Containment and delivery systems for cryogenic storage

Abstract

The present invention provides various systems for containing or delivering products. The system allows for storage of products at low temperatures and includes a container closure inserted in a container (10). The container closure may have an elastic body (12) and include a material (14) having a negative thermal expansion coefficient. In other systems, the material having a negative thermal expansion coefficient may be inserted between the elastic container closure and the seal. Other systems may include an insert at least partially embedded in the elastic body of the container closure, an actuator having a distal end movably attached to the insert, and an elastic element located between the distal end of the actuator and the insert, wherein the elastic material radially expands when the distal end of the actuator is displaced toward the insert.

Description

Background Art

[0001] Various embodiments of the present invention relate to containment and delivery systems, and more particularly to containment and delivery systems including a resilient member configured to maintain a seal within a container at extremely cold temperatures.

[0002] When selecting packaging components for biological and pharmaceutical materials, consider the integrity of the seal between the container and the closure. These materials are typically stored in stoppered glass or plastic containers (e.g., glass or plastic vials or syringes) with elastomeric closures. These materials include, for example, blood, serum, proteins, peptides, stem cells, DNA, and other perishable biological fluids, as well as freeze-dried or lyophilized pharmaceutical products.

[0003] The container must be able to protect the material from a variety of potential sources of contamination, including microbial ingress, moisture, and gas exchange. The primary seal is formed at the interface of the elastomeric sealing component and the container. Assuming there are no defects in the individual packaging components, this interface represents a primary point of potential packaging failure. When selecting and applying an appropriate container closure system for a drug product, multiple factors must be considered to ensure satisfactory container closure integrity.

[0004] Failures in manufacturing (such as improper assembly, insufficient or excessive clamping force, or faulty design) can compromise the integrity of the container closure system. Therefore, it is necessary to ensure that the size of the elastomeric sealing component is correctly matched to the container to establish adequate seal integrity. Loss of vacuum, gas ingress and exchange, pH adjustment, and contaminants can compromise seal integrity, which can result in loss of sterility of the drug product, which can subsequently affect product efficacy and increase patient safety risks.

[0005] With the increasing trend of high-value biologics, cell and gene therapies and other high-value pharmaceutical products, the requirements for reliable container closure systems have become more stringent. Such biologics and pharmaceutical products are often temperature sensitive and have a high probability of degradation if they are not stored under appropriate conditions. It is common for some biologics and pharmaceutical products to be stored in sealed containers at low temperatures, such as as low as 0°C, more preferably -80°C, and in many cases even as low as extremely cold temperatures (e.g., as low as or below -150°C, more preferably as low as or below -180°C, even more preferably as low as or below -196°C), for example to avoid degradation or evaporation losses of these materials.

[0006] As mentioned above, the sealing components of most drug containers are made of elastomers. The common physical property of all elastomers is the glass transition temperature (Tg). All elastomers undergo physical changes at lower temperatures that change elastic properties, making these materials "glassy". Under ambient temperature conditions, molecules are in a constant state of thermal motion and constantly change their configuration, which provides flexibility and can therefore form a seal against another surface. However, at the glass transition temperature, the mobility of molecules is significantly reduced, and the material becomes brittle and glassy. For example, the glass transition temperature of common butyl rubber is about -65 ° C. Similarly, the thermal expansion coefficient of the elastic material used to form the sealing component can be substantially different from the material (e.g., glass or plastic) of the container, so that the elastic material is larger than the shrinkage rate of the container opening. As used herein throughout the specification and claims, "thermal expansion coefficient" means the volumetric thermal expansion coefficient. Therefore, the current elastic sealing component may not be able to maintain closed integrity at extremely cold temperatures, and may potentially damage the sterility of the biological or pharmaceutical products stored in the container.

[0006] Therefore, there is a need for improved cryogenic containment and delivery systems, and components within such systems, that provide a primary seal to ensure container closure integrity. Summary of the invention

[0007] According to a first aspect of an embodiment of the present invention, a system for containing or delivering a product may include a container having an inner surface and a container closure having an outer surface. The container closure may include an elastic body and a material having a negative coefficient of thermal expansion located within the elastic body. At least a portion of the container closure may be inserted into the container so that at least a portion of the outer surface of the container closure contacts at least a portion of the inner surface of the container.

[0008] In some embodiments, the material having a negative coefficient of thermal expansion may include a solid, a liquid at temperatures greater than 0° C., or a gel at temperatures greater than 0° C. In other embodiments, the material may have a negative coefficient of thermal expansion at temperatures less than or equal to 0° C.

[0009] In addition, some of the systems according to various embodiments of the present invention may include a container closure provided in at least one of a syringe plunger, a vial stopper, and a cartridge piston. In other systems, the container may be a vial having a neck portion, and the system may further include a seal surrounding at least a portion of the outer periphery of the container closure provided in the form of a vial stopper and the neck portion.

[0010] According to another aspect of an embodiment of the present invention, a system for containing or delivering a product may include a container having an inner surface, a container closure including an elastic body having an outer surface, at least a portion of the outer surface of the elastic body in contact with the inner surface of the container, an insert at least partially embedded in the elastic body, an actuator having a distal end movably attached to the insert, and an elastic element located between the distal end of the actuator and the insert. The elastic material can expand radially toward the inner surface of the container when the distal end of the actuator is displaced toward the insert.

[0011] In some embodiments, at least a portion of the elastic material is located within the elastic body. In other embodiments, the elastic material includes a material having a negative coefficient of thermal expansion. The material may be a liquid or gel at a temperature greater than 0°C. The material may also have a negative coefficient of thermal expansion at a temperature less than or equal to 0°C.

[0012] According to yet another aspect of an embodiment of the present invention, a system for containing or delivering a product may include a vial having an inner surface and a neck portion, a stopper including an elastomeric body having an outer surface, an insert including a material having a negative coefficient of thermal expansion, and a seal surrounding an outer periphery of the stopper and at least a portion of the neck portion. The insert may be located between a surface of the stopper and a surface of the seal.

[0013] In some embodiments, the material comprises a solid, a liquid, or a gel at a temperature greater than 0° C. Additionally, the material may have a negative coefficient of thermal expansion at a temperature less than or equal to 0° C.

[0014] These and other aspects of the invention will be apparent in view of the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Various aspects and embodiments of the patent application will be described with reference to the following drawings. It should be understood that the drawings are not necessarily drawn to scale. The drawings depict one or more specific implementations of the present invention by way of example only and not by way of limitation. In the drawings, similar reference numerals refer to the same or similar elements.

[0016] Figure 1 is a schematic cross-sectional front plan partial view of a system according to a first embodiment of the present invention.

[0017] Figure 2A and Figure 2B is a schematic cross-sectional front plan partial view of a system according to a second embodiment of the present invention.

[0018] Figure 3A and Figure 3B is a schematic cross-sectional front plan partial view of a system according to a third embodiment of the present invention.

[0019] FIG. 4A to FIG. 4C is a schematic cross-sectional front plan partial view of a system according to a fourth embodiment of the present invention.

[0020] Figure 5A is a front plan view of a system according to a fifth embodiment of the present invention, and Figure 5B yes Figure 5A An enlarged front perspective view of a container closure within a system. Figure 5C and Figure 5D is available in Figure 5A An alternative embodiment of an insert incorporated into the system.

[0021] Fig. 6A is a front plan view of a system according to a sixth embodiment of the present invention, and Figure 6B yes Fig. 6A An enlarged front perspective view of a container closure within a system.

[0022] Fig. 7A is a front plan view of a system according to a seventh embodiment of the present invention, and Figure 7B yes Fig. 7A An enlarged front perspective view of a container closure within a system.

[0023] Fig. 8A is a schematic front perspective view of a container closure according to an eighth embodiment of the present invention, and Figure 8B is included Fig. 8A Schematic cross-sectional front plan partial view of a system of closures.

[0024] Fig.9A is a schematic front perspective view of a container closure according to a ninth embodiment of the present invention, and Fig. 9B is included Fig.9A Schematic cross-sectional front plan partial view of a system of closures.

[0025] Fig. 10A is a schematic front perspective view of a container closure according to a tenth embodiment of the present invention, and Fig. 10B yes Fig. 10A A cross-sectional front plan view of a container closure.

[0026] Fig.11 is a schematic cross-sectional front plan partial view of a system according to an eleventh embodiment of the present invention.

[0027] Fig.12 is a schematic cross-sectional front plan partial view of a system according to a twelfth embodiment of the present invention.

[0028] Fig.13is a schematic cross-sectional front plan partial view of a system according to a thirteenth embodiment of the present invention.

[0029] Fig.14 is a schematic cross-sectional front plan partial view of a system according to a fourteenth embodiment of the present invention. DETAILED DESCRIPTION

[0030] Generally speaking, the system according to various embodiments of the present invention includes a container closure, which includes an elastic body and a material whose thermal expansion coefficient is less than the thermal expansion coefficient of the elastic body. Preferably, the material has a negative thermal expansion coefficient at a certain temperature, which is less than or equal to 0°C, more preferably less than or equal to -80°C, and in many cases, even less than or equal to -150°C, more preferably less than or equal to -180°C, and even more preferably less than or equal to -196°C. In some embodiments, the material may have a negative thermal expansion coefficient at extremely cold temperatures (e.g., temperatures less than -150°C). Materials with substantially different thermal expansion coefficients help maintain the seal within the system, thereby preventing the integrity of the container closure from possible failures and preserving the contents of the container when stored at low temperatures. After warming up the system at ambient temperature, the elastic portion of the container closure can expand to maintain the seal. Materials with low or negative thermal expansion coefficients can be blended or combined with elastic materials used to form the container closure body. Alternatively, the container closure may have an elastic body that includes a chamber filled with material. The chamber is preferably an internal chamber surrounded by an elastic body.

[0031] For example, refer to Figure 1 , a partial cross-sectional side view of a system according to a first embodiment of the present invention is provided. The system intended to hold a product for cryogenic storage may be a sealed vial, cartridge or syringe. The system comprises a container 10 having an inner surface and a container closure 11 having an outer surface. The container closure 11 is at least partially inserted into the container 10 so that at least a portion of the outer surface of the container closure 11 contacts the inner surface of the container 10 and forms a seal against the inner surface of the container 10. The container closure 11 may comprise a variety of materials. Preferably, the container closure 11 comprises at least a body 12 and a second material 14, the body being made of an elastic material having a thermal expansion coefficient less than that of the elastic material.

[0032] The second material 14 is preferably positioned within the container closure 11 in a manner that will resist the contraction of the elastic body 12. For example, the system may have a centerline axis AA, wherein the container closure 11 is coaxial with the container 10 along the centerline axis AA when assembled. When stored at low temperatures, such as extremely cold temperatures, the elastic material of the body 12 may contract radially toward the centerline axis AA; however, if the thermal expansion coefficient of the second material 14 is negative at the storage temperature, then the second material 14 with a lower thermal expansion coefficient preferably contracts less, or more preferably may expand radially away from the centerline axis AA. The amount of the second material 14 incorporated into the container closure 11 depends on the difference between the thermal expansion coefficient of the second material 14 and the thermal expansion coefficient of the elastic body 12. For example, if the thermal expansion coefficient of the second material 14 is much smaller than that of the elastic material, less second material 14 may be required to obtain the desired reaction to the expected contraction of the elastic material. However, if the difference between the thermal expansion coefficients between the two materials is small, a larger amount of the second material 14 may be required to achieve the same resistance to contraction of the elastic material.

[0033] For example, the container closure of the system according to various embodiments of the present invention can be provided in the form of a syringe plunger, a vial stopper, or a cartridge piston. Thus, the container can be provided as a syringe, a vial, or a cartridge. Figure 1 As shown, the container closure 11 can be provided in the form of a cartridge piston or syringe plunger having a plurality of ribs 16a, 16b, 16c, each rib extending radially in a plane generally perpendicular to the centerline axis AA, wherein the outer circumference of at least one of the plurality of ribs 16a, 16b, 16c forms a seal with the inner surface of the container 10. The material 14 with a lower coefficient of thermal expansion is preferably positioned within the elastomeric body 12 along the same plane as the one or more ribs 16a, 16b, 16c that provide the seal. Figure 1 In some embodiments, the second material 14 occupies a single internal chamber within the elastic body 12. In other embodiments, the second material 14 may occupy multiple internal chambers. For example, if the second material is immiscible in the elastic material, an emulsion or mixture of the materials may be formed prior to curing the elastic material so that upon curing, the elastic material forms a continuous phase that includes the second material in the form of a discontinuous phase. Alternatively, the system may be configured by providing the second material having a lower coefficient of thermal expansion outside the body of the container closure, as will be described in more detail below.

[0034] Systems according to various embodiments of the present invention can be used to contain and / or deliver pharmaceutical products. For container closures provided in the form of syringe plungers or cartridge pistons, the materials selected to prevent the container closures from shrinking as a whole at low temperatures (such as extremely cold temperatures) should not provide excessively positive interference at higher ambient temperatures. For example, the force required to insert a syringe plunger or cartridge piston into a position where a medicinal article is filled into a container on a fill line at ambient temperature or the force required to operate a syringe or cartridge when a product is manually applied by a medical professional should not exceed acceptable limits. In other words, no excessive force is required to actuate the container closure at ambient temperature.

[0035] To limit or prevent potential interaction between the material with the lower coefficient of thermal expansion and the drug product contained within the system, the outer surface of the container closure may be provided with an optional barrier layer, such as Figure 1 The barrier layer 17 in the container closure preferably covers at least a portion of the outer surface of the container closure that is most likely to contact any drug product in the container of the system and prevent the second material from leaching into the drug product. As will be appreciated by those skilled in the art, the barrier is not limited to Figure 1 Instead of the embodiment shown in , an optional barrier film may be applied to the surface of any of the embodiments of the present invention.

[0036] In a preferred embodiment, the barrier layer 17 is an inert film, preferably a fluoropolymer film. Fluoropolymers are well known in the art, and a specific description of fluoropolymers is not necessary for a complete understanding of the present invention. Exemplary fluoropolymers include, but are not limited to, polytetrafluoroethylene (PTFE), ethylene copolymers (ETFE), tetrafluoroethylene (TFE) homopolymers and copolymers, perfluoroalkoxy polymer resins (PFA), copolymers of hexafluoropropylene and tetrafluoroethylene, polyethylene tetrafluoroethylene (PETFE), polyvinyl fluoride (PVF), fluorinated ethylene propylene copolymers (FEP), polyethylene chlorotrifluoroethylene (PECTFE), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene (PCTFE) and derivatives thereof. Preferably, the barrier layer 17 is formed of PTFE or ETFE.

[0037] Examples of elastic materials for forming the body of the container closure according to various embodiments of the present invention include, but are not limited to, polyisoprene; polybutadiene; styrene-butadiene copolymer; ethylene-propylene copolymer; ethylene-propylene-diene copolymer; chlorosulfonated polyethylene; ethylene-vinyl acetate copolymer; styrene-isoprene copolymer; fluorine-containing elastomers such as FKM, perfluoroelastomer (FFKM) and tetrafluoroethylene / propylene rubber (FEPM); synthetic or natural rubbers such as butyl rubber, isoprene rubber, butadiene rubber, halogenated butyl rubber (e.g., bromobutyl rubber), ethylene propylene terpolymer, silicone rubber; combinations thereof, etc. Preferably, the elastic material is a butyl or halogenated butyl elastomer. The elastic material may further include one or more additives such as a vulcanizing agent, a vulcanization accelerator, a vulcanization activator, a processing aid, a filler and a reinforcing agent to improve or enhance the properties of the elastic material.

[0038] As previously mentioned, the container included in the system according to various embodiments of the present invention can be provided, for example, in the form of a syringe, a vial or a cartridge. Various common materials known to those skilled in the art can be used to form the container. The material can include, but is not limited to, polypropylene, COP, COC, glass and combinations thereof. If necessary, other features of the system (such as a plunger rod for actuating a syringe) can also be made of common materials known to those skilled in the art. The material can include metal or polymer materials, including, but not limited to, stainless steel, aluminum, HDPE, LDPE, COP, COC, POM, nylon, polypropylene and combinations thereof.

[0039] In some embodiments, the second material may be a liquid or gel with a desired freezing temperature, which is selected based on the expected storage temperature of the system. After freezing, the thermal expansion coefficient of the second material should show a thermal expansion coefficient less than that of the elastic material at the storage temperature, more preferably a negative thermal expansion coefficient. The liquid or gel may include one or more solvents and optionally include one or more solutes so that the liquid / gel has a desired freezing temperature and thermal expansion coefficient when combined. One or more solvents may include, but are not limited to, water and aqueous mixtures. One or more solutes may include, but are not limited to, salt, sugar, glycerol, sorbitol and combinations thereof, and other excipients that can change the freezing characteristics of the solution. In other embodiments, the second material may include one or more solid materials, preferably a material with a negative thermal expansion coefficient. One or more solid materials may include, but are not limited to, alloys containing zirconium or hafnium and molybdenum or tungsten, titanium-based alloys (such as titanium alloys manufactured by Alvar (ALLVAR)), silicates (such as, β eucryptite, β spodumene and cordierite), graphene and combinations thereof.

[0040] Reference again Figure 1If the material with a low coefficient of thermal expansion is provided in the form of a liquid or gel, the elastic body 12 can be molded to include an internal chamber that can be filled with the second material 14 by, for example, injecting a liquid into the chamber. Any injection holes created to allow filling of the chamber can be closed after filling. Alternatively, the second material 14 can be an insert that includes a solid material or a liquid material injected into a bladder or balloon, which is then inserted or molded into the elastic material to form the container closure 11. In some embodiments, the container closure may include multiple chambers or inserts such as Figure 5A and Figure 5B , in which a container closure 54 is attached to the distal end 53 of the plunger rod 52 and inserted into the barrel 50 of the syringe. The container closure 54 can be made of an elastic material and include a plurality of disc-shaped inserts or chambers 56a, 56b, 56c, which include a material having a negative thermal expansion coefficient when the syringe is stored at low temperatures (e.g., extremely cold temperatures). In a preferred embodiment, the container closure may include a single chamber or insert, such as Figure 5C The insert 58 shown in FIG. 1 includes a spacer or Figure 5D The insert 59 in the embodiment of the present invention is a plurality of disc-shaped elements separated by a spring shape having a plurality of coils. Using a single insert will reduce the molding steps necessary for forming a resilient container closure comprising a plurality of spaced apart expandable inserts.

[0041] Similarly, FIG. 6A to FIG. 7B The embodiment shown in also includes a container closure having a single expandable insert. Fig. 6A and Figure 6B In the embodiment of the present invention, the container closure comprises an elastic outer sheath 64 formed over a single inner insert 66 comprising a material having a negative coefficient of thermal expansion. The insert 66 can be attached to the distal end 61 of the plunger rod 60 using various means known in the art, such as threads or interference / snap fit. Fig. 7A and Figure 7B The embodiment of similarly includes an insert 76 that includes a material having a negative coefficient of thermal expansion and that can be fixedly attached to the distal end of the plunger rod 72. The insert 76 can be further provided with threads that allow the insert 76 to be coupled to the outer elastomeric sheath 74, which has a corresponding threaded female socket for receiving the insert 76. The insert 76 is preferably threaded into the outer sheath 74 prior to cryogenic storage to take advantage of radial expansion of the insert 76 and promote a tight fit between the sheath 74 and the insert 76.

[0042] In some embodiments, first, the insert may be inserted into a mold having the shape of the outer surface of the container closure, and then the insert may be completely encapsulated with the elastic material by injecting the elastic material or filling the compression mold with an elastic material layer. The insert is preferably made of a thermally stable material. However, in order to prevent heat damage to the insert provided in the form of a balloon or bladder during the molding process, the container closure 11 may be partially cured, and then the container closure 11 may be post-cured as needed by a secondary process, such as oven post-curing, microwave curing, electron beam curing, etc. In order to provide container closures including various depth inserts, such as Figure 5A and Figure 5B In the embodiment shown in , the container closure can be molded in parts in several repeated steps. For example, in a first step, the first part of the elastic component can be molded and partially cured with the cutter for the insert. Then, the second part of the elastic component can be molded onto the first part and then cured with the insert in the middle of the two elastic parts of the component. This can be performed in a two-step or multi-step compression molding process, as known to those skilled in the art. Alternatively, a gap can be left in a single cured component and filled with liquid or unpolymerized material. For systems in which the material with a negative thermal expansion coefficient is located outside the elastic component, the material can be provided in the form of a solid covering that is mounted to the elastic component.

[0043] Various methods of embedding components into elastic articles are known in the art, such as the methods described in International Application Publication No. WO 2018 / 226780, the entire contents of which are incorporated herein by reference.

[0044] In an alternative embodiment, a system for containing and / or delivering a product may be configured to include a structure that will allow at least a portion of the container closure to selectively expand in a direction toward the sealing surface (i.e., radially outward), thereby providing a means for mechanically adjusting the radial force of the sealing member against the inner surface of the container. This structure may be provided by a rigid member, such as a plunger rod provided in the form of a syringe in the system. For example, referring to Figure 2A and Figure 2B, showing a partial cross-sectional side view of a second embodiment of the present invention. The system includes a container 10 having an interior surface and a container closure 20 in the form of a syringe piston, preferably made of an elastic material and having an outer surface, wherein at least a portion of the outer surface contacts the inner surface of the container 10 and forms a seal with the inner surface of the container. The container closure 20 also has a product contact surface 27 at a first end and an orifice in an opposite second end. Embedded within the container closure 20 is an insert 24 having a center pin 25 that extends axially into the orifice of the container closure 20. An elastic material in the form of an expandable O-ring is located around the center pin 25. The O-ring may be made of an elastic material that is the same or similar to the container closure 20 or other elastic material. An actuator in the form of a plunger rod 22 may include a tip having a concave socket that is configured to receive and connect to the center pin 25, preferably via threads. The orifice of the container closure 20 may similarly include threads that correspond to the threads of the outer circumferential surface around the side of the plunger rod 22. After the distal end of the plunger rod 22 is coupled to the container closure 20 and the insert 24, the O-ring 26 is compressed between the distal tip of the plunger rod 22 and the annular surface around the center pin 25 of the insert 24, thereby providing a rigid surface on either side of the O-ring 26. Figure 2B As indicated by the arrows in , compression of the O-ring 26 causes the O-ring 26 to expand radially toward the inner surface of the container 10, thereby increasing the radial force of the seal between the container closure 20 and the inner surface of the container 10 in the plane of the O-ring 26, i.e., the plane perpendicular to the longitudinal axis of the container closure 20. If desired, the O-ring 26 may optionally include a material having a negative coefficient of thermal expansion to further promote expansion in the radial direction and sealing at low temperatures. Optionally, as previously described, an inert film 27 may be applied to at least a portion of the surface of the container closure that may potentially contact the contents of the container 10, such as, for example, the front distal surface of the container closure 20 and up to the plane of the O-ring 26. When the system is removed from the cold storage device and prepared for administration of the contents to a patient at ambient temperature, the plunger rod 22 may be removed from the pin 25 to loosen the elastic O-ring 26 and return the system to the cold storage device. Figure 2A This will remove any excessive radial force and ensure that the plunger rod 22 can be easily depressed to allow the container closure 20 to slide along the inner surface of the container 10.

[0045] Figure 3A and Figure 3B Another embodiment is shown in , which is configured to allow selective mechanical adjustment of the radial force of the sealing member against the inner surface of the container. Figure 3A and Figure 3B The implementation plan is different from Figure 2A and Figure 2B The embodiment of the container closure 30 is that the O-ring 36 is disposed on the outside of the container closure 30. The insert 34 embedded in the container closure 30 may include a central axially extending pin 35, and the O-ring 36 is located on an annular surface around the central pin 35; however, Figure 2A and Figure 2B Unlike the embodiment of the present invention, no part of the center pin 35 or the bladder 36 is located in the container closure 30. The distal tip of the plunger rod 32 may similarly include a concave socket, which may preferably be coupled to the center pin 35 via threads. When the plunger rod 32 is connected to the insert 34, the O-ring 36 is compressed between the distal tip of the plunger rod 32 and the annular surface around the center pin 35, so that the outer periphery of the O-ring 36 contacts the inner surface of the container 10 and forms a seal. Increasing the compression of the O-ring 36 will proportionally increase the magnitude of the radial force of the outer periphery of the O-ring 36 against the inner surface of the container 10. The O-ring 36 similar to the previous embodiment may optionally include a material with a negative thermal expansion coefficient to further promote expansion in the radial direction and sealing at low temperatures. It is also preferred that the container closure 30, the insert 34 and the O-ring 36 can be made of an inert material or at least coated with an inert film, because the surfaces of these components are likely to contact the contents of the container 10.

[0046] In yet another embodiment, a method of forming or assembling a system for containing and / or delivering a product is provided. FIG. 4A to FIG. 4C , the container closure 40 can be molded to include an insert 42 embedded within the container closure 40, the insert having an inert film on at least a portion of the surface of the container closure 40. Figure 2A and Figure 2B In an embodiment of the present invention, the insert 42 may have a central axially extending pin 45 that extends into an aperture 44 located on the non-product contacting side of the container closure 40. The bottom portion 46 of the aperture 44 may be provided with a smaller diameter than the top portion of the aperture 44 to form a recess around the central pin 45. The container closure 40 may then be inserted into the container closure 10. In subsequent steps, such as Figure 2B As shown, the recess can be filled with an insert, such as the compressible O-ring described previously, or a material 48 with a negative thermal expansion coefficient (such as an aqueous liquid, gel, or solid material), such as a metal disk or a gasket made of a material with a negative thermal expansion coefficient. After the recess is filled with the material 48, a plunger rod 49 having a concave socket in the distal tip can be preferably connected to the center pin 45 by threading, and the material 48 is sealed in the recess. The outer circumference of the distal tip of the plunger rod 49 can also be provided with threads so that the plunger rod 49 can be attached to the top portion of the orifice 44.

[0047] As will be appreciated by those skilled in the art, Figures 2A to 4C The embodiment shown in can be reconfigured so that a center pin is provided on the distal tip of the plunger rod and a corresponding female socket provided within the insert.

[0048] As previously mentioned, the containment and delivery system according to various embodiments of the present invention may include a vial and a vial stopper. Fig. 8A and Figure 8B , a container closure in the form of a vial stopper 81 may include an elastic body 82 and a material 84 having a negative coefficient of thermal expansion. For example, the material 84 may be a solid, a liquid, or a gel. For example, the material 84 may be located in an internal chamber that is filled with the material 84 (e.g., a liquid material is injected into the internal chamber of a molded stopper) or an insert including the material 84 to form the elastic body 82. The material 84 is preferably located in a portion below the flange 83 of the stopper 81 that will be inserted into the neck portion 85 of the vial 80. At low storage temperatures, such as extremely cold temperatures, the material 84 will expand to offset any radial contraction of the elastic body 82 and ensure a seal between the outer surface of the stopper 81, which is in contact with the inner surface of the neck portion 85 of the vial 80. Similarly, an optional inert film 87 may be applied to at least a portion of the outer surface of the stopper, most preferably to the portion of the surface that is most likely to contact the contents of the vial 80.

[0049] like Fig. 8A and Figure 8B As shown, the shape of the internal chamber or insert including the material 84 can be, for example, spherical; however, the shape is not limited. Preferably, the internal chamber or bladder / insert can be tubular, annular, disc-shaped or spiral-shaped, such as 9A to 10B The shape of the insert 94 or 102 in the container closure. These embodiments will all ensure that a radial sealing surface is maintained between the outer surface of the main portion of the main portion of the container closure (81, 91, 100) which contacts the inner surface of the container (80, 90). By providing a shape with an internal through hole, a syringe needle for piercing the stopper and extracting the contents of the container can be inserted through the container closure without passing through the insert, thereby preventing potential exposure of the product within the container to materials with negative thermal expansion coefficients. Fig.9A and Fig. 9B As shown, the material having a negative coefficient of thermal expansion may be provided in a plurality of annular inserts 94a, 94b, rather than in a single ring or tubular insert.

[0050] The containment and delivery systems according to various embodiments of the present invention may further include a seal configured to capture or retain a container closure within the container opening, such as Figure 11 to Figure 14 These embodiments will all ensure that an axial sealing surface is maintained between the bottom surface of the flange of the container closure and the top surface of the container. For example, referring to Fig.11 , a container closure in the form of a stopper 112 can be inserted into the opening and neck portion 110 of the vial. The stopper 112 can further include a flange portion 117 that rests on the top surface of the vial. An annular insert 114 comprising a material having a negative coefficient of thermal expansion can be located on the top surface above the flange portion 117 of the stopper 112. Finally, a seal, preferably a metal seal 116, such as an aluminum seal, can be clamped over the annular insert 114 and under the annular collar 115 of the vial. The clamping provides the seal 116 with an annular lip 118 that abuts the annular collar 115 around the opening of the vial. The annular lip 118 abuts the underside of the annular collar 115 and assists in maintaining the axial force on the top surface of the stopper 112. When the containment and delivery system is stored at low temperatures (e.g., extremely cold temperatures), the material 114 will expand in the axial direction to promote or maintain the axial force applied to the top surface of the flange portion 117 of the plug 112, which will shrink at lower temperatures. In addition, the insert can be configured to promote axial rather than radial expansion of the material 114 having a negative thermal expansion coefficient. For example, the annular insert can be a bladder with a rectangular cross-section, wherein the inner circumferential wall and the outer circumferential wall (i.e., the vertical wall) of the ring are made of a rigid material, and the top wall and the bottom wall (i.e., the horizontal wall) of the ring can be made of a more elastic material so that the expansion of the material in the bladder is mainly in the axial direction. In another example, a pair of concentric rings made of a rigid material can be configured and attached to the bottom surface of the seal so that the annular insert can be inserted and nested between the concentric rings under installation conditions.

[0051] In another embodiment such as Fig.12 In an embodiment of the present invention, an annular insert 124 comprising a material having a negative coefficient of thermal expansion may be located within the flange portion 127 of the stopper 122. The inner diameter of the annular insert 124 is preferably greater than the inner diameter of the neck portion 110 of the vial. As previously explained, axial expansion of the annular insert 124 against the pinch seal 116 will maintain the annular lip 128 of the seal 116 in close contact with the annular surface below the collar 125 around the vial opening, as well as forcing the flange portion 127 of the stopper 122 to the top surface of the vial. To facilitate axial expansion of the annular insert 124, an optional ring made of a rigid material may be applied around the outer circumferential surface of the flange portion 127 of the stopper 122.

[0052] In yet another embodiment such as Fig.13In an embodiment of the present invention, the top flange portion of the stopper 132 can be provided with an annular recess 138. After the stopper 132 is inserted into the opening in the neck portion 110 of the vial, a material having a negative coefficient of thermal expansion (such as a solid, liquid, or gel) can be inserted or injected into the recess 138. A rigid cover 136 can be applied to the top surface of the stopper 132 before the crimp seal 116 to seal the material in the recess 138 and the stopper 132 in the neck portion 110 of the vial.

[0053] exist Figures 11 to 13 In each of the systems described in FIG. 8A to FIG. 10B In an embodiment, the plug may further optionally include a material having a negative coefficient of thermal expansion within the body of the plug so as to also maintain a seal between the outer surface of the main portion of the plug below the flange portion and the inner surface of the small bottleneck portion.

[0054] Reference now Fig.14 , another containment and delivery system may include a stopper 142 having an orifice 148 extending along the central axis of the body of the stopper 142. A cover 146 made of a rigid material and having an axial protrusion extending into the orifice 148 may be used to seal the chamber between the outer surface of the axial protrusion and the inner surface of the orifice 148. The axial protrusion of the cover 146 preferably includes an axially extending through hole 149 to allow the needle of a syringe to be inserted through the stopper 142 and access the contents of the vial 110 sealed with the stopper 142. The chamber may be filled with a material 147 having a negative thermal expansion coefficient. The system may further include a seal 116 that is clamped around the opening of the vial 110 above the cover 146 and below the annular surface below the collar 145, as previously described. When stored at low temperatures, rigid cover 146 can cause material 147 to expand radially outwardly within orifice 148 to help maintain a seal between the outer surface of stopper 142, which is in contact with the inner surface of the neck portion of vial 110. As will be appreciated by those skilled in the art, additional annular recesses (such as Fig.13 The recessed portion 138 in the Fig.14 The flange portion of the plug 142 is filled with the same or similar material 147 having a negative coefficient of thermal expansion. In an alternative preferred embodiment of the present invention, the cover 146 can be made of a solid having a negative coefficient of thermal expansion (e.g., an alloy such as that manufactured by Alvar, College Station, Texas) that is molded with an elastomeric material to form the plug. In such an embodiment, the cavity can be eliminated. Similarly, similar to Figure 8B In the embodiments of the present invention, an optional inert film may be applied to at least a portion of the exterior surface of any of the stoppers in the disclosed embodiments, most preferably to the portion of the surface most likely to come into contact with the contents of the vial.

[0055] The components of the containment and delivery system manufactured according to various embodiments of the present invention can be manufactured as previously described and bulked into secondary packaging suitable for maintaining the sterility and cleanliness of the components. The components can then be sterilized by steam, alcohol, gamma irradiation, or electron beam irradiation. The sterile bulk product can then, for example, be introduced into a sterile filling environment.

[0056] It will be appreciated by those skilled in the art that changes may be made to the above embodiments without departing from the broad inventive concept of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A system for containing or delivering a product, the system comprising: a container having an inner surface; and a container closure configured to be at least partially received in the container to close the container, the container closure comprising an elastic body and a material having a negative coefficient of thermal expansion disposed within an outer surface of the elastic body, Wherein at least a portion of the outer surface of the elastomeric body is configured to contact at least a portion of the inner surface of the container, and the material defines an internal through hole configured to receive a needle that pierces the elastomeric body.

2. The system of claim 1, wherein the material comprises a solid.

3. The system of claim 1, wherein the material comprises a liquid at a temperature greater than 0°C.

4. The system of claim 1, wherein the material comprises a gel at a temperature greater than 0°C.

5. The system of claim 1, wherein the material has a negative coefficient of thermal expansion at a temperature less than or equal to 0°C.

6. The system of claim 1, wherein the container closure is a vial stopper.

7. The system of claim 6, wherein the container is a vial having a neck portion, and the system further comprises a seal surrounding an outer periphery of the vial stopper and at least a portion of the neck portion.

8. The system of claim 1, wherein the material has a shape of a tube, a ring, a disk, or a spiral.

9. The system of claim 1, wherein the container closure comprises a second material having a negative coefficient of thermal expansion within the elastic body spaced apart from the material.

10. A system for containing or delivering a product, the system comprising: a container having an inner surface; a container closure comprising a resilient body having an outer surface, at least a portion of the outer surface of the resilient body being configured to contact the inner surface of the container; an insert at least partially embedded in the elastic body; an actuator having a distal end movably attached to the inserter; and an elastic element located between and in contact with the distal end of the actuator and the insert, the elastic element comprising a material having a negative coefficient of thermal expansion; wherein the resilient element expands radially toward the inner surface of the container when the distal end of the actuator is displaced toward the inserter.

11. The system of claim 10, wherein at least a portion of the elastic element is located within the elastic body.

12. The system of claim 10, wherein the material having the negative coefficient of thermal expansion comprises a liquid at a temperature greater than 0°C.

13. The system of claim 10, wherein the material having the negative coefficient of thermal expansion comprises a gel at a temperature greater than 0°C.

14. The system of claim 10, wherein the material has a negative coefficient of thermal expansion at a temperature less than or equal to 0°C.

15. A system for containing or delivering a product, the system comprising: a vial having an inner surface and a neck portion; a plug including a resilient body having an outer surface; an insert comprising a material having a negative coefficient of thermal expansion; as well as a seal surrounding an outer periphery of the stopper and at least a portion of the neck portion, The insert is located between a surface of the plug and a surface of the seal.

16. The system of claim 15, wherein the material comprises a solid.

17. The system of claim 15, wherein the material comprises a liquid at a temperature greater than 0°C.

18. The system of claim 15, wherein the material comprises a gel at a temperature greater than 0°C.

19. The system of claim 15, wherein the material has the negative coefficient of thermal expansion at a temperature less than or equal to 0°C.

20. A system for containing or delivering a product, the system comprising: a container having an inner surface; and A container closure configured to be at least partially received in the container to close the container, the container closure having a plurality of ribs each extending radially in a plane perpendicular to a central axis of the container closure and contacting at least a portion of the inner surface of the container, the container closure comprising an elastomeric body and a material having a negative coefficient of thermal expansion, and the material is disposed within the elastomeric body in the same plane as one or more of the plurality of ribs.

21. The system of claim 20, wherein the container is a syringe and the container closure is a plunger.

22. The system of claim 20, wherein the material has the negative coefficient of thermal expansion at a temperature less than or equal to 0°C.

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