Containment and delivery systems for cryogenic storage

Abstract

To provide various systems for the containment or delivery of a product which allow the storage of the product at low temperatures.SOLUTION: A system for containment or delivery of a product comprises a vial, a stopper, an insert, and a seal. The vial has an inner surface and a neck portion. The stopper comprises an elastomeric body having an outer surface. The insert comprises a material having a negative coefficient of thermal expansion. The seal is located around an outer periphery of the stopper and at least a portion of the neck portion of the vial. The insert is located between a surface of the stopper and a surface of the seal.SELECTED DRAWING: Figure 11

Description

[Technical field]

[0001] Various embodiments of the present invention are directed to containment and transport systems, and more particularly, to those that include elastomeric components configured to maintain a seal within a vessel at cryogenic temperatures. [Background technology]

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

[0003] The container's essential function is to protect the material from various potential sources of contamination, such as microbial ingress, moisture, and gas exchange. The primary seal is formed at the interface between the elastomeric sealing component and the container. This interface is the primary site of packaging failure, assuming that the individual packaging components are free of defects. When a suitable closure system for pharmaceutical containers is selected and applied, several factors must be considered to ensure satisfactory closure integrity.

[0004] Manufacturing defects such as incorrect assembly, over or under crimping, or design errors can compromise the integrity of the container closure system. It is therefore essential to ensure that the elastomeric sealing components are properly dimensioned with the container to ensure sufficient seal integrity. Vacuum loss, gas ingress and exchange, pH adaptation, and contamination can compromise seal integrity, potentially compromising drug sterility and affecting drug efficacy and jeopardizing patient safety.

[0005] With the trend towards an increasing number of expensive biologics, cell therapies, gene therapies, and other expensive drugs, the need for a reliable occlusion system becomes more critical. Such biologics and drugs are generally temperature sensitive and are highly susceptible to degradation if not stored under proper conditions. It is not uncommon for some biologics and drugs to be stored at temperatures as low as 0°C, preferably at -80°C, in sealed containers to avoid, for example, material degradation or loss due to evaporation. In many cases, they are to be stored at even lower cryogenic temperatures (e.g., -150°C or lower, preferably -180°C or lower, and more preferably -196°C or lower).

[0006] As mentioned above, most medicine containers have sealing components made of elastomers. A common physical property of all elastomers is the glass transition temperature (Tg), below which all elastomers undergo a physical change, changing their elastic properties and becoming glass-like. At room temperature, the thermal motion of the molecules is in a steady state, and the molecular configuration is constantly changing, so elastomers are flexible and can form a seal with another surface. However, at the glass transition temperature, the mobility of the molecules is significantly reduced, making the elastomer brittle and glass-like. For example, the glass transition temperature of common butyl rubber is about -65°C. Also, the elastomer material utilized to form the sealing components may shrink more than the opening of the container, since its thermal expansion coefficient is significantly different from that of the container material (e.g., glass or plastic). As used hereinafter throughout this specification and claims, "thermal expansion coefficient" means the volumetric expansion coefficient. As a result, existing elastomeric sealing components may not be capable of maintaining closure integrity at cryogenic temperatures, potentially compromising the sterility of the biological product or drug stored within the container. Thus, there is a need for improvements in cryogenic containment and transfer systems, and the components of those systems that provide the primary seal that ensures complete closure of the container. Summary of the Invention

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

[0008] In some embodiments, the material with a negative coefficient of thermal expansion may comprise a solid, and may comprise a liquid or gel at temperatures above 0° C. In other embodiments, the material may have a negative coefficient of thermal expansion at temperatures below 0° C.

[0009] Additionally, in some systems according to various embodiments of the present invention, the closure may define at least one of a syringe plunger, a bottle stopper, and a cartridge piston, while in other systems the container may be a bottle with a neck, and the system may further include a seal around the periphery of the closure in the form of a bottle stopper and at least a portion of the neck of the container.

[0010] In accordance with another aspect of an embodiment of the invention, a system for storing or delivering a product may include a container, an closure, an insert, an actuator, and an elastomeric material. The container has an interior surface. The closure includes an elastomeric body having an exterior surface. At least a portion of the exterior surface of the elastomeric body contacts the interior surface of the container. The insert is at least partially embedded within the elastomeric body. The actuator has a distal end movably attached to the insert. The elastomeric material is sandwiched between the distal end of the actuator and the insert. When the distal end of the actuator is moved toward the insert, the elastomeric material may expand radially toward the interior surface of the container.

[0011] In some embodiments, at least a portion of the elastic material is within the elastomeric body. In other embodiments, the elastic material comprises a material with a negative coefficient of thermal expansion. The material may be a liquid or a gel at temperatures above 0° C. Also, the material may have a negative coefficient of thermal expansion at temperatures below 0° C.

[0012] In accordance with yet another aspect of an embodiment of the present invention, a system for storing or transporting a product may include a bottle having an interior surface and a neck, a closure including an elastomeric body having an exterior surface, an insert including a material having a negative coefficient of thermal expansion, and a seal surrounding an outer periphery of the closure and at least a portion of the neck of the bottle, The insert may be located between a surface of the closure and a surface of the seal.

[0013] In some embodiments, the material may comprise a solid, and may comprise a liquid or gel at temperatures above 0° C. Additionally, the material may have a negative coefficient of thermal expansion at temperatures below 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 present application are 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 implementations in accordance with the concepts of the present invention, for purposes of illustration only, and not limitation. In the drawings, like reference numbers represent the same or similar elements. [Figure 1] 1 is a schematic diagram of a part of a cross section seen from the front of a system according to a first embodiment of the present invention. [Figure 2A] FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a second embodiment of the present invention. [Figure 2B] FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a second embodiment of the present invention. [Figure 3A]FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a third embodiment of the present invention. [Figure 3B] FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a third embodiment of the present invention. [Figure 4A] FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a fourth embodiment of the present invention. [Figure 4B] FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a fourth embodiment of the present invention. [Figure 4C] FIG. 11 is a schematic diagram of a part of a cross section seen from the front of a system according to a fourth embodiment of the present invention. [Figure 5A] FIG. 13 is a front view of a system according to a fifth embodiment of the present invention. [Figure 5B] FIG. 5B is an enlarged front perspective view of the obturator in the system of FIG. 5A. [Figure 5C] 5B is another embodiment of an insert that can be incorporated into the system of FIG. 5A. [Figure 5D] 5B is another embodiment of an insert that can be incorporated into the system of FIG. 5A. [Figure 6A] FIG. 13 is a front view of a system according to a sixth embodiment of the present invention. [Figure 6B] FIG. 6B is an enlarged front perspective view of the obturator in the system of FIG. 6A. [Figure 7A] FIG. 13 is a front view of a system according to a seventh embodiment of the present invention. [Figure 7B] FIG. 7B is an enlarged front perspective view of the obturator in the system of FIG. 7A. [Figure 8A] FIG. 23 is a schematic perspective view of an obturator according to an eighth embodiment of the present invention, as seen from the front. [Figure 8B] FIG. 8B is a schematic diagram of a portion of a cross-section taken from the front of a system including the obturator of FIG. 8A. [Figure 9A] FIG. 13 is a schematic perspective view of an obturator according to a ninth embodiment of the present invention, as seen from the front. [Figure 9B] FIG. 9B is a schematic diagram of a portion of a cross-section taken from the front of a system including the obturator of FIG. 9A. [Figure 10A] FIG. 23 is a schematic perspective view of an obturator according to a tenth embodiment of the present invention, as seen from the front. [Figure 10B] FIG. 10B is a cross-sectional view of the obturator of FIG. 10A taken from the front. [Figure 11] FIG. 23 is a schematic diagram of a part of a cross section seen from the front of a system according to an eleventh embodiment of the present invention. [Figure 12] FIG. 23 is a schematic diagram of a part of a cross section seen from the front of a system according to a twelfth embodiment of the present invention. [Figure 13] FIG. 23 is a schematic diagram of a portion of a cross section seen from the front of a system according to a thirteenth embodiment of the present invention. [Figure 14] FIG. 23 is a schematic diagram of a portion of a cross section seen from the front of a system according to a fourteenth embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Generally, a system according to various embodiments of the present invention includes an occluder. The occluder includes an elastomeric body and a material having a coefficient of thermal expansion less than that of the elastomeric body. Preferably, the material has a negative coefficient of thermal expansion at temperatures below 0° C., more preferably below −80° C. The coefficient of thermal expansion is often negative at lower cryogenic temperatures (below −150° C., preferably below −180° C., more preferably below −196° C.). In some embodiments, the material may have a negative coefficient of thermal expansion at cryogenic temperatures (e.g., below −150° C.). Materials with significantly different coefficients of thermal expansion help maintain a seal within the system by preventing failures that may compromise the integrity of the container closure and protecting the contents of the container during storage at low temperatures. When the system is warmed to room temperature, the elastomeric portion of the occluder may expand to maintain the seal. Materials with low or negative coefficients of thermal expansion may be mixed or combined with the elastomeric material utilized to form the body of the occluder. Alternatively, the occluder may include an elastomeric body that contains a chamber that is filled with the substance, the chamber being preferably an internal cavity surrounded by the elastomeric body.

[0017] For example, referring to Figure 1, a portion of a longitudinal section of a system according to a first embodiment of the present invention is shown. The system, intended to hold a product during cryogenic storage, may be a sealed bottle, cartridge, or syringe. The system includes a container 10 having an inner surface and a closure 11 having an outer surface. The closure 11 is at least partially inserted into the container 10 such that at least a portion of the outer surface of the closure 11 contacts the inner surface of the container 10 to form a seal with the inner surface of the container 10. The closure 11 may include multiple materials. Preferably, the closure 11 includes at least a body 12 made of an elastomeric material and a secondary material 14 having a thermal expansion coefficient less than that of the elastomeric material.

[0018] The secondary material 14 is preferably disposed within the closure 11 in such a manner that it opposes the contraction of the elastomeric body 12. For example, the system may have a central axis AA. When assembled, the closure 11 and the container 10 are aligned along the central axis AA. When they are stored at low temperatures, particularly cryogenic temperatures, the elastomeric material of the body 12 may contract radially toward the central axis AA. However, the secondary material 14, which preferably has a smaller coefficient of thermal expansion than the elastomeric material, does not contract as much as the elastomeric material. More preferably, the coefficient of thermal expansion of the secondary material 14 is negative at storage temperatures. If so, the secondary material 14 may expand radially away from the central axis AA. The amount of secondary material 14 incorporated within the closure 11 depends on the difference in the coefficient of thermal expansion between the secondary material 14 and the elastomeric body 12. For example, if the coefficient of thermal expansion of the secondary material 14 is much smaller than the coefficient of thermal expansion of the elastomeric material, less secondary material 14 may be needed to provide the desired resistance to anticipated elastomeric contraction. However, if the difference in the coefficients of thermal expansion between the two materials is smaller, more secondary material 14 may be needed to provide the same degree of resistance to elastomeric contraction.

[0019] The obturator of the system according to various embodiments of the present invention may be shaped, for example, as a syringe plunger, a bottle stopper, or a cartridge piston. Thus, the container may be provided as a syringe barrel, a bottle, or a cartridge. As shown in FIG. 1, the obturator 11 may be shaped as a cartridge piston or a syringe plunger. The obturator 11 has a number of ribs 16a, 16b, 16c, each extending radially in a plane substantially perpendicular to the central axis AA. At least one of the number of ribs 16a, 16b, 16c has an outer periphery that forms a seal with the inner surface of the container 10. The secondary material 14, which has a smaller coefficient of thermal expansion, is preferably disposed in the elastomeric body 12 along substantially the same plane as the one or more ribs 16a, 16b, 16c that form the seal. In the embodiment of FIG. 1, the secondary material 14 fills a single chamber in the elastomeric body 12. In other embodiments, the secondary material 14 may fill multiple chambers. For example, if the secondary material is immiscible with the elastomeric material, the secondary material may be emulsified or mixed into the elastomeric material prior to curing the elastomeric material, such that when the elastomeric material cures, it forms a continuous phase containing the secondary material as a discontinuous phase. Alternatively, the system may include a secondary material having a lower coefficient of thermal expansion disposed on the exterior of the body of the occluder, as will be described in more detail below.

[0020] Systems according to various embodiments of the present invention may be used to store and / or deliver drugs. For the obturator forming the plunger of the syringe or the piston of the cartridge, materials are selected to prevent the entire obturator from shrinking at low temperatures, especially at cryogenic temperatures, but they should not interfere too much diametrically at higher room temperatures. For example, at the filling line, the drug is filled into the container at room temperature, but the force required to insert the plunger of the syringe or the piston of the cartridge at room temperature should not exceed acceptable limits. Also, when the drug is administered by the hand of a medical professional, the force required to manipulate the syringe or cartridge should not exceed acceptable limits. In other words, excessive force should not be required to move the obturator at room temperature.

[0021] If desired, a barrier layer, such as barrier layer 17 in FIG. 1, may be applied to the exterior surface of the closure to limit or eliminate potential interactions between secondary materials having lower coefficients of thermal expansion and the drug contained within the system. The barrier layer preferably covers at least those portions of the exterior surface of the closure that are most likely to come into contact with the drug within the system's container and does not allow the secondary materials to leach into the drug. As will be appreciated by those skilled in the art, the barrier layer is not limited to the embodiment shown in FIG. 1. If desired, a barrier layer may be applied to any surface of the embodiments of the present invention.

[0022] In a preferred embodiment, the barrier layer 17 is a film made of an inert material, preferably a film made of a fluoropolymer. Fluoropolymers are already well known in the art, and a detailed description thereof is not necessary for a complete understanding of the present invention. Examples of fluoropolymers include polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), homopolymers and copolymers of tetrafluoroethylene (TFE), perfluoroalkoxy polymers (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. However, they are not limited thereto. Preferably, the barrier layer 17 is formed of PTFE or ETFE.

[0023] Examples of elastomeric materials for forming the body of the obturator according to various embodiments of the present invention include, but are not limited to, polyisoprene, polybutadiene, styrene-butadiene copolymers, ethylene-propylene copolymers, ethylene-propylene-diene copolymers, chlorosulfonated polyethylene, ethylene-vinyl acetate copolymers, styrene-isoprene copolymers, fluoroelastomers (e.g., FKM, perfluoroelastomers (FFKM), tetrafluoroethylene / propylene rubber (FEPM)), synthetic or natural rubbers (e.g., butyl rubber, isoprene rubber, butadiene rubber, halogenated butyl rubber (e.g., bromobutyl rubber), ethylene propylene terpolymers, silicone rubber), and combinations thereof. Preferably, the elastomeric material is a butyl elastomer or a halobutyl elastomer. The elastomeric material may further include one or more additives, such as vulcanizing agents, vulcanization accelerators, vulcanization activators, processing aids, fillers, and reinforcing agents, to improve or enhance its properties.

[0024] As mentioned above, the container included in the system according to various embodiments of the present invention may be in the form of, for example, a syringe, a bottle, or a cartridge. Various common materials known to those skilled in the art may be used to make the container, including, but not limited to, polypropylene, COP, COC, glass, and combinations thereof. If necessary, other devices of the system, such as a plunger rod for operating the syringe, may also be made from common materials known to those skilled in the art. The materials may include metals or polymers, including, but not limited to, stainless steel, aluminum, HDPE, LDPE, COP, COC, POM, nylon, polypropylene, and combinations thereof.

[0025] In some embodiments, the secondary material may be a liquid or gel with a desired freezing point. The freezing point is selected based on the storage temperature of the system. After freezing, the secondary material should exhibit a coefficient of thermal expansion at the storage temperature, which is less than the coefficient of thermal expansion of the elastomeric material, and preferably is negative. The liquid or gel may be comprised of one or more solvents and, if desired, one or more solutes. When the solutes are melted, the liquid or gel exhibits a desired freezing point and coefficient of thermal expansion. The one or more solvents include, but are not limited to, water and aqueous mixtures. The one or more solutes include, but are not limited to, salts, sugars, glycerol, sorbitol, and combinations thereof, as well as other excipients that may alter the freezing characteristics of the solution. In other embodiments, the secondary material may include one or more solid materials, preferably those with a negative coefficient of thermal expansion. The one or more solid materials may include, but are not limited to, alloys of zirconium or hafnium with molybdenum or tungsten, titanium-based alloys (e.g., ALLVAR titanium alloys), silicates (e.g., β-eucryptite, β-spodumene, cordierite), graphene, and combinations thereof.

[0026] Referring again to FIG. 1, if the secondary material with a low coefficient of thermal expansion is provided in the form of a liquid or gel, the body 12, for example made of an elastomer, may be molded to include a chamber therein, into which the liquid is injected to fill the chamber with the secondary material 14. Any inlets made to allow the liquid to fill the chamber may be closed after filling. Alternatively, the secondary material 14 may be an insert. The insert may consist of an air bladder or balloon injected with either a solid or liquid material, which is inserted into the elastomeric material or molded with the elastomeric material to form the obturator 11. In some embodiments, the obturator may include multiple chambers or inserts, such as the embodiment shown in FIGS. 5A and 5B. In the embodiment shown in FIGS. 5A and 5B, the obturator 54 is attached to the distal end 53 of the plunger rod 52 and is inserted into the syringe barrel 50. The obturator 54 may be made of an elastomeric material and may include multiple disk-shaped inserts or chambers 56a, 56b, 56c. These may include materials that exhibit a negative coefficient of thermal expansion when the syringe is stored at low temperatures (e.g., cryogenic temperatures). In preferred embodiments, the obturator may include only one chamber or insert. For example, insert 58 shown in FIG. 5C is in the form of multiple disk-shaped elements separated by spacers, and insert 59 shown in FIG. 5D is in the form of a multiple-turn spring. The use of only one insert may reduce the number of molding steps required to produce an elastomeric obturator compared to an obturator that includes multiple spaced apart expandable inserts.

[0027] Similarly, the embodiment shown in Figures 6A-7B includes an obturator with only one expandable insert. In Figures 6A and 6B, the obturator includes an elastomeric outer sheath 64 that is formed to enclose a single insert 66 that includes a material with a negative coefficient of thermal expansion. The insert 66 can be attached to the distal end 61 of the plunger rod 60 by a variety of means known in the art, such as threads, an interference fit, or a snap fit. The embodiment of Figures 7A and 7B similarly includes an insert 76 that includes a material with a negative coefficient of thermal expansion and that is secured to the distal end of the plunger rod 72. The insert 76 is further threaded to allow the insert 76 to be fastened to an elastomeric outer sheath 74 that has a corresponding internal thread. The insert 76 is preferably threaded into the outer sheath 74 prior to cryogenic storage. This utilizes the radial expansion of the insert 76 to promote an interference fit between the outer sheath 74 and the insert 76 .

[0028] In some embodiments, the insert may first be inserted into a mold that has the shape of the exterior surface of the closure. The mold may then be filled with the elastomeric material by injecting or compressing multiple layers of the elastomeric material into the mold, completely encasing the insert. Preferably, the insert is made of a heat resistant material. However, to prevent thermal damage to the balloon or bladder shaped insert during the molding process, the closure 11 may be post cured, if desired, by a secondary process such as oven curing, microwave curing, or electron beam curing after a portion of the closure 11 has been cured. The closure may be molded in multiple stages, one portion at a time, to provide an closure that includes inserts at various depths, such as the embodiment shown in Figures 5A and 5B. For example, in an initial stage, a first portion of the elastomeric part may be molded and partially cured to include a cutout for the insert. A second portion may then be molded over the first portion of the elastomeric part and cured with the insert intermediate the two portions. This process may be performed in two or more compression molding steps, as is well known to those skilled in the art. Alternatively, a single part may be cured leaving gaps therein which are then filled with a liquid or unpolymerized material. For systems in which the negative thermal expansion material is located on the exterior of the elastomeric part, the material may be provided in the form of a solid cover that is attached over the elastomeric part.

[0029] Various methods are known in the art for embedding components within elastomeric articles, such as those described in WO 2018 / 226780, the contents of which are incorporated herein by reference in their entirety.

[0030] In another embodiment, a system for storing and / or transporting a product may be configured to include a structure for selectively expanding at least a portion of the closure toward the sealing surface, i.e., in a circumferential direction. This provides a means for mechanically adjusting the radial force that presses the sealing component against the inner surface of the container. This structure may be provided by a rigid component, such as a plunger rod for a syringe-shaped system. For example, referring to Figures 2A and 2B, a partial cross-section from a side view of a second embodiment of the invention is shown. The system includes a container 10 having an inner surface and an closure 20 having an outer surface. The closure 20 is in the form of a syringe piston and is preferably made of an elastomeric material. At least a portion of the outer surface of the closure 20 contacts the inner surface of the container 10 to form a seal. The closure 20 has a drug contact surface 27 at a first end and a hole at an opposite second end. An insert 24 is embedded within the closure 20. The insert 24 has a pin 25 at its center that extends axially into the hole in the closure 20. An elastic material in the form of an expandable O-ring is disposed around the pin 25. The O-ring may be made of the same or similar elastomeric material as the obturator 20, or may be made of other elastic materials. The actuator in the form of a plunger rod 22 may include a female connector at its tip. The female connector is configured to receive the pin 25 and to be connected thereto, preferably by threads. Similarly, a bore in the obturator 20 may include threads that correspond to the threads along the outer circumferential surface of the plunger rod 22. When the distal end of the plunger rod 22 is coupled to the obturator 20 and the insert 24, the O-ring 26 is compressed between the distal end of the plunger rod 22 and the annular surface of the insert 24 that surrounds the pin 25. This creates a rigid surface on either side of the O-ring 26. When the O-ring 26 is compressed, it expands radially toward the inner surface of the container 10, as represented by the arrows in FIG. 2B. This increases the radial sealing force between the closure 20 and the inner surface of the container 10 in the flat space containing the O-ring 26 (ie, the space extending perpendicular to the longitudinal axis of the closure 20).If desired, the O-ring 26 may optionally comprise a material with a negative coefficient of thermal expansion to further promote radial expansion at low temperatures to maintain a seal. If necessary, a film 27 of an inert material may be applied to at least a portion of the surface of the closure that may come into contact with the contents of the container 10, as described above, for example from the most distal surface of the closure 20 to the flat space containing the O-ring 26. When the system is removed from the refrigerator and is prepared to administer the contents to a patient at room temperature, the plunger rod 22 may be disengaged from the pin 25, allowing the O-ring 26 to relax due to its elasticity, and the system may return to its original state shown in FIG. 2A. This ensures that any excess radial force is removed, making it easier to push down the plunger rod 22 and slide the closure 20 along the inner surface of the container 10.

[0031] 3A and 3B show another embodiment that is configured to mechanically adjust the selection of the radial force that presses the sealing component against the inner surface of the container. The embodiment of FIGS. 3A and 3B differs from the embodiment of FIGS. 2A and 2B in that an O-ring 36 is provided on the outside of the obturator 30. An insert 34 embedded in the obturator 30 may include a central, axially extending pin 35. The O-ring 36 is located on an annular surface surrounding the pin 35. However, unlike the embodiment of FIGS. 2A and 2B, neither the pin 35 nor the bladder 36 have portions that are located within the obturator 30. The distal end of the plunger rod 32 may include a female connector, similar to that described above, preferably threadably connectable to the pin 35. When the plunger rod 32 is connected to the insert 34, the O-ring 36 is compressed between the distal end of the plunger rod 32 and the annular surface around the pin 35, bringing the outer circumferential surface of the O-ring 36 into contact with the inner surface of the container 10 to form a seal. As the compression of the O-ring 36 increases, the radial force applied from the outer circumferential surface of the O-ring 36 to the inner surface of the container 10 increases proportionately. As in the previous embodiment, the O-ring 36 may contain a material with a negative thermal expansion coefficient, if necessary, to further promote radial expansion at low temperatures and maintain the seal. In addition, since the surfaces of the closure 30, the insert 34, and the O-ring 36 may come into contact with the contents of the container 10, it is also preferable that these parts are all made of an inert material or at least covered with a film made of an inert material.

[0032] In yet another embodiment, a method of forming or assembling a system for containing and / or transporting a product is provided. For example, referring to FIGS. 4A-4C, an obturator 40 may be molded to include an insert 42. The insert 42 is embedded in the obturator 40. At least a portion of the surface of the obturator 40 is covered with a film of an inert material. As with the embodiment of FIGS. 2A and 2B, the insert 42 may have a central axially extending pin 45 that extends into a hole 44 located on the side of the obturator 40 that does not contact the drug. A bottom 46 of the hole 44 may be narrower in diameter than the top of the hole 44, creating a well-like recess around the pin 45. The obturator 40 can later be inserted into the container 10. In a next step, the recess may be filled with either an insert such as a compressible O-ring as described above, or a material 48 with a negative coefficient of thermal expansion, as shown in FIG. 4B. The material 48 may be, for example, an aqueous liquid, a gel, or a solid (such as a metal disk or washer) made of a substance with a negative coefficient of thermal expansion. After the recess is filled with the material 48, a plunger rod 49 having a female fitting at its distal end may be connected, preferably threadedly, to the pin 45 to seal the material 48 within the recess. The distal end of the plunger rod 49 may also be threaded on its outer periphery, and the plunger rod 49 may be attached to the top of the hole 44.

[0033] As will be appreciated by those skilled in the art, the embodiment shown in Figures 2A-4C may be reconfigured such that a pin is provided in the center of the distal end of the plunger rod and a corresponding female fitting is provided in the insert.

[0034] As previously mentioned, the storage and delivery system according to various embodiments of the present invention may include a bottle and a bottle stopper. For example, referring to Figures 8A and 8B, the closure in the form of a bottle stopper 81 may include an elastomeric body 82 and a material 84 having a negative coefficient of thermal expansion. The material 84 may be, for example, a solid, liquid, or gel. The material 84 is disposed within an internal chamber of the molded stopper 81 (e.g., injected into the chamber if liquid) to fill the chamber. Alternatively, an insert containing the material 84 may form the elastomeric body 82, for example, by overmolding. The material 84 is preferably disposed within the portion of the stopper 81 that is located below the flange 83 and inserted into the neck 85 of the bottle 80. At low temperatures during storage, such as cryogenic temperatures, the material 84 expands to oppose the radial contraction of the elastomeric body 82 and ensure a seal between the exterior surface of the stopper 81 and the interior surface of the neck 85 of the bottle 80 that it contacts. Again, if desired, a film 87 of an inert material may be applied to at least a portion of the exterior surface of the stopper, most preferably the surface portion most likely to come into contact with the contents of the bottle 80 .

[0035] As shown in Figures 8A and 8B, the chamber or insert in the stopper containing the substance 84 may be, for example, spherical, but is not limited to such a shape. The chamber or insert (bladder) is preferably tubular, annular, coiled, or helical, for example, as in the form of insert 94 or 102 in Figures 9A-10B. All of these embodiments will ensure that a radially pressurized seal is maintained between the exterior surface of the closure body (81, 91, 100) and the interior surface of the container (80, 90) with which they are in contact. The insert is made with an internal through hole so that a needle can be inserted into the stopper without passing through the insert when piercing the stopper to withdraw the contents of the container. This reduces the possibility of exposing the drug in the container to the substance with a negative coefficient of thermal expansion. As shown in Figures 9A and 9B, the substance with a negative coefficient of thermal expansion may be incorporated into multiple annular inserts 94a, 94b, rather than a single annular or tubular insert.

[0036] The storage and delivery system according to various embodiments of the present invention may further include a seal configured to capture or retain the closure in the opening of the container, such as the embodiment of Figures 11-14. All of these embodiments will reliably maintain an axially pressurized sealing surface between the bottom surface of the closure flange and the top surface of the container. For example, referring to Figure 11, a closure in the form of a stopper 112 may be inserted into the opening and neck 110 of the bottle. Stopper 112 may further include a flange portion 117 that rests on the top surface of the bottle. An annular insert 114 comprising a material with a negative coefficient of thermal expansion may be placed on the top surface of stopper 112 above flange portion 117. Finally, a seal, preferably a metal seal 116 such as made of aluminum, may be crimped over the annular insert 114 and under an annular collar 115 of the bottle. The crimping causes seal 116 to form an annular lip 118 that contacts annular collar 115 that surrounds the opening of the bottle. The annular lip 118 contacts the underside of the annular collar 115 and helps maintain an axial force against the top surface of the plug 112. When the containment and delivery system is stored at low temperatures (e.g., cryogenic temperatures), the insert 114 expands axially, enhancing or maintaining the axial force applied to the top surface of the flange portion 117 of the plug 112 (which contracts at low temperatures). Additionally, the insert 114 may be configured to encourage a material with a negative coefficient of thermal expansion to expand axially rather than radially. For example, the annular insert may be an air bladder having a rectangular cross section. In this case, the inner and outer circumferential walls, i.e., the vertical walls, of the annulus may be made of a stiff material, while the top and bottom, i.e., the horizontal walls, of the annulus may be made of a more flexible material, allowing the material inside the air bladder to expand primarily axially. In another example, a pair of rings of stiff material may be attached to the bottom surface of the seal in a concentric arrangement. With the seal attached to the annular insert, the insert may be nested between the concentric rings.

[0037] In another embodiment, such as the embodiment of FIG. 12, an annular insert 124 comprising a material with a negative coefficient of thermal expansion may be disposed within the flange portion 127 of the stopper 122. Preferably, the inside diameter of the annular insert 124 is wider than the inside diameter of the bottle neck 110. As previously explained, the annular insert 124 expands axially against the seal 116 it is crimping, thereby maintaining intimate contact between the annular lip 128 of the seal 116 and the lower annular surface of the collar 125 surrounding the opening of the bottle, and maintaining the force pressing the flange portion 127 of the stopper 122 against the upper surface of the bottle. If necessary, a ring of stiff material may be placed around the outer periphery of the flange portion 127 of the stopper 122 to encourage the axial expansion of the annular insert 124.

[0038] In yet another embodiment, such as the embodiment of Figure 13, a flange portion on the top of the stopper 132 may include an annular recess 138. After the stopper 132 is inserted into the opening of the neck 110 of the bottle, a material with a negative coefficient of thermal expansion (such as a solid, liquid, or gel) may be inserted or injected into the recess 138. A rigid cover 136 is attached to the top of the stopper 132, and then the seal 116 is crimped on, trapping the stopper 132 within the neck 110 of the bottle and trapping the material with a negative coefficient of thermal expansion within the recess 138.

[0039] In each of the systems described in Figures 11-13, the closure may optionally further include a material in its body that has a negative coefficient of thermal expansion, in a manner similar to the embodiment of Figures 8A-10B, such that the closure maintains a seal between the exterior surface of the closure body below the flange and the interior surface of the bottle neck.

[0040] 14, an alternative storage and transport system may include a plug 142. The plug 142 has a hole 148 extending along the central axis of the body of the plug 142. A cover 146 is made of a solid material and has an axial projection extending into the hole 148. The cover 146 may be used to seal a gap between the outer surface of the axial projection and the inner surface of the hole 148. The axial projection of the cover 146 preferably includes a through hole 149 extending in the axial direction. The through hole 149 allows a needle of a syringe to pass through the plug 142 and reach the contents of the vial 110 sealed by the plug 142. The gap may be filled with a material 147 having a negative coefficient of thermal expansion. The system may further include a seal 116. The seal 116 is crimped from above onto the cover 146 and from below onto the lower annular surface of the collar 145 surrounding the opening of the vial 110, as previously described. When the bottle 110 is stored at low temperatures, the rigid cover 146 may encourage the material 147 in the hole 148 to expand circumferentially. This helps maintain a seal between the inner surface of the neck of the bottle 110 and the outer surface of the stopper 142 in contact therewith. As will be appreciated by those skilled in the art, an annular recess, such as recess 138 of FIG. 13, may be incorporated into the flange of the stopper 142 of FIG. 14 and filled with the same material 147 or a similar material having a negative coefficient of thermal expansion. In other preferred embodiments of the invention, the cover 146 may be formed of a solid having a negative coefficient of thermal expansion (e.g., an alloy manufactured by ALLVAR, Inc., College Station, Texas) and overmolded onto the elastomeric material to form the stopper. In such embodiments, the gap may be eliminated. Also, as with the embodiment of FIG. 8B, an optional film of an inert material may be applied to at least a portion of the outer surface of any of the stoppers in the disclosed embodiments, most preferably the surface portion most likely to come into contact with the contents of the bottle.

[0041] Containment and transport systems made in accordance with various embodiments of the present invention may be manufactured with each component as described above, or may be packaged in bulk in secondary packaging suitable for maintaining the sterility and cleanliness of the components. The components may then be sterilized by steam, ethanol, gamma radiation, or electron beam irradiation. The sterilized bulk package may then be introduced into a sterile environment, for example, where drug loading occurs.

[0042] Those skilled in the art will appreciate that changes may be made to the above-described embodiments without departing from the broader concept of the invention. It is understood, therefore, that the invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the invention as defined by the appended claims.

Claims

1. 1. A system for storing or transporting a product, comprising: a bottle having an interior surface and a neck; a plug comprising an elastomeric body having an exterior surface; an insert material including a material having a negative coefficient of thermal expansion; a seal positioned around an outer periphery of the plug and at least a portion of the neck; Equipped with The insert is positioned between the plug surface and the seal surface. A system characterized by:

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

3. The system of claim 1 , wherein the substance comprises a liquid at a temperature above 0° C.

4. The system of claim 1 , wherein the substance comprises a gel at temperatures above 0° C.

5. The system of claim 1 , wherein the material has a negative coefficient of thermal expansion at temperatures below 0° C.

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