Container closure system

Abstract

The present disclosure relates to a container closure system (1, 1') comprising a vial (10) with an opening at one end, a stopper (20) configured for sealing interaction with the opening and a seal cap (30) configured to encase the stopper (20) and the end of the vial (10) comprising the opening. The vial (10) may consist of a material having a coefficient of thermal expansion αs which is less than the coefficient of thermal expansion αs of the stopper (20) material. The container closure integrity may be maintained even at extreme low temperatures, if the stopper (20) comprises a plug portion (21) configured to be inserted into the opening, a skirt portion (22) configured to encase a wall section of the vial (10) surrounding the opening and a lid portion (23) connecting the plug portion (21) and the skirt portion (22).

Description

[0001] SANOFI PAT25027

[0002] Description

[0003] CONTAINER CLOSURE SYSTEM

[0004] The present disclosure is generally directed to improvements in a container closure system (CCS), in particular to improvements in reliably sealing a vial, e.g. a small bottleshaped container, for storing drugs and / or biological material.

[0005] Liquid drugs and biological products are often stored in vials which are flask-like containers typically made of glass or sometimes of a polymer-based material. For example, glass vials are the most common type of primary container for injectable drugs. Such vials are closed containers with one opening at one end of the vial and have standardized dimensions (e.g. IS08362-1 for manufactured from glass cane and IS08362-4 for molded glass vials). A key functions of a vial is to maintain closure integrity during the whole life cycle of a liquid product which is mainly achieved by a stopper, often a rubber stopper, closing the opening of the vial. In most cases, a container closure system further comprises a seal cap, e.g. an aluminum seal cap, configured to encase the stopper and the end of the vial comprising the opening.

[0006] Examples of container closure systems with a vial and a stopper partially inserted into the opening of the vial are known e.g. from US 4,441,621 A, EP 0 922 648 A2, US 4,230,231 A, US 2022 / 226191 A1 or EP 1 634819 B1.

[0007] Deep cold storage and cryogenic storage could cause a breach in the container closure system at extreme low temperatures. Especially, the different thermal contraction coefficients among different materials of construction of the distinct components of the container closure system in a traditional ISO configuration, i.e. with a vial according to ISO standard, a mating stopper according to ISO standard and a mating seal cap according to ISO standard, might cause creation of gaps and possible breaches of the container closure integrity at extreme low temperature, for example below the glass transition temperature (Tg) of a rubber stopper inserted a glass vial container. At a temperature belowthe stopper glass transition temperature (Tg), the stopper will lose its viscoelastic properties and may become brittle.

[0008] It is an object of the present disclosure to provide an improved container closure system (CCS), especially suitable for maintaining container closure integrity at extreme low temperatures with components of different materials.

[0009] This object is solved with a container closure system according to claim 1.

[0010] A container closure system according to the present disclosure comprises a vial with an opening at one end surrounded by an, e.g. substantially, cylindrical wall section or rim, a stopper configured for sealing interaction with the opening and a seal cap configured to encase the stopper and the end of the vial comprising the opening. The stopper may be partially inserted into the opening of the vial for sealing interaction, i.e. to close-off the vial. Typically, the vial, its opening and the stopper are circular in cross-section. One of the functions of the seal cap is to prevent that dirt enters the interface between the stopper and the vial. In addition, a broken seal cap may indicate that the vial was opened. Thus, the seal cap may at least cover and encase the portion of the interface between the stopper and the vial. However, the seal cap may be substantially cup-shaped covering and encasing the whole stopper and the end portion of the vial comprising the opening. The vial may consist of a material, e.g. glass or a polymer-based material, having a coefficient of thermal expansion avwhich is less than the coefficient of thermal expansion Os of the stopper material, e.g. rubber or an elastomer.

[0011] According to an aspect of the present disclosure, the container closure system uses a geometry of the component parts, e.g. mainly the vial and the stopper, with differential thermal contraction resulting in reinforcement of the sealing properties by using an adapted geometry. For example, the stopper comprises a plug portion configured to be inserted into the opening, a skirt portion configured to encase a substantially cylindrical wall section of the vial surrounding the opening and a lid portion connecting the plug portion and the skirt portion. In other words, the stopper has a geometry providing a gap or groove between the radially inner plug portion and the radially outer skirt portion which gap or groove receives the edge of the vial wall or rim surrounding the opening. Thisgeometry has the effect that in case of very low temperatures, i.e. when the vial and the stopper shrink compared to room temperature, the rubber stopper will contract in a larger magnitude than the glass vial at extremely low temperatures, which contraction will reinforce the sealing area due to the geometry, that is the stopper will contract towards the rim and / or the external wall of the vial. It is preferred if the outer wall section or rim surrounding the opening is not conically tapered, i.e. not having a smaller diameter at the free upper end, such that the radially outer skirt portion of the stopper is sufficiently held on the wall or rim even if the stopper contracts due to low temperatures.

[0012] The seal cap of the container closure system may comprise a substantially planar top, a substantially cylindrical skirt and a flange protruding radially inwards from the edge of the skirt which is opposite to the edge of the skirt connected to the top. In other words, the seal cap may have a substantially cup-shaped form defined by the top and the skirt with the free edge of the skirt being crimped or bent inwardly to hook or engage behind the stopper or a vial portion, e.g. a vial flange. With such an exemplary geometry, the seal cap supports reinforcing the sealing between the stopper and the vial when the seal cap shrinks at low temperatures. The seal cap may consist of a material, e.g. aluminum, having a coefficient of thermal expansion acwhich is less than the coefficient of thermal expansion of the stopper material. As an alternative, the seal cap may consist of a plastic material, e.g. an elastically deformable thermoplastic material, having a coefficient of thermal expansion acwhich is only slightly less than the coefficient of thermal expansion of the stopper material. The seal cap may be a press-fit cap as described for example in EP 4098572 A1 or in US 02024 / 0000660 A1. Such press-fit caps may have elastically deformable legs holding the stopper on the vial by means of elastic force. The stopper and the cap may be provided as a unit which is simultaneously fastened on the vial after filling. Further, the vial may consist of a material having a coefficient of thermal expansion which is less than the coefficient of thermal expansion of the seal cap material.

[0013] The container closure system may comprise a vial consisting of a material having a coefficient of thermal expansion avbetween 0.5 * 10'6 / K at 20 °C and 20 * 10'6 / K at 20 °C, e.g. glass, a seal cap consisting of a material having a coefficient of thermal expansion acbetween 22 * 10'6 / K at 20 °C and 25 * 10'6 / K at 20 °C, e.g. aluminum, or between 50 * 10'6 / Kat 20 °C and 150 * 10'6 / Kat20 °C, e.g. a plastic material, and a stopper consistingof a material having a coefficient of thermal expansion asabove 100 * 10'6 / K at 20 °C, preferably between 150 * 10'6 / K at 20 °C and 250 * 10'6 / K at 20 °C. The stopper may be made from a material, e.g. rubber, being substantially flexible at room temperature or a material, e.g. an elastomer, substantially rigid at room temperature.

[0014] The vial may be provided with one of the three IS08362 standard vial neck designs, namely European blowback, American blowback or non-blowback. A so-called blowback is an inwardly protruding bead (European blowback) or an inner groove (American blowback) on the inner vial wall side surrounding the opening. The vial is not limited to a specific design but may have variants. For example, it may be made without neck and collar on the vial container, i.e. it is like a flask, or the vial may have a shoulder or neck and a collar, i.e. similar to a bottle. The stopper and the seal cap may be adapted to that geometry.

[0015] The container closure system according to the present disclosure may have a geometry with a radially outwards protruding flange, neck or collar at the outer wall section of the vial surrounding the opening. The radially outwards protruding flange may be arranged off-set from the edge of the wall section. For example, the axial distance between the edge of the wall section surrounding the opening and the flange is at least 6 mm, e.g. between 6.5 mm and 12 mm, preferably about 7 mm. With these dimensions, the skirt portion of the stopper may be made long enough in axial direction to maintain a large sealing area even if the skirt portion shrinks axially due to low temperatures. This maintains good sealing properties. If the ratio of the axial distance between the edge of the wall section surrounding the opening and the flange to the diameter of the opening of the vial is between 1:1.5 to 1:3, e.g. about 1:2 the skirt portion is tightened towards the preferably cylindrical wall section or rim if the stopper shrinks axially due to low temperatures. This tightening may compensate for a reduced axial length of the skirt portion at extremely low temperatures.

[0016] In an example, the flange may protrude radially by at least 3 mm, e.g. between 3.0 mm and 7.5 mm, from the outer surface of the wall. The axial distance between the edge of the wall section surrounding the opening and the flange may be at least two times of this radial extension of the flange. This provides for a large sealing surface.The thickness of the stopper walls may be similar to or equal to the radial extension of the flange.

[0017] The inner diameter of the cylindrical wall section of the vial may be at least four times larger than the radial extension of the flange, e.g. more than 12 mm. The wall thickness of the vial may be above 1 mm in the cylindrical wall section, e.g. between 1.1 mm to 2.0 mm.

[0018] The skirt portion of the stopper may abut the radially outwards protruding flange of the vial. In an example, a free edge of the skirt portion of the stopper may abut the radially outwards protruding flange of the vial. As an alternative, the skirt portion of the stopper may comprise a groove receiving the radially outwards protruding flange. In the latter arrangement, the sealing properties at low temperatures are further increased.

[0019] The skirt of the seal cap may encase the radially outwards protruding flange. For example, the flange of the seal cap may engage or hook behind the radially outwards protruding flange. Again, this design improves the sealing properties at low temperatures.

[0020] The vial of the container closure system may be filled with an, e.g. liquid, drug.

[0021] The terms “drug” or “medicament” are used synonymously herein and describe a pharmaceutical formulation containing one or more active pharmaceutical ingredients or pharmaceutically acceptable salts or solvates thereof, and optionally a pharmaceutically acceptable carrier. An active pharmaceutical ingredient (“API”), in the broadest terms, is a chemical structure that has a biological effect on humans or animals. In pharmacology, a drug or medicament is used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. A drug or medicament may be used for a limited duration, or on a regular basis for chronic disorders.

[0022] As described below, a drug or medicament can include at least one API, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Examples of API may include small molecules having a molecular weight of 500Da or less; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more drugs are also contemplated.

[0023] The drug or medicament may be contained in a primary package or “drug container” adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other solid or flexible vessel configured to provide a suitable chamber for storage (e.g., short- or long-term storage) of one or more drugs. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years. Storage may occur at room temperature (e.g., about 20°C), or refrigerated temperatures (e.g., from about - 4°C to about 4°C). In some instances, the drug container may be or may include a dual-chamber cartridge configured to store two or more components of the pharmaceutical formulation to-be-administered (e.g., an API and a diluent, or two different drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components prior to and / or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body.

[0024] The drugs or medicaments contained in the drug delivery devices as described herein can be used for the treatment and / or prophylaxis of many different types of medical disorders. Examples of disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further examples of disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis. Examplesof APIs and drugs are those as described in handbooks such as Rote Liste 2014, for example, without limitation, main groups 12 (anti-diabetic drugs) or 86 (oncology drugs), and Merck Index, 15th edition.

[0025] Examples of APIs for the treatment and / or prophylaxis of type 1 or type 2 diabetes mellitus or complications associated with type 1 or type 2 diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the terms “analogue” and “derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, by deleting and / or exchanging at least one amino acid residue occurring in the naturally occurring peptide and / or by adding at least one amino acid residue. The added and / or exchanged amino acid residue can either be codable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues. Insulin analogues are also referred to as "insulin receptor ligands". In particular, the term ..derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, in which one or more organic substituent (e.g. a fatty acid) is bound to one or more of the amino acids. Optionally, one or more amino acids occurring in the naturally occurring peptide may have been deleted and / or replaced by other amino acids, including non-codeable amino acids, or amino acids, including non-codea-ble, have been added to the naturally occurring peptide.

[0026] Examples of insulin analogues are Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulin glulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28) human insulin (insulin aspart); human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Vai or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

[0027] Examples of insulin derivatives are, for example, B29-N-myristoyl-des(B30) human insulin, Lys(B29) (N- tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®); B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-pal-mitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-gamma-glutamyl)-des(B30) human insulin, B29-N-omega-carboxypentadecanoyl-gamma-L-glutamyl-des(B30) human insulin (insulin degludec, Tresiba®); B29-N-(N-lithocholyl-gamma-glu-tamyl)-des(B30) human insulin; B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(w-carboxyheptadecanoyl) human insulin.

[0028] Examples of GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, for example, Lixisenatide (Lyxumia®), Exenatide (Exendin-4, Byetta®, Bydureon®, a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide (Vic-toza®), Semaglutide, Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®), rEx-endin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide / HM-11260C (Efpegle-natide), HM-15211, CM-3, GLP-1 Eligen, ORMD-0901, NN-9423, NN-9709, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, ZP-DI-70, TT-401 (Pega-pamodtide), BHM-034. MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, Tir-zepatide (LY3298176), Bamadutide (SAR425899), Exenatide-XTEN and Glucagon-Xten.

[0029] An example of an oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia or RG012 for the treatment of Alport syndrom.

[0030] Examples of DPP4 inhibitors are Linagliptin, Vildagliptin, Sitagliptin, Denagliptin, Sax-agliptin, Berberine.

[0031] Examples of hormones include hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Fol litropi n, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.

[0032] Examples of polysaccharides include a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra-low molecular weight heparin or a derivative thereof, or a sulphated polysaccharide, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and / or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weightheparin is enoxaparin sodium. An example of a hyaluronic acid derivative is Hylan G-F 20 (Synvisc®), a sodium hyaluronate.

[0033] The term “antibody”, as used herein, refers to an immunoglobulin molecule or an anti-gen-binding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab')2 fragments, which retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. The term antibody also includes an antigen-binding molecule based on tetravalent bispecific tandem immunoglobulins (TBTI) and / or a dual variable region anti-body-like binding protein having cross-over binding region orientation (CODV).

[0034] The terms “fragment” or “antibody fragment” refer to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy and / or light chain polypeptide) that does not comprise a full-length antibody polypeptide, but that still comprises at least a portion of a full-length antibody polypeptide that is capable of binding to an antigen. Antibody fragments can comprise a cleaved portion of a full length antibody polypeptide, although the term is not limited to such cleaved fragments. Antibody fragments that are useful in the present invention include, for example, Fab fragments, F(ab')2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, tetraspecific and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), monovalent or multivalent antibody fragments such as bivalent, trivalent, tetravalent and multivalent antibodies, minibodies, chelating recombinant antibodies, tribodies or bibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins, camelized antibodies, and VHH containing antibodies. Additional examples of antigenbinding antibody fragments are known in the art.

[0035] The terms “Complementarity-determining region” or “CDR” refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term “framework region” refers to amino acid sequences within the variable region of both heavyand light chain polypeptides that are not CDR sequences, and are primarily responsible for maintaining correct positioning of the CDR sequences to permit antigen binding. Although the framework regions themselves typically do not directly participate in antigen binding, as is known in the art, certain residues within the framework regions of certain antibodies can directly participate in antigen binding or can affect the ability of one or more amino acids in CDRs to interact with antigen.

[0036] Examples of antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

[0037] Pharmaceutically acceptable salts of any API described herein are also contemplated for use in a drug or medicament in a drug delivery device. Pharmaceutically acceptable salts are for example acid addition salts and basic salts.

[0038] Those of skill in the art will understand that modifications (additions and / or removals) of various components of the APIs, formulations, apparatuses, methods, systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.

[0039] An example drug delivery device may involve a needle-based injection system as described in Table 1 of section 5.2 of ISO 11608-1 :2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems may be broadly distinguished into multidose container systems and single-dose (with partial or full evacuation) container systems. The container may be a replaceable container or an integrated non-replaceable container.

[0040] As further described in ISO 11608-1 :2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). As further described in ISO 11608-1 :2014(E), a single-dose container system may involve a needle-based injection device with a replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation). Asalso described in ISO 11608-1 :2014(E), a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).

[0041] In the following, non-limiting, examples of a container closure system are described in more detail by making reference to the drawings, in which:

[0042] Figure 1 shows a sectional view of a container closure system according to a first example of the present disclosure;

[0043] Figure 2 shows a sectional view of a container closure system according to a second example of the present disclosure; and

[0044] Figures 3A - 3C show details of different vial designs for a container closure system according to the present disclosure in a partially sectional view.

[0045] The Figures show different examples of a container closure system 1 , T according to the present disclosure, which generally consist of a comprising a vial 10, a stopper 20 and a seal cap 30 (shown in dashed lines in Figures 1 and 2). While Figures 1 and 2 depict the vial 10 only schematically in cross section, Figures 3A to 3C depict three more detailed alternatives for an end portion of a vial 10.

[0046] The terms "radially" and "axially" refer to the central longitudinal axis of the vial 10 if not specified differently. The term "upper" is used in the following with reference to the Figures in which the upper end of the vial is the outlet end with the opening.

[0047] The vial 10 is a substantially flask like container, e.g. in the form of a small bottle, which may be made of glass. The vial 10 comprises an opening at an upper end (as seen in the Figures). A cylindrical wall or rim 14 surrounds the vial opening. The vial 10 may have a generally cylindrical body and a neck, e.g. as depicted in more detail in Figures 3A to3C. The wall section of the vial 10 surrounding the opening comprises a radially outwards protruding flange 11 which is arranged axially off-set from the upper end of the vial (as seen in the Figures) in the example depicted in Figures 1 and 2 by an axial distance d and the flange 11 may protrude radially by a distance a. The axial distance d is for example about 6 mm or more and the ratio of the axial distance d to the diameter of the opening of the vial 10 may be between 1 :2 and 1:2.5. The radial distance a may be 3 mm or more. As an alternative, a neck with a collar-like flange 11 may be provided as shown in Figures 3A to 3C.

[0048] The stopper 20 is a one-piece component configured for sealing interaction with the opening of the vial. More specifically, the stopper 20 comprises a plug portion 21 configured to be inserted into the opening of the vial 10, a skirt portion 22 configured to encase the wall section of the vial 10 surrounding the opening and a lid portion 23 connecting the plug portion 21 and the skirt portion 22 and forming a top surface of the stopper 20 (as seen in the Figures). In other words, the stopper 20 forms a circular groove between the plug portion 21 and the skirt portion 22 receiving the wall of the vial 10.

[0049] The seal cap 30 has a cup-shaped configuration and is configured to encase the stopper 20 and the end of the vial 10 comprising the opening. The seal cap 30 comprises a substantially planar top 31, a substantially cylindrical skirt 32 and a flange 33 protruding radially inwards from the lower edge of the skirt 32 (as seen in the Figures) which is opposite to the edge of the skirt 32 connected to the top 31. The top 31 and the skirt 32 encase and surround the stopper 20 and a portion of the vial 10. The flange 33 hooks behind flange 11 and / or behind the skirt portion 22 of the stopper 20.

[0050] In the example of Figure 1, the container closure system 1 has a free edge of the skirt portion 22 of the stopper 20 abutting the radially outwards protruding flange 11 of the vial 10. In other words, the skirt portion 22 encases the (upper) portion of the vial wall surrounding the opening but does not encase the flange 11. In contrast to that, the stopper 20 of the container closure system T depicted in Figure 2 has a skirt portion 22 encasing not only the (upper) portion of the vial wall surrounding the opening but also the radially outwards protruding flange 11 of the vial 10. In other words, in the example of Figure 2,the skirt portion 22 of the stopper 20 comprises a radially extending groove receiving the radially outwards protruding flange 11.

[0051] In Figures 3A to 3C three examples of the inner contour of the vial 10 opening are shown, wherein Figure 3A depicts a so-called American blowback with a groove 12 on the inner side of the wall, Figure 3B depicts a so-called European blowback with a bead 13 on the inner side of the wall, and Figure 3C depicts a vial 10 with no blowback.

[0052] These container closure systems 1, T can be used for deep cold or cryostatic applications because the geometry of the stopper 20 and seal cap 30 are adapted such that differential thermal contractions compared to the vial 10 result in reinforcing the sealing area. For example, the vial 10 consists of a material, e.g. glass, having a coefficient of thermal expansion avbetween 0.5 * 10'6 / K at 20 °C and 20 * 10'6 / K at 20 °C, the seal cap 30 consists of a material, e.g. aluminum, having a coefficient of thermal expansion acbetween 22 * 10'6 / K at 20 °C and 25 * 10'6 / K at 20 °C and the stopper 20 consists of a material, e.g. flexible rubber or more rigid elastomer, having a coefficient of thermal expansion Os between 150 * 10'6 / K at 20 °C and 250 * 10'6 / K at 20 °C. In an alternative example, the seal cap may consist of an elastically deformable, e.g. thermoplastic, material having a coefficient of thermal expansion asbetween 50 * 10'6 / K at 20 °C and 200 * 10'6 / K at 20 °C. An example for such a plastic seal cap is a press-fit cap as described in EP 4098572 A1 or in US 02024 / 0000660 A1.

[0053] In the examples depicted in Figures 1 and 2, the rubber stopper 20 will contract in a larger magnitude than the glass vial 10 at extremely low temperatures. However, this contraction will maintain the sealing area due to the geometry described above in that the skirt portion 22 of the stopper 20 contract towards the external side of the wall of the vial 10. A similar effect exists for the seal cap 30 which is also contracted towards the vial 10.

[0054] The stopper 20 and the seal cap 30 may be adapted to different inner and outer contours of the vial 10, especially as depicted in Figures 3A to 3C. For example, the stopper 20 and the seal cap 30 may encase the collar 11 located at or close to the open end of the vial 10.Reference Numerals

[0055] 1, T container closure system

[0056] 10 vial

[0057] 11 flange

[0058] 12 groove

[0059] 13 bead

[0060] 14 rim

[0061] 20 stopper

[0062] 21 plug portion

[0063] 22 skirt portion

[0064] 23 lid portion

[0065] 30 seal cap

[0066] 31 top

[0067] 32 skirt

[0068] 33 flange

[0069] a radial extension of flange 11

[0070] d axial distance between edge of vial 10 and flange 11

Claims

SANOFI PAT25027Claims1. A container closure system comprising a vial (10) with an opening at one end surrounded by a substantially cylindrical wall or rim (14), a stopper (20) configured for sealing interaction with the opening and a seal cap (30) configured to encase the stopper (20) and the end of the vial (10) comprising the opening, wherein the vial (10) consists of a material having a coefficient of thermal expansion avwhich is less than the coefficient of thermal expansion asof the stopper (20) material, characterized in that the stopper (20) comprises a plug portion (21) configured to be inserted into the opening, a skirt portion (22) configured to encase a substantially cylindrical wall section of the vial (10) surrounding the opening and a lid portion (23) connecting the plug portion (21) and the skirt portion (22).

2. The container closure system according to claim 1, wherein the seal cap (30) comprises a substantially planartop (31), a substantially cylindrical skirt (32) and a flange (33) protruding radially inwards from an edge of the skirt (32) which is opposite to an edge of the skirt (32) connected to the top (31).

3. The container closure system according to claim 1 or 2, wherein the seal cap (30) consists of a material having a coefficient of thermal expansion acwhich is less than the coefficient of thermal expansion of the stopper (20) material.

4. The container closure system according to any one of the preceding claims, wherein the vial (10) consists of a material having a coefficient of thermal expansion which is less than the coefficient of thermal expansion of the seal cap (30) material.

5. The container closure system according to any one of the preceding claims, wherein the vial (10) consists of a material having a coefficient of thermal expansion avbetween 0.5 * 10’6 / K at 20 °C and 20 * 10’6 / K at 20 °C.

6. The container closure system according to any one of the preceding claims, wherein the seal cap (30) consists of a material having a coefficient of thermal expansion Oc between 22 * 10’6 / K at 20 °C and 25 * 10’6 / K at 20 °C.

7. The container closure system according to any one of the preceding claims, wherein the stopper (20) consists of a material having a coefficient of thermal expansion asbetween 150 * 10’6 / K at 20 °C and 250 * 10’6 / K at 20 °C.

8. The container closure system according to any one of the preceding claims, wherein the wall section or rim (14) of the vial (10) surrounding the opening comprises a radially outwards protruding flange (11), neck or collar.

9. The container closure system according to claim 8, wherein the radially outwards protruding flange (11) is arranged off-set from the edge of the wall section or rim (14) by an axial distance (d) of at least 6 mm.

10. The container closure system according to claim 8 or 9, wherein the ratio of the axial distance (d) to the diameter of the opening of the vial (10) is between 1:2 and 1:3, and / or wherein the flange (11) extends radially from the wall section or rim (14) of the vial (10) surrounding the opening by at least 3 mm.

11. The container closure system according to any one of claims 8 to 10, wherein the skirt portion (22) of the stopper (20) abuts the radially outwards protruding flange (11).

12. The container closure system according to any one of claims 8 to 11 , wherein the skirt portion (22) of the stopper (20) comprises a groove receiving the radially outwards protruding flange (11).

13. The container closure system according to claim 2 and any one of claims 8 to 12, wherein the skirt (32) of the seal cap (30) encases the radially outwards protruding flange (11).

14. The container closure system according to claim 13, wherein the flange (33) of the seal cap (30) engages behind the radially outwards protruding flange (11).

15. The container closure system according to any one of the preceding claims, wherein the vial (10) is filled with a drug.

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