Pharmaceutical container and liquid composition

Abstract

To provide a pharmaceutical container comprising a stopper properly sealing the container and having proper break loose force and glide force.SOLUTION: There is provided a pharmaceutical container 1 for drug delivery comprising: a barrel 2; and a stopper 3. The stopper 3 is arranged in the barrel 2 in a slidable manner and comprises one or a plurality of annular protrusions 12 which contact an inner surface 5 of the barrel 2 when moving in a distal direction. The annular protrusions 12 have rising edges and falling edges in a proximal-distal direction. A ratio X / A of an angle X of the annular protrusion closest to the stopper 3 and an angle A of the annular protrusion farthest is at least 1.05, a ratio of break loose force (BLF) to glide force (GF) satisfies BLF / GF≤2, and a total glide force variation TGFV=GFmax-GFmin which is measured when the stopper 3 is moved from a start end position to its end position satisfies TGFV<2 N, for achieving a smooth operation.SELECTED DRAWING: Figure 4

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical container and a liquid composition for drug delivery. [Background technology]

[0002] Pharmaceutical containers for drug delivery are known in the art. These containers typically feature a stopper that must be slid within the container to help elute the contents of the container through an outlet.

[0003] In most of these containers, the stopper is moved from a proximal start position to a distal end position using finger force. Because finger force is limited, the force required to dislodge the stopper from its start position (release force) cannot be too large. Also, this release force cannot be too small to prevent the stopper from being accidentally moved before the intended application of the drug. Moreover, for the same reason, the force required to move the stopper from its start position to its end position (sliding force) must not be too large.

[0004] Generally, very low release and sliding force values ​​can be achieved by selecting a stopper with a very small outer diameter compared to the inner diameter of the container, however, if the outer diameter of the stopper is too small, the stopper will not adequately seal the container and the contents of the container, i.e., the pharmaceutical composition, may leak through the stopper.

[0005] WO 2018 / 157097 teaches a stopper for a pharmaceutical container. To achieve proper sealing of the container, the stopper has a very large outer diameter compared to the inner diameter of the container. The stopper taught in this prior art document needs to be plasma treated or autoclaved to achieve proper release and sliding forces, which increases production costs. Furthermore, the strong compression required to set the stopper in the container increases the risk of tilting the stopper in the container, which may interrupt the production process. Summary of the Invention [Problem to be solved by the invention]

[0006] SUMMARY OF THE PRESENT EMBODIMENT It is therefore an object of the present invention to provide a pharmaceutical container that overcomes the shortcomings of the prior art. [Means for solving the problem]

[0007] In one embodiment, the present invention provides a pharmaceutical container for drug delivery, comprising: - a barrel and a stopper, the stopper being slidably disposed within the barrel; the stopper having a proximal end adapted to contact the plunger rod and a distal end adapted to contact the pharmaceutical composition; the stopper has a circumferential surface partially in contact with the inner surface of the barrel; the stopper has one or more annular projections that contact an inner surface of the barrel as the stopper moves in a distal direction; The annular projections each relate to a medicament container for drug delivery, the medicament container having rising and falling edges in a proximal-distal direction.

[0008] The proximal-distal direction is the same as 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 subtend an angle X in the distal direction, and the falling edge of the distal-most annular projection and this inner surface subtend an angle A in the proximal direction, and the ratio X / A may preferably be at least 1.05.

[0009] The container may exhibit a ratio of the release force (BLF) to the glide force (GF) during the release force and glide force (BLGF) test 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 must push too hard to remove the stopper from its starting position, which may cause the stopper to be pushed too quickly all the way to the end position after the stopper is released. Keeping the ratio BLF / GF in a balanced range facilitates controlled drug delivery without causing unnecessary pain to the patient. Also, there is less risk of leakage of the contents of the container if the acceleration of the stopper is limited after release. The ratio BLF / GF may be >1. It is an aspect of the present invention to keep the BLF / GF ratio essentially constant, even after storage of the container during administration.

[0010] Preferably, the total sliding force variation TGFV measured when the stopper is moved from its starting position to its end position = GF max -GF min may be a TGFV<2N. Controlling the TGFV is important because the difference between the maximum and minimum GF greatly affects the ability of a user to properly dose the pharmaceutical composition contained in the container.

[0011] In another embodiment, the present invention provides a medication container for drug delivery having a barrel configured to slidably receive a stopper, comprising: During the BLGF test, the container exhibits a ratio of BLF to GF of BLF / GF≦2 and the total sliding force variation TGFV=GF measured when the stopper is moved from its start position to its end position. max -GF min is TGFV<2N, the stopper having a proximal end adapted to contact the plunger rod, a distal end adapted to contact the pharmaceutical composition, a circumferential surface adapted at least in part to contact an inner surface of the barrel, and one or more annular projections that contact the inner surface of the barrel when the stopper is moved in a distal direction, each annular projection having a rising edge and a falling edge in the proximal-distal direction; The stopper further relates to a pharmaceutical container for drug delivery, characterized in that a rising edge of the most proximal annular projection and an inner surface of the barrel diverge at an angle X in a distal direction, and a falling edge of the most distal annular projection and said inner surface diverge at an angle A in a proximal direction, the ratio X / A being at least 1.05.

[0012] BLF, GF and BLGF can be measured according to the method described herein below as the BLGF Test.

[0013] Angles X, A and their ratio X / A The rising edge of the proximal-most annular projection and the inner surface of the barrel subtend an angle X in the distal direction, and the falling edge of the distal-most annular projection and this inner surface subtend an angle A in the proximal direction. A "rising edge" in the context of the present invention is an 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 "falling edge" is an 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.

[0014] In a preferred embodiment, the ratio X / A is between 1.1 (>1.1) and 1.7. The BLGF value is improved when the ratio 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. This 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.

[0015] The angle X and / or the angle A may be 90° (>90°) to 180° (<180°). Preferably, A is 130° to 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 131° to 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°.

[0016] Keeping these angles and their ratios within the appropriate range will contribute to solving the problem underlying the present invention. In particular, if the angle X is too small, the ratio BLF / GF will increase. In relation to the angle ratio, the force input by the plunger rod needs to be distributed and distributed in a uniform and controlled manner inside the plunger towards the sealing lip, which can be depicted by the strength line, and uncontrolled deformation of the plunger can be avoided by the aforementioned ratio of the design angles.

[0017] Annular protrusion The stopper may have at least two annular protrusions. In one embodiment, the stopper has one to five annular protrusions, for example two to four annular protrusions. In certain embodiments, the stopper may have one, two, three, four or five annular protrusions. The annular protrusions serve to close the connection between the inner surface of the barrel and the circumferential surface of the stopper. The diameter of the stopper is greater than the average diameter of the stopper at the location of the annular protrusions. When the stopper moves distally, for example when the stopper is used to expel the contents of a pharmaceutical container from the container, the annular protrusions contact the inner surface of the barrel. The surface of the annular protrusions forms a part of the circumferential surface of the stopper.

[0018] At least one, and preferably all, of the annular projections may have a diameter that exceeds the inner diameter of the barrel. At least one, and preferably all, of the annular projections may have a diameter that 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 the same as the outer diameter of the stopper. The diameter is measured perpendicular to the longitudinal axis of the barrel.

[0019] 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 may have a surface roughness Ra of less than 100 nm. The surface roughness Ra given herein may be an average or 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 may 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.

[0020] The surface roughness may additionally or alternatively be given as 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 or 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.

[0021] The surface roughness of the inner surface of the barrel may decrease by at least 3% Ra and / or Rms from the beginning to the end position of the stopper relative to the roughness value at the beginning position. In a preferred embodiment, 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 beginning to the end position of the stopper. 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 beginning to the end position of the stopper.

[0022] The start position of the stopper is where the stopper is located in the barrel before the container is used for drug delivery. In an embodiment, the pharmaceutical container is a pre-filled syringe. In a pre-filled syringe, the start position is where the stopper is located before use. This will typically be the most proximal position of the stopper. The end position of the stopper is where the stopper is located after the nominal volume of the container is expelled from the barrel, for example when the stopper touches the distal end of the barrel. The start position of the stopper may be located within a distance of up to 20% of the length of the container from the proximal end of the container. The end position may be located within a distance of 80% to 100% of the length of the container from the proximal end of the container.

[0023] The inner surface of the barrel may 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 may be located midway between the start position and the end position: SP 100% MP 40~60% EP 20~35%

[0024] Controlling the surface roughness can contribute to a very low TGFV. Surface roughness can be controlled by adjusting production parameters such as melt temperature, molding time, polymer blend, or by surface treatments such as coating or plasma treatment. Pharmaceutical containers may be fabricated by injection molding. Injection molding requires the container to be at least slightly conical, meaning that the inner diameter of the barrel decreases from the beginning to the end position. Therefore, the GFV decreases due to the increasing compression of the stopper from the beginning to the end position. max increases, so does the TGFV. In this specification, unless otherwise specified, references to the inside diameter of a barrel mean the maximum inside diameter of the barrel.

[0025] The described surface roughness distribution may be achieved, for example, by positioning the injection nozzle closer to the end than to the beginning during injection molding, so that the polymer melt temperature is higher at the end than at the beginning during injection, or the mold temperature may be subject to partial heating and / or cooling, resulting in a temperature gradient along the barrel.

[0026] The surface roughness values ​​can be measured using white light interferometry in accordance with DIN EN ISO 25178-2:2012, DIN EN ISO 25178-6:2010 and DIN EN ISO 25178-604:2013-12 (in conjunction with DIN EN ISO 4288:1998 and DIN EN ISO 3274:1998).

[0027] 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 touches the inner surface of the barrel when the stopper is inserted into the barrel.

[0028] 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 touches the inner surface of the barrel to seal the connection between the stopper and the barrel. Any portion of a stopper that is greater than the average diameter but does not touch the inner surface of the barrel to an extent of at least 80%, 90%, 99.9% or 100% during the movement of the stopper in the distal direction is not considered an "annular protrusion." The annular protrusion helps to keep the stopper in its intended position within the barrel and stabilizes the proximal-distal orientation, thereby affecting the BLF and GF values ​​of the container. Additionally, the annular protrusion seals the connection between the stopper and the inner surface of the barrel.

[0029] The stopper may optionally feature one or more trailing ribs. A "trailing rib" is a portion of the stopper having 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 it does not significantly contact the inner surface of the barrel as the stopper 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 connection 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.

[0030] 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), high density expanded polytetrafluoroethylene (ePTFE), tetrafluoroethylene (TFE), tetrafluoroethylene-perfluoroethylene copolymer, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-ethylene copolymer, trichlorotrifluoroethylene, polyvinylidene fluoride, polyvinyl fluoride, perfluoropropyl vinyl ether, perfluoroalkoxy polymer, and copolymers, blends, and combinations thereof. The coating may be formed by a layer comprising polyethylene, polypropylene, polyparaxylxylene, polylactic acid, and copolymers, blends, and combinations thereof. PTFE coatings are 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 will be in contact with the inner surface of the barrel is coated.

[0031] The stopper may have an elastomer body with a yield stress of at least 10 MPa, measured according to ISO 527-2:2012(E), and / or a low coefficient of sliding friction against steel of less than 0.23, measured according to DIN EN ISO 8295 / 2004-10. The stopper may be made of a thermoplastic elastomer and / or made of rubber, such as natural or synthetic rubber. Suitable rubber materials may be selected from the group consisting of butyl rubber, halogenated butyl rubber, acrylonitrile-butadiene rubber, isoprene rubber, 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 rubber and / or thermoplastic elastomer as listed above.

[0032] 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 have proven to be easy to apply and sufficient for the desired friction effect.

[0033] The circumferential surface of the stopper may have a water contact angle of at least 100°, or even at least 110°. The circumferential surface of the stopper may be superhydrophobic. The use of superhydrophobic stoppers in the containers of the invention contributes to beneficial BLGF values ​​in combination with low adhesion due to the low coefficient of sliding friction.

[0034] The pharmaceutical container of the present invention allows for excellent sealing between the annular protrusion and the inner surface of the barrel, even when 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 even less than 0.05. Using low stopper compression allows the stopper to slide easily in the barrel, thus keeping the TGFV very low and reducing the BLF.

[0035] The circumferential surface of the stopper and the inner surface of the barrel may at least partially contact one another at a contact area, which may also be referred to as a sealing 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. If the contact area is too large, the BLGF value may increase too much.

[0036] Medicine containers The pharmaceutical container may be selected from a syringe, a cartridge and a carpule.

[0037] The inner surface of the barrel may have a water contact angle of at least 80°. A large 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 also be as large as at least 95°, or at least 100°. In a preferred embodiment, the inner surface of the barrel is not plasma treated and / or otherwise made more hydrophilic. A typical plasma treated inner surface will have a water contact angle significantly less than 90°.

[0038] Preferably, the water contact angle θ of the circumferential surface of the stopper C and the water contact angle θ on the inner surface of the barrel I The ratio of C / θ I >0.9. Preferably, θ C / θ I is 0.9 to 2, or 1 (>1) to 1.5. C / θ I is >1, >1.1 or >1.2. Controlling the water contact angle enhances the properties of the BLGF. It has been found that maintaining the water contact angle of the inner surface of the stopper and barrel within certain ranges helps to achieve the desired properties.

[0039] The water contact angle can be measured using the static method with a drop volume of 2 μl according to chapter 5.2.2 of DIN 55660-2:2011-12.

[0040] 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 circumferential surface of the stopper. The surface energy can be measured indirectly by calculating the value using the Owens-Wendt-Rabel-Kaelble (OWRK) method from contact angle measurements according to DIN 55660-2:2011-12, chapter 6.2.

[0041] The pharmaceutical container may be essentially lubricant-free. "Lubricant-free" 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.

[0042] The pharmaceutical container and / or barrel may be partially or entirely made of a material suitable for pharmaceutical primary packaging. 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 advantages in 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.

[0043] The barrel and / or the pharmaceutical container may be made of a polymer. Preferably, the polymer has a density of 0.9 to 1.2 g / cm 3 Density, preferably 1 (>1) to 1.1 g / cm 3 A polymer is selected that has a low density compared to glass, such as a density of 0.1% to 0.2%. If a low density material is used, shipping costs can be reduced. Density may be determined using the method described in ISO 1183-1:2013-04.

[0044] For long-term storage, water vapor permeability of 0.1g mm / m 2 Less than d, preferably 0.07 g mm / m 2 Less than d, even 0.05g mm / m 2 It is preferred to use materials with a viscosity of less than 100 psi for the barrel. Water vapor permeability may be tested using the method described in ISO 15106-3:2003.

[0045] For the BLF and GF to remain sufficiently constant over the temperature range relevant to biologically active agents, such as 4°C to 25°C, the coefficient of linear thermal expansion (CTE) of the material used for the barrel must be between 0.3 and 0.8 × 10 -4 K -1 , or 0.4 to 0.7 × 10 -4 K -1 , or 0.3 to 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 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 in a refrigerator, for example to 4° C. This may cause leakage.

[0046] The present invention provides great design freedom since the effects of the present invention can be achieved with an uncoated barrel, so the inner surface of the barrel does not have to be coated.

[0047] The barrel has an inside diameter ID measured perpendicular to the longitudinal axis of the container. The inside diameter ID may range from 3 mm to 40 mm, preferably from 4 mm to 20 mm. Generally, the larger the barrel volume, the larger the inside diameter. As the diameter increases, the contact area between the circumferential surface of the stopper and the inner surface of the barrel increases, so the BLF and GF values ​​often increase correspondingly.

[0048] 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%.

[0049] The barrel wall material may have a refractive index of 1.5-1.6 and / or a diffraction characterized by an Abbe number of 50-60. Using a material with an appropriate refractive index is useful to allow good visual inspection of the contents of the pharmaceutical composition. The pharmaceutical container of the present invention is suitable for administration of parenteral drug compositions, and therefore visual inspection of the container for impurities, precipitation, crystallization, and particles is of paramount importance.

[0050] The thickness of the barrel wall may be from 1 mm to 2.5 mm, or from 1.2 mm to 2 mm, or from 1.3 mm to 1.9 mm.

[0051] liquid composition The invention also relates to a liquid composition for use in a method for treating 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 may be liquid and / or sterile. The pharmaceutical container may contain the liquid composition within a barrel.

[0052] The composition comprises at least one pharma- ceutical active ingredient. A "pharma- ceutical active ingredient" includes a therapeutic active ingredient and / or a diagnostic active ingredient.

[0053] The method comprises administering to the subject an effective amount of the pharma- ceutical active ingredient described above using a pharmaceutical container of the present invention.

[0054] The medicament active ingredient may 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 and proteins, because the container is highly resistant to temperature changes with respect to the BLGF. This means that the BLGF does not change significantly within the temperature range of 4°C to 25°C. This is important because biological agents are usually stored in a refrigerator to extend the shelf life of the product.

[0055] In embodiments, the medicament active ingredient is an immunosuppressant or an anti-cancer drug. The active ingredient may be an immune checkpoint inhibitor or a TNFα antibody.

[0056] 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.

[0057] Release and sliding forces The pharmaceutical container of the present invention may exhibit a maximum BLGF of 12 N or less during the BLGF test. In preferred embodiments, the maximum BLGF may be limited to 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.

[0058] In an embodiment, 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, BLGF / ID may be at least 0.5 N / mm, or at least 0.6 N / mm. In an embodiment, BLGF / ID may be limited to ≦0.95 N / mm, ≦0.9 N / mm, ≦0.85 N / mm, or ≦0.8 N / mm.

[0059] 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 BLF / GF≦3 even after 105 days of accelerated aging. In a preferred embodiment, for the container of the invention, the ratio BLF / GF is <2, <1.8, <1.7, or even <1.5. In a preferred embodiment, for the container of the invention after 105 days of accelerated aging, the ratio BLF / GF may be <2, <1.8, <1.7, or even <1.5. Preferably, the relative difference in the BLF / GF ratio between the aged container (105 days of accelerated aging) and the non-aged container (BLF / GF 105d -BLF / GF 0d ) / BLF / GF 105dis less than 10%, preferably less than 5%.

[0060] The total sliding force variation TGFV = GF measured when the stopper is moved from its starting position to its end position max -GF min may be a TGFV < 2N, < 1.8N or even < 1.6N. Preferably, the relative difference in TGFV between the aged container (accelerated aging for 105 days) and the unaged container (TGFV 105d -TGFV 0d ) / TGFV 105d is less than 40%, preferably less than 35%.

[0061] The average BLF and average GF may be calculated using at least 12 containers, preferably at least 15 containers. The average BLF of the pharmaceutical containers of the present invention may be <9N, <8N, <7N, <6N, <5N, <4N, <3N, or even <2N. The average GF of the pharmaceutical containers of the present invention may be <9N, <8N, <7N, <6N, <5N, <4N, <3N, or even <2N. Preferably, the relative difference in BLF between aged containers (105 days accelerated aging) and unaged containers (BLF 105d -BLF 0d ) / BLF 105d The relative difference in GF between the aged container (accelerated aging for 105 days) and the unaged container (GF 105d -GF 0d ) / GF 105d is less than 25%, <20%, <15%, <10%, or even <5%.

[0062] Keeping 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 larger than the GF, a large chunk may dissolve 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 not be uniform.

[0063] "Accelerated aging" refers to an aging process in which each container is stored at 40°C and 75% relative humidity. For example, some containers may 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 containers of the present invention.

[0064] Release and sliding force tests The BLGF test is carried out in a universal testing machine at room temperature, e.g. 23° C. For this purpose, a BLGF test device with a test cup of 50 N is used. The samples are fixed in a vertical orientation in a universal testing machine model 106.2 kN, manufactured by TesT AG, CH-6331 Hünenberg, Switzerland.

[0065] In this test a plunger is used which has a flat end, i.e. without any threads.

[0066] BLF is the force required to move the stopper from its home position. GF is the force required to keep the plunger moving after it is released.

[0067] The pharmaceutical container is filled with water for injection. After loading the specimens, they are either stored or tested immediately, depending on the test purpose. The specimens are tested without a needle.

[0068] The specimen 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 tester 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.

[0069] The BLF is the maximum force measured in the first 4 mm of travel of the stopper. The average and maximum GF are measured within the test range starting after 4 mm of travel and ending 10 mm before reaching the distal end of the barrel. [Brief description of the drawings]

[0070] [Figure 1] FIG. 1 shows a prior art medicine container. [Diagram 2] FIG. 1 shows a stopper used in the prior art. [Figure 3A] 11A-11C show stoppers used in accordance with an embodiment of the present invention. [Figure 3B] 11A-11C show stoppers used in accordance with an embodiment of the present invention. [Figure 4] 1 illustrates a pharmaceutical container with a stopper according to an embodiment of the present invention. [Diagram 5] FIG. 1 shows a BLGF graph for a pharmaceutical container according to the present invention. [Figure 6] FIG. 6 shows a BLGF graph for the pharmaceutical container of FIG. 5 after 105 days of accelerated aging. [Figure 7] FIG. 1 shows a BLGF graph for a pharmaceutical container according to the present invention. [Figure 8] FIG. 8 shows a BLGF graph for the pharmaceutical container of FIG. 7 after 105 days of accelerated aging. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] In FIG. 1, a pharmaceutical container 1 is shown. The pharmaceutical container comprises a barrel 2 and a stopper 3. The stopper 3 is slidably disposed within the barrel 2. The stopper 3 has a circumferential surface 4 that is in partial contact with an inner surface 5 of the barrel 2. The stopper 3 is connected to a plunger rod 6. The pharmaceutical container further features a flange 7. The container has a thread 8 at its distal end for attachment to an injection device (not shown) or a cap 9. The pharmaceutical container may contain a liquid composition 10. The liquid composition 10 may be pushed out of the barrel 2 by manipulation of the plunger rod 6. Pushing the plunger rod 6 into the barrel 2 will move the stopper 3 towards the outlet 11. The distal end of the stopper may have a conical shape that may fit the shape of the barrel in the region of the outlet 11. In this specification, "proximal" is used to describe a location closer to the flange 7, while "distal" is used to indicate a location closer to the outlet 11.

[0072] In FIG. 2, a prior art stopper 3 is shown. The stopper has a coating 11 covering the body 13 of the stopper. The stopper also has an annular projection 12, where the outer diameter of the stopper is larger than the average outer diameter. The stopper shown in this figure has two annular projections with rising and falling edges. The rising edge 15 of the most proximal annular projection and the falling edge 16 of the most distal annular projection extend at the same angle (X / A=1) to the inner surface of the barrel (not shown). The stopper also has a trailing rib 14. The stopper has a smaller outer diameter at the trailing rib 14 compared to the outer diameter at the annular projection 12. When the stopper moves distally in the barrel (not shown), the trailing rib 14 does not touch the inner surface of the barrel. Therefore, the trailing rib is not considered an annular projection according to the present invention, since it cannot affect the release and sliding forces.

[0073] In Figure 3A a stopper 3 according to the invention is shown. The stopper has two annular projections 12 such that when the stopper is placed in the barrel of a pharmaceutical container, a rising edge 15 of the proximal projection diverges distally from the inner surface of the barrel (not shown) at an angle X, and a falling edge 16 of the distal projection diverges proximally from this inner surface at an angle A. The ratio X / A is at least 1.05. The stopper body 13 is provided with a threaded receiver 17 for insertion of a plunger rod (not shown).

[0074] 3B shows a stopper 3 according to an embodiment of the invention having three annular projections 12 such that when the stopper is placed in the barrel of a pharmaceutical container, a rising edge 15 of the proximal-most annular projection diverges distally from the inner surface of the barrel (not shown) at an angle X, and a falling edge 16 of the distal-most annular projection diverges proximally from the inner surface at an angle A. The ratio X / A is at least 1.05.

[0075] 4 shows a pharmaceutical container 1 according to an embodiment of the invention. The pharmaceutical container has an inner surface 5 and a stopper 3 slidably disposed within a barrel 2. The stopper has two annular projections 12, with a rising edge 15 of the proximal-most annular projection subtending an angle X in the distal direction from the inner surface 5 of the barrel 2, and a falling edge 16 of the distal-most annular projection subtending an angle A in the proximal direction from the inner surface 5. The ratio X / A is at least 1.05. An outlet 11 is also shown in this figure. EXAMPLES

[0076] Tests were performed using 1 ml pharmaceutical containers with stoppers 1-3 and comparative stopper 4, which is an example of a stopper from WO 2018 / 157097. All containers used in the tests had an uncoated inner surface.

[0077] The tested containers were filled with water for injection or pure water. They were fixed in a vertical orientation in a universal testing machine model 106.2 kN manufactured by TesT AG, CH-6331 Hünenberg, Switzerland. In the universal testing machine, the stopper was pushed into the container at a speed of 20 mm / min until an initial force of 0.25 N was reached. The stopper was then pushed into the container at a test speed of 100 mm / min and the force was recorded until a cutoff value of 35 N was reached.

[0078] [Table 1]

[0079] The results for Stopper 1 are illustrated in Figure 5. Figure 6 shows that the values ​​are still excellent even after accelerated aging.

[0080] The results for Stopper 2 are illustrated in Figure 7. Figure 8 shows that the values ​​are still excellent even after accelerated aging.

[0081] Roughness Value Surface roughness values ​​were obtained for the inner surfaces of the barrels used in Examples 1 to 3. The results are shown in the table below. All barrels were uncoated.

[0082] [Table 2]

[0083] The surface roughness values ​​were determined with a white light interferometer in accordance with DIN EN ISO 25178-2:2012, DIN EN ISO 25178-6:2010 and DIN EN ISO 25178-604:2013-12 (in conjunction with DIN EN ISO 4288:1998 and DIN EN ISO 3274:1998).

[0084] Dye penetration test A dye penetration test was performed on a set of 15 aged and 15 unaged samples under the following test conditions:

[0085] Test sample preparation The syringes to be tested are filled with water to their nominal capacity after closing their tips. The plunger stopper is then carefully inserted leaving 2-5 mm of air in the syringe. Syringes that already contain liquid between the sealing projections are excluded from the test.

[0086] Test procedure The desiccator is filled with the fluorescein sodium salt solution and the prepared syringe is placed in this solution. The syringe is then covered with a lid with a hole to ensure that it is completely immersed in the solution. The desiccator is then closed and connected to a vacuum pump (e.g., model PC2001 Vario [brand number 29951114-299512] manufactured by Vacuubrand GmbH & Co. KG, CH-8484 Teilingen, Switzerland). The desiccator is kept at a pressure of 270 mbar below atmospheric pressure for 30 minutes. The desiccator is then evacuated to atmospheric pressure and the syringe is left in the solution for another 30 minutes. Finally, the syringe is removed from the solution, carefully rinsed with water, dried with a lint-free cloth and visually inspected under UV light. The result of the visual inspection is recorded as pass or fail. In case of failure, the location of the leak is also recorded in detail.

[0087] [Table 3]

[0088] These results demonstrate that the pharmaceutical container of the present invention provides a tight seal between the stopper and the inner surface of the barrel, even after 105 days of accelerated aging.

[0089] Axial Compression Axial compression tests were performed on a set of 15 aged and 15 unaged samples. The test conditions were as follows: The syringe to be tested was filled with water, closed and fixed in a vertical orientation in a universal testing machine model 106.2 kN, manufactured by TesT AG, CH-6331 Hünenberg, Switzerland. In the universal testing machine, a pressure of 2.5 bar was applied to the plunger for 30 seconds. The syringe was then visually inspected for water droplets formed between the sealing projections and the result was recorded as pass or fail.

[0090] [Table 4]

[0091] These results demonstrate that the pharmaceutical containers of the present invention pass the axial compression test even after 105 days of accelerated aging.

Claims

1. 1. A pharmaceutical container for drug delivery, comprising: - the medicament container has a barrel and a stopper, the stopper being slidably disposed within the barrel; - the stopper has a proximal end adapted to contact the plunger rod and a distal end adapted to contact the pharmaceutical composition; - the stopper has a circumferential surface partially in contact with the inner surface of the barrel; - the stopper has one or more annular projections that contact the inner surface of the barrel when the stopper is moved in a distal direction; A medicament container for drug delivery, wherein the annular projections each have a rising edge and a falling edge in the proximal-distal direction, the rising edge of the proximal-most annular projection and the inner surface of the barrel subtend an angle X in the distal direction, and the falling edge of the distal-most annular projection and the inner surface subtend an angle A in the proximal direction, the ratio X / A being at least 1.05; The pharmaceutical container exhibits a ratio of release force (BLF) to glide force (GF) during the opening and sliding force test of BLF / GF≦2, and a total sliding force variation TGFV=GF measured as the stopper is moved from its start position to its end position. ｍａｘ -GF ｍｉｎ is TGFV<2N; Pharmaceutical container.

2. 1. A medication container for drug delivery having a barrel configured to slidably receive a stopper, comprising: The pharmaceutical container exhibits a ratio of release force (BLF) to glide force (GF) during the opening and sliding force test of BLF / GF≦2, and a total sliding force variation TGFV=GF measured as the stopper is moved from its start position to its end position. ｍａｘ -GF ｍｉｎ is TGFV<2N; the stopper having a proximal end adapted to contact a plunger rod, a distal end adapted to contact a pharmaceutical composition, a circumferential surface adapted at least in part to contact an inner surface of the barrel, and one or more annular projections that contact the inner surface of the barrel when the stopper is moved in a distal direction, each annular projection having a rising edge and a falling edge in a proximal-distal direction; The stopper is further characterized in that the rising edge of the proximal-most annular projection and the inner surface of the barrel subtend an angle X in the distal direction, and the falling edge of the distal-most annular projection and the inner surface subtend an angle A in the proximal direction, the ratio X / A being at least 1.

05. Pharmaceutical container.

3. The ratio X / A is 1.1 (1.1>) to 1.7; 3. The pharmaceutical container according to claim 1 or 2.

4. The A is 130° to 170°. A pharmaceutical container according to any one of claims 1 to 3.

5. The stopper has at least two annular projections. A pharmaceutical container according to any one of claims 1 to 4.

6. The pharmaceutical container is selected from a syringe, a cartridge and a carpule. A pharmaceutical container according to any one of claims 1 to 5.

7. The inner surface of the barrel has a water contact angle of at least 80°. A pharmaceutical container according to any one of claims 1 to 6.

8. The inner surface of the barrel is - Surface roughness Ra of less than 100 nm, Surface roughness Rms less than 150 nm, - a surface energy of less than 45 mN / m, and / or - has a silicone content of less than 100 μg per barrel; A pharmaceutical container according to any one of claims 1 to 7.

9. The stopper is coated with a resin of a fluorinated polymer selected from the group consisting of polytetrafluoroethylene (PTFE), high density 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; A pharmaceutical container according to any one of claims 1 to 8.

10. The barrel is made partially or entirely of glass or a polymer such as COC or COP. A pharmaceutical container according to any one of claims 1 to 9.

11. The pharmaceutical container exhibits a maximum opening and sliding force of 12 N or less during an opening and sliding force test. A pharmaceutical container according to any one of claims 1 to 10.

12. The ratio of the release force (BLF) to the sliding force (GF) is characterized by BLF / GF≦3 after 105 days of accelerated aging; A pharmaceutical container according to any one of claims 1 to 11.

13. the interior surface of the barrel is uncoated; A pharmaceutical container according to any one of claims 1 to 12.

14. the surface roughness of the inner surface of the barrel decreases by at least 3% Ra and / or Rms from the beginning of the stopper to its end; A pharmaceutical container according to any one of claims 1 to 13.

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