore, such freezing temperatures require equally suitable and capable packaging components, and it is crucial to ensure that any contamination, including microbial intrusion, is avoided before, during, and ultimately after thawing.

[0010] For several reasons, currently available elastomeric closure solutions for medical containers are not optimized for significantly lower freezing temperatures.

[0011] Currently, most container closures for PFS, such as elastomer plungers and vial stoppers, are made from butyl rubber, which can be further coated with perfluorinated compounds such as polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer (ETFE), or similar coatings. These coatings are commonly used to prevent undesirable rubber leaching from contaminating the formulation and, in the case of PFS, can also provide lubrication. However, the very different material properties between butyl rubber and perfluorinated surface coatings are a major factor in the selection of elastomer closures. g Freezing at temperatures below a certain level presents challenges in maintaining the critical container closure integrity (CCI) of medical containers, ultimately leading to a lack of precautions against microbial intrusion and thus a risk of contamination of medical formulations. Hereinafter, the terms elastomer stopper, PFS plunger, plunger, vial stopper, and stopper may be used interchangeably.

[0012] For example, butyl rubber is volatile at approximately -60°C. g It has a PTFE coating, but the surrounding PTFE coating has a significantly low T gThe coating exhibits little to no brittleness at low temperatures of around -200°C. This significant difference in materials leads to improper closure behavior, as butyl rubber tends to shrink more than PTFE coatings, which may not shrink at all depending on the degree of freezing. Furthermore, butyl rubber PFS plungers and vial stoppers generally shrink by about 4.5%, thus causing an excessive reduction in the cross-sectional diameter of the stopper during freezing, resulting in an imminent risk of leakage. These improper differences in materials and their behavior during rapid freezing of medical containers from -80°C to below -90°C impose different material responses from the combined closure material for coated butyl rubber closures. This can cause localized folding of the coating, thereby partially or completely destroying the seal between the closure and the medical container wall, and thus causing CCI failure. The folding of the coating ultimately allows for microbial intrusion and contamination of the medical formulation.

[0013] Aseptic Technologies SA (Jambreu, Belgium) offers a vial technology known as AT-Closed Vial, in which the vial is closed using a stopper prepared from TPE. Aseptic's approach involves filling the vial by penetrating the TPE stopper and then resealing the stopper using laser welding. This technology allows the vial to be T g Aseptic involves freezing below the limit, and TPE is T gIt has been observed that it is a particularly suitable material for use in stoppers for vials stored at sub-zero cryogenic temperatures. This is because the integrity of the container is maintained by the TPE stopper. This technology was described by Aseptic Technologies in Container Closure Integrity at Cryogenic Temperatures: How the AT-Closed Vial® ensures safe cryopreservation of novel therapies, 2020, and is available from the Aseptic Technologies SA download center (www.aseptictech.com / en / download-center). The TPE designed to absorb laser light is disclosed in WO2004 / 018317, WO2005 / 014419, WO2005 / 005128, and WO2006 / 122757; see also WO2007 / 020366. http: / / www.aseptictech.com / en / download-center

[0014] The object of the present invention is to provide a medical container that enables storage at extreme temperatures. A further object of the present invention is to enable the medical container to be used at ambient temperature.

Summary of the Invention

[0015] The present invention relates to a medical container for storing liquid pharmaceuticals, the medical container comprising a cylinder extending along a longitudinal axis, the cylinder having an inner wall, an inlet opening at an inlet end, and a bottom end opposite the inlet end, the inlet opening defining a transverse diameter, a stopper inserted into the cylinder through the inlet opening, the stopper having a stopper body and a sealing surface surrounding the stopper body and having an outer diameter larger than the transverse diameter so as to seal an annular gap between the inner wall and the stopper body when the stopper is inserted into the cylinder, the stopper being made of a thermoplastic elastomer (TPE), the stopper having a glass transition temperature (T gexposed to a temperature below and a liquid medicament within the cylinder between the bottom end and the stopper.

[0016] The medical container comprises a cylinder having an inlet end and a bottom end opposite the inlet end. The medical container has a "bottom end", but the term "bottom end" is not intended to mean any particular orientation of the medical container, but simply that the bottom end is opposite the inlet end. The bottom end is also referred to as the closed end, and the two terms may be used interchangeably. The cylinder can be made from any material commonly used for medical containers such as vials and syringes. For example, the cylinder can be made of glass, such as borosilicate glass, or a polymer, such as cyclic olefin copolymer (COC), such as TOPAS polymer (supplied by TOPAS Advanced Polymers GmbH), cyclic olefin polymer (COP), such as Zeonor, polypropylene (PP), polyethylene (PE), or polystyrene. Borosilicate glass generally has superior barrier properties compared to plastics. COC and COP polymers are advantageous due to their excellent barrier properties and thus are suitable for the need for long-term storage of pharmaceuticals.

[0017] Medical containers are equipped with stoppers. In this context, the term “stopper” is used regardless of the type of medical container, for example, when the medical container is a syringe, e.g., a pre-filled syringe (PFS), or a vial. However, depending on the specific use of the stopper and the corresponding medical container, the stopper may also be called, for example, a “piston” when the medical container is a syringe, or a “closure” when the medical container is a vial. In this context, regardless of whether the medical container is a vial, a PFS, or another type of medical container, the stopper is considered to have an “acting surface” that faces the outer periphery of the medical container after the stopper has been inserted into the medical container, e.g., a cylinder, and the surface of the stopper opposite the acting surface is called the “inner surface” of the stopper. However, in this context, the terms “acting surface” and “inner surface” are also used in the description of the stopper regardless of insertion into the medical container. Generally, the stopper is considered to have a length between the acting surface and the inner surface, and this length is also called the “stopper length.”

[0018] A stopper comprises a stopper body and a sealing surface surrounding the stopper body. Generally, any portion of the stopper that contacts the inner wall of the cylinder when the stopper is inserted into the cylinder, thereby sealing the annular gap between the inner wall and the stopper body, is considered the sealing surface. For example, the sealing surface may be the surface of the stopper body or a section of the stopper body, the section of which contacts the inner wall of the cylinder after the stopper is inserted into the cylinder, for example, along the length of the stopper body, and the sealing surface, for example the stopper body, may have an outer diameter that is 0.5% to 10%, for example 1% to 9%, 2% to 8%, 3% to 7%, or 4% to 6% larger than the transverse diameter when the stopper is in a relaxed state. In a particular example, the outer diameter is 2% to 5% larger than the transverse diameter. In one example, the stopper has a deformable sealing element, in particular a convex deformable sealing element, and the sealing surface is any section of the deformable sealing element that contacts the inner wall of the cylinder. If the stopper has a deformable sealing element, particularly a convex deformable sealing element, the deformable sealing element also has an outer diameter, and the outer diameter of the deformable sealing element is larger than the outer diameter of the stopper body. For example, the outer diameter of the stopper body may be smaller than the transverse diameter, and the outer diameter of the deformable sealing element may be 0.5% to 10%, e.g., 1% to 9%, 2% to 8%, 3% to 7%, or 4% to 6%, larger than the transverse diameter when the stopper is in a relaxed state. In a particular example, when the stopper and the deformable sealing element are in a relaxed state, the outer diameter is 2% to 5% larger than the transverse diameter. The term “outer diameter” can refer to the diameter of the deformable sealing element, or, if the stopper does not have a deformable sealing element, the diameter of the stopper body, as is clear from the context. In one example, the medical container is a PFS, and the stopper has a convex deformable sealing element having an outer diameter that is 1% to 8%, 2% to 7%, or 3% to 6% larger than the transverse diameter when the stopper is in a relaxed state. In another example, the medical container is a vial, and the stopper has a convex, deformable sealing element that, when the stopper is in a relaxed state, has an outer diameter that is 1% to 8%, 2% to 7%, or 3% to 6% larger than the transverse diameter.

[0019] A cylinder generally has an inner wall and an outer wall and extends along its longitudinal axis. A cylinder also has an inlet opening at one end and a bottom end opposite the inlet end. Generally, the inlet opening extends into the cylinder from the inlet end. Both the cylinder and the inlet opening have cross-sectional shapes, and the cross-sectional shape and size of the inlet opening may be the same as that of the cylinder. If the inlet opening has a different cross-sectional shape and / or dimensions as necessary, the cylinder is considered to define an inlet section having a transverse diameter, and a container section between the inlet section and the bottom end, the container section having a different cross-sectional shape and / or dimensions than the inlet section. If the cylinder has an inlet section, the inlet opening is located in the inlet section. In one example, the inlet opening and the cylinder have the same cross-sectional shape and dimensions, and the medical container is a PFS. In another example, the inlet opening and the cylinder have the same cross-sectional shape and dimensions, and the medical container is a vial. In a further example, the inlet opening and cylinder may have at least different cross-sectional dimensions and optionally different cross-sectional shapes, and the medical container may be a vial. If the medical container is a vial, the vial may have any size in accordance with ISO standard 8362, or the vial may have any size in accordance with standard YBB00302002.

[0020] The cross-sectional shape of the cylinder, inlet opening, and, if associated, the inlet section may be freely selected. If the cross-sectional shape is not circular, the maximum cross-sectional dimension of the shape may be referred to as the “diameter” in this context. The cylinder, inlet opening, and, if associated, the inlet section preferably have a circular cross-section. The cross-section may also be oval, elliptical, polygonal, etc. If the medical container is PFS, the transverse diameter, e.g., the inner diameter, may have any value conventionally used in syringes. For example, the medical container may be PFS, and the cylinder may have a transverse diameter in the range of 2 mm to 12 mm, such as 4.65 mm, 6.35 mm, 8.80 mm, or 11.85 mm, but may have a larger value according to the present invention.

[0021] The medical container of the present invention is suitable for storing liquid pharmaceuticals. The liquid pharmaceutical is generally contained in the space between the bottom end and a stopper inserted into the inlet opening within the cylinder. The space between the bottom end and the stopper may also be referred to as the internal space of the cylinder. In this context, the stopper has a surface facing the medical liquid, for example, an inner surface, and a surface facing away from the medical liquid, for example, an operating surface, for example, the outer periphery of the medical container.

[0022] The stopper is made from TPE. Specifically, the stopper may be made by solidifying TPE from a molten state to, for example, the intended form of the stopper. Any manufacturing method that can solidify a molten thermoplastic polymer in particular to its final form can be used to manufacture the stopper of this disclosure. For example, the stopper may be injection molded from TPE. Generally, when any part of the stopper, for example, a deformable sealing element, is not deformed, for example, when the stopper is not inserted into a medical container, the corresponding part, for example, the deformable sealing element, is considered to be in a “relaxed state,” i.e., a state of non-deformation. In the context of the present invention, “deformable sealing element” may refer to any section of the stopper having a diameter greater than the diameter of the stopper body so that the deformable sealing element surrounds the stopper body. In the context of the present invention, the term “diameter” does not mean that the corresponding element, for example, the stopper body or the deformable sealing element, must have a circular cross-section, i.e., a cross-section in the lateral plane of the stopper, and any desired cross-sectional shape may be used for the stopper body and / or the deformable sealing element. For example, the cross-section may be a polygon, such as a triangle, square, pentagon, or hexagon, and the term diameter in this case refers to the cross-sectional dimension, such as the maximum cross-sectional dimension of the corresponding cross-sectional shape. The polygonal cross-section is not limited to a polygon with equal angles and side lengths, i.e., a regular polygon, and similarly, the cross-section may be an ellipse. The cross-sectional shape of the inlet opening, and the inlet section where applicable, and optionally the vessel section of the cylinder also correspond to the cross-sectional shape of the deformable sealing element. When the stopper has a deformable sealing element, the stopper body generally does not interact with the inner walls of the cylinder inlet opening, inlet section, and vessel section, where applicable, and the cross-sectional shape of the stopper body can be freely selected regardless of the cross-sectional shape of the deformable sealing element.

[0023] A cylinder, and therefore a medical container, also has an inlet opening and optionally an inlet section at the inlet end, and a stopper is inserted into the cylinder through the inlet opening. Thus, the stopper has a stopper body, a sealing surface, and optionally a deformable sealing element surrounding the stopper body and having an outer diameter larger than the transverse diameter, and as a result the sealing surface, or the deformable sealing element if present, seals the annular gap between the inner wall and the stopper body when the stopper is inserted into the cylinder.

[0024] In one example, the stopper has a convex, deformable sealing element. In particular, the stopper may have a convex, deformable sealing element on the stopper body. For example, the stopper body may have a diameter smaller than the transverse diameter, and the deformable sealing element may have a diameter larger than the transverse diameter so that the deformable sealing element provides a sealing surface. 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 intended, but the deformable sealing element preferably has a point that represents the maximum extension from the central axis of the stopper, for example, a point in the axial plane of the stopper. When the deformable sealing element has a convex surface, the force acting on the inner wall of the container through the deformable sealing element is maximized because the deformation of the deformable sealing element in the direction of the longitudinal axis of the cylinder is minimized. Contact may be, for example, the contact interface between the deformable sealing element and the inner wall of the cylinder. The degree of contact between the deformable sealing element and the inner wall of the injector cylinder into which the stopper is inserted is preferably as small as possible. In one example, the deformable sealing element has an outer diameter that is 1.5% to 10%, for example 2% to 5%, larger than the transverse diameter when the deformable sealing element is in a relaxed state. A convex deformable sealing element on a stopper injection-molded from TPE is particularly advantageous because the tolerances provided by injection molding are lower compared to technologies such as vulcanization, which are commonly used in the manufacture of conventional rubber pistons. If the medical container is a PFS, the stopper can be injection-molded to a size that provides CCI and simultaneously has a low release force (BLF). If the medical container is a vial, the stopper can be injection-molded to a size that is large enough to ensure CCI compliance without the stopper being too large to be inserted into the inlet opening of the medical container cylinder. For example, if the stopper has a deformable sealing element, the outer surface may be in the range of 2% to 7% larger than the transverse diameter, thereby ensuring CCI without the need for a crimp cap. In one example, the stopper has a deformable sealing element, and the medical container does not include a crimped cap, and in particular, the medical container does not need to include an aluminum crimped cap.

[0025] The stopper of the medical container is prepared by solidifying the TPE from a molten form. For example, the stopper may be injection molded from TPE. Generally, thermoplastic polymers have a solid phase, and in particular, TPE is solid at ambient temperature and lower temperatures, and the melting point allows the polymer to melt by increasing the temperature and re-solidify by decreasing the temperature again, thereby recovering the solid form or state it had before melting. Thus, thermoplastic polymers can be injection molded. The stopper may be injection molded from TPE, but it is also contemplated that other preparation methods may be used for the stopper. For example, the stopper may be compression molded. For the same reason that injection molding is useful for processing TPE, stoppers made of TPE can also be manufactured by extrusion molding. Thus, in one example, the stopper is prepared using extrusion molding.

[0026] The stopper is exposed to a temperature T of the TPE g lower than. Generally, T g can be defined for a polymer material, and "hard" polymers are typically used at temperatures lower than its T g , while "soft" polymers, such as elastomers, are typically used at temperatures higher than its T g . Cooling the polymer below its T g can result in the brittleness of the polymer being observed, and the determination of the T value of a particular polymer, including TPE, is within the knowledge of those skilled in the art. The TPE relevant to the present disclosure generally has a T value in the range of -50°C to -70°C. For example, Evoprene R9970 has a T of about -67°C. g Thereby, when the PFS or vial of the present disclosure containing a sensitive drug, such as an mRNA-based drug, is subjected to a typical storage temperature of -80°C or lower, the PFS or vial is cooled below the T of the TPE of the stopper of the medical container. The stopper is exposed to a temperature T of the TPE g lower than. However, this exposure may alternatively be at T g g g lower than. However, this exposure may alternatively be at T g lower than. However, this exposure may alternatively be at Tg The temperature may be referred to without referring to the stopper. For example, in another expression, the stopper is exposed to temperatures below -50°C, such as -60°C, -70°C, or -80°C. g The duration of exposure to temperatures below -50°C, e.g., -60°C, -70°C, or -80°C, is not significant. Generally, medical containers are cooled to these temperatures to store medical containers containing liquid drugs for periods such as several weeks or months, otherwise the TPE's T g The cooling effect on temperatures below a certain level is thought to occur instantaneously, for example, after 10 seconds.

[0027] TPE refers to a special type of thermoplastic material that is an elastomer in solid form, resulting in reversible deformation, such as instantaneous reversibility. Different types of TPE exist, and certain types of TPE are known as styrene-based TPEs. Styrene-based TPEs contain block copolymers of polystyrene and other polymer components, where the styrene portion is generally rigid and the other components are generally flexible, with the flexible components providing elasticity. A block copolymer may contain two or more blocks of polymers, for example, two, three, or four, and the same polymer may be contained in different blocks, as reflected in the polymer name. Styrene-based block copolymers are generally abbreviated as "SBC" in this context. Exemplary non-styrene polymer components of SBCs are ethylene, butylene, and butadiene. By having a rigid portion, such as a styrene portion, and a flexible portion, such as an ethylene, butylene, or butadiene portion, SBCs acquire thermoplasticity while also retaining the elasticity of SBCs in solid form. Specific examples of SBCs include hydrogenated H-SBCs and non-hydrogenated SBCs. Related styrene-based TPEs include styrene-butadiene styrene (SBS), styrene-ethylene butadiene styrene (SEBS), styrene-ethylene butylene styrene (SEBS), styrene-butadiene (styrene-butadiene rubber, or SBR), styrene-isobutylene styrene (SIBS), styrene-isoprene styrene (SIS), styrene-ethylene propylene (SEP) or styrene-ethylene propylene styrene (SEPS), and methacrylate butadiene styrene (MBS). In addition to styrene block copolymers, styrene-based TPEs may also include other polymers, such as polyolefins like polyethylene or polypropylene, and other components, such as processing aids, oils, fillers, and stabilizers.Various TPEs are known by the following trade names: Styroflex (INEOS) and Styrolux (BASF Corporation, Wyandot, Michigan, USA), Septon Q, Septon V, and Hybar (Kuraray America, Inc., Houston, Texas, USA), Maxelast TPE (Nantong Polymax Elastomer Technology Co., Ltd), GLOBALPRENE Polymers (LCY Chemical Corporation), Elexar and Monprene (Teknor Apex Company), Elastocon series (Elastocon TPE Technologies, Inc.), TPR (Washington Penn), Evoprene (Alpha Gary), Versaflex, OnFlex, Versalloy, Versollan, Dynaflex (GLS Thermoplastic Elastomers), Sevrene (Vichem Corporation), Vector (Dexco Polymers LP), Calprene and Solprene (Dynasol), Multiflex TEA and Multiflex TPE (Multibase, Inc.), Europrene Sol T (Polimeri Europe), Sunprene (PolyOne), Leostomer (Riken Technos Corporation), RTP 2700 and 6000 series (RTP), Invision (A. Schulman), Dryflex (VTC Elastotechnik), Quintac (Zeon), Megol and Raplan (API spa), Asaprene and Tufprene (Asahi Kasei), Lifoflex (Miiller Kunststoffe, Germany), Thermolast (Kraiburg TPE GmbH & Co.KG, Waldkraiburg, Germany), or Kraton, e.g., Kraton D, Kraton G, or Kraton FG (Kraton Polymers, Houston, Texas, USA).

[0028] The TPE of the stopper preferably contains another polymer, such as polyethylene or polyolefin such as polypropylene, and the TPE may further comprise other components. However, it is preferable that the other polymers and other components do not comprise perfluorinated compounds. In the context of the present invention, a perfluorinated compound is an organic molecule in which one or more carbon atoms have only fluorine atoms in addition to bonds to other carbon atoms, such as single bonds. Therefore, it is preferable that the TPE does not comprise polytetrafluoroethylene (PTFE) and ethylene-tetrafluoroethylene copolymer (ETFE). It is even more preferable that the TPE does not contain polymers having a melting point above 170°C or above 150°C, such as polyolefin polymers. It is particularly preferable that the stopper does not contain perfluorinated compounds on its surface, for example, it is preferable that the stopper is not coated with perfluorinated compounds, such as PTFE or ETFE.

[0029] Generally, stoppers are homogeneous and are composed of the same material throughout the entire volume of the stopper, including the deformable sealing element and the stopper body. Stoppers preferably do not contain coatings, such as PTFE or ETFE coatings, although it is also intended that stoppers may be coated with materials that do not contain fluorine atoms, in particular perfluorinated compounds. For example, stoppers may be coated from the gas phase using vapor deposition, such as atomic layer deposition, or stoppers may be coated from a liquid, such as liquid phase deposition. Homogeneity is relevant regardless of the presence of additional components in the TPE. For example, the TPE may be SBC, or the TPE may be SPC with additional components. Additional components may or may comprise polymers other than SBC, such as polyolefins such as polyethylene and / or polypropylene, and oils. The TPE may also comprise fillers and other auxiliary components. In this context, the term "TPE" refers to the material of the stopper. Due to their elasticity, TPEs are generally classified according to their hardness, measured according to the Shore scale, particularly the Shore A scale. For example, TPE may have a Shore A hardness in the range of 30 to 90, e.g., 40 to 75, e.g., 40 to 70, 45 to 65, or 50 to 60, when the medical container is a vial, and in the range of 60 to 90, e.g., 70 to 80, when the medical container is a PFS. "Shore hardness" is also called "Shore durometer," and these terms may be used interchangeably. However, it should be noted that the Shore A durometer is only one of many methods for characterizing the material properties of a chosen material, and other tests may be used to characterize the material. The measurement of Shore A hardness is well known to those skilled in the art, and in particular, Shore A hardness is commonly recorded according to the ISO 868 standard. The hardness of TPE is generally affected by the composition of the TPE, for example, TPE may contain oil to reduce its Shore A hardness.The proportion of oil in a TPE generally varies depending on the Shore hardness of a given embodiment of the TPE, with a Shore A value of 50 typically containing an oil proportion in the range of 50 to 55 by weight, while a Shore A value of 72 typically contains an oil proportion in the range of 30 to 40. Therefore, in one example, the stopper is made from a TPE comprising a block copolymer providing thermoplasticity, e.g., SBC, and oil, e.g., process oil or mineral oil. In a specific example, the stopper is made from an SBC-based TPE, e.g., SEBS or SBS, containing oil in the range of 50% to 55% by weight and having a Shore A hardness in the range of 45 to 55. For this stopper, the medical container is preferably a vial. In another specific example, the stopper is made from an SBC-based TPE, e.g., SEBS or SBS, containing oil in the range of 30% to 40% by weight and having a Shore A hardness in the range of 65 to 75. For this stopper, the medical container is preferably a PFS.

[0030] TPE may contain polymers other than polymers, such as polyethylene or polyolefins such as polypropylene, i.e., copolymers, such as SBC, and TPE may further comprise other components. These other components may include slip agents. Generally, slip agents can be used to avoid material degradation during the formulation of TPE and to facilitate the release of polymers from molds used in injection molding, but slip agents can also provide a lubricating effect when the surface of the TPE comes into contact with the surface of another material, such as glass or a polymer. Slip agents are typically derived from waxes and / or fatty acids, such as polyethylene wax, paraffin wax, wax esters, metal stearate salts, long-chain fatty acids, long-chain fatty acid amides (compounds known as oleamide and erucamide) and their salts, which can be used as slip agents. Specific slip agents are salts of divalent metals and stearates, such as magnesium stearate, calcium stearate, or zinc stearate. In one example, TPE comprises a slip agent, for example, in the TPE or on the surface of the TPE. In another example, TPE does not comprise a slip agent. In one example, the TPE does not contain a slip agent. In a specific example, the surface of the stopper, for example, the surface of the TPE, does not contain a slip agent. In a specific example, the TPE does not have a slip agent based on divalent metal ions and stearates. In particular, salts of divalent metal ions and stearates are generally considered undesirable in substances that come into contact with pharmaceuticals, especially liquids, and therefore, salts of divalent metal ions and stearates should not be included in stoppers for medical containers such as vials or PFSs. Despite providing a lubricating effect, slip agents are not necessary for PFSs. Therefore, in one example, the medical container is a PFS, the TPE does not have a slip agent, and the stopper does not contain an external lubricant, especially a silicone lubricant. Similarly, it is preferable that the stopper does not contain perfluorinated compounds, especially on the surface of the stopper.

[0031] TPE may contain fillers. Fillers are typically particles with appropriate properties and can generally affect the physical, mechanical, and / or optical properties of the TPE. Fillers may be, for example, pigments to provide color to the TPE or to increase its opacity. Fillers may be, for example, inorganic particles, such as metals or other elements, such as oxides of aluminum and / or silicone. Fillers may be, for example, kaolin. Generally, fillers increase the hardness of the TPE, such as the Shore A hardness, and the more filler there is, the harder the TPE becomes. Therefore, the amount of filler can be selected from the desired hardness, along with the oil content in the TPE. Fillers can also reduce material penetration as the amount of filler increases. If present, fillers, such as kaolin, can constitute up to 20% by weight of the TPE. For example, TPE may contain fillers, such as kaolin, in amounts ranging from 1% to 15% by weight, or from 2% to 10% by weight. If the TPE contains a filler, it is preferable that the filler does not contain a pigment.

[0032] TPE may contain polyolefins, such as polyethylene or polypropylene. For example, TPE may contain polyethylene or polypropylene, or a combination or mixture of polyethylene and polypropylene, in an amount ranging from 5% to 40% by weight, for example, from 10% to 30% by weight, or from 15% to 25% by weight.

[0033] In certain embodiments, the TPE comprises SBC, polyolefin, and process oil. For example, the SBC may be SEBS or SBS, and the polyolefin may be polypropylene. The TPE may contain SBC in the range of 20% to 70% by weight, for example, 30% to 60% by weight, polyolefin in the range of 1% to 20% by weight, for example, 5% to 15% by weight, and oil in the range of 20% to 60% by weight, for example, 30% to 40% by weight.

[0034] TPEs may also be defined by their compression set value, which corresponds to the deformation remaining after the force applied to the TPE is removed (and is typically expressed as a percentage). Compression set values ​​are typically recorded over a specific time period, for example, in the range of 18 to 96 hours or 22 to 72 hours, and over a specific temperature, in accordance with the ISO 815 standard, for example. In the context of this disclosure, compression set is generally recorded at “ambient temperature,” for example, in the range of 10°C to 40°C. However, the temperature range may extend beyond ambient temperature, for example, to 23°C to 100°C. Generally, the higher the temperature, the shorter the time associated with recording compression set. Compression set should generally be as low as possible, but for the stoppers of this disclosure, compression set may be in the range of 15% to 45% at ambient temperature, for example. At higher temperatures, such as 100°C, the compression set is typically higher, for example, up to 60% or 50%. However, at ambient temperatures, the compression set is preferably in the range of 10% to 45%. The compression set value is generally related to pre-filled injectors in which the stopper is inserted into the cylinder, and therefore compresses when the pre-filled injector is stored for a long period of time. Correspondingly, the compression set value is also related to vials with stoppers made from TPE.

[0035] Particularly relevant TPEs are those supplied by Alphagary (Melton Mowbray, Leicestershire, UK), such as Evoprene, for example, TPEs called the G series or R series. For example, the medical container may be a PFS, which may have a stopper, such as a piston, made from Evoprene G970 or Evoprene R9970. Alternatively, the medical container may be a vial, which may have a stopper made from Evoprene G968, G967, G962, G958, or G960, or Evoprene R9068 or R9067. Evoprene G970 and Evoprene R9970 are also particularly suitable for single-dose vials.

[0036] The medical container may be a PFS. In particular, the medical container may be a PFS having a cylinder with a diameter equal to the transverse diameter of the inlet opening. As it is a pre-filled syringe, the medical container contains liquid medication, and the stopper is made of TPE before filling the medical container with liquid medication. g It is exposed to temperatures below a certain level. Therefore, for example, a medical container is filled with liquid medication before inserting a stopper into the inlet opening, and then the TPE T g The PFS may be cooled to a temperature below [temperature]. Surprisingly, the inventors have found that when the syringe contains a stopper made of TPE, the syringe is made of TPE. g Cooled to a lower temperature, the TPE is cooled from the cooling stage, for example, to ambient temperature or a moderately lowered temperature, for example, 5°C or -18°C. g The syringe container closure integrity (CCI) can be maintained during cooling, and furthermore, the temperature of the TPE can be controlled. g We found that the temperature can be raised again from the ambient temperature or another temperature at which the liquid drug is injected into the patient, without losing any CCI. g Therefore, it is expected that polymer materials will become brittle, and combined with the shrinkage of the polymer material caused by cooling, the polymer material will lose its CCI, creating a risk of microorganisms entering syringes with stoppers made from polymer material. However, this does not happen astonishingly with PFS having stoppers made from TPE, and the CCI is retained. Furthermore, the inventors observed that the CCI is still retained even when cooling continues to lower temperatures, e.g., -80°C, -100°C, or -196°C, and in one example, the stopper was exposed to temperatures below -80°C, -100°C, or -196°C. Subsequently, the stopper was exposed to TPE T gIt can be heated from low temperatures to ambient temperature. Thus, the present invention provides a PFS that can be stored at cryogenic temperatures before being adjusted to ambient temperature to allow the liquid drug of the PFS to be injected into a patient. This effect has been observed for PFS having polymer cylinders, such as cylinders made from COC or COP, as well as glass cylinders.

[0037] By providing a medical container that can be stored at extreme freezing temperatures while maintaining CCI, the present invention provides a medical container particularly suitable for storing liquid drugs containing susceptible drugs, such as nucleic acids such as RNA, such as mRNA and DNA, or amino acid-based drugs, such as proteins or peptide-based drugs.

[0038] The inventors have found that the TPE has an extreme freezing temperature. g Furthermore, it was observed that even when exposed to -80°C, -100°C, or -196°C, PFS can be used without the need for an external lubricant, and moreover, the TPE does not need to contain a slip agent. In particular, the inventors have surprisingly found that the stopper can be used at the temperature of the TPE. gExposure to extreme temperatures does not cause the stopper to stick, for example, does not form a stronger bond between the TPE of the stopper and the inner wall of the cylinder, and as a result, the BLF of the PFS is generally not affected by exposure to extreme freezing temperatures. Therefore, in one example, the medical container is PFS and the stopper does not contain an external lubricant, such as silicone oil. In a further example, the medical container is PFS and the TPE of the stopper and / or the surface of the stopper do not contain a slip agent, such as a divalent metal and stearate, such as a salt of magnesium stearate, calcium stearate or zinc stearate. In yet another example, the medical container is PFS and the stopper does not contain an external lubricant, such as silicone oil, and the TPE of the stopper does not contain a slip agent, such as a divalent metal and stearate, such as a salt of magnesium stearate, calcium stearate or zinc stearate. Certain materials commonly used for syringe stoppers can cause what is known as the stick-in effect, where the stopper adheres to the cylinder wall after prolonged storage, thereby appearing to increase BLF (Blood Flow Rate). Therefore, the stick-in effect can be expected with respect to PFS (Prescription Fluid Flow). Accordingly, the present invention provides a lubricant-free PFS, which is particularly suitable for long-term storage because it minimizes or eliminates the stick-in effect, provides long-term sealing, avoids negative effects on the pharmaceutical from lubricants, while still maintaining a smooth end-user experience.

[0039] In one example, the medical container is a vial. In another example, the medical container is a PFS, particularly for parenteral administration of liquid medications. As a PFS, the medical container has a tubular outlet at its bottom, and the PFS may be a fully integrated tool ready for use in injecting liquid medications into a patient, for example, the medical container may include a piston rod and a subcutaneous injection needle. However, the medical container may also be a cartridge, etc., used with a suitable tool for injecting liquid medications into a patient. In one example, the medical container is a PFS, and its bottom has a tubular outlet. The tubular outlet may have any shape suitable for a syringe to inject the medical fluid contained in the cylinder of the medical container. Preferably, the tubular outlet extends from the bottom along the longitudinal axis of the cylinder, particularly away from the internal space of the cylinder. The tubular outlet may be equipped with a fitting for attaching a subcutaneous injection needle. For example, the tubular outlet may be equipped with an engagement device for engaging a complementary engagement device of a subcutaneous injection needle, for example, the engagement device and the complementary engagement device may have a male-female interaction, the tubular outlet optionally having an external thread, e.g., a helical external thread, and the subcutaneous injection needle optionally having a complementary internal thread, e.g., a helical internal thread. The subcutaneous injection needle may be adapted to allow for simple removal or replacement of the subcutaneous injection needle, or the subcutaneous injection needle may be permanently mounted on the injector. In particular, the subcutaneous injection needle may be mounted on the injector such that its removal requires the destruction of the injector, thereby preventing reuse, which is considered "permanent" in the context of the present invention. In an example, the injector is equipped with a subcutaneous injection needle that is permanently mounted, e.g., attached to the outlet of a cylinder.

[0040] In another example, the medical container is a PFS in the form of a cartridge, typically having an outlet located at the outlet end, which may only have a limited extension from the bottom end. The cartridge outlet is generally configured to provide fluid communication with the subcutaneous needle of an injector. The injector used with the cartridge may also include a piston rod configured to push a stopper from the inlet end to the bottom end of the cylinder. In yet another example, the medical container is a PFS in the form of a cartridge used in a needleless injector. The cartridge is sometimes called a "carpoole".

[0041] If the medical container is a PFS, it may also be equipped with a needle cap for use as a piston rod. For example, the piston has an operating surface facing the inlet end of the cylinder and an outlet surface opposite the operating surface and therefore facing the tubular outlet of the cylinder. Generally, the "operating length" of the cylinder is defined by subtracting the dimension of the piston parallel to the longitudinal axis of the cylinder from the distance from the inlet end of the cylinder to the tubular outlet of the cylinder. The needle cap may have a tubular section for housing a subcutaneous injection needle, the tubular section having a needle insertion end with an engagement device for engaging with the outlet or a complementary engagement device of the subcutaneous injection needle, and a needle protection end opposite the needle insertion end, the tubular section being equipped with a device for actinguating the piston, and the length of the tubular section being equal to or longer than the operating length of the cylinder. The piston may be moved from the inlet end toward the tubular outlet by any means, for example, the piston may be moved toward the tubular outlet using a needle cap that also functions as a piston rod.

[0042] Generally, it is preferable that the stopper does not contain external lubricants, such as silicone lubricants. For example, a medical container may be a PFS that does not contain lubricants, particularly silicone lubricants. It is even more preferable that the TPE of the stopper does not contain slip agents. It is particularly preferable that the TPE of the stopper does not contain slip agents and the stopper does not contain lubricants. A medical container may be a PFS that is considered to be lubricant-free, particularly silicone lubricants. Similarly, a medical container may be a PFS that is considered to be lubricated only by the liquid drug in the PFS. If the medical container is a non-lubricated PFS, it is preferable that the stopper has a Shore A hardness in the range of 50 to 80, for example, 60 to 80, or 70 to 80. For example, a stopper, for example, a stopper of the PFS of this disclosure, may be made from Evoprene G970, Evoprene R9070, or Evoprene R9970 TPE (all three are supplied by Alphagary).

[0043] The medical container may be sterilized after filling with liquid medication, or the components of the medical container may be sterilized before filling with liquid medication. Sterilization after packaging is typically called “final sterilization,” and in this context, the term “gamma irradiation” is used to describe sterilization that uses gamma irradiation at any stage, e.g., final sterilization or sterilization of individual components of a medical container. However, sterilization can be achieved using any appropriate procedure, such as using ethylene oxide (EtO), nitrogen dioxide (NO2) or vapor in an autoclave, chlorine dioxide, hydrogen peroxide or liquid (glutaraldehyde, formaldehyde, etc.), other chemicals, or UV-ozone treatment. Generally, sterilization is performed in a location where the contents of the medical container will not be adversely affected, but the medical container is sterilized to achieve a sterilization assurance level (SAL) of 10⁻⁶. For example, the components of a medical container may be sterilized using nitrogen dioxide (NO2), EO, or steam before filling the medical container with liquid medication, or the medical container may be sterilized using nitrogen dioxide (NO2), EO, or steam after filling the medical container with liquid medication.

[0044] TPEs are generally suitable for sterilization using irradiation such as gamma rays, electron beams (E-beams), and X-ray irradiation. Sterilization using gamma rays, E-beams, and X-ray irradiation is well known to those skilled in the art. Sterilization using irradiation, for example, gamma ray irradiation, is generally referred to using the term "VDmax" followed by a number indicating the intended minimum dose. For example, irradiation may be VDmax 25 or VDmax, where the doses are 25 kGy to 45 kGy and 50 kGy to 90 kGy, respectively. In one example of this disclosure, the stopper is sterilized using irradiation, for example gamma ray irradiation, at a dose in the range of 25 kGy to 45 kGy, for example 25 kGy to 35 kGy or 29 kGy to 33 kGy, and the stopper is irradiated under VDmax 25. In another example, the stopper is irradiated at VDmax 50, i.e., at a dose in the range of 50 kGy to 90 kGy. Regardless of irradiation time, irradiation is generally classified by irradiation dose. Stoppers may be gamma-irradiated after medical containers, such as vials or PFSs, are filled with liquid drugs; that is, medical containers may be ultimately sterilized using gamma irradiation. However, gamma irradiation of drug-filled vials can damage drugs, particularly nucleic acids such as RNA, e.g., mRNA or DNA, or amino acid-based drugs, e.g., protein or peptide-based drugs, and accordingly, small molecule drugs can also be damaged by gamma irradiation. Therefore, it is preferable not to subject medical containers to final sterilization by gamma irradiation. In another example, the stopper is gamma-irradiated before the medical container is filled with liquid drugs. In yet another example, the stopper is gamma-irradiated before the medical container is filled with liquid drugs, and the medical container is not subjected to final sterilization, in particular, the medical container is not subjected to final sterilization by gamma irradiation. The inventors have surprisingly found that if the stopper is subjected to gamma radiation exceeding 45 kGy, particularly exceeding 50 kGy, or even higher, before being inserted into the cylinder, the irradiation poses a risk of leakage to medical containers having the irradiated stopper. As a result, the irradiated TPE stopper may not meet CCI requirements.The inventors believe that the cause of this loss of CCI due to gamma irradiation is the crosslinking of TPE molecules. Generally, gamma rays can crosslink polymer molecules, and it is thought that if a material is brought into contact with another material before irradiation, the polymer molecules can also be crosslinked with the molecules of the material in contact with the polymer. This effect is useful when medical vials with TPE stoppers are final sterilized using gamma irradiation, which ensures that the final sterilized vials comply with CCI requirements, in which case final sterilization can use gamma irradiation to an acceptable level for the relevant polymer or TPE. Accordingly, the present invention provides a gamma-sterilized TPE stopper that provides a long-term sealing effect by sterilizing the TPE stopper with gamma irradiation at doses ranging from 25 kGy to 45 kGy before inserting the gamma-sterilized TPE stopper into a medical container, and as a result, medical containers with gamma-sterilized TPE stoppers comply with CCI requirements, particularly for the storage of liquid pharmaceuticals for more than one month.

[0045] The inventors have, even more surprisingly, observed that adequate sterilization of the stopper can be achieved at lower irradiation doses. Therefore, in one example of this disclosure, the stopper is sterilized using irradiation at doses in the range of 10 kGy to 25 kGy, for example, gamma irradiation. Correspondingly, the stopper may be irradiated at doses in the range of 10 kGy to 45 kGy.

[0046] When medical containers are supplied in a sterile form, they may be packaged in secondary packaging. Secondary packaging may enclose the medical container within further packaging such as plastic packaging, foil packaging, paper packaging, or other suitable packaging, e.g., blister packs, and secondary packaging may contain multiple units of the medical container. The medical container before being packaged in secondary packaging is generally called “primary packaging,” and in this context, the sterile medical container may be referred to as “primary medical container.” A sterile, for example, primary medical container is conventionally removed from a sterile state before being packaged in secondary packaging, thereby posing a risk that the surface of the primary packaging may not be sterile, even if the contents of the primary medical container are sterile. In one example, the primary medical container is packaged in secondary packaging, and then the secondary packaging is sterilized. In particular, the secondary packaging may be sterilized to sterilize the outer surface of the primary medical container within the secondary packaging. Sterilization of secondary packaging is performed using TPE T g This can be performed before or after cooling the stopper to a lower temperature. Any sterilization method can be used to sterilize the secondary packaging. However, the sterilization method is preferably selected to minimize the risk of damaging the drugs in the primary medical container contained in the secondary packaging. For example, the secondary packaging may be irradiated using gamma rays or an E-beam at doses in the range of 0.1 kGy to 10 kGy, for example, 1 kGy to 5 kGy. However, the secondary packaging may alternatively be irradiated at doses in the range of 0.1 kGy to 45 kGy, for example, 25 kGy to 45 kGy. TPE materials, particularly styrene-based TPEs, such as Evoprenes such as R9970 and R9070, as well as the G series, such as G970, are irradiation resistant and therefore, by using irradiation for sterilization in this dose range for secondary packaging having the medical containers of this disclosure, a sterile medical container can be used in a sterile environment, such as a hospital operating room, without concern for contamination of the primary medical product surface.

[0047] Therefore, despite the crosslinking caused by gamma irradiation, TPE retains its elastic properties, and thus gamma-irradiated TPE can be used to guarantee the CCI of medical containers, and the effect obtained by sterilizing stoppers using gamma irradiation at doses in the range of 25 kGy to 45 kGy is relevant both when the stopper is a stopper for vials and when the stopper is a piston for syringes. Furthermore, the stopper is made of TPE T g They may be exposed to lower temperatures and may be irradiated with gamma rays at doses in the range of 25 kGy to 45 kGy without impairing the CCI. In one example, the medical container is a vial, and the stopper is sterilized using gamma irradiation at doses in the range of 25 kGy to 45 kGy. In another example, the medical container is a PFS, and the stopper is sterilized using gamma irradiation at doses in the range of 25 kGy to 45 kGy.

[0048] Exemplary stoppers for PFS in this disclosure are described in WO2019 / 185101, EP3003440, and WO2017 / 157396, which are incorporated herein by reference in their entirety.

[0049] In one example, a stopper includes a cavity that extends from the stopper cavity opening to the base of the stopper cavity, defining the entire length of the stopper cavity. The stopper cavity opening may be located on the operating surface of the stopper, and the cavity may extend from the operating surface into the stopper. Alternatively, the cavity may extend from the inner surface into the stopper. A stopper having a cavity extending from the operating surface into the stopper is generally referred to in this context as a "cavity stopper." For example, the cavity may be located within a stopper body having a deformable sealing element surrounding the stopper body. Cavity stoppers are related to vials and also to PFS.

[0050] Generally, a cavity stopper is inserted into an inlet opening such that the cavity opening faces the surrounding exterior of the medical container and the base of the stopper cavity faces the liquid drug. A cavity stopper may have one deformable sealing element, or it may have two or more deformable sealing elements. If the cavity stopper has two or more deformable sealing elements, each of the deformable sealing elements may be identical, for example, with respect to its outer diameter, or the deformable sealing elements may be different. Generally, the deformable sealing elements are positioned on the cavity stopper between the working surface and the base of the cavity.

[0051] In one example, the medical container is a vial. Generally, when the medical container is a vial, the vial includes a cylinder having an internal space, and the cylinder may have a cross-sectional shape and cross-sectional dimensions different from at least one of the cross-sectional shapes and cross-sectional dimensions of the inlet opening and the inlet section. The vial may have any volume commonly observed for vials used to store liquid drugs, for example, the volume of the vial may range from 1 ml to 50 ml.

[0052] A vial has an inlet opening for receiving a stopper, and therefore, along the periphery of the inlet opening, the vial also has a circumferential surface, the area of ​​which, in its simplest form, corresponds to the thickness of the vial material and the cross-sectional size and shape of the inlet opening. In one example, the medical container is a vial, and the stopper has a circumferential ridge surrounding the stopper body. If present, the circumferential ridge is located between the working surface of the stopper and a deformable sealing element. The circumferential ridge is sized such that the stopper cannot be inserted beyond the circumferential ridge into the inlet opening. For example, the inlet opening is circular, and the circumferential ridge is also circular with a diameter larger than the cross-sectional diameter. The diameter of the circumferential ridge is also larger than the diameter of the deformable sealing element. The circumferential ridge has a contact surface facing the inner surface of the stopper. After the stopper is inserted into the inlet opening, the contact surface abuts against the circumferential surface. When the contact surface abuts against the circumferential surface, a sealing effect is achieved.

[0053] In certain cases, the medical container is a vial, which further comprises a flange surrounding the inlet opening, thereby increasing the area of ​​the surrounding surface. For example, the inlet opening may be circular, and the flange may also be circular, having a diameter in the range of 105% to 150% of the transverse diameter, for example, 110% to 125%. The diameter of the flange is also called the flange diameter. However, the flange does not need to have the same cross-sectional shape as the inlet opening. Vials for medical containers are conventionally closed with a stopper made of elastomer and sealed using a crimped cap, for example, a crimped cap made of aluminum. By being larger than the inlet opening, the flange provides the vial with a capping surface on the opposite side of the surrounding surface. The crimped cap may be folded around the flange so that the crimped cap engages with the capping surface. The crimped cap thereby ensures the CCI of the vial.

[0054] The stopper is preferably inserted into the vial after the medical container has been filled with the liquid drug. Once the vial is closed by the insertion of the stopper, the liquid drug can be extracted by puncturing the stopper with a subcutaneous needle attached to a suitable syringe and extracting the liquid drug through the subcutaneous needle. The stopper may have a puncture area, which may be marked on the stopper. The thickness of the stopper in the puncture area is appropriate, for example, to be configured so that the puncture area is punctured by a subcutaneous needle, and in particular, the thickness is thin enough to avoid the subcutaneous needle losing its sharpness, and can be used to administer the liquid drug to the patient without causing excessive pain when puncturing the patient's skin with the subcutaneous needle. For example, the thickness of the stopper in the puncture area may be in the range of 0.3 mm to 3 mm. Surprisingly, the inventors have found that by using TPE with a high Shore A hardness, the thickness of the TPE in the stopper in the puncture area can be reduced compared to stoppers prepared from softer TPE. In one example, the TPE of the stopper has a Shore A hardness in the range of 50 to 65, for example, 50 to 60, or 50 to 55, and the thickness of the stopper in the drilling area is in the range of 0.3 mm to 2 mm, for example, 0.4 mm to 1.9 mm, or 0.5 mm to 1.8 mm. The higher hardness of the TPE further provides that the sealing between the deformable sealing element and the inner wall of the cylinder in the inlet section or inlet opening is improved, and the sealing effect can be improved to the extent that the deformable sealing element guarantees CCI. A TPE stopper having a Shore A hardness in the range of 50 to 60 and a thickness in the drilling area in the range of 0.3 mm to 2 mm, for example, 0.4 mm to 1.9 mm, or 0.5 mm to 1.8 mm is provided by the TPE gThis is particularly useful for vials intended for storing liquid drugs at temperatures below a certain level. For example, the TPE of the stopper has a Shore A hardness in the range of 50 to 60, and the deformable sealing element has an outer diameter 2% to 10%, e.g., 3% to 5%, larger than the transverse diameter when the deformable sealing element is in a relaxed state. The sealing effect is further improved by having two or more deformable sealing elements on the stopper. The thickness of the stopper in the perforation area is more preferably in the range of 0.3 mm to 2 mm, e.g., 0.4 mm to 1.9 mm, or 0.5 mm to 1.8 mm. In a further example, the stopper has no circumferential ridges, the TPE of the stopper has a Shore A hardness in the range of 50 to 60, the stopper has one, two, or three deformable sealing elements having an outer diameter 2% to 10%, e.g., 3% to 5%, larger than the transverse diameter when the deformable sealing elements are in a relaxed state, the stopper has a perforated area, and the thickness of the stopper material in the perforated area is in the range of 0.3 mm to 2 mm, e.g., 0.4 mm to 1.9 mm, or 0.5 mm to 1.8 mm. It is even more preferable that the vial does not have a flange surrounding the inlet opening. In this example, CCI is ensured by the interaction between the deformable sealing elements and the inner wall of the cylinder in the inlet section or inlet opening, resulting in no need for a crimp cap. Thus, the present invention particularly favors TPE T g We provide vials for storing liquid medications at lower temperatures, which do not require a crimped cap. In certain cases, the vials do not include a crimped cap.

[0055] In one example, the medical container is a vial, and the stopper is a cavity stopper. For example, the stopper may have a cavity extending from the working surface to the cavity base within the stopper, and the stopper further has at least one deformable sealing element between the working surface and the cavity base, for example, along the length of the stopper. In another example, the deformable sealing element is positioned at the location of the cavity base, for example, with respect to the working surface. When the vial has a cavity stopper, the perforation area is preferably located at the cavity base. The cavity stopper is inserted into the vial using the method disclosed in PCT / DK2022 / 050297 (published as WO2023 / 232208), which is advantageous as it can minimize the amount of air in the vial after the stopper is in place. In a further example, the medical container is a vial, the stopper is a cavity stopper, and the stopper does not include a circumferential ridge. In particular, the cavity stopper may have two or more deformable sealing elements.

[0056] In one example, the stopper has a hollow section extending from the inner surface of the stopper, and the stopper does not have a deformable sealing element, so that at least one section of the stopper body, i.e., a section along the length of the stopper, is the sealing surface. The stopper may further have a circumferential ridge, for example, a circumferential ridge extending from the working surface of the stopper, and the hollow section may extend from the inner surface to the base of the hollow section. The base of the hollow section may correspond to the position of the circumferential ridge. The stopper has a perforated area located on the working surface of the stopper, and the thickness of the material stopper in the perforated area corresponds to the distance from the working surface to the base of the hollow section. In this example, the TPE of the stopper is particularly preferably in the range of 50 to 65, for example, 50 to 60 or 50 to 55 Shore A hardness. The thickness of the TPE in the perforated area is more preferably in the range of 0.3 mm to 2 mm, for example, 0.4 mm to 1.9 mm or 0.5 mm to 1.8 mm. The vial having this stopper may also be equipped with a crimped cap, for example, a crimped cap made of aluminum.

[0057] Conventional vials, such as stoppers having a hollow section as described above, are filled by puncturing the closure with a subcutaneous injection needle, injecting the drug into the vial, and then resealing the closure using laser welding. The need to puncture the vial closure creates an unnecessary risk of contaminating or soiling the inside of the vial. Furthermore, laser welding heats and melts the TPE, thereby exposing the contents of the vial to heat that can damage sensitive drugs, particularly mRNA-based drugs as well as DNA or protein-based drugs. Therefore, the use of laser welding is undesirable. Moreover, the use of laser welding requires TPE that can absorb laser light, typically infrared laser light with wavelengths above 800 nm. Laser absorption is generally achieved by including dyes or pigments in the TPE. For the vials of this disclosure, it is preferable that the TPE does not contain pigments or dyes.

[0058] A cavity stopper may be used in conjunction with the PFS of this disclosure. If the medical container is a PFS and the stopper is a cavity stopper, the cavity stopper may conform to any stopper disclosed in WO2019 / 185101. For example, a cavity stopper may have an operating surface opposite to the inner surface and an axial length between the operating surface and the inner surface, and a deformable sealing element may be positioned axially from the operating surface, and an enlarged cavity may also be positioned at the axial position having an axial extension in the range of 5% to 50% of the axial length of the stopper body and a lateral extension which is at least 50% of the outer diameter of the deformable sealing element. Generally, the section of the cavity from the operating surface to the enlarged cavity has a diameter smaller than the diameter of the enlarged cavity.

[0059] In another aspect, the present invention relates to a method for manufacturing a medical container according to the present disclosure. The method comprises the following steps: The steps include providing a cylinder that extends along its longitudinal axis, wherein the cylinder has an inner wall, an inlet opening at the inlet end, and a bottom end opposite the inlet end, the inlet opening defining the transverse diameter, the cylinder being made of glass or polymer material, and the medical container being made of glass or polymer material. The steps include applying a liquid drug into a medical container, The steps include inserting a stopper into the opening to provide a filled medical container, The temperature of the filled medical container is controlled by the thermoplastic elastomer of the stopper. g A step to lower the temperature to an even lower level.

[0060] This method controls the temperature of the filled medical container, specifically the temperature of the thermoplastic elastomer stopper. g The method may further include a step of raising the temperature from the ambient temperature. The cylinder used in the method of this disclosure may be any example of the cylinders disclosed in the embodiments relating to the medical containers of this disclosure. In general, any variation or feature described for the medical containers of this disclosure is equally relevant to the method of this disclosure.

[0061] In one example, the method further comprises the step of sterilizing at least one, for example both, of the cylinder and the stopper with nitrogen dioxide (NO2). The cylinder and / or stopper may be sterilized with nitrogen dioxide (NO2) before or after the step of applying a liquid drug into the cylinder, for example, the cylinder and / or stopper may be sterilized with nitrogen dioxide (NO2) after inserting the stopper into the inlet opening. Generally, the temperature of the filled medical container is controlled by the thermoplastic elastomer of the stopper. g The material is sterilized using nitrogen dioxide (NO2) before the step of lowering the temperature to below a certain level. Sterilization using nitrogen dioxide (NO2) is known to those skilled in the art, and any conventional procedure can be used for sterilization.

[0062] In one example, the stopper is a cavity stopper, which is inserted into a medical container, such as a PFS or vial, as disclosed in WO2023 / 232208, which is entirely incorporated herein by reference. Thus, the stopper may have an operating surface facing the circumferential exterior of the medical container, and the stopper includes a cavity extending from the stopper cavity opening of the operating surface to the base of the stopper cavity, and the method is as follows: The step of providing a stopper extension rod having an overall length at least 5% longer than the overall length of the cavity and a collision surface, The steps include inserting a stopper extension rod into the stopper cavity so as to extend the stopper along the longitudinal axis of the cylinder and cause the deformable sealing element to contract, thereby creating an air bypass in the space between the stopper and the drug surface, and impacting the impact surface against the cavity base at a speed of at least 25 mm / min, The system further comprises the step of maintaining the speed of the stopper extension rod to move the piston to its final piston position.

[0063] In certain cases, this method, A medical container comprising a cylinder having an inlet opening, a longitudinal axis and an inner wall, and a liquid drug defining the drug surface, Steps include providing a cavity stopper, The steps include inserting a cavity stopper into an inlet opening such that a deformable sealing element abuts against the inner wall of the inlet opening and seals the annular gap between the piston and the inner wall of the inlet opening, The step of providing a stopper extension rod having an overall length at least 5% longer than the overall length of the cavity and a collision surface, The steps include: extending the cavity stopper along the longitudinal axis of the cylinder, causing the deformable sealing element to contract, inserting the stopper extension rod into the cavity of the cavity stopper to form an air bypass in the space between the cavity stopper and the drug surface, and impacting the cavity base with the impact surface at a speed of at least 25 mm / min; The procedure may include a step of maintaining the speed of the stopper extension rod to move the piston to the final piston position. The speed may be, for example, in the range of 50 mm / min to 120,000 mm / min, for example 1,000 mm / min to 50,000 mm / min, for example 2,000 mm / min to 40,000 mm / min, 3,000 mm / min to 30,000 mm / min, 4,000 mm / min to 20,000 mm / min, or 5,000 mm / min to 10,000 mm / min.

[0064] Cavity stoppers are advantageous for vials, particularly when they are inserted into the inlet opening using a stopper extension rod as outlined above. Cavity stoppers can be inserted into the inlet opening of a vial, i.e., a medical container, such that there is a minimum distance, for example, no distance, between the inner surface of the cavity stopper and the drug surface. This allows the present invention to provide a vial in which the amount of air or gas inside the vial is minimized after the vial is closed with the stopper.

[0065] Any embodiment of the present invention may be used in any aspect of the present invention, and any advantages of a particular embodiment apply equally when the embodiment is used in a particular aspect. [Brief explanation of the drawing]

[0066] The present invention will be described in more detail below with the help of examples and with reference to schematic diagrams. [Figure 1] Figure 1 shows an embodiment of the vial of the present invention. [Figure 2] Figure 2 shows an embodiment of the vial of the present invention. [Figure 3] Figure 3 shows an embodiment of the vial of the present invention. [Figure 4] Figure 4 shows an embodiment of the vial of the present invention. [Figure 5] Figure 5 shows an embodiment of the stopper for vials according to the present invention. [Figure 6]Figure 6 shows an embodiment of the stopper for vials according to the present invention. [Figure 7] Figure 7 shows an embodiment of the stopper for vials according to the present invention. [Figure 8] Figure 8 shows an embodiment of the stopper for the PFS of the present invention. [Figure 9] Figure 9 shows details of an embodiment of the PFS of the present invention. [Figure 10] Figure 10 shows an embodiment of the PFS of the present invention. [Figure 11] Figure 11 shows the filling of a medical container using the method of the present invention. [Figure 12] Figure 12 shows the measured values ​​of the release force and sliding force of the PFS of the present invention.

[0067] The present invention is not limited to the embodiments illustrated in the drawings. Therefore, where reference numerals follow features described in the appended claims, such numerals are included solely for the purpose of enhancing the understanding of the claims and are not intended to limit the claims in any way.

[0068] As used herein and in the claims, the term “comprising” means “consisting at least in part of.” When interpreting any description containing the term “comprising” within this specification and in the claims, other features may exist in each description besides those preceded by this term. Related terms such as “comprise” and “comprised” should be interpreted similarly. [Modes for carrying out the invention]

[0069] The present invention relates to a medical container 1 for storing a liquid drug 2. The medical container 1 may be a vial 1 or a pre-filled syringe (PFS) 1 in particular. A vial 1 of the present invention is shown in Figures 1 and 2, where Figure 1 shows a stopper 3 before insertion into the vial 1, and Figure 2 shows the stopper 3 inserted into the vial 1. Corresponding figures show another embodiment of the stopper 3 in Figures 3 and 4. Modifications of the stopper 3 for the vial 1 are shown in Figures 5, 6 and 7. Figure 8 shows a stopper 3 for use with a PFS 1 of the present invention, and Figure 9 shows a cylinder 10 of the PFS 1 of the present invention with the stopper 3 inserted into the cylinder 10.

[0070] Therefore, Figures 1, 2, 3, and 4 show vials 1 made from borosilicate glass with a stopper 3 injection-molded from Evoprene TPE, the relevant examples being R9068 or R9067. The same vial 1 is shown in Figures 1 and 2, and Figures 3 and 4, respectively. Vial 1 includes a cylinder 10 having an inlet opening 13 at an inlet end 14, the inlet end 14 being opposite the bottom end 15. The length of the cylinder 10 along its longitudinal axis x is 35 mm. The cylinder 10 has an outer wall 16. The inlet opening 13 has a transverse diameter d and defines an inlet section 131. The length of the inlet section 131 along the longitudinal axis x of the cylinder 10 is 8 mm. The transverse diameter d is 7 mm. A flange 141 surrounds the inlet opening 13, and this flange 14 defines the area of ​​the surrounding surface 132. The flange 14 has a flange diameter F. Before inserting the stopper 3, the cylinder 10 is filled with liquid agent 12.

[0071] In Figures 1 and 2, the stopper 3 is of a conventional design and therefore has a stopper body 30 that defines a sealing surface 31 having an outer diameter D. The outer diameter D in Figures 1 and 2 corresponds to the outer diameter of the stopper body 30. The transverse diameter d is 7 mm and the outer diameter D is 7.2 mm. The stopper 3 has an operating surface 33 opposite the inner surface 34. When the stopper 3 is inserted into the inlet opening 13 of the inlet section 131, the inner surface 34 faces the liquid drug 2, and the operating surface 33 faces the outer periphery 4 of the medical container 1 after being inserted into the inlet opening 13. The stopper 3 has a circumferential ridge 37 with a contact surface 371. When the stopper 3 is inserted into the inlet opening 13, the contact surface 371 abuts against the outer circumferential surface 132. After the stopper 3 is inserted into the inlet opening 13, the medical container may be provided with an aluminum crimp cap (not shown) to further ensure container closure integrity (CCI). The stopper 3 includes a hollow section 36 having a base 361 of the hollow section 36. When the stopper 3 is inserted into the inlet opening 13, the base 361 faces the liquid drug 2. The stopper 3 has a perforation area 38 on its working surface 33. By perforating the stopper 3 in the perforation area 38 with a subcutaneous injection needle (not shown) or the like, the material of the stopper 3 is penetrated, providing access to the liquid drug 2. The thickness of the material of the stopper 3 between the perforation area 38 and the base 361 of the hollow section is 2 mm.

[0072] In Figures 3 and 4, the cylinder 10 is the same as that described in Figures 1 and 2, and the stopper 3 has a convex, deformable sealing element 311. The convex, deformable sealing element 311 defines the outer diameter D and provides a sealing surface 31. The transverse diameter d is 7 mm, and the outer diameter D is 7.3 mm. The stopper body 30 has a diameter of 6.5 mm such that an annular gap 32 exists between the inner wall 12 and the stopper body 30 when the stopper 3 is inserted into the cylinder 10. The stopper 3 includes a cavity 35 that extends from the stopper cavity opening 350 of the working surface 33 to the base 351 of the cavity 35. When the stopper 3 is inserted into the inlet opening 13, the base 361 faces the surrounding exterior 4. The stopper 3 has a perforated area 38 at the base 351. By puncturing the stopper 3 in the puncture area 38 with a subcutaneous injection needle (not shown), the material of the stopper 3 is penetrated, providing access to the liquid drug 2. The thickness of the material of the stopper 3 in the puncture area 38 is 2 mm.

[0073] A stopper 3 corresponding to the stopper 3 in Figure 1 is shown in Figure 5, and modified versions of the stopper 3 are shown in Figures 6 and 7. The stoppers 3 in Figures 6 and 7 have different designs of the deformable sealing element 311, but in both cases the deformable sealing element 311 is a convex deformable sealing element 311.

[0074] A stopper 3 for the PFS1 of the present invention is shown in Figure 8, and Figure 9 shows the cylinder 10 of the PFS1 with the stopper 3 inserted into the cylinder 10. The cylinder 10 of the PFS1 has an inner wall 12 that defines a transverse diameter d. In both Figures 8 and 9, the stopper 3 has two convex, deformable sealing elements 311 that provide a sealing surface 31. When the stopper 3 is inserted into the cylinder 10, an annular gap 32 is formed between the inner wall 12 and the stopper body 30. As shown in Figures 8 and 9, the stopper has a cavity 35 for receiving a piston rod (not shown). The cavity 35 includes a helical thread 352 complementary to the helical thread of the piston rod (not shown). The cavity 35 has a cavity base 351, and in Figure 9, the stopper 3 further comprises a wide cavity 353 as defined in WO2019 / 185101.

[0075] Figure 10 illustrates the PFS1 of the present invention. Figure 10 shows a cylinder 10 made from COP. Specifically, the cylinder 10 is for 0.5 ml of PFS and has an inner diameter of 4.65 mm, i.e., a transverse diameter d. The cylinder has a finger grip 142 at the inlet end 14 and a tubular outlet 17 at the bottom end 15. A subcutaneous injection needle (not shown) can be attached to the tubular outlet 17. The cylinder 10 has an inner wall 12 and an outer wall 16.

[0076] The stopper 3 is injection molded from Evoprene R9070 to have two convex deformable sealing elements 311 and a cavity 35. The cavity 35 is an enlarged cavity 35 located axially close to the inner surface 34 of the stopper 3 from the working surface 33 of the convex deformable sealing elements 311. The enlarged cavity 35 allows the stopper 3 to be inserted into the PFS using the method disclosed in PCT / DK2022 / 050297. The enlarged cavity 35 further reduces BLF as disclosed in WO2019 / 185101.

[0077] In the PFS shown in Figure 10, stopper 3 was inserted into the PFS at a speed of 20,000 mm / min; however, speeds ranging from 500 mm / min to 120,000 mm / min are also useful.

[0078] Figure 1 illustrates the filling of a medical container 1 in the method of the present invention using a stopper extension rod 354. Specifically, the stopper 3 has an operating surface 33 facing the outer periphery 4 of the medical container 1, and the stopper 3 includes a cavity 35 extending from a stopper cavity opening 350 of the operating surface 33 to a stopper cavity base 351, and a convex, deformable sealing element 311 having a diameter greater than the transverse diameter d. The cylinder 10 is filled with liquid drug 2 to provide a drug surface 356, and the stopper 3 is inserted into the cylinder 10 at a rate that causes the stopper 3 to deform as its impact surface 355 impacts the cavity base 351, causing the deformable sealing element 311 to contract and create a bypass of air 357 in the space between the stopper 3 and the drug surface 356, before the stopper extension rod 354 is inserted. This allows the stopper 3 to move to its final stopper position by maintaining the speed of the stopper extension rod 354, thereby avoiding air between the stopper 3 and the drug surface 356.

[0079] Example 1 Two groups of 0.5 ml PFS of the present invention were manufactured, one group having a cylinder made from borosilicate glass and the other group having a cylinder made from cyclic olefin copolymer (COC). Stoppers were injection molded from Evoprene G970 (supplied by Alphagary) to have two convex, deformable sealing elements. Specifically, the stoppers were as disclosed and illustrated in Figure 1 of EP3003440B1. The cylinders were unlubricated and had an inner diameter of 4.65 mm, i.e., a transverse diameter d, and the stoppers were not silicone-treated or had no other lubricants or coatings.

[0080] A subset of the stoppers was exposed to 30 kGy of gamma radiation, while another subset of the stoppers was not. The irradiated and unirradiated stoppers were then placed in a cylinder filled with water for injection (WFI) to provide a PFS, after which the PFS was cooled to -80°C, i.e., the glass transition temperature (T) of G970TPE. g It was frozen when it was less than ).

[0081] In the CCI test, PFS was stored at -80°C for 6 days, then readjusted to ambient temperature, and stored in a climate chamber at 40°C / 75% relative humidity (RH) for 4 days before measuring the release force (BLF) and sliding force. The test was based on ISO 7886-3:2005 Annex B Sterile subcutaneous injection syringes for single use - Part 3: Auto-deactivating syringes for fixed-dose immunization, and the force test method required manipulating a plunger. An Instron mechanical testing machine equipped with a 100N load cell was used at 100 mm / min.

[0082] The CCI test was based on Pharmaceutical Package Integrity, Parenteral Drug Association's Technical Report No. 27, 1998. The PFS was placed on absorbent paper in a desiccator under vacuum after readjusting to ambient temperature. No leakage was observed in any sample, and it was concluded that the PFS met the CCI requirements. Therefore, the PFS with an injection-molded stopper from TPE is made of TPE, namely Evoprene G970 T g Unaffected by freezing below a certain level, the PFS met the requirements for CCI. Correspondingly, gamma irradiation did not affect the sealing ability, and gamma irradiation, i.e., gamma irradiation at doses in the range of 25 kGy to 45 kGy, did not jeopardize CCI.

[0083] The results of the BLF and sliding force tests are shown in Figure 12. In Figure 12, "Sterile" indicates samples exposed to gamma irradiation, and "Non-Sterile" indicates samples not exposed to gamma irradiation. The Y-axis represents the force in Newtons (N), white markers indicate BLF, and gray markers indicate sliding force. For PFS with glass cylinders, gamma irradiation did not change BLF or sliding force. However, for COC cylinders, gamma irradiation surprisingly decreased BLF, but did not jeopardize the CCI of the corresponding PFS.

[0084] The test results observed for the PFS of the present invention are equally applicable to vials having injection-molded TPE stoppers. In particular, Evoprene G970 has a Shore A hardness of 70 to 72, and at this Shore A hardness, the convex deformable sealing element thus provides a stopper for the vial, and the CCI is secured by the convex deformable sealing element, and as a result the vial does not require a crimp cap to seal the vial, for example, via the circumferential ridge of the stopper that is in contact with the periphery of the inlet opening.

[0085] List of reference symbols 1. Medical container 2. Liquid medication 3 Stopper 10 cylinders 11 Interior space 12 Inner wall 13 Entrance opening 14 Inlet end 15 bottom end 16. Exterior Wall 17 tubular outlet 30 Stopper body 31 Sealing surface 32 Annular gap 33 Operating surface 34. Inner self 35 Cavity 36 Hollow Section 37 Circumferential Ridge 38 Perforation Area 4. Surroundings outside 131 Entrance Section 132 Surrounding surface 141 Flange 142 Finger Grips 311 Deformable sealing element 350 Cavity opening 351 Cavity base 352 helical threads 353 Wide Cavity 354 Stopper Extension Rod 355 Collision surface 356 Top surface of drug 357 Air Bypass 361 Hollow section base 371 Contact surface d Cross-sectional diameter D Outer diameter of stopper F flange outer diameter x Longitudinal axis

Claims

1. A medical container (1) for storing liquid medication (2), A cylinder (10) extending along a longitudinal axis (x), the cylinder (10) having an inner wall (12), an inlet opening (13) at an inlet end (14), and a bottom end (15) opposite the inlet end (14), the inlet opening (13) defining the transverse diameter (d), A stopper (3) is inserted into the cylinder (10) through the inlet opening (13), and the stopper has a stopper body (30) and a sealing surface (31) surrounding the stopper body (30) and having an outer diameter (D) larger than the transverse diameter (d) to seal the annular gap (32) between the inner wall (12) and the stopper body (30) when the stopper (3) is inserted into the cylinder (10), the stopper (3) is made of a thermoplastic elastomer, and the glass transition temperature (T) of the thermoplastic elastomer is ｇ Exposed to temperatures below ) A medical container (1) comprising the liquid drug (2) in the cylinder (10) between the bottom end (15) and the stopper (3).

2. The medical container (1) according to claim 1, wherein the stopper (3) comprises a stopper body (30) having a diameter smaller than the transverse diameter (d) and a convex, deformable sealing element (311) having a diameter larger than the transverse diameter (d), and the deformable sealing element (311) provides the sealing surface (31).

3. The medical container (1) according to claim 1 or 2, wherein the thermoplastic elastomer comprises a styrene block copolymer, a polyolefin, and an oil.

4. The thermoplastic elastomer is a medical container (1) according to any one of claims 1 to 3, wherein the thermoplastic elastomer does not contain a slip agent.

5. The medical container (1) according to any one of claims 1 to 4, wherein the stopper (3) is sterilized using gamma irradiation at a dose in the range of 25 kGy to 45 kGy before inserting the stopper (3) into the medical container (1).

6. The medical container (1) according to any one of claims 1 to 5, wherein the thermoplastic elastomer does not contain a perfluorinated compound.

7. The medical container (1) according to any one of claims 1 to 6, wherein the outer diameter (D) is 0.5% to 10% larger than the transverse diameter (d).

8. The medical container (1) according to any one of claims 1 to 7, wherein the cylinder (10) is made of glass or polymer.

9. The thermoplastic elastomer TPE is free of pigments or dyes, and is a medical container (1) according to any one of claims 1 to 8.

10. The medical container (1) is a pre-filled syringe, and the bottom end (15) has a tubular outlet (17), according to any one of claims 2 to 9.

11. The medical container (1) is a vial, according to any one of claims 1 to 9.

12. The medical container (1) according to claim 11, wherein the thermoplastic elastomer has a Shore A hardness in the range of 50 to 75.

13. The medical container (1) according to claim 11 or 12, wherein the stopper (3) has an operating surface (33) facing the surrounding outer surface (4) of the medical container (1), and the stopper (3) includes a cavity (35) extending from the stopper cavity opening (350) of the operating surface (33) to the stopper cavity base (351).

14. The medical container (1) according to claim 12 or 13, wherein the stopper (3) has a perforation area (38) configured to be perforated by a subcutaneous injection needle, and the perforation area has a thickness in the range of 0.3 mm to 3 mm.

15. The stopper (3) is manufactured by solidifying the thermoplastic elastomer from a molten state, as described in any one of claims 1 to 14.

16. The stopper (3) is injection molded from the thermoplastic elastomer, as described in any one of claims 1 to 15.

17. A secondary package comprising a medical container (1) according to any one of claims 1 to 16, wherein the medical container (1) is enclosed and irradiated with a dose in the range of 0.1 kGy to 10 kGy.

18. A method for manufacturing a medical container (1), The steps include providing a cylinder (10) extending along a longitudinal axis (x), wherein the cylinder (10) has an inner wall (12), an inlet opening (13) at an inlet end (14), and a bottom end (15) opposite the inlet end (14), the inlet opening (13) defining a transverse diameter (d), and the cylinder (10) being made of glass or polymer material. The steps include applying a liquid drug (2) into the cylinder (10) medical container (1), To provide a filled medical container (1), the steps include inserting a stopper (3) into the inlet opening (13), The temperature of the filled medical container (1) is determined by the glass transition temperature (T) of the thermoplastic elastomer of the stopper (3). ｇ A method comprising the step of lowering the temperature to a lower temperature.

19. The temperature of the filled medical container (1) is determined by the glass transition temperature (T) of the thermoplastic elastomer of the stopper (3). ｇ The method according to claim 18, further comprising the step of raising the temperature from ) to ambient temperature.

20. The above method involves discharging at least one of the cylinder (10) and the stopper (3) into nitrogen dioxide (NOx). ２ The method according to claim 18 or 19, further comprising the step of sterilizing with )

21. The stopper (3) has an operating surface (33) facing the surrounding outer surface (4) of the medical container (1), and the stopper (3) includes a cavity (35) extending from the stopper cavity opening (350) of the operating surface (33) to the stopper cavity base (351), and a convex, deformable sealing element (311) having a diameter larger than the transverse diameter (d), and the method is as follows: The steps include providing a stopper extension rod (354) having an overall length at least 5% longer than the overall length of the cavity, and a collision surface (355), The steps include: inserting the stopper extension rod (354) into the cavity (35) of the stopper (3), and causing the stopper (3) to collide with the cavity base (351) at the impact surface (355) at a speed of at least 25 mm / min so as to extend along the longitudinal axis of the cylinder, thereby causing the deformable sealing element (311) to contract to create an air bypass (357) in the space between the stopper (3) and the drug surface (356); The method according to any one of claims 18 to 20, further comprising the step of maintaining the speed of the stopper extension rod (354) in order to move the stopper (3) to the final stopper position.

22. The method according to any one of claims 18 to 21, wherein the medical container (1) is the medical container (1) according to any one of claims 1 to 16.

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