Medicament container and liquid composition

Abstract

The present invention relates to a medicament container for administration, the medicament container having a barrel configured to slidably receive a stopper. In order to elute the contents of the container for passage through an outlet, the stopper must be slid within the container. Proper release and sliding forces must be achieved for smooth action. The barrel of the present invention achieves these forces by decreasing the surface roughness of the inner surface of the barrel from the start position of the stopper to its end position.

Description

TECHNICAL FIELD

[0001] The present invention relates to a pharmaceutical container for administration and a liquid composition. BACKGROUND

[0002] Pharmaceutical containers for administration are known in the art. These containers are usually provided with a stopper which can be used to elute the contents of the container through an outlet. The stopper has to slide within the container.

[0003] In most of these containers, the stopper is moved from a proximal starting position to a distal end position using finger force. The finger force is limited so that the force required to move the stopper away from its starting position (break loose force) cannot be too high. Also, it cannot be too low so that the stopper does not move unintentionally before the intended application of the drug product. In addition, for the same reason, the force required to move the stopper from its starting position to its end position (slide force) should not be too high.

[0004] Usually, very low break loose and slide force values can be achieved by choosing a stopper with an outer diameter which is very small relative to the inner diameter of the container. However, if the outer diameter of the stopper is too small, it will not seal the container sufficiently so that the contents of the container, i.e. the drug composition, can leak out through the stopper.

[0005] WO 2018 / 157097 A1 teaches a stopper for a pharmaceutical container. The stopper has an outer diameter which is very large relative to the inner diameter of the container in order to achieve a sufficient sealing of the container. The stopper taught in this prior art document has to be plasma treated or autoclaved to achieve sufficient break loose and slide forces which increases the production costs. In addition, the strong compression required to put the stopper into the container can increase the risk of the stopper tilting within the container which can interrupt the production process.

[0006] It is therefore an object of the present invention to provide a pharmaceutical container which overcomes the drawbacks of the prior art. SUMMARY

[0007] In one embodiment, the present invention relates to a pharmaceutical container for administration, the pharmaceutical container having

[0008] - a barrel configured to slidably receive a stopper,

[0009] - the stopper having a proximal end adapted to contact a plunger rod and a distal end adapted to contact a drug composition,

[0010] - a circumferential surface of the stopper partially contacting an inner surface of the barrel,

[0011] wherein the surface roughness of the inner surface of the barrel decreases by at least 3% Ra and / or Rms from the starting position to the end position of the stopper.

[0012] In an embodiment, the present invention relates to a drug container for administration, the drug container having

[0013] - a barrel and a stopper slidably arranged within the barrel,

[0014] - the stopper has a proximal end adapted to contact a plunger rod and a distal end adapted to contact a drug composition,

[0015] - a circumferential surface of the stopper partly contacts an inner surface of the barrel,

[0016] - the stopper has one or more annular protrusions contacting the inner surface of the barrel when the stopper is moved in a distal direction,

[0017] - each annular protrusion has an ascending edge and a descending edge in a proximal-distal direction.

[0018] The proximal-distal direction is equivalent to a vector direction pointing from the proximal end to the distal end. The ascending edge of the proximal-most annular protrusion spans an angle X in the distal direction with the inner surface of the barrel and the descending edge of the distal-most annular protrusion spans an angle A in the proximal direction with the inner surface. The ratio X / A can preferably be at least 1.05.

[0019] Surface roughness

[0020] The surface roughness value can for example be controlled 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 indicated herein can be an average 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 of surface roughness Ra values include: 1 nm to 80 nm, 3 nm to 70 nm or 7 nm to 50 nm.

[0021] Additionally or alternatively, the surface roughness can be given as Rms roughness. In an embodiment, the inner surface of the barrel can have a surface roughness Rms of less than 150 nm. The surface roughness Rms indicated herein can be an average 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 can be at least 2 nm, at least 5 nm or at least 8 nm. Preferred ranges of surface roughness Rms values include: 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 when contacting the inner surface of the barrel. For example, if the surface roughness is very high, the coefficient of friction can be very high.

[0022] The surface roughness of the inner surface of the barrel can 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 preferred embodiments, the surface roughness Ra decreases 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 to the end position of the stopper. The surface roughness Rms can decrease by at least 5%, at least 7%, at least 10%, at least 20%, at least 30%, 40%, at least 50%, at least 60%, or at least 70% from the start position to the end position of the stopper.

[0023] The start position of the stopper is the position of the stopper within the barrel prior to use of the container for drug administration (i.e. the position of the stopper corresponding to the nominal volume of the container). In embodiments, the drug container is a pre-filled syringe. In a pre-filled syringe, the start position is the position of the stopper prior to use. This is typically the most proximal position of the stopper. The end position of the stopper is the position of the stopper after the nominal volume of the container has been expelled from the barrel (e.g. when the stopper contacts the distal end of the barrel). The start position of the stopper can be within a distance of 20% of the length of the container from the proximal end of the container. The end position can be within a distance of 80% to 100% of the length of the container from the proximal end of the container.

[0024] The inner surface of the barrel can have a surface roughness profile such that the surface roughness measured at the start position SP, the middle position MP and the end position EP is as follows, where the middle position can be at half way between the start position and the end position:

[0025] SP 100%,

[0026] MP 40% to 60%,

[0027] EP 20% to 35%.

[0028] Controlling the surface roughness can contribute to very low TGFV. The surface roughness can be controlled by adjusting production parameters (such as melt temperature, moulding time and polymer blend) or by surface treatment (such as coating or plasma treatment). The drug container can be made by injection moulding. Injection moulding requires the container to be at least slightly conical, i.e. the inner diameter of the barrel will decrease from the start position to the end position. Thus, the compression of the stopper increases from the start position to the end position, such that GF max will increase, and the TGFV will also increase. In this specification, any reference to the inner diameter of the barrel refers to the maximum inner diameter of the barrel, unless otherwise indicated.

[0029] The surface roughness profile can be achieved, for example, by positioning the injection nozzle closer to the end position than to the start position during injection moulding, such that the polymer melt temperature at the end position is higher than the polymer melt temperature at the start position during injection. Alternatively, the mould temperature can be influenced by segmented heating and / or cooling, resulting in a temperature gradient in the barrel direction.

[0030] 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).

[0031] Ratio of break loose force to glide force

[0032] During the break loose and glide force (BLGF) test, the container can exhibit a ratio BLF / GF of break loose force (BLF) to glide force (GF) of BLF / GF < 2. It has been found that it is important to control the ratio of BLF to GF, because if the BLF is too high compared to the GF, the user of the container will have to push with force to move the stopper from its start position, such that after the stopper has been released, the stopper can be accelerated too fast during the pushing of the stopper to its end position. Keeping the ratio BLF / GF in a balanced range will help to control the dosing without causing unnecessary pain to the patient. Moreover, if the acceleration of the stopper is limited after the break loose, the risk of leakage of the contents of the container will be less. The ratio BLF / GF can be greater than 1. It is an aspect of the present invention to keep the BLF / GF ratio substantially constant even after the container has been stored during dosing.

[0033] The total glide force variation TGFV = GF measured when the stopper is moved from the start position to its end position max - GF min It can be preferred that TGFV < 2 N. It is important to control the TGFV, because the difference between the maximum GF and the minimum GF will greatly influence the ability of the user to properly determine the dose of the pharmaceutical composition stored in the container.

[0034] In another embodiment, the present invention relates to a pharmaceutical container for dosing, the pharmaceutical container having a barrel configured to slidably receive a stopper,

[0035] wherein, during the BLGF test, the container exhibits a ratio BLF / GF of break loose force (BLF) to glide force (GF) of BLF / GF < 2, and wherein the total glide force variation TGFV = GF measured when the stopper is moved from the start position to its end position max - GF min is TGFV < 2 N,

[0036] The test plug has a proximal end adapted to contact the plunger rod and a distal end adapted to contact the drug composition, a circumferential surface adapted at least partly to contact the inner surface of the barrel,

[0037] When the plug is moved in the distal direction, one or more annular protrusions contact the inner surface of the barrel, each annular protrusion having a rising edge and a falling edge in the proximal-distal direction,

[0038] wherein the plug is further characterized in that the rising edge of the proximal-most annular protrusion spans an angle X with the inner surface of the barrel in the distal direction and the falling edge of the distal-most annular protrusion spans an angle A with the inner surface in the proximal direction, the ratio X / A being at least 1.05.

[0039] BLF, GF and BLGF can be measured according to the method described herein below as the BLGF test.

[0040] Angle X, A and their ratio X / A

[0041] The rising edge of the proximal-most annular protrusion spans an angle X with the inner surface of the barrel opening in the distal direction and the falling edge of the distal-most annular protrusion spans an angle A with the inner surface in the proximal direction. In the context of the present invention, the "rising edge" is the annular protrusion edge extending in the direction of the inner surface of the barrel when the plug is inserted into the barrel along the circumferential surface of the plug in the proximal-distal direction. The "falling edge" is the annular protrusion edge extending in the direction towards the central longitudinal axis of the barrel when the plug is inserted into the barrel along the circumferential surface of the plug in the proximal-distal direction.

[0042] In preferred embodiments, the ratio X / A is from >1.1 to 1.7. If the ratio X / A is at least 1.05, the BLGF value is improved. In preferred embodiments, the ratio X / A is at least 1.1, at least 1.15, at least 1.2 or at least 1.25. The ratio can preferably be limited to at most 1.7, at most 1.65, at most 1.6, at most 1.55, at most 1.5 or at most 1.45.

[0043] The angle X and / or A can be from >90° to <180°. Preferably, A is 130° to 170°. The minimum value of A can be at least 100°, at least 110°, at least 120° or at least 130°. The upper limit of A can be 170°, 160°, 150° or 140°. Preferably, X is 131° to 175°. The minimum value of X can be at least 101°, at least 111°, at least 121° or at least 131°. The upper limit of X can be 170°, 160°, 150° or 140°.

[0044] Keeping the angles and their ratios within the proper range will help to solve the problem the present invention is based on. In particular, if the angle X is too small, the ratio BLF / GF will increase. For the relevant angle ratio, the force inserted by the plunger rod needs to be distributed and shared within the plunger towards the sealing lip in a uniform and controlled manner, which can be assumed by the strength line and can be avoided by the mentioned design angle ratio for uncontrolled deformation of the plunger.

[0045] annular protrusion

[0046] The stopper can have at least two annular protrusions. In one embodiment, the stopper has from 1 to 5 annular protrusions, for example from 2 to 4 annular protrusions. In a particular embodiment, the stopper can have 1, 2, 3, 4, or 5 annular protrusions. The annular protrusions can serve to close the joint between the inner surface of the barrel and the circumferential surface of the stopper. The diameter of the stopper at the annular protrusions is greater than the average diameter of the stopper. The annular protrusions contact the inner surface of the barrel when the stopper is moved in the distal direction, for example when the contents of the drug container are pushed out of the container using the stopper. The surface of the annular protrusions forms part of the circumferential surface of the stopper.

[0047] The diameter of at least one and preferably all annular protrusions can exceed the inner diameter of the barrel. The diameter of at least one and preferably all annular protrusions 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 protrusions can be equal to the outer diameter of the stopper. The diameter is measured perpendicular to the longitudinal axis of the barrel.

[0048] stopper

[0049] The stopper has a body with at least one annular protrusion and a circumferential surface. The “circumferential surface” is the surface of the stopper facing the inner surface of the barrel when the stopper is arranged in the barrel. The circumferential surface includes the surface of the annular protrusions. If the stopper has a coating, the surface of the coating facing the inner surface of the barrel is part of or constitutes the circumferential surface. The “contact surface” is the part of the circumferential surface that contacts the inner surface of the barrel when the stopper is inserted into the barrel.

[0050] The “annular protrusion” is a part of the stopper with 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. Any part of the stopper with a diameter greater than the average diameter but not contacting the inner surface of the barrel to the extent of at least 80%, 90%, 99.9%, or 100% during movement of the stopper in the distal direction is not considered an “annular protrusion”. The annular protrusions help to keep the stopper in a predetermined position within the barrel, stabilize its orientation in the proximal-distal direction, and thereby influence the BLF and GF values of the container. In addition, the annular protrusions seal the joint between the stopper and the inner surface of the barrel.

[0051] The stopper may optionally be provided with one or more tail ribs. A "tail rib" is a portion of the stopper with a diameter greater than the average diameter measured perpendicular to the longitudinal axis of the barrel. However, the diameter of the tail rib is smaller than the diameter of the annular protrusion, so that the tail rib does not significantly contact the inner surface of the barrel when the stopper moves in a proximal-distal direction. This tail rib can be used to stabilize the orientation of the stopper within the barrel when there is no effective seal between the stopper and the inner surface. The tail rib typically does not significantly affect the BLF and GF, as their contact with the inner surface is limited (if contact exists).

[0052] The stopper may be coated. This coating may be a polymer. In one embodiment, the coating comprises a resin, such as a fluorinated polymer, for example, a polymer selected from the group consisting of polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), tetrafluoroethylene (TFE), tetrafluoroethylene-perfluoroethylene copolymer, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-ethylene copolymer, trichlorotrifluoroethylene, polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymers, and copolymers, blends, and combinations thereof. The coating may also be formed from layers comprising polyethylene, polypropylene, polyparaxylene, polylactic acid, and copolymers, blends, and combinations thereof. A PTFE coating is a preferred coating option. These coatings reduce the coefficient of friction of the circumferential surface of the stopper on the inner surface of the barrel. In embodiments, at least the portion of the circumferential surface of the stopper that should contact the inner surface of the barrel has a coating.

[0053] The stopper may have an elastic body having a yield stress of at least 10 MPa as measured according to ISO 527-2:2012(E) and / or a low coefficient of sliding friction with steel of less than 0.23 as 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 rubbers. Suitable rubber materials may be selected from the group comprising butyl rubber, halogenated butyl rubber, acrylonitrile-butadiene rubber, isoprene rubber, chloroprene rubber, butadiene rubber, styrene-butadiene rubber, ethylene-propylene rubber, isoprene-isobutylene rubber, nitrile rubber, and combinations and mixtures thereof. Specifically, the body of the stopper may be made of the rubbers and / or thermoplastic elastomers listed above.

[0054] The substrate can be coated with the resin as described above. The coating thickness can be less than 1 mm, particularly 0.5 μm to 200 μm, particularly 10 μm to 125 μm, or 30 to 100 μm. These thicknesses have proven to be easy to apply and sufficient to produce the desired effect on friction.

[0055] The circumferential surface of the stopper can have a water contact angle of at least 100° or even at least 110°. The circumferential surface of the stopper can be superhydrophobic. The use of a superhydrophobic stopper in the container of the present invention contributes to a beneficial BLGF value due to the combination of low sliding friction coefficient and low adhesion.

[0056] The drug container of the present invention achieves an excellent seal between the annular protrusion and the inner surface of the barrel even at relatively low compression amounts of the stopper. The stopper compression amount (SC) can be calculated as follows. SC = (OD - ID) / OD, wherein OD denotes the outer diameter of the stopper and ID denotes the inner diameter of the barrel. The stopper compression amount can be less than 0.1, less than 0.075, or even less than 0.05. The use of a low stopper compression amount enables the stopper to slide easily within the barrel and thereby keeps the TGFV very low and reduces the BLF.

[0057] The circumferential surface of the stopper and the inner surface of the barrel can at least partially contact each other in a contact area. The contact area is sometimes also referred to as a sealing area. In embodiments, the contact area will be at least 8 mm 2 and at most 48 mm 2 . The contact area can be 8-48 mm 2 or 10-40 mm 2 , 15-30 mm 2 , 16-24 mm 2 . In case of multiple annular protrusions, each protrusion contributes to the contact area. A minimum contact area will help to achieve a sufficient seal. If the contact area is too large, the BLGF value can increase too much.

[0058] The drug container

[0059] The drug container can be selected from the group consisting of a syringe, a cartridge and a carpule.

[0060] The inner surface of the barrel can 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 exceeds 90°, the surface is referred to as superhydrophobic. Preferably, the inner surface of the barrel is superhydrophobic. Its water contact angle can be as high as at least 95° or at least 100°. In preferred embodiments, the inner surface of the barrel is not plasma treated and / or otherwise increased in hydrophilicity. A typical plasma treated inner surface will have a water contact angle significantly below 90°.

[0061] Preferably, the ratio of the water contact angle between the circumferential surface of the stopper θ C and the inner surface of the barrel θ I is θ C / θ I > 0.9. Preferably, θ C / θI is 0.9 to 2, or >1 to 1.5. In preferred embodiments, the ratio θ C / θ I >1, >1.1 or >1.2. Controlling the water contact angle improves the BLGF properties. It has been found that keeping the water contact angle of the plug to the inner surface of the barrel within a certain range helps to achieve the desired properties.

[0062] The water contact angle can be measured according to DIN 55660-2:2011-12, chapter 5.2.2 using the static method (wherein the droplet volume is 2 pl).

[0063] The inner surface of the barrel can 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 circumferential surface of the plug. The surface energy can be indirectly measured by the Owens-Wendt-Rabel-Kaelble (OWRK) method calculated values from contact angle measurements according to DIN 55660-2:2011-12, chapter 6.2.

[0064] The drug container can be substantially lubricant-free. By "lubricant-free" is meant that the amount of lubricant per container is less than 100 pg, less than 30 pg, or even less than 10 pg. The above limitations can be particularly applicable in the case of silicone as lubricant.

[0065] The drug container and / or the barrel can be partly or entirely made of a material suitable for primary packaging of drugs. Suitable materials include glass or a polymer. The polymer can be an amorphous polymer. A transparent polymer is preferred. Suitable polymers can be selected from the group consisting of cyclic olefin copolymer (COC), cyclic olefin polymer (COP), polyethylene terephthalate (PET), polycarbonate (PC), polypropylene (PP) and methyl methacrylate acrylonitrile butadiene styrene polymer (MABS). These polymers have the advantages of low density, high transparency, low birefringence, very low water absorption, excellent water vapor barrier, high rigidity, strength and hardness, excellent biocompatibility, excellent resistance to acids and bases, and excellent melt processability.

[0066] The barrel and / or the drug container can be made of a polymer. Preferably, a polymer with a low density compared to glass is chosen, for example a density of 0.9 to 1.2 g / cm 3 , preferably >1 to 1.1 g / cm 3 If a low density material is used, the transportation costs can be reduced. The density can be determined using the method described in ISO 1183-1 :2013-04.

[0067] For long term storage, it is preferred that the water vapor permeability of the material used for the barrel is less than 0.1 g*mm / m2 * d, preferably less than 0.07 g*mm / m 2 * d or even less than 0.05 g*mm / m 2 * d. The water vapour permeability can be tested using the method described in ISO 15106-3:2003.

[0068] In order to keep the BLF and GF sufficiently constant in the temperature range relevant for the biologically active agent, e.g. 4°C to 25°C, it is preferred that the coefficient of linear thermal expansion (CTE) of the material used for the barrel is in the range of 0.3*10 -4 K -1 to 0.8*10 -4 K -1 , or 0.4*10 -4 K -1 to 0.7*10 -4 K -1 In preferred embodiments, the ratio CTE S / CTE B of the CTE of the material of the plug to the CTE of the material of the barrel is less than 7, preferably less than 6 or at most 5. If this ratio is too high, the plug will shrink significantly when the container is cooled in a refrigerator to e.g. 4°C. This can lead to leakage.

[0069] The present invention provides a great deal of design freedom, as the effect of the present invention can even be achieved with an uncoated barrel. Thus, the inner surface of the barrel can be uncoated.

[0070] The barrel has an inner diameter ID measured perpendicular to the longitudinal axis of the container. The inner diameter ID can range from 3 mm to 40 mm, preferably from 4 mm to 20 mm. To obtain a larger barrel volume, the inner diameter is typically larger. A larger diameter typically corresponds to larger BLF and GF values, as the contact area of the circumferential surface of the plug with the inner surface of the barrel increases.

[0071] The wall of the barrel can be made of a transparent material. The transparent material can have a minimum transmission of at least 60% (measured in a 1 mm thick material) in a wavelength interval of at least 100 nm width in the wavelength range of 400 to 700 nm. Preferably, the minimum transmission is at least 70%.

[0072] The material of the barrel wall can have a refractive index of 1.5 to 1.6 and / or be characterized by a diffraction featuring an Abbe number of 50 to 60. The use of a material with an appropriate refractive index can serve to allow good visual inspection of the contents of the pharmaceutical composition. The pharmaceutical container of the present invention is suitable for the administration of parenteral pharmaceutical compositions, and thus visual inspection of the container for impurities, precipitates, crystals and particles is of great importance.

[0073] The wall thickness of the barrel can be 1 mm to 2.5 mm or 1.2 mm to 2 mm or 1.3 mm to 1.9 mm.

[0074] Liquid composition

[0075] The present application 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. The liquid composition can be liquid and / or sterile. The pharmaceutical container can contain the liquid composition inside the barrel.

[0076] The composition comprises at least one pharmaceutical active ingredient. A “pharmaceutical active ingredient” comprises a therapeutically and / or diagnostically active ingredient.

[0077] The method comprises administering to a subject an effective amount of a pharmaceutical active ingredient using the pharmaceutical container of the present application.

[0078] The pharmaceutical active ingredient can be a peptide or a protein, such as an antibody, an enzyme, a vaccine, a receptor, etc. The pharmaceutical container of the present application is particularly suitable for administering a biologically active ingredient, such as a peptide or a protein, as the container is very resistant to temperature variations in terms of BLGF. This means that the BLGF does not change significantly over a temperature range of 4°C to 25°C. This is meaningful as biological agents are usually stored in a refrigerator to extend the shelf life of the product.

[0079] In embodiments, the pharmaceutical active ingredient is an immunosuppressant or an anti-cancer agent. The active ingredient can be an immune checkpoint inhibitor or a TNF alpha antibody.

[0080] The pharmaceutical container can be combined with an injection device. The injection device can be attached to the container at the distal opening of the container. The injection device can be a needle. The pharmaceutical container can be part of an auto-injector.

[0081] Unscrewing and sliding force

[0082] The maximum BLGF that can be exhibited by the pharmaceutical container of the present application during a BLGF test is not more than 12 N. In preferred embodiments, the maximum BLGF can be limited to 9 N, 8 N, 7 N, 6 N, 5 N or even 4 N. The BLF can be at least 0.1 N or at least 0.5 N to avoid any accidental movement of the stopper.

[0083] In embodiments, the maximum BLGF can be related 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, BLGF / ID can be at least 0.5 N / mm or at least 0.6 N / mm. In embodiments, BLGF / ID can be limited to < 0.95 N / mm, < 0.9 N / mm, < 0.85 N / mm or < 0.8 N / mm.

[0084] The ratio of BLF to GF exhibited by the container during the BLGF test is BLF / GF < 2. Preferably, the ratio of BLF to GF is characterized by BLF / GF < 3 even after 105 days of accelerated aging. In preferred embodiments, the ratio of BLF / GF is < 2, < 1.8, < 1.7 or even < 1.5 for the containers of the present invention. In preferred embodiments, the ratio of BLF / GF can be < 2, < 1.8, < 1.7 or even < 1.5 for the containers of the present invention after 105 days of accelerated aging. Preferably, the relative difference in the ratio BLF / GF of the aged containers (accelerated aging for 105 days) to the non-aged containers (T0) is (BLF / GF 105d -BLF / GF 0d ) / BLF / GF 105d is less than 10%, preferably less than 5%.

[0085] The total glide force variation TGFV measured when the stopper is moved from the starting position to its ending position is GFV = GF max –GF min may be TGFV < 2 N, < 1.8 N or even < 1.6 N. Preferably, the relative difference in TGFV of the aged containers (accelerated aging for 105 days) to the non-aged containers (T0) is (TGFV 105d -TGFV 0d ) / TGFV 105d is less than 40%, preferably less than 35%.

[0086] The average of BLF and GF can be calculated using at least 12 containers, preferably at least 15 containers. The average BLF of the pharmaceutical containers of the present invention can be < 9 N, < 8 N, < 7 N, < 6 N, < 5 N, < 4 N, < 3 N or even < 2 N. The average GF of the pharmaceutical containers of the present invention can be < 9 N, < 8 N, < 7 N, < 6 N, < 5 N, < 4 N, < 3 N or even < 2 N. Preferably, the relative difference in BLF of the aged containers (accelerated aging for 105 days) to the non-aged containers (T0) is (BLF 105d -BLF 0d ) / BLF 105d is less than 25%, < 20%, < 15%, < 10% or even < 5%. The relative difference in GF of the aged containers (accelerated aging for 105 days) to the non-aged containers (T0) is (GF 105d -GF 0d ) / GF 105d is less than 25%, < 20%, < 15%, < 10% or even < 5%.

[0087] Keeping the BLF and GF values within the ranges of the present invention helps to sufficiently uniformly elute the liquid composition from the container during application. In particular, if the BLF is much higher than the GF, a large dose can be eluted when the stopper is released from the inner surface of the barrel. Also, if the GF is not constant enough, the elution rate of the liquid composition can vary.

[0088] "Accelerated aging" refers to the aging process of the respective container when stored at 40°C and 75% relative humidity. For example, some containers are stored under these conditions for 105 days for comparison. Accelerated aging can be performed to estimate the influence of aging on the properties of the pharmaceutical containers of the present invention.

[0089] Release and glide force test

[0090] The BLGF test is performed on a universal testing machine at room temperature (e.g. 23°C). For this purpose, a BLGF test device with a 50 N test cup is used. The sample is fixed in a vertical orientation in a 2kN universal testing machine type 106 from TesT AG (Hunenberg, CH-6331, Switzerland).

[0091] For this test, a plunger is used which has a flat end, i.e. does not have any threads.

[0092] The BLF is the force required to move the stopper from its original position. The GF is the force required to keep the plunger moving after release.

[0093] The pharmaceutical container is filled with water for injection. After filling the test specimen, it is either stored depending on the test purpose or immediately tested. The test specimen is not used with a needle.

[0094] The test specimen is inserted into the holder and the presser is moved towards the plunger at a rate of 20 mm / min. As soon as a force of 0.25 N is measured, the machine switches to a test rate of 100 mm / min and starts recording the data. The experiment ends when the measured force exceeds 35 N, which is usually the case when the distal end of the barrel is reached.

[0095] The BLF is the maximum force measured within the first 4 mm of movement of the stopper. The average and maximum GF values are measured within a test range starting after 4 mm of movement and ending 10 mm before the distal end of the barrel is reached. BRIEF DESCRIPTION OF DRAWINGS

[0096] Figure 1 A prior art pharmaceutical container is shown.

[0097] Figure 2 A stopper used in the prior art is shown.

[0098] Figure 3A A stopper used according to an embodiment of the present invention is shown.

[0099] Figure 3B A stopper used according to an embodiment of the application is shown.

[0100] Figure 4 A drug container comprising a stopper according to an embodiment of the application is shown.

[0101] Figure 5 A BLGF plot of a drug container according to the application is shown.

[0102] Figure 6 A BLGF plot of a drug container according to the application is shown. Figure 5 A BLGF plot of a drug container according to the application is shown.

[0103] Figure 7 A BLGF plot of a drug container according to the application is shown.

[0104] Figure 8 A BLGF plot of a drug container according to the application is shown. Figure 7 A BLGF plot of a drug container according to the application is shown. DETAILED DESCRIPTION

[0105] Figure 1 A drug container 1 is shown. The drug container comprises a barrel 2 and a stopper 3. The stopper 3 is slidably arranged within the barrel 2. The stopper 3 has a circumferential surface 4 which partially contacts an inner surface 5 of the barrel 2. The stopper 3 is connected to a plunger rod 6. The drug container is further provided with a flange 7. At its distal end, the container has a thread 8 for mounting a cap 9 or an injection device (not shown). The drug container can contain a liquid composition 10. The liquid composition 10 can be pushed out of the barrel 2 by operating the plunger rod 6. Pushing the plunger rod 6 into the barrel 2 will move the stopper 3 in the direction of an outlet 11. The distal end of the stopper can have a conical shape which can fit the shape of the barrel in the area of the outlet 11. Throughout the specification, "proximal" will be used to describe a position closer to the flange 7, while "distal" will be used to indicate a position closer to the outlet 11.

[0106] Figure 2A prior art stopper 3 is shown. The stopper has a coating 11 covering the stopper body 13. The stopper also has an annular protrusion 12 where the outer diameter of the stopper is larger than the average outer diameter. The stopper shown in this figure has two annular protrusions with an ascending edge and a descending edge. The ascending edge 15 of the proximal-most annular protrusion and the descending edge 16 of the distal-most annular protrusion span the same angle (X / A = 1) with the inner surface of the barrel (not shown). The stopper also has a tail rib 14. The stopper has a smaller outer diameter in the location of the tail rib 14 compared to the outer diameter in the location of the annular protrusions 12. The tail rib 14 will not contact the inner surface of the barrel when the stopper is moved in the distal direction within the barrel (not shown). It is therefore not considered to be an annular protrusion according to the present invention since it cannot influence the unthreading and sliding forces.

[0107] Figure 3A A stopper 3 according to the present invention is shown. The stopper has two annular protrusions 12 where, when this stopper is arranged in the barrel of a drug container, the ascending edge 15 of the proximal-most annular protrusion will span an angle X in the distal direction with the inner surface of the barrel (not shown) and the descending edge 16 of the distal-most annular protrusion will span an angle A in the proximal direction with the inner surface. The ratio X / A is at least 1.05. The stopper body 13 comprises a socket 17 with threads for insertion of a plunger rod (not shown).

[0108] Figure 3B A stopper 3 according to an embodiment of the present invention is shown. The stopper has three annular protrusions 12 where, when this stopper is arranged in the barrel of a drug container, the ascending edge 15 of the proximal-most annular protrusion will span an angle X in the distal direction with the inner surface of the barrel (not shown) and the descending edge 16 of the distal-most annular protrusion will span an angle A in the proximal direction with the inner surface. The ratio X / A is at least 1.05.

[0109] Figure 4 A drug container 1 according to an embodiment of the present invention is shown. The drug container has an inner surface 5 and a stopper 3 slidably arranged within the barrel 2. The stopper has two annular protrusions 12 where the ascending edge 15 of the proximal-most annular protrusion spans an angle X in the distal direction with the inner surface 5 of the barrel 2 and the descending edge 16 of the distal-most annular protrusion spans an angle A in the proximal direction with the inner surface 5. The ratio X / A is at least 1.05. The figure also shows an outlet 11.

[0110] Examples

[0111] Tests were performed with stoppers 1 to 3 using drug containers with a 1 ml volume and an inner diameter (ID) of 6.5 mm. Stopper 4, which is an example of a stopper from WO 2018 / 157097 A1, was tested in a container with an inner diameter of 6.35 mm. The inner surface of all containers used for testing was free of coating. Stoppers with different outer diameters (OD) were investigated. The number of annular protrusions (AP) is given in the table below.

[0112] The containers to be tested were filled with water for injection or demineralized water. They were fixed in vertical orientation in a 2kN universal testing machine from TesTAG (Hünenberg, CH-6331, Switzerland) type 106. The universal testing machine pushed the stopper into the container at a speed of 20 mm / min until an initial force of 0.25 N was reached. Thereafter, the stopper was pushed into the container at a test speed of 100 mm / min and the force was recorded until a shut-off value of 35 N was reached.

[0113] Table 1 - Stopper

[0114] # OD [mm] SC* AP X / A Plug 1 6.65 2.3％ 2 ＞1.05 Plug 2 6.8 4.4％ 3 ＞1.05 Plug 3 6.9 5.8％ 3 ＞1.05 Plug 4 7.4 14.4％ 2 ＝1.00

[0115] The stopper compression (SC) was calculated as follows: SC = (OD-ID) / OD.

[0116] Table 2 - BLGF test

[0117] # BLF [N] Average GF [N] TGFV BLF / GF Plug 1 1.9 1.5 0.6 1.2 Pass 2.2 1.9 1.5 1.16 Pass / / / / Plug 2 9.6 6.6 / 1.45

[0118] The results for stopper 1 are shown in Pass . Pass It is shown that the values are still excellent even after accelerated aging.

[0119] The results for stopper 2 are shown in Unaged (0 days) . Aged (105 days) It is shown that the values are still excellent even after accelerated aging.

[0120] Roughness values

[0121] The surface roughness values were obtained with the inner surface of the barrels used in examples 1 to 3. The results are given in the table below. All barrels were free of coating.

[0122] Plug 1 Pass Pass Plug 2 79 62 Pass 40 27 Pass 19 14

[0123] The surface roughness values were 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).

[0124] Dye penetration test

[0125] The dye penetration test was performed on a set of 15 aged and 15 unaged samples. The test conditions were as follows.

[0126] Unaged (0 days)

[0127] After closing the needle tip of the syringe to be tested, the syringe was filled with water to the nominal volume. Then, the plunger stopper was carefully inserted, leaving 2-5 mm of air in the syringe. Syringes that already had liquid between the sealing protrusions should be discarded from the test.

[0128] Aged (105 days)

[0129] The solution of sodium fluorescein salt was filled in a desiccator and the prepared syringes were put into the solution. Then, the syringes were covered with a perforated lid in order to ensure that the syringes were completely immersed in the solution. Thereafter, the desiccator was closed and connected to a vacuum pump (e.g. PC2001 Vario vacuum pump from Vacuubrand GmbH & Co. KG, Theilingen, CH-8484 [product number 29951114-299512]). The desiccator was kept at a pressure of 270 mbar below atmospheric pressure for 30 minutes. Thereafter, the desiccator was vented to atmospheric pressure and the syringes were left in the solution for another 30 minutes. Finally, the syringes were taken out of the solution, carefully rinsed with water, wiped dry with a lint-free cloth and visually inspected under ultraviolet light. The result of the visual inspection was recorded as pass or fail. If a failure occurred, the location of the leak was also recorded.

[0130] Plug 1 Pass Pass Plug 2 Pass Pass ​ ​

[0131] The results show that even after 105 days of accelerated aging, the drug container of the present invention enables a tight sealing of the stopper to the inner surface of the barrel.

[0132] Axial compression

[0133] Axial compression tests were performed on a set of 15 aged and 15 unaged samples. The test conditions were as follows. The syringes to be tested were filled with water, closed and fixed in vertical orientation in a 2kN universal testing machine type 106 from TesT AG (Hünenberg, CH-6331, Switzerland). With the universal testing machine a pressure of 2.5 bar was applied on the plunger for 30 s. Thereafter, the water droplets formed in the syringe between the sealing protrusions were visually inspected and the result was recorded as pass or fail.

[0134] ​ ​ ​ ​ ​ ​ ​ ​

[0135] The results show that even after 105 days of accelerated aging the pharmaceutical containers of the present application passed the axial compression test.

Claims

1. A drug container for administration, the drug container having - a barrel configured to slidably receive a stopper, - the stopper having a proximal end adapted to contact a plunger rod and a distal end adapted to contact a drug composition, - a circumferential surface of the stopper partially contacting an inner surface of the barrel, wherein a surface roughness of the inner surface of the barrel decreases by at least 3% Ra and / or Rms from a start position of the stopper, defined as a position of the stopper corresponding to a nominal volume of the container, to an end position of the stopper, defined as a position of the stopper after the nominal volume of the container has been expelled from the barrel.

2. The medicine container according to claim 1, wherein the inner surface of the barrel has a water contact angle of at least 80°.

3. The drug container according to claim 1 or 2, wherein During the unthreading and gliding force test, the container exhibits a ratio BLF / GF of the unthreading force (BLF) with respect to the gliding force (GF) BLF / GF < 2, and a total gliding force variation TGFV = GF measured when the plug moves from the starting position to its end position max - GF min is TGFV < 2 N.

4. The drug container according to claim 1 or 2, wherein the stopper has one or more annular protrusions contacting the inner surface of the barrel when the stopper is moved in a distal direction, each of the annular protrusions has an ascending edge and a descending edge in a proximal-distal direction, the ascending edge of the proximally most annular protrusion crosses the inner surface of the barrel in the distal direction over an angle X and the descending edge of the distally most annular protrusion crosses the inner surface in a proximal direction over an angle A and the ratio X / A is at least 1.

05.

5. The drug container according to claim 4, wherein the ratio X / A is from > 1.1 to 1.7, and / or A is 130° to 170°.

6. The pharmaceutical container according to claim 1 or 2, wherein the stopper has at least two annular protrusions.

7. The pharmaceutical container according to claim 1 or 2, wherein the container is selected from a syringe, a cartridge and a carpule.

8. The pharmaceutical container according to claim 1 or 2, wherein the inner surface of the barrel has - 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 pg or less than 30 pg or less than 1 pg per barrel.

9. The pharmaceutical container according to claim 1 or 2, wherein the stopper is coated with a resin.

10. The drug container according to claim 9, wherein the resin is a fluorinated polymer.

11. The drug container according to claim 10, wherein the fluorinated polymer is selected from the group consisting of polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), tetrafluoroethylene (TFE), tetrafluoroethylene-perfluoroalkylvinyl ether copolymer, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-ethylene copolymer, trichlorotrifluoroethylene, polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymer, and copolymers, blends and combinations thereof.

12. The pharmaceutical container according to claim 1 or 2, wherein the barrel is made partly or entirely from glass or a polymer.

13. The drug container according to claim 12, wherein the polymer is COC or COP.

14. The drug container according to claim 1 or 2, which exhibits a maximum unthreading and sliding force of no more than 12 N in an unthreading and sliding force test.

15. The drug container of claim 3, wherein, The ratio of the break loose force (BLF) to the glide force (GF) is characterized by BLF / GF < 3 after 105 days of accelerated aging.

16. The pharmaceutical container according to claim 1 or 2, wherein The inner surface of the barrel is free of coating or has a coating.

17. The pharmaceutical container according to claim 1 or 2, wherein The inner surface of the barrel has a water contact angle of at least 85°. The inner surface of the barrel has a water contact angle of at least 85°.

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