WO2025051759A1

WO2025051759A1 - Stopper and medicament container for injection devices

Info

Publication number: WO2025051759A1
Application number: PCT/EP2024/074644
Authority: WO
Inventors: Martin Otten; Sebastian Thiel
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2023-09-07
Filing date: 2024-09-04
Publication date: 2025-03-13
Anticipated expiration: 2026-03-07

Abstract

In one aspect the present disclosure relates to a stopper (100) for insertion into a barrel (151) of an injection device, the stopper (100) comprising: - a stopper body (101) comprising an elastomeric material (102) and a contact surface (104) to sealingly engage with an inside surface (27) of the barrel (151), - a distally facing surface portion (110), - a proximally facing surface portion (130) opposite to the distally facing surface portion (110) and - an intermediate surface portion (120) located between the distally facing surface portion (110) and the proximally facing surface portion (130), - wherein at least one of the distally facing surface portion (110), the proximally facing surface portion (130) and the intermediate surface portion (120) comprises a convex shape.

Description

Stopper and Medicament Container for Injection Devices

Description

Field

The present disclosure relates to the field of medicament containers comprising a barrel, which is sealed by a stopper movably disposed inside the barrel for expelling the medicament from the barrel.

Background

Drug delivery devices allowing for multiple discrete or continuous dosing of a required dosage of a liquid medicinal product and further providing administration of such liquid drug to a patient, are as such well known in the prior art. Generally, such devices have substantially the same purpose as that of an ordinary syringe.

Medicament containers, such as cartridges or pre-filled syringes are typically used as a primary container system to protect a drug formulation located inside the respective medicament container. Cartridges and pre-filled syringes can be directly used to expel an amount, e.g. a dose of predefined size from the medicament container, typically by moving a stopper towards an outlet end of the medicament container. Such stoppers are typically made of an elastomeric material in order to provide a sufficient sealing capability with regard to a barrel of the respective medicament container.

On the one hand such stoppers should be easily movable, i.e. by only applying a comparatively low force thus enabling an easy and straightforward administering of the medicament.

Accordingly, the break loose forces and gliding forces between the stopper and the barrel of the medicament container should be comparatively low.

On the other hand, medicament containers, such as cartridges or pre-filled syringes, are not only used for administering but also for storage of a respective medicament, e.g., during transportation and marketing. Here, the stopper not only serves to expel the medicament from the medicament container but also has to provide a long-term seal that fulfills pre-defined requirements in regard of a container closure integrity. Here, it must be guaranteed that the medicinal product stored inside the medicament container is and remains effectively protected against environmental influences during the entire lifetime or shelf life of the medicament container.

It is therefore desirable to provide improvements for the interface between the movable stopper and the barrel of such medicament containers. The stopper should be movable relative to the barrel for expelling of a dose of the medicament with low effort and/or in response to the application of a comparatively low injection force acting onto the stopper. At the same time, the interface between the movable stopper and the barrel should provide excellent sealing capabilities over a comparatively long time interval.

Summary

In one aspect there is a provided a stopper for insertion into a barrel of an injection device. The stopper comprises a stopper body. The stopper body comprises an elastomeric material and a contact surface to sealingly engage with an inside surface of the barrel. The stopper further comprises a distally facing surface portion, a proximally facing surface portion opposite to the distally facing surface portion and an intermediate surface portion, which is located between the distally facing surface portion and the proximally facing surface portion. At least one of the distally facing surface portion, the proximally facing surface portion and the intermediate surface portion comprises a convex shape.

By way of the convex shape of at least one of the distally facing surface portion, the proximally facing surface portion and the intermediate surface portion there can be provided both, an improvement regarding the container closure integrity and improvements in terms of a comparatively low break loose force and a comparatively low gliding force required for moving the stopper relative to the barrel, e.g., for the purpose of expelling of a dose of the medicament from the barrel. The stopper may be in permanent sealing engagement with the inside surface of the barrel as the stopper is subject to a longitudinal movement relative to the barrel.

The convex shape of at least a portion of the outside surface of the stopper or stopper body allows to implement a comparatively small and well-defined contact surface that is in direct mechanical engagement with the inside surface of the barrel. In this way, comparatively low friction forces, i.e. , break loose forces and/or gliding forces for moving the stopper relative to the barrel can be provided. Moreover, and by way of the convex shape of at least portions of the stopper or stopper body there can be provided a contact surface of the stopper body in a rather precise and reliable manner, which provides excellent sealing capabilities and a comparatively high degree of a container closure integrity.

Furthermore, a convex shape of at least portions of the stopper body may facilitate assembly of the stopper inside the barrel. Insofar, the stopper may be also beneficial in regards to a mass manufacturing of medicament containers for injection devices, which comprise a barrel and a stopper movably disposed inside the respective barrel.

By way of a convex shape of at least a portion of the outer surface of the stopper or stopper body there may be no longer required a trimming edge of a stopper. Moreover, the stopper may also no longer require any lamellae or distance spacers. Hence, the stopper or stopper body may be void of a rim or trimming edge. It may be also void of lamellae, annular protrusions, or grooves on its outside surface. This may facilitate the production of such stoppers and their assembly inside a barrel of a medicament container or injection device. Accordingly, due to the stopper geometry the process of assembling the stopper inside the barrel as well as the process of filling the barrel with the medicament can be simplified and thus optimized. Such a simplified assembly process may lead to a higher degree of mass manufacturing process robustness and to a higher throughput, e.g., in a highly automated or semi-automated assembly and manufacturing process of medicament containers or injection devices.

According to a further example at least one of the distally facing surface portion, the proximally facing surface portion and the intermediate surface portion is of convex shape. In some examples, the entirety of a distally facing surface portion, the entirety of a proximally facing surface portion and/or the entirety of an intermediate surface portion may be of convex shape. In some examples, the distally facing surface portion adjoins the intermediate surface portion. The intermediate surface portion may also directly adjoin the proximally facing surface portion. In some examples, the distally facing surface portion may directly adjoin the proximally facing surface portion, while the intermediate surface portion forms or constitutes a transitional area between the distally facing surface portion and the proximally facing surface portion. Here, the transitional area formed or constituted by the intermediate surface portion may also overlap or at least partially overlap with portions of the distally facing surface portion and the proximally facing surface portion.

The terms distally facing surface portion and proximally facing surface portion refer to opposite surfaces of the outside surface of the stopper or stopper body. Generally, the terms distally facing and proximally facing only specify opposite sides or opposite faces of the stopper or stopper body. When duly arranged or assembled inside the barrel of the injection device the distally facing surface portion distally faces towards the distally located outlet of the barrel. The proximally facing surface portion faces in an opposite direction, hence towards a proximal end of the barrel, which typically faces away from the outlet end of the barrel.

The proximally facing surface portion may be configured to mechanically engage with a plunger or piston rod in order to receive a distally directed pressure or force effect by way of which the stopper is movable relative to the barrel in distal direction, hence towards the outlet or outlet end of the barrel.

In some examples, the distally facing surface portion and the proximally facing surface portion directly adjoin and merge into each other. Here, the intermediate surface portion may form or constitute the contact surface of the stopper body. In some examples, the intermediate surface portion may form or constitute a crest or crest portion having a maximum diameter of the stopper body as seen in a transverse plane, i.e. , in a plane perpendicular to the elongation of the stopper body, wherein the elongation of the stopper body is defined by a distance between a distal end and a proximal end of the stopper body or stopper. Typically, the distal end of the stopper is located on the distally facing surface portion. The proximal end of the stopper is located on the proximally facing surface portion of the stopper or stopper body.

When at least one of the distally facing surface portion, the proximally facing surface portion and the intermediate surface portion is of convex shape, the respective surface portion may be rather homogeneous and void of any recesses, protrusions, or irregularities. Such a geometric design may be easy to manufacture, e.g., by a molding process. It may be rather robust and may also allow and support a rather easy and straightforward assembly.

Moreover, the convex shape of at least a portion of the stopper or stopper body may also prevent a mutual fixing or adhering of a plurality of stoppers after manufacturing or when transported in a bulk.

According to another example at least one of the distally facing surface portion, the proximally facing surface portion and the intermediate surface portion is of spherical or ellipsoidal shape. This way, the stopper may comprise a half sphere or half of an ellipsoid as seen from a proximal side, from a distal side or as seen from a lateral side, e.g., facing towards the intermediate surface.

With a spherical or ellipsoidal shape of at least a portion of the stopper or stopper body a highly precise and comparatively small contact surface can be provided, which is beneficial to reduce friction forces between the stopper and the barrel. At the same time, the contact surface can be provided with rather low dimensional tolerances and with a high degree of size accuracy, which is beneficial to achieve a high degree of a container closure integrity.

In a further example the stopper body comprises one of a sphere, a spheroid, and an ellipsoid. Typically, the diameter of a sphere is sized to match with an inside diameter of the barrel. Typically, and since the stopper body comprises an elastomeric material, the outside diameter or size of the stopper body, especially when implemented as a sphere, is slightly larger than an inside diameter of the barrel of the medicament container or injection device. Accordingly, and upon insertion of the stopper or stopper body into the barrel the stopper body is slightly squeezed radially inwardly to provide a sufficient seal with the inside surface of the barrel.

When implemented as a spheroid, the stopper body typically comprises three principal axes, wherein two of which are of the same length. Here, the spheroid may be implemented as an oblate spheroid, wherein the two axes of common length are larger than the remaining third axis. In other examples, the spheroid is implemented as a prolate spheroid, wherein the two axes of common length are smaller than the remaining third axes. Here, the third axis may have to be aligned along the longitudinal extent of the barrel for inserting the stopper into the barrel.

With the two possible implementations of a spheroid there can be provided different effects in terms of container closure integrity and friction forces between the barrel and the stopper.

According to another example the stopper body comprises an ellipsoid, wherein all three main axes are of slightly different length. Here, one of the three main axes, i.e., a first axis of the ellipsoid may be substantially longer than the remaining two main axes, namely the second and the third main axes. The size variation between the second and the third main axes may be comparatively small. The second and the third axes may extend in a plane perpendicular to the elongation of the barrel when the stopper is inserted into the barrel. Hence, the first axis of the ellipsoid may have to be aligned along the longitudinal extent of the barrel for stopper insertion. Then, and when the barrel is of substantially tubular shape, at least one of the second and the third main axes of the ellipsoid may be slightly larger than an inside diameter of the barrel.

In this way, the stopper body has to be squeezed along at least one transverse direction for insertion into the barrel. Along the other direction, insertion of the stopper into the barrel may be comparatively easy since the outside diameter or outer dimensions of the stopper in this direction may match with or maybe even slightly smaller than an inside diameter of the barrel. With a slightly elliptical cross-section of the ellipsoidal stopper perpendicular to the first main axis, there can be induced a well-defined radial compression of the ellipsoidal stopper upon insertion into the barrel, thereby providing a well-defined degree of radial elastic compression of the stopper when inserted into the barrel, thereby improving the container closure integrity and hence the sealing capability of the stopper relative to the barrel.

According to a further example the stopper body comprises a prolate spheroid. The distally facing surface portion and the proximally facing surface portion of the stopper are separated along a longitudinal axis of the prolate spheroid.

Compared to a sphere, a prolate spheroid comprises at least one symmetry breaking feature and has a defined preferential direction along which it has to be inserted into the barrel.

Accordingly, a stopper body comprising the shape of a prolate spheroid inherently defines an orientation according to which it can or has to be inserted into the barrel. This way, stopper insertion into the barrel can be facilitated and optimized.

According to a further example a longitudinal distance L between a distal end of the distally facing surface portion and a proximal end of the proximally facing surface portion is larger than a diameter D of an inside of the barrel. This may particularly arise with stopper bodies comprising a shape of a prolate spheroid. However, a prolate spheroid is only an example of many other possible geometries of stopper bodies, where the longitudinal distance between a distal end and a proximal end of the stopper body is larger than a diameter D of the inside of the barrel. Generally, such stopper designs inherently define a preferential direction along which insertion of the stopper into the barrel has to be conducted.

According to a further example the longitudinal distance L between the distal end and the proximal end, e.g. between the distally facing surface portion and the proximally facing surface portion of the stopper is larger than or equal F times D, wherein F is one of 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

With stoppers or stopper bodies comprising a longitudinal extend being up to one 1.5 or even 2 times larger than their diameter there can be provided various stopper designs all of which featuring a preferential direction, which facilitates stopper insertion into the barrel. Also, such stopper designs and geometries are beneficial in that during the course of stopper insertion into the barrel, the respective stopper, due its rather longitudinal extent, is effectively hindered to rotate.

According to another example the distally facing surface portion and the intermediate surface portion comprises a convex shape and the proximally facing surface portion comprises a planar shape or even shape. Thus, the stopper or stopper body may comprise a kind of a bullet-type shape, e.g., resembling a bullet or projectile of a gun cartridge. The planar or even shape of the stopper body towards the proximal direction may be beneficial to engage with a complementary and planar - shaped pressure piece or plunger of an injection device, which serves to apply a distally directed pressure onto the stopper. A planar shaped or even shaped proximal side or proximal surface extending all over the cross-section of the stopper body may be of particular benefit to receive or to absorb respective dispensing or driving forces acting in distal direction onto the stopper. At the same time and with the convex shape of at least one of the distally facing surface portion and the intermediate surface portion the beneficial aspects of an improved container closure integrity and/or of reduced friction forces between the stopper and the barrel still remain.

In some examples, the proximally facing surface portion comprising a planar shape or even shape may be rather homogeneous and may be void of any recesses, protrusions, or irregularities.

In some examples the stopper comprises a unitarily shaped stopper body, which may comprise a homogeneous inner structure. The stopper body may be made of a single elastomeric material and/or the entire stopper may consist of the stopper body.

Also here, the longitudinal distance and hence the total longitudinal extent of the stopper may be larger than its diameter. This way it can be effectively provided that the stopper does not twist or rotate while it is inserted or moved relative to the barrel of the medicament container or injection device.

Of course, and with a planar shape towards the proximal end the distally facing surface portion and/or the intermediate surface portion may be of spherical or ellipsoidal shape. The distal portion of the stopper may comprise a halfsphere, half of a spheroid or half of an ellipsoid.

In another example the contact surface of the stopper is of annular shape and is located in the intermediate surface portion or coincides with the intermediate surface portion.

The longitudinal extent of the intermediate surface portion may be comparatively small compared to a longitudinal extent of the distally facing surface portion and/or of the proximally facing surface portion. Generally, the distally facing surface portion may be defined by that portion of the outer surface of the stopper that comprises a surface normal which has at least a component that points in distal direction. Accordingly, the proximally facing surface portion may be defined as that portion or part of the outer surface of the stopper or stopper body that has a surface normal with at least one component facing in proximal direction. Accordingly, the intermediate surface portion may be defined by those portions of the outside surface of the stopper body that comprises a surface normal that points in radial direction as seen with regard to the cylindrical geometry of the barrel. Hence, the intermediate surface portion may be defined by a surface normal being void of a distal component and being void of a proximal component.

In a further example the stopper body comprises a stopper core comprising a first material comprising a degree of rigidity larger than a degree of rigidity of the elastomeric material. The stopper further comprises a stopper shell at least partially enclosing the stopper core and comprising the elastomeric material.

This way, the stopper may be provided with a stiffening core or with a comparatively rigid core, thus enhancing the overall stiffness and mechanical stability of the stopper. In some examples the stopper core may be completely enclosed by the stopper shell. The stopper core may be wrapped inside the stopper shell. The stopper shell may be applied as a layer on top of the stopper core. It may provide a comparatively soft and/or elastic outside portion of the stopper or stopper body.

In some examples the stopper core may also comprise an elastomeric interior. But then, the material of the stopper core comprises a higher degree of rigidity compared to the material of the stopper shell surrounding or enclosing the stopper core.

In some examples the stopper core comprises a comparatively hard or rigid elastomeric material. In other examples the stopper core comprises a plastic material, such as a thermoplastic material, which is entirely enclosed by the material of the stopper shell.

In some examples, the stopper core comprises one of a spherical or ellipsoidal shape. The elastomeric material enclosing the stopper core may be of constant thickness. It may comprise a layer entirely covering the stopper core. In this way, the outside surface of the stopper or stopper body is equivalent and corresponds to the geometry of the stopper core. Here, the geometry of the core may define the outer geometry of the entire stopper.

In another example the stopper core may comprise a geometry that differs from the outer geometry of the stopper body or stopper. Here, the stopper shell may comprise or exhibit a nonconstant thickness over the cross-section or outer surface of the stopper core.

In this way, the stopper or stopper body may be designed for specific application purposes and may thus fulfill specific demands in terms of closure integrity and friction between the stopper and the barrel of the medicament container or injection device.

Generally, the stopper or stopper body may exhibit different modulus of elasticity in different directions. Hence, in longitudinal direction, e.g., the direction defined by the distance between the proximally facing surface portion and the distally facing surface portion, the stopper or stopper body may exhibit a first modulus of elasticity. In radial direction, i.e. , in a direction perpendicular to the longitudinal direction the stopper body may exhibit a second modulus of elasticity. The first and the second modulus of elasticity may differ from each other.

The elasticity in transverse or radial direction may govern the friction forces and the sealing capability of the stopper with regard to the inside surface of the barrel. The elasticity in longitudinal direction may define the degree of longitudinal compressibility of the stopper in the course of expelling a dose of the medicament from the barrel. The longitudinal compressibility may have an impact on the generation of droplets at the distal tip of an injection needle connected to the outlet of the barrel, especially at the end of an injection procedure.

According to another aspect the present disclosure relates to a medicament container. The medicament container comprises a distal end and a proximal end, wherein the proximal end is opposite to the distal end. The medicament container further comprises an elongated barrel extending from the proximal end towards the distal end. The medicament container also comprises an outlet at the distal end. The medicament container also comprises a stopper as described above. The stopper is located inside the elongated barrel and seals the barrel towards the proximal end of the barrel. Typically, the stopper is movable in longitudinal direction relative to the barrel. It may be frictional ly engaged with the barrel to such an extent that it is effectively hindered to rotate relative to the barrel with the longitudinal axis of the barrel as an axis of rotation. A non-rotating engagement between the stopper and the barrel is beneficial to maintain or improve the container closure integrity.

Apart from that, the stopper is in mechanical contact with the inside of the barrel, typically with the inside of a tubular-shaped sidewall of the barrel by its outside facing contact surface. The contact surface provides or defines a sealing surface. The sealing surface may be provided or formed by the intermediate surface portion, which may be located between or in a transitional area of the convex-shaped distally facing surface portion and the proximally facing surface portion, which may be only optionally of convex shape.

Since the medicament container comprises a stopper as described above, all features, effects and beneficial aspects as described above with regard to the stopper equally apply to the medicament container; and vice versa.

In a further example the elongated barrel of the medicament container comprises a tubularshaped sidewall portion and a narrowing, e.g., radially narrowing shoulder portion adjoining the tubular-shaped sidewall portion towards the distal end. An inside of the narrowing shoulder portion comprises a concave shape, which shape corresponds to the convex shape of the distally facing surface portion of the stopper. Typically, a radius of curvature and/or the entire geometry of the shoulder portion closely matches with an outside surface or surface profile of the convex shape of the distally facing surface portion at the distal end of the stopper.

In this way and when the stopper approaches a distal end position inside the barrel it can be somehow guaranteed that the entirety of the medicament located between the distally facing surface portion of the stopper and the outlet of the medicament container is almost or even entirely expelled through the outlet. Hence, there does not remain a lumen between the distal end of the tubular-shaped sidewall of the barrel and the distally facing surface portion of the stopper as the stopper approaches or reaches a distally located final end position inside the barrel.

In some examples, the barrel is made of a vitreous material. It may be made of glass. In other examples the barrel is made of a plastic material, e.g., a cyclic olefin copolymer (COC), or polycarbonate (PC), which are at least partially transparent and which may be chemically inert for a large variety of medicaments.

With both materials for the barrel there can be provided respective shoulder portion that geometrically matches with the concave shape of the stopper. Vice versa, the stopper design at the distally facing surface portion can be adapted and formed in close conformity to the inside geometry of the radially narrowing shoulder portion of the barrel.

According to a further example the medicament container comprises one of a syringe barrel and a cartridge for use with a handheld pen-type injector or for use with an injection pump or infusion device. Generally, the medicament container and/or the stopper as described herein can be used with a large variety of injection or infusion devices. The handheld pen-type injector may be implemented as a multidose or single dose injection device. The handheld injector may be also implemented as an auto injector. In some examples the injection device may be entirely mechanically implemented, such that an injection force necessary for injecting a dose of the medicament is entirely provided by a user of the device.

In other examples the injector is of semi-automated type. Here, an energy storage, such as a mechanical spring provides at least a portion of the injection force. With still other examples the hand-held injector or injection device comprises an electromechanical drive, which is operated by a controller. In still other examples the medicament container is part of an injection pump or infusion device. The medicament container may be readily assembled in any of these injection or infusion devices. The respective devices may be implemented as reusable devices. In other examples the respective devices may be implemented as disposable injection or infusion devices, which after consumption or use of the medicament are intended to be discarded at least partially or entirely.

Generally, the stopper and the medicament container as described herein are usable with many different injection or infusion devices. When used in an autoinjector or when used with a springbased expelling or pump device the risk of a dysfunction of the respective device due to stalling can be reduced and minimized due to reduced friction forces between the stopper and the barrel. When used in electronic devices, reduced break loose forces and/or reduced driving forces between stopper and barrel sidewall enable to reduce the power which is needed for driving a plunger or stopper. This way, the size of a battery and/or a torque or force to be provided by a motor can be reduced which might be beneficial to achieve a miniaturization of the device. In addition, the shelf life and the battery lifetime can be prolonged. Also, smaller batteries with a reduced capacity could be used or intended.

In addition, and due to the reduced friction effect, there can be provided positive side effects in terms of dosing precision. With a reduction of the friction between the stopper and the barrel the plunger stopper travel may become more direct, which has a positive impact on the dosage precision and an eventual priming of the injection device. This is of particular benefit for higher concentrated drug formulations. A reduced fiction may come along with a reduced dispensing force, which leads to a reduction of an elastomeric deformation of the stopper during the stopper movement. This may also lead to a comparatively direct feed stroke of a plunger or piston rod acting on the stopper, which direct feed stroke may be important to fulfill requirements according to dosing security and/or priming. Moreover, by way of a reduced friction even a rather inhomogeneous siliconization of an inside wall of the barrel of the medicament container and/or of the contact surface or outside surface of the stopper could be tolerated.

The at least partial spherical or convex shape of the stoppers inherently prevents a mutual sticking of stoppers during transportation and storage and during the processing of the stoppers until reaching a final assembly configuration inside a barrel. This way, any distance features, such as distance nips or distance rings to be provided on a proximal or distal surface of conventional stoppers will be no longer required.

With a symmetrical spherical or ellipsoidal design of the stopper a feeding and insertion process of stoppers into a barrel can be simplified. Due to the preferential direction inherently provided by a spheroid less complex tools will be needed for arriving at an insertion of the stopper into the barrel of the medicament container. Moreover, and with a spherical stopper, the orientation of the stopper does not longer play any role. It is somewhat rotationally or orientationally invariant and provides a seal with regard to the sidewall of the barrel in either orientation or direction.

In another aspect the present disclosure also relates to an injection device for injecting or infusing a liquid medicament into biological tissue. The injection device comprises a medicament container as described above and one of a plunger and a piston rod operable to exert a pressure onto the stopper of the medicament container, wherein the pressure or force exerted by the plunger or piston rod is sufficient to move the stopper relative to the barrel for expelling a dose of the liquid medicament from the medicament container.

Typically, and since the injection device comprises a medicament container and hence a stopper as described herein, all features, effects and benefits as described above in connection with the stopper and the medicament container equally apply to the injection device; and vice versa.

In some examples the injection device comprises a syringe, e.g., a prefilled syringe. Here, the medicament container coincides with a syringe barrel and the plunger of the injection device is a syringe plunger.

In other examples the injection device comprises one of a pen-type injector, an injection pump, and an infusion device. The injection device may be implemented all mechanically. It may be spring driven or it may be driven or controllable by an electric drive.

In some examples, the injection device comprises an infusion device or an injection pump configured for attachment to a body part of a person or animal and configured to expel or to inject a dose of the medicament in regular time intervals.

According to a further example of the injection device at least one of the plunger and the piston rod comprises a concave-shaped receptacle facing towards a distal direction and hence facing towards the proximally facing surface portion of the stopper or stopper body of the medicament container. The concave-shaped receptacle is complementary shaped to the proximally facing surface portion of the stopper. The concave-shaped receptacle is sized to receive a proximal end of the stopper. By way of the concave-shaped receptacle the entirety or at least portions of the proximally facing surface portion of the stopper or stopper body can be precisely received and fitted into the receptacle thus allowing to provide a well-defined transfer of a dispensing force from the plunger or piston rod onto the stopper or stopper body.

In still another aspect the present disclosure relates to a method of manufacturing at least one of an injection device and a medicament container. Typically, the method is configured to manufacture or to assemble at least one of the above-mentioned medicament containers and injection devices. Insofar, all effects, features, and benefits as described above in connection with the medicament container and the injection device equally apply to the method of manufacturing the same.

The method comprises the steps of providing of an elongated barrel comprising a proximal end and a distal end opposite to the proximal end. The method further comprises the step of providing a stopper as described above and the further step of inserting the stopper into the elongated barrel.

Stopper insertion into the barrel may be conducted in accordance to the stopper geometry. With a stopper of spherical shape, the stopper can be inserted into the barrel totally invariant of its orientation relative to the barrel. With a stopper of spheroid or ellipsoidal shape, the convex and ellipsoidal shape may facilitate stopper insertion since the distally facing surface portion with a reduced transverse size towards a free end inherently fulfills a kind of a guiding function and serves to facilitate stopper insertion into the tubular shaped barrel. Hence, for a mass manufacturing of medicament containers equipped with such stoppers less complex tools and manufacturing steps will be required thereby facilitating the assembly and production of the respective medicament containers.

Generally, the scope of the present disclosure is defined by the content of the claims. The disclosure is not limited to specific embodiments or examples but comprises any combination of elements of different embodiments or examples. Insofar, the present disclosure covers any combination of claims and any technically feasible combination of the features disclosed in connection with different examples or embodiments.

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

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

The drug or medicament may be contained in a primary package or “drug container” adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other solid or flexible vessel configured to provide a suitable chamber for storage (e.g., shorter long-term storage) of one or more drugs. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years or even three years. Storage may occur at room temperature (e.g., about 20°C or above at about 30°C - 40°C), or refrigerated temperatures (e.g., from about - 4°C to about 4°C). In some instances, the drug container may be or may include a dual-chamber cartridge configured to store two or more components of the pharmaceutical formulation to-be-administered (e.g., an API and a diluent, or two different drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components prior to and/or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body.

The drugs or medicaments contained in the drug delivery devices as described herein can be used for the treatment and/or prophylaxis of many different types of medical disorders.

Examples of disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further examples of disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs and drugs are those as described in handbooks such as Rote Liste 2014, for example, without limitation, main groups 12 (antidiabetic drugs) or 86 (oncology drugs), and Merck Index, 15th edition.

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

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

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

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

An example of an oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia or RG012 for the treatment of Alport syndrom. Examples of DPP4 inhibitors are Linagliptin, Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.

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

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

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

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

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

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

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

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

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

As further described in ISO 11608-1 :2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).

As further described in ISO 11608-1 :2014(E), a single-dose container system may involve a needle-based injection device with a replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation). As also described in ISO 11608-1:2014(E), a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).

Brief description of the drawings

In the following, numerous examples of an imaging arrangement with an imaging apparatus and components thereof will be described in greater detail by making reference to the drawings, in which:

Fig. 1 shows an example of an injection device,

Fig. 2 shows the injection device of Fig. 1 in an exploded perspective view,

Fig. 3 schematically shows one example of a stopper comprising a spherical shape,

Fig. 4 shows another example of a stopper with a spheroid shape,

Fig. 5 shows another example of a stopper with a semi-spheroid shape and with a planar shaped proximal surface,

Fig. 6 shows an example of a medicament container provided with a spherical stopper,

Fig. 7 shows a cross-section through a medicament container equipped with an ellipsoidal stopper,

Fig. 8 shows a medicament container in connection with a plunger or piston rod specifically adapted to the design of the stopper,

Fig. 9 shows a further example of a plunger,

Fig. 10 shows another example of a plunger,

Fig. 11 shows a cross-section through a stopper comprising a stopper core and a stopper shell,

Fig. 12 shows a cross section through a further example of a stopper comprising a stopper core and a stopper shell,

Fig. 13 shows an example of an injection device equipped with a spherical stopper and implemented as a syringe,

Fig. 14 shows an example of an infusion pump or injection pump equipped with a stopper as described herein and

Fig. 15 shows an example of a flowchart of a method of assembly or manufacturing of at least one of an injection device and a medicament container.

Detailed Description

The injection device 1 as shown in Figs. 1 and 2 is a pre-filled disposable injection device that comprises a housing 10 to which an injection needle 15 can be affixed. The injection needle 15 is protected by an inner needle cap 16 and either an outer needle cap 17 or a protective cap 18 that is configured to enclose and to protect a distal section of the housing 10 of the injection device 1. The housing 10 may comprise and form a main housing part configured to accommodate a drive mechanism 8 as shown in Fig. 2. The injection device 1 may further comprise a distal housing component denoted as cartridge holder 14. The cartridge holder 14 may be permanently or releasably connected to the main housing 10. The cartridge holder 14 is typically configured to accommodate a cartridge 6 that is filled with a liquid medicament. The cartridge 6 comprises a cylindrically-shaped or tubular-shaped barrel 151 sealed in proximal direction 3 by way of a stopper 100 or bung located inside the barrel 151. The bung or stopper 100 is displaceable relative to the barrel 151 of the cartridge 6 in a distal direction 2 by way of a piston rod 20. A distal end of the cartridge 6 is sealed by a pierceable seal 26 configured as a septum and being pierceable by a proximally directed tipped end of the injection needle 15. The cartridge holder 14 comprises a socket 28, e.g. a threaded socket 28, at its distal end to engage or threadedly engage with a correspondingly threaded portion of the injection needle 15. By attaching the injection needle 15 to the distal end of the cartridge holder 14 the seal 26 of the cartridge 6 is penetrated thereby establishing a fluid transferring access to the interior of the cartridge 6.

When the injection device 1 is configured to administer e.g., human insulin, the dosage set by a dose dial 12 at a proximal end of the injection device 1 may be displayed in so-called international units (III, wherein 1 IU is the biological equivalent of about 45.5 pg of pure crystalline insulin (1/22 mg). The dose dial 12 may comprise or may form a dose dial.

As shown further in Figs. 1 and 2, the housing 10 comprises a dosage window 13 that may be in the form of an aperture in the housing 10. The dosage window 13 permits a user to view a limited portion of a number sleeve 80 that is configured to move when the dose dial 12 is turned, to provide a visual indication of a currently set dose. The dose dial 12 is rotated on a helical path with respect to the housing 10 when turned during setting and/or dispensing or expelling of a dose.

The injection device 1 may be configured so that turning the dosage knob 12 causes a mechanical click sound to provide acoustical feedback to a user. The number sleeve 80 mechanically interacts with a piston in the insulin cartridge 6. When the needle 15 is stuck into a skin portion of a patient, and when the trigger 11 or injection button is pushed, the insulin dose displayed in display window 13 will be ejected from injection device 1. When the needle 15 of the injection device 1 remains for a certain time in the skin portion after the trigger 11 is pushed, a high percentage of the dose is actually injected into the patient's body. Ejection of an insulin dose may also cause a mechanical click sound, which is however different from the sounds produced when using the dose dial 12.

In this embodiment, during delivery of the insulin dose, the dose dial 12 is turned to its initial position in an axial movement, that is to say without rotation, while the number sleeve 80 is rotated to return to its initial position, e.g., to display a dose of zero units.

The injection device 1 may be used for several injection processes until either the cartridge 6 is empty or the expiration date of the medicament in the injection device 1 (e.g., 28 days after the first use) is reached.

Furthermore, before using injection device 1 for the first time, it may be necessary to perform a so-called "prime shot" to remove air from the cartridge 6 and the needle 15, for instance by selecting two units of the medicament and pressing trigger 11 while holding the injection device 1 with the needle 15 upwards. For simplicity of presentation, in the following, it will be assumed that the ejected amounts substantially correspond to the injected doses, so that, for instance the amount of medicament ejected from the injection device 1 is equal to the dose received by the user.

An example of the drive mechanism 8 is illustrated in more detail in Fig. 2. It comprises numerous mechanically interacting components. A flange like support of the housing 10 comprises a threaded axial through opening threadedly engaged with a first thread or distal thread 22 of the piston rod 20. The distal end of the piston rod 20 comprises a bearing 21 on which a pressure foot 23 is free to rotate with the longitudinal axis of the piston rod 20 as an axis of rotation. The pressure foot 23 is configured to axially abut against a proximally facing thrust receiving face of the stopper 100 of the cartridge 6. During a dispensing action the piston rod 20 rotates relative to the housing 10 thereby experiencing a distally directed advancing motion relative to the housing 10 and hence relative to the barrel 151 of the cartridge 6. As a consequence, the stopper 100 of the cartridge 6 is displaced in distal direction 2 by a well- defined distance due to the threaded engagement of the piston rod 20 with the housing 10.

The piston rod 20 is further provided with a second thread 24 at its proximal end. The distal thread 22 and the proximal thread 24 are oppositely handed.

There is further provided a drive sleeve 30 having a hollow interior to receive the piston rod 20. The drive sleeve 30 comprises an inner thread threadedly engaged with the proximal thread 24 of the piston rod 20. Moreover, the drive sleeve 30 comprises an outer threaded section 31 at its distal end. The threaded section 31 is axially confined between a distal flange portion 32 and another flange portion 33 located at a predefined axial distance from the distal flange portion 32. Between the two flange portions 32, 33 there is provided a last dose limiter 35 in form of a semicircular nut having an internal thread mating the threaded section 31 of the drive sleeve 30.

The last dose limiter 35 further comprises a radial recess or protrusion at its outer circumference to engage with a complementary-shaped recess or protrusion at an inside of the sidewall of the housing 10. In this way the last dose limiter 35 is splined to the housing 10. A rotation of the drive sleeve 30 in a dose incrementing direction 4 or clockwise direction during consecutive dose setting procedures leads to an accumulative axial displacement of the last dose limiter 35 relative to the drive sleeve 30. There is further provided an annular spring 40 that is in axial abutment with a proximally facing surface of the flange portion 33. Moreover, there is provided a tubular-shaped clutch 60. At a first end the clutch 60 is provided with a series of circumferentially directed saw teeth. Towards a second opposite end of the clutch 60 there is located a radially inwardly directed flange.

Furthermore, there is provided a dose dial sleeve also denoted as number sleeve 80. The number sleeve 80 is provided outside of the spring 40 and the clutch 60 and is located radially inward of the housing 10. A helical groove 81 is provided about an outer surface of the number sleeve 80. The housing 10 is provided with the dosage window 13 through which a part of the outer surface of the number 80 can be seen. The housing 10 is further provided with a helical rib at an inside sidewall portion of an insert piece 62, which helical rib is to be seated in the helical groove 81 of the number sleeve 80. The tubular shaped insert piece 62 is inserted into the proximal end of the housing 10. It is rotationally and axially fixed to the housing 10. There are provided first and second stops on the housing 10 to limit a dose setting procedure during which the number sleeve 80 is rotated in a helical motion relative to the housing 10. As will be explained below in greater detail, at least one of the stops is provided by a preselector stop feature 71 provided on a preselector 70.

The dose dial 12 in form of a dose dial grip is disposed about an outer surface of the proximal end of the number sleeve 80. An outer diameter of the dose dial 12 typically corresponds to and matches with the outer diameter of the housing 10. The dose dial 12 is secured to the number 80 to prevent relative movement there between. The dose dial 12 is provided with a central opening.

The trigger 11 , also denoted as dose button is substantially T-shaped. It is provided at a proximal end of the injection device 10. A stem 64 of the trigger 11 extends through the opening in the dose dial 12, through an inner diameter of extensions of the drive sleeve 30 and into a receiving recess at the proximal end of the piston rod 20. The stem 64 is retained for limited axial movement in the drive sleeve 30 and against rotation with respect thereto. A head of the trigger 11 is generally circular. The trigger side wall or skirt extends from a periphery of the head and is further adapted to be seated in a proximally accessible annular recess of the dose dial 12.

To dial a dose a user rotates the dose dial 12. With the spring 40 also acting as a clicker and the clutch 60 engaged, the drive sleeve 30, the spring or clicker 40, the clutch 60 and the number sleeve 80 rotate with the dose dial 12. Audible and tactile feedback of the dose being dialed is provided by the spring 40 and by the clutch 60. Torque is transmitted through saw teeth between the spring 40 and the clutch 60. The helical groove 81 on the number sleeve 80 and a helical groove in the drive sleeve 30 have the same lead. This allows the number sleeve 80 to extend from the housing 10 and the drive sleeve 30 to climb the piston rod 20 at the same rate. At a limit of travel a radial stop on the number sleeve 80 engages either with a first stop or a second stop provided on the housing 10 to prevent further movement in a first sense of rotation, e.g. in a dose incrementing direction 4. Rotation of the piston rod 20 is prevented due to the opposing directions of the overall and driven threads on the piston rod 20.

The last dose limiter 35 keyed to the housing 10 is advanced along the threaded section 31 by the rotation of the drive sleeve 30. When a final dose dispensed position is reached, a radial stop formed on a surface of the last dose limiter 35 abuts a radial stop on the flange portion 33 of the drive sleeve 30, preventing both, the last dose limiter 35 and the drive sleeve 30 from rotating further.

Should a user inadvertently dial beyond the desired dosage, the injection devicel, configured as a pen-injector allows the dosage to be dialed down without dispense of the medicament from the cartridge 6. For this the dose dial 12 is simply counter-rotated. This causes the system to act in reverse. A flexible arm of the spring or clicker 40 then acts as a ratchet preventing the spring 40 from rotating. The torque transmitted through the clutch 60 causes the saw teeth to ride over one another to create the clicks corresponding to dialed dose reduction. Typically, the saw teeth are so disposed that a circumferential extent of each saw tooth corresponds to a unit dose. Here, the clutch may serve as a ratchet mechanism.

When the desired dose has been dialed the user may simply dispense the set dose by depressing the trigger 11. This displaces the clutch 60 axially with respect to the number sleeve 80 causing dog teeth thereof to disengage. However, the clutch 60 remains keyed in rotation to the drive sleeve 30. The number sleeve 80 and the dose dial 12 are now free to rotate in accordance with the helical groove 81.

The axial movement deforms the flexible arm of the spring 40 to ensure the saw teeth cannot be overhauled during dispense. This prevents the drive sleeve 30 from rotating with respect to the housing 10 though it is still free to move axially with respect thereto. The deformation is subsequently used to urge the spring 40 and the clutch 60 back along the drive sleeve 30 to restore the connection between the clutch 60 and the number sleeve 80 when the distally directed dispensing pressure is removed from the trigger 11.

The longitudinal axial movement of the drive sleeve 30 causes the piston rod 20 to rotate through the through opening of the support of the housing 10, thereby to advance the stopper in the cartridge 6. Once the dialed dose has been dispensed, the number sleeve 80 is prevented from further rotation by contact of at least one stop extending from the dose dial 12 with at least one corresponding stop of the housing 10. A zero-dose position may be determined by the abutment of one of axially extending edges or stops of the number sleeve 80 with at least one or several corresponding stops of the housing 10.

The expelling mechanism or drive mechanism 8 as described above is only exemplary for one of a plurality of differently configured drive mechanisms that are generally implementable in a disposable pen-injector. The drive mechanism as described above is explained in more detail e.g., in W02004/078239A1 , WO 2004/078240A1 or WO 2004/078241A1 the entirety of which being incorporated herein by reference.

The dose setting mechanism 9 as illustrated in Fig. 2 comprises at least the dose dial 12 and the number sleeve 80. As the dose dial 12 is rotated during and for setting of a dose the number sleeve 80 starts to rotate relative to the housing along a helical path as defined by the threaded engagement of its outer thread or helical groove 81 with a correspondingly shaped threaded section at the inside surface of the housing.

During dose setting and when the drive mechanism 8 or the dose setting mechanism 9 is in the dose setting mode the drive sleeve 30 rotates in unison with the dose dial 12 and with the number sleeve 80. The drive sleeve 30 is threadedly engaged with the piston rod 20, which during dose setting is stationary with regard to the housing 10. Accordingly, the drive sleeve 30 is subject to a screwing or helical motion during dose setting. The drive sleeve 30 starts to travel in proximal direction as the dose dial is rotated in a first sense or rotation or in a dose incrementing direction 4, e.g., in a clockwise direction. For adjusting of or correcting a size of a dose the dose dial 12 is rotatable in an opposite second sense of rotation, hence in a dose decrementing direction 5, e.g., counterclockwise.

In Figs. 3 and 4 there are illustrated two examples of stoppers 100 each comprising a stopper body 101 and further comprising a proximally facing surface portion 130 and an oppositely located distally facing surface portion 110. The stoppers 100 each comprise an elastomeric material 102. The stoppers 100 also comprise a contact surface 104, by way of which the respective stoppers 100 make contact with an inside surface 27 of a barrel 151 of a medicament container 150 as e.g., illustrated in Figs. 6 and 7. As it is immediately apparent from Figs. 3 and 4 at least one of the proximally facing surface portion 130 and the distally facing surface portion 110 is of convex shape or comprises a convex shape.

In the example of Fig. 3 the entire stopper body 101 comprises a sphere 106. In the example of Fig. 4, the stopper body 101 comprises a spheroid 108.

The distally facing surface portion 110 may be defined by such surface portions of the stopper body 101 that comprise a surface normal facing in distal direction 2 or comprising a surface normal comprising at least a directional component that faces in distal direction 2. Likewise, the proximally facing surface portion 130 may be defined by those surface portions of the stopper body 101 that comprise a surface normal with a component that faces in proximal direction 3 as shown in Fig. 6.

The stopper 100 also comprises an intermediate surface portion 120 which is located longitudinally between the proximally facing surface portion 130 and the distally facing surface portion 110. In the example of Fig. 4 the intermediate surface portion 120 coincides with the contact surface 104 of the stopper body 101. The intermediate surface portion 120 may be characterized in that it comprises a surface normal that is void of a component facing either in distal direction 2 or in proximal direction 3. Hence, the intermediate surface portion 120 may be defined by a surface portion, whose surface normal faces in transverse or radial direction with regard to the tubular geometry of the medicament container 150.

Typically, and as it is immediately apparent from e.g., Figs. 4 and 7 the proximally facing surface portion 130 is located at and forms the proximal end 131 of the stopper body 101. Correspondingly, the distal end 111 is provided at or forms a portion of the distally facing surface portion 110.

As it is apparent from the illustration of Fig. 7 the longitudinal distance L between the proximal end 131 and the distal end 111 of the stopper 100 or stopper body 101 is substantially larger than a diameter D of an inside of the barrel 151 of the medicament container 150. In either way and with a spherical or ellipsoidal shape of the stopper body 101 there can be provided a well- defined and highly precise contact surface 104, which has a limited size in longitudinal direction, thereby allowing to minimize the total size of the contact surface between an outside of the stopper body 101 and the inside 27 of the barrel 150. In this way friction forces between the stopper 100 and the barrel 150 can be effectively reduced to a minimum. This applies to static as well as to dynamic friction forces, namely to an initial force or a break loose force for setting the stopper 100 in motion relative to the barrel 151 and to a sustaining force, i.e. a driving or sliding force required for constantly or repeatedly moving the stopper 100 relative to the barrel 151.

The stopper 100 according to the example of Fig. 5 comprises a planar-shaped proximally facing surface portion 130. Towards the distal direction 2 the stopper 100 or stopper body 101 comprises a spheroid 108. Hence, the stopper geometry of Fig. 5 may resemble a half spheroid. The planar-shaped proximally facing surface portion 130 may be particularly configured to form a well-defined interface with a planar-shaped pressure foot 23 of a drive mechanism 8 of an injection device 1, e.g., as described in connection with Fig. 2. The medicament container 150 as shown in Fig. 6-8 is implemented as a cartridge 6. It comprises an elongated barrel 151 extending in longitudinal direction. Towards a distal direction and towards a distal end 152 the medicament container 150 and hence the barrel 151 is closed by a seal 26. The seal 26 is provided at a radially narrowed head portion 157. The barrel 151 comprises a somewhat tubular shaped sidewall portion 155, which transitions into the head portion 157 via a radially narrowing shoulder portion 156 towards the distal end 152. An oppositely located proximal end 154 of the barrel 151 one is effectively sealed by the stopper 100.

As it is particularly illustrated in Fig. 8 an inside surface of the shoulder portion 156 is of concave shape and matches substantially or even perfectly with the convex shape of the distally facing surface portion 110 of the stopper 100. In this way and when the stopper 100 reaches a distal end position inside the barrel 151 almost the entirety of the medicament can be expelled through the outlet 153 and the distal end 152 of the medicament container. In the examples of Figs. 6-8, the outlet 153 is provided with a seal 26, e.g., implemented as a pierceable septum. The seal 26 may be fastened to the head portion 157 by way of a crimped cap, e.g., by a metal cap. With other examples and when the medicament container 150 is e.g., implemented as a syringe barrel 201 as shown in Fig. 13 the distally located outlet 202 may be provided with an injection needle 203. Even though not particularly illustrated with the syringe barrel 201 also here, a shoulder portion at the distal end of the tubular shaped syringe barrel 201 may be of concave shape to conform with the convex shape of the distally facing surface portion 110 of the stopper 100.

The injection device 1 as shown in Figs. 1 and 2 comprises an elongated piston rod 20 that serves as a plunger for driving the stopper 100 in distal direction 2. Likewise, the syringe 200 comprises a plunger 220 with a plunger rod 221, which is equipped with a radially widened plunger head 224. As illustrated in Fig. 8 the plunger head 224 comprises a receptacle 222 complementary shaped to the proximally facing surface portion 130 of the stopper 100. In the presently illustrated example, the receptacle 222 is of concave shape to provide a comparatively large contact area between a distally facing surface of the plunger head 224 and the proximally facing surface portion 130 of the stopper 100.

The syringe 200 as shown in Fig. 13 comprises a radially outwardly extending finger flange 204 at the proximal end of the syringe barrel 201. Likewise, the plunger rod 221 comprises a radially widened plunger flange 226 by way of which a user may apply a driving pressure onto the plunger 220 for moving the stopper 100 towards the outlet 202.

With the example of a syringe 200 the stopper 100 may be readily attached with the plunger 220 and may be non-detachably or detachably connected with the plunger 220, in particular with the plunger rod 221. Insofar, the syringe 200 and the syringe barrel 201 may be just another example of the medicament container 150 as described above, e.g., in connection with Figs. 6-10.

In the illustration of Fig. 9 the plunger head 224 is rotationally supported at a distal end of the plunger rod 221. It may freely rotate relative to the plunger rod 221. The respective plunger 220 may replace the piston rod 20 and the pressure piece 23 as described with the injection device 1 according to Fig. 2. Hence, such a plunger 220 or plunger assembly may be typically used with a pen-type injector, where the plunger rod 221 is subject to a rotation during dose delivery.

In the example of Fig. 10 there is provided a conventional plunger 220 with a radially widened plunger head 224. Here, the plunger head 224 is provided with a spacer 225 to be mounted at a distal side or distal end of the plunger head 224. The spacer 225 comprises the receptacle 222 as described above in connection with Figs. 8 and 9. The receptacle 222 is complementary shaped to the proximally facing surface portion 130 of the stopper 100. By way of the spacer 225 even existing syringes 200 or injection devices 1 can be retrofitted in order to enable use of a rather conventional and planar-shaped plunger head 224 or pressure piece 23 with the stopper 100 as described herein. In the examples of Fig. 11 and 12 the stopper 100 comprises a stopper core 105 comprising a first material with a degree of rigidity being larger than a degree of rigidity of the elastomeric material 102. The elastomeric material 102 may be provided in a stopper shell 107 surrounding or at least partially enclosing the stopper core 105. The elastomeric material 102 may exhibit a higher degree of deformability than the material of the stopper core 105 when subject to an externally applied force effect. In effect, the stopper core 105 provides an enhanced mechanical stability and rigidity for the stopper 100. As illustrated in Figs. 11 and 12 the stopper shell 107 may comprise a constant thickness. The stopper shell 107 may be implemented as a surrounding or covering layer entirely enclosing the stopper core 105. Hence, the design and shape of the stopper core 105 may define the overall shape and geometry of the stopper body 101.

In Fig. 14 there is illustrated another example of an injection device 300. The injection device 300 comprises a housing 301 and a plunger 302 that is movable by way of a drive mechanism 304 in longitudinal direction to move the stopper 100 relative to the barrel 151 of the medicament container 150, which is located inside the housing 301. The drive mechanism 304 comprises a battery 306, a controller 310 and an electromechanical drive 308. Electrical energy as provided by the battery 306 can be controlled by the controller 310 in order to activate and/or to control operation of the drive 308. The drive 308 is operable to move the plunger 302 in distal direction to expel a well-defined amount of the medicament through the outlet 153 of the medicament container 150. The outlet 153 of the medicament container 150 is connected via an infusion line 312 with an infusion needle 314. In the same or like manner the injection device 300 may be also implemented as an injection pump, where an injection needle 314 is fluidically connected with the outlet 153 and wherein the injection needle 314 protrudes from the housing 301.

Alternative to the illustrated example, the injection device may comprise a suction pump operable to withdraw a dose of the medicament from the medicament container by way of a fluid line in fluid communication with the interior of the barrel through a suction effect. Here, the injection device may be void of an expelling mechanism and/or void of a piston rod operable to exert a distally directed pressure onto the stopper. Rather, and with a suction-based withdrawal of the medicament the stopper will be subject to a movement relative to the sidewall of the barrel through a reduced pressure inside the barrel when a portion of the medicament is withdrawn from the barrel by way of suction.

The various examples of stoppers 100 as described herein can be universally used with any kind of medicament containers 150 comprising an elongated barrel 151 , such as injection cartridges 6 for use with hand-held injection devices 1. Likewise, the stopper 100 can be used in injection devices implemented as a manually operated syringe 200. In further examples the stopper one can be used in connection with medicament containers 150 dedicated for injection or infusion devices 300.

The flowchart according to Fig. 15 is indicative of the method of manufacturing at least one of an injection device 1, a syringe 200 and a medicament container 150 as described herein. Here, and in a first step 400 there is provided an elongated barrel 151 comprising a proximal end 154 and a distal end 152 opposite to the proximal end. In step 402 there is provided a stopper 100 as described herein. In step 404 the stopper 100 is inserted into the barrel. It may be inserted in distal direction 2 into the barrel 150 one from the proximal end 154 of the barrel 151. Thereafter, the barrel may be filled with a medicament, e.g., with an injectable liquid medicament.

Stopper insertion into the barrel 151 may be conducted in a rather automated or semiautomated way. Since the stopper comprises a convex surface portion stopper insertion into the tubular or cylindrical shape proximal end 154 of the barrel 151 may be simplified. Here, the convex surface portion inherently provides a radial centering and hence radial guiding for inserting the stopper 100 into the barrel 151.

Reference Numbers

List of reference numbers

1 injection device

2 distal direction

3 proximal direction

4 dose incrementing direction

5 dose decrementing direction

6 cartridge

8 drive mechanism

9 dose setting mechanism

10 housing

11 trigger

12 dose dial

13 dosage window

14 cartridge holder

15 injection needle

16 inner needle cap

17 outer needle cap

18 protective cap

19 protrusion

20 piston rod

21 bearing

22 first thread

23 pressure foot

24 second thread

26 seal

27 inside surface

28 threaded socket

30 drive sleeve

31 threaded section

32 flange

33 flange

35 last dose limiter

40 spring

60 clutch

62 insert piece 4 stem

80 number sleeve

81 groove

100 stopper

101 stopper body

102 elastomeric material

104 contact surface

105 stopper core

106 sphere

107 stopper shell

108 spheroid

110 surface portion

111 distal end

120 surface portion

130 surface portion

131 proximal end

150 medicament container

151 elongated barrel

152 distal end

153 outlet

154 proximal end

155 sidewall portion

156 shoulder portion

157 head portion

200 syringe

201 syringe barrel

202 outlet

203 needle

204 finger flange

220 plunger

221 plunger rod

222 receptacle

224 plunger head

225 spacer

226 plunger flange

300 injection device

301 housing 302 plunger

304 drive mechanism

306 battery

308 drive 310 controller

312 infusion line

314 infusion needle

Claims

PAT23238-WO-PCT Claims

1. A stopper (100) for insertion into a barrel (151) of an injection device, the stopper (100) comprising: a stopper body (101) comprising an elastomeric material (102) and a contact surface (104) to sealingly engage with an inside surface (27) of the barrel (151), a distally facing surface portion (110), a proximally facing surface portion (130) opposite to the distally facing surface portion (110) and an intermediate surface portion (120) located between the distally facing surface portion (110) and the proximally facing surface portion (130), wherein at least one of the distally facing surface portion (110), the proximally facing surface portion (130) and the intermediate surface portion (120) comprises a convex shape.

2. The stopper (100) according to claim 1 , wherein at least one of the distally facing surface portion (110), the proximally facing surface portion (130) and the intermediate surface portion (120) is of convex shape.

3. The stopper (100) according to claim 1 or 2, wherein at least one of the distally facing surface portion (110), the proximally facing surface portion (130) and the intermediate surface portion (120) is of spherical or ellipsoidal shape.

4. The stopper (100) according to any one of the preceding claims, wherein the stopper body (101) comprises one of a sphere (106), a spheroid (108) and an ellipsoid.

5. The stopper (100) according to any one of the preceding claims, wherein the stopper body (101) comprises a prolate spheroid (108), wherein the distally facing surface portion (110) and the proximally facing surface portion (130) are separated along a longitudinal axis of the prolate spheroid (108).

6. The stopper (100) according to claim 5, wherein a longitudinal distance L between a distal end (111 ) of the distally facing surface portion (110) and a proximal end (131 ) of the proximally facing surface portion (130) is larger than a diameter D of an inside of the barrel (151).

7. The stopper (100) according to any one of the preceding claims, wherein in longitudinal direction as defined by a distance between the proximally facing surface portion (130) and the distally facing surface portion (110), the stopper body (101) exhibits a first modulus of elasticity and wherein in a radial direction perpendicular to the longitudinal direction the stopper body (101) exhibits a second modulus of elasticity, wherein the first modulus of elasticity and the second modulus of elasticity differ from each other. <pg. 9, Ins. 3 - 8>

8. The stopper (100) according to any one of the preceding claims, wherein at least one of the distally facing surface portion (110) and the intermediate surface portion (120) comprises a convex shape and wherein the proximally facing surface portion (130) comprises a planar shape or even shape.

9. The stopper (100) according to any one of the preceding claims, wherein the contact surface (104) is of annular shape and is located in the intermediate surface portion (120) or coincides with the intermediate surface portion (120).

10. The stopper (100) according to any one of the preceding claims, wherein the stopper body (101) comprises: a stopper core (105) comprising a first material comprising a degree of rigidity larger than a degree of rigidity of the elastomeric material (102) and a stopper shell (107) at least partially enclosing the stopper core (105) and comprising the elastomeric material (102).

11. The stopper (100) according to claim 10, wherein the stopper core (105) is completely enclosed by the stopper shell (107). <pg. 8, Ins. 12 -13>

12. A medicament container (150) comprising: a distal end (152) and a proximal end (154) opposite the distal end (152), an elongated barrel (151) extending from the proximal end (154) towards the distal end (152), an outlet (153) at the distal end (152), and a stopper (100) according to any one of the preceding claims located inside the elongated barrel (151) and sealing the barrel (151) towards the proximal end (154).

13. The medicament container (150) according to claim 12, wherein the elongated barrel (151) comprises a tubular-shaped sidewall portion (155) and a narrowing shoulder portion (156) adjoining the tubular-shaped sidewall portion (155) towards the distal end (152), wherein an inside of the narrowing shoulder portion (156) comprises a concave shape that corresponds to the convex shape of the distally facing surface portion (110) of the stopper (100).

14. The medicament container (150) according to claim 12 or 13, wherein the medicament container (150) comprises one of a syringe barrel (201) and a cartridge (6) for use with a handheld pen-type injector (1) or for use with an injection pump or infusion device (300).

15. The medicament container (150) according to any one of the preceding claims 12-14, wherein the stopper (100) is movable relative to the elongated barrel (151) for expelling of a dose of the medicament from the barrel (151). <pg. 2; Ins. 23 - 28>

16. An injection device (1) for injecting or infusing a liquid medicament into biological tissue, the injection device (1) comprising: a medicament container (150) according to any one of the preceding claims 10-12 and one of a plunger (220) and a piston rod (20) operable to exert a pressure onto the stopper (100) sufficient to move the stopper (100) relative to the barrel (151) for expelling a dose of the liquid medicament.

17. The injection device (1) according to claim 16, wherein at least one of the plunger 220) and the piston rod (20) comprises a concave-shaped receptacle (222) complementary shaped to the proximally facing surface portion (130) of the stopper (100) sized to receive a proximal end (131) of the stopper (100).

18. A method of manufacturing at least one of an injection device (1) and a medicament container (150), the method comprising the steps of: providing of an elongated barrel (151) comprising a proximal end (154) and a distal end (152) opposite to the proximal end (154), providing of a stopper (100) according to any one of the preceding claims 1-11, and inserting the stopper (100) into the elongated barrel (151).