Container closure with reverse thermal expansion coefficient material

Abstract

The present invention relates to a pre-filled syringe comprising a syringe barrel having a proximal end and a distal end and defining a chamber, the syringe barrel having an opening at the proximal end. The pre-filled syringe also comprises a plunger assembly inserted through the opening and movable axially within the chamber of the syringe barrel, the plunger assembly further comprising a plunger rod having an elongated body extending between the proximal and distal ends and a stopper attached to the distal end of the plunger rod and positioned within the barrel chamber. The stopper is composed of a mixed material comprising an elastomer material and a mixed material having a lower coefficient of thermal expansion than the elastomer material.

Description

[Technical Field] 【0001】 (Cross-reference of related applications) This application claims priority to U.S. Patent Application No. 18 / 203,127, filed on 30 May 2023, entitled “Container Closure with Reverse Coefficient of Thermal Expansion Materials,” the disclosure of which is incorporated herein by reference in its entirety. 【0002】 This disclosure relates in general to sealed containers such as pre-filled syringes, and more specifically to sealing components for use with pre-filled syringes that exhibit minimal contraction and / or possible expansion at low temperatures in order to maintain the seal integrity of the syringe liquid contents during transport or storage. [Background technology] 【0003】 Closed containers are used in the medical field to store and potentially dispense fluids such as pharmaceuticals or drugs. Closed containers are supplied as stopper glass or plastic containers with elastomer closures (e.g., glass or plastic vials or syringes). Drugs or medications stored in closed containers may include, for example, vaccines or cell therapies. 【0004】 When a closed container is supplied as a pre-filled syringe for dispensing fluid, the syringe typically includes a syringe barrel having an opening at its distal end and a plunger assembly inserted through the proximal end opposite the barrel. The plunger assembly typically includes an elongated plunger rod extending from the barrel and a plunger head or stopper positioned at the distal end of the plunger rod. The stopper or plunger stopper typically comprises a body made of elastomer material and having a tail positioned at its proximal end, suitable for attachment to the distal end of the plunger rod, and a head positioned at its distal end. The outer cylindrical wall of the body is defined with a number of annular outward-projecting ribs adapted to ensure the integrity of the syringe container closure when the stopper is inserted into the syringe. 【0005】 During the period of transport and / or storage, while delivering the drug to the patient, the opening of the distal end of the syringe barrel is adapted to communicate fluidly with the patient via a needle already attached to the syringe barrel (stacked needle syringe barrel), via a subcutaneous injection needle attached to the distal end of the syringe barrel (Luer syringe barrel), or via a Luer fitting attached to the distal end of the syringe barrel and connected to the patient's fluid line (needleless access device). When the user applies force to move the plunger assembly through the syringe barrel toward the distal end of the syringe barrel, the contents of the syringe are thereby drawn out of the syringe barrel through the opening at the distal end for delivery to the patient. Such operations are well known in the medical field, and healthcare professionals are familiar with the use of such common fluid delivery procedures using pre-filled syringes. 【0006】 Many syringes are supplied as pre-filled syringes, offering the convenience of rapid administration of liquids to patients without the need to draw medication from another container and measure the amount. At the same time, it is necessary to maintain the sterility of the drug within the pre-filled syringe and the integrity of the container seal over long periods and through exposure to various storage and transport conditions. In some situations, pre-filled syringes are exposed to very low temperatures, including -80 to -196°C (i.e., liquid nitrogen temperature), to properly store the drug they contain (e.g., vaccine or cell therapy). In other situations, pre-filled syringes are exposed to a combination of low temperature and high pressure, such as when transported on a flat surface. Maintaining the integrity of the container seal under these conditions is a significant challenge for pre-filled syringes, at least partially based on a mismatch in the coefficient of thermal expansion (CTE) between the stopper and barrel material. This CTE mismatch is even more pronounced when the barrel of the pre-filled syringe is made of glass, and the glass substrate (i.e., barrel) is typically CTE g It has a concentration of 5 ppm / ℃, and rubbers such as bromobutyl (i.e., stoppers) have a CTE at room temperature. S It is known to have a CTE of 200 ppm / °C (T_amb). Assuming a constant CTE from room temperature to deep cold conditions, this level of CTE mismatch can reduce the interference rate between the stopper and the barrel by approximately 30%. This is at least partially due to the elastomer stopper reaching its glass transition temperature (Tg), causing the elastic properties of the stopper to change to a "glassy" state, losing its ability to exert strong contact pressure on the barrel and maintain a seal. Fluctuations / declines in the contact pressure between the stopper and the barrel during thermal cycling can pose a risk to the integrity of the container closure by creating a leak channel (partial lack of contact) at the barrel-stopper interface and / or by allowing movement of the stopper within the barrel during freeze-thaw cycles. 【0007】 A large CTE mismatch between the barrel and the stopper can cause problems with the integrity of the subsequent container closure when the stopper is first inserted into the barrel. Specifically, during the initial assembly of a pre-filled syringe, the stopper is typically positioned by using a vent tube stopper, which consists of compressing the stopper (using a vent tube stopper tool) to have a diameter significantly smaller than the barrel's inner diameter before the stopper is positioned inside the barrel and allowed to expand backward to seal within the barrel. For many stopper materials, including where rubber stoppers are coated with PTFE, this can result in damage to the rubber material and / or the coating thereon, which can impair the integrity of the container closure and / or particle formation. 【0008】 Therefore, in this field, there is a need for sealed containers, including pre-filled syringes, that can maintain sterility and the integrity of the container closure even at very low refrigerated storage temperatures. There is also a need for a method of manufacturing such sealed containers that maintains the integrity of the container closure throughout the manufacturing process and thereafter. [Overview of the Initiative] 【0009】 Provided herein is a pre-filled syringe comprising a syringe barrel having a proximal and distal end and defining a chamber, the syringe barrel having an opening at the proximal end. The pre-filled syringe also comprises a plunger assembly inserted through the opening and movable axially within the chamber of the syringe barrel, the plunger assembly further comprising a plunger rod having an elongated body extending between the proximal and distal ends and a stopper attached to the distal end of the plunger rod and positioned within the barrel chamber. The stopper is composed of a mixed material comprising an elastomer material and a mixed material having a lower coefficient of thermal expansion than the elastomer material. 【0010】 In certain configurations, the mixed materials have a negative coefficient of thermal expansion. 【0011】 In certain configurations, the blended material of the stopper has a thermal expansion coefficient that matches or is lower than that of the syringe barrel. 【0012】 In certain configurations, the stopper is configured to expand at room temperature or below 0°C to maintain a complete seal between the stopper and the syringe barrel. 【0013】 In certain configurations, the mixed materials are graphene, hexagonal boron nitride compounds (coronene), ScF3 compounds, ZrW2O8, or β-eucryptite and Ca2RuO4. 【0014】 In certain configurations, the stopper includes an inert coating applied to at least a portion of its outer surface. 【0015】 In certain configurations, the inert coating is a parylene coating. 【0016】 In certain configurations, the syringe barrel is made from a glass substrate. 【0017】 In certain configurations, the syringe barrel is made from a polymer substrate. 【0018】 In certain configurations, the stopper is a molded stopper formed by molding a blend of elastomer material and mixed material. 【0019】 In a particular configuration, the syringe includes a distal end cap positioned above the nozzle at the distal end of the barrel chamber, and the distal end cap is composed of a blend material comprising a polymer material and a mixed material having a lower coefficient of thermal expansion than the polymer material. 【0020】 Also provided herein is an apparatus for storing and / or delivering a fluid. The apparatus has a proximal end and a distal end and includes a container that defines a chamber, the container having an opening at the proximal end. The apparatus also includes a sealing component at least partially disposed within the chamber such that at least a portion of the sealing component forms an interference fit with the container, the sealing component being composed of a blend material that includes an elastomeric material and a hybrid material having a lower coefficient of thermal expansion than the elastomeric material. 【0021】 In certain configurations, the hybrid material has a negative coefficient of thermal expansion (NCTE). 【0022】 In certain configurations, the hybrid material is graphene, a hexagonal boron nitride (coronene) compound, a ScF3 compound, ZrW2O8, or β-eucryptite and Ca2RuO4. 【0023】 In certain configurations, the stopper includes an inert coating applied to at least a portion of its outer surface. 【0024】 In certain configurations, the container is composed of one of a glass substrate and a polymer substrate. 【0025】 In certain configurations, the apparatus is a prefilled syringe, the container is the syringe barrel, and the sealing component is a stopper fixed to the distal end of the plunger rod. 【0026】 In certain configurations, the apparatus includes a distal end cap disposed over a nozzle at the distal end of the chamber, the distal end cap including another polymeric material and a hybrid material having a lower coefficient of thermal expansion than the polymeric material. 【0027】 Furthermore, this specification also provides a method for assembling a pre-filled syringe. This method comprises providing a syringe barrel having a proximal end and a distal end, defining a chamber, the syringe barrel having an opening at the proximal end. The method also comprises providing a plunger assembly that can be inserted into the opening, the plunger assembly comprising an elongated body and a plunger rod extending between the proximal and distal ends, and a stopper attached to the distal end of the plunger rod and positioned within the barrel chamber, the stopper comprising an elastomer material and a mixed material having a negative coefficient of thermal expansion lower than the coefficient of thermal expansion of the elastomer material. The method further comprises heating a vent tube stopper tool that holds the plunger assembly with the vent tube stopper tool heated to a temperature that will cause the stopper to contract for the mixed material having a negative coefficient of thermal expansion, and inserting the plunger assembly into the syringe barrel using the vent tube stopper tool. 【0028】 In certain configurations, the method also involves filling the barrel with a liquid solution before inserting the plunger assembly. [Brief explanation of the drawing] 【0029】 [Figure 1] Figure 1 is a perspective view of a cap assembly according to a non-limiting embodiment or aspect described herein. [Figure 2] Figure 2 is an exploded view of the pen needle shown in Figure 1. [Figure 3] Figure 3 is a side cross-sectional view of the syringe shown in Figure 1, with the plunger assembly in its initial or pre-use position. [Figure 4] Figure 4 is a detailed view of the stopper located inside the barrel of the syringe shown in Figure 1. [Figure 5] Figure 5 is a side cross-sectional view of a stopper according to another non-limiting embodiment described herein. [Modes for carrying out the invention] 【0030】 The following description is provided to enable those skilled in the art to create and use the described embodiments intended for carrying out the invention. However, various modifications, equivalents, variations, and substitutes will be readily apparent to those skilled in the art. Any and all such modifications, variations, equivalents, and substitutes are intended to fall within the spirit and scope of the invention. 【0031】 Hereinafter, for illustrative purposes, “top,” “bottom,” “right,” “left,” “vertical,” “horizontal,” “top,” “bottom,” “horizontal,” “vertical,” and their derivatives shall be used in relation to the present invention as oriented in the drawings. However, it should be understood that the present invention may presuppose various alternative modifications unless expressly otherwise specified. It should also be understood that the specific devices shown in the accompanying drawings and described in the following specification are merely exemplary embodiments of the present invention. Therefore, specific dimensions and other physical features relating to the embodiments disclosed herein should not be considered restrictive. 【0032】 In this disclosure, the distal end of a component or device means the end furthest from the user's hand when the component or device is in use, i.e., when the user is holding the syringe in preparation for or during use, and the proximal end means the end closest to the user's hand. Similarly, in this application, the terms “distally” and “distally” mean the direction toward the distal tip of the syringe, and the terms “proximal” and “proximal” mean the direction opposite to the direction toward the distal tip of the syringe. 【0033】 Aspects and embodiments of this disclosure relate to the use of low or negative coefficient of thermal expansion (NCTE) materials in container closure or sealing components. The use of low or negative CTE materials allows a sealing component to have a CTE that more closely matches the CTE of the container in which it sits. In embodiments in which the sealing component has a negative CTE, the sealing component may be configured to expand when the container is exposed to low-temperature storage temperatures. 【0034】 Referring to Figures 1 and 2, Figures 1 and 2 illustrate non-limiting embodiments of a syringe 10 in which aspects or embodiments of the present disclosure may be implemented. As shown in Figures 1 and 2, the syringe 10 generally includes a syringe barrel 12 and a plunger assembly 14. The plunger assembly 14 is movable within the syringe barrel 12 to an advanced position along its longitudinal axis to facilitate, for example, the administration of an injectable fluid (e.g., a drug) to a patient. 【0035】 The syringe barrel 12 is generally formed from a cylindrical outer wall 16 and an end member 18 that collectively defines a chamber 20 for holding fluid therein. The syringe barrel 12 includes an open proximal end 22 configured to receive a plunger assembly 14 therein and a distal end 24 where the end member 18 is located. The proximal end 22 of the syringe barrel 12 may include a flange 26 for facilitating the handling and positioning of the syringe 10 and for maintaining the relative position of the syringe barrel 12 with respect to the plunger assembly 14 during drug administration. In one embodiment, the distal end 24 of the syringe barrel 12 may include a tip 28 that extends distally outward from the end wall 18 and defines a lumen 30 that communicates fluid with the chamber 20. A Luer lock adapter 29 is attached to the outer surface of the tip 28 and / or is connectable to a rigid cap 31 covering the tip 28 and / or a corresponding needle hub (not shown) with which the syringe 10 engages to administer fluid to a patient. The adapter 29 comprises a cylindrical body having a threaded inner surface configured to engage with the outer surface of the threaded portion of the rigid cap 31. In other embodiments, it can be understood that the syringe 10 may be provided as a stake needle syringe, with a needle shield fixed to the syringe barrel 12 and extending distally therefrom, positioned above the needle. 【0036】 As best shown in Figure 3, the rigid cap 31 may be configured as a rigid cap that fits with the adapter 29 to provide a fluid-sealing seal on the tip 28, having a proximal end and a distal end configured as a closed end of the rigid cap 31, which covers the tip 28 and is positioned inside the rigid cap 31 so as to be partially inserted into the lumen 30 of the tip 28. 【0037】 The plunger assembly 14 of the syringe 10 is formed from an elongated plunger rod 32 (more commonly, the "plunger 32" as used below) and a plunger head or stopper 34. The plunger 32 may include a body 36 extending between the proximal end 38 and the distal end 40 of the plunger. In some embodiments, the body 36 may include a plurality of elongated vanes or walls 42 extending axially along its length between the proximal end 38 and the distal end 40 of the plunger. A thumb press 44 is positioned on the proximal end 38 of the plunger and engaged by the user's thumb (or other fingers) to apply distal force to the plunger assembly 14, thereby moving the plunger 36 relative to the syringe barrel 12. In some embodiments, a flanged extension member 46 (e.g., a disc-shaped flange) is positioned on the distal end 40 of the plunger and configured to engage with the stopper 34. In other embodiments, the distal end 40 of the plunger may include a female receptacle formed therein, which is configured to receive and connect a projection (e.g., a pin) extending proximal from the stopper 34 such that the projection and the receptacle engage via threads. 【0038】 The stopper 34 of the plunger assembly 14 is positioned at the distal end 40 of the plunger so as to be movable with the plunger 36 within the chamber 20 of the syringe barrel 12. The stopper 34 may be made of a different material from the material of the plunger 32 and may form a seal with the syringe barrel 12 as the syringe barrel 22 advances through it. In some embodiments, the stopper 34 includes a receptacle 56 (Figure 4) formed therein to receive a flanged extension member 46 of the plunger 32, the flanged extension member 46 is coupled to the receptacle 56 via a press-fit connection to fix the stopper 34 to the plunger 32, for example, but it may be understood that the mounting member 48 and the distal end 40 of the plunger may be fixed by other techniques known in the art. The mounting member 48 may further include a pair of spaced-apart annular flanges 58 (i.e., O-rings) formed thereon, which form a sealing seal with the cylindrical outer wall 16 of the syringe barrel 12. 【0039】 As described above, syringe 10 may be provided as a pre-filled syringe so that syringe 10 contains a drug or substance pre-filled in the chamber 20. In some embodiments, the drug or substance in the chamber 20 of the pre-filled syringe 10 may be a drug or substance that requires cryogenic storage (i.e., low-temperature storage) at temperatures of -80 to -196°C. Therefore, in order to maintain the integrity of the container closure at these deep low-temperature storage temperatures, syringe 10 may be specifically configured to maintain sterility and the integrity of the container closure at low-temperature storage temperatures. According to aspects of the present disclosure, the stopper 34 is composed of a desired material that minimizes the CTE mismatch between the stopper 34 and the barrel material and allows the stopper 34 to maintain some contact pressure at low-temperature storage temperatures. In other words, according to aspects or embodiments of the present disclosure, the syringe barrel 12 may be formed of glass having a coefficient of thermal expansion of CTE_g = 5 ppm / °C, or of a polymer material having a coefficient of thermal expansion of CTE_p = 50 ppm / °C, and the stopper 34 may be formed of a mixture of elastomer material and other low or negative CTE material, providing an improvement over a typical elastomer stopper 34 having a high CTE such as bromobutyl with CTE_S = 200 ppm / °C at room temperature, by providing the overall CTE of the stopper 34 to be close to or less than the CTE of the barrel material, i.e., matching the CTE of the barrel material or being less than the CTE of the barrel material. By making the CTE of the stopper 34 more closely match the CTE of the barrel 12, or making the CTE of the stopper 34 smaller than the CTE of the barrel 12, the interference rate between the stopper 34 and the barrel 12 can be kept low even at the very low refrigeration temperature at which the elastomer material of the stopper 34 reaches its glass transition temperature (Tg). 【0040】 According to aspects or embodiments of the present disclosure, as shown in Figure 4, the stopper 34 is formed of a flexible elastomer material 60 mixed with another (mixed) material 62 having a CTE smaller than that of the elastomer material, and in some embodiments having a negative CTE at storage temperature, which may be below 0°C and as low as -80°C to -196°C. The mixed material 62 is preferably interspersed with the elastomer material 60 to counteract the shrinkage of the elastomer material 60 when the elastomer is close to or below the Tg of the elastomer, thus allowing the stopper 34 to maintain contact pressure with the barrel 12. For example, the syringe 10 may have a central axis 64, and the barrel 12 and stopper 34 are coaxial along the central axis 64 when assembled, and when the syringe 10 is stored at a low temperature such as a low temperature, the elastomer material 60 of the stopper 34 may shrink radially toward the central axis 64. However, a mixed material 62 having a lower coefficient of thermal expansion can preferably shrink radially away from the central axis 64 if the CTE of the mixed material 62 is negative at the storage temperature. 【0041】 The amount of mixed material 62 incorporated into the stopper 34 depends on the difference between the CTE of the mixed material 62 and the elastomer material 60, and / or the CTE of the substrate material (e.g., glass or polymer material) on which the barrel 12 is formed. For example, if the mixed material 62 has a much smaller CTE than the elastomer material 60, more of the mixed material 62 may be needed to achieve the desired counteracting effect against the expected shrinkage of the elastomer material 60 and / or to achieve a negative CTE for the overall stopper 34. However, if the difference in CTE between the two materials is small, less of the mixed material 62 may be needed to achieve the same degree of resistance to the shrinkage of the elastomer material 60 and / or to configure the stopper 34 to expand at low temperatures. Furthermore, if the barrel 12 is made of glass and has a very low CTE (i.e., CTE_g = 5 ppm / °C), more of the mixed material 62 may be required to bring the total CTE of the stopper 34 closer to (or below) the CTE of the barrel 12. However, if the barrel 12 is made of polymer material and has a very high CTE (i.e., CTE_g = 50 ppm / °C), less of the mixed material 62 may be required to bring the total CTE of the stopper 34 closer to (or below) the CTE of the barrel 12. 【0042】 Examples of elastomer materials 60 for forming steppers according to various embodiments of the present disclosure include, but are not limited to, synthetic rubbers or natural rubbers such as butyl rubber, isoprene rubber, butadiene rubber, halogenated butyl rubber (e.g., bromobutyl rubber), ethylene propylene polymer, and silicone rubber. Preferably, the elastomer material 60 is a butyl or halobutyl elastomer. The elastomer material 60 may further contain one or more additives such as vulcanizing agents, vulcanization accelerators, vulcanization activators, processing aids, fillers, and reinforcing agents to improve or enhance the properties of the elastomer material 60. 【0043】 Examples of the mixed material 62 included in the stopper 34 according to various embodiments of this disclosure include, but are not limited to, graphene, hexagonal boron nitride (coronene) compounds, ceramic types such as ScF3 and zirconium ZrW2O8, or nanometal oxides such as β-eucryptite and Ca2RuO4, perovskite BiNiO3, and CuO. 【0044】 According to one non-limiting aspect or embodiment of the present disclosure, the stopper 34 is formed from a rubber-graphene blend having a graphene content of 0.1 to 19%. The amount of graphene or other NCTE material can partially or completely replace typical rubber-reinforced materials such as clay or silica. According to another embodiment under this approach, the stopper 34 may be a rubber blend with up to 40% of any of the above NCTE compounds. 【0045】 According to aspects or embodiments of the present disclosure, the stopper 34 may be manufactured via a molding process, in which the elastomer material 60 and the mixed material 62 are blended together before molding. Once the materials are blended, the stopper 34 is molded at a relatively high temperature (e.g., 120-190°C) to allow crosslinking of molecules within it, thereby obtaining the elastic and resilient properties of the stopper 34. By including a mixed material 62 such as graphene, the stopper 34 may be molded while avoiding charring of the elastomer material 60 within it, and the graphene provides improved functional performance of the stopper 34 by increasing the uniformity of the rubber curing state and toughness, as described above, and by lowering the CTE of the stopper 34. 【0046】 According to some aspects or embodiments of this disclosure, the stopper 34 may also include a protective coating 66 on at least a portion thereof to prevent potential interaction between the drug or drug mixture 62 contained in the chamber 20 of the barrel 12. The coating 66 preferably covers at least a portion of the outer surface of the stopper 34 that is most likely to come into contact with the drug or drug in the barrel 12, preventing the leaching of the mixture 62 into the drug or drug. Although the coating 66 is shown in Figure 4 as being applied only to the bottom of the stopper 34, the coating 66 may cover the entire outer surface of the stopper 34 according to other embodiments. In preferred embodiments, the coating 66 is an inert film, preferably a parylene or fluoropolymer coating. According to one embodiment, the coating is a parylene coating. 【0047】 According to aspects or embodiments of this disclosure, if the mixed material 62 selected to prevent overall shrinkage of the stopper 34 at low temperatures (i.e., cryogenic temperature) has a negative CTE, it is recognized that when the syringe 10 is exposed to higher temperatures, the mixed material 62 may potentially jeopardize the integrity of the container closure. That is, as the negative CTE material shrinks at higher temperatures, if the temperature to which the stopper 34 is exposed becomes unacceptably high (e.g., above 25°C), the interference rate between the stopper 34 and the barrel 12 may fall below an acceptable amount, resulting in the formation of a leak channel at the barrel-stopper interface and / or the stopper 34 moving inward into the barrel 12. Therefore, when blending a negative CTE mixed material 62 with the elastomer material 60, a maximum temperature below which the syringe 10 should be kept should be defined. 【0048】 According to an embodiment of the present disclosure, it is desirable that the stopper 34 be designed such that the interference between the stopper 34 and the barrel 12 does not decrease beyond 30% of the initial interference, which can be, for example, an interference of 0.35 mm. This is because it may endanger the integrity of the container closure. The temperature at which the interference decreases by 30%, T30%, can be defined as follows: 【0049】 【Number】 【0050】 where T amb is the ambient temperature, S OD is the outer diameter of the stopper, B ID is the inner diameter of the barrel, CTE S is the CTE of the stopper, CTE g is the CTE of the (glass) barrel, and the above relationship assumes that the CTE is constant over the entire temperature range. 【0051】 Using the above definition of T 30% the relationship of the interaction between various stoppers (i.e., stoppers with various CTEs S including the stopper 34 having a negative CTE that shrinks at high temperatures S with various CTEs) and a glass barrel substrate or a plastic barrel substrate is shown in Table 1 provided below. In the following example, an interference of 0.35 mm between the stopper 34 and the barrel 12 (e.g., stopper outer diameter P OD = 6.7 mm, barrel inner diameter B ID = 6.35 mm) can be assumed. Thus, Table 1 shows the minimum / maximum temperature at which T 30% is reached. 【0052】 【Table 1】 【0053】 It is recognized that the above example is purely illustrative, as the calculated temperature also depends on the product design (barrel ID, stopper OD, CTE over the temperature range, etc.). 【0054】 It is recognized that exposing the stopper 34 to high temperatures during storage / transportation may cause the interference rate between the stopper 34 and the barrel 12 to fall below an acceptable level, when the stopper 34 contains a mixed material 62 having a negative CTE, thereby jeopardizing the integrity of the container closure. However, it is further recognized that such high temperatures may be beneficial during the initial assembly of the container or syringe 10. Specifically, a stopper 34 containing a mixed material 62 having a negative CTE may show advantages during assembly because the dimensions of the stopper 34 shrink at temperatures above room temperature. When inserting the stopper 34 into the syringe 10, the vent tube stopper tool used to insert the stopper 34 can be heated to facilitate the stopper insertion process. Heating the tool shrinks the dimensions of the stopper 34 and therefore reduces the interference rate between the stopper 34 and the vent tube stopper tool, which reduces the possibility of damage to the stopper 34 (and / or the coating 66 thereon) during assembly, thereby ensuring the integrity of the subsequent container closure when the stopper 34 is inserted into the barrel 12. 【0055】 Accordingly, according to aspects or embodiments of the present disclosure, a method for assembling a pre-filled syringe may be provided, comprising: providing a syringe barrel; providing a plunger assembly insertable into the syringe barrel; a stopper comprising a mixed material including an elastomer material and a mixed material having a negative coefficient of thermal expansion lower than the coefficient of thermal expansion of the elastomer material; heating a vent tube stopper tool that holds the plunger assembly; heating the vent tube stopper tool to a temperature that causes the stopper to contract (e.g., 25°C or higher); and using the vent tube stopper tool to insert the plunger assembly into the syringe barrel. This method may also include filling the barrel with a liquid solution before inserting the plunger assembly. 【0056】 According to aspects or embodiments of the present disclosure, in addition to the stopper 34 which contains a material having a low or negative CTE, a portion of the rigid cap 31 (or needle shield) may be composed of a portion of a low or negative CTE material. In some embodiments, the inner cap 33 (or the rubber inner portion of the needle shield) may be formed of a blended material which includes an elastomer material and a mixed material which has a negative coefficient of thermal expansion lower than the coefficient of thermal expansion of the elastomer material, as described above for the stopper 34. Thus, the inner cap 33 may be configured to have a CTE that closely matches the CTE of the barrel 12 (i.e., the tip of the barrel 28) so that the closure of the tip 28 is ensured and the closure integrity of the syringe 10 is maintained. 【0057】 In yet another embodiment, other portions of the rigid cap 31 (or needle shield) may be formed from a blend of a rigid polymer material and a mixed material 62 having a low or negative CTE. The cap portion may be formed as a graphene-based polymer nanocomposite, where graphene is mixed with any suitable polymer material, including, in non-limiting examples, polypropylene or polyethylene. Thus, the polymer portion of the rigid cap 31 may also be specifically configured to have a CTE that closely matches the CTE of the glass barrel 12 (i.e., tip 28). 【0058】 While the embodiments and aspects of the present disclosure described above relate to a pre-filled syringe 10 comprising a plunger assembly 14 having a barrel 12 and a stopper 34, it is recognized that additional embodiments of the present disclosure may relate to other devices, i.e., other containers and sealing elements, including, for example, a vial and associated vial stopper. Figure 5 generally shows such a device comprising a container (vial) 70 and a sealing element (vial stopper) 72, where the vial 70 may be made of glass or polymer material, and the vial stopper 72 may be formed from a blend of elastomer material and a material having a low or negative CTE, as described in detail above with respect to the syringe 10 of Figures 1 to 4. 【0059】 According to one embodiment, a negative CTE material 62, such as graphene, may be blended with an elastomer material 60 to form a vial stopper 72 in order to counteract the shrinkage of the vial stopper 72. That is, when the vial 70 and vial stopper 72 are stored at low temperatures, such as cold temperatures, the elastomer material 60 of the vial stopper 72 may shrink radially inward and away from the vial 70. However, a mixed material 62 having a lower coefficient of thermal expansion may expand less, or more preferably, radially outward toward the vial 70, preferably if the CTE of the mixed material 62 is negative at the storage temperature. 【0060】 Therefore, beneficially, embodiments of the present invention provide container closure or sealing components comprising a low or negative coefficient of thermal expansion (CTE) material mixed with another material, such as an elastomer material. The use of a low or negative CTE material allows the sealing component to have a CTE that more closely matches the CTE of the container in which it sits. In embodiments in which the sealing component has a negative CTE, the sealing component may be configured to expand when the container is exposed to a low-temperature storage temperature, thereby further ensuring the integrity of the container closure even at extremely low-temperature storage temperatures. 【0061】 This disclosure has been described in detail for illustrative purposes based on what is currently considered to be the most practical and preferred embodiments or aspects, but such details are for that purpose only, and this disclosure is not limited to the disclosed embodiments or aspects, but rather intended to encompass modifications and equivalent arrangements that fall within the spirit and scope of the appended claims. For example, this disclosure is intended to be, wherever possible, to allow one or more features of any embodiment to be combined with one or more features of any other embodiment.

Claims

[Claim 1] It is a pre-filled syringe, A syringe barrel having a proximal end and a distal end, defining a chamber, wherein the syringe barrel has an opening at the proximal end, A plunger assembly that is inserted through the opening and is movable axially within the chamber of the syringe barrel, It has a long, slender body and a plunger rod extending between its proximal and distal ends, A plunger assembly comprising: a stopper attached to the distal end of the plunger rod and positioned within the barrel chamber; Equipped with, The stopper is a pre-filled syringe comprising a blended material containing an elastomer material and a mixed material having a lower coefficient of thermal expansion than the elastomer material. [Claim 2] The syringe according to claim 1, wherein the mixed material has a negative coefficient of thermal expansion. [Claim 3] The syringe according to claim 2, wherein the blend material of the stopper has a coefficient of thermal expansion that matches the coefficient of thermal expansion of the syringe barrel, or a coefficient of thermal expansion that is lower than the coefficient of thermal expansion of the syringe barrel. [Claim 4] The syringe according to claim 2, wherein the stopper is configured to expand at room temperature or a low-temperature storage temperature of 0°C or below to maintain the integrity of the closure between the stopper and the syringe barrel. [Claim 5] The syringe according to claim 2, wherein the mixed material comprises graphene, a hexagonal boron nitride (coronene) compound, an ScF3 compound, ZrW2O8, or β-eucryptite and Ca2RuO4. [Claim 6] The syringe according to claim 1, wherein the stopper is provided with an inert coating applied to at least a portion of its outer surface. [Claim 7] The syringe according to claim 6, wherein the inert coating comprises a parylene coating. [Claim 8] The syringe according to claim 1, wherein the syringe barrel is made of a glass substrate. [Claim 9] The syringe according to claim 1, wherein the syringe barrel is made of a polymer substrate. [Claim 10] The syringe according to claim 1, wherein the stopper comprises a molded stopper formed by molding a blend of the elastomer material and the mixed material. [Claim 11] The syringe according to claim 1, further comprising a distal end cap disposed on a nozzle at the distal end of the barrel chamber, wherein the distal end cap comprises a blend material including a polymer material and a mixed material having a lower coefficient of thermal expansion than the polymer material. [Claim 12] A device for storing and / or delivering fluids, A container having a proximal end and a distal end, defining a chamber, wherein the container has an opening at the proximal end, The invention comprises a sealing component at least partially positioned within the chamber such that at least a portion of the sealing component forms a tight fit with the container, The apparatus comprises a sealing component which includes a blended material comprising an elastomer material and a mixed material having a lower coefficient of thermal expansion than the elastomer material. [Claim 13] The apparatus according to claim 12, wherein the mixed material has a negative coefficient of thermal expansion. [Claim 14] The apparatus according to claim 13, wherein the mixed material comprises graphene, a hexagonal boron nitride (coronene) compound, a ScF3 compound, ZrW2O8, or β-eucryptite and Ca2RuO4. [Claim 15] The apparatus according to claim 12, wherein the stopper is provided with an inert coating applied to at least a portion of its outer surface. [Claim 16] The apparatus according to claim 12, wherein the container is made of a glass substrate or a polymer substrate. [Claim 17] The apparatus according to claim 12, wherein the apparatus is a pre-filled syringe, the container comprises a syringe barrel, and the sealing component comprises a stopper fixed to the distal end of the plunger rod. [Claim 18] The apparatus according to claim 17, further comprising a distal end cap positioned above the nozzle at the distal end of the chamber, wherein the distal end cap comprises a blend material including another polymer material and a mixed material having a lower coefficient of thermal expansion than the polymer material. [Claim 19] A method for assembling a pre-filled syringe, A step of providing a syringe barrel having a proximal end and a distal end and defining a chamber, wherein the syringe barrel has an opening at the proximal end, A step of providing a plunger assembly that can be inserted into the opening, wherein the plunger assembly is It has a long, slender body and a plunger rod extending between its proximal and distal ends, A stopper is attached to the distal end of the plunger rod and positioned within the barrel chamber, The stopper comprises a blend material including an elastomer material and a mixed material having a negative thermal expansion coefficient lower than the thermal expansion coefficient of the elastomer material, and the steps of providing: The steps include heating a ventilation tube stopper tool that holds the plunger assembly therein, and heating the ventilation tube stopper tool to a temperature that causes the stopper to contract for the mixed material having a negative coefficient of thermal expansion, A method comprising the step of inserting the plunger assembly into the syringe barrel using the ventilation tube stopper tool. [Claim 20] The method according to claim 19, further comprising the step of filling the barrel with a liquid solution before inserting the plunger assembly.

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