Systems, liquid compositions, methods and uses for low temperature storage of pharmaceutical compositions

Abstract

The present invention relates to a system for the low temperature storage of pharmaceutical compositions. The present invention also relates to liquid compositions, methods and uses.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 167,869, filed March 30, 2021, U.S. Provisional Patent Application No. 63 / 243,477, filed September 13, 2021, U.S. Provisional Patent Application No. 63 / 243,485, filed September 13, 2021, U.S. Provisional Patent Application No. 63 / 243,558, filed September 13, 2021, and U.S. Provisional Patent Application No. 63 / 266,734, filed January 13, 2022, all of which are incorporated by reference in their entireties herein.

[0002] The present invention relates to a system for the low temperature storage of pharmaceutical compositions. The present invention also relates to liquid compositions, methods and uses.

[0003] Pharmaceutical containers for drug delivery are thus known in the prior art. These containers usually feature an outlet and a stopper that serves to elute the contents of the container through the closure. The stopper must slide within the container but provide a tight seal so that the composition remains safely stored for extended periods of time.

[0004] However, when such pharmaceutical containers pre-filled with a pharmaceutical composition are stored at low temperatures, there is a risk that the seal will be compromised during cooling or thawing.

[0005] It is therefore an object of the present invention to provide a means which overcomes the problems of the prior art and which can also be used to store compositions at low temperatures. It is a further object of the present invention to provide compositions, methods and uses.

[0006] DISCLOSURE OF THEINVENTION This object is solved by the present invention according to a first aspect, in which a system for storing a pharmaceutical composition at low temperature comprises: - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between the stopper and the closure; It is proposed to have In one embodiment, the pharmaceutical composition comprises or is a liquid.

[0007] For example, the material of the barrel may be or may include a cycloolefin copolymer (COC). Alternatively or additionally, the material of the barrel may have a linear thermal expansion coefficient of 10 -3 K -1 ~10 -4 K -1 , especially 0.6 10 -4 K -1 The coefficient of linear thermal expansion may be measured according to ISO 11359, part 1 / 2.

[0008] In one embodiment, the system is maintained at a storage temperature below 0° C., particularly below the freezing point of the pharmaceutical composition.

[0009] In one embodiment, the pharmaceutical container is a syringe.This is particularly preferred, because in this way, the pharmaceutical composition can be stored directly in the syringe in the form of prefilled syringe at low temperature.This makes the composition very easy to handle, because the syringe is prefilled and can be used for administration without transferring the composition to another container.Furthermore, this is also possible when the storage temperature of the composition is lower than the temperature at which the expansion of the composition occurs.

[0010] Throughout this application room temperature is preferably a temperature of 293.15 K, especially at 101.325 kPa.

[0011] For example, at least a portion of the second end may be in the form of or include a threaded portion or a luer lock.

[0012] For example, the closure may be in the form of or may include a threaded portion, a luer lock, a tip cap, and / or a hard cap. In one embodiment, the closure is additionally or alternatively reclosably connected to the barrel. In one embodiment, the closure is additionally or alternatively non-destructively removable from the barrel.

[0013] In one embodiment, it may be preferred to define the volume enclosed by the barrel that the gas occupies as the headspace of the system, particularly for a particular orientation of the vessel.

[0014] In one embodiment, for a vertical orientation of the container with the first end at the bottom and the second end at the top, the volume occupied by the gas enclosed by the barrel between the stopper and the closure may be preferably defined as the headspace A of the system.

[0015] In one embodiment, for a vertical orientation of the container with the second end at the bottom and the first end at the top, the volume occupied by the gas enclosed by the barrel between the stopper and the closure may be preferably defined as the headspace B of the system.

[0016] A headspace, such as headspace A and / or headspace B, can be variable depending on the ambient temperature, ambient pressure, etc. This is because a headspace, such as headspace A and / or headspace B, corresponds to a volume of gas within the barrel, which volume is subject to change. For example, the volume of gas depends on the environmental conditions and / or the volume of the composition within the barrel.

[0017] In one embodiment, at room temperature, it may be preferred that the volume occupied by the headspaces, such as headspace A and / or headspace B, is 1% or more of the volume occupied by the composition.

[0018] It is therefore based on the surprising discovery that storage of the composition is possible even at low temperatures if a suitable sized gas volume is provided in the container. It turns out that this allows a change in the volume of the composition without affecting the integrity of the container during cooling or thawing. This is because the proposed headspaces such as headspace A and / or headspace B make the system resistant to expansion or contraction of the pharmaceutical composition when the composition is cooled, especially below 0° C. or below the freezing point of the composition. The same is true when the system is thawed and the pharmaceutical composition expands or contracts. Furthermore, degradation of material properties is prevented by the proposed system due to the reduced effects during the cooling or thawing process.

[0019] In other words, the system allows the use of pre-filled containers and the freezing with the composition. At the same time, the risk of stopper migration or container leakage due to the change in volume of the composition during cooling or thawing is greatly reduced. This is very useful for pharmaceutical compositions that need to be stored at low temperatures, especially when the storage temperature is lower than the freezing point of the composition.

[0020] Furthermore, during cooling below the freezing point, the space required by the container within the additional packaging is compact and may not change, and safety is maintained since the container remains closed even at low temperatures.

[0021] The advantage is achieved in that the headspace, such as headspace A and / or headspace B, is variable, reducing the force applied to the stopper. In other words, the volume of the gas can be varied, for example compressed or expanded, by the space occupied by the composition, so that the force applied to the stopper or barrel is reduced. Thus, uncontrolled movement of the stopper or damage to the barrel can be prevented. This prevents leakage of the pharmaceutical composition due to the stopper coming out of the barrel. Thus, the expansion of the composition can occur within the volume occupied by the gas, rather than by moving the stopper. Thus, the expansion can be controlled.

[0022] This is an important finding because at lower temperatures two aspects must be considered: First, the release stress of the stopper in the barrel may change due to changes in the properties of the stopper and container materials; Second, the force acting on the stopper may change and may increase, particularly over at least some temperature ranges, due to the different volumes occupied by the composition at different temperatures.

[0023] For systems with the proposed headspaces, such as headspace A and / or headspace B at room temperature, the stopper can provide sufficient resistance to expansion of the pharmaceutical composition and still function at low temperatures, e.g., below 4° C. or below 0° C., below −20° C., below −40° C. or below −60° C. Thus, the pharmaceutical composition held by the barrel can be forced to expand in another available space rather than displacing the stopper.

[0024] The proposed system is therefore well suited for low temperature storage of pharmaceutical compositions.

[0025] The release stress can be considered as the force acting on the stopper, particularly in the axial direction away from the pharmaceutical composition, required to initiate the movement of the stopper in the barrel. To initiate and continue such movement, only a slippage force acts on the stopper, which is less than the release stress. The release stress can be considered as a measure of "how tightly the stopper rests in the barrel."

[0026] In one embodiment, the headspace B may preferably have a cylindrical volume region portion, which has a specific diameter equal to the inner diameter of the barrel and a specific height, which is preferably measured from the center point of the stopper to the surface of the liquid pharmaceutical composition facing the stopper, and which has a value of 0.1 mm or more.

[0027] The surprising finding is that a height ratio selected accordingly results in a beneficial situation in which the interaction between the expansion of the composition and the compression of the gas during the freezing and thawing process is such that only reduced or no movement of the stopper is observed at all. The inventors have found that a height ratio of at least 0.1 mm constitutes an optimal basis for said interaction.

[0028] It should be noted that in the case of a stopper in which the surface facing the liquid composition is a flat surface, the volume of the cylindrical volume region portion may be equal to the volume of headspace B.

[0029] Preferably, when measuring the specific height, the container has a vertical orientation with the second end at the bottom and the first end at the top.

[0030] In one embodiment, the specific height is: (i) 0.2 mm or more, preferably 0.5 mm or more, preferably 0.7 mm or more, preferably 1 mm or more, preferably 2 mm or more, preferably 3 mm or more, preferably 4 mm or more, preferably 5 mm or more, preferably 6 mm or more, preferably 7 mm or more, preferably 8 mm or more, preferably 9 mm or more, preferably 10 mm or more, preferably 11 mm or more, preferably 12 mm or more, preferably 13 mm or more, preferably 14 mm or more, preferably 15 mm or more, (ii) 15 mm or less, preferably 14 mm or less, preferably 13 mm or less, preferably 12 mm or less, preferably 11 mm or less, 10 mm or less, preferably 9 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, preferably 5 mm or less, preferably 4 mm or less, preferably 3 mm or less, preferably 2 mm or less, and / or (iii) It may be preferred that the length is 1 mm to 15 mm, preferably 1 mm to 10 mm, preferably 1 mm to 8 mm, preferably 1 mm to 3 mm, for example 2 mm, or 3 mm to 5 mm, for example 4 mm, or 5 mm to 7 mm, for example 6 mm, or 7 mm to 9 mm, for example 8 mm.

[0031] The specific height can be further specified depending on the context in which the system is used. The proposed specific height provided favorable results with regard to reducing or even eliminating stopper movement during the freeze and thaw process.

[0032] In one embodiment, the ratio of the inner diameter to the specific height of the barrel [mm / mm] is (i) 0.3 or more, preferably 0.7 or more, preferably 1 or more, preferably 1.05 or more, preferably 1.1 or more, preferably 1.3 or more, preferably 1.5 or more, preferably 2 or more, preferably 2.5 or more, preferably 3 or more, preferably 3.5 or more, preferably 4 or more, preferably 4.5 or more, preferably 5 or more, preferably 7 or more, preferably 10 or more, (ii) 10 or less, preferably 6 or less, preferably 5 or less, preferably 4 or less, preferably 3 or less, preferably 2 or less, preferably 1.5 or less, preferably 1.3 or less, preferably 1.0 or less, preferably 0.7 or less, preferably 0.5 or less, and / or (iii) It may be preferable that the ratio is 0.3 to 10, preferably 1 to 10, preferably 1 to 5, and preferably 1 to 2 or 2 to 4 or 3 to 5.

[0033] This ratio relates geometric aspects of the system, i.e. the inner diameter of the barrel, to aspects not inherently related to the geometry of the system, however, it has been found that a ratio selected along the lines of the proposed values ​​provides a reliable basis for providing a system with little or no stopper movement during freeze / thaw.

[0034] In one embodiment, the overall length of the barrel, specifically measured along the axial extension of the barrel, is: (i) 40 mm or more, preferably 45 mm or more, preferably 50 mm or more, preferably 55 mm or more, preferably 60 mm or more, preferably 65 mm or more, preferably 70 mm or more, preferably 75 mm or more, preferably 80 mm or more, (ii) 80 mm or less, preferably 75 mm or less, preferably 70 mm or less, preferably 65 mm or less, preferably 60 mm or less, preferably 55 mm or less, preferably 50 mm or less, preferably 45 mm or less, preferably 40 mm or less, and / or (iii) It may be preferable that the thickness is 40 mm to 80 mm, preferably 40 mm to 60 mm, particularly 45 mm to 55 mm, especially 45 mm to 50 mm, or 60 mm to 70 mm, especially 63 mm to 67 mm.

[0035] For example, the overall barrel length can be 65.7mm or 48.4mm.

[0036] In one embodiment, the inside diameter of the barrel is: (i) 5 mm or more, preferably 6 mm or more, preferably 7 mm or more, preferably 8 mm or more, preferably 9 mm or more; (ii) 10 mm or less, preferably 9 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, preferably 5 mm or less; and / or (iii) It may be preferred that the thickness is 5 mm to 10 mm, preferably 5 mm to 7 mm, particularly 6 mm to 7 mm, especially 6 mm to 6.5 mm, for example 6.35 mm, or 7 mm to 9 mm, particularly 8 mm to 9 mm, especially 8.5 mm to 9 mm, for example 8.65 mm.

[0037] For example, the inside diameter of the barrel can be 6.35 mm or 8.65 mm.

[0038] In one embodiment, (i) the overall length of the barrel, specifically measured along the axial extension of the barrel, is between 45 mm and 50 mm, and the inside diameter of the barrel is between 8 mm and 9 mm; or (ii) It may be preferred that the overall length of the barrel, particularly as measured along the axial extension of the barrel, is between 60 mm and 70 mm, and that the inside diameter of the barrel is between 5 mm and 7 mm.

[0039] Each selected combination of barrel overall length and barrel inside diameter results in a particular preferred system.

[0040] In one embodiment, it may be preferable that the following formula be satisfied:

[0041] (X / Y) / Z≦V, and / or W≦(X / Y) / Z, where X is the volume (ml) of the pharmaceutical composition at room temperature; Y is the headspace volume at room temperature (ml), Z is the inside diameter of the barrel (mm), V(1 / mm) is 1.5, preferably 1.4, preferably 1.3, preferably 1.2, preferably 1.1, preferably 1.0, preferably 0.9, preferably 0.8, preferably 0.7, preferably 0.6, preferably 0.5, preferably 0.4, preferably 0.3, preferably 0.2, preferably 0.1; and / or W(1 / mm) is 0.01, preferably 0.05, preferably 0.1, preferably 0.2, preferably 0.3, preferably 0.4, preferably 0.5, preferably 0.6, preferably 0.7.

[0042] In one embodiment, it may be preferred that the liquid pharmaceutical composition includes an excipient.

[0043] It is a surprising finding that the addition of an additive to the composition improves the movement of the stopper during freezing and / or thawing of the composition.

[0044] In one embodiment, it may be preferred that the additive is selected from the group consisting of salts, sugars, lipids and acids.

[0045] In one embodiment, the additive may be selected from the group consisting of NaCl, KCl, sucrose, sodium acetate, acetic acid, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, SM (sphingomyelin)-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC], cholesterol, polyethylene glycol (PEG), H3PO4, XH2PO4, X2HPO4 and X3PO4, where X is Na and / or K.

[0046] In one embodiment, the additive may preferably be NaCl.

[0047] In one embodiment, the additive may preferably be KCl.

[0048] In one embodiment, it may be preferred that the additive is sucrose.

[0049] In one embodiment, the additive may preferably be sodium acetate.

[0050] In one embodiment, it may be preferred that the additive is acetic acid.

[0051] In one embodiment, the additive may be a lipid, preferably ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, SM (sphingomyelin)-102, polyethylene glycol [PEG] 2000 dimyristoylglycerol [DMG], 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC] and / or cholesterol.

[0052] In one embodiment, the additive may preferably be polyethylene glycol (PEG).

[0053] In one embodiment, it may be preferred that the additive is H3PO4.

[0054] In one embodiment, the additive is XH2PO4, where X may be preferably Na and / or K.

[0055] In one embodiment, the additive is X2HPO4, where X may be preferably Na and / or K.

[0056] In one embodiment, the additive is X3PO4, where X may preferably be Na and / or K.

[0057] In one embodiment, it may be preferred that the additive is cholesterol.

[0058] In one embodiment, the concentration of the additive is: (i) 0.01 mol / l or more, preferably 0.05 mol / l or more, preferably 0.1 mol / l or more, preferably 0.2 mol / l or more, preferably 0.3 mol / l or more, preferably 0.4 mol / l or more, preferably 0.5 mol / l or more, preferably 0.7 mol / l or more, preferably 1 mol / l or more, (ii) 1 mol / l or less, preferably 0.9 mol / l or less, preferably 0.8 mol / l or less, preferably 0.7 mol / l or less, preferably 0.6 mol / l or less, preferably 0.5 mol / l or less, preferably 0.4 mol / l or less, preferably 0.3 mol / l or less, preferably 0.2 mol / l or less, and / or (iii) In some cases, it may be preferable that the concentration is 0.1 mol / l to 1 mol / l, preferably 0.1 mol / l to 0.8 mol / l, preferably 0.1 mol / l to 0.5 mol / l, preferably 0.2 mol / l to 0.4 mol / l, and preferably 0.25 mol / l.

[0059] Such concentrations have been found to result in particularly favorable systems.

[0060] In one embodiment, the concentration of the additive is: (i) 1 g / l or more, preferably 2 g / l or more, preferably 5 g / l or more, preferably 10 g / l or more, preferably 20 g / l or more, preferably 30 g / l or more, preferably 40 g / l or more, preferably 50 g / l or more, preferably 75 g / l or more, preferably 100 g / l or more, preferably 150 g / l or more, preferably 200 g / l or more, (ii) 300 g / l or less, preferably 200 g / l or less, preferably 150 g / l or less, preferably 120 g / l or less, preferably 100 g / l or less, preferably 90 g / l or less, preferably 80 g / l or less, preferably 70 g / l or less, preferably 60 g / l or less, preferably 50 g / l or less, preferably 40 g / l or less, preferably 30 g / l or less, preferably 20 g / l or less, preferably 10 g / l or less, preferably 5 g / l or less, and / or (iii) It may be preferable that the amount is 1 g / l to 300 g / l, preferably 5 g / l to 200 g / l, preferably 20 g / l to 150 g / l, preferably 50 g / l to 120 g / l, preferably 60 g / l to 100 g / l, preferably 70 g / l to 90 g / l.

[0061] Such concentrations have been found to result in particularly favorable systems.

[0062] In one embodiment, the concentrations of all compounds in the pharmaceutical composition are: (i) 0.01 mol / l or more, preferably 0.05 mol / l or more, preferably 0.1 mol / l or more, preferably 0.2 mol / l or more, preferably 0.3 mol / l or more, preferably 0.4 mol / l or more, preferably 0.5 mol / l or more, preferably 0.7 mol / l or more, preferably 1 mol / l or more, (ii) 1 mol / l or less, preferably 0.9 mol / l or less, preferably 0.8 mol / l or less, preferably 0.7 mol / l or less, preferably 0.6 mol / l or less, preferably 0.5 mol / l or less, preferably 0.4 mol / l or less, preferably 0.3 mol / l or less, preferably 0.2 mol / l or less, and / or (iii) In some cases, it may be preferable that the concentration is 0.1 mol / l to 1 mol / l, preferably 0.1 mol / l to 0.8 mol / l, preferably 0.1 mol / l to 0.5 mol / l, preferably 0.2 mol / l to 0.4 mol / l, and preferably 0.25 mol / l.

[0063] In one embodiment, at room temperature, a headspace, such as headspace A and / or headspace B, of the volume occupied by the composition, respectively. (i) 1.3% or more, preferably 1.5% or more, preferably 1.7% or more, preferably 2% or more, preferably 2.5% or more, preferably 3% or more, preferably 3.5% or more, preferably 4% or more, preferably 4.5% or more, preferably 5% or more, preferably 6% or more, preferably 7% or more, preferably 8% or more, preferably 9% or more, preferably 10% or more, preferably 11% or more, preferably 12% or more, preferably 13% or more, preferably 14% or more, preferably 15% or more, preferably 17% or more, preferably 20% or more, (ii) 20% or less, preferably 17% or less, preferably 15% or less, preferably 14% or less, preferably 13% or less, preferably 12% or less, preferably 11% or less, preferably 10% or less, preferably 9% or less, preferably 8% or less, preferably 7% or less, preferably 6% or less, preferably 5% or less, preferably 4.5% or less, preferably 4% or less, preferably 3.5% or less, preferably 3% or less, preferably 2.5% or less, preferably 2% or less, preferably 1.7% or less, preferably 1.5% or less, preferably 1.3% or less, and / or (iii) It may be preferred that it is between 1% and 20%, in particular between 1.5% and 3%, between 2% and 5%, between 4% and 8%, between 7% and 12%, between 10% and 15%, between 12% and 17% and / or between 15% and 20%.

[0064] A larger headspace is preferred if the composition needs to be shaken before use, as this is easier the larger the headspace.

[0065] For example, for a barrel with a nominal volume of 1 ml, the headspaces, such as headspace A and / or headspace B, may be 2 mm along the axial direction of the container.

[0066] In one embodiment, (i) the stopper is slidably disposed within the barrel; (ii) the stopper has a peripheral surface that at least partially contacts an inner surface of the barrel; and / or (iii) It may be preferred that the first end is a proximal end of a container, particularly a barrel, and / or that the second end is a distal end of a container, particularly a barrel.

[0067] In one embodiment, when vertically oriented, the stopper, pharmaceutical composition and gas may be arranged in the barrel from bottom up.

[0068] In one embodiment, the system or parts thereof are adapted to prevent headspaces, such as headspace A and / or headspace B, particularly at room temperature, from expanding the pharmaceutical composition, particularly preferably during expansion of the composition during cooling of the system, particularly from (a) above 4° C., particularly from room temperature, and / or (b) to a temperature below 0° C., particularly below the freezing point of the composition, and / or below the storage temperature of the system. (i) the pharmaceutical composition is capable of expanding or expanding by displacing and / or compressing gas, thus reducing the volume of a headspace, such as headspace A and / or headspace B; (ii) the maximum force exerted on the stopper by the pharmaceutical composition and / or gas, particularly in the axial direction, is lower than the release stress of the stopper; (iii) the stopper moves by 5 mm or less, preferably by 4 mm or less, preferably by 3.5 mm or less, preferably by 3 mm or less, preferably by 2.7 mm or less, preferably by 2.5 mm or less, preferably by 2.3 mm or less, preferably by 2.0 mm or less, preferably by 1.7 mm or less, preferably by 1.5 mm or less, preferably by 1.3 mm or less, preferably by 1.0 mm or less, preferably by 0.8 mm or less, preferably by 0.6 mm or less, preferably by 0.5 mm or less, preferably by 0.4 mm or less, preferably by 0.3 mm or less, preferably by 0.2 mm or less, preferably by 0.1 mm or less, and / or (iv) the stopper moves by 0.01 mm or more, preferably by 0.05 mm or more, preferably by 0.1 mm or more, preferably by 0.3 mm or more, preferably by 0.5 mm or more, preferably by 0.7 mm or more, preferably by 1.0 mm or more; Preferably, the barrel is oriented during cooling such that (a) the first end is at the bottom and / or the second end is at the top, and / or (b) the pharmaceutical composition and gas are disposed along the axial direction of the container, in particular the barrel. It may be preferable for the two components to be designed to be compatible with each other in such a way that

[0069] Thus, the headspaces, such as headspace A and / or headspace B, can be reduced, resulting in additional space to accommodate the expanded material of the composition, thereby reducing the risk of the container being damaged and / or the stopper becoming dislodged.

[0070] The headspaces, such as headspace A and / or headspace B at a particular temperature, e.g., room temperature, can be easily adapted, e.g., by changing the default position of the stopper in the barrel, or by the size of the barrel. Thus, the system can be conveniently and efficiently adapted to withstand nearly the maximum expected forces that may act on the stopper during cooling, thawing and storage of the system for a particular composition.

[0071] It may also be acceptable for the stopper to move during expansion of the material of the composition, for example, in this manner to reduce headspaces such as headspace A and / or headspace B.

[0072] If the movement of the stopper is permitted, it is preferred that the movement of the stopper is limited within certain boundaries. The proposed values ​​are the preferred permissible distances of the permitted movement, since the proposed distances correspond to the typical distances between the two sealing lips of the stopper that have the greatest distance from each other, especially when the stopper is inserted inside the barrel and / or measured along the axial direction of the barrel.

[0073] At least one sealing lip typically functions as a sterile barrier between the sterile part of the inner surface of the barrel and the non-sterile part of the inner surface of the barrel. It is necessary that the pharmaceutical composition is in contact only with the sterile part of the inner surface of the barrel. Using the distance of such two lips as a criterion is beneficial because if the movement of the stopper does not exceed the respective distance, the composition enclosed in the barrel will always be in contact only with the sterile part of the inner surface of the barrel.

[0074] Thus, if the travel of the stopper is limited due to the cool-thaw cycle of the system, the system passes the adaptive CCI test as defined elsewhere in the description. In one embodiment, the system passes the adaptive CCI test as defined elsewhere in this specification.

[0075] In one embodiment, the maximum travel can correspond to the distance between two sealing lips of the stopper that have a maximum distance from each other, especially when the stopper is inserted inside the barrel and / or measured along the axial direction of the barrel. Alternatively or additionally, the maximum travel may correspond to the distance between two directly adjacent sealing lips of the stopper, which can further improve safety.

[0076] In one embodiment, (i) Storage temperature: (a) -100°C or higher, preferably -80°C or higher, preferably -60°C or higher, preferably -40°C or higher, preferably -20°C or higher, preferably -10°C or higher; (b) 0° C. or less, -1° C. or less, preferably -5° C. or less, preferably -15° C. or less, preferably -25° C. or less, preferably -35° C. or less, preferably -55° C. or less, preferably -75° C. or less, preferably -95° C. or less and / or (c) -100 to 0°C, preferably -80 to -5°C, preferably -60 to -20°C, preferably -50 to -40°C, and / or (d) 0°C, -10°C, -20°C, -30°C, -40°C or -50°C, and / or (ii) It may be preferable for the storage temperature to be below the freezing point temperature of the composition.

[0077] The storage temperature can be selected according to the requirements posed by the pharmaceutical composition.

[0078] In one embodiment, (i) the pharmaceutical composition comprises HO, in particular more than 80% (w / w), preferably more than 90% (w / w), preferably more than 95% (w / w), preferably more than 97% (w / w), preferably more than 98% (w / w) of the composition is HO; and / or (ii) The gas may comprise, or preferably be, air, CO2, N2, Ar and / or O2.

[0079] The pharmaceutical composition may contain HO, which undergoes high expansion during the freezing process.

[0080] If the gas is air, CO2, N2, Ar and / or O2, a particular inexpensive provision of the system is possible.

[0081] In one embodiment, the overall length of the vessel, particularly measured along the axial extension of the vessel, is: (i) 30 mm or more, preferably 40 mm or more, preferably 50 mm or more, preferably 60 mm or more, preferably 70 mm or more, preferably 80 mm or more, preferably 90 mm or more, preferably 100 mm or more, preferably 110 mm or more, preferably 120 mm or more, preferably 130 mm or more, preferably 150 mm or more, preferably 170 mm or more, preferably 190 mm or more, (ii) 200 mm or less, preferably 150 mm or less, preferably 140 mm or less, preferably 130 mm or less, preferably 110 mm or less, preferably 100 mm or less, preferably 90 mm or less, preferably 80 mm or less, preferably 70 mm or less, preferably 60 mm or less, preferably 50 mm or less, preferably 40 mm or less, and / or (iii) It may be preferable that the thickness is 30 mm to 200 mm, preferably 50 mm to 150 mm, and particularly 50 mm to 100 mm, for example 60 mm to 90 mm and / or 90 mm to 150 mm.

[0082] For example, the overall length of the container can be 73.9mm, 74.6mm, 92.4mm, 72.7mm, 55.4mm, 59.9mm, 62.5mm, 74mm, 91.7mm, 72.6mm, 54mm, 72.5mm, 90.5mm, 85mm, 105.8mm, 128.3mm or 136.9mm.

[0083] To measure the overall length of the container, a closure may be placed over each end of the barrel.

[0084] Preferably, in this application, the term "between X and Y," where X and Y are particular values, should be understood to include the values ​​X and Y. For example, a parameter having a value of 1 to 2 means that the parameter can have a value between 1 and 2, inclusive.

[0085] In one embodiment, the overall length of the barrel, specifically measured along the axial extension of the barrel, is: (i) 30 mm or more, preferably 40 mm or more, preferably 50 mm or more, preferably 60 mm or more, preferably 70 mm or more, preferably 80 mm or more, preferably 90 mm or more, preferably 100 mm or more, preferably 110 mm or more, preferably 120 mm or more, preferably 130 mm or more, preferably 150 mm or more, preferably 170 mm or more, preferably 190 mm or more, (ii) 200 mm or less, preferably 150 mm or less, preferably 140 mm or less, preferably 130 mm or less, preferably 110 mm or less, preferably 100 mm or less, preferably 90 mm or less, preferably 80 mm or less, preferably 70 mm or less, preferably 60 mm or less, preferably 50 mm or less, preferably 40 mm or less, and / or (iii) It may be preferable that the thickness is 30 mm to 200 mm, preferably 40 mm to 130 mm, and particularly 40 mm to 80 mm, 50 mm to 80 mm, and / or 70 mm to 130 mm.

[0086] For example, the overall barrel length can be 65.7mm, 67mm, 84.7mm, 65.7mm, 48.4mm, 52.9mm, 55.5mm, 67mm, 84.7mm, 64.5mm, 45.9mm, 64.4mm, 82.4mm, 76.9mm, 97.7mm, 120.2mm, or 128.8mm.

[0087] In one embodiment, the inside diameter of the barrel is: (i) 5 mm or more, preferably 8 mm or more, preferably 10 mm or more, preferably 13 mm or more, preferably 15 mm or more, preferably 18 mm or more, preferably 20 mm or more, preferably 25 mm or more, preferably 30 mm or more, (ii) 30 mm or less, preferably 28 mm or less, preferably 25 mm or less, preferably 20 mm or less, preferably 15 mm or less, preferably 13 mm or less, preferably 10 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, and / or (iii) It may be preferable that the thickness is 5 mm to 30 mm, preferably 5 mm to 10 mm, 10 mm to 15 mm, 14 mm to 18 mm, 17 mm to 20 mm, and / or 20 mm to 30 mm.

[0088] For example, the inner diameter of the barrel can be 6.35 mm, 8.65 mm, 6.5 mm, 8.75 mm, 12.2 mm, 14.7 mm, 18.2 mm, or 27.9 mm.

[0089] In one embodiment, the outer diameter of the barrel is: (i) 5 mm or more, preferably 8 mm or more, preferably 10 mm or more, preferably 13 mm or more, preferably 15 mm or more, preferably 18 mm or more, preferably 20 mm or more, preferably 25 mm or more, preferably 30 mm or more, preferably 35 mm or more, preferably 40 mm or more, (ii) 40 mm or less, preferably 35 mm or less, 30 mm or less, preferably 28 mm or less, preferably 25 mm or less, preferably 20 mm or less, preferably 15 mm or less, preferably 13 mm or less, preferably 10 mm or less, preferably 7 mm or less, preferably 5 mm or less, and / or (iii) It may be preferable that the thickness is 5 mm to 40 mm, preferably 5 mm to 9 mm, 8 mm to 13 mm, 12 mm to 16 mm, 15 mm to 20 mm, 19 mm to 25 mm, and / or 25 mm to 35 mm.

[0090] For example, the outer diameter of the barrel can be 8.15 mm, 10.85 mm, 9.4 mm, 11.4 mm, 11.6 mm, 15 mm, 18 mm, 21.6 mm, or 31.5 mm.

[0091] In one embodiment, the volume of the composition at room temperature is: (i) 0.1 ml or more, preferably 0.2 ml or more, preferably 0.3 ml or more, preferably 0.5 ml or more, preferably 0.7 ml or more, preferably 1 ml or more, preferably 1.5 ml or more, preferably 2 ml or more, preferably 3 ml or more, preferably 5 ml or more, preferably 10 ml or more, preferably 15 ml or more, preferably 20 ml or more, preferably 30 ml or more, preferably 50 ml or more, preferably 70 ml or more, (ii) 100 ml or less, preferably 70 ml or less, preferably 55 ml or less, preferably 25 ml or less, preferably 15 ml or less, preferably 10 ml or less, preferably 7 ml or less, preferably 6 ml or less, preferably 5 ml or less, preferably 4 ml or less, preferably 3 ml or less, preferably 1 ml or less, preferably 0.7 ml or less, preferably 0.5 ml or less, preferably 0.3 ml or less, preferably 0.2 ml or less, and / or (iii) It may be preferable that the amount is 0.1 ml to 100 ml, preferably 0.1 ml to 1 ml or 1 ml to 100 ml, for example 1 ml to 50 ml, and particularly 1 ml to 3 ml, 1 ml to 10 ml, 10 ml to 20 ml, 20 ml to 30 ml, 30 ml to 40 ml, and / or 40 ml to 50 ml.

[0092] For example, at room temperature the composition may have a volume of 1 ml, 1.25 ml, 2.25 ml, 3 ml, 5 ml, 10 ml, 20 ml or 50 ml.

[0093] In one embodiment, it may be preferred that when the system is cooled from room temperature (20°C) to -20°C, preferably -50°C, preferably -80°C, the position of the stopper moves along the axis of rotation of the barrel by no more than 4.0mm, preferably no more than 3.0mm, preferably no more than 2.5mm, preferably no more than 2.0mm, preferably no more than 1.5mm, preferably no more than 1.0mm, preferably no more than 0.8mm, preferably no more than 0.5mm, preferably no more than 0.3mm, preferably no more than 0.1mm.

[0094] In one embodiment, it may be preferred that the system has a temperature below -20°C and above -200°C, preferably below -40°C and above -120°C, preferably below -50°C and above -90°C.

[0095] In one embodiment it may be preferred that the system is stored for 5 days or more, preferably 1 month or more, preferably 3 months or more, preferably 6 months or more, preferably 1 year or more.

[0096] In one embodiment, it may be preferred that the stopper comprises at least one internal recess.

[0097] More precisely, the recess can be provided on the inside of the stopper and preferably extend from one end of the stopper along the longitudinal axis of the stopper. In particular, the stopper can be provided with such an inner recess both when used with a syringe barrel or when used with a cartridge barrel. Such a recess allows the stopper to be placed in the barrel in an easy and safe manner. When used with a syringe barrel, the inner recess can serve to receive the plunger rod.

[0098] In one embodiment, it may be preferred that the barrel comprises a polymer, preferably a cyclic olefin copolymer (COC) and / or a cyclic olefin polymer (COP).

[0099] In one embodiment, the closure preferably comprises bromobutyl rubber, and preferably the closure is a siliconized closure comprising bromobutyl rubber.

[0100] In one embodiment, the barrel may preferably comprise a polymer, preferably COC and / or COP, and the closure may preferably comprise bromobutyl rubber, preferably the closure is a siliconized closure comprising bromobutyl rubber.

[0101] Surprisingly, it has been found that the combination of a polymer syringe, preferably comprising COC and / or COP, and a polymer closure, preferably made of bromobutyl, results in improved airtightness. Thus, in one embodiment, it may be preferred to provide a polymer syringe, preferably comprising COC and / or COP, and a polymer closure, preferably made of bromobutyl.

[0102] This object is solved by the present invention according to a second aspect, in which the method comprises the steps of: It is proposed to comprise the step of administering to a subject an effective amount of at least one pharma- ceutical active ingredient comprised in a pharmaceutical composition using a system according to the first aspect of the invention.

[0103] Surprisingly, it has been found that administration can be improved, and in particular made safer, after thawing the system, which is a system according to the first aspect of the invention, since such a system is resistant to low temperatures. In this regard, reference may be made to the explanations provided above with respect to the first aspect of the invention.

[0104] This object is solved by the present invention according to a third aspect, wherein the liquid composition comprises In methods of treatment of the human or animal body by surgery or therapy, or For use in diagnostic procedures performed on the human or animal body The composition includes at least one pharma- ceutical active ingredient and the method includes: It is proposed to include the step of administering an effective amount of said active ingredient to a subject using a system according to the first aspect of the invention.

[0105] This object is solved by the present invention according to a fourth aspect, in which a system according to the first aspect of the present invention comprises: In methods of treatment of the human or animal body by surgery or therapy, or For use in diagnostic methods carried out on the human or animal body, The composition comprises at least one pharma- ceutical active ingredient, and the method comprises: It is proposed to include the step of administering an effective amount of said active ingredient to a subject using the system.

[0106] In one embodiment, in the case of the system according to the first aspect of the invention, the method according to the second aspect of the invention, the use according to the third aspect of the invention and / or the use according to the fourth aspect of the invention, it may be preferred that the composition comprises mRNA.

[0107] This object is solved by the present invention according to a fifth aspect, in which it is proposed that an apparatus for manufacturing a system according to the first aspect of the present invention comprises a servomotor and a laser fixedly attached to the servomotor, in particular mechanically fixedly attached.

[0108] Such an apparatus is particularly useful for positioning the stopper of the system by translating the stopper by a servo motor to a specific position within the barrel along the axial extension of the barrel.

[0109] The particular location can be determined by a positioning system that includes a laser.

[0110] Therefore, a laser may also be included in the positioning system.

[0111] This object is solved by the present invention according to a sixth aspect, in which it is proposed that a method for producing a system according to the first aspect of the invention comprises the steps of: (i) using an apparatus according to the fifth aspect of the invention; and / or (ii) (a) providing a barrel, preferably having one end which is open and / or another end which is closed, (b) filling the barrel with a liquid pharmaceutical composition, (c) providing a stopper, and / or (d) positioning the stopper by translating the stopper along an axial extension of the barrel to a specific position within the barrel by means of a servo motor, in particular a servo motor comprised in the apparatus, the specific position being determined by a positioning system comprising a laser, in particular the laser being mechanically fixedly attached to the servo motor.

[0112] This object is solved by the present invention according to a seventh aspect, in which the use of a system according to the first aspect of the invention for long-term storage at low temperatures is proposed.

[0113] In one embodiment, it may be preferred that long term storage is 5 days or more, preferably 1 month or more, preferably 3 months or more, preferably 6 months or more, preferably 1 year or more.

[0114] In one embodiment, it may be preferred that the low temperature is -20°C or lower, preferably -50°C or lower, preferably -80°C or lower.

[0115] This object is solved by the present invention according to an eighth aspect, in which there is proposed a bundle comprising 5 or more, preferably 10 or more, preferably 30 or more, preferably 50 or more, preferably 100 or more systems according to the first aspect of the invention, wherein for each two of the systems the volume of the system's headspace such as system headspace A and / or system headspace B differs by not more than 0.5ml, preferably not more than 0.4ml, preferably not more than 0.3ml, preferably not more than 0.2ml, preferably not more than 0.1ml.

[0116] This object is solved by the present invention according to a further aspect, wherein the system comprises a pharmaceutical container for storing a pharmaceutical composition at low temperature, the container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel.

[0117] Further Preferred Embodiments Further optional features and design options are presented below.

[0118] Medicine containers The pharmaceutical container may be selected from a syringe, a cartridge, and a carpule.

[0119] The inner surface of the barrel may have a water contact angle of at least 80°. A high water contact angle indicates that the inner surface is hydrophobic. If the water contact angle is greater than 90°, the surface is called superhydrophobic. Preferably, the inner surface of the barrel is superhydrophobic. The water contact angle may be at least 95°, or even as high as at least 100°. In a preferred embodiment, the inner surface of the barrel is not plasma treated and / or other hydrophilicity enhancing treatment. Typical plasma treated inner surfaces have water contact angles significantly less than 90°.

[0120] If the inner surface is hydrophobic, microleakage and / or protein absorption can be reduced.

[0121] Preferably, the peripheral surface θ of the stopper C and the inner surface of the barrel θ I The ratio of the water contact angles between C / θ I >0.9. Preferably, θ C / θ I is greater than 0.9 to 2, or greater than 1 to 1.5. C / θ Iis greater than 1, greater than 1.1 or greater than 1.2. Controlling the water contact angle improves BLGF properties. It has been found that maintaining the water contact angle between the stopper and the inner surface of the barrel within a certain range helps achieve the desired properties.

[0122] The water contact angle can be measured using the static method with a drop volume of 2 μl according to DIN 55660-2:2011-12, chapter 5.2.2.

[0123] The inner surface of the barrel may have a surface energy of less than 45 mN / m, or less than 40 mN / m. Preferably, the surface energy of the inner surface is higher than the surface energy of the peripheral surface of the stopper. The surface energy can be measured indirectly by calculating values ​​from contact angle measurements with the Owens-Wendt-Rabel-Kaelble (OWRK) method according to DIN 55660-2:2011-12, chapter 6.2.

[0124] The pharmaceutical container may be essentially free of lubricants. "Free of lubricants" means that the amount of lubricant per container is less than 100 μm, less than 30 μg, or even less than 10 μg. The above restrictions may be particularly applicable to silicone as a lubricant.

[0125] The pharmaceutical container and / or barrel may be made partially or entirely of a material suitable for primary packaging of pharmaceutical products. Suitable materials include glass or polymers. The polymer may be an amorphous polymer. Transparent polymers are preferred. Suitable polymers may be selected from the group including cyclic olefin copolymers (COC), cyclic olefin polymers (COP), polyethylene terephthalate (PET), polycarbonate (PC), polypropylene (PP), and methyl methacrylate acrylonitrile butadiene styrene polymers (MABS). These polymers have the advantages of low density, high transparency, low birefringence, very low water absorption, excellent water vapor barrier properties, high stiffness, strength and hardness, excellent biocompatibility, very good resistance to acids and alkalis, and very good melt processability.

[0126] The barrel and / or pharmaceutical container may be made of a polymer, preferably one with a low density compared to glass, e.g., between 0.9 and 1.2 g / cm 3 , preferably 1 to 1.1 g / cm 3 A polymer with a greater density is selected. If a lower density material is used, shipping costs can be reduced. Density can be determined using the method described in ISO 1183-1:2013-04.

[0127] For long-term storage, 0.1g*mm / m 2 *d, preferably less than 0.07g*mm / m 2 *Less than d, or 0.05g*mm / m 2 It is preferred that a material having a water vapor permeability of less than *d is used for the barrel. Water vapor permeability can be tested using the method described in ISO 15106-3:2003.

[0128] For the release stress (BLF) and balance stress (GF) to remain sufficiently constant over the temperature range relevant to the bioactive agent, e.g., 4°C to 25°C, the coefficient of linear thermal expansion (CTE) of the material used for the barrel should be within 0.3 to 0.8*10 -4 K -1 , or 0.4~0.7*10 -4 K -1 , or 0.3~0.8*10 -4 K -1 In a preferred embodiment, the ratio of the CTE of the stopper material to the CTE of the barrel material is preferably in the range of S / CTE B is less than 7, preferably less than 6 or at most 5. If this ratio is too high, the stopper will shrink significantly when the container is cooled, for example to 4° C. in a refrigerator. This can cause leakage.

[0129] The present invention provides a large degree of freedom in design because the effects of the present invention can be achieved with an uncoated barrel, and therefore the inner surface of the barrel does not need to be coated.

[0130] The barrel has an inside diameter ID measured perpendicular to the longitudinal axis of the container. The inside diameter ID can range from 3 mm to 40 mm, preferably from 4 mm to 20 mm. The inside diameter is generally larger for larger barrel volumes. Larger diameters often result in higher values ​​of BLF and GF due to the increased contact area between the circumferential surface of the stopper and the inner surface of the barrel.

[0131] The barrel wall may be made of a transparent material that has a minimum transmittance of at least 60% within a wavelength interval at least 100 nm wide in the wavelength range of 400-700 nm, measured at a material thickness of 1 mm. Preferably, the minimum transmittance is at least 70%.

[0132] The material of the barrel wall can have a refractive index of 1.5-1.6 and / or a diffraction characterized by an Abbe number of 50-60. The use of a material with an appropriate refractive index is useful to allow good visual inspection of the contents of the pharmaceutical composition. Because the pharmaceutical container of the present invention is suitable for administration of parenteral drug compositions, visual inspection of the container for impurities, precipitation, crystallization and particles is of paramount importance.

[0133] The wall thickness of the barrel may be from 0.7 mm to 2.5 mm, or from 1 mm to 2 mm, or from 1.3 mm to 1.9 mm.

[0134] Stopper The stopper has a body having at least one annular projection and a circumferential surface. The "circumferential surface" is the surface of the stopper that faces the inner surface of the barrel when the stopper is placed in the barrel. The circumferential surface includes the surface of the annular projection. If the stopper is coated, the surface of the coating that faces the inner surface of the barrel is part of or constitutes the circumferential surface. The "contact surface" is the portion of the circumferential surface that contacts the inner surface of the barrel when the stopper is inserted into the barrel.

[0135] An "annular protrusion" is a portion of a stopper having a diameter greater than the average diameter measured perpendicular to the longitudinal axis of the barrel. The annular protrusion contacts the inner surface of the barrel to seal the joint between the stopper and the barrel. A portion of a stopper that is greater than the average diameter of the stopper but does not contact the inner surface of the barrel to the extent of at least 80%, 90%, 99.9%, or 100% during distal movement of the stopper is not considered an "annular protrusion." The annular protrusion helps to maintain the stopper in its intended position within the barrel and stabilizes its orientation in the proximal-distal direction, thereby affecting the BLF and GF values ​​of the container. Additionally, the annular protrusion seals the joint between the stopper and the inner surface of the barrel.

[0136] The stopper may optionally feature one or more trailing ribs. A "trailing rib" is a portion of the stopper that has a diameter greater than the average diameter measured perpendicular to the longitudinal axis of the barrel. However, the trailing rib has a smaller diameter than the annular projection so that the stopper does not significantly contact the inner surface of the barrel as it moves in the proximal-distal direction. Such trailing ribs may serve the purpose of stabilizing the orientation of the stopper within the barrel without effectively sealing the joint between the stopper and the inner surface. Trailing ribs typically do not significantly affect the BLF and GF because they have limited, if any, contact with the inner surface.

[0137] The stopper may be coated with a coating. The coating may be a polymer. In one embodiment, the coating comprises a resin such as polytetrafluoroethylene (PTFE), densified expanded polytetrafluoroethylene (ePTFE), tetrafluoroethylene (TFE), fluorinated polymers such as polymers selected from the group consisting of tetrafluoroethylene-perfluoroethylene copolymers, tetrafluoroethylene-hexafluoropropylene copolymers, tetrafluoroethylene-ethylene copolymers, trichlorotrifluoroethylene, polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymers, and copolymers, blends, and combinations thereof. The coating may also be formed by a layer comprising polyethylene, polypropylene, polyparaxylxylene, polylactic acid, and copolymers, blends, and combinations thereof. PTFE coating is the preferred coating choice. These coatings reduce the coefficient of friction of the circumferential surface of the stopper on the inner surface of the barrel. In an embodiment, at least a portion of the circumferential surface of the stopper that would be in contact with the inner surface of the barrel is coated.

[0138] The stopper may have an elastomeric body having a yield stress of at least 10 MPa measured according to ISO 527-2:2012(E) and / or a low sliding friction coefficient against steel of less than 0.23 measured according to DIN EN ISO 8295 / 2004-10. The stopper may be made of thermoplastic elastomers and / or rubbers, 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, neoprene rubber, butadiene rubber, styrene-butadiene rubber, ethylene propylene rubber, isoprene-isobutylene rubber, nitrile rubber, and combinations and mixtures thereof. In particular, the body of the stopper may be made of the above-mentioned rubbers and / or thermoplastic elastomers.

[0139] The body may be coated with a resin as described above. The coating may have a thickness of less than 1 mm, in particular 0.5 μm to 200 μm, in particular 10 μm to 125 μm, or 30 to 100 μm. These thicknesses are easily applied and have proven sufficient for the desired effect on friction.

[0140] The peripheral surface of the stopper may have a water contact angle of at least 100°, or at least 110°. The peripheral surface of the stopper may be superhydrophobic. The use of superhydrophobic stoppers in the containers of the invention contributes to beneficial BLGF values ​​due to a combination of a low coefficient of sliding friction and a low adhesive arrangement.

[0141] The pharmaceutical container of the present invention allows for an excellent seal between the annular protrusion and the inner surface of the barrel, even if the compression of the stopper is relatively low. The stopper compression (SC) can be calculated as follows: SC=(OD-ID) / OD, where OD indicates the outer diameter of the stopper and ID indicates the inner diameter of the barrel. The stopper compression can be less than 0.1, less than 0.075, or less than 0.05. Using a low stopper compression allows the stopper to slide easily in the barrel, thereby keeping the total balanced force variation (TGFV) very low and reducing the BLF.

[0142] The peripheral surface of the stopper and the inner surface of the barrel may at least partially contact one another at a contact area, sometimes referred to as a seal area. In an embodiment, the contact area is at least 8 mm 2 , up to 48mm 2 The contact area is 8 to 48 mm 2 Or 10~40mm 2 , 15~30mm 2 , 16~24mm 2 In the case of multiple annular projections, each projection contributes to the contact area. A minimum contact area is useful to achieve an adequate seal. Too large a contact area may result in too large a BLGF value.

[0143] Liquid Composition The present invention also relates to a liquid composition for use in a method of treatment of the human or animal body by surgery or therapy and / or for use in a diagnostic method performed on the human or animal body. Such a liquid composition may also be included in the proposed system. The liquid composition may be liquid and / or sterile. The pharmaceutical container may contain the liquid composition in a barrel.

[0144] The compositions comprise at least one pharma- ceutical active ingredient. A "pharma- ceutical active ingredient" includes therapeutic and / or diagnostic active ingredients.

[0145] The method includes the step of administering to a subject an effective amount of the pharma- ceutical active ingredient using the pharmaceutical container of the present invention.

[0146] The pharma- ceutical active ingredient can be a peptide or protein, such as an antibody, an enzyme, a vaccine, a receptor, etc. The pharmaceutical container of the present invention is particularly suitable for administering biologically active ingredients, such as peptides or proteins, since it is highly resistant to temperature changes with respect to BLGF. This means that BLGF does not change significantly within the temperature range of 4°C to 25°C. This is relevant, since biological agents are usually stored in a refrigerator to extend the shelf life of the product.

[0147] In an embodiment, the pharma- ceutical active ingredient is or comprises mRNA.

[0148] The medicament container may be combined with an injection device. The injection device may be attached to the container at a distal opening of the container. The injection device may be a needle. The medicament container may be part of an automatic injector.

[0149] Annular protrusion The stopper may have at least two annular protrusions. In one embodiment, the stopper has one to five annular protrusions, such as two to four. In certain embodiments, the stopper may have one, two, three, four, or five annular protrusions. The annular protrusions are useful for closing the joint between the inner surface of the barrel and the circumferential surface of the stopper. The diameter of the stopper may be larger at the annular protrusions than the average diameter of the stopper. The annular protrusions may contact the inner surface of the barrel when the stopper is moved distally, for example, when the stopper is used to push the contents of a pharmaceutical container from a container. The surface of the annular protrusion may form a portion of the circumferential surface of the stopper.

[0150] At least one, and preferably all, of the annular projections may have a diameter that exceeds the inner diameter of the barrel. Preferably, the diameter of at least one, and preferably all, of the annular projections exceeds the inner diameter of the barrel by at least 0.05 mm, or at least 0.1 mm, or at least 0.15 mm. The outer diameter of the annular projection may be equal to the outer diameter of the stopper. The diameter is measured perpendicular to the longitudinal axis of the barrel.

[0151] Surface roughness The surface roughness value can be controlled, for example, by adjusting the temperature during injection molding. In an embodiment, the inner surface of the barrel can have a surface roughness Ra of less than 100 nm. The surface roughness Ra given herein can be an average surface roughness or a maximum surface roughness. Preferably, the surface roughness Ra of the inner surface of the barrel is less than 80 nm, less than 70 nm, less than 60 nm, less than 50 nm, or less than 40 nm. The surface roughness Ra can be at least 1 nm, at least 3 nm, or at least 7 nm. Preferred ranges include surface roughness Ra values ​​of 1 nm to 80 nm, 3 nm to 70 nm, or 7 nm to 50 nm.

[0152] Additionally or alternatively, the surface roughness may be given as an Rms roughness. In an embodiment, the inner surface of the barrel may have a surface roughness Rms of less than 150 nm. The surface roughness Rms given herein may be an average surface roughness or a maximum surface roughness. Preferably, the surface roughness Rms of the inner surface of the barrel is less than 120 nm, less than 100 nm, less than 80 nm, less than 70 nm, or less than 60 nm. The surface roughness Rms may be at least 2 nm, at least 5 nm, or at least 8 nm. Preferred ranges include surface roughness Ra values ​​of 2 nm to 120 nm, 5 nm to 100 nm, or 8 nm to 60 nm. The surface roughness affects the ability of the stopper to move while in contact with the inner surface of the barrel. For example, if the surface roughness is very high, the coefficient of friction may be very high.

[0153] The surface roughness of the inner surface of the barrel may decrease by at least 3% Ra and / or Rms from the start position of the stopper to its end position relative to the roughness value at the start position. In a preferred embodiment, the surface roughness Ra may decrease by at least 5%, at least 7%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% from the start position of the stopper to its end position. The surface roughness Rms may decrease by at least 5%, at least 7%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% from the start position of the stopper to its end position.

[0154] The start position of the stopper is the position where the stopper is placed in the barrel before the container is used for drug delivery. In an embodiment, the pharmaceutical container is a pre-filled syringe (particularly in the case of the proposed system). In a pre-filled syringe, the start position is the position of the stopper before use. This is usually the most proximal position of the stopper. The end position of the stopper is the position where the stopper is placed after expelling the nominal volume of the container from the barrel, for example when the stopper contacts the distal end of the barrel. The start position of the stopper can be located within a distance of up to 20% of the length of the container from its proximal end. The end position can be located within a distance of 80% to 100% of the length of the container from its proximal end.

[0155] The inner surface of the barrel can have a surface roughness distribution such that the surface roughness measured at a start position SP, an intermediate position MP, and an end position EP is as follows, and the intermediate position can be located halfway between the start position and the end position:

[0156] SP 100% MP 40~60% EP 20~35% Controlling the surface roughness can contribute to a very low TGFV. Surface roughness can be controlled by adjusting manufacturing parameters such as melt temperature, molding time and polymer blend, or by surface treatments such as coating or plasma treatment. The pharmaceutical container may be made by injection molding. Injection molding requires the container to be at least slightly conical, i.e., the inner diameter of the barrel decreases from the start position to the end position. Thus, the compression of the stopper reduces the GF max increases from the start position to the end position such that as TGFV increases, so does TGFV. References herein to the inside diameter of a barrel mean the maximum inside diameter of the barrel, unless otherwise indicated.

[0157] The above-mentioned surface roughness distribution can be achieved, for example, by positioning the injection nozzle closer to the end position than the beginning position during injection molding, so that the polymer melt temperature is higher at the end position than at the beginning position during injection, or the molding temperature can be influenced by local heating and / or cooling to create a temperature gradient in the barrel direction.

[0158] The surface roughness values ​​can be measured using a white light interferometer according to DIN EN ISO 25178-2:2012, DIN EN ISO 25178-6:2010 and DIN EN ISO 25178-604:2013-12 (together with DIN EN ISO 4288:1998 and DIN EN ISO 3274:1998).

[0159] Release and balance stresses The pharmaceutical container of the present invention may exhibit a maximum BLGF of 15 N or less during the BLGF test. In preferred embodiments, the maximum BLGF may be limited to 13 N, 10 N, 9 N, 8 N, 7 N, 6 N, 5 N, or even 4 N. The BLF may be at least 0.1 N or at least 0.5 N to avoid unintended movement of the stopper.

[0160] In embodiments, the maximum BLGF may be correlated to the inner diameter of the barrel. Preferably, the ratio of the maximum BLGF to the inner diameter ID of the barrel is BLGF / ID<1 N / mm. Preferably, the BLGF / ID may be at least 0.5 N / mm, or at least 0.6 N / mm. In embodiments, the BLGF / ID may be limited to ≦0.95 N / mm, ≦0.9 N / mm, ≦0.85 N / mm, or ≦0.8 N / mm.

[0161] The container exhibits a ratio of BLF to GF during the BLGF test of BLF / GF≦2. Preferably, the ratio of BLF to GF is characterized by a BLF / GF≦3 even after 105 days of accelerated aging. In a preferred embodiment, the ratio BLF / GF is less than 2, less than 1.8, less than 1.7, or even less than 1.5 for the container of the invention. In a preferred embodiment, the ratio BLF / GF may be less than 2, less than 1.8, less than 1.7, or even less than 1.5 for the container of the invention after 105 days of accelerated aging. Preferably, the ratio BLF / GF is ... 105d -BLF / GF 0d ) / BLF / GF 105d The relative difference in the ratio is less than 10%, preferably less than 5%.

[0162] Total balance stress variation TGFV = GF measured when the stopper moves from the start position to its end position max -GF min may have a TGFV of less than 2N, less than 1.8N, or even less than 1.6N. Preferably, the aged container (accelerated aging 105 days) and the non-aged container (TGFV 105d -TGFV 0d ) / TGFV 105d The relative difference in TGFV between the two is less than 40%, preferably less than 35%.

[0163] The average BLF and GF values ​​can be calculated using at least 12 containers, preferably at least 15 containers. The average BLF of the pharmaceutical container of the present invention can be less than 9N, less than 8N, less than 7N, less than 6N, less than 5N, less than 4N, less than 3N, or even less than 2N. The average GF of the pharmaceutical container of the present invention can be less than 9N, less than 8N, less than 7N, less than 6N, less than 5N, less than 4N, less than 3N, or even less than 2N. Preferably, the average GF of the pharmaceutical container of the present invention is ... 105d -BLF 0d ) / BLF 105d The relative difference in BLF between the aged vessel (accelerated aging for 105 days) and the non-aged vessel (GF 105d -GF0d ) / GF 105d The relative difference in GF is less than 25%, less than 20%, less than 15%, less than 10% or even less than 5%.

[0164] Maintaining the BLF and GF values ​​within the range of the present invention contributes to a sufficiently constant dissolution of the liquid composition from the container during application. In particular, if the BLF is much higher than the GF, a large bolus may be dissolved when the stopper is released from the inner surface of the barrel. Also, if the GF is not sufficiently constant, the dissolution rate of the liquid composition may fluctuate.

[0165] "Accelerated aging" refers to an aging process in which each container is stored at 40°C and 75% relative humidity. For example, some containers can be stored under these conditions for 105 days for comparison. Accelerated aging can be performed to estimate the effect of aging on the properties of the pharmaceutical container of the present invention.

[0166] ratio The container may exhibit a ratio of release stress (BLF) to balance stress (GF) during release stress and balance stress (BLGF) testing of BLF / GF≦2. It has been found that it is important to control the ratio of BLF to GF. This is because if the BLF is too high compared to the GF, the user of the container will have to push too hard to remove the stopper from its starting position, which may result in the stopper being pushed too quickly to the end position after it is released. Maintaining the ratio BLF / GF in a balanced range facilitates controlled drug delivery without unnecessary pain for the patient. Also, there is less risk of leakage of the contents of the container if the acceleration is limited after the stopper is released. The ratio BLF / GF may be greater than 1. One aspect of the present invention is to keep the BLF / GF ratio essentially constant, even after storage of the container during administration.

[0167] Total balance stress variation TGFV = GF measured when the stopper moves from the start position to its end position max -GF minPreferably, the TGFV is <2N. It is important to control the TGFV because the difference between the maximum GF and the minimum GF strongly affects the user's ability to properly administer the drug composition stored in the container.

[0168] Preferably, BLF and GF at room temperature are used here.

[0169] Release and Balance Stress Tests The BLGF test is carried out in a universal testing machine at room temperature, e.g. 293.15 K, 20 °C or 23 °C. For this purpose, a BLGF test device with a 50 N test cup is used. The specimens were fixed vertically in a universal testing machine model 106 (2 kN) from TeS AG (CH-6331 Hunenberg, Switzerland).

[0170] In this test, a plunger with a flat end, i.e. without threads, is used.

[0171] BLF is the force required to move the stopper from its original position. GF is the force required for the plunger to continue moving after it is released.

[0172] The pharmaceutical containers are filled with water for injection. After the samples are filled, they are stored or tested immediately depending on the test purpose. The samples are tested without a needle.

[0173] The sample is inserted into the holder and the pressure stamp is moved towards the plunger at a rate of 20 mm / min. Once a force of 0.25 N is measured, the machine switches to a test speed of 100 mm / min and begins recording data. The experiment ends when the measured force exceeds 35 N, which is usually when the distal end of the barrel is reached.

[0174] The BLF is the highest force measured within the first 4 mm of stopper travel. The average and maximum GF values ​​are measured within the test range starting after 4 mm of travel and extending to 10 mm before the distal end of the barrel is reached.

[0175] Ratio of release stress to balance stress The container may exhibit a ratio of release stress (BLF) to balance stress (GF) during release stress and balance stress (BLGF) testing of BLF / GF≦2. It has been found that it is important to control the ratio of BLF to GF. This is because if the BLF is too high compared to the GF, the user of the container will have to push too hard to remove the stopper from its starting position, which may result in the stopper being pushed too quickly to the end position after it is released. Maintaining the ratio BLF / GF in a balanced range facilitates controlled drug delivery without unnecessary pain for the patient. Also, there is less risk of leakage of the contents of the container if the acceleration is limited after the stopper is released. The ratio BLF / GF may be greater than 1. One aspect of the present invention is to keep the BLF / GF ratio essentially constant, even after storage of the container during administration.

[0176] Total balance stress variation TGFV = GF measured when the stopper moves from the start position to its end position max -GF min Preferably, the TGFV is <2N. It is important to control the TGFV because the difference between the maximum GF and the minimum GF strongly affects the user's ability to properly administer the drug composition stored in the container.

[0177] BLF, GF and BLGF can be measured according to the method described herein as the BLGF test.

[0178] Angles X, A and their ratio X / A The raised edge of the proximal-most annular projection and the inner surface of the barrel extend over an angle X opening in the distal direction, and the dropped edge and inner surface of the distal-most annular projection extend over an angle A opening in the proximal direction. A "raised edge" in the context of the present invention is the edge of the annular projection that, when the stopper is inserted into the barrel, follows the circumferential surface of the stopper in the proximal-distal direction and extends toward the inner surface of the barrel. A "dropped edge" is the edge of the annular projection that, when the stopper is inserted into the barrel, follows the circumferential surface of the stopper in the proximal-distal direction and extends toward the central longitudinal axis of the barrel.

[0179] In a preferred embodiment, the ratio X / A is greater than 1.1 and less than or equal to 1.7. The BLGF value is improved when the ratio of X / A is at least 1.05. In a preferred embodiment, the ratio X / A is at least 1.1, at least 1.15, at least 1.2 or at least 1.25. The ratio may preferably be limited to a maximum of 1.7, a maximum of 1.65, a maximum of 1.6, a maximum of 1.55, a maximum of 1.5 or a maximum of 1.45.

[0180] The angles X and / or A may be greater than 90° and less than 180°. Preferably, A is between 130° and 170°. The minimum value of A may be at least 100°, at least 110°, at least 120°, or at least 130°. The upper limit of A may be 170°, 160°, 150°, or 140°. Preferably, X is between 131° and 175°. The minimum value of X may be at least 101°, at least 111°, at least 121°, or at least 131°. The upper limit of X may be 170°, 160°, 150°, or 140°.

[0181] Keeping the angles and their ratios within the appropriate range contributes to solving the problem underlying the present invention. In particular, if the angle X is too small, the ratio BLF / GF increases. At the relevant angle ratio, the force inserted by the plunger rod needs to be distributed and shared inside the plunger towards the sealing lip in a uniform and controlled manner that can be inferred by the strength lines, and uncontrolled deformation of the plunger can be avoided by the above-mentioned design angle ratio.

[0182] direction The proximal-distal direction corresponds to the direction of a vector pointing from the proximal end to the distal end. The rising edge of the proximal-most annular projection and the inner surface of the barrel extend over an angle X in the distal direction, and the falling edge and the inner surface of the distal-most annular projection extend over an angle A in the proximal direction, and the ratio X / A may preferably be at least 1.05.

[0183] Further options The container may be selected from a syringe, a cartridge, and a carpule.

[0184] The inner surface of the barrel may have a surface roughness Ra of less than 100 nm, a surface roughness Rms of less than 150 nm, a surface energy of less than 45 mN / m, and / or a silicone content of less than 100 μg, or less than 30 μg, or less than 1 μg per barrel.

[0185] The inner surface of the barrel may have a water contact angle of at least 80°, preferably at least 85°.

[0186] The stopper can have a proximal end adapted to contact the plunger rod and a distal end adapted to contact the pharmaceutical composition.

[0187] The medication container may further comprise a plunger rod connected to the proximal end of the stopper.

[0188] The stopper can have one or more, preferably at least two, annular projections that contact the inner surface of the barrel when the stopper is moved distally.

[0189] Each annular projection can have a rising edge and a falling edge in the proximal-distal direction.

[0190] The rising edge of the proximal-most annular projection and the inner surface of the barrel may extend in the distal direction through an angle X, and / or the falling edge of the distal-most annular projection and the inner surface may extend in the proximal direction through an angle A, preferably the ratio X / A is at least 1.05. Preferably, the ratio X / A is greater than 1.1 and less than or equal to 1.7, and / or A is between 130° and 170°.

[0191] Preferably, throughout this application, room temperature is 293K (293.15K), which is 20°C (20.00°C).

[0192] Unless otherwise specified, dimensions (volume, distance) are at room temperature (20° C.).

[0193] (Further favorable viewpoint) (Preferred embodiment for carrying out the invention) The following exemplary embodiments are particularly preferred.

[0194] Example 1. A system for storing a pharmaceutical composition at low temperature, the system comprising: - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between the stopper and the closure.

[0195] Example 2. A system for storing a pharmaceutical composition at low temperature, in particular according to example 1, the system - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between a stopper and a closure, The volume enclosed by the barrel that is occupied by the gas is defined as the headspace of the system.

[0196] Example 3. A system for storing a pharmaceutical composition at low temperature, particularly according to any one of the previous examples, wherein the system - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between a stopper and a closure, The liquid pharmaceutical composition comprises an excipient.

[0197] Example 4. A system for storing a pharmaceutical composition at low temperature, particularly according to any one of the previous examples, wherein the system - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between a stopper and a closure, For a vertical orientation of the vessel, with the first end at the bottom and the second end at the top, the volume enclosed by the barrel between the stopper and the closure that is occupied by the gas is defined as the headspace of the system, At room temperature, the volume occupied by the headspace is at least 1% of the volume occupied by the composition.

[0198] Example 5. The system of any one of Examples 1 to 3, wherein the volume enclosed by the barrel occupied by the gas, particularly for a particular orientation of the vessel, is defined as the headspace of the system.

[0199] Example 6. The system described in Example 5, wherein in the vertical orientation of the vessel with the first end at the bottom and the second end at the top, the volume occupied by the gas and enclosed by the barrel between the stopper and the closure is defined as the headspace A of the system.

[0200] Example 7. The system of Example 4 or 5, wherein in the vertical orientation of the vessel with the second end at the bottom and the first end at the top, the volume occupied by the gas and enclosed by the barrel between the stopper and the closure is defined as the headspace B of the system.

[0201] Example 8. A system according to any one of Examples 1 to 3 and 5 to 7, wherein at room temperature, the volume occupied by the headspaces, such as headspace A and / or headspace B, is 1% or more of the volume occupied by the composition.

[0202] Example 9. Headspace B may preferably have a cylindrical volumetric region portion, which has a specific diameter equal to the inner diameter of the barrel and a specific height, which is preferably measured from the center point of the stopper to the surface of the liquid pharmaceutical composition facing the stopper, and the specific height has a value of 0.1 mm or more. The system of any one of the preceding examples.

[0203] Example 10. Relative height is, (i) 0.2 mm or more, preferably 0.5 mm or more, preferably 0.7 mm or more, preferably 1 mm or more, preferably 2 mm or more, preferably 3 mm or more, preferably 4 mm or more, preferably 5 mm or more, preferably 6 mm or more, preferably 7 mm or more, preferably 8 mm or more, preferably 9 mm or more, preferably 10 mm or more, preferably 11 mm or more, preferably 12 mm or more, preferably 13 mm or more, preferably 14 mm or more, preferably 15 mm or more, (ii) 15 mm or less, preferably 14 mm or less, preferably 13 mm or less, preferably 12 mm or less, preferably 11 mm or less, 10 mm or less, preferably 9 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, preferably 5 mm or less, preferably 4 mm or less, preferably 3 mm or less, preferably 2 mm or less, and / or (iii) The system according to Example 9, which is 1 mm to 15 mm, preferably 1 mm to 10 mm, preferably 1 mm to 8 mm, preferably 1 mm to 3 mm, such as 2 mm, or 3 mm to 5 mm, for example 4 mm, or 5 mm to 7 mm, for example 6 mm, or 7 mm to 9 mm, for example 8 mm.

[0204] Example 11. The ratio of the inner diameter of the barrel to its height [mm / mm] is (i) 0.3 or more, preferably 0.7 or more, preferably 1 or more, preferably 1.05 or more, preferably 1.1 or more, preferably 1.3 or more, preferably 1.5 or more, preferably 2 or more, preferably 2.5 or more, preferably 3 or more, preferably 3.5 or more, preferably 4 or more, preferably 4.5 or more, preferably 5 or more, preferably 7 or more, preferably 10 or more, (ii) 10 or less, preferably 6 or less, preferably 5 or less, preferably 4 or less, preferably 3 or less, preferably 2 or less, preferably 1.5 or less, preferably 1.3 or less, preferably 1.0 or less, preferably 0.7 or less, preferably 0.5 or less, and / or (iii) 0.3 to 10, preferably 1 to 10, preferably 1 to 5, preferably 1 to 2 or 2 to 4 or 3 to 5; The system of Example 9 or 10.

[0205] Example 12. The total length of a barrel, measured specifically along the axial extension of the barrel, is (i) 40 mm or more, preferably 45 mm or more, preferably 50 mm or more, preferably 55 mm or more, preferably 60 mm or more, preferably 65 mm or more, preferably 70 mm or more, preferably 75 mm or more, preferably 80 mm or more, (ii) 80 mm or less, preferably 75 mm or less, preferably 70 mm or less, preferably 65 mm or less, preferably 60 mm or less, preferably 55 mm or less, preferably 50 mm or less, preferably 45 mm or less, preferably 40 mm or less, and / or (iii) 40 mm to 80 mm, preferably 40 mm to 60 mm, particularly 45 mm to 55 mm, in particular 45 mm to 50 mm, or 60 mm to 70 mm, in particular 63 mm to 67 mm; The system of any one of the preceding examples.

[0206] Example 13. The inside diameter of the barrel is (i) 5 mm or more, preferably 6 mm or more, preferably 7 mm or more, preferably 8 mm or more, preferably 9 mm or more; (ii) 10 mm or less, preferably 9 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, preferably 5 mm or less; and / or (iii) 5 mm to 10 mm, preferably 5 mm to 7 mm, particularly 6 mm to 7 mm, in particular 6 mm to 6.5 mm, for example 6.35 mm, or 7 mm to 9 mm, particularly 8 mm to 9 mm, in particular 8.5 mm to 9 mm, for example 8.65 mm; The system of any one of the preceding examples.

[0207] Example 14. (i) The overall length of the barrel, specifically measured along the axial extension of the barrel, is between 45 mm and 50 mm, and the inside diameter of the barrel is between 8 mm and 9 mm; or (ii) the overall length of the barrel, specifically measured along the axial extension of the barrel, is between 60 mm and 70 mm, and the inside diameter of the barrel is between 5 mm and 7 mm; The system of any one of the preceding examples.

[0208] Example 15. The following expression (X / Y) / Z≦V, and / or W≦(X / Y) / Z is satisfied, where X is the volume (ml) of the pharmaceutical composition at room temperature; Y is the headspace volume at room temperature (ml), Z is the inside diameter of the barrel (mm), V(1 / mm) is 1.5, preferably 1.4, preferably 1.3, preferably 1.2, preferably 1.1, preferably 1.0, preferably 0.9, preferably 0.8, preferably 0.7, preferably 0.6, preferably 0.5, preferably 0.4, preferably 0.3, preferably 0.2, preferably 0.1; and / or W(1 / mm) is 0.01, preferably 0.05, preferably 0.1, preferably 0.2, preferably 0.3, preferably 0.4, preferably 0.5, preferably 0.6, preferably 0.7; The system of any one of the preceding examples.

[0209] Example 16. A liquid pharmaceutical composition comprising an additive. The system of any one of the preceding examples.

[0210] Example 17. The additive is selected from the group consisting of salts, sugars, lipids and acids. The system of Example 16.

[0211] Example 18. The additive is selected from the group consisting of NaCl, KCl, sucrose, sodium acetate, acetic acid, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, SM (sphingomyelin)-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC], cholesterol, polyethylene glycol (PEG), H3PO4, XH2PO4, X2HPO4 and X3PO4, where X is Na and / or K; The system of Example 16 or 17.

[0212] Example 19. The system described in Example 16, wherein the additive is NaCl.

[0213] Example 20. The system of Example 16, wherein the additive is KCl.

[0214] Example 21. The system described in Example 16, wherein the additive is sucrose.

[0215] Example 22. The system of Example 16, wherein the additive is sodium acetate.

[0216] Example 23. The system of example 16, wherein the additive is acetic acid.

[0217] Example 24. The system according to example 16, wherein the additive is a lipid, preferably ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, SM (sphingomyelin)-102, polyethylene glycol [PEG] 2000 dimyristoylglycerol [DMG], 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC] and / or cholesterol.

[0218] Example 25. The system described in Example 16, wherein the additive is polyethylene glycol (PEG).

[0219] Example 26. The system according to example 16, wherein the additive is H3PO4.

[0220] Example 27. The system according to example 16, wherein the additive is XH2PO4, where X is Na and / or K.

[0221] Example 28. The system described in Example 16, wherein the additive is X2HPO4, where X is Na and / or K.

[0222] Example 29. The system according to Example 16, wherein the additive is X3PO4, where X is Na and / or K.

[0223] Example 30. The system of example 16, wherein the additive is cholesterol.

[0224] Example 31. The concentration of the additive is (i) 0.01 mol / l or more, preferably 0.05 mol / l or more, preferably 0.1 mol / l or more, preferably 0.2 mol / l or more, preferably 0.3 mol / l or more, preferably 0.4 mol / l or more, preferably 0.5 mol / l or more, preferably 0.7 mol / l or more, preferably 1 mol / l or more, (ii) 1 mol / l or less, preferably 0.9 mol / l or less, preferably 0.8 mol / l or less, preferably 0.7 mol / l or less, preferably 0.6 mol / l or less, preferably 0.5 mol / l or less, preferably 0.4 mol / l or less, preferably 0.3 mol / l or less, preferably 0.2 mol / l or less, and / or (iii) The system according to any one of Examples 16 to 30, wherein the concentration is 0.1 mol / l to 1 mol / l, preferably 0.1 mol / l to 0.8 mol / l, preferably 0.1 mol / l to 0.5 mol / l, preferably 0.2 mol / l to 0.4 mol / l, preferably 0.25 mol / l.

[0225] Example 32. The concentration of the additive is (i) 1 g / l or more, preferably 2 g / l or more, preferably 5 g / l or more, preferably 10 g / l or more, preferably 20 g / l or more, preferably 30 g / l or more, preferably 40 g / l or more, preferably 50 g / l or more, preferably 75 g / l or more, preferably 100 g / l or more, preferably 150 g / l or more, preferably 200 g / l or more, (ii) 300 g / l or less, preferably 200 g / l or less, preferably 150 g / l or less, preferably 120 g / l or less, preferably 100 g / l or less, preferably 90 g / l or less, preferably 80 g / l or less, preferably 70 g / l or less, preferably 60 g / l or less, preferably 50 g / l or less, preferably 40 g / l or less, preferably 30 g / l or less, preferably 20 g / l or less, preferably 10 g / l or less, preferably 5 g / l or less, and / or (iv) The system according to any one of Examples 16 to 31, which is 1 g / l to 300 g / l, preferably 5 g / l to 200 g / l, preferably 20 g / l to 150 g / l, preferably 50 g / l to 120 g / l, preferably 60 g / l to 100 g / l, preferably 70 g / l to 90 g / l.

[0226] Example 33. The concentrations of all compounds in the pharmaceutical composition are (i) 0.01 mol / l or more, preferably 0.05 mol / l or more, preferably 0.1 mol / l or more, preferably 0.2 mol / l or more, preferably 0.3 mol / l or more, preferably 0.4 mol / l or more, preferably 0.5 mol / l or more, preferably 0.7 mol / l or more, preferably 1 mol / l or more, (ii) 1 mol / l or less, preferably 0.9 mol / l or less, preferably 0.8 mol / l or less, preferably 0.7 mol / l or less, preferably 0.6 mol / l or less, preferably 0.5 mol / l or less, preferably 0.4 mol / l or less, preferably 0.3 mol / l or less, preferably 0.2 mol / l or less, and / or (iii) The system according to any one of the preceding examples, wherein the concentration is 0.1 mol / l to 1 mol / l, preferably 0.1 mol / l to 0.8 mol / l, preferably 0.1 mol / l to 0.5 mol / l, preferably 0.2 mol / l to 0.4 mol / l, preferably 0.25 mol / l.

[0227] Example 34. At room temperature, a headspace such as headspace A and / or headspace B of the volume occupied by the composition, respectively. (i) 1.3% or more, preferably 1.5% or more, preferably 1.7% or more, preferably 2% or more, preferably 2.5% or more, preferably 3% or more, preferably 3.5% or more, preferably 4% or more, preferably 4.5% or more, preferably 5% or more, preferably 6% or more, preferably 7% or more, preferably 8% or more, preferably 9% or more, preferably 10% or more, preferably 11% or more, preferably 12% or more, preferably 13% or more, preferably 14% or more, preferably 15% or more, preferably 17% or more, preferably 20% or more, (ii) 20% or less, preferably 17% or less, preferably 15% or less, preferably 14% or less, preferably 13% or less, preferably 12% or less, preferably 11% or less, preferably 10% or less, preferably 9% or less, preferably 8% or less, preferably 7% or less, preferably 6% or less, preferably 5% or less, preferably 4.5% or less, preferably 4% or less, preferably 3.5% or less, preferably 3% or less, preferably 2.5% or less, preferably 2% or less, preferably 1.7% or less, preferably 1.5% or less, preferably 1.3% or less, and / or (iii) The system according to any one of the preceding examples, wherein the pH is between 1% and 20%, in particular between 1.5% and 3%, between 2% and 5%, between 4% and 8%, between 7% and 12%, between 10% and 15%, between 12% and 17% and / or between 15% and 20%.

[0228] Example 35. (i) The stopper is slidably disposed within the barrel; (ii) the stopper has a peripheral surface that at least partially contacts the inner surface of the barrel; and / or (iii) the first end is a proximal end of a container, particularly a barrel, and / or the second end is a distal end of a container, particularly a barrel; The system of any one of the preceding examples.

[0229] Example 36. When the system or parts thereof, in particular the headspaces such as headspace A and / or headspace B at room temperature, the barrel, the stopper and / or the composition, are in a state where the pharmaceutical composition is expanded, particularly preferably during cooling of the system, from (a) above 4°C, in particular from room temperature, and / or (b) to a temperature below 0°C, in particular below the freezing point of the composition and / or below the storage temperature of the system, (i) the pharmaceutical composition is capable of expanding or expanding by displacing and / or compressing gas, thus reducing the volume of a headspace, such as headspace A and / or headspace B; (ii) the maximum force exerted on the stopper by the pharmaceutical composition and / or gas, particularly in the axial direction, is lower than the release stress of the stopper; (iii) the stopper moves by 5 mm or less, preferably by 4 mm or less, preferably by 3.5 mm or less, preferably by 3 mm or less, preferably by 2.7 mm or less, preferably by 2.5 mm or less, preferably by 2.3 mm or less, preferably by 2.0 mm or less, preferably by 1.7 mm or less, preferably by 1.5 mm or less, preferably by 1.3 mm or less, preferably by 1.0 mm or less, preferably by 0.8 mm or less, preferably by 0.6 mm or less, preferably by 0.5 mm or less, preferably by 0.4 mm or less, preferably by 0.3 mm or less, preferably by 0.2 mm or less, preferably by 0.1 mm or less, and / or (iv) the stopper moves by 0.01 mm or more, preferably by 0.05 mm or more, preferably by 0.1 mm or more, preferably by 0.3 mm or more, preferably by 0.5 mm or more, preferably by 0.7 mm or more, preferably by 1.0 mm or more; Preferably, the barrel is oriented vertically during cooling such that (a) the first end is at the bottom and / or the second end is at the top, and / or (b) the pharmaceutical composition and gas are disposed along the axial direction of the container, in particular the barrel. The system of any one of the preceding examples, wherein the systems are designed to be compatible with one another such that

[0230] Example 37. (i) Storage temperature is (a) -100°C or higher, preferably -80°C or higher, preferably -60°C or higher, preferably -40°C or higher, preferably -20°C or higher, preferably -10°C or higher; (b) 0° C. or less, -1° C. or less, preferably -5° C. or less, preferably -15° C. or less, preferably -25° C. or less, preferably -35° C. or less, preferably -55° C. or less, preferably -75° C. or less, preferably -95° C. or less and / or (c) -100 to 0°C, preferably -80 to -5°C, preferably -60 to -20°C, preferably -50 to -40°C, and / or (d) 0°C, -10°C, -20°C, -30°C, -40°C or -50°C, and / or (ii) the storage temperature is below the freezing point temperature of the composition; The system of any one of the preceding examples.

[0231] Example 38. (i) The pharmaceutical composition comprises HO, in particular more than 80% (w / w), preferably more than 90% (w / w), preferably more than 95% (w / w), preferably more than 97% (w / w), preferably more than 98% (w / w) of the composition is HO, and / or (ii) the gas comprises or is air, CO2, N2, Ar and / or O2; The system of any one of the preceding examples.

[0232] Example 39. The overall length of a vessel, measured specifically along the axial extension of the vessel, (i) 30 mm or more, preferably 40 mm or more, preferably 50 mm or more, preferably 60 mm or more, preferably 70 mm or more, preferably 80 mm or more, preferably 90 mm or more, preferably 100 mm or more, preferably 110 mm or more, preferably 120 mm or more, preferably 130 mm or more, preferably 150 mm or more, preferably 170 mm or more, preferably 190 mm or more, (ii) 200 mm or less, preferably 150 mm or less, preferably 140 mm or less, preferably 130 mm or less, preferably 110 mm or less, preferably 100 mm or less, preferably 90 mm or less, preferably 80 mm or less, preferably 70 mm or less, preferably 60 mm or less, preferably 50 mm or less, preferably 40 mm or less, and / or (iii) 30 mm to 200 mm, preferably 50 mm to 150 mm, in particular 50 mm to 100 mm, for example 60 mm to 90 mm and / or 90 mm to 150 mm; The system of any one of the preceding examples.

[0233] Example 40. The total length of a barrel, measured specifically along the axial extension of the barrel, is (i) 30 mm or more, preferably 40 mm or more, preferably 50 mm or more, preferably 60 mm or more, preferably 70 mm or more, preferably 80 mm or more, preferably 90 mm or more, preferably 100 mm or more, preferably 110 mm or more, preferably 120 mm or more, preferably 130 mm or more, preferably 150 mm or more, preferably 170 mm or more, preferably 190 mm or more, (ii) 200 mm or less, preferably 150 mm or less, preferably 140 mm or less, preferably 130 mm or less, preferably 110 mm or less, preferably 100 mm or less, preferably 90 mm or less, preferably 80 mm or less, preferably 70 mm or less, preferably 60 mm or less, preferably 50 mm or less, preferably 40 mm or less, and / or (iii) 30 mm to 200 mm, preferably 40 mm to 130 mm, in particular 40 mm to 80 mm, 50 mm to 80 mm and / or 70 mm to 130 mm; The system of any one of the preceding examples.

[0234] Example 41. The inside diameter of the barrel is (i) 5 mm or more, preferably 8 mm or more, preferably 10 mm or more, preferably 13 mm or more, preferably 15 mm or more, preferably 18 mm or more, preferably 20 mm or more, preferably 25 mm or more, preferably 30 mm or more, (ii) 30 mm or less, preferably 28 mm or less, preferably 25 mm or less, preferably 20 mm or less, preferably 15 mm or less, preferably 13 mm or less, preferably 10 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, and / or (iii) 5 mm to 30 mm, preferably 5 mm to 10 mm, 10 mm to 15 mm, 14 mm to 18 mm, 17 mm to 20 mm, and / or 20 mm to 30 mm; The system of any one of the preceding examples.

[0235] Example 42. The outer diameter of the barrel is (i) 5 mm or more, preferably 8 mm or more, preferably 10 mm or more, preferably 13 mm or more, preferably 15 mm or more, preferably 18 mm or more, preferably 20 mm or more, preferably 25 mm or more, preferably 30 mm or more, preferably 35 mm or more, preferably 40 mm or more, (ii) 40 mm or less, preferably 35 mm or less, 30 mm or less, preferably 28 mm or less, preferably 25 mm or less, preferably 20 mm or less, preferably 15 mm or less, preferably 13 mm or less, preferably 10 mm or less, preferably 7 mm or less, preferably 5 mm or less, and / or (iii) 5 mm to 40 mm, preferably 5 mm to 9 mm, 8 mm to 13 mm, 12 mm to 16 mm, 15 mm to 20 mm, 19 mm to 25 mm, and / or 25 mm to 35 mm; The system of any one of the preceding examples.

[0236] Example 43. At room temperature, the volume of the composition is (i) 0.1 ml or more, preferably 0.2 ml or more, preferably 0.3 ml or more, preferably 0.5 ml or more, preferably 0.7 ml or more, preferably 1 ml or more, preferably 1.5 ml or more, preferably 2 ml or more, preferably 3 ml or more, preferably 5 ml or more, preferably 10 ml or more, preferably 15 ml or more, preferably 20 ml or more, preferably 30 ml or more, preferably 50 ml or more, preferably 70 ml or more, (ii) 100 ml or less, preferably 70 ml or less, preferably 55 ml or less, preferably 25 ml or less, preferably 15 ml or less, preferably 10 ml or less, preferably 7 ml or less, preferably 6 ml or less, preferably 5 ml or less, preferably 4 ml or less, preferably 3 ml or less, preferably 1 ml or less, preferably 0.7 ml or less, preferably 0.5 ml or less, preferably 0.3 ml or less, preferably 0.2 ml or less, and / or (iii) 0.1 ml to 100 ml, preferably 0.1 ml to 1 ml or 1 ml to 100 ml, for example 1 ml to 50 ml, in particular 1 ml to 3 ml, 1 ml to 10 ml, 10 ml to 20 ml, 20 ml to 30 ml, 30 ml to 40 ml and / or 40 ml to 50 ml; The system of any one of the preceding examples.

[0237] Example 44. When the system is cooled from room temperature (20°C) to -20°C, preferably -50°C, preferably -80°C, the position of the stopper moves along the axis of rotation of the barrel by no more than 4.0 mm, preferably no more than 3.0 mm, preferably no more than 2.5 mm, preferably no more than 2.0 mm, preferably no more than 1.5 mm, preferably no more than 1.0 mm, preferably no more than 0.8 mm, preferably no more than 0.5 mm, preferably no more than 0.3 mm, preferably no more than 0.1 mm. The system of any one of the preceding examples.

[0238] Example 45. The system of any one of the preceding examples, wherein the system has a temperature below -20°C and above -200°C, preferably below -40°C and above -120°C, preferably below -50°C and above -90°C.

[0239] Example 46. The system of any one of the preceding examples, wherein the system is stored for 5 days or more, preferably 1 month or more, preferably 3 months or more, preferably 6 months or more, preferably 1 year or more.

[0240] Example 47. The system of any one of the previous examples, wherein the stopper includes at least one internal recess.

[0241] Example 48. The system of any one of the previous examples, wherein the barrel comprises a polymer, preferably a cyclic olefin copolymer (COC) and / or a cyclic olefin polymer (COP).

[0242] Example 49. The system of any one of the previous examples, wherein the closure preferably comprises bromobutyl rubber, and preferably the closure is a siliconized closure comprising bromobutyl rubber.

[0243] Example 50. The system of any one of the previous examples, wherein the barrel comprises a polymer, preferably COC and / or COP, and the closure comprises bromobutyl rubber, preferably the closure is a siliconized closure comprising bromobutyl rubber.

[0244] Example 51. A method comprising: A method comprising administering to a subject an effective amount of at least one pharma- ceutical active ingredient contained in a pharmaceutical composition using a system according to any one of Examples 1 to 47.

[0245] Example 52. A liquid composition comprising: In methods of treatment of the human or animal body by surgery or therapy, or For use in diagnostic methods carried out on the human or animal body, The composition includes at least one pharma- ceutical active ingredient and the method includes: A liquid composition comprising administering to a subject an effective amount of the active ingredient using the system of any one of Examples 1 to 50.

[0246] Example 53. In a method for the treatment of the human or animal body by surgery or therapy, or For use in diagnostic methods carried out on the human or animal body, The composition includes at least one pharma- ceutical active ingredient and the method includes: administering to a subject an effective amount of the active ingredient using the system; The system of any one of Examples 1 to 50.

[0247] Example 54. The composition comprises mRNA. The system according to any one of examples 1 to 50, the method according to example 51, the use according to example 52 and / or the use according to example 53.

[0248] Example 55. An apparatus for manufacturing a system according to any one of examples 1 to 50, comprising a servomotor and a laser fixedly attached to the servomotor, in particular mechanically fixedly attached.

[0249] Example 56. A method for manufacturing a system according to any one of Examples 1 to 50, comprising the steps of: (i) using the apparatus according to Example 55; and / or (ii) (a) providing a barrel, preferably having an open end at one end thereof and / or a closed end at another end thereof; (b) filling the barrel with a liquid pharmaceutical composition; (c) providing a stopper; and / or (d) positioning the stopper by translating the stopper along an axial extension of the barrel to a specific position within the barrel by means of a servo motor, in particular a servo motor comprised in the apparatus, the specific position being determined by a positioning system comprising a laser, in particular a laser being mechanically fixedly attached to the servo motor.

[0250] Example 57. Use of a system according to any one of examples 1 to 50 for long-term storage at low temperatures.

[0251] Example 58. The use according to example 57, wherein the long-term storage is more than 5 days, preferably more than 1 month, preferably more than 3 months, preferably more than 6 months, preferably more than 1 year.

[0252] Example 59. The use according to any one of examples 57 to 58, wherein the low temperature is below -20°C, preferably below -50°C, preferably below -80°C.

[0253] Example 60. A bundle comprising 5 or more, preferably 10 or more, preferably 30 or more, preferably 50 or more, preferably 100 or more of the systems according to any one of Examples 1 to 47, wherein for each two of the systems, the volumes of the system headspaces such as system headspace A and / or system headspace B differ by 0.5ml or less, preferably 0.4ml or less, preferably 0.3ml or less, preferably 0.2ml or less, preferably 0.1ml or less.

[0254] Working Example In the table below, two embodiments of the system of the invention are compared with a conventional system known from the state of the art.

[0255] For each system, information is provided regarding the volume occupied by the composition in the barrel (ml, room temperature), the height of the headspace in the barrel (mm, room temperature), and the (initial) volume occupied by the headspace in the barrel (ml, room temperature).

[0256] Note that the headspace height (mm) is taken from a system oriented with the stopper at the top and the closure at the bottom. The headspace height then corresponds to the distance from the surface of the composition to the (flat) surface of the stopper facing the composition. The barrel of each system has an internal diameter of 6.5 mm (SCHOTT TopPac® 1 ml / g).

[0257] It should be particularly noted that the definition of headspace used in this example is the definition of headspace B, and the heights referenced in this example are relative heights, as each is explained elsewhere.

[0258] Additionally, each system is verified with an adaptive CCI test. In the adaptive CCI test, the system under test is cooled and thawed, and the maximum movement of the stopper during this cycle is evaluated. More precisely, in the adaptive CCI test, the system is cooled from room temperature (20°C) to -50°C at a constant cooling rate for 12 hours. The system is then held at a temperature of -50°C for 24 hours. Finally, the system is thawed at a constant heating rate from -50°C to room temperature over a period of 12 hours. If the maximum movement of the stopper in the barrel is limited during the cooling and thawing of the system, the system passes the adaptive CCI test. If not, the system fails.

[0259] Since this is the maximum axial distance between the two sealing lips of the stopper in the system, the maximum allowable movement is 3 mm to pass the applicable CCI test.

[0260] The table also lists for each system the maximum distance the stopper traveled during the adaptive CCI test.

[0261] [Table 1]

[0262] As can be seen from the table, the inventive system 1 and the inventive system 2 pass the adaptive CCI test, where the maximum stopper movement during cooling and thawing is 2.35 mm and 1.05 mm, respectively, which is less than the maximum allowable movement of 3 mm. However, the conventional system without headspace fails the adaptive CCI test, as the maximum stopper movement is 3.85 mm.

[0263] In further experiments, the influence of additives was tested. To do so, a syringe barrel (SCHOTT TopPac® 1 ml syringe barrel closed with Tipcap) was filled with an aqueous solution (0.75 ml) containing additives (see table) and then closed with a stopper (West NovaPure® 1 ml lg) to a specific height of 2 mm. The position of the stopper was marked and then the system was cooled to −20° C. (12 h) in a freezer. Finally, the movement of the stopper immediately after freezing was quantified.

[0264] [Table 2]

[0265] Similar results were obtained using Datwyler FM 257, Datwyler FM 457 and West FluroTec® as stoppers.

[0266] In further experiments, the influence of the filling volume was tested. To do so, a syringe barrel (SCHOTT TopPac® 1 ml syringe barrel closed with Tipcap) was filled with an aqueous solution (volumes shown in the table below) containing sucrose (87 g / l) and then closed with a stopper (West NovaPure® 1 ml lg) to a specific height of 2 mm. The position of the stopper was marked and then the system was cooled to −20° C. (12 hours) in a freezer. Finally, the movement of the stopper immediately after freezing was quantified.

[0267] [Table 3]

[0268] In further experiments, the effect of the specific height was tested. To do so, a syringe barrel (syriQ® sterile 1 ml long LL RF SRC W 7025) was filled with an aqueous solution (water for injection, 0.5 ml) and then closed with a stopper (West NovaPure® 1 ml lg) with a specific height as shown in the table below. The position of the stopper was marked and then the system was cooled to -80°C (12 hours) in a freezer. Finally, the movement of the stopper immediately after freezing was quantified.

[0269] [Table 4]

[0270] *"-" indicates that the stopper moves towards the closure, in all other cases the stopper moves away from the closure.

[0271] t Similar results were obtained when using the stopper "1 ml Datwyler FM 257" instead of the stopper "West NovaPure® 1 ml lg" (2 mm headspace: 0.4 mm plunger movement, 4 mm headspace: 0.2 mm plunger movement, 6 mm headspace: 0.0 mm plunger movement).

[0272] As can be seen, the best values ​​were obtained for specific heights between 1 mm and 10 mm, especially between 2 mm and 10 mm. Similar experiments with specific heights adjusted to 2-6 mm (below 0.5 for specific heights between 2-4 mm) and using syriQ® sterile 1 ml short LL RF SRC W 7025 as syringe barrels and 1-3 ml Datwyler FM 257 and 1-3 ml West NovaPure® as stoppers gave plunger travels below 0.7 mm. Further experiments were performed using Datwyler FM 457 and West FluroTec®, as well as equivalent silicone-free barrels and GORE™ ImproJect™ as stoppers. These experiments show similar results.

[0273] In further experiments, the tightness of the closures during freezing and storage of the syringes was tested. For this purpose, empty syringes were closed with stoppers (here Datwyler, V 9283 FM 257 / 2 ISAF 2 067, Plunger 1ml lg FM 257 ISAF 2) and closures (here Datwyler V 9317 FM 257 / 2 ISAF 1 002), and each stopper was additionally sealed with glue (here Loctite HYSOL 3421 liquid epoxy glue) to eliminate stopper-side leakage. The amount of CO2 was then measured by FM-TDLAS (here lighthouse FMS-CO2, serial number 742). The samples were stored vertically for 24 h in a -80 °C freezer with dry ice and then thawed for at least 20 min before the measurements. The amount of CO2 was measured again by FM-TDLAS (here lighthouse FMS-CO2, serial number 742). Two syringes were tested (here SCHOTT TopPac® 1 ml lg and syriQ® sterile 1 ml long LL RF SRC). With the glass syringe syriQ® sterile 1 ml long LL RF SRC the CO2 level after freezing was higher compared to the value obtained before freezing, whereas with the polymer syringe TopPac® 1 ml lg it was identical before and after freezing, indicating that no gas exchange occurred when using the polymer syringe (here TopPac® 1 ml lg) and the closure (here Datwyler V 9317 FM 257 / 2 ISAF 1 002). The same trend was observed when using "Wild und Kupfer AG: TopPac® hard cap FM 257 (ISAF 1)" as the closure.

[0274] The subject matter of the present application will be explained in more detail with reference to the following figures, without limiting said subject matter to the illustrated embodiments. [Brief description of the drawings]

[0275] [Figure 1]1 shows a system according to a first embodiment of the present invention; [Diagram 2] 4 shows parts of another system according to a first aspect of the invention. [Diagram 3] 3 shows another system according to a first aspect of the present invention; [Figure 4] 1 shows a schematic diagram of an arrangement for carrying out the method according to the invention;

[0276] FIG. 1 shows a system 1 for cryogenic storage of a pharmaceutical composition according to a first embodiment of the present invention. The system 1 comprises a pharmaceutical container 3. The container 3 has a barrel 5 and a stopper 7. The stopper 7 is slidably disposed within the barrel 5. The stopper 7 has a peripheral surface 9 (which is a surface of one sealing lip of the stopper 7) that partially contacts an inner surface 11 of the barrel 5. The stopper 7 fluidly closes a first end 13 of the barrel 5. The stopper 7 is connected to a plunger rod 15. A second end 17 of the container 3 is threaded for attachment of an injection device (not shown) or a closure 19. The closure 19 fluidly closes the second end 17 of the barrel 5 and is further included in the container 3.

[0277] Within barrel 5, liquid pharmaceutical composition 21 and gas 23 are disposed between stopper 7 and closure 19. As shown in Figure 1, composition 21 and gas 23 are disposed along the axial direction of container 1. The volume enclosed by barrel 5 between stopper 7 and closure 19 occupied by gas 23 is defined as headspace A 25 of system 1.

[0278] At room temperature (293.15 K), the volume occupied by headspace A 25 is 1% or more of the volume occupied by composition 21.

[0279] The system 1 is designed such that in the case of expansion of the pharmaceutical composition 21, the pharmaceutical composition 21 can expand by reducing the volume of the headspace A 25. This is possible because the gas 23 can be displaced and / or compressed.

[0280] Thus, when system 1 is cooled from room temperature (the situation shown in FIG. 1) to below the freezing point of composition 21, stopper 7 does not move, even though composition 21 takes up more space due to expansion during cooling (at least some of the time during cooling). Instead, composition 21 expands during cooling into the volume previously occupied by gas 23 by compressing gas 23. In other words, it is easier for composition 21 to compress gas 23 than it is to move stopper 7 against the release stress.

[0281] Figure 2 shows in perspective cutaway view parts of another system 1' according to a first embodiment of the invention. Structural features of system 1' that are the same as or similar to those of system 1 described above with respect to Figure 1 are labelled with the same reference numbers but in dashed and dotted lines. System 1' is empty, i.e. without composition or gas, and the stopper has been removed.

[0282] 2, the overall length of the container 3' is shown as L1', and the overall length of the barrel 5' is shown as L2'. Additionally, the inner diameter D1' and the outer diameter D2' of the barrel 5' are also shown.

[0283] FIG. 3 illustrates a system 1″ similar to system 1 described above with respect to FIG. 1. System 1″ in FIG. 3 has an orientation rotated 180 degrees compared to system 1 in FIG. 1. Thus, for system 1″ in FIG. 3, first end 13″ (i.e., closed by stopper 7″) is at the top and second end 17″ (i.e., closed by closure 19″) is at the bottom. Structural features of system 1′ that are the same as or similar to features of system 1 described above with respect to FIG. 1 are labeled with the same reference numbers but in dashed double-dashed lines.

[0284] In FIG. 3, the headspace B25'' can be identified. Apparently, the headspace B25'' has a cylindrical volumetric region portion having a specific diameter indicated by 27''. The specific diameter 27'' is equal to the inner diameter of the barrel 5''. The volumetric region portion further has a specific height indicated by 29''.

[0285] 4 shows a schematic diagram of an arrangement 31 for carrying out a method according to an embodiment of the invention. The arrangement 31 comprises an apparatus 33 for manufacturing a system according to an embodiment of the invention, such as the system 1 described above with respect to FIG.

[0286] The device 33 comprises a servomotor 35 and a laser 37 fixedly attached mechanically to the servomotor 35. In the sense that the servomotor 35 translates, the stopper 39 can also be translated along the vertical axis of the barrel 43 by some kind of translation means 41 (which is part of the servomotor 35). More precisely, the stopper 39 is attached to the translation means 41. And, by translating the translation means 41, the stopper 39 can be positioned in the barrel 43.

[0287] As the stopper 39 translates, the laser 37 also translates synchronously as it is fixedly attached to the servo motor 35. This allows a positioning system 45, which may be coupled to and / or control the servo motor 35 and the laser 37, to detect a surface 47 of the liquid composition 49 held within the barrel 43 when the surface 47 is aligned with a laser beam 51 emitted by the laser 37. The stopper 39 can therefore be precisely positioned with respect to the detected surface 47 of the liquid composition 49.

[0288] The method includes:

[0289] The step of providing a barrel 43, one end of the barrel 43 being an open end and another end of the barrel 43 being a closed end. In particular, the second end of the barrel 43 can be closed with a closure. Then, the step of filling the barrel 43 with a liquid pharmaceutical composition 49 is performed. Also included is the step of providing a stopper 39 and positioning the stopper 39 by translating the stopper 39 along the axial extension of the barrel 43 to a specific position within the barrel 43 by a servo motor 35 (in particular a translation means 41), where the specific position is determined by a positioning system 45 comprising a laser 37. The positioning can further include the step of retracting the translation means, thereby releasing the stopper 39, which expands at a predetermined position within the barrel 43.

[0290] The features disclosed in the specification, the drawings and the claims may, alone or in any combination, be essential for realizing the invention in its different embodiments. [Explanation of symbols]

[0291] 1,1',1'' system 3,3',3'' medicine container 5,5',5'' barrel 7,7'' stopper 9,9'' surface 11,11',11'' surface 13,13',13'' First end 15,15'' plunger rod 17,17',17'' Second end 19,19',19'' closure 21,21'' Pharmaceutical Composition 23,23'' Gas 25,25'' Headspace 27'' diameter 29'' specific height 31 Mechanism 33 Equipment 35 Servo motor 37 Laser 39 Stopper 41 Translation means 43 barrels 45 Positioning System 47 Surface 49 Liquid Composition L1',L2' length D1',D2' Diameter

Claims

1. 1. A system for storing a pharmaceutical composition at low temperature, comprising: - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between the stopper and the closure; A system comprising:

2. A system for storing the pharmaceutical composition of claim 1 at low temperature, comprising: especially, - a pharmaceutical container for storing a pharmaceutical composition at low temperature, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between the stopper and the closure; wherein the volume enclosed by the barrel occupied by the gas is defined as the headspace of the system; especially, - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between the stopper and the closure; and / or especially, - a pharmaceutical container for cryogenic storage of a pharmaceutical composition, the pharmaceutical container having a barrel, a stopper fluidly closing a first end of the barrel, and a closure fluidly closing a second end of the barrel; a liquid pharmaceutical composition and a gas disposed within the barrel of the container between the stopper and the closure; wherein, for a vertical orientation of the container occupied by the gas, with the first end at the bottom and the second end at the top, the volume enclosed by the barrel between the stopper and the closure is defined as the headspace of the system; A system wherein, at room temperature, the volume occupied by the headspace is 1% or more of the volume occupied by the composition.

3. the volume enclosed by the barrel that the gas occupies, particularly for a particular orientation of the vessel, is defined as the headspace of the system; especially, In the case of a vertical orientation of the container, with the first end at the bottom and the second end at the top, the volume enclosed by the barrel between the stopper and the closure that is occupied by the gas is defined as the headspace A of the system; and / or especially, 3. The system of claim 1 or 2, wherein, for a vertical orientation of the container with the second end at the bottom and the first end at the top, the volume enclosed by the barrel between the stopper and the closure occupied by the gas is defined as the headspace B of the system.

4. at room temperature, the volume occupied by the headspaces, such as headspace A and / or headspace B, is 1% or more of the volume occupied by the composition; and / or 4. The system of claim 1, wherein the headspace B has a cylindrical volumetric region portion, the volumetric region portion having a specific diameter and specific height equal to the inner diameter of the barrel, the specific height being preferably measured from the center point of the stopper to the surface of the liquid pharmaceutical composition facing the stopper, the specific height having a value of 0.1 mm or more.

5. The specific height is (i) 0.2 mm or more, preferably 0.5 mm or more, preferably 0.7 mm or more, preferably 1 mm or more, preferably 2 mm or more, preferably 3 mm or more, preferably 4 mm or more, preferably 5 mm or more, preferably 6 mm or more, preferably 7 mm or more, preferably 8 mm or more, preferably 9 mm or more, preferably 10 mm or more, preferably 11 mm or more, preferably 12 mm or more, preferably 13 mm or more, preferably 14 mm or more, preferably 15 mm or more, (ii) 15 mm or less, preferably 14 mm or less, preferably 13 mm or less, preferably 12 mm or less, preferably 11 mm or less, 10 mm or less, preferably 9 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, preferably 5 mm or less, preferably 4 mm or less, preferably 3 mm or less, preferably 2 mm or less, and / or (iii) from 1 mm to 15 mm, preferably from 1 mm to 10 mm, preferably from 1 mm to 8 mm, preferably from 1 mm to 3 mm, for example 2 mm, or from 3 mm to 5 mm, for example 4 mm, or from 5 mm to 7 mm, for example 6 mm, or from 7 mm to 9 mm, for example 8 mm; and / or The ratio [mm / mm] of the inner diameter of the barrel to the specific height is (i) 0.3 or more, preferably 0.7 or more, preferably 1 or more, preferably 1.05 or more, preferably 1.1 or more, preferably 1.3 or more, preferably 1.5 or more, preferably 2 or more, preferably 2.5 or more, preferably 3 or more, preferably 3.5 or more, preferably 4 or more, preferably 4.5 or more, preferably 5 or more, preferably 7 or more, preferably 10 or more, (ii) 10 or less, preferably 6 or less, preferably 5 or less, preferably 4 or less, preferably 3 or less, preferably 2 or less, preferably 1.5 or less, preferably 1.3 or less, preferably 1.0 or less, preferably 0.7 or less, preferably 0.5 or less, and / or (iii) 0.3 to 10, preferably 1 to 10, preferably 1 to 5, preferably 1 to 2 or 2 to 4 or 3 to 5; The system of claim 4.

6. In particular, the overall length of the barrel, measured along the axial extension of the barrel, is: (i) 40 mm or more, preferably 45 mm or more, preferably 50 mm or more, preferably 55 mm or more, preferably 60 mm or more, preferably 65 mm or more, preferably 70 mm or more, preferably 75 mm or more, preferably 80 mm or more, (ii) 80 mm or less, preferably 75 mm or less, preferably 70 mm or less, preferably 65 mm or less, preferably 60 mm or less, preferably 55 mm or less, preferably 50 mm or less, preferably 45 mm or less, preferably 40 mm or less, and / or (iii) 40 mm to 80 mm, preferably 40 mm to 60 mm, particularly 45 mm to 55 mm, in particular 45 mm to 50 mm, or 60 mm to 70 mm, in particular 63 mm to 67 mm; and / or The inner diameter of the barrel is (i) 5 mm or more, preferably 6 mm or more, preferably 7 mm or more, preferably 8 mm or more, preferably 9 mm or more; (ii) 10 mm or less, preferably 9 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, preferably 5 mm or less; and / or (iii) 5 mm to 10 mm, preferably 5 mm to 7 mm, in particular 6 mm to 7 mm, in particular 6 mm to 6.5 mm, for example 6.35 mm, or 7 mm to 9 mm, in particular 8 mm to 9 mm, in particular 8.5 mm to 9 mm, for example 8.65 mm; A system according to any one of claims 1 to 5.

7. (i) the overall length of the barrel, particularly measured along the axial extension of the barrel, is between 45 mm and 50 mm, and the inside diameter of the barrel is between 8 mm and 9 mm; or (ii) the overall length of the barrel, particularly measured along the axial extension of the barrel, is between 60 mm and 70 mm, and the inside diameter of the barrel is between 5 mm and 7 mm; A system according to any one of claims 1 to 6.

8. The following formula: (X / Y) / Z≦V, and / or W≦(X / Y) / Z is fulfilled, where X is the volume (ml) of the pharmaceutical composition at room temperature; Y is the volume of the headspace at room temperature (ml); Z is the inner diameter of the barrel (mm); V(1 / mm) is 1.5, preferably 1.4, preferably 1.3, preferably 1.2, preferably 1.1, preferably 1.0, preferably 0.9, preferably 0.8, preferably 0.7, preferably 0.6, preferably 0.5, preferably 0.4, preferably 0.3, preferably 0.2, preferably 0.1; and / or W(1 / mm) is 0.01, preferably 0.05, preferably 0.1, preferably 0.2, preferably 0.3, preferably 0.4, preferably 0.5, preferably 0.6, preferably 0.7; A system according to any one of claims 1 to 7.

9. the liquid pharmaceutical composition comprises an excipient; Preferably, the additive is selected from the group consisting of salts, sugars, lipids and acids; Preferably, the additive is selected from the group consisting of NaCl, KCl, sucrose, sodium acetate, acetic acid, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, SM (sphingomyelin)-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC], cholesterol, polyethylene glycol (PEG), H ３ P.O. ４ , XH ２ P.O. ４ , X ２ H.P.O. ４ and X ３ P.O. ４ X is Na and / or K; Preferably, the additive is NaCl or Preferably, the additive is KCl or Preferably, the additive is sucrose or Preferably, the additive is sodium acetate or Preferably, the additive is acetic acid or Preferably, said additive is a lipid, preferably ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, SM (sphingomyelin)-102, polyethylene glycol [PEG] 2000 dimyristoylglycerol [DMG], 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC] and / or cholesterol, Preferably, the additive is polyethylene glycol (PEG) or Preferably, the additive is H ３ P.O. ４ or Preferably, the additive is XH ２ P.O. ４ and X is Na and / or K; Preferably, the additive is X ２ H.P.O. ４ and X is Na and / or K; Preferably, the additive is X ３ P.O. ４ and X is Na and / or K; The system according to any one of claims 1 to 8, wherein the additive is preferably cholesterol.

10. The concentration of the additive is (i) 0.01 mol / l or more, preferably 0.05 mol / l or more, preferably 0.1 mol / l or more, preferably 0.2 mol / l or more, preferably 0.3 mol / l or more, preferably 0.4 mol / l or more, preferably 0.5 mol / l or more, preferably 0.7 mol / l or more, preferably 1 mol / l or more; (ii) 1 mol / L or less, preferably 0.9 mol / L or less, preferably 0.8 mol / L or less, preferably 0.7 mol / L or less, preferably 0.6 mol / L or less, preferably 0.5 mol / L or less, preferably 0.4 mol / L or less, preferably 0.3 mol / L or less, preferably 0.2 mol / L or less, and / or (iii) from 0.1 mol / l to 1 mol / l, preferably from 0.1 mol / l to 0.8 mol / l, preferably from 0.1 mol / l to 0.5 mol / l, preferably from 0.2 mol / l to 0.4 mol / l, preferably 0.25 mol / l; and / or The concentration of the additive is (i) 1 g / l or more, preferably 2 g / l or more, preferably 5 g / l or more, preferably 10 g / l or more, preferably 20 g / l or more, preferably 30 g / l or more, preferably 40 g / l or more, preferably 50 g / l or more, preferably 75 g / l or more, preferably 100 g / l or more, preferably 150 g / l or more, preferably 200 g / l or more, (ii) 300 g / l or less, preferably 200 g / l or less, preferably 150 g / l or less, preferably 120 g / l or less, preferably 100 g / l or less, preferably 90 g / l or less, preferably 80 g / l or less, preferably 70 g / l or less, preferably 60 g / l or less, preferably 50 g / l or less, preferably 40 g / l or less, preferably 30 g / l or less, preferably 20 g / l or less, preferably 10 g / l or less, preferably 5 g / l or less, and / or (iii) from 1 g / l to 300 g / l, preferably from 5 g / l to 200 g / l, preferably from 20 g / l to 150 g / l, preferably from 50 g / l to 120 g / l, preferably from 60 g / l to 100 g / l, preferably from 70 g / l to 90 g / l.

11. The concentrations of all compounds in the pharmaceutical composition are (i) 0.01 mol / l or more, preferably 0.05 mol / l or more, preferably 0.1 mol / l or more, preferably 0.2 mol / l or more, preferably 0.3 mol / l or more, preferably 0.4 mol / l or more, preferably 0.5 mol / l or more, preferably 0.7 mol / l or more, preferably 1 mol / l or more; (ii) 1 mol / L or less, preferably 0.9 mol / L or less, preferably 0.8 mol / L or less, preferably 0.7 mol / L or less, preferably 0.6 mol / L or less, preferably 0.5 mol / L or less, preferably 0.4 mol / L or less, preferably 0.3 mol / L or less, preferably 0.2 mol / L or less, and / or (iii) 0.1 mol / l to 1 mol / l, preferably 0.1 mol / l to 0.8 mol / l, preferably 0.1 mol / l to 0.5 mol / l, preferably 0.2 mol / l to 0.4 mol / l, preferably 0.25 mol / l; A system according to any one of claims 1 to 10.

12. At room temperature, the headspaces, such as the headspace A and / or the headspace B, each represent a volume of the composition that is (i) 1.3% or more, preferably 1.5% or more, preferably 1.7% or more, preferably 2% or more, preferably 2.5% or more, preferably 3% or more, preferably 3.5% or more, preferably 4% or more, preferably 4.5% or more, preferably 5% or more, preferably 6% or more, preferably 7% or more, preferably 8% or more, preferably 9% or more, preferably 10% or more, preferably 11% or more, preferably 12% or more, preferably 13% or more, preferably 14% or more, preferably 15% or more, preferably 17% or more, preferably 20% or more, (ii) 20% or less, preferably 17% or less, preferably 15% or less, preferably 14% or less, preferably 13% or less, preferably 12% or less, preferably 11% or less, preferably 10% or less, preferably 9% or less, preferably 8% or less, preferably 7% or less, preferably 6% or less, preferably 5% or less, preferably 4.5% or less, preferably 4% or less, preferably 3.5% or less, preferably 3% or less, preferably 2.5% or less, preferably 2% or less, preferably 1.7% or less, preferably 1.5% or less, preferably 1.3% or less, and / or (iii) between 1% and 20%, in particular between 1.5% and 3%, between 2% and 5%, between 4% and 8%, between 7% and 12%, between 10% and 15%, between 12% and 17% and / or between 15% and 20%, A system according to any one of claims 1 to 11.

13. (i) the stopper is slidably disposed within the barrel; (ii) the stopper has a peripheral surface that at least partially contacts an inner surface of the barrel; and / or (iii) the first end is a proximal end of the container, in particular the barrel, and / or the second end is a distal end of the container, in particular the barrel; A system according to any one of claims 1 to 12.

14. in the case of expansion of the pharmaceutical composition, particularly preferably during cooling of the system, from (a) above 4° C., particularly from room temperature, and / or (b) below 0° C., particularly below the freezing point of the composition, and / or below the storage temperature of the system, (i) the pharmaceutical composition is capable of expanding or expands by displacing and / or compressing the gas, thus reducing the volume of the headspace, such as the headspace A and / or the headspace B; (ii) the maximum force exerted on the stopper, particularly in the axial direction, by the pharmaceutical composition and / or the gas is lower than the release stress of the stopper; (iii) the stopper moves 5 mm or less, preferably 4 mm or less, preferably 3.5 mm or less, preferably 3 mm or less, preferably 2.7 mm or less, preferably 2.5 mm or less, preferably 2.3 mm or less, preferably 2.0 mm or less, preferably 1.7 mm or less, preferably 1.5 mm or less, preferably 1.3 mm or less, preferably 1.0 mm or less, preferably 0.8 mm or less, preferably 0.6 mm or less, preferably 0.5 mm or less, preferably 0.4 mm or less, preferably 0.3 mm or less, preferably 0.2 mm or less, preferably 0.1 mm or less, and / or (iv) the stopper moves by 0.01 mm or more, preferably by 0.05 mm or more, preferably by 0.1 mm or more, preferably by 0.3 mm or more, preferably by 0.5 mm or more, preferably by 0.7 mm or more, preferably by 1.0 mm or more; Preferably, the barrels are designed to be adapted to one another such that during cooling, (a) the first end is at the bottom and / or the second end is at the top, and / or (b) the pharmaceutical composition and the gas are vertically oriented such that they are disposed along the axial direction of the container, in particular the barrel. A system according to any one of claims 1 to 13.

15. (i) the storage temperature is (a) -100°C or higher, preferably -80°C or higher, preferably -60°C or higher, preferably -40°C or higher, preferably -20°C or higher, preferably -10°C or higher; (b) 0° C. or less, −1° C. or less, preferably −5° C. or less, preferably −15° C. or less, preferably −25° C. or less, preferably −35° C. or less, preferably −55° C. or less, preferably −75° C. or less, preferably −95° C. or less and / or (c) -100 to 0°C, preferably -80 to -5°C, preferably -60 to -20°C, preferably -50 to -40°C, and / or (d) 0°C, -10°C, -20°C, -30°C, -40°C or -50°C. That is, and / or (ii) the storage temperature is below the freezing point temperature of the composition; A system according to any one of claims 1 to 14.

16. (i) the pharmaceutical composition comprises, in particular, more than 80% (w / w), preferably more than 90% (w / w), preferably more than 95% (w / w), preferably more than 97% (w / w), preferably more than 98% (w / w) of H of the composition; ２ Contains O. and / or (ii) The gas is air, CO ２ , N ２ , Ar and / or O ２ or air, CO ２ , N ２ , Ar and / or O ２ That is, 16. A system according to any one of claims 1 to 15.

17. The overall length of the vessel, in particular the overall length of the vessel measured along the axial extension of the vessel, is (i) 30 mm or more, preferably 40 mm or more, preferably 50 mm or more, preferably 60 mm or more, preferably 70 mm or more, preferably 80 mm or more, preferably 90 mm or more, preferably 100 mm or more, preferably 110 mm or more, preferably 120 mm or more, preferably 130 mm or more, preferably 150 mm or more, preferably 170 mm or more, preferably 190 mm or more, (ii) 200 mm or less, preferably 150 mm or less, preferably 140 mm or less, preferably 130 mm or less, preferably 110 mm or less, preferably 100 mm or less, preferably 90 mm or less, preferably 80 mm or less, preferably 70 mm or less, preferably 60 mm or less, preferably 50 mm or less, preferably 40 mm or less, and / or (iii) from 30 mm to 200 mm, preferably from 50 mm to 150 mm, in particular from 50 mm to 100 mm, for example from 60 mm to 90 mm and / or from 90 mm to 150 mm; In particular, the overall length of the barrel, measured along the axial extension of the barrel, is: (i) 30 mm or more, preferably 40 mm or more, preferably 50 mm or more, preferably 60 mm or more, preferably 70 mm or more, preferably 80 mm or more, preferably 90 mm or more, preferably 100 mm or more, preferably 110 mm or more, preferably 120 mm or more, preferably 130 mm or more, preferably 150 mm or more, preferably 170 mm or more, preferably 190 mm or more, (ii) 200 mm or less, preferably 150 mm or less, preferably 140 mm or less, preferably 130 mm or less, preferably 110 mm or less, preferably 100 mm or less, preferably 90 mm or less, preferably 80 mm or less, preferably 70 mm or less, preferably 60 mm or less, preferably 50 mm or less, preferably 40 mm or less, and / or (iii) from 30 mm to 200 mm, preferably from 40 mm to 130 mm, in particular from 40 mm to 80 mm, 50 mm to 80 mm and / or 70 mm to 130 mm; The inner diameter of the barrel is (i) 5 mm or more, preferably 8 mm or more, preferably 10 mm or more, preferably 13 mm or more, preferably 15 mm or more, preferably 18 mm or more, preferably 20 mm or more, preferably 25 mm or more, preferably 30 mm or more, (ii) 30 mm or less, preferably 28 mm or less, preferably 25 mm or less, preferably 20 mm or less, preferably 15 mm or less, preferably 13 mm or less, preferably 10 mm or less, preferably 8 mm or less, preferably 7 mm or less, preferably 6 mm or less, and / or (iii) between 5 mm and 30 mm, preferably between 5 mm and 10 mm, between 10 mm and 15 mm, between 14 mm and 18 mm, between 17 mm and 20 mm, and / or between 20 mm and 30 mm; The outer diameter of the barrel is (i) 5 mm or more, preferably 8 mm or more, preferably 10 mm or more, preferably 13 mm or more, preferably 15 mm or more, preferably 18 mm or more, preferably 20 mm or more, preferably 25 mm or more, preferably 30 mm or more, preferably 35 mm or more, preferably 40 mm or more, (ii) 40 mm or less, preferably 35 mm or less, 30 mm or less, preferably 28 mm or less, preferably 25 mm or less, preferably 20 mm or less, preferably 15 mm or less, preferably 13 mm or less, preferably 10 mm or less, preferably 7 mm or less, preferably 5 mm or less, and / or (iii) between 5 mm and 40 mm, preferably between 5 mm and 9 mm, 8 mm and 13 mm, 12 mm and 16 mm, 15 mm and 20 mm, 19 mm and 25 mm, and / or between 25 mm and 35 mm; and / or At room temperature, the volume of the composition is: (i) 0.1 ml or more, preferably 0.2 ml or more, preferably 0.3 ml or more, preferably 0.5 ml or more, preferably 0.7 ml or more, preferably 1 ml or more, preferably 1.5 ml or more, preferably 2 ml or more, preferably 3 ml or more, preferably 5 ml or more, preferably 10 ml or more, preferably 15 ml or more, preferably 20 ml or more, preferably 30 ml or more, preferably 50 ml or more, preferably 70 ml or more, (ii) 100 ml or less, preferably 70 ml or less, preferably 55 ml or less, preferably 25 ml or less, preferably 15 ml or less, preferably 10 ml or less, preferably 7 ml or less, preferably 6 ml or less, preferably 5 ml or less, preferably 4 ml or less, preferably 3 ml or less, preferably 1 ml or less, preferably 0.7 ml or less, preferably 0.5 ml or less, preferably 0.3 ml or less, preferably 0.2 ml or less, and / or (iii) 0.1 ml to 100 ml, preferably 0.1 ml to 1 ml or 1 ml to 100 ml, for example 1 ml to 50 ml, in particular 1 ml to 3 ml, 1 ml to 10 ml, 10 ml to 20 ml, 20 ml to 30 ml, 30 ml to 40 ml and / or 40 ml to 50 ml; 17. A system according to any one of claims 1 to 16.

18. 18. A system according to any one of claims 1 to 17, wherein when the system is cooled from room temperature (20°C) to -20°C, preferably -50°C, preferably -80°C, the position of the stopper moves along the axis of rotation of the barrel by no more than 4.0mm, preferably no more than 3.0mm, preferably no more than 2.5mm, preferably no more than 2.0mm, preferably no more than 1.5mm, preferably no more than 1.0mm, preferably no more than 0.8mm, preferably no more than 0.5mm, preferably no more than 0.3mm, preferably no more than 0.1mm.

19. 19. The system according to any one of claims 1 to 18, wherein the system has a temperature below -20°C and above -200°C, preferably below -40°C and above -120°C, preferably below -50°C and above -90°C.

20. 20. The system according to any one of claims 1 to 19, which is stored for 5 days or more, preferably 1 month or more, preferably 3 months or more, preferably 6 months or more, preferably 1 year or more.

21. The system of claim 1 , wherein the stopper includes at least one internal recess.

22. the barrel comprises a polymer, preferably a cyclic olefin copolymer (COC) and / or a cyclic olefin polymer (COP); the closure comprises bromobutyl rubber, preferably the closure is a siliconized closure comprising bromobutyl rubber; and / or 22. The system of any one of claims 1 to 21, wherein the barrel comprises a polymer, preferably COC and / or COP, and the closure comprises bromobutyl rubber, preferably the closure is a siliconized closure comprising bromobutyl rubber.

23. 23. A method comprising administering to a subject an effective amount of at least one pharma- ceutical active ingredient contained in a pharmaceutical composition using a system according to any one of claims 1 to 22.

24. A liquid composition comprising: In methods of treatment of the human or animal body by surgery or therapy, or For use in diagnostic methods carried out on the human or animal body, The composition comprises at least one pharma- ceutical active ingredient, and the method comprises:

23. A liquid composition comprising the step of administering to a subject an effective amount of the active ingredient using a system according to any one of claims 1 to 22.

25. In methods of treatment of the human or animal body by surgery or therapy, or For use in diagnostic methods carried out on the human or animal body, The composition comprises at least one pharma- ceutical active ingredient, and the method comprises: administering to a subject an effective amount of the active ingredient using the system.

23. A system according to any one of claims 1 to 22.

26. The composition comprises mRNA. A system according to any one of claims 1 to 22, a method according to claim 23, a liquid composition according to claim 24 and / or a system according to claim 25.

27. 23. An apparatus for manufacturing a system according to any one of claims 1 to 22, comprising a servomotor and a laser fixedly attached to the servomotor, in particular mechanically fixedly attached.

28. 27. A method for manufacturing a system according to any one of claims 1 to 22, comprising the steps of: (i) using an apparatus according to claim 27; and / or (ii) (a) providing a barrel, preferably having an open end at one end and / or a closed end at another end of the barrel; (b) filling the barrel with a liquid pharmaceutical composition; (c) providing a stopper; and / or (d) positioning the stopper by translating it along the axial extension of the barrel to a specific position within the barrel by means of a servo motor, in particular a servo motor comprised in the apparatus, said specific position being determined by a positioning system including a laser, in particular a laser being mechanically fixedly attached to the servo motor.

29. Use of the system according to any one of claims 1 to 22 for long-term storage at low temperatures, comprising: In particular, the long-term storage is for more than 5 days, preferably more than 1 month, preferably more than 3 months, preferably more than 6 months, preferably more than 1 year; and / or In particular, the low temperature is -20°C or lower, preferably -50°C or lower, and preferably -80°C or lower.

30. 23. A bundle comprising 5 or more, preferably 10 or more, preferably 30 or more, preferably 50 or more, preferably 100 or more of the systems according to any one of claims 1 to 22, wherein for each two of said systems the volumes of the headspaces of said systems, such as headspace A of said system and / or headspace B of said system, differ by no more than 0.5ml, preferably no more than 0.4ml, preferably no more than 0.3ml, preferably no more than 0.2ml, preferably no more than 0.1ml.

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