Pharmaceutical container with closure assembly having fill material - Patents.com

Abstract

1. A sealed pharmaceutical container comprising: a shoulder; a neck extending from the shoulder; a flange extending from the neck, the flange having a back surface extending from the neck, an outer surface extending from the back surface defining an outer diameter of the flange, and an upper sealing surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container; and a closure assembly comprising: a stopper having a first CTE extending over the upper sealing surface of the flange and including a sealing portion covering the opening and an insert portion extending into the opening and contacting the inner surface of the flange, the stopper having a first CTE, and a filler member received within the stopper and having a second CTE lower than the first CTE.

Description

Priority

[0001] This application claims the benefit of priority under 35 U.S.C. §119 of U.S. Provisional Patent Application No. 63 / 277,492, filed November 9, 2021, the contents of which are relied upon and incorporated herein in their entirety by reference. [Technical field]

[0002] The present specification relates generally to containers for storing pharmaceutical compositions, and more particularly to containers including a closure assembly formed from a material having a high coefficient of thermal expansion and a filler member having a low coefficient of thermal expansion to improve hermeticity when exposed to relatively low temperatures. [Background technology]

[0003] Pharmaceutical containers, such as vials and syringes, are typically sealed with stoppers or other closures to maintain the integrity of the contained material. The closures are typically manufactured from synthetic rubber or other elastomers. Such materials beneficially have elasticity and high permeation resistance that facilitates their insertion into a container to seal the interior of the container. However, the elasticity of typically used closure materials may decrease at low temperatures. For example, synthetic rubbers currently used as closure materials will have a transition temperature above -70°C and below -10°C. A closure made from such synthetic rubber will behave as a solid below its transition temperature and will not be able to elastically expand to compensate for the relatively large difference in thermal expansion coefficient between the glass and the crimped cap used to secure the closure to the container. Given this, existing closure assemblies for pharmaceutical containers will not function at temperatures below -10°C.

[0004] Some biological materials (e.g., blood, serum, proteins, stem cells, and other perishable biological fluids) must be stored below the glass transition temperature of conventional elastomers to remain useful. For example, certain RNA-based vaccines may need to be stored at dry ice temperatures (e.g., about -80°C) or liquid nitrogen temperatures (e.g., about -180°C) to remain active. At such low temperatures, closures (e.g., glass or plastic containers, stoppers, aluminum caps) may undergo dimensional changes, raising issues with seal integrity and potentially contaminating materials stored therein. Summary of the Invention

[0005] In one embodiment, the sealed pharmaceutical container includes a shoulder; a neck extending from the shoulder; a flange extending from the neck, the flange having a back surface extending from the neck, an outer surface extending from the back surface defining an outer diameter of the flange, and an upper sealing surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container; and a closure assembly including a stopper extending over the upper sealing surface of the flange and including a sealing portion covering the opening and an insert portion extending into the opening and contacting the inner surface of the flange, the stopper having a first CTE, and a filler member received within the stopper and having a second CTE lower than the first CTE.

[0006] In another embodiment, a sealed pharmaceutical container includes a syringe having a tubular barrel having an open end and a closed end opposite the open end, and a needle extending from the closed end and in fluid communication with an interior of the tubular barrel defined by an inner wall of the tubular barrel; and a closure assembly movably disposed within the tubular barrel, the closure assembly having an inner wall and an outer wall opposite the inner wall in at least partial contact with the inner wall of the tubular barrel, the closure assembly including a stopper having a first CTE, a filler member at least partially contained within the stopper and having a second CTE lower than the first CTE, and a plunger coupled to the stopper and extending through the open end of the tubular barrel.

[0007] In yet another embodiment, a method of sealing a pharmaceutical container includes the steps of providing a pharmaceutical container including a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange having a back surface extending from the neck, an outer surface extending from the back surface defining an outer diameter of the flange, and an upper sealing surface extending from the outer surface to an inner surface of the pharmaceutical container defining an opening; placing a pharmaceutical composition in the pharmaceutical container; and providing a stopper having a first CTE, the stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening and an insert portion extending into the opening and contacting the inner surface of the flange, and a filler member received within the stopper, the second CTE being lower than the first CTE.

[0008] These and additional features provided by the embodiments described herein will be better understood in view of the following detailed description taken in conjunction with the drawings. [Brief description of the drawings]

[0009] The embodiments set forth in the drawings are illustrative and exemplary in nature and are not intended to limit the subject matter defined in the claims. The following detailed description of illustrative embodiments can be understood when read in conjunction with the following drawings, in which like structure is indicated with like reference numerals and in which: [Figure 1] 1 is a cross-sectional view of an embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; [Diagram 2] 1 is a partial cross-sectional view of another embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; [Diagram 3] 1 is a partial cross-sectional view of another embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; [Figure 4] 1 is a cross-sectional view of another embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; [Diagram 5] 1 is a cross-sectional view of another embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; [Figure 6]1 is a cross-sectional view of another embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; [Figure 7] 1 is a cross-sectional view of another embodiment of a pharmaceutical container according to one or more embodiments shown and described herein; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Reference will now be made in detail to embodiments of sealed pharmaceutical containers with closure assemblies that maintain the sealed integrity of the container at relatively low storage temperatures (e.g., -30°C or less, -40°C or less, -50°C or less, -60°C or less, -70°C or less, -80°C or less, -100°C or less, -125°C or less, -150°C or less, -175°C or less, -180°C or less). In embodiments, the structure of the pharmaceutical container described herein may differ in one or more aspects from existing pharmaceutical container structures to facilitate maintenance of a seal at the interface between the pharmaceutical container and the closure assembly inserted therein. For example, an embodiment of the pharmaceutical container described herein may be a vial (although other container shapes are within the scope of the present disclosure) with a shoulder, a neck, and a flange that includes an upper sealing surface against which the stopper of the closure assembly is pressed by a cap. Various features of the upper sealing surface may be adapted to facilitate maintenance of a seal when the sealed pharmaceutical container is cooled to such low storage temperatures. For example, in embodiments, the upper sealing surface may include an inclined sealing surface that drops with increasing radial distance from the central axis of the pharmaceutical container. The inclined sealing surface may drop at an angle greater than 0 degrees (e.g., greater than 0 degrees and less than or equal to 45 degrees) relative to a plane that spans the end of the pharmaceutical container to increase the initial force applied to the stopper during the crimping process and increase the resistance of the stopper to shrink when cooled to a lower temperature. In embodiments, the upper sealing surface extends perpendicular to the central axis of the pharmaceutical container (e.g., extends at an angle greater than or equal to 89.5 degrees and less than or equal to 90 degrees) to maximize the contact area between the upper sealing surface and the stopper. In embodiments, various other characteristics of the upper sealing surface (e.g., surface roughness, flatness, etc.) may be tailored to increase the seal integrity.

[0011] In embodiments, the closure assembly of the pharmaceutical container described herein may be formed from various combinations of materials to facilitate maintaining the seal at low storage temperatures. The closure assembly herein may include a stopper, a filler member encased within the stopper, and a metal-containing cap formed from a composition adapted to prevent excessive deformation of the stopper relative to the metal-containing cap at low storage temperatures to maintain sufficient sealing force applied to the stopper by the metal-containing cap. For example, in embodiments, the metal-containing cap may be made from a material that increases its CTE over existing aluminum crimp caps. In embodiments, the metal-containing cap may be made from at least one of Zn and Mg instead of Al to provide a higher CTE. In embodiments, the metal-containing cap is made from an aluminum-containing polymer composite. In embodiments, the metal-containing cap is made from a metal alloy including at least one of Zn, Al, Mg, and Cu. The stopper has a first CTE and the filler member has a second CTE that is lower than the first CTE. Thus, the filler member reduces the amount of shrinkage of the stopper when exposed to a relatively low temperature.

[0012] As used herein, the term "container closure integrity" refers to the maintenance of a seal at the interface between the pharmaceutical container and the closure assembly (e.g., between the top sealing surface of the pharmaceutical container and the closure assembly) that does not contain gaps greater than a threshold size to maintain the probability of contaminant ingress or reduce the potential for gas permeability below a predetermined threshold based on the material stored in the pharmaceutical container. For example, in an embodiment, container closure integrity is measured using a method according to USP <1207> During the helium leak test described in (2016), the helium leak rate was 1.4 × 10 -6 cm 3 If it remains below / seconds, it will be maintained.

[0013] In the pharmaceutical container embodiments described herein, concentrations of components of the glass compositions forming the pharmaceutical container (e.g., SiO, AlO, BO, etc.) are specified in mole percent (mol%) on an oxide basis unless otherwise specified.

[0014] The term "substantially free," when used to describe the concentration and / or absence of a particular component in a glass composition, means that the component is not intentionally added to the glass composition. However, the glass composition may contain trace amounts of the component as contaminants or admixtures in amounts less than 0.05 mole percent.

[0015] As used herein, unless otherwise specified, the term "CTE" refers to the coefficient of thermal expansion over a temperature range of about -200°C to about 300°C.

[0016] As used herein, the term "about" means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement errors, and the like, and other factors known to those of skill in the art. When the term "about" is used in describing a value or an endpoint of a range, the particular value or endpoint referred to is included. Whether or not a numerical value or range endpoint is referred to herein as "about," two embodiments are described: those modified by "about" and those not modified by "about." It will be further understood that each endpoint of a range is significant both in relation to the other endpoint and independently of the other endpoint.

[0017] As used herein, directional terms - e.g., up, down, right, left, front, back, upper and bottom - are used only with reference to the drawings as depicted and are not intended to imply absolute orientation.

[0018] As used herein, nouns include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to an element includes aspects having two or more of such elements unless the context clearly indicates otherwise.

[0019] Referring now to FIG. 1, one embodiment of a pharmaceutical container 100 for storing a pharmaceutical formulation is shown generally in cross section. The pharmaceutical container 100 comprises a glass container 102 and a closure assembly 104 coupled to the glass container 102 at an opening 105 of the glass container 102. Although referred to herein as a glass container 102, it should be appreciated that in embodiments, the glass container 102 may be formed from plastic or any other suitable material. The closure assembly 104 comprises a stopper 106, a filler member 107, and a metal-containing cap 108. In the embodiment shown in FIG. 1, the stopper 106 includes an insert portion 117 and a sealing portion 119. It should be appreciated that in embodiments, the insert portion 117 may not be provided. Thus, the stopper 106 may not extend into the opening 105 of the glass container 102.

[0020] The filler member 107 is placed within the plug 106, and more specifically, within the sealed portion 119 of the plug 106. The filler member 107 includes a filler body 121 having an upper surface 121a, a lower surface 121b opposite the upper surface 121a, and an outer edge 121c. Although not shown, it should be appreciated that the filler body 121 may have a circular or elliptical shape when viewed in plan view, as defined by the outer edge 121c, which corresponds to the shape of the outer edge of the sealed portion 119 of the plug 106. Thus, the distance between the outer edge of the sealed portion 119 and the outer edge 121c of the filler body 121 remains substantially constant along the entire outer edge 121c of the filler body 121. As shown in FIG. 1, the filler member 107 is positioned within the plug 106 such that the filler body 121 overlaps with the insert portion 117 of the plug 106 (shown inserted through the opening 105 formed in the glass container 102). Thus, the filler body 121 has a body diameter D1 that is greater than the opening diameter D2 of the opening 105 of the glass container 102. In an embodiment, a body passageway 121d is formed in the filler body 121 and extends through the upper surface 121a and the lower surface 121b of the filler body 121 such that a needle, such as a syringe needle, can extend through the filler member 107 and into the glass container 102. In an embodiment, the body passageway 121d has a length that is greater than the opening diameter D2.

[0021] In an embodiment, the filler member 107 is formed from a first material, such as, for example, glass, a crystalline material, a polymer, a metal, or the like, or any combination thereof. In an embodiment, the first material may include, for example, an oxide, a halide, a nitride, a chalcogen, or a combination thereof. In an embodiment, the first material forming the filler member 107 is coated with a second material. The second material may be, for example, butyl rubber, nitrile rubber, fluoro rubber, butyl silicone rubber, polyacrylate elastomer, or the like, or any combination thereof. Thus, the plug 106 has a first CTE and the filler member has a second CTE that is lower than the first CTE. In an embodiment, the second material has a glass transition temperature (Tg) of -200°C to 300°C. In an embodiment, the plug 106 also has a Tg of -200°C to 300°C.

[0022] The insert portion 117 is inserted into the opening 105 of the glass container 102 until the sealing portion 119 contacts the upper sealing surface 110 of the glass container 102. The sealing portion 119 is then compressed against the upper sealing surface 110 by crimping of the metal-containing cap 108 to form a seal at the upper sealing surface 110. Various aspects of the glass container 102 and closure assembly 104, as described herein, are designed to ensure maintenance of container closure integrity of the glass container 102 at low storage temperatures.

[0023] The glass container 102 generally comprises a body 112. The body 112 has a wall thickness T that extends between an inner surface 114 and an outer surface 116 of the glass container 102. W , has a central axis A, and generally encloses an interior volume 118. In the embodiment of the glass container 102 shown in FIG. 1, the body 112 generally includes a wall portion 120 and a floor portion 122. The wall portion 120 transitions to the floor portion 122 through a heel portion 124. In the illustrated embodiment, the wall portion 120 of the glass container 102 defines a flange 126, a neck 128 extending from the flange 126, a body 115, and a shoulder 130 extending between the neck 128 and the body 115. The floor portion 122 is coupled to the body 115 through the heel portion 124. In the embodiment, the glass container 102 is symmetrical about the central axis A, and each of the body 115, the neck 128, and the flange 126 are substantially cylindrical.

[0024] In an embodiment, the glass container 102 is a U.S.P. <660> borosilicate glass compositions, such as Type 1B borosilicate glass compositions conforming to U.S.P. <660> The glass container 102 may be formed from a Type I, Type II, or Type III glass as defined in US Pat. No. 6,393,636. Alternatively, the glass container 102 may be formed from an alkali aluminosilicate glass composition, such as those disclosed in U.S. Pat. No. 8,551,898, which is incorporated herein in its entirety, or an alkaline earth aluminosilicate glass composition, such as those described in U.S. Pat. No. 9,145,329, which is incorporated herein in its entirety. In an embodiment, the glass container 102 may be comprised of a soda-lime glass composition. In an embodiment, the glass container 102 may be comprised of a 0×10 -7 / K or more and 100 x 10 -7 / K or less (e.g., 30×10 -7 / K or higher and 70×10 -7 The thermal expansion coefficient of the composition is 0.1 - 1.5 kPa (1.5 / K or less).

[0025] 1 having a particular form factor (i.e., a vial), it should be understood that, as described in more detail herein, the glass container 102 may have other form factors including, without limitation, Vacutainers®, cartridges, syringes, ampoules, bottles, flasks, phials, tubes, beakers, etc. Additionally, it should be understood that the glass containers described herein may be used in a wide variety of applications including, without limitation, pharmaceutical packaging, beverage containers, etc.

[0026] Although referred to herein as a glass container 102, it should be appreciated that the glass container 102 may be formed from materials other than glass, such as, for example, polymers, metals, ceramics, etc. Additionally, the thermal expansion coefficients of these materials are generally in the range of 0×10 -7 / K or higher and 8,000 x 10 -7 / K or less.

[0027] The wall thickness T of the glass container 102 Wmay vary depending on the implementation. In an embodiment, the wall thickness T of the glass container 102 W can be 6 millimeters (mm) or less, e.g., 4 mm or less, 2 mm or less, 1.5 mm or less, or 1 mm or less. In some embodiments, the wall thickness T W may be 0.1 mm or more and 6 mm or less, 0.3 mm or more and 4 mm or less, 0.5 mm or more and 4 mm or less, 0.5 mm or more and 2 mm or less, or 0.5 mm or more and 1.5 mm or less. W The wall thickness T may be greater than or equal to 0.9 mm and less than or equal to 1.8 mm. W may vary depending on the axial position within the glass container 102.

[0028] As shown in FIG. 1 , the flange 126 has a back surface 132, an exterior surface 136, and an upper sealing surface 110. The exterior surface 136 may define an outer diameter of the flange 126. In an embodiment, the metal-containing cap 108 of the closure assembly 104 is crimped around the flange 126 by any suitable crimping method (e.g., a pneumatic crimping device, etc.). During the closure process, the plug 106 is inserted into the opening 105, and a compressive force is applied to the metal-containing cap 108 during crimping. For example, as shown in FIG. 1 , the metal-containing cap 108 includes a bottom portion 109 that contacts the back surface 132 of the flange 126 to maintain the plug 106 in compression and form a seal after the crimping process. Compressing the plug 106 creates a residual sealing force in the flange 126 that maintains compression on the plug 106 after the metal-containing cap 108 is crimped in place. In an embodiment, the length of the bottom portion 109 of the metal-containing cap 108 that is in direct contact with the underside 132 of the flange 126 has a length 111 (e.g., in the X direction shown in FIG. 1 ) of 1 mm or more to help maintain a residual sealing force within the plug 106 at storage temperatures of −80° C. or below.

[0029] When the glass container 102 is cooled to a relatively low storage temperature below -80°C (e.g., below -80°C, below -100°C, below -125°C, below -150°C, below -175°C, below -180°C), each of the components of the glass container 102 may undergo volumetric shrinkage that depends on the thermal properties of that component. As shown in FIG. 1, the volume of material disposed between the bottom portion 109 and the top portion 113 of the metal-containing cap 108 surrounds the sealing portion 119 of the plug 106 and the flange 126 of the glass container 102. If the combination of the plug 106 and the flange 126 shrinks by an amount greater than the amount of shrinkage of the metal-containing cap 108, the compression of the plug 106 provided by the metal-containing cap 108 will be less, increasing the likelihood of a seal being compromised at the top sealing surface 110. However, a filler member 107 having a CTE lower than the CTE of the plug reduces the amount of shrinkage that the plug 106 would otherwise exhibit. Therefore, the seal assembly 104 including the filler member 107 encased within the plug 106 lowers the overall CTE of the seal assembly 104 , thereby reducing the likelihood of a seal being compromised at the upper sealing surface 110 .

[0030] For example, as shown in FIG. 1 , the combined height 138 of the flange 126 and the bung 106 (i.e., in the Z direction as shown in FIG. 1 ) is approximately equal to the distance between the top 113 and bottom portion 109 of the metal-containing cap 108. In such a condition, the metal-containing cap 108 can compress the bung 106 against the upper sealing surface 110 to form a seal. However, if the combined height 138 shrinks to an extent that is greater than the metal-containing cap 108, the compression of the bung 106 will decrease and the residual sealing force will decrease. To maintain the compression of the bung 106, the shrinkage ΔL of the metal-containing cap 108, the bung 106, and the glass container 102 will be in accordance with the following relationship:

[0031]

number

[0032] where the contraction of ΔL of each component is

[0033]

number

[0034] It may be approximated by, where L i are the initial dimensions of the components, and α(T) is the temperature-dependent CCTE of the materials that make up each of the metal-containing cap 108, the plug 106, and the glass container 102.

[0035] In an embodiment, the plug 106 is made from a polymeric material (e.g., butyl rubber or other synthetic rubber). Such a material may have a Tg of -70° C. or higher and -10° C. or lower. Below its Tg, the plug 106 will behave like a solid (e.g., lose elasticity) and will have a reduced sealing force at the upper sealing surface 110. For example, if the plug 106 is cooled below its Tg, the plug 106 may not fill all of the gap between the upper sealing surface 110 and the top 113 of the metal-containing cap 108, increasing the likelihood of compromising the seal. That is, when the plug 106 is cooled below its glass transition temperature, it effectively behaves as two different materials: an elastic material above the transition temperature, and a solid glass below the transition temperature. Now, according to Equation 2, the contraction of the plug 106 disposed between the flange 126 and the top 113 of the metal-containing cap 108 is expressed as the contraction of the plug 106 at an initial temperature T i to the final temperature T F When cooled to:

[0036]

number

[0037] where α ガラスrefers to the CTE of a glass-like material at which the rubber of the stopper 106 changes below its glass transition temperature, Tg. In embodiments, to maintain a seal, the metal-containing cap 108 and stopper 106 may be configured such that the shrinkage of the metal-containing cap 108 is equal to or greater than the combined shrinkage of the glass container 102 and stopper 106. To facilitate satisfying such a relationship, the shrinkage of the metal-containing cap 108 may be increased, the shrinkage of the stopper 106 and flange 126 may be decreased, or any combination thereof. Additionally or alternatively, the structure of the glass container 102 may be designed to increase the initial capping compression imparted to the stopper 106, thereby making the stopper 106 more resistant to shrinkage.

[0038] In addition, to maintain compression of the plug 106, the CTE and the thickness of the filler member 107 extending between the upper surface 121a and the lower surface 121b of the filler body 121 must satisfy the following conditions:

[0039]

number

[0040] should be satisfied, where h ゴム refers to the thickness of the rubber coating on the plug 106, and α キャップ refers to the CTE of the metal-containing cap 108, and α カートリッジ refers to the CTE of the glass container 102, and α 栓 refers to the CTE of the plug 106, and α 充填材 refers to the CTE of the filler member 107, and h フランジ refers to the thickness or distance 156 of the flange 126, and h ゴム refers to the thickness of the plug 106 (including the rubber coating and the filling member 107 in the vertical direction).

[0041] In an embodiment, the metal-containing cap 108 is approximately 240×10 -7 / K. A typical rubber from which the plug 106 is made (e.g., Butyl 325, Butyl 035, etc.) has a CTE of 1,400×10-7 / K or greater. That is, from a purely CTE difference standpoint, the metal-containing cap 108 will tend to shrink less than the plug 106, resulting in reduced sealing force at lower storage temperatures. In addition to the CTE mismatch discussed above, as shown in FIG. 1, the plug 106 will comprise a greater volume percentage of the closure assembly 104 than the metal-containing cap 108, further increasing the tendency of the plug 106 to experience greater thermal shrinkage.

[0042] In the embodiment shown in FIG. 1, to counter such tendency of the bung shrinkage to overwhelm the metal-containing cap 108 shrinkage at low storage temperatures, the structure of the glass container 102 has been modified to deviate from existing glass containers to provide greater compression of the bung 106 during the process of crimping the metal-containing cap 108. Specifically, in the embodiment, the upper sealing surface 110 includes an angled sealing surface 140, such as that disclosed in U.S. Patent Application Publication No. 2021 / 0212893, which is incorporated herein by reference in its entirety. The angled sealing surface 140 extends between the outer surface 136 of the flange 126 and the inner surface 114 of the glass container 102. The angled sealing surface 140 extends at an angle 150 relative to a plane 152 that spans an edge 154 of the opening 105. The plane 152 can be a plane that is at the top of the glass container 102 at the opening 105 (e.g., at the top of the angled sealing surface 140). In an embodiment, plane 152 connects a point extending around top sealing surface 110 that is furthest from a reference point (e.g., floor portion 122, see FIG. 1) of glass container 102. Plane 152 spans the top of glass container 102 in a direction perpendicular to central axis A of glass container 102 (e.g., X direction shown in FIG. 1). In an embodiment, plane 152 extends perpendicular to the portion of inner surface 114 that defines opening 105.

[0043] The angle 150 described herein may be referred to as the "flange angle." The flange angle relative to the plane 152 may be measured in a variety of different ways. For example, in an embodiment, to determine the extension direction of the angled seal surface 140, an image of the glass container 102 may be captured and image processing techniques may be used to determine the angle 150 (relative to the plane 152) of the angled seal surface 140. In an embodiment, the extension direction of the angled seal surface 140 is measured by finding a plane that extends between the apex of the angled seal surface 140 (e.g., having the greatest distance in the Z direction from the back surface 132) and a second highest point on the angled seal surface 140 (e.g., the extension direction of the angled seal surface 140 is measured by a plane at another point on the angled seal surface 140 that is lower than the apex relative to the apex of the angled seal surface 140 and the plane 152). In an embodiment, the direction of extension of the angled seal surface 140 is measured by connecting a number of points on the angled seal surface 140 that are a predetermined distance (e.g., 0.1 mm, 0.2 mm, 0.5 mm, 1.0 mm, etc.) outward from the inner surface 114 and inward from the outer surface 136 (e.g., these points may be interpreted as a uniform distribution of spatial points extending between the inner surface 114 and the outer surface 136). In an embodiment, the direction of extension of the angled seal surface 140 is measured by curve fitting a linear plane to a number of different points distributed across the angled seal surface 140.

[0044] In embodiments, the angle 150 is greater than 5 degrees and less than or equal to 45 degrees (e.g., greater than 5 degrees and less than or equal to 40 degrees, greater than 5 degrees and less than or equal to 40 degrees, greater than 5 degrees and less than or equal to 30 degrees, greater than 5 degrees and less than or equal to 20 degrees, greater than 5 degrees and less than or equal to 10 degrees). In embodiments, the angle 150 is substantially uniform around the circumference of the glass container 102 (e.g., when measured at multiple azimuthal orientations, each of the measurements may be within 0.5 degrees of each other). In existing glass containers, the angle 150 is typically approximately 3 degrees. Thus, in the glass container 102, the inclination of the upper sealing surface 110 relative to the plane 152 is increased by at least 50% over existing glass containers. The increased inclination of the upper sealing surface 110 tends to increase the compression of the plug at low storage temperatures. The angle 150 will create a compression gradient in the plug 106 as a result of crimping the metal-containing cap 108. For example, in embodiments, compression of the plug 106 may increase with increasing radial distance from the exterior surface 136, such that the compression of the plug 106 is greater closer to the interior surface 114. Such greater compression closer to the interior surface 114 may prevent gaps from forming in the seal when the plug 106 shrinks due to cooling.

[0045] Still referring to FIG. 1 , as a result of angle 150, distance 156 between top 113 of metal-containing cap 108 and top sealing surface 110 may vary as a function of radial distance from central axis A to a greater extent than existing glass containers. With this in mind, plug 106 is compressed to a greater extent proximate opening 105 than the peripheral area of ​​plug 106 disposed near outer surface 136 of flange 126. Such greater compression results in greater compression of plug 106 and greater resistance to shrinkage of plug 106 using the same crimping process. Additionally, angled sealing surface 140 reduces the term L of Equation 3 above when proximate opening 105. i、栓 This reduces the amount of shrinkage.

[0046] Although not described herein, it should be understood that alternatives to the glass container 102 described herein with respect to FIG. 1 may be used while maintaining the seal integrity of the container at storage temperatures of −80° C. or below. For example, the upper sealing surface 110 may extend in a plane 152 that spans an edge 154 of the opening 105 in the glass container 102. In embodiments, the upper sealing surface 110 extends substantially perpendicular (e.g., greater than or equal to 89.5 degrees and less than or equal to 90.5 degrees) to the central axis A of the glass container 102. In embodiments, the upper sealing surface 110 extends substantially perpendicular to the inner surface 114 of the glass container 102 that defines the opening 105. Such an upper sealing surface 110 would effectively increase the contact area between the plug 106 and the upper sealing surface 110, increasing the likelihood of maintaining the seal integrity.

[0047] 2, a further embodiment of a pharmaceutical container 200 is shown comprising a glass container 102 and a closure assembly 202. The closure assembly 202 includes a stopper 106 and a filler member 204. Rather than a filler member 107 comprising a filler body 121 extending across an opening 105 formed in the glass container 102, the filler member 204 extends at least partially into and through the opening 105. However, it should be appreciated that the above characteristics of the filler member 107, such as the material of formation and CTE, are equally applicable to the filler member 204 described herein.

[0048] The filler member 204 is at least partially received within the plug 106, specifically, within the insert portion 117 of the plug 106, but not within the sealing portion 119 of the plug 106. More specifically, the filler member 204 includes a filler projection 206 having an upper surface 206a, a lower surface 206b opposite the upper surface 206a, and an outer edge 206c. In embodiments, the filler member 204 may not be received within the plug 106 at its lower surface 206b. In other embodiments, the filler member 204 may be fully received within the plug 106. In embodiments, the upper surface 206a of the filler projection 206 may taper radially outward to match a taper formed in the upper surface 121a of the sealing portion 119 of the plug 106, as shown in FIG. 2. Although not shown, it should be appreciated that the filling protrusion 206 may have a circular or elliptical shape when viewed in plan view, as defined by the outer edge 206c, which corresponds to the shape of the outer edge of the insert portion 117 of the plug 106. Thus, the distance between the outer edge of the insert portion 117 and the outer edge 206c of the filling protrusion 206 remains substantially constant all along the outer edge 206c of the filling protrusion 206. As shown in FIG. 2, the filling member 204 is positioned within the plug 106 such that the filling protrusion 206 passes through the insert portion 117 of the plug 106 (shown inserted through the opening 105 formed in the glass container 102) and extends parallel to the inner surface 114 of the glass container 102. Thus, the filling protrusion 206 has a protrusion diameter D3 that is smaller than the opening diameter D2 of the opening 105 of the glass container 102. In an embodiment, a protrusion passage 206d is formed in the fill protrusion 206 and extends through the top surface 206a and the bottom surface 206b of the fill protrusion 206 to allow a needle, such as a syringe needle, to extend through the fill member 204 and into the glass container 102. In an embodiment, the protrusion passage 206d may be filled with a sealing material 206e.

[0049] 3, a further embodiment of a pharmaceutical container 300 is shown comprising a glass container 102 and a closure assembly 302. The closure assembly 302 includes a plug 106 and a filler member 304. The filler member 304 includes a filler body 306 similar to the filler body 121 and a filler protrusion 308 similar to the filler protrusion 206 described herein. The filler body 306 and the filler protrusion 308 may be formed as a one-piece monolithic structure. Thus, the filler member 304 extends both across and into the opening 105 formed in the glass container 102, rather than either one or the other, as described in the above embodiment. It should be appreciated that the above characteristics of the filler members 107, 204, such as the material of formation and CTE, are equally applicable to the filler member 304 described herein.

[0050] The filler member 304 is at least partially received within the plug 106. Specifically, the filler body 306 is received within the sealing portion 119 of the plug 106, and the filler projection 308 is at least partially received within the insert portion 117 of the plug 106. More specifically, the filler body 306 has an upper surface 306a, a lower surface 306b opposite the upper surface 306a, and an outer edge 306c, and the filler projection 308 also has an upper surface 308a, a lower surface 308b opposite the upper surface 308a, and an outer edge 308c. In an embodiment, the upper surface 306a of the filler body 306 may taper radially outward to match a taper formed in the upper surface 121a of the sealing portion 119 of the plug 106, as shown in FIG. Although not shown, it should be appreciated that the filler body 306 and the filler projection 308 may have a circular or elliptical shape when viewed in plan view, as defined by outer edge 306c and outer edge 308c, respectively, corresponding to the shape of the outer edge of the seal portion 119 and the outer edge of the insert portion 117 of the plug 106. Thus, the distance between the outer edge of the seal portion 119 and the outer edge 306c of the filler body 306 remains substantially constant along the entirety of the outer edge 306c of the filler body 306. Similarly, the distance between the outer edge of the insert portion 117 and the outer edge 308c of the filler projection 308 remains substantially constant along the entirety of the outer edge 308c of the filler projection 308. In an embodiment, a body passage 306d, such as body passage 121d, is formed in the filler body 306, and a protrusion passage 308d, such as protrusion passage 206d, is formed in the filler projection 308. The body passage 306d and the protrusion passage 308d may extend completely through the filler member 304 and be coaxial with one another such that a needle, such as a syringe needle, may extend through the filler member 304 and into the glass container 102. In an embodiment, the body passage 306d and the protrusion passage 308d may be filled with a sealing material 306e.

[0051] It should be appreciated that gaps may be formed between the outer surface of the sealing portion and the metal-containing cap, and between the outer surface of the flange and the metal-containing cap, as shown in Figures 1-3. Alternatively, as described herein, the outer surface of the sealing portion and the metal-containing cap, and the outer surface of the flange and the metal-containing cap, may be in contact with one another such that no gaps are provided. Additionally, it should be noted that in embodiments, no sharp angles are provided in the sealing assemblies described herein, and instead, any angled surfaces should be chamfered or rounded to avoid stress concentrations.

[0052] 4-7, there is shown an embodiment of a pharmaceutical container with a container, shown here as a syringe, and a filler member disposed within the closure of the pharmaceutical container for sealing the syringe. Referring to FIG. 4, there is shown a pharmaceutical container 400 with a container, shown here as a syringe 402, and a closure assembly 404. It should be appreciated that the characteristics of the glass container 102 described herein, such as material of formation and CTE, are equally applicable to the syringe 402 described herein. However, in embodiments, the syringe 402 may be formed from a material other than glass, such as, for example, plastic. The syringe 402 includes a tubular barrel 406 having an open end 408 and a closed end 410 opposite the open end 408. In embodiments, the closed end 410 of the syringe 402 is tapered. The tubular barrel 406 has an interior 412 defined by an interior wall 414 of the tubular barrel 406. A needle 416 is provided at the closed end 410 of the syringe 402 and is in fluid communication with the interior 412 of the tubular barrel 406 for directing fluid from the interior 412 out of the syringe 402 .

[0053] The closure assembly 404 is movably disposed within the interior 412 of the tubular barrel 406 and includes a plug 418, a filler member 420, and a plunger 422. The plug 418 has an outer wall 418a and an inner wall 418b opposite the outer wall 418a. When the plug 418 is disposed within the tubular barrel 406, the outer wall 418a contacts the inner wall 414 of the tubular barrel 406. The inner wall 418b of the plug 418 defines a recess 418c that receives the filler member 420. Thus, the filler member 420 is at least partially contained within the plug 418.

[0054] The plunger 422 has a first end 422a and a second end 422b opposite the first end 422a. The first end 422a of the plunger 422 may be secured to one or both of the bung 418 and the filler member 420 by gluing, ultrasonic welding, or the like. As can be seen, the first end 422a of the plunger 422 is secured to and extends from the filler member 420. The plunger 422 may include a rim 422c formed on its second end 422b opposite the bung 418 and the filler member 420. The rim 422c aids in manual placement of the plunger 422, and more particularly, the seal assembly 404, within the interior 412 of the syringe 402.

[0055] It should be appreciated that the above-described characteristics of plug 106 and filler member 107, such as the material of formation and CTE, are equally applicable to plug 418 and filler member 420, respectively, described herein. Thus, plug 418 has a first CTE and filler member 420 has a second CTE that is lower than the first CTE. Additionally, in an embodiment, tubular barrel 406 has a third CTE that is greater than the second CTE of filler member 420. Thus, filler member 420 is formed from a first material, such as, for example, glass, a crystalline material, a polymer, a metal, or the like, or any combination thereof. In an embodiment, the first material forming filler member 420 is coated with a second material. The second material may be, for example, butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, polyacrylate elastomer, or the like, or any combination thereof.

[0056] If the CTE of the plug 418 is approximately the same as or lower than the CTE of the tubular barrel 406, the likelihood of gaps forming therebetween is significantly reduced. The CTE and thickness of the filler member 420 are determined according to the following formula:

[0057]

number

[0058] In the formula, α 充填 , α カートリッジ , and α プランジャー are the CTEs of the filler member 420, the tubular barrel 406, and the plug 418, respectively, Δr is the thickness of the plug 418, and r 充填 is the size or radius of the filler member 420.

[0059] It should be appreciated that the tubular barrel 406 may be formed from a material other than glass, such as, for example, plastic. However, if the tubular barrel 406 is formed from glass, the difference in CTE between the plug 418 and the tubular barrel 406 will be relatively large. Since the CTE of glass is already low, it is therefore better to reduce the thickness of the plug 418 so that the CTE requirements of the filler member 420 can be more easily met. In this case, the CTE of the filler member 420 may be calculated based on the following formula:

[0060]

number

[0061] should be satisfied.

[0062] 5, a pharmaceutical container 500 is shown including a syringe 402 and a closure assembly 504. The pharmaceutical container 500 is substantially similar to the pharmaceutical container 400 shown in FIG. 4, and therefore, like reference numerals are used to refer to like parts. The closure assembly 540 includes a bung 418, a filling member 520, and a plunger 522. The filling member 520 is the same as the filling member 420, except that a cavity 520a is formed therein. Thus, the overall mass of the filling member 520 is reduced while still providing the benefit of reducing shrinkage and deformation of the bung 418 when the pharmaceutical container 500 is exposed to relatively low temperatures. As a result, the seal formed by contact between the outer wall 418a of the bung 418 and the inner wall 414 of the tubular barrel 406 is maintained.

[0063] Additionally, the plunger 522 has a first end 522a and a second end 522b opposite the first end 522a. A flange 522c is formed at the first end 522a of the plunger 522 and extends across a cavity 520a formed in the filler member 520. The flange 522c thus closes the cavity 520a from the remainder of the interior 412 defined by the tubular barrel 406. The flange 522c extends across at least the filler member 520, and in an embodiment, across the bung 418 as well. In an embodiment, the flange 522c has a width that extends across the interior 412 of the tubular barrel 406, and therefore across both the filler member 520 and the bung 418, such that opposite ends of the flange 522c are in contact with the inner wall 414 of the tubular barrel 406. This ensures a fluid-tight seal between the plunger 522, the plug 418, and the tubular barrel 406. The first end 522a of the plunger 522 may be secured to one or both of the plug 418 and the filler member 520 by adhesive, ultrasonic welding, or the like. It should be appreciated that the above characteristics of the filler member 107, such as the material of formation and CTE, are equally applicable to the filler member 520 described herein. Thus, the filler member 520 has a second CTE that is lower than the first CTE of the plug 418. Additionally, in an embodiment, the second CTE of the filler member 520 is lower than the third CTE of the tubular barrel 406.

[0064] Referring now to FIG. 6, a pharmaceutical container 600 is shown with a syringe 402 and a closure assembly 604. The pharmaceutical container 600 is substantially similar to the pharmaceutical containers 400, 500 shown in FIGS. 4 and 5, respectively, and therefore similar reference numbers are used to refer to similar parts. The closure assembly 604 includes a stopper 418, a filling member 620, and a plunger 622. The filling member 620 is similar to the filling member 520, except that the cavity 520a is not closed at one end, but has an open passageway 620a formed therein at its opposite ends. Thus, the filling member 620 is annular. The overall mass of the filling member 620 is reduced while still providing the benefit of reduced shrinkage and deformation of the stopper 418 when the pharmaceutical container 600 is exposed to relatively low temperatures. Additionally, a passageway 620a formed in the filler member 620 allows the plunger 622 to extend completely through the filler member 620 and contact the plug 418 at its first end 222a. The first end 622a of the plunger 622 may be secured to the plug 418 by adhesive, ultrasonic welding, or the like. It should be appreciated that the above characteristics of the filler member 107, such as the material of formation and CTE, are equally applicable to the filler member 620 described herein. Thus, the filler member 620 has a second CTE that is lower than the first CTE of the plug 418. Additionally, in an embodiment, the second CTE of the filler member 620 is lower than the third CTE of the tubular barrel 406.

[0065] 7, there is shown a pharmaceutical container 700 including a syringe 402 and a closure assembly 704. The closure assembly 704 includes a bung 718, a filler member 720, and a plunger 722. It should be appreciated that the above-described characteristics of the bung 106 and filler member 107, such as the materials of formation and CTE, are equally applicable to the bung 718 and filler member 720, respectively, described herein. Thus, the bung 718 has a first CTE and the filler member 720 has a second CTE that is lower than the first CTE.

[0066] As shown in FIG. 7, the plug 718 has an inner wall 718a and an outer wall 718b opposite the inner wall 718a. The inner wall 718a defines a cavity 718c. The outer wall 718b defines one or more lobes 718d. The lobes 718d extend radially and contact the inner wall 414 of the tubular barrel 406. As can be seen, a pair of the lobes 718d are shown defining one or more recesses 718e between adjacent lobes 718d. However, it should be appreciated that more than two lobes 718d may be provided, such as, for example, three, four, or five lobes. The plug 718 has a constant thickness defined between its inner wall 718a and outer wall 718b. In embodiments, the inner wall 414 of the tubular barrel 406 may be provided with a lubricant, the interior may be coated with a lubricant, and / or a lubricant may be provided within the recess 718e to facilitate sliding of the sealing assembly 704 within the interior 412 of the tubular barrel 406.

[0067] A filler member 720 is disposed within a cavity 718c defined by an inner wall 718a of the plug 718. The filler member 720 conforms to the shape of the cavity 718c and contacts and extends along the inner wall 718a of the plug 718. Thus, the filler member 720 similarly defines one or more lobes 720a. In embodiments in which the plug 718 has multiple lobes 718d defining one or more recesses 718e, the filler member 720 similarly has multiple lobes 720a defining one or more recesses 720b, as shown in FIG. 7. The plunger 722 has a first end 722a that may be secured to one or both of the plug 718 and the filler member 720 by adhesive, ultrasonic welding, or the like. As can be seen, the first end 722a is secured to the filler member 720.

[0068] In view of the above, it should be appreciated that there is defined herein a sealed pharmaceutical container including a closure assembly and a container having a CTE lower than the CTE of the container such that when the sealed pharmaceutical container is exposed to relatively low temperatures, shrinkage of the closure assembly relative to the container does not result in gaps in the seal formed between the container and the closure assembly. In particular, the closure assembly includes a closure including a filler member at least partially encased within the closure. The filler member has a CTE lower than the CTE of the closure and approximately the same as or lower than the CTE of the container.

[0069] Further aspects of the embodiments described herein are provided by the subject matter of the following sections.

[0070] Item 1. A sealed pharmaceutical container comprising: a shoulder; a neck extending from the shoulder; a flange extending from the neck, the flange having a back surface extending from the neck, an outer surface extending from the back surface defining an outer diameter of the flange, and an upper sealing surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container; and a closure assembly including a stopper having a first CTE, the stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening and an insert portion extending into the opening and contacting the inner surface of the flange, and a filler member received within the stopper and having a second CTE lower than the first CTE.

[0071] Item 2. The sealed pharmaceutical container of item 1, wherein the packing member is made from a first material, the first material including at least one of a glass, a crystalline material, a polymer, and a metal.

[0072] Item 3. The sealed pharmaceutical container of item 2, wherein the first material comprises at least one of an oxide, a halide, a nitride, and a chalcogen.

[0073] Item 4. The sealed pharmaceutical container of item 2, wherein the first material is coated with a second material, the second material comprising at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and a polyacrylate elastomer.

[0074] Item 5. The sealed pharmaceutical container of item 4, wherein the second material has a glass transition temperature (Tg) of -200°C to 300°C.

[0075] Item 6. The sealed pharmaceutical container of any one of Items 1 to 5, wherein the filling member includes a filling body having a body diameter larger than an opening diameter of the opening of the sealed pharmaceutical container.

[0076] Item 7. The sealed pharmaceutical container of item 6, wherein a body passageway is formed that extends through an upper surface of the fill body and a lower surface of the fill body.

[0077] Item 8. The sealed pharmaceutical container of item 7, wherein the filling member includes a filling protrusion extending at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container.

[0078] Item 9. The sealed pharmaceutical container of item 8, wherein a protrusion passage is formed that extends through an upper surface of the filling protrusion and a lower surface of the protrusion, the body and the protrusion form a one-piece monolithic structure, and the protrusion passage and the body passage are coaxial with each other.

[0079] Item 10. The sealed pharmaceutical container of any of items 1 to 9, wherein the filling member includes a filling protrusion that extends at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container, the filling protrusion having a protrusion diameter that is smaller than an opening diameter of the opening of the sealed pharmaceutical container.

[0080] Item 11. The sealing assembly reduces the helium leak rate of the sealed drug container to 1.4 x 10 when the sealed drug container is cooled to a temperature of -45°C or less. -6 cm 3 A sealed pharmaceutical container of any of items 1 to 10, maintained at or below 1 / sec.

[0081] Item 12. The sealed pharmaceutical container of any of items 1 to 11, wherein the upper sealing surface is an inclined sealing surface that extends at an angle relative to a plane extending through the edge of the opening, such that the distance between the inclined sealing surface and that plane increases as the radial distance from the outer surface decreases.

[0082] Item 13. Flange is 0×10 -7 / K or higher and 70×10 -7 13. The sealed pharmaceutical container according to any one of items 1 to 12, which is composed of a composition having a thermal expansion coefficient of 0.1 to 1.5 K or less.

[0083] Item 14. A sealed pharmaceutical container comprising: a syringe having a tubular barrel having an open end and a closed end opposite the open end, and a needle extending from the closed end and in fluid communication with an interior of the tubular barrel defined by an inner wall of the tubular barrel; and a closure assembly movably disposed within the tubular barrel, the closure assembly having an inner wall and an outer wall opposite the inner wall in at least partial contact with the inner wall of the tubular barrel, the closure assembly including a stopper having a first CTE, a filling member at least partially contained within the stopper and having a second CTE lower than the first CTE, and a plunger coupled to the stopper and extending through the open end of the tubular barrel.

[0084] Item 15. The sealed pharmaceutical container of item 14, wherein the packing member is made from a first material, the first material including at least one of a glass, a crystalline material, a polymer, and a metal.

[0085] Item 16. The sealed pharmaceutical container of item 15, wherein the first material comprises at least one of an oxide, a halide, a nitride, and a chalcogen.

[0086] Item 17. The sealed pharmaceutical container of item 15, wherein the closure is made from a second material, the second material including at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and a polyacrylate elastomer.

[0087] Item 18. The sealed pharmaceutical container of item 17, wherein the second material has a Tg of -200°C to 300°C.

[0088] Item 19. The sealed pharmaceutical container of any of items 14 to 18, wherein the plunger includes a first end provided inside the tubular barrel and a second end opposite the first end provided outside the interior of the tubular barrel, and the first end of the plunger is fixed to the filling member.

[0089] Item 20. The sealed pharmaceutical container of item 19, wherein the filling member has a cavity formed therein.

[0090] Item 21. The sealed pharmaceutical container of item 20, wherein the plunger includes a flange formed on a first end thereof that extends across a cavity formed in the filler member.

[0091] Item 22. The sealed pharmaceutical container of item 20, wherein the first end of the plunger is received within a cavity formed in the filler member.

[0092] Item 23. The sealed pharmaceutical container of any of items 19-22, wherein the bung and the filling member each include a pair of lobes defining one or more recesses, the pair of lobes in contact with the inner wall of the tubular barrel, and the one or more recesses are spaced apart from the inner wall of the tubular barrel.

[0093] Item 24. Tubular cylinder, 0×10 -7 / K or higher and 70×10 -7 24. The sealed pharmaceutical container according to any one of items 14 to 23, which is composed of a composition having a thermal expansion coefficient of 0.1 to 1.5 kPa (1 / K) or less.

[0094] Item 25. When a sealed pharmaceutical container is cooled to the above temperature at a rate of 5°C or less per minute, the helium leak rate is reduced to 1.4 x 10 -6 cm 3 A sealed pharmaceutical container according to any of items 14 to 24, which is maintained at or below 1 / sec.

[0095] Item 26. The sealing assembly reduces the helium leak rate of a sealed drug container to 1.4 x 10 when the sealed drug container is cooled to a temperature of -20°C or less. -6 cm 3 A sealed pharmaceutical container according to any of items 14 to 24, which is maintained at or below 1 / sec.

[0096] Item 27. The sealing assembly shall reduce the helium leak rate of the sealed drug container to 1.4 x 10 when the sealed drug container is cooled to a temperature of -120°C or less. -6 cm 3 A sealed pharmaceutical container according to any of items 14 to 24, which is maintained at or below 1 / sec.

[0097] Item 28. The sealing assembly reduces the helium leak rate of a sealed drug container to 1.4 x 10 when the sealed drug container is cooled to a temperature of -180°C or less. -6 cm 3 A sealed pharmaceutical container according to any of items 14 to 24, which is maintained at or below 1 / sec.

[0098] Item 29. A method of sealing a pharmaceutical container, comprising the steps of: providing a pharmaceutical container including a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange having a back surface extending from the neck, an outer surface extending from the back surface defining an outer diameter of the flange, and an upper sealing surface extending from the outer surface to an inner surface of the pharmaceutical container defining an opening; placing a pharmaceutical composition in the pharmaceutical container; and providing a stopper having a first CTE, the stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening and an insert portion extending into the opening and contacting the inner surface of the flange, and a filler member placed within the stopper, the filler member having a second CTE lower than the first CTE.

[0099] Item 30. The pharmaceutical container further comprises a step of cooling the pharmaceutical container to a temperature of −20° C. or lower, and after cooling the pharmaceutical container, the helium leak rate of the pharmaceutical container is 1.4×10 at said temperature. -6 cm 3 30. The method of claim 29, wherein compression on the upper sealing face is maintained so that compression is equal to or less than 1 / second.

[0100] Item 31. The method of items 29 or 30, wherein the packing member is made from a first material, the first material including at least one of a glass, a crystalline material, a polymer, and a metal.

[0101] Item 32. The method of item 31, wherein the first material is coated with a second material, the second material comprising at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and a polyacrylate elastomer.

[0102] Item 33. The method of item 32, wherein the second material has a Tg of -200°C to 300°C.

[0103] Item 34. The method of any one of Items 29 to 33, wherein the filling member includes a filling body having a body diameter equal to or greater than the opening diameter of the opening of the pharmaceutical container.

[0104] Item 35. The method of item 34, wherein a body passageway is formed extending through an upper surface of the body and a lower surface of the body.

[0105] Item 36. The method of item 35, wherein the filling member includes a filling protrusion that extends at least partially through the opening in the pharmaceutical container and parallel to an inner surface of the pharmaceutical container.

[0106] Item 37. The method of item 36, wherein a protrusion passage is formed extending through an upper surface of the protrusion and a lower surface of the filler protrusion, the filler body and the filler protrusion forming a one-piece monolith structure, and the protrusion passage and the body passage being coaxial with one another.

[0107] Item 38. The method of item 29, wherein the filling member includes a filling protrusion extending at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container, the filling protrusion having a protrusion diameter smaller than an opening diameter of the opening of the pharmaceutical container.

[0108] It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments described herein without departing from the scope of the claimed subject matter. Thus, it is intended that this specification cover modifications and variations of the various embodiments described herein, provided such modifications and variations come within the scope of the claims and their equivalents.

[0109] Preferred embodiments of the present invention will be described below in detail.

[0110] EMBODIMENT 1 In sealed pharmaceutical containers, shoulder, a neck extending from said shoulder; a flange extending from the neck, A back surface extending from the neck portion; an outer surface extending from the back surface and defining an outer diameter of the flange; an upper sealing surface extending between the exterior surface and an interior surface defining an opening in the sealed pharmaceutical container; a flange having 1. A sealing assembly comprising: a plug having a first CTE, the plug including a sealing portion extending over the upper sealing surface of the flange and covering the opening and an insert portion extending into the opening and contacting an inner surface of the flange; a filler member disposed within the plug and having a second CTE lower than the first CTE; 13. A sealed pharmaceutical container comprising:

[0111] EMBODIMENT 2 2. The sealed pharmaceutical container of embodiment 1, wherein the filling member is made from a first material, the first material comprising at least one of a glass, a crystalline material, a polymer, and a metal.

[0112] EMBODIMENT 3 3. The sealed pharmaceutical container of embodiment 2, wherein the first material comprises at least one of an oxide, a halide, a nitride, and a chalcogen.

[0113] EMBODIMENT 4 3. The sealed pharmaceutical container of embodiment 2, wherein the first material is coated with a second material, the second material comprising at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and polyacrylate elastomer.

[0114] EMBODIMENT 5 5. The sealed pharmaceutical container of embodiment 4, wherein the second material has a Tg of -200°C to 300°C.

[0115] EMBODIMENT 6 2. The sealed pharmaceutical container of embodiment 1, wherein the filling member comprises a filling body having a body diameter larger than an opening diameter of the opening of the sealed pharmaceutical container.

[0116] EMBODIMENT 7 7. The sealed pharmaceutical container of embodiment 6, wherein a body passageway is formed that extends through an upper surface of the fill body and a lower surface of the fill body.

[0117] EMBODIMENT 8 8. The sealed pharmaceutical container of embodiment 7, wherein the filling member comprises a filling protrusion extending at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container.

[0118] EMBODIMENT 9 9. The sealed pharmaceutical container of embodiment 8, wherein a protrusion passage is formed that extends through an upper surface of the filling protrusion and a lower surface of the protrusion, the body and the protrusion form a one-piece monolithic structure, and the protrusion passage and the body passage are coaxial with each other.

[0119] EMBODIMENT 10 2. The sealed pharmaceutical container of embodiment 1, wherein the filling member includes a filling protrusion that extends at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container, the filling protrusion having a protrusion diameter that is smaller than an opening diameter of the opening of the sealed pharmaceutical container.

[0120] EMBODIMENT 11 The closure assembly reduces the helium leak rate of the sealed pharmaceutical container to 1.4×10 when the sealed pharmaceutical container is cooled to a temperature of −45° C. or less. -6 cm 3 13. The sealed pharmaceutical container of embodiment 1, wherein the sealed pharmaceutical container maintains a constant temperature for 15 minutes or less.

[0121] EMBODIMENT 12 2. The sealed pharmaceutical container of embodiment 1, wherein the top sealing surface is an angled sealing surface extending at an angle relative to a plane extending through the edge of the opening, such that the distance between the angled sealing surface and the plane increases as the radial distance from the outer surface decreases.

[0122] EMBODIMENT 13 The flange is 0×10 -7 / K or higher and 70×10 -7 2. The sealed pharmaceutical container of embodiment 1, comprising a composition having a coefficient of thermal expansion of no more than 1 / K.

[0123] EMBODIMENT 14 In sealed pharmaceutical containers, 1. A syringe, comprising: a tubular cylinder having an open end and a closed end opposite the open end; a needle extending from the closed end and in fluid communication with an interior of the tubular barrel defined by an interior wall of the tubular barrel; A syringe comprising: a sealing assembly movably disposed within the tubular barrel, a plug having an inner wall and an outer wall opposed to the inner wall in at least partial contact with the inner wall of the tubular barrel, the plug having a first CTE; a filler member at least partially disposed within the plug and having a second CTE lower than the first CTE; a plunger connected to the plug and extending through an open end of the tubular barrel; A sealing assembly comprising: 13. A sealed pharmaceutical container comprising:

[0124] EMBODIMENT 15 15. The sealed pharmaceutical container of embodiment 14, wherein the filling member is made from a first material, the first material comprising at least one of a glass, a crystalline material, a polymer, and a metal.

[0125] EMBODIMENT 16 16. The sealed pharmaceutical container of embodiment 15, wherein the first material comprises at least one of an oxide, a halide, a nitride, and a chalcogen.

[0126] EMBODIMENT 17 16. The sealed pharmaceutical container of embodiment 15, wherein the stopper is made from a second material, the second material comprising at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and a polyacrylate elastomer.

[0127] EMBODIMENT 18 18. The sealed pharmaceutical container of embodiment 17, wherein the second material has a Tg of -200°C to 300°C.

[0128] EMBODIMENT 19 15. The sealed pharmaceutical container of embodiment 14, wherein the plunger includes a first end disposed within the interior of the tubular barrel and a second end disposed outside the interior of the tubular barrel opposite the first end, the first end of the plunger being secured to the filling member.

[0129] EMBODIMENT 20 20. The sealed pharmaceutical container of embodiment 19, wherein the filling member has a cavity formed therein.

[0130] EMBODIMENT 21 21. The sealed pharmaceutical container of embodiment 20, wherein the plunger includes a flange formed at a first end thereof that extends across the cavity formed in the filler member.

[0131] EMBODIMENT 22 21. The sealed pharmaceutical container of embodiment 20, wherein a first end of the plunger is received within the cavity formed in the filling member.

[0132] EMBODIMENT 23 20. The sealed pharmaceutical container of embodiment 19, wherein the bung and the filling member each include a pair of lobes defining one or more recesses, the pair of lobes in contact with an inner wall of the tubular barrel, and the one or more recesses are spaced apart from the inner wall of the tubular barrel.

[0133] EMBODIMENT 24 The tubular cylinder is 0×10 -7 / K or higher and 70×10 -7 15. The sealed pharmaceutical container of embodiment 14, comprised of a composition having a thermal expansion coefficient of less than or equal to 1 / K.

[0134] EMBODIMENT 25 When the sealed pharmaceutical container is cooled to the temperature at a rate of 5° C. per minute or less, the helium leak rate is reduced to 1.4×10 -6 cm 3 15. The sealed pharmaceutical container of embodiment 14, wherein the temperature is maintained at 0.5 to 1.5° C. for 1 second or less.

[0135] EMBODIMENT 26 The closure assembly reduces the helium leak rate of the sealed pharmaceutical container to 1.4×10 when the sealed pharmaceutical container is cooled to a temperature of −20° C. or less. -6 cm 3 15. The sealed pharmaceutical container of embodiment 14, wherein the temperature is maintained at 0.5 to 1.5° C. for 1 second or less.

[0136] EMBODIMENT 27 The closure assembly reduces the helium leak rate of the sealed pharmaceutical container to 1.4×10 when the sealed pharmaceutical container is cooled to a temperature of −120° C. or less. -6 cm 3 15. The sealed pharmaceutical container of embodiment 14, wherein the temperature is maintained at 0.5 to 1.5° C. for 1 second or less.

[0137] EMBODIMENT 28 The closure assembly reduces the helium leak rate of the sealed pharmaceutical container to 1.4×10 when the sealed pharmaceutical container is cooled to a temperature of −180° C. or less. -6 cm 315. The sealed pharmaceutical container of embodiment 14, wherein the temperature is maintained at 0.5 to 1.5° C. for 1 second or less.

[0138] EMBODIMENT 29 1. A method for sealing a pharmaceutical container, comprising the steps of: A pharmaceutical container comprising a shoulder, a neck extending from the shoulder, and a flange extending from the neck, A back surface extending from the neck portion; an outer surface extending from the back surface and defining an outer diameter of the flange; an upper sealing surface extending from the exterior surface to an interior surface of the pharmaceutical container defining an opening; providing a pharmaceutical container including a flange having placing a pharmaceutical composition in said pharmaceutical container; and providing a plug having a first CTE, the plug including a sealing portion extending over an upper sealing surface of the flange and covering the opening and an insert portion extending into the opening and contacting an inner surface of the flange; and a filler member disposed within the plug, the filler member having a second CTE lower than the first CTE; The method includes:

[0139] EMBODIMENT 30 and cooling the pharmaceutical container to a temperature of −20° C. or less, wherein after cooling the pharmaceutical container, the pharmaceutical container has a helium leak rate of 1.4×10 at said temperature. -6 cm 3 30. The method of embodiment 29, wherein compression on the upper sealing surface is maintained such that compression is equal to or less than 1 / second.

[0140] EMBODIMENT 31 30. The method of embodiment 29, wherein the filler member is made from a first material, the first material comprising at least one of a glass, a crystalline material, a polymer, and a metal.

[0141] EMBODIMENT 32 32. The method of embodiment 31, wherein the first material is coated with a second material, the second material comprising at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and polyacrylate elastomer.

[0142] EMBODIMENT 33 33. The method of embodiment 32, wherein the second material has a Tg of -200°C to 300°C.

[0143] EMBODIMENT 34 30. The method of embodiment 29, wherein the filling member comprises a filling body having a body diameter equal to or greater than an opening diameter of the opening of the pharmaceutical container.

[0144] EMBODIMENT 35 35. The method of embodiment 34, wherein a body passageway is formed extending through an upper surface of the body and a lower surface of the body.

[0145] EMBODIMENT 36 36. The method of embodiment 35, wherein the filling member comprises a filling protrusion extending at least partially through an opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container.

[0146] EMBODIMENT 37 37. The method of embodiment 36, wherein a protrusion passage is formed extending through an upper surface of the protrusion and a lower surface of the filler protrusion, the filler body and the filler protrusion form a one-piece monolith structure, and the protrusion passage and the body passage are coaxial with one another.

[0147] EMBODIMENT 38 30. The method of embodiment 29, wherein the filling member includes a filling protrusion extending at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container, the filling protrusion having a protrusion diameter smaller than an opening diameter of the opening of the pharmaceutical container. [Explanation of symbols]

[0148] 100, 200, 300, 400, 500, 600, 700 Pharmaceutical containers 102 Glass container 104, 202, 302, 404, 504, 604, 704 Sealing Assembly 105 Aperture 106, 418, 718 Stopper 107, 204, 304, 420, 520, 620, 720 Filling material 108 Metal-containing cap 109 Bottom part 110 Upper sealing surface 112 Main unit 114 Inner surface of glass container 115 Torso 116 Outer surface of glass container 117 Insertion 118 Internal volume 119 Seal part 120 Wall section 121, 306 Filling 122 Floor part 126 Flange 128 Neck 130 Shoulder 136 Outer surface of flange 140 Inclined seal surface 150 Angle of inclined seal surface relative to plane 152 plane 154 End of opening 206, 308 Filling protrusion 306 Filling 402 Syringe 406 Tubular tube 408 Open End 410 Closed end 414 Inner wall of tubular cylinder 416 needles 422, 522, 622, 722 Plunger

Claims

1. In sealed pharmaceutical containers, shoulder, a neck extending from the shoulder; a flange extending from the neck, a back surface extending from the neck portion; an outer surface extending from the rear surface and defining an outer diameter of the flange; an upper sealing surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container; a flange having 1. A sealing assembly comprising: a plug having a first CTE, the plug including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and an insert portion extending into the opening and contacting an inner surface of the flange; a filler member disposed within the plug, the filler member having a second CTE lower than the first CTE; 1. A sealed pharmaceutical container comprising:

2. 10. The sealed pharmaceutical container of claim 1, wherein the filler member is made from a first material, the first material comprising at least one of a glass, a crystalline material, a polymer, and a metal.

3. 3. The sealed pharmaceutical container of claim 2, wherein the first material comprises at least one of an oxide, a halide, a nitride, and a chalcogen.

4. 3. The sealed pharmaceutical container of claim 2, wherein the first material is coated with a second material, the second material comprising at least one of butyl rubber, nitrile rubber, fluororubber, butyl silicone rubber, and a polyacrylate elastomer.

5. 5. The sealed pharmaceutical container of claim 4, wherein the second material has a Tg of -200°C to 300°C.

6. 2. The sealed pharmaceutical container of claim 1, wherein the filling member comprises a filler body having a body diameter larger than the opening diameter of the opening of the sealed pharmaceutical container.

7. 7. The sealed pharmaceutical container of claim 6, further comprising a body passageway formed therein that extends through an upper surface of the filler body and a lower surface of the filler body.

8. 8. The sealed pharmaceutical container of claim 7, wherein the filler member includes a filler projection extending at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container.

9. 9. The sealed pharmaceutical container of claim 8, wherein a protrusion passage is formed that extends through an upper surface of the filling protrusion and a lower surface of the protrusion, the body and the protrusion form a one-piece monolithic structure, and the protrusion passage and the body passage are coaxial with each other.

10. 10. The sealed pharmaceutical container of claim 1, wherein the filling member includes a filling protrusion extending at least partially through the opening of the pharmaceutical container and parallel to an inner surface of the pharmaceutical container, the filling protrusion having a protrusion diameter smaller than an opening diameter of the opening of the sealed pharmaceutical container.

11. The sealing assembly reduces the helium leak rate of the sealed pharmaceutical container to 1.4 x 10 when the sealed pharmaceutical container is cooled to a temperature of -45°C or less. －６ cm ３ 10. The sealed pharmaceutical container of claim 1, wherein the temperature is maintained at 100°C / sec or less.

12. 2. The sealed pharmaceutical container of claim 1, wherein the upper sealing surface is an angled sealing surface that extends at an angle relative to a plane that extends through the edge of the opening, such that the distance between the angled sealing surface and the plane increases as the radial distance from the outer surface decreases.

13. The flange is 0x10 －７ / K or more and 70 x 10 －７ 2. The sealed pharmaceutical container of claim 1, which is made from a composition having a thermal expansion coefficient of 0.1 / K or less.

14. In sealed pharmaceutical containers, A syringe, a tubular tube having an open end and a closed end opposite the open end; a needle extending from the closed end and in fluid communication with an interior of the tubular barrel defined by an inner wall thereof; a syringe comprising: a sealing assembly movably disposed within the tubular barrel, a plug having an inner wall and an outer wall opposite the inner wall in at least partial contact with the inner wall of the tubular barrel, the plug having a first CTE; a filler member at least partially disposed within the plug and having a second CTE lower than the first CTE; a plunger connected to the stopper and extending through the open end of the tubular barrel; a sealing assembly comprising:

1. A sealed pharmaceutical container comprising:

15. The sealed pharmaceutical container of claim 14, wherein the sealing assembly maintains a helium leak rate of the sealed pharmaceutical container of 1.4 x 10-6 cm3 / sec or less when the sealed pharmaceutical container is cooled to a temperature of -20°C or less.

16. The sealed pharmaceutical container of claim 15, wherein the sealed pharmaceutical container maintains a helium leak rate of 1.4 x 10-6 cm3 / sec or less when cooled to said temperature at a rate of 5°C per minute or less.

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