Method for storing pharmaceutical composition at-80 DEG C or less and glass container

Abstract

The present invention relates to a method for storing a pharmaceutical composition at a temperature of-80 DEG C or less comprising a defined cooling rate and a glass container suitable for this purpose comprising a coating having a crystallization temperature range overlapping a melting temperature range.

Description

Technical Field

[0001] The present invention relates to a method for storing a pharmaceutical composition at -80 °C or lower temperature, which includes a defined cooling rate; and a glass container suitable for this purpose, the glass container including a coating whose crystallization temperature range overlaps with the melting temperature range. Background Art

[0002] Glass containers for storing and delivering pharmaceutical compositions are known in the prior art. Such containers generally mainly consist of a stopper for eluting the contents in the container through an outlet and a closure. The stopper must slide within the container but provide a tight seal so that the composition can be safely stored even for a long time.

[0003] However, if a drug container of such a pre-filled pharmaceutical composition is stored at a low temperature, there is a risk of seal failure during the cooling or thawing process or during storage and transportation. The safe storage and transportation of many drugs such as mRNA vaccines require a temperature of -80 °C or lower, which is usually achieved by using dry ice with a sublimation temperature of -80 °C. During transportation, the temperature may reach -96 °C on time. Therefore, it is necessary to ensure the container closure integrity (CCI) at -80 °C for a long time and at -96 °C for a short time.

[0004] Therefore, the object of the present invention is to provide a glass container that overcomes the problems of the prior art and can be used to store a pharmaceutical composition at -80 °C or lower temperature. Another object of the present invention is to provide a method for storing a pharmaceutical composition. Summary of the Invention

[0005] In a first aspect, the present invention relates to a method for storing a pharmaceutical composition at -80 °C or lower temperature, including: - providing a glass container, the glass container including a hollow cylinder having at least one open end and at least one stopper closing the at least one open end, wherein at least a part of the inner surface of the glass container includes a coating, the coating having a crystallization temperature range and a melting temperature range determined by differential scanning calorimetry at a temperature change rate of 10 °C / min, wherein the crystallization temperature range overlaps with the melting temperature range at a temperature of -75 °C to -100 °C, especially at -80 °C; - filling the pharmaceutical composition into the glass container; and - cooling the glass container at a cooling rate of ≤6.0 °C / min in the range of -50 °C to -80 °C, and cooling the glass container at a cooling rate of ≤5.0 °C / min in the range of -80 °C to -96 °C.

[0006] In a second aspect, the present invention relates to a glass container for storing a pharmaceutical composition at a temperature of -80 °C or lower, comprising a hollow cylinder having at least one open end and at least one stopper for closing the at least one open end, wherein at least a portion of the inner surface of the glass container comprises a coating having a crystallization temperature range and a melting temperature range determined by differential scanning calorimetry at a temperature change rate of 10 °C / min, wherein, - the crystallization temperature range and the melting temperature range overlap at a temperature of -75 °C to -100 °C, especially at -80 °C, and - the thickness of the coating is 400.0 nm or more, or 800.0 nm or more, and / or 2000.0 nm or less, or 1500.0 nm or less, and - when the glass container is cooled at a cooling rate of ≤ 6.0 °C / min in the range of -50 °C to -80 °C and at a cooling rate of ≤ 5.0 °C / min in the range of -80 °C to -96 °C, the distance change between the outer surface of the stopper and the inner surface of the glass container including the coating does not exceed 1.0% at a temperature between the glass transition temperature of the coating and the storage temperature.

[0007] The distance here refers to the distance between the uncoated glass surface and the stopper surface. Therefore, it corresponds to the space occupied by the coating when the seal is intact, i.e., when there are no voids. In addition, the change in this distance is also a measure of the stress applied to the coating during the cooling process. Description of the Drawings

[0008] Figure 1 Is a glass container with a coating.

[0009] Figure 2 Is an illustration of the container closure integrity test for the entry of ethanol-modified dye.

[0010] Figure 3 Is a DSC graph of the coating according to the present invention.

[0011] Figure 4 Is a DSC graph of the coating according to the present invention.

[0012] Figure 5 Is a DSC graph of a prior art coating.

[0013] Figure 6 Is a DSC graph of a prior art coating.

[0014] Figure 7 Is a TMA analysis graph of the coating according to the present invention.

[0015] Figure 8 TMA analysis chart of the coating according to the present invention. Detailed implementation mode

[0016] The detailed description of the present invention relates to various aspects described in the summary of the invention of the present invention. Any feature of the embodiments described below may relate to a method for storing a pharmaceutical composition at a temperature of -80°C or lower and a glass container for this purpose.

[0017] In this application, room temperature is preferably a temperature of 293.15 K, especially under 1013.25 hPa.

[0018] The glass container can be any type of container including a vial, a syringe or a cartridge.

[0019] In one embodiment, the glass container is a pre-filled syringe or cartridge, which is very advantageous because in this way the pharmaceutical composition can be directly stored in the syringe or cartridge at a low temperature. This makes it very easy to handle the composition because the syringe or cartridge is pre-filled and can be used for administration without transferring the composition to a different container. More importantly, this is even feasible if the storage temperature of the composition is lower than the temperature at which the composition expands.

[0020] Exemplary container

[0021] Referring to the accompanying drawings, Figure 1 There is shown a glass container 1, which in an exemplary embodiment is a syringe 3 for administering a drug or a cosmetic. The syringe 3 is made of glass and includes a glass wall 5 surrounding the lumen. The container includes a hollow cylinder 7 and a Nestling Surface 18 on which, for example, an injection needle or a cap can be placed. A stopper 12 is inserted into the column part and is axially slidable by the pressure on a push rod 13. The column part has a flange 15 for operating purposes at the end of the introduction opening for the stopper 12.

[0022] The glass container 1 is provided with a coating 10 on its inner surface (specifically, on the inner surface of the hollow cylinder 7 here). In this example, the coating 10 covers the area of the inner surface of the hollow cylinder 7 on which the stopper 12 can slide when the syringe is emptied or used for aspiration.

[0023] The present invention is not particularly limited to the volume of the container. In one embodiment, the volume enclosed by the hollow cylinder is at least 0.10 ml, at least 0.50 ml, or at least 1.00 ml. Optionally, the volume can be up to 1000 ml, up to 200 ml, up to 100 ml, or up to 25 ml. In an embodiment, the volume ranges from 0.1 ml to 1000 ml, 0.50 ml to 200 ml, or 1.00 ml to 25 ml. In one embodiment, the volume enclosed by the hollow cylinder is less than 10.0 ml.

[0024] The hollow cylinder has a lumen surrounded by a glass wall, wherein the wall thickness of the glass wall can be at least 0.50 mm, at least 0.80 mm, or at least 1.00 mm. Optionally, the range of the glass wall thickness can be up to 10.0 mm, up to 8.0 mm, up to 5.0 mm, or up to 4.0 mm. In an embodiment, the glass wall thickness is from 0.50 mm to 10.0 mm, 0.80 mm to 8.0 mm, or 1.00 mm to 4.00 mm. As used herein, the term "wall thickness" describes the shortest distance between the inner surface and the outer surface of the hollow cylinder.

[0025] As used herein, the term "outer diameter" refers to the maximum distance between two points on the outer surface of the hollow cylinder, wherein the two points are connected by a straight line that is perpendicular and intersects the longitudinal axis of the hollow cylinder. As used herein, the term "inner diameter" refers to the maximum distance between two points on the inner surface of the hollow cylinder, wherein the two points are connected by a straight line that is perpendicular and intersects the longitudinal axis of the hollow cylinder.

[0026] The hollow cylinder of the container can have a substantially constant inner diameter. This means that the total inner diameter variation is small. "Total inner diameter variation" refers to the difference between the maximum inner diameter and the minimum inner diameter of the same hollow cylinder. For example, the total inner diameter variation of the hollow cylinder can be less than 200 μm, less than 100 μm, less than 50 μm, or less than 25 μm. Optionally, the total inner diameter variation can be 0.01 μm or greater, 0.10 μm or greater, or 1.0 μm or greater.

[0027] Cooling procedure

[0028] The inventors have found that the key factors for achieving container closure integrity (CCI) of glass containers at -80 °C or lower temperatures are the cooling procedures and container configurations applicable in this regard. Although certain siloxane-based coatings have been proven to be suitable for achieving CCI at temperatures of -60 °C and below, they face CCI problems at temperatures of -80 °C and below, especially at a temperature of -96 °C. Further studies on the sealing between the stopper and the glass container through the coating have shown that during the cooling process, different forces act on the coating that loses elasticity at such low temperatures, resulting in defects in the coating. The different thermal expansion or contraction responses of the components of the system (i.e., the rubber of the stopper, the glass of the container, the coating components, and the pharmaceutical composition) generate axial and radial forces on the coating, and when these forces are unbalanced, the embrittled coating will rupture. The elasticity of the stopper and / or the coating determines the container closure integrity of the container under dynamic conditions. Once the glass transition temperatures of the two materials intersect, the system will approach its equilibrium state as much as possible, that is, no further force should be applied to the stopper / coating interface. If the stopper moves, the embrittled coating will be damaged, and thus CCI can no longer be maintained.

[0029] It has been found that the solution to this problem is a specific cooling procedure, in which the cooling rate is ≤ 6.0 °C / min in the range of -50 °C to -80 °C and ≤ 5.0 °C / min in the range of -80 °C to -96 °C. Above -50 °C, the cooling rate can be set to a higher rate, but it must be ensured that when the temperature exceeds -50 °C, the temperature will drop at a rate of ≤ 6.0 °C / min. That is to say, the "overshoot" of the temperature must be avoided by timely reducing the cooling rate. Preferably, a cooling rate of ≤ 6.0 °C / min is used throughout the room temperature range, that is, 20 °C to -80 °C. Using these rates, an optimal balance can be achieved among the shrinkage and relaxation of the stopper rubber, the shrinkage of the coating and the glass container, and the expansion of the filling medium. The coating used in this procedure must have a crystalline temperature range and a melting temperature range that overlap at a temperature of -75 °C to -100 °C, especially at a temperature of -80 °C. On the one hand, such a coating can maintain CCI at the desired temperature when cooled at these cooling rates. On the other hand, the cooling procedure is customized according to the applicable temperature range of these properties of the coating.

[0030] Therefore, the inventors have overcome the prevalent bias in the prior art that glass containers, especially those in the form of prefilled syringes, with silicone oil as a lubricant cannot maintain CCI at temperatures below about -60 °C. This bias is attributed to the fact that silicone oil reaches its glass transition temperature at about -60 °C. In addition, the known dilemma of glass containers is that there is a relatively large difference in the coefficient of thermal expansion between the container material and the stopper material, which is usually a rubber material, compared with polymer containers. The lower the temperature becomes, the greater the stress generated on the sealing surface.

[0031] In an embodiment, the cooled glass container may maintain a constant temperature within a range of 1.0 °C to 5.0 °C above the glass transition temperature of both the stopper and the coating for at least 1.0 minute, or at least 2.0 minutes, or at least 3.0 minutes, or at least 4.0 minutes, or at least 5.0 minutes.

[0032] By introducing these temperature plateaus slightly above, especially the critical glass transition temperature, in the cooling process, the system can reach equilibrium before crossing these temperature plateaus. This can help further reduce the forces occurring on the coating.

[0033] Coating

[0034] The coating may be disposed on the inner surface of the hollow cylinder of the glass container and / or on one or more other surfaces of the glass container, including the surface of the syringe tip, such as the nested surface on the syringe tip side. At least a portion of the inner surface of the glass container includes the coating. The coatings and coating compositions described herein help achieve a tight seal at low temperatures.

[0035] The coating may be amorphous or partially crystalline at 20 °C. Optionally, the coating has a crystallinity of less than 20% (v / v) at 20 °C.

[0036] In an embodiment, the glass transition temperature of the coating may be -60 °C or below, or -70 °C or below, or -75 °C or below, or -80 °C or below; and / or the glass transition temperature of the stopper may be -80 °C or below, or -85 °C or below, or -90 °C or below, or -95 °C or below, or -100 °C or below, or below the storage temperature.

[0037] Optionally, the glass transition temperature of the coating may be -200 °C or higher, -150 °C or higher, -120 °C or higher, -100 °C or higher. Differential scanning calorimetry (DSC) or thermomechanical analysis (TMA) can be used to measure the glass transition temperature. Exemplary ways to determine the glass transition temperature of the coating include thermomechanical analysis in the expansion mode, such as using a Q400 thermomechanical analyzer from TA Instruments. According to the present invention, samples are prepared by coating the glass container, scraping off the coating with a scalpel, and performing thermomechanical analysis in the expansion mode (i.e., measuring the expansion or contraction of the sample as a function of temperature). In an embodiment, the glass transition temperature of the coating is in the range of -200 °C to -60 °C, -150 °C to -70 °C, -120 °C to -75 °C, or -100 °C to -80 °C. In one embodiment, the glass transition temperature is -90 °C to -80 °C.

[0038] In an embodiment of the present invention, the coating has a crystallization temperature range and a melting temperature range determined by differential scanning calorimetry at a temperature change rate of 10 °C / min, wherein the crystallization temperature range overlaps with the melting temperature range at -75 °C to -100 °C, particularly at -80 °C. For example, DSC can be performed in the temperature range of -120 °C to -60 °C. A suitable instrument is DSC Q2000 (TA Instruments).

[0039] Without wishing to be bound by this theory, the inventors hypothesize that within the overlapping range, both the crystalline and molten portions of the coating are present. This is believed to impart to the coating properties in terms of mechanical resistance and elasticity required to form a tight seal at low temperatures. The crystallization temperature range and the melting temperature range are considered to overlap if the crystallization and melting peak areas extend into the same temperature range. For example, crystallization can start at -55 °C and end at -95 °C, i.e., the range of the exothermic crystallization peak area can be from -55 °C to -95 °C; melting can start at -90 °C and end at -40 °C, i.e., the range of the endothermic melting peak area can be from -90 °C to -40 °C. In this example, the overlapping temperature range is from -90 °C to -55 °C. This example meets the requirement of overlapping at -75 °C to -100 °C because there is an overlap at at least one temperature within the indicated range.

[0040] In an embodiment, the thickness of the coating can be 400.0 nm or greater, or 800.0 nm or greater, and / or 2000.0 nm or less, or 1500.0 nm or less. In some embodiments, the thickness of the coating can be 400.0 nm or greater, or 500.0 nm or greater, 600.0 nm or greater, or 700.0 nm or greater, 800.0 nm or greater, or 900.0 nm or greater, or 1000.0 nm or greater. In some embodiments, the thickness of the coating can be 2000.0 nm or less, or 1900.0 nm or less, or 1800.0 nm or less, or 1700.0 nm or less, or 1600.0 nm or less, or 1500.0 nm or less, or 1400.0 nm or less. Optionally, the thickness of the coating can be in the range of 400.0 nm to 2000.0 nm, or 500.0 nm to 1900.0 nm, or 600.0 nm to 1800.0 nm, or 700.0 nm to 1700.0 nm, or 800.0 nm to 1600.0 nm, or 900.0 nm to 1500.0 nm, or 1000.0 nm to 1400.0 nm.

[0041] The inventors have found that for achieving CCI at -80 °C or lower temperatures, a coating of a certain minimum thickness is preferred. The thickness must be sufficient to seal the contact surface between the glass container and the stopper during freezing and thawing processes, as well as during transportation and storage. For this purpose, there must be sufficient material to fill the gap between the glass wall and the stopper, which increases with decreasing temperature due to the different coefficients of thermal expansion of the corresponding glass and rubber materials. However, if the coating is too thick, difficulties can arise when the elasticity decreases during temperature reduction, and shear forces can occur on the sealing area due to shrinkage or expansion of the container and filling and / or plunger movement. Therefore, the thickness of the coating should be optimized for the corresponding container - coating - stopper configuration to extend the storage and transportation times and temperatures to their longest and deepest values, respectively.

[0042] The coating can comprise one or more silicone polymers. A "silicone polymer" is a polymeric material composed of monomer units that include both silicon (Si) and carbon (C) atoms. An example of a silicone polymer is polysiloxane. In an embodiment, the coating comprises one or more polysiloxane structural units. A "polysiloxane structural unit" can refer to a polysiloxane structure within a larger molecule (e.g., covalently bonded to a larger molecule or a part of a larger molecule) or a polysiloxane molecule itself. For example, a cross-linked polysiloxane structural unit is part of a polymer network (covalently linked to), while a non-cross-linked polysiloxane structural unit exists as a molecule in the coating and is not covalently linked to other molecules in the coating. Thus, the coating can comprise cross-linked and / or non-cross-linked polysiloxane structural units. In this context, "cross-linked" means that the polysiloxane structural unit is covalently linked to a polymer network. Specifically, the term "cross-linked" includes the preferred case where polysiloxane structures are covalently linked to other polysiloxane structures, for example, through the polymer backbone. Optionally, due to a hydrosilylation reaction, cross-linked polysiloxane structural units are covalently bonded to other polysiloxane structures. The polymer backbone can be formed, for example, by polymerizing a polysiloxane bearing polymerizable functional groups such as vinyl groups. In contrast, "non-cross-linked" means that the polysiloxane is not covalently linked to other polysiloxane structures through the polymer backbone, or preferably, is not covalently linked to other polysiloxanes in the coating at all.

[0043] In one embodiment, the crosslinked polysiloxane structural units are crosslinked via one or more (e.g., two) end groups. The end groups can be selected from vinyl, propenyl, methacrylyl, styrene, and combinations thereof. In one embodiment, the coating comprises the hydrosilylation reaction product of a crosslinkable polysiloxane compound and a crosslinking polysiloxane compound, such as a vinyl polysiloxane compound and a polysiloxane having at least two Si-H groups. The crosslinked polysiloxane can crosslink with the crosslinkable polysiloxane by reacting its multiple Si-H groups with the vinyl groups of the crosslinkable polysiloxane. The reaction can be catalyzed by a metal such as Pt, Pd, Cu, Ti, or V. Preferably, the reaction can be platinum-catalyzed.

[0044] In the present invention, "polysiloxane" or "polysiloxane structural unit" can refer to polyalkylsiloxane structural units, such as polydialkylsiloxane structural units. Optionally, one or more of the alkyl groups in the polyalkylsiloxane or polydialkylsiloxane are independently selected from branched or unbranched C1 to C8 alkyl groups. The alkyl group can be a straight-chain alkyl group. For example, the alkyl group can be independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. Preferably, the alkyl group is independently selected from methyl and ethyl.

[0045] In an embodiment, the coating can comprise one or more crosslinked polysiloxane structural units and one or more non-crosslinked polysiloxane structural units, wherein the weight ratio of the crosslinked polysiloxane structural units to the non-crosslinked polysiloxane structural units in the coating is less than 3.00, optionally at least 0.40.

[0046] Optionally, the weight ratio of the crosslinked polysiloxane structural units to the non-crosslinked polysiloxane structural units in the coating is less than 3.00, less than 2.50, less than 1.80, or less than 1.20. The weight ratio of the crosslinked polysiloxane structural units to the non-crosslinked polysiloxane structural units in the coating can be at least 0.40, at least 0.60, or at least 0.70. In an embodiment, the ratio ranges from 0.40 to 3.00, 0.60 to 2.50, or 0.70 to 1.80. The non-crosslinked polysiloxane structural units can contribute to achieving the desired elasticity and low-temperature sealing function, which is preferred for the methods and containers of the present invention.

[0047] Non-crosslinked polysiloxane structural units can contribute to achieving the desired elasticity and low-temperature sealing function, which is preferred for the methods and containers of the present invention. The inventors believe that the crosslinked polysiloxane provides a polymer network in which the non-crosslinked polysiloxane remains embedded, resulting in a hybrid coating structure that combines the properties of the cured polymer network and the liquid silicone oil. This is believed to contribute to achieving a tight seal at low temperatures.

[0048] In one embodiment, the coating can include both crosslinked polydialkylsiloxane structural units and non-crosslinked polysiloxane structural units. Specifically, the coating can include crosslinked polydialkylsiloxane structural units and non-crosslinked polysiloxane structural units, where the non-crosslinked polysiloxane structural units can be one or more silicone oils, i.e., polydialkylsiloxane structural units, such as polydimethylsiloxane silicone oil.

[0049] The coating can include more than one type (e.g., at least two types or at least three types) of non-crosslinked polysiloxane structural units. The viscosities of these types can be different. In an embodiment, the coating can include at least two non-crosslinked polysiloxane structural units with different viscosities. In some embodiments, the coating includes a high-viscosity non-crosslinked polysiloxane structural unit with a viscosity greater than 10000 cSt and / or a low-viscosity non-crosslinked siloxane structural unit with a viscosity of 10000 cSt or lower. The viscosity can be measured using a coaxial cylinder system according to DIN EN ISO 3219:1993 at 23 °C and a shear rate of 10 s -1 . Optionally, the high-viscosity non-crosslinked polysiloxane structural unit has a viscosity of at least 15000 cSt, and / or the low-viscosity non-crosslinked polysiloxane structural unit has a viscosity of 5000 cSt or lower.

[0050] In one embodiment, the coating includes a high-viscosity non-crosslinked polysiloxane structural unit, but does not necessarily include a low-viscosity non-crosslinked polysiloxane structural unit.

[0051] The weight ratio (mass 高 : mass 低 ) of the low-viscosity non-crosslinked polysiloxane structural unit to the high-viscosity non-crosslinked polysiloxane structural unit can be at least 0.10, at least 0.50, at least 1.00, at least 1.50, or at least 2.00. In some embodiments, the range of this ratio can be up to 5.00, up to 4.00, or up to 3.00. For example, the weight ratio of the low-viscosity non-crosslinked polysiloxane structural unit to the high-viscosity non-crosslinked polysiloxane structural unit can be in the range of 0.10 to 5.00, 0.50 to 4.00, or 1.00 to 3.00.

[0052] The crosslinked polysiloxane structural unit, the low-viscosity non-crosslinked polysiloxane structural unit, and / or the high-viscosity non-crosslinked polysiloxane structural unit may comprise or consist of dialkylsiloxane monomer units (especially dimethylsiloxane monomer units).

[0053] Optionally, the low-viscosity non-crosslinked polysiloxane structural unit has a weight-average molecular weight of 1200 to 30000 g / mol, and / or the high-viscosity non-crosslinked polysiloxane structural unit has a weight-average molecular weight of 15000 to 300000 g / mol. In one embodiment, the weight-average molecular weight of the high-viscosity non-crosslinked polysiloxane structural unit is 32000 to 210000 g / mol, or 100000 to 150000 g / mol. In one embodiment, the weight-average molecular weight of the low-viscosity non-crosslinked polysiloxane structural unit is 5000 to 25000 g / mol, or 10000 to 20000 g / mol.

[0054] In an embodiment, the low-viscosity non-crosslinked polysiloxane structural unit has a weight-average molecular weight of at least 1200 g / mol, at least 5000 g / mol, or at least 10000 g / mol. The range of the weight-average molecular weight can be up to 30000 g / mol, 25000 g / mol, or up to 20000 g / mol.

[0055] In an embodiment, the high-viscosity non-crosslinked polysiloxane structural unit has a weight-average molecular weight of at least 15000 g / mol, at least 32000 g / mol, or at least 100000 g / mol. The range of the weight-average molecular weight can be up to 300000 g / mol, up to 210000 g / mol, or up to 150000 g / mol.

[0056] Using polystyrene standards as a reference and toluene as an eluent, the weight-average molecular weight can be determined by gel permeation chromatography (GPC) according to DIN EN ISO 13885-1:2021-11.

[0057] In an embodiment, the coating composition may have the following components by weight percentage: One or more crosslinkable polysiloxane compounds 3.0％～20.0％ One or more non-crosslinkable polysiloxane compounds 2.0％～15.0％ One or more crosslinked polysiloxane compounds 0.10％～1.50％ One or more catalysts 0.03％～0.50％ One or more diluents 65.0％～92.0％

[0058] In an embodiment, the coating composition may have the following components by weight percentage:

[0059] In an embodiment, the coating composition may have the following components by weight percentage:

[0060] Without wishing to be bound by this theory, the inventors considered the curing temperature of the coating composition related to achieving a tight seal. The coating can be cured at a curing temperature below 150 °C, below 125 °C, or below 110 °C. Excessively high curing temperatures may result in a coating with low elasticity. On the other hand, excessively low curing temperatures may also be insufficient to obtain good sealing performance. Thus, in an embodiment, the curing temperature can be 50 °C or higher, 60 °C or higher, or 70 °C or higher. It is noted that the curing temperature is the effective temperature of the coating composition. It should not be confused with the nominal oven temperature. The oven temperature may be much higher than the curing temperature because, during the curing time, there may not be enough time for the entire oven temperature to reach equilibrium at the nominal temperature. Optionally, the coating can be cured at 50 °C to below 150 °C, 60 °C to below 125 °C, or 70 °C to below 110 °C. A preferred range is 50 °C to <110 °C.

[0061] In an embodiment, a coating can be obtained by applying the coating composition disclosed herein to at least a portion of the surface of a glass container (e.g., the inner surface and / or the nested surface), and curing the coating composition on the surface, wherein the curing temperature of the coating composition is below 150 °C, particularly between 50 °C and <110 °C.

[0062] In an embodiment, the coating on the glass container can be cured at a temperature below 150 °C, or below 125 °C, and / or 50 °C or higher, or 60 °C or higher.

[0063] The inventors found that both the coating thickness and the curing temperature affect the sealing performance at very low temperatures. In particular, the curing temperature should not be too high to avoid unwanted chemical reactions, such as overcrosslinking or polymerization. In some cases, coatings cured at very high temperatures do not have sufficient elasticity at low temperatures to maintain a tight seal. Additionally, the sliding force increases at high curing temperatures.

[0064] Optionally, the curing temperature can be maintained for at least 10 seconds, at least 30 seconds, at least 45 seconds, or at least 60 seconds. In an embodiment, the curing temperature is maintained for at most 3000 seconds, at most 300 seconds, or at most 180 seconds. Prolonged curing time at high temperatures may impair the elasticity and the sliding force.

[0065] Optionally, the coating can be used without a separate curing step. Since glass containers are typically sterilized at high temperatures before assembly with the stopper, this temperature treatment can be used to simultaneously cure the coating on the glass surface. When using this option, the curing temperature of the coating will generally be closer to the lower limit of the above range. The inventors found that this combined sterilization and curing step does not result in adverse consequences regarding CCI compared to a separate curing step using the same curing temperature.

[0066] For a proper sealing effect, it is generally sufficient to apply the coating only to the areas that need to be tightly sealed, namely the contact area between the inner surface and the plug, and / or the contact area between the nested surface and the cap. The coating can be arranged on at least 25% or at least 50% (by area) of the inner surface of the hollow cylinder. However, the coating can also have a beneficial effect on the sliding properties of the plug on the inner surface of the hollow cylinder. Thus, in some embodiments, the coating can be arranged on at least 65% or at least 85% (by area) of the inner surface of the hollow cylinder. Optionally, the coating can be arranged on at least 90% or substantially the entire inner surface of the hollow cylinder. Alternatively or additionally, the coating can be arranged on at least 65% or at least 85% (by area) of the nested surface of the glass container. Optionally, the coating can be arranged on at least 90% or substantially the entire nested surface.

[0067] Plug

[0068] The plug has a body, which can have at least one annular protrusion and a circumferential surface. The plug can also have at least two annular protrusions. In one embodiment, the plug can have one to five annular protrusions, for example, two to four annular protrusions. In a specific embodiment, the plug can have one, two, three, four or five annular protrusions.

[0069] The "circumferential surface" means the surface of the plug that faces the inner surface of the hollow cylinder when the plug is placed in the hollow cylinder. The circumferential surface includes the surfaces of any annular protrusions. If the plug is coated, the coated surface facing the inner surface of the hollow cylinder is part of or constitutes the circumferential surface. The "contact surface" is the part of the circumferential surface that contacts the inner surface of the hollow cylinder when the plug is inserted into the hollow cylinder (e.g., at 20 °C). In the present invention, it may be beneficial if the plug is not coated. It has been found that an uncoated plug can form a tighter seal at low temperatures compared to a coated plug. In one embodiment, the plug does not include a fluoropolymer coating.

[0070] An "annular protrusion" is a part of the plug that has a diameter greater than the average diameter as measured along the longitudinal axis perpendicular to the hollow cylinder (such as a cylinder). The annular protrusion contacts the inner surface of the hollow cylinder, thereby sealing the connection between the plug and the hollow cylinder. Any part of the plug that has a diameter greater than the average diameter but does not contact the inner surface of the hollow cylinder to an extent of at least 80.0%, 90.0%, 99.9% or 100% during the distal movement of the plug is not considered an "annular protrusion".

[0071] The diameter of at least one annular protrusion (preferably, all annular protrusions) exceeds the inner diameter of the hollow cylinder. Preferably, the diameter of at least one annular protrusion (preferably, all annular protrusions) exceeds the inner diameter of the hollow cylinder by at least 0.05 mm, or at least 0.1 mm, or at least 0.15 mm. The outer diameter of the annular protrusion may be equal to the outer diameter of the plug. The diameter is measured along a direction perpendicular to the longitudinal axis of the hollow cylinder.

[0072] The annular protrusion helps to hold the plug in the intended position within the hollow cylinder, stabilizing its positioning in the proximal-distal direction, thereby affecting the BLF and GF values of the container. In addition, the annular protrusion seals the connection between the plug and the inner surface of the hollow cylinder.

[0073] The plug may optionally have one or more tail ribs. A "tail rib" refers to a portion of the plug whose diameter, measured along a direction perpendicular to the longitudinal axis of the hollow cylinder, is greater than the average diameter. However, the diameter of the tail rib is smaller than that of the annular protrusion. Thus, when the plug moves in the proximal-distal direction, the tail rib does not significantly contact the inner surface of the hollow cylinder. Such tail ribs can serve to stabilize the orientation of the plug within the hollow cylinder without effectively sealing the connection between the plug and the inner surface. Tail ribs generally do not significantly affect BLF and GF because of their limited contact with the inner surface, if any.

[0074] The plug may be coated with a coating. The coating may be a polymer. In one embodiment, the coating includes a resin, such as a fluorinated polymer, for example, a polymer selected from the group consisting of polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), tetrafluoroethylene (TFE), tetrafluoroethylene-perfluoroethylene copolymer, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-ethylene copolymer, trichlorotrifluoroethylene, polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymer, and their copolymers, mixtures, and combinations. The coating may also be formed by a layer comprising polyethylene, polypropylene, parylene, polylactic acid, and their copolymers, mixtures, and combinations. The PTFE coating is a preferred coating option. These coatings reduce the coefficient of friction of the circumferential surface of the plug on the inner surface of the hollow cylinder. In an embodiment, at least the portion of the circumferential surface of the plug that should contact the inner surface of the hollow cylinder is coated.

[0075] The plug may have an elastic body having a yield stress of at least 10 MPa measured according to ISO 527-2:2012(E), and / or a low coefficient of sliding friction relative to steel of less than 0.23 measured according to DIN EN ISO 8295 / 2004-10. The plug may be made of a thermoplastic elastomer and / or a rubber (such as natural or synthetic rubber). Suitable rubber materials may be selected from the group consisting of butyl rubber, halogenated butyl rubber, acrylonitrile-butadiene rubber, isoprene rubber, chloroprene rubber, butadiene rubber, styrene-butadiene rubber, ethylene-propylene rubber, isoprene-isobutene rubber, nitrile rubber, and combinations and mixtures thereof. In one embodiment, the plug is made of bromobutyl rubber. In particular, the body of the plug may be made of the rubbers and / or thermoplastic elastomers listed above.

[0076] The body may be coated with the above-mentioned resin. The thickness of the plug coating may be less than 1 mm, particularly between 0.5 μm and 200 μm, particularly between 10 μm and 125 μm, or between 30 μm and 100 μm. It has been shown that these thicknesses are easy to apply and are sufficient to achieve the desired frictional effect.

[0077] The water contact angle of the peripheral surface of the plug is at least 100°, or even at least 110°. The peripheral surface of the plug may be superhydrophobic. Due to the combination of a low coefficient of sliding friction and low adhesion, the use of a superhydrophobic plug in the container of the present invention helps to obtain a beneficial BLGF value.

[0078] The peripheral surface of the plug and the inner surface of the hollow cylinder may be at least partially in contact within the contact area. The contact area is sometimes also referred to as the sealing area. In an embodiment, the contact area will be at least 8 mm 2 and at most 48 mm 2 . The contact area may be 8 to 48 mm 2 or 10 to 40 mm 2 , 15 to 30 mm 2 , 16 to 24 mm 2 . In the presence of multiple annular protrusions, each protrusion will contribute to the contact area. The minimum contact area will help to achieve sufficient sealing. If the contact area is too large, the BLGF value may increase too much.

[0079] The system may include a plug having a Shore hardness A not exceeding 70. The Shore hardness A may be tested using the ISO 7619-1 (February 2012, 1-second indentation) method. The Shore hardness A may be at least 35, at least 40, or at least 45. Optionally, it may be up to 65 or up to 60. In an embodiment, the Shore hardness A reaches 35 to 70, 40 to 65, or 45 to 60.

[0080] The density of the stopper can be at least 1.200 g / cm 3 、at least 1.250 g / cm 3 、or at least 1.300 g / cm 3 。Optionally, the density can be at most 1.450 g / cm 3 、at most 1.400 g / cm 3 、or at most 1.385 g / cm 3 。In an embodiment, the density range is from 1.200 g / cm 3 to 1.450 g / cm 3 ,1.250 g / cm 3 to 1.400 g / cm 3 、or 1.300 g / cm 3 to 1.385 g / cm 3 。

[0081] In an embodiment, when inserting into the hollow cylinder of a glass container, the stopper compression ratio of at least one stopper is defined as (D s -D b ) / D s ,where D s = the outer diameter of the uncompressed stopper, D b = the inner diameter of the hollow cylinder, which can be: -8.0% or higher, or 10.0% or higher, or 12.0% or higher, or 14.0% or higher, or 15.0% or higher; and / or -18.0% or lower, or 17.5% or lower, or 17.0% or lower, or 16.5% or lower, or 16.0% or lower.

[0082] The range of the stopper compression ratio can be from 8.0% to 18.0%, or from 10.0% to 17.5%, or from 12.0% to 17.0%, or from 14.0% to 16.5%, or from 15.0% to 16.0%. For example, the stopper compression ratio can be determined by measuring the outer diameter of the uncompressed stopper and the inner diameter of the hollow cylinder using calipers. Optionally, the stopper compression ratio is limited to not more than 35.0%, not more than 30.0%, or not more than 25.0%.

[0083] The inventors have found that, for glass containers, another important factor in achieving CCI at such low temperatures is relaxation kinetics, especially at temperatures below the glass transition temperature of the stopper material. When cooling pre-filled and sealed containers for storage, different forces will be generated. Due to i) the shrinkage of the stopper as the temperature decreases, ii) the shrinkage of the coating as the temperature decreases, and iii) the suppression or slowdown of the relaxation of the stopper below its glass transition temperature, radial forces will act on the cylinder / coating / stopper interface. In addition, due to the movement of the stopper caused by the freezing of the filling medium (especially aqueous solution) in the container, shear forces will act on the coating interface.

[0084] At temperatures above the glass transition temperature of the stopper material, the decrease in the stopper diameter can be compensated by the relaxation of the initial compression of the stopper applied by the cylinder of the container. However, at temperatures below the glass transition temperature, the mobility of the elastomer molecules is very strongly restricted, and the material exhibits pure energetic elasticity. As the temperature decreases, the size recovery becomes very slow. It has surprisingly been found that even at low temperatures, stoppers with a higher initial degree of compression can recover their size more quickly. Therefore, the stopper compression ratio is an additional factor for further improving CCI at -80 °C and lower temperatures. The magnitude of the stopper compression ratio must be balanced between improving the relaxation of the shrinkage stopper and its usability at room temperature, which includes maintaining a very low total glide force variation (TGFV) and reducing the pull-off force. A ratio that is too high will greatly increase the pull-off force and the glide force. When the stopper moves within the cylinder of the container, over-compression may even damage the coating.

[0085] In an embodiment, it may be preferred that the total length of the hollow cylinder, especially the length measured along the axial extension of the barrel, is: (i) 40 mm or higher, preferably 45 mm or higher, preferably 50 mm or higher, preferably 55 mm or higher, preferably 60 mm or higher, preferably 65 mm or higher, preferably 70 mm or higher, preferably 75 mm or higher, preferably 80 mm or higher; (ii) 80 mm or lower, preferably 75 mm or lower, preferably 70 mm or lower, preferably 65 mm or lower, preferably 60 mm or lower, preferably 55 mm or lower, preferably 50 mm or lower, preferably 45 mm or lower, preferably 40 mm or lower; and / or (iii) between 40 mm and 80 mm, preferably between 40 mm and 60 mm, especially between 45 mm and 55 mm, particularly between 45 mm and 50 mm, or between 60 mm and 70 mm, especially between 63 mm and 67 mm.

[0086] For example, the total length of the hollow cylinder can be 65.7 mm or 48.4 mm.

[0087] In an embodiment, the inner diameter of the hollow cylinder can be: (i) 5.0 mm or greater, or 6.0 mm or greater, or 7.0 mm or greater, or 8.0 mm or greater, or 9.0 mm or greater; (ii) 10.0 mm or less, or 9.0 mm or less, or 8.0 mm or less, or 7.0 mm or less, or 6.0 mm or less, or 5.0 mm or less; and / or (iii) between 5.0 mm and 10.0 mm, or between 5.0 mm and 7.0 mm, especially between 5.0 mm and 6.0 mm or between 6.0 mm and 7.0 mm, particularly between 5.5 mm and 6.0 mm (e.g., 5.85 mm), or between 6.0 mm and 6.5 mm (e.g., 6.35 mm), or between 7.0 mm and 9.0 mm, especially between 8.0 mm and 9.0 mm, particularly between 8.5 mm and 9.0 mm, for example 8.65 mm.

[0088] For example, the inner diameter of the hollow cylinder can be 5.85 mm or 6.35 mm or 8.65 mm.

[0089] In an embodiment, the outer diameter of the plug can be: (i) 6.0 mm or greater, or 7.0 mm or greater, or 8.0 mm or greater, or 9.0 mm or greater, or 10.0 mm or greater; (ii) 11.0 mm or less, or 10.0 mm or less, or 9.0 mm or less, or 8.0 mm or less, or 7.0 mm or less, or 6.0 mm or less; and / or (iii) between 6.0 mm and 11.0 mm, or between 6.0 mm and 8.0 mm, especially between 6.5 mm and 7.5 mm, particularly between 6.75 mm and 7.25 mm, for example 6.9 mm or 7.0 mm.

[0090] For example, the outer diameter of the plug can be 6.9 mm or 7.0 mm.

[0091] Loosening force and sliding force

[0092] According to an aspect of the present invention, the glass container can have a standardized sliding force that can be no more than 5.0 N.

[0093] The sliding force represents the force required to push the stopper into the hollow cylinder, while the pull-off force represents the force required for the initial movement of the stopper within the hollow cylinder. The "standardized sliding force" is the sliding force (GF) measured under standard conditions. Similarly, the "standardized pull-off force" refers to the pull-off force (BLF) measured under standard conditions. The standard conditions include a standard stopper, namely the Datwyler FM257 / 2 stopper made of bromobutyl rubber, with a Shore A hardness of 52 and a density of 1.355 g / cm 3 which can be obtained from Datwyler Pharma Packaging International NV, Industrieterrein Kolmen 1519, BE-3570 Alken, Belgium. The BLF and GF can be measured simultaneously. The test for BLF and GF can be referred to as the "BLGF" test. The "specific" BLF or GF refers to the pull-off force or sliding force measured in a certain system, that is, including the stopper of the system, rather than the standard stopper. Otherwise, the measurement is the same as the standard test.

[0094] The standardized BLGF test is carried out on a universal testing machine at room temperature (i.e., 20 °C). For this purpose, a standardized BLGF test device with a 50 N test cup is used. The sample is fixed in a vertical orientation on a 2 kN universal testing machine of type 106 from TesT AG, CH-6331 Hünenberg, Switzerland.

[0095] The BLF is the force required to move the stopper from its original position. The GF is the force required to keep the stopper moving after it has become loose.

[0096] The containers are filled with water for injection. After filling the samples, they are either stored immediately or tested according to the test purpose. The samples are tested without a needle.

[0097] The sample is inserted into the holder, and the pressure punch moves towards the stopper at a rate of 20 mm / min. Once a force of 0.25 N is measured, the machine switches to a test rate of 100 mm / min and starts recording data. When a force exceeding 35 N is measured, the experiment ends, which is usually the case when the distal end of the hollow cylinder is reached.

[0098] The BLF is the maximum force measured within the first 4 mm of the movement of the stopper. The GF value is measured within the test range that starts after 4 mm of movement and ends 10 mm before reaching the distal end of the cylinder. The GF according to the present invention is the maximum sliding force measured in this experiment.

[0099] The glass container of the present invention can exhibit a standardized BLF of no more than 12.0 N. In some embodiments, the upper limit of the standardized BLF can be restricted to 9.0 N, 8.0 N, 7.0 N, 6.0 N, 5.0 N, or even 4.0 N. The standardized BLF can be at least 0.1 N, at least 0.5 N, or at least 1.0 N to avoid any accidental movement of the stopper.

[0100] The glass container exhibits a ratio of standardized BLF to standardized GF of BLF / GF > 1.30. Optionally, the ratio of standardized BLF to standardized GF is characterized by BLF / GF ≤ 3.0, especially after storing the glass container at -80 °C for 168 hours. In an embodiment, for the container of the present invention, the BLF / GF ratio > 1.40, > 1.50, or even > 1.60. In some embodiments, for the container of the present invention, after storing the glass container at -80 °C for 168 hours (the "low-temperature stored container"), the BLF / GF ratio can be < 2.5, < 2.2, < 2.0, or even < 1.9. In particular, the relative difference in the BLF / GF ratio between the low-temperature stored container and the non-stored container (BLF / GF -80℃ -BLF / GF 0 ) / BLF / GF -80℃ can be less than 10%, preferably less than 5%. This means that the freeze-thaw cycle has little effect on the BLF / GF ratio. On the other hand, the BLF / GF ratio described above is quite high, which means that it is quite difficult to loosen the stopper from its initial position. This may be due to the interaction between the coating and the stopper. A higher BLF is beneficial for the stopper to remain in its initial position at low temperatures (i.e., when the pharmaceutical composition expands due to freezing).

[0101] The standardized GF of the glass container of the present invention can be < 7.5 N, < 6.5 N, < 5.5 N, < 4.5 N, < 3.5 N, or even < 2.5 N. Optionally, the relative difference in the standardized BLF between the low-temperature stored container and the non-stored container (BLF -80℃ -BLF 0 ) / BLF -80℃ is less than 25%, < 20%, < 15%, < 10%, or even < 5%. The relative difference in GF between the low-temperature stored container and the non-stored container (GF -80℃ -GF 0 ) / GF -80℃ is less than 25%, < 20%, < 15%, < 10%, or even < 5%. Keeping the GLF relatively low helps to completely discharge the contents of the container with a stopper after low-temperature storage.

[0102] Appropriate sliding force and loosening force are related to the convenient use of the glass containers of the present invention. Generally, a tight seal corresponds to a higher loosening force and / or sliding force. Some glass containers of the present invention exhibit very low standardized loosening force and sliding force. However, a sufficiently large loosening force may be beneficial for suppressing unwanted plug movement during storage.

[0103] Optionally, the glass container according to the present invention has a standardized sliding force of at least 0.5 N.

[0104] In order to ensure a tight seal by suppressing plug movement during low-temperature storage, the glass container of the present invention may have a standardized loosening force that exceeds the standardized sliding force of the container by at least 30%, at least 60%, at least 100%, or at least 200%.

[0105] In one embodiment, the container of the present invention has a specific loosening force that is at least 600% greater than a specific sliding force, and the specific loosening force is at least 4.0 N or at least 4.9 N.

[0106] Glass composition

[0107] There is no particular limitation on the glass of the glass container. Preferably, the glass is borosilicate glass, aluminosilicate glass, lithium aluminosilicate (LAS) glass, and more preferably borosilicate glass.

[0108] In one embodiment, the composition of the glass comprises, by mass%: SiO 2 : 30% to 98%, preferably 50% to 90%, more preferably 70.0% to 74.0%; and / or B 2 O 3 : 0% to 30%, preferably 3% to 20%, more preferably 7.0% to 16.0%; and / or Al 2 O 3 : 0% to 30%, preferably 1% to 15%, more preferably 3.0% to 6.5%; and / or X 2 O: 0% to 30%, preferably 1% to 15%, more preferably 2.0% to 7.2%, where X is selected from Na, K, and Li, and preferably, X is Na and / or K; and / or YO: 0% to 30%, preferably 0.1% to 5%, more preferably 0.5% to 1.0%, where Y is selected from Ca, Mg, and Ba, and preferably, Y is Ca and / or Mg.

[0109] More preferably, the composition of the glass comprises, by mass%: SiO 2: 30% to 98%, preferably 50% to 90%, more preferably 70.0% to 74.0%; B 2 O 3 : 0% to 30%, preferably 3% to 20%, more preferably 7.0% to 16.0%; Al 2 O 3 : 0% to 30%, preferably 1% to 15%, more preferably 3.0% to 6.5%; X 2 O: 0% to 30%, preferably 1% to 15%, more preferably 2.0% to 7.2%, wherein X is selected from Na, K and Li, preferably, X is Na and / or K; YO: 0% to 30%, preferably 0.1% to 5%, more preferably 0.5% to 1.0%, wherein Y is selected from Ca, Mg and Ba, preferably, Y is Ca and / or Mg.

[0110] In another preferred embodiment, the composition of the glass comprises, by mass%: SiO 2 : 20% to 98%, preferably 40% to 75%, more preferably 50% to 65%; and / or B 2 O 3 : 0% to 30%, preferably 1% to 15%, more preferably 3% to 9%; and / or Al 2 O 3 : 0% to 30%, preferably 10% to 20%, more preferably 13% to 18%; and / or X 2 O: 0% to 30%, preferably 0% to 5%, more preferably 0% to 3%, wherein X is selected from Na, K and Li, preferably, X is Na and / or K; and / or YO: 0% to 50%, preferably 0.1% to 40%, more preferably 10% to 35%, wherein Y is selected from Ca, Mg and Ba, preferably, Y is Ca and / or Mg.

[0111] More preferably, the composition of the glass comprises, by mass%: SiO 2 : 20% to 98%, preferably 40% to 75%, more preferably 50% to 65%; B 2 O 3 : 0% to 30%, preferably 1% to 15%, more preferably 3% to 9%; Al 2 O 3: 0% to 30%, preferably 10% to 20%, more preferably 13% to 18%; X 2 O: 0% to 30%, preferably 0% to 5%, more preferably 0% to 3%, wherein X is selected from Na, K, and Li, preferably, X is Na and / or K; YO: 0% to 50%, preferably 0.1% to 40%, more preferably 10% to 35%, wherein Y is selected from Ca, Mg, and Ba, preferably, Y is Ca and / or Mg.

[0112] The volume of the glass container is not particularly limited. Preferably, the brimful volume of the container is 0.1 ml to 1000 ml, preferably 0.5 ml to 500 ml, more preferably 1 ml to 250 ml, more preferably 2.0 ml to 30.0 ml, more preferably 2.0 ml to 15.0 ml, more preferably approximately 1.0 ml, 2.0 ml, 3.0 ml, 4.0 ml, 5.0 ml, 6.0 ml, 7.0 ml, 8.0 ml, 9.0 ml, 10.0 ml, 11.0 ml, 12.0 ml, 13.0 ml, 14.0 ml, or 15.0 ml; more preferably 5.0 ml to 15.0 ml.

[0113] In one embodiment, the glass of the glass container has a glass composition comprising 50 wt.% to 90 wt.% of SiO 2 and 3 wt.% to 25 wt.% of B 2 O 3 .

[0114] In one embodiment, the glass of the glass container has a glass composition comprising aluminosilicate, optionally comprising 55.0 wt.% to 75.0 wt.% of SiO 2 and 11.0 wt.% to 25.0 wt.% of Al 2 O 3 .

[0115] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 70.0 wt.% to 81.0 wt.% of SiO 2 , 1.0 wt.% to 10.0 wt.% of Al 2 O 3 , 6.0 wt.% to 14.0 wt.% of B 2 O 3 , 3.0 wt.% to 10.0 wt.% of Na 2 O, 0.0 wt.% to 3.0 wt.% of K 2 O, 0.0 wt.% to 1.0 wt.% of Li2 O, 0.0 wt.% to 3.0 wt.% of MgO, 0.0 wt.% to 3.0 wt.% of CaO, and 0.0 wt.% to 5.0 wt.% of BaO.

[0116] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 72.0 wt.% to 82.0 wt.% of SiO 2 , 5.0 wt.% to 8.0 wt.% of Al 2 O 3 , 3.0 wt.% to 6.0 wt.% of B 2 O 3 , 2.0 wt.% to 6.0 wt.% of Na 2 O, 3.0 wt.% to 9.0 wt.% of K 2 O, 0.0 wt.% to 1.0 wt.% of Li 2 O, 0.0 wt.% to 1.0 wt.% of MgO, and 0.0 wt.% to 1.0 wt.% of CaO.

[0117] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 60.0 wt.% to 78.0 wt.% of SiO 2 , 7.0 wt.% to 15.0 wt.% of B 2 O 3 , 0.0 wt.% to 4.0 wt.% of Na 2 O, 3.0 wt.% to 12.0 wt.% of K 2 O, 0.0 wt.% to 2.0 wt.% of Li 2 O, 0.0 wt.% to 2.0 wt.% of MgO, 0.0 wt.% to 2.0 wt.% of CaO, 0.0 wt.% to 3.0 wt.% of BaO, and 4.0 wt.% to 9.0 wt.% of ZrO 2 .

[0118] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 50.0 wt.% to 70.0 wt.% of SiO 2 , 10.0 wt.% to 26.0 wt.% of Al 2 O 3 , 1.0 wt.% to 14.0 wt.% of B 2 O 3, 0.0 wt.% to 15.0 wt.% of MgO, 2.0 wt.% to 12.0 wt.% of CaO, 0.0 wt.% to 10.0 wt.% of BaO, 0.0 wt.% to 2.0 wt.% of SrO, 0.0 wt.% to 8.0 wt.% of ZnO, and 0.0 wt.% to 2.0 wt.% of ZrO 2 .

[0119] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 55.0 wt.% to 70.0 wt.% of SiO 2 , 11.0 wt.% to 25.0 wt.% of Al 2 O 3 , 0.0 wt.% to 10.0 wt.% of MgO, 1.0 wt.% to 20.0 wt.% of CaO, 0.0 wt.% to 10.0 wt.% of BaO, 0.0 wt.% to 8.5 wt.% of SrO, 0.0 wt.% to 5.0 wt.% of ZnO, 0.0 wt.% to 5.0 wt.% of ZrO 2 and 0.0 wt.% to 5.0 wt.% of TiO 2 .

[0120] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 65.0 wt.% to 72.0 wt.% of SiO 2 , 11.0 wt.% to 17.0 wt.% of Al 2 O 3 , 0.1 wt.% to 8.0 wt.% of Na 2 O, 0.0 wt.% to 8.0 wt.% of K 2 O, 3.0 wt.% to 8.0 wt.% of MgO, 4.0 wt.% to 12.0 wt.% of CaO, and 0.0 wt.% to 10.0 wt.% of ZnO.

[0121] In one embodiment, the glass of the glass container has a glass composition comprising the following components: 64.0 wt.% to 78.0 wt.% of SiO 2 , 4.0 wt.% to 14.0 wt.% of Al 2 O 3 , 0.0 wt.% to 4.0 wt.% of B 2 O 3 , 6.0 wt.% to 14.0 wt.% of Na 2 O, 0.0 wt.% to 3.0 wt.% of K 2O, 0.0 wt.% to 10.0 wt.% of MgO, 0.0 wt.% to 15.0 wt.% of CaO, 0.0 wt.% to 2.0 wt.% of ZrO 2 and 0.0 wt.% to 2.0 wt.% of TiO 2 .

[0122] In one embodiment, the average linear coefficient of thermal expansion (CTE) of the glass of the glass container is measured in the range of 20 °C to 300 °C to be between 3.0*10 -6 K -1 and 8.0*10 -6 K -1 or between 3.5*10 -6 K -1 and 7.0*10 -6 K -1 or between 4.0*10 -6 K -1 and 6.0*10 -6 K -1 Optionally, the CTE can be less than 5.2*10 -6 K -1 or less than 5.1*10 -6 K -1 . In some embodiments, the CTE is limited to not exceeding 6.9*10 -6 K -1 or not exceeding 5.9*10 -6 K -1 . The CTE can be measured according to DIN ISO 7991:1987.

[0123] Headspace

[0124] In an embodiment, in addition to the pharmaceutical composition, the glass container can be filled with a gas, and the volume enclosed by the glass container and occupied by the gas can be defined as the headspace of the glass container.

[0125] The headspace can vary according to the ambient temperature, ambient pressure, etc. This is because the headspace corresponds to the volume of gas within the hollow cylinder of the glass container, and this volume can change. For example, the volume of the gas depends on the ambient conditions and / or the volume of the pharmaceutical composition within the hollow cylinder.

[0126] In one embodiment, it may be preferred that at room temperature, the volume occupied by the headspace is 1% or more of the volume occupied by the pharmaceutical composition.

[0127] The inventors have found that if an appropriate-sized gas volume is provided within a glass container, CCI at -80 °C or lower can be further improved. It has been proven that this allows the volume of the pharmaceutical composition to change during cooling or thawing without affecting the integrity of the container. This is because when the pharmaceutical composition is cooled, especially below the freezing point of the pharmaceutical composition, the proposed headspace enables the system to resist the expansion or contraction of the pharmaceutical composition. The same is true when the system thaws and the pharmaceutical composition expands or contracts. In this way, the above-mentioned radial forces acting on the coating interface can be minimized or eliminated.

[0128] In other words, the method including the headspace can achieve a further significant reduction in the risk due to volume changes of the pharmaceutical composition, stopper movement, or container leakage during cooling or thawing. Since the headspace is variable, i.e., the volume of the gas can be changed by the space occupied by the composition, e.g., compressed or expanded, the force applied to the stopper is reduced. Therefore, uncontrolled movement of the stopper can be prevented, which may cause damage to the coating interface.

[0129] In an embodiment, the gas can be or can include air, CO 2 、N 2 、Ar and / or O 2 and one or more of them.

[0130] If the gas is air, CO 2 、N 2 、Ar and / or O 2 , then the method can be provided particularly inexpensively.

[0131] In an embodiment, the glass container can be vertically oriented and placed after filling and before cooling so that the headspace of the glass container is near the stopper.

[0132] The inventors have found that the position of the headspace can have a positive impact on CCI. They speculate that the freezing of the pharmaceutical composition starts at the gas / liquid interface. Therefore, if the headspace is at the distal end of the stopper, the frozen and thus expanding liquid will exert an increasing pressure on the stopper during freezing. If the generated force becomes greater than the release force of the stopper, the stopper will start to move; or if the force on the coating interface becomes too large, the coating may be damaged and CCI may be lost. When the headspace is near the stopper, the increased force mainly points to the less important lid side of the container, e.g., the cone with a syringe tip cap, which compensates for the pressure through the lid while further contracting onto the cone. The continuously contracting gas volume can protect the stopper from excessive pressure.

[0133] In an embodiment, the headspace may have a body portion of cylindrical volume, the body portion of the volume having a specific diameter equal to the inner diameter of the barrel and a specific height, which specific height is preferably measured from the center point of the stopper to the surface of the pharmaceutical composition facing the stopper, wherein the value of the specific height is 0.1 mm or higher.

[0134] Preferably, when measuring the specific height, the container has a vertical orientation, with the open end closed by the stopper at the top.

[0135] It is noted that for a stopper having a surface facing the pharmaceutical composition and a flat surface, the volume of the body portion of the cylindrical volume may be equal to the volume of the headspace.

[0136] The surprising finding is that the correspondingly selected specific height results in a beneficial situation: the interaction between the swelling of the pharmaceutical composition and the compression of the gas results in only a reduced movement or even no movement of the stopper being observed during the freezing and thawing processes. The inventors have found that a specific height of at least 0.1 mm constitutes an optimal basis for said interaction.

[0137] In an embodiment, the headspace may have a body portion of cylindrical volume, the body portion of the volume having a specific height and a specific diameter equal to the inner diameter of the hollow cylinder, preferably, the specific height is measured from the center point of at least one stopper to the surface of the pharmaceutical composition facing at least one stopper, wherein the value of the specific height is: - 2.0 mm or higher, or 3.0 mm or higher, or 4.0 mm or higher, or 5.0 mm or higher, or 6.0 mm or higher, or 7.0 mm or higher, or 8.0 mm or higher, or 9.0 mm or higher, or 10.0 mm or higher, or 11.0 mm or higher, or 12.0 mm or higher, or 13.0 mm or higher, or 14.0 mm or higher, or 15.0 mm or higher; and / or - 15.0 mm or lower, or 14.0 mm or lower, or 13.0 mm or lower, or 12.0 mm or lower, or 11.0 mm or lower, or 10.0 mm or lower, or 9.0 mm or lower, or 8.0 mm or lower, or 7.0 mm or lower, or 6.0 mm or lower, or 5.0 mm or lower, or 4.0 mm or lower, or 3.0 mm or lower; and / or - between 2.0 mm and 15.0 mm, or between 2.0 mm and 10.0 mm, or between 3.0 mm and 9.0 mm, or between 3.0 mm and 5.0 mm (e.g., 4.0 mm), or between 5.0 mm and 7.0 mm (e.g., 6.0 mm), or between 7.0 mm and 9.0 mm (e.g., 8.0 mm).

[0138] A specific height can be further specified according to the usage of the system. The proposed specific height provides a preferred result related to the plug movement reduced or even eliminated during freezing and thawing.

[0139] Ethanol-modified dye immersion test

[0140] In an embodiment, the glass container can have container closure integrity (CCI) of a standard ethanol-modified dye immersion test at -80 °C for at least 168 hours and / or O of a headspace analysis test at -96 °C for at least 1 hour 2 of the container closure integrity.

[0141] In one embodiment, a system includes the glass container and the plug of the present invention, wherein the system has container closure integrity (CCI) of a specific ethanol-modified dye immersion test at -80 °C for at least 168 hours and / or O of a headspace analysis test at -96 °C for at least 1 hour 2 of the container closure integrity.

[0142] Optionally, the system can have container closure integrity of a specific ethanol-modified dye immersion test at -80 °C for at least 300 hours, at least 600 hours, or at least 1200 hours.

[0143] Optionally, the system can have O of a headspace analysis test at -96 °C for at least 2 hours or at -96 °C for at least 3 hours 2 of the container closure integrity.

[0144] The container closure integrity of the specific ethanol-modified dye immersion test may be related to the plug and / or related to the tip. "Related to the plug" means checking the seal formed by the plug in the hollow cylinder to determine its closure integrity. "Related to the tip" means checking the seal formed by the cap located on the tip side opening to determine its closure integrity. Different from the standard container closure integrity tests relying on standard plugs, plungers, and / or caps, the container closure integrity of the specific ethanol-modified dye immersion test is measured using a specific plug and / or cap that is part of the system under test.

[0145] Now will refer to Figure 2 the container closure integrity test of ethanol-modified dye immersion will be explained.

[0146] Figure 2 Schematically and exemplarily shows a configuration 200 for determining the ethanol-modified dye immersion closure integrity of a container at different stages. The configuration 200 includes a submersion system 270 and a container 201 used together with the submersion system 270.

[0147] The container 201 is a glass container, such as a glass container according to the present invention, and includes a hollow cylinder 210 having two openings, an open end 212-1 and an open end 212-2 provided on different sides of the glass container. Each opening 212-1, 212-2 is sealed by a closing device 230-1 (i.e., a stopper) or a closing device 230-2 (i.e., a cap), respectively. The container volume 205 of the container 201 is defined by a part of the inner wall of the container body 210 and the inner surfaces of each closing device 230-1, 230-2.

[0148] In the case of the container closure integrity test with standard ethanol-modified dye immersion, the stopper is Datwyler FM257, and the cap is West W7025 in a Luer Lock SRC type rigid cap (as disclosed in, for example, EP 3569 272A1). In the case of the container closure integrity test with specific ethanol-modified dye immersion, the stopper is the stopper of the system under discussion, and the cap (if any) is the cap of the system under discussion.

[0149] In the illustrated example, the container 201 is a medical glass syringe or a pharmaceutical glass cartridge. This test can also be carried out on other types of glass containers in the same manner. The open end 212-1 at the proximal end of the container is sealed by a closing device in the form of a stopper 230-1. The open end 212-2 at the distal end of the container is provided at the tip of the container 201 and is sealed by a closing device in the form of a cap 230-2.

[0150] For the purpose of this test, the container volume 205 is filled with air at 1 atm pressure and sealed with a suitable closing device. The immersion system 270 includes an immersion device 272. In the immersion device 272, a reservoir containing an ambient liquid 274 is provided. The immersion device 272 also includes adjustment facilities for adjusting and maintaining the temperature of the ambient liquid 274 according to the test protocol.

[0151] At the start of the test, the container volume 205 is completely filled with air. In addition, the container 201, which includes the gas within the container volume 205, is adjusted to 20°C. The ambient liquid 274 is adjusted to -80°C. The ambient liquid 274 is ethanol containing a fluorescein dye (1 g / l of sodium fluorescein).

[0152] As Figure 2As shown in b) thereof, in the next step, the container 201 is completely immersed in the ambient liquid 274. When immersed in the ambient liquid 274, the container 201 will gradually adopt a temperature of at least close to -80 °C. The absolute heat capacity of the container 201 is small relative to the absolute heat capacity of the ambient liquid 274. In this way, the temperature change of the ambient liquid 274 caused by the immersion of the container 201 is minimal. When the temperature of the container 201 drops due to immersion in the ambient liquid 274, the temperature of the gas in the container volume 205 will also drop accordingly. Therefore, the gas in the container volume 205 will contract, and the air pressure in the container volume 205 will drop below the ambient pressure.

[0153] From the moment the container is completely immersed in the ambient liquid 274 until the container 201 is removed from the ambient liquid 274 and allowed to equilibrate at ambient temperature (preferably 20 °C), the container 201 remains in the ambient liquid 274 for at least a predetermined period of time.

[0154] Figure 2 c) thereof schematically shows two possible results that may occur once the container 201 is removed from the ambient liquid 274. In the above example, i), the amount L of the ambient liquid is detected inside the container volume 205. In particular, the amount L of the ambient liquid 274 has crossed the boundary of the tip region of the container 201. This indicates that there is a leak in the tip region of the container 201 under the conditions adopted in the previous a) and b) phases. In the following example, ii), no portion of the ambient liquid 274 is detected inside the container 201. This indicates that the container 201 is sealed under the conditions adopted in the previous a) and b) phases.

[0155] If no ambient liquid is detected inside the container, including no ambient liquid is found between the annular protrusions of the stopper or between the closure device and the coating surface, the container is considered to have passed the test.

[0156] Container Closure Integrity Testing Using Headspace Analysis

[0157] Headspace analysis is a deterministic container closure integrity (CCI) test. Non-destructive headspace analysis as a CCI test method is based on detecting changes in the headspace gas composition caused by gas entering the sealed container through leaks. To detect gas ingress, a sample is placed in a container filled with a tracer gas (CO 2 CO in the case of headspace analysis (entry method) 2 ) or other gases (e.g., N 2 in the case of headspace analysis (depletion method) 2) into the chamber. Containers with leakage defects will naturally admit air, and the headspace concentration of the tracer gas will increase while the headspace concentration of other gases will decrease, indicating the absence of CCI.

[0158] The headspace gas analyzer uses tunable diode laser absorption spectroscopy (TDLAS) and incorporates high-sensitivity signal processing technology (known as frequency modulation spectroscopy (FMS)) to provide gas analysis of the headspace inside a sealed container. This optical technology can measure many physical parameters within the container headspace, including the specific gas number density and the total headspace pressure.

[0159] In TDLAS applications, light from a near-infrared (NIR) semiconductor laser is tuned to match the internal vibration frequency of the target molecule (such as the tracer gas). When the NIR laser encounters the target molecule in the sample headspace, any absorption by the target molecule will modulate the amplitude of the laser frequency leaving the sample. A photodetector detects this signal, which is then processed by an electrical mixer to generate an FMS absorption signal related to the target molecule in the sample headspace. The FMS technology increases the detection sensitivity by approximately 10,000 times and compensates for the relatively weak absorption intensity of the near-infrared transitions of the target molecule and the relatively short path length associated with the container headspace. It should be noted that this FMS signal processing converts the original absorption peak into its first derivative. The area and width characteristics of the FMS absorption signal provide information about the target molecule number density and / or pressure.

[0160] Principle of Headspace Carbon Dioxide Measurement

[0161] FMS-CO 2 The headspace carbon dioxide analyzer operates based on the principle of frequency modulation spectroscopy (FMS), with a diode laser tuned to match the specific transition energy of carbon dioxide molecules. During the measurement, the laser frequency is repeatedly scanned over the absorption feature, and the average of consecutive scans is taken to improve the signal-to-noise ratio. The average intensity of the FMS absorption signal is proportional to the headspace carbon dioxide number density. The standard is filled with a certified gas mixture containing a prescribed amount of carbon dioxide for calibration.

[0162] The sealed sample is measured before testing, then stored in a -80 °C freezer containing dry ice for a predetermined period, and subsequently allowed to thaw for at least 20 minutes before measurement. The CO 2 quantity is measured again by FM-TDLAS. 2 An increase in the concentration indicates the loss of CCI in the freezer.

[0163] Principle of Headspace Oxygen Measurement

[0164] The FMS - Oxygen Headspace Analyzer operates on the principle of Frequency - Modulation Spectroscopy (FMS), using a diode laser tuned to match the specific transition energy of oxygen molecules. During measurement, the laser frequency is repeatedly scanned over the absorption feature, and the average of consecutive scans is taken to improve the signal - to - noise ratio. Since the absorption cross - section associated with the oxygen transition is relatively weak, an additional low - bandpass filter is used that distorts the standard FMS absorption signal. Despite this distortion, the average intensity of the FMS absorption signal is related to the headspace oxygen number density. The FMS spectrum of oxygen absorption in a standard, using a certified gas mixture filled with oxygen in nitrogen at a total pressure of about 1 atm, is used for calibration.

[0165] The advantage of the CCI test method is that the controlled - rate cryostat used freezes with liquid nitrogen. This creates a highly nitrogen - rich environment inside the cryostat. When the sample contains a defect / leak, the initial headspace air (about 20% oxygen) in the test sample will be replaced by nitrogen. Thus, a comparison of the headspace oxygen analysis before and after storage will show oxygen depletion, indicating CCI loss.

[0166] Examples

[0167] Coating composition

[0168] An array of glass syringes (Schott syriQ 1.0 ml long, Fiolax transparent) was coated with the coating composition. The following coating compositions were used:

[0169] The glass syringes were coated using the spraying method. Subsequently, the coating was cured in an oven at a high temperature. During the curing process, the diluent evaporated, and a cross - linkable polysiloxane formed a network in a hydrosilylation reaction.

[0170] Coating thickness

[0171] Coatings of different thicknesses were applied to the glass syringes and cured for 60 seconds at a curing temperature of 70 °C. The coatings were applied to the inner surface of the syringe barrel and the nested surface of the syringe tip. Then, the two open ends were sealed. One open end was sealed with a Datwyler FM257 plug, and the other open end was sealed with a West W7025 tip cap. As described above, the container - closure integrity test with ethanol - modified dye immersion was performed on the samples at - 80 °C. Samples F and G are prior - art silicone oils (DuPont D360), with viscosities of 1000 cSt and 12500 cSt respectively. Sample A Sample B Sample C Sample D Sample E Sample F Sample G Coating thickness 1000nm 800nm 500nm 400nm 200nm 800nm 800nm CCI test Passed Passed Passed Failed Failed Failed Failed

[0172] Curing temperature

[0173] The coatings of Composition A (Samples H and I) and Composition B (Samples J and K) were cured for 60 seconds at different curing temperatures, and standardized peel force and slip force tests were conducted. The coating thickness was 800 nm. Sample H Sample I Sample J Sample K Curing temperature 40℃ 70℃ 40℃ 70℃ BLF 7.4±0.29N 7.6±0.21N 7.4±0.32N 4.9±0.41N GF 1.0±0.08N 1.0±0.03N 3.5±0.79N 2.8±0.33N

[0174] DSC measurement

[0175] After curing and scraping the cured coating from the glass, differential scanning calorimetry (according to DIN 51007:2019) was performed on the coating samples. The experiment was carried out on a DSC Q2000 (TA Instruments) with a temperature gradient of 10 °C / min and a temperature range of -120 °C to -60 °C. The measurement results were confirmed by two repetitions.

[0176] The results of Composition A are as Figure 3 shown. The exothermic crystallization peak is located at -72.52 °C. It extends from -90 °C to -60 °C. The endothermic melting peak is located at -42.11 °C and extends from -90 °C to -30 °C. There is an overlap between the two peaks in the temperature range including -80 °C.

[0177] The results of Composition B are as Figure 4 shown. The exothermic crystallization peak is located at -73.48 °C. It extends from -93 °C to -65 °C. The endothermic melting peak extends from -90 °C to -50 °C and above. There is an overlap between the two peaks in the temperature range including -80 °C.

[0178] Figure 5 The results of a prior art silicone oil with a viscosity of 1000 cSt are shown. The exothermic crystallization peak is located at -84.06 °C. It extends from -100 °C to -70 °C. The endothermic melting peak extends from -70 °C to -50 °C and above. There is no overlap between the two peaks in the temperature range including -80 °C.

[0179] Figure 6 The results of a prior art silicone oil with a viscosity of 12500 cSt are shown. The exothermic crystallization peak is located at -80.25 °C. It extends from -88 °C to -73 °C. The endothermic melting peak extends from -60 °C to -40 °C and above. There is no overlap between the two peaks in the temperature range including -80 °C.

[0180] Glass transition temperature

[0181] To determine the glass transition temperature, thermomechanical analysis was performed in the expansion mode using a Q400 thermomechanical analyzer from TA Instruments. The samples were prepared in the same way as for the DSC measurement. The glass transition temperature of Composition A is -81.50 °C, and the glass transition temperature of Composition B is -94.96 °C. The results are shown in Figure 7 and Figure 8 respectively.

[0182] Container closure integrity

[0183] Using a Datwyler FM257 stopper, the CO was used on a glass syringe coated with Compositions A and B as described above 2 Plunger side CCI test for headspace analysis. The cooling rate was about 1 °C / min. The headspace in the water-filled sample was 4 mm, where the position of the headspace was close to the stopper of the sample placed vertically. * Leakage value of CO below 10 mbar 2 Is considered to pass.

[0184] It can be seen that when the syringe is stored filled, unfilled and in different orientations, the stopper / barrel interface meets CCI at -80 °C.

[0185] The same test was repeated with a cooling rate of 2 °C to 4 °C between room temperature and -80 °C.

[0186] This comparison again demonstrates that with the cooling rate of the present invention, both coating compositions can achieve complete CCI for 168 hours at -80 °C for horizontally and vertically oriented empty syringes and water-filled syringes.

[0187] To further test the effect of the cooling rate on CCI at -80 °C and -96 °C, four groups of syringes were coated with Composition B in the same manner as described above. The coating thickness was 1400 nm. Again, all syringes used standard Datwyler FM257 stoppers. Using an O 2 CCI tests with headspace analysis were measured at -80 °C for 24 hours and at -96 °C for 1 hour respectively.

[0188] For Groups A - C, all samples were filled with 0.7 ml of water and vertically distributed in a plastic bucket with the stopper on the top side. The samples in Group D were placed horizontally. In addition, three temperature probes were placed near the group of samples to be tested before each run in the freezer to monitor the rate of temperature change.

[0189] The samples, control devices and sensors were placed in a plastic bucket (or tray), including slots for temperature probes and slots for defective syringe control devices. Similar sensors and control devices were also used for horizontal samples.

[0190] Measurements were made on Group A at -80 °C with a headspace of 4 mm. Four tests were performed on 30 samples, each test being carried out at different cooling rates in the range from -50 °C to -80 °C.

[0191] Measurements were made on Groups B and C at -96 °C with headspaces of 4 mm and 8 mm respectively. The samples were cooled from -50 °C to -80 °C at a cooling rate of 3 °C / min to 4 °C / min and held at this temperature for 15 minutes. After this pre-treatment, three tests were performed on 30 samples in each group, each test being carried out at a different cooling rate from -80 °C to -96 °C.

[0192] Repeated tests were performed on Group D at the highest cooling rate of Groups B and C, this time with the syringe placed horizontally in the tray.

[0193] The results for Group A showed that a cooling rate of ≤ 6 °C / min could reliably achieve CCI at -80 °C, while at higher rates, the number of failed samples increased with increasing rate.

[0194] Furthermore, the results for Groups B, C and D showed that a cooling rate of ≤ 5.0 °C / min could be successfully applied in the range from -80 °C to -96 °C for headspaces of 4 mm and 8 mm, regardless of the orientation of the syringe.

[0195] List of reference numerals: 1 Glass container 3 Syringe 5 Glass wall 7 Hollow cylinder 10 Coating 12 Plug 13 Pusher 15 Flange 18 Nested surface 200 Configuration 201 Container 205 Container volume 210 Body 212-1, 212-2 Open ends 230-1 Sealing device (plug) 230-2 Sealing device (cap) 270 Immersion system 272 Immersion device 274 Ambient liquid L Amount of ambient liquid

Claims

1. A method for storing a pharmaceutical composition at -80°C or lower, comprising: - providing a glass container (1), comprising a hollow cylinder (7) having at least one open end (212-1, 212-2) and at least one stopper (12) closing the at least one open end (212-1, 212-2), wherein at least a portion of the inner surface of the glass container (1) comprises a coating (10), the coating (10) having a crystallization temperature range and a melting temperature range determined using differential scanning calorimetry at a temperature change rate of 10°C / min, wherein the crystallization temperature range overlaps with the melting temperature range in the temperature range of -75°C to -100°C, in particular at -80°C; - filling the glass container (1) with a pharmaceutical composition; and - Cooling the glass container (1) in the range of -50°C to -80°C at a cooling rate of ≤6.0°C / min, and cooling the glass container (1) in the range of -80°C to -96°C at a cooling rate of ≤5.0°C / min.

2. The method according to claim 1, wherein: The thickness of the coating (10) is: -400.0 nm or more, or 500.0 nm or more, or 600.0 nm or more, or 700.0 nm or more, or 800.0 nm or more, or 900.0 nm or more, or 1000.0 nm or more; and / or -2000.0 nm or less, or 1900.0 nm or less, or 1800.0 nm or less, or 1700.0 nm or less, or 1600.0 nm or less, or 1500.0 nm or less, or 1400.0 nm or less.

3. The method according to claim 1 or 2, wherein: - the glass transition temperature of the coating (10) is -60°C or below, or -70°C or below, or -75°C or below, or -80°C or below; and / or - The glass transition temperature of the stopper (12) is -80°C or below, or -85°C or below, or -90°C or below, or -95°C or below, or -100°C or below, or below the storage temperature.

4. The method according to any one of the preceding claims, wherein: When at least one stopper (12) is inserted into the hollow cylinder (7) of the glass container (1), it is defined as (D s -D b ) / D s The plug compression ratio of the at least one plug (12) is: -8.0% or more, or 10.0% or more, or 12.0% or more, or 14.0% or more, or 15.0% or more; and / or -18.0% or less, or 17.5% or less, 17.0% or less, 16.5% or less, 16.0% or less, Among them, D s = Outer diameter of the uncompressed plug (12), D b =Inner diameter of the hollow cylinder (7).

5. The method according to any one of the preceding claims, wherein: The glass container (1) has a container closure integrity of at least 168 hours at -80°C by a standard ethanol-modified dye immersion test and / or a container closure integrity of at least 1 hour at -96°C by an O2 headspace analysis test.

6. The method according to any one of the preceding claims, wherein: - In addition to the pharmaceutical composition, the glass container (1) is also filled with a gas, - the volume enclosed by the glass container (1) and occupied by the gas is defined as the head space of the glass container (1); Preferably, the gas is or includes one or more of air, CO2, N2, Ar and / or O2.

7. The method according to claim 6, wherein: The glass container (1) is oriented vertically after filling and before cooling so that the head space of the glass container (1) is located near the stopper (12); Preferably, wherein the head space has a main part of a cylindrical volume, the main part of the volume has a specific height and a specific diameter equal to the inner diameter of the hollow cylinder (7), wherein the specific height is preferably measured from the center point of the at least one stopper (12) to the surface of the pharmaceutical composition facing the at least one stopper (12), wherein the value of the specific height is: - 2.0 mm or more, or 3.0 mm or more, or 4.0 mm or more, or 5.0 mm or more, or 6.0 mm or more, or 7.0 mm or more, or 8.0 mm or more, or 9.0 mm or more, or 10.0 mm or more, or 11.0 mm or more, or 12.0 mm or more, or 13.0 mm or more, or 14.0 mm or more, or 15.0 mm or more; and / or - 15.0 mm or less, or 14.0 mm or less, or 13.0 mm or less, or 12.0 mm or less, or 11.0 mm or less, or 10.0 mm or less, or 9.0 mm or less, or 8.0 mm or less, or 7.0 mm or less, or 6.0 mm or less, or 5.0 mm or less, or 4.0 mm or less, or 3.0 mm or less; and / or - between 2.0 mm and 15.0 mm, or between 2.0 mm and 10.0 mm, or between 3.0 mm and 9.0 mm, or between 3.0 mm and 5.0 mm (e.g. 4.0 mm), or between 5.0 mm and 7.0 mm (e.g. 6.0 mm), or between 7.0 mm and 9.0 mm (e.g. 8.0 mm).

8. The method according to any one of the preceding claims, wherein: Cooling the glass container (1) includes: maintaining a constant temperature within a range of 1.0°C to 5.0°C above the glass transition temperature of both the stopper (12) and the coating (10) for at least 1.0 minute, or at least 2.0 minutes, or at least 3.0 minutes, or at least 4.0 minutes, or at least 5.0 minutes.

9. The method according to any one of the preceding claims, wherein: The coating (10) comprises one or more cross-linked polysiloxane structural units and one or more non-cross-linked polysiloxane structural units, wherein the ratio of the weight of the cross-linked polysiloxane structural units to the weight of the non-cross-linked polysiloxane structural units in the coating (10) is less than 3.00, and optionally at least 0.

40.

10. The method according to any of the preceding claims, wherein: The coating (10) comprises at least two non-crosslinked polysiloxane structural units having different viscosities.

11. A glass container (1) for storing a pharmaceutical composition at a temperature of -80°C or lower, comprising: A hollow cylinder (7) having at least one open end (212-1, 212-2) and at least one stopper (12) closing the at least one open end (212-1, 212-2), wherein at least a portion of the inner surface of the glass container (1) comprises a coating (10), the coating (10) having a crystallization temperature range and a melting temperature range determined using differential scanning calorimetry at a temperature change rate of 10°C / min, wherein: - the crystallization temperature range overlaps with the melting temperature range in the temperature range of -75°C to -100°C, in particular at -80°C; and - the thickness of the coating (10) is 400.0 nm or more, or 800.0 nm or more, and / or 2000.0 nm or less, or 1500.0 nm or less; and - When the glass container (1) is cooled at a cooling rate of ≤6.0°C / min in the range of -50°C to -80°C and at a cooling rate of ≤5.0°C / min in the range of -80°C to -96°C, the distance between the outer surface of the stopper (12) and the inner surface of the glass container (1) including the coating (10) does not change by more than 1.0% at a temperature between the glass transition temperature of the coating (10) and the storage temperature.

12. The glass container (1) according to claim 11, wherein: When the at least one stopper (12) is inserted into the hollow cylinder (7) of the glass container (1), it is defined as (D s -D b ) / D s The plug compression ratio of the at least one plug (12) is: -8.0% or more, or 10.0% or more, or 12.0% or more, or 14.0% or more, or 15.0% or more; and / or -18.0% or less, or 17.5% or less, or 17.0% or less, or 16.5% or less, or 16.0% or less, Among them, D s = Outer diameter of the uncompressed plug (12), D b =Inner diameter of the hollow cylinder (7).

13. The glass container (1) according to claim 11 or 12, wherein: The coating (10) composition has the following ingredients in weight percentage: and / or, Wherein, the coating (10) composition has the following components in weight percentage: and / or, Wherein, the coating (10) composition has the following components in weight percentage:

14. The glass container (1) according to any one of claims 11 to 13, wherein: The coating (10) is cured at the following temperature: - below 150°C, or below 125°C; and / or -50°C or higher, or 60°C or higher.

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