Injection device with dose size adjuster

Abstract

The present disclosure relates to an injection device (30) configured to eject a dose of a medicament, the injection device (30) comprising: - an elongated housing (1) extending in the longitudinal direction; - a piston rod (5) movable in a longitudinal distal direction (22) relative to the housing (1) to apply a dosing pressure to a bung (13) of a cartridge (12) at least partially filled with an injectable medicament (35); - a rod extension (50) movably disposed on or in the distal end of the piston rod (5); - a driver (8) operably engaged with the piston rod (5) and movable in a longitudinal proximal direction (23) relative to the housing (1) for setting the dose and movable in a longitudinal distal direction (22) relative to the housing (1) for dispensing the dose; and - a regulator (70) disposed on or in the driver (8) and operably engaged with the rod extension (50) to move the rod extension (50) longitudinally relative to the piston rod (5). [Selection diagram] Figure 5

Description

Technical Field

[0001] In one aspect, the present disclosure relates to an injection device, such as a pen-type syringe, for setting and dispensing a dose of a drug. Specifically, the present disclosure relates to so-called fixed-dose injection devices configured to set and discharge a fixed-size, and thus invariant-size, dose of a drug.

Background Art

[0002] Injection devices for setting and dispensing single or multiple doses of a liquid drug are themselves well known in the art. Generally, the purpose of such devices is substantially similar to that of a conventional syringe.

[0003] Injection devices, particularly pen-type syringes, must meet a plurality of user-specific requirements. For example, if a patient has a chronic disease such as diabetes, the patient may be physically weak and may also have visual impairments. Therefore, a suitable injection device, particularly for home-use pharmaceuticals, must be structurally robust and easy to use. Furthermore, the operation and general handling of the device and its components should be understandable and easy to understand. Furthermore, the dose setting as well as the dose dispensing procedure should be easily operable and straightforward.

[0004] Typically, such a device includes a housing that includes a specific cartridge holder adapted to receive a cartridge at least partially filled with the drug scheduled for dispensing. Such a device further includes a drive mechanism, which usually has a longitudinally movable piston rod configured to operably engage the piston of the cartridge. By the drive mechanism and its piston rod, the piston of the cartridge is displaceable in the distal or dispensing direction, and thus can discharge a predetermined amount of the drug through a piercing assembly releasably connected to the distal end of the housing of the injection device.

[0005] The medication to be administered by the injection device is supplied and contained in a multi-dose cartridge. Such a cartridge typically includes a glassy body, which is sealed distally by a perforable seal and further sealed proximal by a piston. In the case of reusable injection devices, empty cartridges can be replaced with new ones. In contrast, disposable injection devices are discarded once the medication in the cartridge has been administered or used up.

[0006] In some applications, it is sufficient for the injection device to be configured to dispense and dispense doses of equal size. Such injection devices are typically called fixed-dose devices. These devices repeatedly dispense and dispense a single predetermined dose of a drug. The general handling and operation of such fixed-dose injection devices are fairly straightforward and simple. Such fixed-dose injection devices can be configured and supplied as disposable injection devices. These devices are intended to be discarded when the drug contained within the device has been used up.

[0007] In some application scenarios, it is desirable to vary the size of a predetermined fixed dose within a given tolerance range. Therefore, it is desirable to provide temporary or prior reduction or increase of the fixed dose. It is desirable to provide at least one modification of the fixed dose. In this way, the patient themselves can decide to reduce or increase the fixed size of the dose to avoid accidental discomfort or intolerance to the drug. Some patients may experience discomfort when administered a predetermined fixed dose of the drug, at least under certain circumstances, for example, in the morning or at the beginning of treatment. In such specific circumstances, it is desirable to provide an injection device that sets and dispenses a dose slightly different from the predetermined fixed dose. [Overview of the project] [Problems that the invention aims to solve]

[0008] Therefore, it is desirable to provide a fixed-dose injection device having a dose size adjuster. [Means for solving the problem]

[0009] In one embodiment, an injection device configured to dispense a dose of a drug is provided. The injection device includes an elongated housing extending in the longitudinal direction. The injection device further includes a piston rod movable longitudinally distal to the housing to apply dispensing pressure to a cartridge stopper or piston. The cartridge is at least partially filled with an injectable drug. The injection device further includes a rod extension movably positioned on or within the distal end of the piston rod. The injection device further includes a driver operably engaged with the piston rod and movable longitudinally proximal to the housing for dose setting. The driver is further movable longitudinally distal to the housing for dose dispensing. The injection device further includes a regulator positioned on or within the driver. The regulator operably engages with the rod extension to move the rod extension longitudinally relative to the piston rod.

[0010] The regulator is user-operable and enables individual longitudinal displacement of the rod extensions relative to the piston rod. The regulator is configured to vary the length of the rod assembly. The rod assembly can consist of a piston rod and rod extensions connected to the piston rod. The rod assembly is of variable length. The longitudinal extension of the rod assembly, and therefore the length of the rod assembly, depends on the longitudinal or axial position of the rod extensions relative to the piston rod. By reducing the length of the rod assembly, for example by displacing the rod extensions proximal to the piston rod, the size of the dose to be dispensed by the injection device can be reduced. By increasing the length of the rod assembly, for example by displacing the rod extensions distal to the piston rod, the size of the dose to be dispensed by the injection device can be increased.

[0011] The rod assembly may further include a pressing piece positioned at the distal end of the rod extension. The distal end or pressing piece of the rod assembly may directly contact the proximal surface of the cartridge stopper in an axial or longitudinal direction. The regulator is typically operable before, during, or after dose setting. Dose setting is performed by retracting a driver or a button connected to the driver proximal to the housing. The operation of the regulator results in shortening or extending the rod assembly.

[0012] Typically, a regulator is operable, i.e., movable or rotatable, in a first direction to increase the dose size. The regulator is also operable, i.e., movable or rotatable, in a second direction opposite to the first direction to decrease the dose size. Operating the regulator in the first direction results in distal displacement of the rod extension relative to the piston rod. Operating the regulator in the second direction results in proximal displacement of the rod extension relative to the piston rod. Moving or rotating the regulator in the first direction results in a reduction in the length of the rod assembly. Moving or rotating the regulator in the second direction results in an increase in the length of the rod assembly. Both operations of the regulator, and therefore the dose-increasing and dose-decreasing operations of the regulator, can be performed when the distal end of the rod assembly is in direct contact with the cartridge stopper.

[0013] Moving the regulator in the second direction results in proximal retraction of the rod extension. The rod extension then ceases to contact the proximal surface of the cartridge stopper. Moving the regulator in the first direction results in increased longitudinal extension of the rod assembly, and therefore distal displacement of the rod extension relative to the piston rod. Typically, the overall displacement of the rod extension relative to the piston rod induced by the regulator introduces pretension or prestress into the discharge or drive mechanism of the injection device without distally displacing the stopper. Therefore, the distal displacement of the rod extension relative to the piston rod induced by the regulator is less than or equal to the longitudinal displacement of the rod assembly required to overcome the piston's disengagement force relative to the cartridge body.

[0014] The driver is accessible to the user directly or indirectly. When displaced distally to the housing, the driver is at least operably engaged with the piston rod. When displaced proximal to the housing, the driver is operably disconnected from the piston rod, or can be made detachable. The driver can be longitudinally slidably engaged with the housing.

[0015] In one example, the driver is locked to the housing in a non-rotatable manner. Typically, the driver is movable longitudinally along the housing. The driver can be spline-engaged to the housing. The driver is prevented from rotating relative to the housing, but slides freely along the longitudinal direction of the housing.

[0016] In a further example, the driver is screw-engaged to the piston rod. In this way, longitudinal displacement of the driver relative to the housing can result in rotation of the piston rod relative to the housing. The longitudinal displacement of the driver induces torque on the piston rod. Typically, distal displacement of the driver relative to the housing can induce driving torque on the piston rod. Furthermore, the piston rod can be screw-engaged to the housing. The longitudinal displacement of the driver relative to the housing can be induced by the screw-engagement motion of the piston rod relative to the housing. Due to the screw engagement between the piston rod and the housing, when the driver is displaced distally relative to the housing, the piston rod also undergoes distal displacement relative to the housing.

[0017] Depending on the lead of the screw engagement of the piston rod to the driver and the lead of the screw engagement of the piston rod to the housing, a reduction ratio can be provided between the distal motion of the driver relative to the housing and the distal motion of the piston rod. Typically, the piston rod includes a first threaded section that screw engages with the housing, and the piston rod further includes a second threaded section that screw engages with the driver. The ratio of the lead of the first threaded section to the lead of the second threaded section defines the reduction ratio. The first and second threaded sections can be oriented in opposite directions.

[0018] In another example, the piston rod includes at least one flexible guide function screw-engaged to the threads of the driver. The flexible guide function may be located at the proximal end of the piston rod. The flexible guide function may be located within the hollow section of the driver. The threads of the driver screw-engaged to the flexible guide function may be located on the inner wall of the driver. The flexible guide function is radially deflectable. The flexible guide function is radially inward when the driver is displaced proximal to the housing. During such proximal displacement of the driver, rotation of the piston rod can be prevented.

[0019] The flexible guide function can be deflected inward so as to temporarily disengage from the screw threads of the driver. This allows for proximal or longitudinal displacement of the driver relative to the housing while the piston rod remains immobilely fixed to the housing. When the driver reaches a predetermined operating position relative to the housing, the flexible guide function of the piston rod reengages with the progressing screw threads of the driver. In other words, the flexible guide function enables proximal displacement of the driver relative to the piston rod, and therefore temporary disengagement of the driver and piston rod. During dose dispensing, the flexible guide function is further configured to convert distal displacement of the driver relative to the housing into rotational motion of the piston rod relative to the housing for dose dispensing.

[0020] In a further example, the regulator is axially engaged with the driver. The regulator is axially coupled to the driver. In other words, when the driver is displaced proximal to the working state from the idle state, and when the driver returns from the proximal working state to the most distal idle or initial state, the regulator moves back and forth in the proximal and distal directions relative to the housing. Because the regulator is axially engaged with the driver, it is accessible to the user and remains in that state. This makes individual dose size adjustments available whenever needed.

[0021] In a further example, the regulator slides longitudinally with respect to the rod extension. In this way, the regulator is able to slide axially with respect to the rod extension when the driver undergoes longitudinal displacement relative to the housing. During proximal displacement of the driver relative to the housing, the rod extension is fixed to the housing and the piston rod and remains in that state. During distal displacement of the driver relative to the housing, the rod extension is configured to rotate and move together with the piston rod.

[0022] The longitudinal sliding engagement between the regulator and the rod extension enables fairly flexible and universal operation or movement of the rod extension. Regardless of the axial position of the driver, the regulator slides into and remains in that position with the rod extension. Therefore, the longitudinal position of the rod extension relative to the piston rod can be manipulated by the regulator at any longitudinal position of the regulator and / or driver.

[0023] In a further example, the regulator is locked to the rod extension in a non-rotatable manner. In this way, the rotation of the regulator can be converted into the rotation of each part of the rod extension. Typically, the regulator is spline-engaged to the rod extension. The spline engagement is configured to transmit angular momentum or torque between the regulator and the rod extension. Thus, the rotation of the regulator relative to the piston rod can be converted into the rotation of the rod extension relative to the piston rod.

[0024] In a further example, the rod extension is screw-engaged to the distal end of the piston rod. Thus, rotation of the rod extension relative to the piston rod results in a longitudinal displacement of the rod extension relative to the piston rod. By rotating the rod extension relative to the piston rod, the overall longitudinal size of the rod assembly can be varied.

[0025] Typically, the piston rod is hollow. The piston rod may include a hollow cavity. The cavity may open towards the proximal and / or distal ends. The regulator includes a threaded section configured as an external thread, which is threaded into an internal thread of a corresponding shape on the internal section of the hollow piston rod. The rod extension further includes a rod section having at least one spline function, which spline engages with a corresponding spline function of the regulator. The corresponding spline functions of the rod extension and the regulator include at least one radial projection, which is located in a radial recess of a corresponding or complementary shape.

[0026] The rod extension is typically located within the cavity of the piston rod. The adjuster is typically located within the cavity of the piston rod. One of the rod extension and the adjuster includes a hollow cavity for receiving the other of the rod extension and the adjuster; or vice versa. In this way, an axially and radially overlapping arrangement of the rod extension and the adjuster can be provided, thus enabling a permanent torque-resistant engagement and allowing axial longitudinal displacement relative to each other.

[0027] For example, at least one of the rod extension and the adjuster includes a radial protrusion that is located within a corresponding or complementary radial recess of the other of the rod extension and the adjuster. At least one of the corresponding spline functions of the adjuster and the rod extension includes a longitudinal extension that is greater than the longitudinal displacement path of the driver between at least an initial or idle state and an operating state. In this way, when the driver is longitudinally moved for dosage setting and / or dispensing, the rod extension and the adjuster remain in spline engagement even when the adjuster undergoes longitudinal displacement.

[0028] Typically, the spline function of the rod extension is provided at the proximal end of the rod extension, and the threaded section is located at the distal end of the rod extension. The cross-section of the rod section can include a smaller diameter than the threaded section of the rod extension. The difference in diameter between the threaded section and the rod section can correspond to the radial thickness of the distal section of the adjuster. In this way, at least the distal section of the adjuster can be arranged to radially overlap the rod section within the hollow piston rod. Both the rod extension and the adjuster can be axially or longitudinally guided within the hollow piston rod by the hollow piston rod. The piston rod itself can be longitudinally or axially guided by an internal thread or threaded insert located within the housing of the injection device.

[0029] According to a further example, the regulator is rotatable relative to the piston rod when an adjustment torque exceeding a predetermined holding torque is applied to the regulator. The holding torque is greater than the drive torque required to displace the piston rod in the distal direction during dosing of the dose. During the adjustment operation, for example, before, during, or after setting of the dose, the piston rod is also locked against rotation relative to the housing by a screw engagement between the piston rod and the driver when the driver is at least temporarily axially fixed relative to the housing. Then, an adjustment torque in a first direction or a second direction can be applied to the regulator. Typically, the regulator can be rotated clockwise or counterclockwise relative to the driver or the housing to adjust to increase or decrease the fixed dose, respectively.

[0030] For the purpose of dose dosing, under normal operating conditions, the drive torque applied to the piston rod typically does not exceed the holding torque. The rotational engagement between the piston rod and the rod extension is torque-limited by a predetermined holding torque. This prevents rotation of the rod extension relative to the piston rod during dose dosing or dose expulsion procedures. To adjust the size of the fixed dose, a torque exceeding the predetermined holding torque must be applied to the regulator to overcome the rotational engagement between the piston rod and the rod extension.

[0031] According to a further example, at least one of a frictional engagement and a ratchet engagement is provided between the regulator and the piston rod. The mutual mechanical engagement between the regulator and the piston rod defines a predetermined holding torque. The regulator is permanently non-rotatably engaged with the rod extension, and the rod extension is screw-engaged with the piston rod. To correct the overall axial extension of the rod assembly, the regulator must be rotated relative to the piston rod. At least one of the ratchet engagement and the frictional engagement between the regulator and the piston rod can effectively prevent self-acting or automatic length adjustment of the rod assembly.

[0032] The overall length of the rod assembly can be fixed by at least one of a ratchet engagement and a friction engagement between the regulator and the piston rod. The overall length of the rod assembly can only be modified when an adjustment torque greater than the holding torque is applied to the regulator on the piston rod. This provides an additional safety feature to prevent unintended modifications to the predetermined and fixed size of the dose.

[0033] In a further example, an intermediate piece is provided positioned between the rod extension and the regulator. The intermediate piece is non-rotatably locked to the rod extension and the regulator. The intermediate piece allows and supports the longitudinal displacement of the regulator relative to the rod extension. The intermediate piece can further provide a dedicated frictional engagement and / or ratchet engagement with the piston rod.

[0034] The intermediate piece can be spline-engaged to at least one of the regulator and the rod extension. The intermediate piece can be spline-engaged to both, i.e., the rod extension and the regulator.

[0035] In a further example, the intermediate piece slides with at least one of the rod extension and the regulator. The intermediate piece can slide with both the rod extension and the regulator. In any case, the intermediate piece is configured to transmit angular momentum or torque from the regulator to the rod extension.

[0036] In further examples, the intermediate piece engages with the piston rod in a rotational ratchet or frictional manner. For this purpose, the intermediate piece typically includes at least one ratchet function, the at least one of which ratchet engages with a ratchet function of a corresponding shape on the piston rod. When frictional engaging, the intermediate piece includes at least one or more friction surfaces, the friction surfaces specifically and distinctly frictionally engage with the corresponding friction surfaces on the piston rod. Typically, the ratchet function or friction surface of the intermediate piece faces radially outward, while the ratchet function or friction surface of a corresponding shape on the hollow piston rod faces radially inward.

[0037] In one example, the intermediate piece can be fixed axially to the piston rod. The intermediate piece can be slidably engaged with the regulator and slidably engaged with the rod extension. The intermediate piece can be spline-engaged with the rod extension. The intermediate piece can be slidably and spline-engaged with the regulator while remaining axially fixed to the piston rod. The intermediate piece can be immobilely locked with the rod extension and further immobilely locked with the regulator. The intermediate piece can be immobilely coupled with the rod extension and further immobilely coupled with the regulator. The rotation of the regulator relative to the piston rod results in the rotation of each intermediate piece, and further the rotation of each rod extension relative to the piston rod. The ratchet engagement and / or friction engagement between the intermediate piece and the piston rod prevents automatic or self-acting rotation, and thus longitudinal displacement, of at least one of the regulator and rod extension relative to the piston rod.

[0038] The intermediate piece may include a sleeve. The intermediate piece may include a hollow sleeve. The distal end of the intermediate piece may be spline-engaged to the rod extension, particularly to the rod section located proximal to the rod extension. The proximal end or proximal section of the intermediate piece may be located within the hollow portion of the regulator. The regulator may also include a hollow sleeve surrounding the proximal section of the intermediate piece. The radially overlapping portions of the rod extension and the intermediate piece may be spline-engaged. The radially overlapping portions of the intermediate piece and the regulator may also be spline-engaged.

[0039] Typically, the distal end of an intermediate piece projecting distally from the distal end of the regulator can be ratcheted or frictionally engaged with the piston rod.

[0040] In a further example, the regulator includes a distal section and a proximal section. The distal section is operably engaged with the rod extension. The distal section may be spline-engaged with the rod extension, for example, by an intermediate piece. The proximal section of the regulator is non-rotatably supported within the driver. The proximal section or proximal end of the regulator may extend axially through the driver. In this way, the proximal section is accessible from outside the driver and also from outside the housing of the injection device.

[0041] In a further example, the injection device includes a button axially engaged or coupled to a driver. The proximal end of the regulator is located within a receptacle on the proximal end face of the button. The button and driver can be integrally formed. Thus, the button can be a part of the driver. Typically, the button forms the proximal end of the driver or is coupled to the proximal end of the driver. The button is operable by the user. The button is displaceable proximally for preparing the injection device and / or setting the dose. The button is displaceable distally for dispensing or discharging a dose of medication.

[0042] The button slides into the injection device, either directly or indirectly through the sliding engagement of the driver with the housing. By positioning the proximal end of the regulator within the receptacle of the proximal end face of the button, the proximal end of the regulator remains accessible to and accessible to the user of the injection device. The proximal end of the regulator can be recessed relative to the proximal end face of the button. In this way, the proximal end of the regulator does not protrude from the proximal end face of the button. The proximal end of the regulator does not affect or interfere with the normal operation of the injection device, for example, when the user applies a distal driving motion to the button or driver using their thumb.

[0043] In another example, the adjuster includes a longitudinally extending sleeve section and a head. The head is radially wider than the sleeve section. The head is located at the proximal end of the sleeve section. The head further forms the proximal end of the adjuster. The radially widening head allows the adjuster to be axially fixed to a button and / or driver. The radially widening head of the adjuster can be axially confined within the driver and button assembly. In this way, the adjuster can be axially fixed to the driver and button assembly. The sleeve section of the adjuster extends distally from the head. The sleeve section may include at least one spline function that is non-rotatably locked to at least one of an intermediate piece and a rod extension.

[0044] In a further example, the head includes a proximal end face located distal to the proximal end face of the button. In other words, the proximal end face of the head is recessed compared to the proximal end face of the button. The proximal end face of the head does not protrude from the button. Furthermore, the proximal end face of the head may be provided with a longitudinal slot or slit. The longitudinal slot or slit may provide a screw slot for shape-fit engagement with a screwdriver or screwing tool. Rotation of the regulator relative to the piston rod may require the use of a dedicated screwdriver or screwing tool. It is conceivable that only authorized persons, such as caregivers, would be equipped with a dedicated screwdriver or screwing tool. In this way, when the filled injection device is handed to the patient, the caregiver or authorized person can adjust the dose size. The screw slot on the proximal end face of the regulator further provides a kind of safety feature, thus preventing unauthorized operation of the regulator and / or injection device.

[0045] In a further example, the injection device is equipped with a cartridge housed within a housing. The cartridge typically includes a tubular or cylindrical body. The body may include a vitreous body. The distal end of the body is sealed by a perforated seal. The proximal end of the body is typically sealed by a stopper that is displaceable distally by the piston rod of the injection device.

[0046] In a further example, the regulator includes a sleeve section, and the rod extension includes a rod section, where both the rod section and the sleeve section are located within a hollow cavity of the piston rod. Typically, the sleeve section includes a hollow cavity, and the rod section of the rod extension is located within a hollow cavity. The rod section and the sleeve section can be locked together so as not to rotate, but can be supported by allowing longitudinal sliding displacement of the rod section relative to the sleeve section. It is also conceivable that the rod section includes a hollow cavity, and the sleeve section of the regulator is located within a hollow cavity and locked together so as not to rotate.

[0047] In this context, the term "distal" or "distal end" refers to the end of an injection device that faces the injection site in a human or animal. The term "proximal" or "proximal end" refers to the end of an injection device that is furthest from the injection site in a human or animal.

[0048] The terms "drug" or "pharmaceutical," as used herein, mean a pharmaceutical preparation comprising at least one pharmaceutically active compound. In one embodiment, the pharmaceutically active compound has a molecular weight up to 1500 Da and / or is a peptide, protein, polysaccharide, vaccine, DNA, RNA, enzyme, antibody or its fragment, hormone, or oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compounds. In further embodiments, the pharmaceutically active compound is useful in the treatment and / or prevention of diabetes or complications associated with diabetes, such as diabetic retinopathy, thromboembolic disorders, such as deep vein thromboembolism or pulmonary thromboembolism, acute coronary syndrome (ACS), anguina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis. In further embodiments, the pharmaceutically active compound comprises at least one peptide for the treatment and / or prevention of diabetes or complications associated with diabetes, such as diabetic retinopathy. In further embodiments, the pharmaceutically active compound comprises at least one human insulin or human insulin analog or derivative, glucagon-like peptide (GLP-1) or its analog or derivative, or exendin-3 or exendin-4 or exendin-3 or exendin-4 analog or derivative.

[0049] Insulin analogs include, for example, Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin in which proline at position B28 may be replaced with Asp, Lys, Leu, Val or Ala and Lys at position B29 may be replaced with Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

[0050] Insulin derivatives include, for example, B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoylLysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29Lys These are B30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin; B29-N-(N-litocoryl-γ-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin; and B29-N-(ω-carboxyheptadecanoyl) human insulin.

[0051] Exendin-4 refers to the peptide exendin-4(1-39) with the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

[0052] Exendin-4 derivatives include, for example, the compounds listed below: H-(Lys)4-desPro36,desPro37 Exendin-4(1-39)-NH2, H-(Lys)5-desPro36,desPro37 Exendin-4(1-39)-NH2, desPro36 Exenzine-4 (1-39), desPro36[Asp28] Exendin-4 (1-39), desPro36[IsoAsp28] Exendin-4 (1-39), desPro36[Met(O)14,Asp28]Exendin-4(1-39), desPro36[Met(O)14,IsoAsp28]Exendin-4(1-39), desPro36[Trp(O2)25,Asp28]Exendin-4(1-39), desPro36[Trp(O2)25,IsoAsp28]Exendin-4(1-39), desPro36[Met(O)14 Trp(O2)25,Asp28]Exendin-4(1-39), desPro36[Met(O)14 Trp(O2)25,IsoAsp28]exendine-4(1-39); or desPro36[Asp28] Exendin-4 (1-39), desPro36[IsoAsp28] Exendin-4 (1-39), desPro36[Met(O)14,Asp28]Exendin-4(1-39), desPro36[Met(O)14,IsoAsp28]Exendin-4(1-39), desPro36[Trp(O2)25,Asp28]Exendin-4(1-39), desPro36[Trp(O2)25,IsoAsp28]Exendin-4(1-39), desPro36[Met(O)14 Trp(O2)25,Asp28]Exendin-4(1-39), desPro36[Met(O)14 Trp(O2)25,IsoAsp28]Exendin-4(1-39), (Here, the group -Lys6-NH2 may be attached to the C-terminus of the exendin-4 derivative);

[0053] Alternatively, exendin-4 derivatives with the following sequence: desPro36 Exendin-4(1-39)-Lys6-NH2(AVE0010), H-(Lys)6-desPro36[Asp28]exendine-4(1-39)-Lys6-NH2, desAsp28Pro36,Pro37,Pro38 Exendin-4(1-39)-NH2, H-(Lys)6-desPro36,Pro38[Asp28]exendine-4(1-39)-NH2, H-Asn-(Glu)5desPro36,Pro37,Pro38[Asp28]exendin-4(1-39)-NH2, desPro36,Pro37,Pro38[Asp28]exendine-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Asp28]exendine-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5-desPro36,Pro37,Pro38[Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36[Trp(O2)25,Asp28]exendin-4(1-39)-Lys6-NH2, H-desAsp28Pro36,Pro37,Pro38[Trp(O2)25]exendine-4(1-39)-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Trp(O2)25,Asp28]exendin-4(1-39)-NH2, H-Asn-(Glu)5-desPro36,Pro37,Pro38[Trp(O2)25,Asp28]exendin-4(1-39)-NH2, desPro36,Pro37,Pro38[Trp(O2)25,Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Trp(O2)25,Asp28]exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5-desPro36,Pro37,Pro38[Trp(O2)25,Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36[Met(O)14,Asp28]exendine-4(1-39)-Lys6-NH2, desMet(O)14 Asp28 Pro36,Pro37,Pro38 Exendin-4(1-39)-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Met(O)14,Asp28]exendine-4(1-39)-NH2, H-Asn-(Glu)5-desPro36,Pro37,Pro38[Met(O)14,Asp28]exendin-4(1-39)-NH2, desPro36,Pro37,Pro38[Met(O)14,Asp28]exendine-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Met(O)14,Asp28]exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5 desPro36,Pro37,Pro38[Met(O)14,Asp28]exendin-4(1-39)-(Lys)6-NH2, H-Lys6-desPro36[Met(O)14,Trp(O2)25,Asp28]exendin-4(1-39)-Lys6-NH2, H-desAsp28Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25]exendine-4(1-39)-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Met(O)14,Asp28]exendine-4(1-39)-NH2, H-Asn-(Glu)5-desPro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exendin-4(1-39)-NH2, desPro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exendin-4(S1-39)-(Lys)6-NH2, H-Asn-(Glu)5-desPro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exendin-4(1-39)-(Lys)6-NH2; or a pharmaceutically acceptable salt or solvate of any one of the aforementioned exendin-4 derivatives. Selected from.

[0054] Hormones include, for example, pituitary hormones or hypothalamic hormones or regulatory active peptides and their antagonists, as listed in Chapter 50 of the Rote Liste, 2008 edition, such as gonadotropins (follitropin, lutropin, choriongonadotropin, menotropin), somatropin (somatropin), desmopressin, terlipressin, gonadrelin, triptorelin, leuprorelin, buserelin, nafarelin, and goserelin.

[0055] Polysaccharides include, for example, glucosaminoglycans, hyaluronic acid, heparin, low molecular weight heparin or very low molecular weight heparin or their derivatives, or the aforementioned polysaccharides in sulfated forms, such as polysulfated forms, and / or pharmaceutically acceptable salts thereof. An example of a pharmaceutically acceptable salt of polysulfated low molecular weight heparin is enoxaparin sodium.

[0056] Antibodies are globular plasma proteins (approximately 150 kDa) that share a common basic structure, also known as immunoglobulins. They are glycoproteins because they have sugar chains attached to amino acid residues. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only Ig units), and secreted antibodies can also be dimers with two Ig units, such as IgA, tetramers with four Ig units, such as IgM in bony fish, or pentamers with five Ig units, such as IgM in mammals.

[0057] Ig monomers are Y-shaped molecules consisting of four polypeptide chains: two identical heavy chains and two identical light chains linked by disulfide bonds between cysteine ​​residues. Each heavy chain is approximately 440 amino acids long, and each light chain is approximately 220 amino acids long. Both the heavy and light chains contain intrachain disulfide bonds that stabilize their folded structure. Each chain consists of a structural domain called the Ig domain. These domains contain 70 to 110 amino acids and are classified into different categories (e.g., variable, i.e., V, and constant, i.e., C) according to their size and function. They possess a characteristic immunoglobulin folding structure in which two β-sheets create a "sandwich" shape in which they are held together by interactions between conserved cysteine ​​and other charged amino acids.

[0058] There are five types of mammalian Ig heavy chains, represented as α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of the antibody, and these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.

[0059] The different heavy chains differ in size and composition, with α and γ containing approximately 450 amino acids, δ containing approximately 500 amino acids, and μ and ε containing approximately 550 amino acids. Each heavy chain has two regions, namely the constant region (C H ) and variable region (V H ) has the following characteristics. In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α, and δ have a constant region consisting of three tandem Ig domains and a hinge region to add flexibility, while heavy chains μ and ε have a constant region consisting of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. Each heavy chain's variable region is approximately 110 amino acids long and consists of a single Ig domain.

[0060] In mammals, there are two types of immunoglobulin light chains, represented as λ and κ. Each light chain has two consecutive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211–217 amino acids. Each antibody always contains two identical light chains, and for each mammalian antibody, only one type of light chain exists: κ or λ.

[0061] While the general structure of all antibodies is quite similar, the unique properties of a given antibody are determined by its variable (V) region, as detailed above. More specifically, three variable loops for each light chain (VL) and three for each heavy chain (VH) are involved in antigen binding, i.e., its antigen specificity. These loops are called complementarity-determining regions (CDRs). Since CDRs from both the VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and light chains, not either one alone, that determines the final antigen specificity.

[0062] An "antibody fragment" contains at least one antigen-binding fragment as defined above and exhibits essentially the same function and specificity as the complete antibody from which the fragment is derived. Limited protein digestion with papain cleaves the Ig prototype into three fragments. Two identical amino-terminal fragments, each containing one complete light chain and approximately half a heavy chain, are the antigen-binding fragment (Fab). A third fragment, of similar size but containing carboxyl terminals at half the position of both heavy chains with interchain disulfide bonds, is the crystallizable fragment (Fc). Fc contains carbohydrates, complementary binding sites, and an FcR site. Limited pepsin digestion yields a single F(ab')2 fragment containing both the Fab piece and a hinge region with an interHH chain disulfide bond. F(ab')2 is divalent for antigen binding. The disulfide bond of F(ab')2 can be cleaved to obtain Fab'. Furthermore, the variable regions of the heavy and light chains can be fused to form a single-chain variable fragment (scFv).

[0063] Pharmaceutically acceptable salts include, for example, acid addition salts and basic salts. Acid addition salts are, for example, HCl or HBr salts. Basic salts are, for example, salts having an alkali or alkaline earth cation selected from, for example, Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), (wherein R1-R4 independently mean: hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, optionally substituted C6-C10 aryl groups, or optionally substituted C6-C10 heteroaryl groups). Further examples of pharmaceutically acceptable salts are listed in Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, Pa., USA, 1985 and the Encyclopedia of Pharmaceutical Technology.

[0064] A pharmaceutically acceptable solvate is, for example, a hydrate.

[0065] It will become further apparent to those skilled in the art that various modifications and changes can be made to the present invention without departing from the true scope of this disclosure. Furthermore, it should be noted that any reference numbers used in the appended claims should not be construed as limiting the scope of injection devices.

[0066] Numerous examples of containers and injection devices are described in more detail below with reference to the drawings. [Brief explanation of the drawing]

[0067] [Figure 1] This figure shows an example of an injection device. [Figure 2] This figure schematically shows the proximal portion of the injection device shown in Figure 1. [Figure 3] This is a diagram showing the piston rod of an injection device. [Figure 4] Figure 3 is an enlarged view of the piston rod. [Figure 5] This is a schematic cross-sectional view of an example of an injection device. [Figure 6] This is a schematic cross-sectional view of another example of an injection device. [Figure 7] This is a schematic diagram showing the proximal end face of an injection device. [Figure 8] This figure schematically shows a cross-section cut along AA in Figure 5. [Figure 9] This figure schematically shows a cross-section cut along BB as shown in Figure 6. [Figure 10] This is a schematic diagram showing a cross-section cut along CC as shown in Figure 6. [Modes for carrying out the invention]

[0068] Figure 1 shows a cutaway view of an injection device 30 configured as a pen syringe, including a drive mechanism 32. The drive mechanism 32 is located within a body 1 or housing, the body 1 having a distal end 2 and a proximal end 3. A piston rod 5 is positioned along the axis 4 of the device. The threads 6 of the piston rod 5 are connected to the drive function of a piston rod nut 7 that engages with the threads 6, guiding the helical motion of the piston rod 5 relative to the piston rod nut 7. In further embodiments, the threads and drive function can be reversed, so that the piston rod has a separate drive function and the piston rod nut has a helical thread. The piston rod nut 7 is non-rotatably locked to the body 1.

[0069] Examples in Figures 1 and 2 include a driver 8, which the user can operate by a button 9 located at the proximal end 3 and protruding from the body 1. The driver 8 is connected to or engaged with a piston rod 5. This is achieved by the threads 18 of the driver 8 and the flexible guide function 15 of the piston rod 5. The driver 8 can, in particular, be an essentially cylindrical drive sleeve, with the axis of the drive sleeve positioned parallel to the axis 4 of the device. The piston rod 5 can be positioned to enter the driver 8.

[0070] A removable and attachable component 11 of the main body 1 can be provided as a cartridge holder. When this component 11 is removed from the rest of the main body 1, a cartridge 12 can be inserted. When the component 11 is attached to the main body 1, the piston rod 5 contacts a piston 13 provided for discharging the drug from the cartridge 12. To prevent any damage that may be caused by the relative motion between the piston rod 5 and the piston 13, a support 14 can be placed between the piston rod 5 and the piston 13. The piston rod 5 functions as a lead screw for advancing the piston 13 distally 22. The distal end of the cartridge 12 is provided with a perforated seal 34 configured to be perforated by a double-ended needle, which is configured to be attached to the attachable component 11 or the distal end of the cartridge holder. The vitreous body 33 is typically translucent to allow visual inspection of the drug located inside the cartridge 12.

[0071] During delivery, the piston rod 5 is moved spirally distally 22 relative to the main body 1. The piston rod 5 is guided by a piston rod nut 7 engaged with the threads 6 of the piston rod 5. To enable the dose setting operation, a stopper function, described later, is provided within the threads 6 of the piston rod 5, allowing a fixed dose to be pre-set by the dose setting operation. For this purpose, the driver 8 is pulled proximal 23 relative to the main body 1 and the piston rod 5. The driver 8 is connected to the piston rod 5. In the embodiments shown in Figures 1 and 2, this connection is achieved by the threads 18 of the driver 8 and the flexible guide function 15 of the piston rod 5.

[0072] During the dose setting operation, the piston rod 5 must not be moved. Therefore, during the setting operation, the engagement between the driver 8 and the piston rod 5 is temporarily released. This can be achieved by the flexible guide function 15 deforming to overcome the threads 18 of the driver 8. Thus, despite the engagement between the driver 8 and the piston rod 5, the piston rod 5 can be moved without rotating the driver 8 while remaining stationary relative to the body. Overcoming the engagement between the driver 8 and the piston rod 5 is facilitated by the flexible guide function 15, which can be bent toward the central axis 4. Rotation of the driver 8 relative to the body 1 can be prevented by the guide function 10, which can be, for example, a protruding element of the body 1 that engages with an axial groove on the outer surface of the driver 8.

[0073] After moving the driver 8 by a distance corresponding to the pitch of the screw threads 18 of the driver 8, the flexible guide function 15 of the piston rod 5 re-engages with the screw threads 18 of the driver 8, and the user can advance the piston rod 5 by pushing the driver 8 distally 22. This method of disengaging and re-engaging the piston rod 5 with respect to the driver 8 relies entirely on the fact that the piston rod 5 remains substantially stationary during the setting operation. If the piston rod 5 rotates or moves axially during setting, the driver 8 is very likely to fail to re-engage with the piston rod 5 accurately, and thus should result in a dosage error. Therefore, the piston rod nut 7 that guides the helical motion of the piston rod 5 relative to the body 1 is locked to the body 1 so as not to rotate, at least during the drug delivery operation, and furthermore, the piston rod 5 is equipped with a stopper function that interferes with the rotation of the piston rod 5, and thus its rotation is prevented at the position of the piston rod 5 obtained after drug delivery and before setting a new dose.

[0074] Therefore, the rotation of the piston rod 5 relative to the piston rod nut 7 is locked, preventing the piston rod nut 7 from rotating relative to the body 1. Thus, when the driver 8 is pulled in the proximal direction 23, the relative linear motion between the driver 8 and the piston rod 5 overcomes the engagement between the driver 8 and the stationary piston rod 5, and thus the engagement between the driver 8 and the piston rod 5 is released. Thus, the locking mechanism is positioned at least on the distal side wall of the thread 6 of the piston rod 5, and the thread 6 is smooth on its proximal side wall and can form a helix. When the driver 8 is pushed distally, the guiding means of the piston rod nut 7 that engages with the thread 6 of the piston rod 5 remains in contact with the smooth proximal side wall of the thread 6, and thus the smooth helical motion of the piston rod 5 sliding through the opening of the piston rod nut 7 is enabled. Thus, the locking mechanism does not interfere with the relative motion of the piston rod 5 relative to the piston rod nut 7 during the dispensing operation.

[0075] The stopper function can be provided in particular by recesses in the helical grooves that form the threads 6 of the piston rod 5. These recesses may have contact surfaces positioned transversely to the shaft 4, and the contact surfaces obstruct the smooth helix of the corresponding side walls of the grooves that form the threads 6. The contact surfaces may be particularly flat portions, which are essentially perpendicular to the shaft 4 or have at least zero helix angle, but may include a radial rake angle. The drive function of the piston rod nut 7 can be formed to enter the recesses and stop at the contact surfaces. When the drive function of the piston rod nut 7 contacts one of the flat portions, the flat portion is oriented approximately perpendicular to the shaft 4, thereby stopping the guidance of the helical motion of the piston rod 5 relative to the body 1. It is preferable that the drive function of the piston rod nut 7 that engages with the threads 6 of the piston rod 5 and stops in the recesses consists of one or more individual drive functions and is not formed by a completely continuous helix.

[0076] The locking mechanisms are positioned such that, after the drug dose has been fully delivered and the device is ready to set the next dose, one of the locking mechanisms is ready to stop the rotation of the piston rod 5 when the driver 8 is pulled proximal. At this time, the axial load on the piston rod 5 is compensated by the drive function of the piston rod nut 7 engaging with the corresponding locking mechanism, and in particular contacting the essentially flat portion of the corresponding recess. This acts to lock the rotation of the piston rod 5 rather than rotate it, since the piston rod nut 7 is immobilely locked to the body 1, at least during the dose-setting and dispensing operation. Essentially, the flat surface of the thread 6 is designed to prevent reverse drive of the piston rod 5 during the setting operation, thereby limiting the distal movement of the piston rod 5.

[0077] Figure 3 shows an enlarged perspective view of one embodiment of the piston rod 5. The piston rod 5 includes a thread 6 and may include at least one further thread 16. If the further thread 16 is provided, the thread 6 and the further thread 16 have the same pitch and are intertwined. This means that the piston rod 5 has two coaxial helical functions having separate starting points at or near the distal end of the piston rod 5. The thread 18 of the driver 8 may also have two separate, intertwined coaxial helical functions. The shape of the flexible guide function 15 at the proximal end of the piston rod 5 is applied to the thread 18 of the driver 8. The flexible guide function 15 may, in particular, include two coaxial helical male thread functions provided to engage with helical grooves that can form the thread 18 of the driver 8. If two coaxial helical functions of the thread 18 are present, there may be two separate members of the flexible guide function 15, each of which engages with one of the helical functions. The flexible guide function 15 can be deformed, and therefore can be disengaged from the screw threads 18 of the driver 8. This makes it possible for the driver 8 to temporarily overcome the connection between the piston rod 5 and the driver 8 when pulled in the proximal direction 23.

[0078] The piston rod 5 is equipped with regularly spaced, continuous spike or spline functions 25. In the example shown in Figure 3, three rows 20 of spline functions 25 are arranged parallel to the shaft 4. The spline functions 25 are primarily located within the area of ​​the threads 6, 16 at the distal end of the piston rod 5. The rows 20 are spaced 120° apart from each other around the circumference of the piston rod 5. Alternatively, this spacing may vary, or another number of rows 20 of spline functions 25 may be located. The spline functions 25 are arranged to interact with a retaining function 19 on the inner surface of the driver 8 facing the piston rod 5.

[0079] The retaining function 19 can be, for example, a single protruding element, or it can instead include two or more separate elements. The retaining function 19 helps prevent the piston rod 5 from rotating when a dose is being set. Each row 20 of the spline function 25 can include a series of positive protrusions located between the helical grooves of the threads 6, 16. As a result, gaps exist between the spline functions 25. The gaps between the spline functions 25 are every other, and are large enough to allow the corresponding retaining function 19 on the inner surface of the driver 8 to pass through during dose dispensing. The spline function 25 can also perform a further function of extending the contact line between the piston rod 5 and the piston rod nut 7 at the transition between the helical thread sections and the retaining functions 17 of the threads 6, 16. This reduces the risk of deformation of the piston rod nut 7 in particular in this area which is subjected to a large dispensing load.

[0080] Figure 4 shows a magnified detail view of the distal end of the piston rod 5. In this embodiment, the piston rod 5 includes thread 6 and further thread 16, which are intertwined and have separate starting points ("double" threads). The piston rod nut 7 engages with the threads 6, 16 of the piston rod 5. The retaining function 17 of the threads 6, 16 can be positioned such that its proximal face extends continuously to at least one spline function 25 of the row 20 of spline functions 25, as can be seen in Figure 4. The threads 6, 16 can be positioned at distances from each other corresponding to different gaps between subsequent spline functions 25. Thus, the spline functions 25 can be positioned adjacent to the grooves of the threads 6, 16, and in particular can be integrally formed with the retaining function 17 of the threads 6, 16. Alternatively, only one thread 6 or three or more threads can be provided on the piston rod 5. In this case, the spline functions 25 are arranged along the row 20, and the gaps between successive spline functions 25 alternately increase and decrease regardless of the position of the helical grooves of the screw thread.

[0081] The larger gap is provided to allow the locking mechanism 19 of the driver 8 to pass through while the piston rod 5 is helically moved relative to the driver 8 during drug dispensing. The smaller gap is small enough to prevent the locking mechanism 19 of the driver 8 from passing through when the driver 8 is pulled proximal to set the dose. In this case, the spline mechanism 25 slides along the locking mechanism 19 of the driver 8. This helps to prevent the piston rod 5 from rotating relative to the driver 8, which is immobilely locked to the body 1 and the piston rod nut 7. Thus, the piston rod 5 does not rotate relative to either the body 1 or the piston rod nut 7.

[0082] Figure 2 shows the arrangement of the piston rod 5 and the driver 8, in this embodiment the driver 8 is a drive sleeve surrounding the piston rod 5. The distal end of the piston rod 5 protrudes from the driver 8. The retaining function 19 is located on the inner wall of the driver 8 and can be, for example, one protruding element, two separate protruding elements, or a plurality of separate protruding elements. Preferably the retaining function 19 is an integral part of the driver 8 and is formed within the inner wall. The axial dimension of each element of the retaining function 19 is small enough to allow the element to pass between two adjacent spline functions 25 if the gap between these spline functions 25 is large. In the stationary position occupied by the driver 8 relative to the piston rod 5 after the dose has been administered, the retaining function 19 is located near the two spline functions 25 separated by a small gap.

[0083] The following setting should be established so that when the driver 8 is pulled proximal to the body 1, the locking function 17 of the thread 6, which engages with the driving function of the piston rod nut 7, prevents the rotation of the piston rod 5. Thus, the locking function 19 of the driver 8 moves axially to a position adjacent to the spline function 25, contacts the spline function 25, and slides along the spline function 25, causing the driver 8 to move further proximal to the piston rod 5. The spline function 25 prevents the locking function 19 of the driver 8 from moving transversely to the shaft 4 around the circumference of the piston rod 5, and thus prevents the rotation of the piston rod 5 relative to the driver 8. Because the gaps between the spline functions 25 are small and the locking function 19 cannot pass between the spline functions 25, when the locking function 19 has passed the first spline function 25, it similarly slides axially along the next spline function 25 in the same row 20. After the dose is set, when the driver 8 is pushed distally and the helical motion of the piston rod 5 is generated, the locking function 19 of the driver 8 moves from its position into the large gap that exists between adjacent spline functions 25. It is preferable to arrange multiple spline functions 25 along the piston rod 5 in order to always provide adjacent spline functions 25 that serve the above purpose, regardless of the position of the piston rod 5 which is advanced distally each time a dose is administered.

[0084] The design of the spline function 25 may deviate from the shape shown in the figure as an example. The spline function 25 is positioned according to the operation of the driver 8, for the purpose of either preventing rotation of the piston rod 5 or enabling the helical motion of the piston rod 5. The embodiment shown in the figure has the advantage that the arrangement of the spline function is applied to the position of the helical groove, which facilitates the manufacturing of the device components.

[0085] Figures 5 and 7 show examples of injection devices equipped with dose size adjusters. As an example, the drive mechanism 32 of injection device 30 is based on the same operating principle as described above in relation to Figures 1 to 4. The dose size adjusters described herein can also be applied to other drive mechanisms of fixed-dose devices.

[0086] As shown in Figure 5, the piston rod 5 is hollow and includes a hollow sleeve. The piston rod 5 includes a hollow cavity 44, within which a rod extension 50 is positioned. The rod extension 50 and the piston rod 5 form or constitute a rod assembly 58. The rod extension 50 protrudes from the distal end of the piston rod 5. The rod extension 50 is axially displaceable relative to the piston rod 5. In this example, the rod extension 50 and the piston rod 5 are screw-engaged. Thus, the rod extension 50 includes an external thread 51, which engages with the internal thread 26 of the piston rod 5.

[0087] The rod assembly 58 can be made of a length of variable in the longitudinal direction by the screw engagement of the rod extension 50 and the piston rod 5. The rod extension 50 includes a spindle 52 projecting distally 22. The spindle 52 forms or constitutes the distal end of the rod extension 50. The spindle 52 non-rotatably supports the support 14. The support 14 is not specifically shown in Figures 5 and 6. The rod extension 50 is displaceable longitudinally relative to the piston rod 5 via rotation relative to the piston rod 5. For this purpose, the rod extension 50 is operably engaged with or operably engageable with the regulator 70. The regulator 70 is located on or within the driver 8.

[0088] The regulator 70 includes a distal section 71 and a proximal section 73. The proximal section 73 is attached to a button 9 and / or a driver 8. The button 9 and the driver 8 can be integrally molded. The proximal section 73 includes a radially expanding head 75 positioned within the receptacle 40 of the button 9. The button 40 includes a through-hole 41 extending distally 22 from the receptacle 40. The through-hole 41 extends axially through a radially narrowing neck portion 42 of the button 9. In particular, the proximal end face of the neck portion 42 of the button 9 engages axially with the distal face of the radially expanding head 75 of the regulator 70. The regulator also includes a sleeve section 76 extending distally 22. The sleeve section 76 extends distally from the radially expanding head 75. The outer diameter of the sleeve section 76 is smaller than the outer diameter of the head 75. The sleeve section 76 extends through the through-hole 41. The radially expanding head is restricted axially within the receptacle 40 of the button 9. In this way, the regulator 70 is axially connected to or engaged with the button 9.

[0089] The regulator 70 is non-rotatably engaged or locked to the rod extension 50. As shown in Figure 5, the sleeve section 76 of the regulator 70 radially overlaps the rod section 56 of the rod extension 50. The sleeve section 76 can form the distal section 71 of the regulator 70 and can overlap the distal section 71. The rod section 56 forms the proximal portion or proximal end of the rod extension 50. Both the rod section 56 and the sleeve section 76 are located within the hollow piston rod 5. The sleeve section 76 and the rod section 56 are spline-engaged. This spline engagement forms a rotational mesh between the regulator 70 and the rod extension 50, but allows for longitudinal sliding displacement of the regulator 70 relative to the rod extension 50. In this way, the regulator 70 slides freely in the proximal direction 23 relative to the rod extension 50 when the dose is set and the button 9 is pulled in the proximal direction 23.

[0090] The spline engagement between the rod extension 50 and the regulator 70 is formed by corresponding spline functions 54 and 74 on the rod extension 50 and the regulator 70, respectively. Here, at least one of the spline functions 54 and 74 includes a radial projection which slides into a radial recess of a corresponding or complementary shape to that of the other spline function 54 or spline function 74. In this example, as shown in Figure 8, the rod extension 50 includes a spline function 54 projecting radially outward, which rotates into a spline function 74 of a corresponding shape on the regulator 70. The spline function 54 includes a radially outward projection on the outer surface of the rod extension 50, particularly on the outward-facing portion of the rod section 56. The spline function 74 is a radial recess provided on the inward-facing side wall section of the sleeve-shaped regulator 70.

[0091] The spline function 74 typically includes an elongated groove on the inner surface of the sleeve section 76. When the regulator 70 is subjected to longitudinal displacement relative to the body 1 and therefore to the housing, the corresponding spline functions 54, 74 remain engaged. This ensures that torque transmission from the regulator 70 to the rod extension 50 is effective regardless of the axial position of the regulator 70, i.e., for each axial position of the regulator 70. The dose size can be adjusted before or after dose setting, and of course before dose dispensing or dispensing.

[0092] As shown in Figure 5, the rod section 56 of the rod extension is located within the cavity 72 of the regulator 70, and therefore within the cavity 72 of the sleeve section 76. In the idle or initial configuration shown in Figure 5, the regulator 70 can be rotated, for example, by a screwdriver or screwing tool, so as to engage with a recess 78 formed as a screw slot in the proximal end face 77 of the regulator 70. The proximal end face 77 of the regulator 70 can be located distal to the proximal end face 43 of the button 9. In this way, the regulator 70 can be rotated and actuated exclusively by a suitable screwing tool. This prevents unauthorized adjustment of the dosage.

[0093] To adjust the dosage, the regulator 70 is rotated clockwise or counterclockwise relative to the button 9. Clockwise or counterclockwise rotation results in rotation of the rod extension 50 relative to the piston rod 5, respectively. In this example shown in Figure 7, the regulator 70 can be rotated clockwise in a first direction or a first rotational direction to increase the dosage size. The regulator 70 can be rotated counterclockwise in a second rotational direction different from the first rotational direction to decrease the dosage size. When the regulator 70 is rotated in the second rotational direction, each screwing motion of the regulator 70 is equally transmitted to the rod extension 50. Depending on the screw engagement of the rod extension 50 with the piston rod, the rod extension 50 undergoes proximal displacement relative to the piston rod 5. Here, the support portion 14 no longer contacts the plug of the cartridge 12 or the proximal surface of the piston 13.

[0094] When the regulator 70 is screwed in or rotated in a first rotational direction, for example clockwise, the rod extension 50 is displaced distally 22 relative to the piston rod 5. Here, pre-tension or pre-stress can be applied to the entire drive mechanism 32, eliminating any final mechanical play or geometric tolerance. The regulator 70 is intended to be able to rotate along the first rotational direction only to such an extent that the distal force applied to the plug or piston 13 is less than the disengagement force required to drive the piston 13 distally 22, and remains in that state.

[0095] To rotate the regulator 70 relative to the piston rod 5, at least one of a ratchet engagement and a friction engagement can be provided between the regulator 70 and the piston rod 5. The mechanical engagement between the regulator 70 and the piston rod may include a unidirectional clutch or unidirectional ratchet engagement that restricts the unidirectional rotation of the regulator 70 relative to the piston rod 5. The mechanical engagement between the regulator 70 and the piston rod may be configured to support only dose-decreasing rotation of the regulator 70, thereby preventing dose-increasing adjustment movement of the regulator 70.

[0096] In this way, patients can be offered only the possibility of decreasing the size of a fixed dose, rather than increasing the size of the dose. This prevents the risk of potential overdose.

[0097] In another example, as shown here, the mechanical engagement between the regulator 70 and the piston rod 5 is of the bidirectional type. Here, the regulator 70 can be rotated or moved relative to the piston rod 5 in either direction or rotationally. This makes it possible to increase or decrease the size of a given fixed dose.

[0098] In the example shown in Figure 5, the outer surface of the regulator 70, particularly the outer surface of the sleeve section 76, can frictionally engage with the inner surface of the piston rod 5. In this way, the regulator 70 can frictionally engage with the piston rod 5. In order to rotate the regulator 70 relative to the piston rod 5, a torque greater than a predetermined adjustment torque must be applied to the regulator 70. The adjustment torque is typically greater than the driving torque required to displace the piston rod 5 distally 22 during dose dispensing, i.e., the torque required to bias the piston 13 distally 22 relative to the body 33 of the cartridge 12. In this way, when the piston rod is subjected to rotation relative to the body 1 during the dose dispensing procedure, the rod extension 50 and the regulator 70 can remain non-rotatably locked to the piston rod 5.

[0099] Figures 6, 9, and 10 show another example of the injection device 30. The example in Figure 6 is further equipped with an intermediate piece 60. The intermediate piece 60 includes a sleeve 61 that is radially sandwiched between the sleeve section 76 of the regulator 70 and the rod section 56 of the rod extension 50. As shown in Figure 9, the intermediate piece 60 is spline-engaged to both the rod extension 50 and the regulator 70. Thus, the intermediate piece 60 includes a spline function 64 that engages with the spline function 74 of the regulator 70. The intermediate piece 60 further includes an additional spline function 66 that spline-engages with the spline function 54 of the rod extension. In this way, the regulator 70 slides freely longitudinally relative to the intermediate piece 60 while remaining non-rotatably locked to the intermediate piece 60.

[0100] Similarly, the rod extension 50 slides freely longitudinally or axially relative to the intermediate piece 60 while remaining non-rotatably locked and connected to it. The adjustment torque applied by the user to the regulator 70 can be transmitted to the rod extension 50 by the intermediate piece 60, thus resulting in a variation in the overall length of the rod assembly 58.

[0101] As is evident from Figures 6 and 10, the intermediate piece 60 permanently ratchet-engages with the piston rod 5. For this purpose, the piston rod 5 includes a ratchet function 45 on its inner wall. The ratchet function 45 includes a toothed ring extending along the inner circumference of the hollow piston rod 5. The toothed ring includes a number of teeth 47 projecting radially inward. A ratchet function 65 of the intermediate piece 60, shaped to match that of the intermediate piece 60, includes at least one tooth 67 extending radially outward, the tooth 67 ratcheting-engaging with a succession of teeth 47 of the ratchet function 45.

[0102] As shown in Figure 10, the intermediate piece 60 includes two ratchet functions 65 positioned opposite each other. The ratchet functions 65 can be located on one or more flexible arms configured to bend or deflect radially inward when the intermediate piece 60 is rotated relative to the piston rod 5. Two or more arms can be provided, positioned opposite or equidistant from each other, and these arms also have ratchet functions 65. In this way, the holding torque can be divided among the various teeth 67 of the ratchet functions 65. The ratchet engagement of the intermediate piece 60 with respect to the piston rod 5 defines the holding torque and prevents the rod extension 50 from self-actualizing or automatically rotating relative to the piston rod 5 during dose-administering procedures.

[0103] To adjust the size of the fixed dose, an adjustment torque must be applied to the adjuster 70, and therefore to the intermediate piece 60, and the adjustment torque is greater than the holding torque. Thus, the ratchet function 65 receives radially inward motion, thereby supporting and enabling clear stepwise rotation of the intermediate piece 60, and therefore to the rod extension 50, relative to the piston rod 5. For setting the dose, the aforementioned interaction of the locking functions 17, 19 and the screw engagement with the driver 8 prevent the piston rod 5 from rotating. [Explanation of Symbols]

[0104] 1 Main unit 2. Distal end 3. Proximal end 4 axes 5 Piston rod 6 threads 7 Screw nuts 8 drivers 9 buttons 10. Guidance function 11 Mountable components 12 cartridges 13 pistons 14 Bearing part 15 Flexible guidance function 16 threads 17. Fastener function 18 threads 19. Fastener function 20 columns 22 Distal direction 23 Proximal direction 25 Spline function 26 threads 30 injection devices 32 Drive mechanism 33 Torso 34 Perforated seal 35. Medications 40 receptacles 41 Through-hole 42 Neck section 43 End face 44 Cavity 45 Ratchet function 47 teeth 50 Rod extension 51 threads 52 Mandrel 54 Spline function 56 Rod Sections 58 Rod Assembly 60 Intermediate piece 61 sleeves 64 Spline Function 65 Ratchet function 66 Spline function 67 teeth 70 Regulator 71 Distal section 72 Cavity 73 Proximal Section 74 Spline function 75 heads 76 Sleeve Section 77 End face 78 recesses 79 Proximal end

Claims

1. An injection device (30) configured to deliver multiple doses of a medicament: A longitudinally extending elongated housing (1); a piston rod (5) movable in a longitudinal distal direction (22) relative to the housing (1) to apply a dosing pressure to a bung (13) of a cartridge (12) at least partially filled with an injectable medicament (35); a rod extension (50) movably disposed on or within the distal end of said piston rod (5); a driver (8) operably engaged with the piston rod (5) and movable in a longitudinal proximal direction (23) relative to the housing (1) for setting a dose and movable in a longitudinal distal direction (22) relative to the housing (1) for dispensing a dose; an adjuster (70) disposed on or within said driver (8), axially engaged with said driver (8) while being rotatable relative thereto, and operably engaged with said rod extension (50) to move said rod extension (50) longitudinally relative to said piston rod (5); When the adjuster (70) is rotated relative to the driver (8), the rotational motion is transferred to the operatively engaged rod extension (74) to rotate longitudinally relative to the piston rod (5). The injection device is adapted to adjust the dose by moving the injection lever.

2. 2. An injection device according to claim 1, wherein the driver (8) is non-rotatably locked in the housing (1), the driver (8) being threadedly engaged with the piston rod (5).

3. 3. An injection device according to claim 1 or 2, wherein the piston rod (5) comprises at least one flexible guiding feature (15) threadedly engaged with a thread (18) of the driver (8).

4. An injection device according to any one of claims 1 to 3, wherein the regulator (70) is in longitudinal sliding engagement with the rod extension (50).

5. An injection device according to any one of claims 1 to 4, wherein the regulator (70) is non-rotatably locked to the rod extension (50), the rod extension (50) being threadedly engaged to the distal end of the piston rod (5).

6. 6. An injection device according to any one of claims 1 to 5, wherein the regulator (70) is rotatable relative to the piston rod (5) when an adjustment torque exceeding a predetermined holding torque is applied to the regulator (70), the holding torque being greater than a driving torque required to displace the piston rod (5) in the distal direction (22) during dispensing of a dose.

7. 7. The injection device according to claim 6, further comprising at least one of a frictional engagement and a ratchet engagement between the regulator (70) and the piston rod (5), the at least one of the frictional engagement and the ratchet engagement defining a predetermined retention torque.

8. 8. The injection device according to any one of claims 1 to 7, further comprising an intermediate piece (60) arranged between the rod extension (50) and the regulator (70), the intermediate piece (60) being non-rotatably locked to the rod extension (50) and the regulator (70).

9. 9. The injection device according to claim 8, wherein the intermediate piece (60) is in longitudinal sliding engagement with at least one of the rod extension (50) and the regulator (70), and the intermediate piece (60) is in rotational ratchet engagement with the piston rod (5).

10. An injection device according to any one of claims 1 to 9, wherein the regulator (70) comprises a distal section (71) and a proximal section (73), the distal section (71) being operably engaged with the rod extension (50), and the proximal section (73) of the regulator (70) being rotatably supported within the driver (8) relative to the driver (8).

11. An injection device according to any one of claims 1 to 10, further comprising a button (9) axially engaged with the driver (8), wherein a proximal end (79) of the regulator (70) is disposed within a receptacle (40) in a proximal end face (43) of the button (9).

12. 12. The injection device of claim 11, wherein the regulator (70) comprises a longitudinally extending sleeve section (76) and a head (75), the head (75) being radially expanded compared to the sleeve section (76), the head (75) being located at a proximal end of the sleeve section (76), and the head (75) forming a proximal end (79) of the regulator (70).

13. An injection device according to claim 11 or 12, wherein the head (75) comprises a proximal end face (77) located distally from the proximal end face (43) of the button (9).

14. Claims 1 to 13 further comprising a cartridge (12) disposed within the housing (1).

13. An injection device according to any one of claims 1 to 12.

15. An injection device according to any one of the preceding claims, wherein the piston rod (5) is threadedly engaged with the housing (1).

16. An injection device according to any one of claims 1 to 15, wherein the regulator (70) comprises a sleeve section (76) and the rod extension (50) comprises a rod section (56), the rod section (56) and the sleeve section (76) being located within a hollow cavity of the piston rod (5).

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