Injection device with dose size adjuster

Abstract

The present disclosure relates to an injection device (30) configured to expel a dose of medicament, the injection device (30) comprising: - an elongated housing (1) extending in a longitudinal direction, - a piston rod (5) movable relative to the housing (1) in a longitudinal distal direction (22) for applying a dispensing pressure onto a bung (13) of a cartridge (12) at least partially filled with an injectable medicament (35), - a rod extension (50) movably arranged over or in a distal end of the piston rod (5), - a driver (8) operably engaged with the piston rod (5) and movable relative to the housing (1) in a longitudinal proximal direction (23) for setting the dose and in the longitudinal distal direction (22) for dispensing the dose, - a governor (70) arranged over or in the driver (8) and operably engaged with the rod extension (50) for moving the rod extension (50) longitudinally relative to the piston rod (5).

Description

Technical Field

[0001] This disclosure relates, in one aspect, to an injection device, such as a pen syringe for setting and dispensing a fixed dose of medication. In particular, this disclosure relates to a so-called fixed-dose injection device configured to set and dispense a fixed dose of medication, and therefore of constant size. Background Technology

[0002] Injection devices for setting and dispensing single or multiple doses of liquid pharmaceuticals are well known in the art. Typically, such devices serve a purpose substantially similar to that of ordinary syringes.

[0003] Injection devices, especially pen injectors, must meet the specific requirements of many users. For example, patients with chronic diseases such as diabetes may be frail and visually impaired. Therefore, suitable injection devices, especially those designed for home use, need to be robust in construction and easy to use. Furthermore, the operation and general handling of the device and its components should be clear and easy to understand. In addition, dosage setting and dispensing procedures must be easy to operate and clearly defined.

[0004] Typically, such devices include a housing comprising a specific cartridge holder adapted to receive a cartridge at least partially filled with the medication to be dispensed. Such devices further include a drive mechanism, typically having a longitudinally movable piston rod configured to operatively engage with a piston of the cartridge. By means of the drive mechanism and its piston rod, the stopper or piston of the cartridge can be displaced in a distal or dispensing direction, and thus a predefined amount of medication can be dispensed via a puncture assembly releasably coupled to a distal section of the housing of the injection device.

[0005] The medication to be dispensed by the injection device is provided and contained in a multi-dose cartridge. This cartridge typically comprises a glass tube that is sealed distally by means of a puncture-resistant seal and further sealed proximally by a piston. For reusable injection devices, empty cartridges can be replaced with new ones. Conversely, disposable injection devices are discarded when the medication in the cartridge has been dispensed or used up.

[0006] For some applications, it is sufficient when the injection device is configured to set and dispense equal doses. Such injection devices are often referred to as fixed-dose devices. They provide repeated setting and dispensing of a single predefined dose of medication. The general handling and operation of such fixed-dose injection devices are quite simple and straightforward. Such fixed-dose injection devices can be configured and provided as disposable injection devices. They are intended to be discarded when the medication contained therein has been used up.

[0007] In some applications, it is desirable to be able to change the size of a predefined fixed dose within a predefined margin. Therefore, it is desirable to provide temporary or initial reductions or increases in the fixed dose. It may also be desirable to provide at least one modification to the fixed dose. In this way, the patient can decide to decrease or increase the fixed dose to avoid any eventual discomfort or intolerance to the medication. For some patients, at least in specific circumstances, such as in the morning or at the start of treatment, administration of a fixed predefined dose may cause illness. For such specific circumstances, it is desirable to provide an injection device that provides setting and dispensing a dose that is slightly different from the fixed predefined dose.

[0008] Therefore, it is desirable to provide a fixed-dose injection device with a dose size adjuster. Summary of the Invention

[0009] On one hand, an injection device is provided, configured to dispense a dose of medication. The injection device includes an elongated housing extending longitudinally. The injection device further includes a piston rod movable relative to the housing in a longitudinally distal direction to apply dispensing pressure to a stopper or piston of a cartridge. The cartridge is at least partially filled with an injectable medication. The injection device further includes a rod extension movably disposed above or within the distal end of the piston rod. The injection device further includes a driver operably engaged with the piston rod and movable relative to the housing in a longitudinally proximal direction to set the dose. The driver is further movable relative to the housing in the longitudinally distal direction to dispense the dose. The injection device further includes an adjuster disposed on or within the driver. The adjuster is operably engaged with the rod extension to move the rod extension relative to the piston rod in a longitudinal direction.

[0010] The adjuster is user-operable and allows the rod extension to be moved longitudinally independently relative to the piston rod. The adjuster is configured to change the length of the rod assembly. The rod assembly may consist of the piston rod and the rod extension connected to the piston rod. The length of the rod assembly is variable. The rod assembly extends longitudinally, therefore its length depends on the longitudinal or axial position of the rod extension relative to the piston rod. By decreasing the length of the rod assembly, for example by moving the rod extension proximally relative to the piston rod, the dose to be dispensed by the injection device can be reduced. By increasing the length of the rod assembly, for example by moving the rod extension distally relative to the piston rod, the dose to be dispensed by the injection device can be increased.

[0011] The lever assembly may further include a pressure element disposed at the distal end of the lever extension. The distal end of the lever assembly or the pressure element may be directly axially abutted or directly longitudinally abutted against the proximal side of the stopper of the cartridge. The regulator is typically operable before, during, or after dose setting. Dose setting can be performed by retracting the actuator or a button connected to the actuator proximally relative to the housing. Operation of the regulator results in shortening or extending of the lever assembly.

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

[0013] Moving the adjuster in the second direction causes the rod extension to retract proximally. The rod extension may then lose contact with the proximal side of the cartridge stopper. Moving the adjuster in the first direction results in an increase in the longitudinal extension of the rod assembly, and thus a distally oriented displacement of the rod extension relative to the piston rod. Typically, the total displacement of the rod extension relative to the piston rod induced by the adjuster results in pre-tensioning or pre-stressing of the dispensing mechanism or drive mechanism of the injection device without distally displacing the stopper. Therefore, the distally oriented displacement of the rod extension relative to the piston rod, which can be induced by the adjuster, is less than or equal to the longitudinal separation displacement of the rod assembly, which is necessary to overcome the separation force of the piston relative to the cartridge.

[0014] The user can access the actuator directly or indirectly. When displaced distally relative to the housing, the actuator is at least operably engaged with the piston rod. When displaced proximally relative to the housing, the actuator is disengaged from the piston rod or can be operably disengaged from the piston rod. The actuator can be longitudinally slidably engaged with the housing.

[0015] In one example, the actuator is locked to the housing in terms of steering. Typically, the actuator can move back and forth in the longitudinal direction relative to the housing. The actuator can engage with the housing via a spline. The actuator is prevented from rotating relative to the housing, but can slide freely along the longitudinal direction of the housing.

[0016] In another example, the actuator is threadedly engaged with the piston rod. In this way, longitudinal displacement of the actuator relative to the housing can cause rotation of the piston rod relative to the housing. The longitudinal displacement of the actuator induces torque on the piston rod. Typically, distally oriented displacement of the actuator relative to the housing can induce a driving torque on the piston rod. Furthermore, the piston rod can be threadedly engaged with the housing. The longitudinal displacement of the actuator relative to the housing can be caused by helical movement of the piston rod relative to the housing. Due to the threaded engagement between the piston rod and the housing, as the actuator displaces distally relative to the housing, the piston rod experiences distally oriented displacement relative to the housing.

[0017] Depending on the lead of the threaded engagement between the piston rod and the actuator, and depending on the lead of the threaded engagement between the piston rod and the housing, a reduction ratio can be provided between the distal directional movement of the actuator relative to the housing and the distal directional movement of the piston relative to the housing. Typically, the piston rod includes a first threaded section that threadedly engages with the housing, and the piston rod further includes a second threaded section that threadedly engages with the actuator. 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 opposite hands.

[0018] According to another example, the piston rod includes at least one flexible guide feature that threadedly engages with the threads of the actuator. The flexible guide feature may be located at the proximal end of the piston rod. It may be located within a hollow section of the actuator. The threads of the actuator that threadedly engage the flexible guide feature may be located on the inner wall of the actuator. The flexible guide feature is radially deflectable. As the actuator shifts proximally relative to the housing, it can deflect radially inward. During this proximal directional shift of the actuator, the piston rod may be prevented from rotating.

[0019] The flexible guide feature is inwardly deflectable to temporarily disengage from the thread of the actuator. This allows the actuator to be oriented proximally or longitudinally relative to the housing, while the piston rod remains fixed to the housing in a directional position. When the actuator reaches a predefined tilted state relative to the housing, the flexible guide feature of the piston rod re-engages with the travel thread of the actuator. In other words, the flexible guide feature allows the actuator to be oriented proximally relative to the piston rod, and thus allows the actuator to be temporarily disengaged from the piston rod. During and for the purpose of dose dispensing, the flexible guide feature is further configured to convert the distal directional displacement of the actuator relative to the housing into rotational movement of the piston rod relative to the housing.

[0020] According to another example, the regulator is axially engaged with the actuator. The regulator is axially connected to the actuator. In other words, as the actuator moves proximally from an idle state to a tilted state and as the actuator returns from the proximally tilted state to the distally idle state or initial state, the regulator moves back and forth relative to the housing in the proximal and distal directions. Because the regulator is axially engaged with the actuator, it is readily available to the user. This allows for individual adjustment of the dose size when needed.

[0021] According to a further example, the adjuster is longitudinally slidably engaged with the rod extension. In this way, as the actuator undergoes longitudinal directional displacement relative to the housing, the adjuster is capable of sliding axially relative to the rod extension. During proximal directional displacement of the actuator relative to the housing, the rod extension remains fixed relative to the housing and relative to the piston rod. During distal directional displacement of the actuator 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 adjuster and the rod extension allows the rod extension to be manipulated or actuated quite flexibly and universally. In any axial position of the actuator, the adjuster is always slidingly engaged with the rod extension. Therefore, in any longitudinal position of the adjuster and / or the actuator, the longitudinal position of the rod extension relative to the piston rod can be manipulated by the adjuster.

[0023] In a further example, the adjuster is locked to the rod extension in steering. In this way, rotation of the adjuster can be converted into a corresponding rotation of the rod extension. Typically, the adjuster and the rod extension are splined together. This splined engagement is configured to transmit angular momentum or torque between the adjuster and the rod extension. Therefore, rotation of the adjuster relative to the piston rod can be converted into rotation of the rod extension relative to the piston rod.

[0024] In a further example, the rod extension is threadedly engaged with the distal end of the piston rod. In this manner, 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 dimension of the rod assembly can be changed.

[0025] Typically, the piston rod is hollow. It may include a hollow cavity. The cavity may open proximally and / or distally. The adjuster includes a threaded section configured with external threads that thread-engage with corresponding internal threads on an inner section of the hollow piston rod. The rod extension further includes a rod section having at least one spline feature that spline-engages with a corresponding spline feature of the adjuster. The corresponding spline features of the rod extension and the adjuster include at least one radial protrusion located in a correspondingly or complementaryly formed radial recess.

[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 to accommodate the other of the rod extension and the adjuster; conversely, the other includes a hollow cavity. In this way, the rod extension and the adjuster can be arranged to overlap axially and radially, thereby enabling 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 located in a corresponding or complementary radial recess of the other of the rod extension and the adjuster. At least one of the corresponding spline features of the adjuster and the rod extension includes a longitudinal extension that is at least equal to or greater than the longitudinal displacement path of the actuator between the initial state or the idle state and the tilted state. In this way, even if the adjuster undergoes longitudinal displacement as the actuator moves in the longitudinal direction to set and / or dispense a dose, the rod extension and the adjuster remain splined engaged.

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

[0029] According to a further example, when an adjusting torque higher than a predefined holding torque is applied to the regulator, the regulator can rotate relative to the piston rod. The holding torque is greater than the drive torque required to displace the piston rod distally during dose dispensing. During adjustment operations, such as before, during, or after dose setting, and while the actuator is at least temporarily axially fixed relative to the housing, the piston rod is also held directionally locked to the housing due to the threaded engagement between the piston rod and the actuator. The adjusting torque can then be applied to the regulator in either the first or second direction. Typically, the regulator can rotate clockwise or counterclockwise relative to the actuator or relative to the housing to adjust the fixed dose in an increasing or decreasing manner, respectively.

[0030] For dosage purposes, and under normal operating conditions, the driving torque applied to the piston rod typically does not exceed the holding torque. The rotational interlock between the piston rod and the rod extension is limited by the predefined holding torque. This prevents rotation of the rod extension relative to the piston rod during dosage dispensing or dispensing. To adjust the fixed dose, a torque higher than the predefined holding torque must be applied to the regulator to overcome the rotational interlock between the piston rod and the rod extension.

[0031] According to a further example, at least one of friction engagement and ratchet engagement is provided between the adjuster and the piston rod. The mutual mechanical engagement between the adjuster and the piston rod defines the predefined holding torque. The adjuster is permanently rotationally interlocked with the rod extension, and the rod extension is threadedly engaged with the piston rod. In order to modify the overall axial extension of the rod assembly, the adjuster must be rotated relative to the piston rod. The ratchet engagement and friction engagement between the adjuster and the piston rod effectively prevent self-acting or automatic length adjustment of the rod assembly.

[0032] The overall length of the lever assembly can be fixed due to at least one of the ratchet engagement and the friction engagement between the regulator and the piston rod. The overall length of the lever assembly can only be modified when an adjusting torque greater than the holding torque is applied to the regulator relative to the piston rod. This provides an additional safety feature to prevent accidental modification of the predefined and fixed dosage.

[0033] According to a further example, an intermediate member is provided between the rod extension and the adjuster. The intermediate member is locked to the rod extension and to the adjuster in steering. The intermediate member allows and supports longitudinal displacement of the adjuster relative to the rod extension. The intermediate member may further be provided with a dedicated friction engagement and / or a dedicated ratchet engagement with the piston rod.

[0034] The intermediate component can be splinedly engaged with at least one of the adjuster and the rod extension. The intermediate component can also be splinedly engaged with both (i.e., with the rod extension and with the adjuster).

[0035] According to a further example, the intermediate member is slidably engaged with at least one of the rod extension and the adjuster. The intermediate member may slidably engage with both the rod extension and the adjuster. In any case, the intermediate member is configured to transfer angular momentum or torque from the adjuster to the rod extension.

[0036] According to a further example, the intermediate member and the piston rod are in rotational ratchet engagement or rotational friction engagement. For this purpose, the intermediate member typically includes at least one ratchet feature that engages with a corresponding shaped ratchet feature of the piston rod. When in friction engagement, the intermediate member includes at least one or more friction surfaces that are specifically and definitively frictionally engaged with a corresponding friction surface of the piston rod. Typically, the ratchet feature or friction surface of the intermediate member faces radially outward, while the corresponding shaped ratchet feature or friction surface of the hollow piston rod faces radially inward.

[0037] In one example, the intermediate component can be axially fixed to the piston rod. It can slidably engage with the adjuster and it can slidably engage with the rod extension. The intermediate component can be splinedly engaged with the rod extension. When axially fixed to the piston rod, it can slidably engage and splinedly engage with the prime adjuster.

[0038] The intermediate member can be locked to the rod extension in steering, and can further be locked to the adjuster in steering. The intermediate member can be connected to the rod extension in steering, and can further be connected to the adjuster in steering. Rotation of the adjuster relative to the piston rod causes a corresponding rotation of the intermediate member, and further causes a corresponding rotation of the rod extension relative to the piston rod. The ratchet engagement and / or the friction engagement between the intermediate member and the piston rod prevents automatic or self-actual rotation, and thus prevents longitudinal displacement of at least one of the adjuster and the rod extension relative to the piston rod.

[0039] The intermediate component may include a sleeve. The intermediate component may include a hollow sleeve. The distal end of the intermediate component may spline engage with the rod extension, particularly with a proximal section of the rod extension. The proximal end or proximal section of the intermediate component may be located inside the hollow portion of the adjuster. The adjuster may also include a hollow sleeve surrounding the proximal section of the intermediate component. The radially overlapping portions of the rod extension and the intermediate component may be splined. The radially overlapping portions of the intermediate component and the adjuster may also be splined.

[0040] Typically, the distal end of the intermediate component, which protrudes distally from the distal end of the regulator, can engage with the piston rod ratchet or friction engagement.

[0041] In a further example, the regulator includes a distal section and a proximal section. The distal section is operatively engaged with the rod extension. It can be splinedly engaged with the rod extension, for example, via the intermediate member. The proximal section of the regulator is steered within the actuator. The proximal section or proximal end of the regulator can extend axially through the actuator. In this way, it can be used from outside the actuator and from outside the housing of the injection device.

[0042] According to a further example, the injection device includes a button that is axially engaged or axially connected to the actuator. The proximal end of the regulator is disposed in a receiver on the proximal face of the button. The button and the actuator may be integrally formed. Therefore, the button may be part of the actuator. Typically, the button is formed in or connected to the proximal end of the actuator. The button is user-operable. The button can be displaced in the proximal direction for assembling the injection device and / or for setting the dosage. The button can be displaced in the distal direction for dispensing or discharging a drug dose.

[0043] The button is slidably engaged with the injection device, either directly or indirectly, through the sliding engagement of the actuator with the housing. The proximal end of the regulator is readily available to the user of the injection device by being positioned in a receiver at the proximal face of the button. The proximal end of the regulator may be recessed compared to the proximal face of the button. In this way, the proximal end of the regulator does not protrude from the proximal face of the button. For example, when the user applies a distal driving motion to the button or the actuator with his thumb, it does not affect or hinder the normal operation of the injection device.

[0044] According to another example, the adjuster includes a longitudinally extending sleeve section and a head. The head widens radially compared to 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. By means of the radially widened head, the adjuster can be axially fixed to the button and / or to the actuator. The radially widened head of the adjuster can be axially confined within the assembly of the actuator and the button. In this way, the adjuster can be axially fixed to the assembly of the actuator and the button. The sleeve section of the adjuster extends distally from the head. The sleeve section may include at least one spline feature that locks in steering to at least one of the intermediate member and the rod extension.

[0045] According to a further example, the head includes a proximal face located distal to the proximal face of the button. In other words, the proximal face of the head is recessed compared to the proximal face of the button. It does not protrude from the button. Moreover, the proximal face of the head may be provided with a longitudinal slot or longitudinal slit. The longitudinal slot or longitudinal slit may provide a threaded slot for engaging with a screwdriver or tightening tool. Rotation of the regulator relative to the piston rod may require the use of a dedicated screwdriver or dedicated tightening tool. It is conceivable that only authorized personnel (such as caregivers) should be equipped with the dedicated screwdriver or dedicated tightening tool. In this way, and when dispensing the pre-filled injection device to the patient, caregivers or authorized personnel can adjust the dosage. The threaded slot at the proximal face of the regulator further provides a safety feature, thus preventing unauthorized operation of the regulator and / or the injection device.

[0046] According to a further example, the injection device is equipped with a cartridge disposed within the housing. The cartridge typically comprises a tubular or cylindrical body. The body may include a glass body. The distal end of the body is sealed by a puncture-resistant seal. The proximal end of the body is typically sealed by a stopper, which is displaceable in a distal direction by means of the piston rod of the injection device.

[0047] In a further example, the regulator includes a sleeve section, and the rod extension includes a rod section. Here, both the rod section and the sleeve section are located within the 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 the hollow cavity. The rod section and the sleeve section can be locked to each other in direction, but longitudinal sliding displacement of the rod section relative to the sleeve section is permitted and supported. It is also conceivable that the rod section includes a hollow cavity, and the sleeve section of the regulator is located within the hollow cavity and locked to the rod section in direction.

[0048] In this article, the term "distal" or "far end" refers to the end of the injection device facing the injection site in a human or animal. The term "proximal" or "proximal end" refers to the opposite end of the injection device, which is furthest from the injection site in a human or animal.

[0049] As used herein, the terms "drug" or "pharmaceutical preparation" refer to a pharmaceutical formulation containing at least one pharmaceutically active compound.

[0050] In one embodiment, the pharmaceutically active compound has a molecular weight of up to 1500 Da and / or is a peptide, protein, polysaccharide, vaccine, DNA, RNA, enzyme, antibody or antibody fragment, hormone or oligonucleotide, or a mixture of the above pharmaceutically active compounds.

[0051] In a further embodiment, the pharmaceutically active compound may be used to treat and / or prevent diabetes or diabetes-related complications (such as diabetic retinopathy), thromboembolism (such as deep vein or pulmonary thromboembolism), acute coronary syndrome (ACS), angina pectoris, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis.

[0052] In a further embodiment, the pharmaceutically active compound includes at least one peptide for treating and / or preventing diabetes or diabetes-related complications such as diabetic retinopathy.

[0053] In a further embodiment, the pharmaceutically active compound includes at least one human insulin or human insulin analog or derivative, glucagon-like peptide-1 (GLP-1) or its analog or derivative, or exendin-3 or exendin-4, or an analog or derivative of exendin-3 or exendin-4.

[0054] 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 the proline at position B28 is replaced by Asp, Lys, Leu, Val, or Ala, and the Lys at position B29 can be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

[0055] 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-myristoyl-LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; and B30-N-myristoyl-ThrB2 9LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithochyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.

[0056] Venomous exopeptide-4, for example, refers to venomous exopeptide-4 (1-39), a peptide having the following 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.

[0057] Venomous lizard exopeptide-4 derivatives, for example, are selected from the following list of compounds:

[0058] H-(Lys)4-des Pro36, des Pro37 venomous lizard exopeptide-4(1-39)-NH2

[0059] H-(Lys)5-des Pro36, des Pro37 venomous lizard exopeptide-4(1-39)-NH2

[0060] des Pro36 Venomous Lizard Exopeptide-4(1-39)

[0061] des Pro36[Asp28] Venomous Lizard Exopeptide-4(1-39),

[0062] des Pro36[IsoAsp28] Venomous Lizard Exopeptide-4(1-39),

[0063] des Pro36[Met(O)14,Asp28]exotropic peptide-4(1-39),

[0064] des Pro36[Met(O)14,IsoAsp28]exotropic peptide-4(1-39),

[0065] des Pro36[Trp(O2)25,Asp28]exotropic peptide-4(1-39),

[0066] des Pro36[Trp(O2)25,IsoAsp28]exotropic peptide-4(1-39),

[0067] des Pro36[Met(O)14Trp(O2)25,Asp28]exotropic peptide-4(1-39),

[0068] des Pro36[Met(O)14Trp(O2)25,IsoAsp28] lizard exopeptide-4(1-39); or

[0069] des Pro36[Asp28] Venomous Lizard Exopeptide-4(1-39),

[0070] des Pro36[IsoAsp28] Venomous Lizard Exopeptide-4(1-39),

[0071] des Pro36[Met(O)14,Asp28]exotropic peptide-4(1-39),

[0072] des Pro36[Met(O)14,IsoAsp28]exotropic peptide-4(1-39),

[0073] des Pro36[Trp(O2)25,Asp28]exotropic peptide-4(1-39),

[0074] des Pro36[Trp(O2)25,IsoAsp28]exotropic peptide-4(1-39),

[0075] des Pro36[Met(O)14Trp(O2)25,Asp28]exotropic peptide-4(1-39),

[0076] des Pro36[Met(O)14Trp(O2)25,IsoAsp28] Lizard Exopeptide-4(1-39),

[0077] Among them, the group -Lys6-NH2 can bind to the C-terminus of the lizard exopeptide-4 derivative;

[0078] Or a lizard exopeptide-4 derivative having the following sequence:

[0079] des Pro36 Venomous Lizard Exopeptide-4(1-39)-Lys6-NH2(AVE0010),

[0080] H-(Lys)6-des Pro36[Asp28]exotropic peptide-4(1-39)-Lys6-NH2,

[0081] des Asp28 Pro36,Pro37,Pro38 Venomous Lizard Exopeptide-4(1-39)-NH2、

[0082] H-(Lys)6-des Pro36,Pro38[Asp28]exotropic peptide-4(1-39)-NH2、

[0083] H-Asn-(Glu)5des Pro36,Pro37,Pro38[Asp28]exotropic peptide-4(1-39)-NH2、

[0084] des Pro36,Pro37,Pro38[Asp28] Venomous Lizard Exopeptide-4(1-39)-(Lys)6-NH2、

[0085] H-(Lys)6-des Pro36,Pro37,Pro38[Asp28] Venomous Lizard Exopeptide-4(1-39)-(Lys)6-NH2、

[0086] H-Asn-(Glu)5-des Pro36,Pro37,Pro38[Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0087] H-(Lys)6-des Pro36[Trp(O2)25,Asp28]exotropic peptide-4(1-39)-Lys6-NH2、

[0088] H-des Asp28 Pro36,Pro37,Pro38[Trp(O2)25]exotropic peptide-4(1-39)-NH2、

[0089] H-(Lys)6-des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]exotropic peptide-4(1-39)-NH2、

[0090] H-Asn-(Glu)5-des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]exotropic peptide-4(1-39)-NH2、

[0091] des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0092] H-(Lys)6-des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0093] H-Asn-(Glu)5-des Pro36,Pro37,Pro38[Trp(O2)25,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0094] H-(Lys)6-desPro36[Met(O)14,Asp28]exotropic peptide-4(1-39)-Lys6-NH2、

[0095] des Met(O)14Asp28 Pro36,Pro37,Pro38 Venomous Lizard Exopeptide-4(1-39)-NH2、

[0096] H-(Lys)6-desPro36,Pro37,Pro38[Met(O)14,Asp28]exotropic peptide-4(1-39)-NH2、

[0097] H-Asn-(Glu)5-des Pro36,Pro37,Pro38[Met(O)14,Asp28]exotropic peptide-4(1-39)-NH2、

[0098] des Pro36,Pro37,Pro38[Met(O)14,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0099] H-(Lys)6-des Pro36,Pro37,Pro38[Met(O)14,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0100] H-Asn-(Glu)5des Pro36,Pro37,Pro38[Met(O)14,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0101] H-Lys6-des Pro36[Met(O)14,Trp(O2)25,Asp28]exotropic peptide-4(1-39)-Lys6-NH2,

[0102] H-des Asp28 Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25]exotropic peptide-4(1-39)-NH2、

[0103] H-(Lys)6-des Pro36,Pro37,Pro38[Met(O)14,Asp28]exotropic peptide-4(1-39)-NH2、

[0104] H-Asn-(Glu)5-des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exotropic peptide-4(1-39)-NH2、

[0105] des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2、

[0106] H-(Lys)6-des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exotropic peptide-4(S1-39)-(Lys)6-NH2,

[0107] H-Asn-(Glu)5-des Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]exotropic peptide-4(1-39)-(Lys)6-NH2;

[0108] Or a pharmaceutically acceptable salt or solvate of any of the above-mentioned lizard exopeptide-4 derivatives.

[0109] Hormones are, for example, pituitary or hypothalamic hormones or regulatory peptides and their antagonists listed in Chapter 50 of the Rote Liste, 2008 edition, such as gonadotropins (follicle-stimulating hormone, luteinizing hormone, human chorionic gonadotropin, gamete maturation hormone), somatropine (growth hormone), desmopressin, terlipressin, gonarelin, triptorelin, leuprorelin, buserrelin, nafarelin, and goserelin.

[0110] Polysaccharides are, for example, glycosaminoglycans, hyaluronic acid, heparin, low molecular weight heparin or ultra-low molecular weight heparin or derivatives thereof, or sulfated forms of the above polysaccharides (e.g., polysulfated forms), and / or pharmaceutically acceptable salts thereof. An example of a pharmaceutically acceptable salt of polysulfated low molecular weight heparin is enoxaparin sodium.

[0111] Antibodies are globular plasma proteins (approximately 150 kDa), also known as immunoglobulins sharing a basic structure. They are glycoproteins because they have sugar chains added to amino acid residues. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimers with two Ig units (such as IgA), tetramers with four Ig units (such as bony fish IgM), or pentamers with five Ig units (such as mammalian IgM).

[0112] Ig monomers are Y-shaped molecules composed of four polypeptide chains; two identical heavy chains and two identical light chains are linked by disulfide bonds between cysteine ​​residues. Each heavy chain is approximately 440 amino acids long; each light chain is approximately 220 amino acids long. Both heavy and light chains contain intrachain disulfide bonds that stabilize their folding. Each chain consists of domains called Ig domains. These domains contain approximately 70–110 amino acids and are categorized according to their size and function (e.g., variable regions or V regions and constant regions or C regions). These domains exhibit a unique immunoglobulin fold, where the two β-folds form a "sandwich" shape, held together by interactions between conserved cysteine ​​residues and other charged amino acids.

[0113] There are five types of mammalian Ig heavy chains, denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of the antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.

[0114] The different heavy chains vary in size and composition; α and γ contain approximately 450 amino acids, δ contains approximately 500 amino acids, and μ and ε contain approximately 550 amino acids. Each heavy chain has a constant region (C0). H ) and variable region (V H The heavy chain has two regions. Within a species, the constant region is substantially the same across all antibodies of the same isotype, but differs across antibodies of different isotypes. Heavy chains γ, α, and δ have a constant region consisting of three tandem Ig domains and a hinge region for increased flexibility; heavy chains μ and ε have a constant region consisting of four immunoglobulin domains. The variable region of the heavy chain differs among antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or a B cell clone. Each variable region of the heavy chain is approximately 110 amino acids long and consists of a single Ig domain.

[0115] In mammals, there are two types of immunoglobulin light chains, denoted by λ and κ. A light chain has two continuous domains: a constant domain (CL) and a variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two identical light chains; in mammals, each antibody possesses only one type of light chain, either κ or λ.

[0116] Although all antibodies share a very similar general structure, the unique properties of a given antibody are determined by variable (V) regions, as detailed above. More specifically, variable loops (three on each light chain (VL) and three on each heavy chain (VH)) are responsible for binding the antigen, i.e., for its antigen specificity. These loops are called complementarity-determining regions (CDRs). Because multiple CDRs from the VH and VL domains constitute the antigen-binding site, it is the combination of the heavy and light chains (rather than each individually) that determines the final antigen-specific combination.

[0117] An "antibody fragment" comprises at least one antigen-binding fragment as defined above and exhibits essentially the same function and specificity as the intact antibody derived from it. Restrictive proteolysis with papain cleaves the Ig prototype into three fragments. Two identical N-terminal fragments are antigen-binding fragments (Fab), each containing a complete L-chain and approximately half an H-chain. The third fragment is a crystallizable fragment (Fc), similar in size but containing half of the carboxyl terminus of both heavy chains and their interchain disulfide bonds. Fc contains a carbohydrate, a complement binding site, and an FcR binding site. Restricted pepsin digestion yields a single F(ab')2 fragment containing both a Fab segment and a hinge region, including the HH interchain disulfide bond. F(ab')2 is divalent for antigen binding. The disulfide bonds of F(ab')2 can be cleaved to obtain Fab'. Furthermore, the variable regions of the heavy and light chains can be fused together to form a single-chain variable fragment (scFv).

[0118] Pharmacologically acceptable salts are, 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 cations selected from: alkali or alkaline earth metals, such as Na+, or K+, or Ca2+, or ammonium ions N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently represent: 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. Other examples of pharmaceutically acceptable salts are described in: Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, Pa., USA, 1985, and Encyclopedia of Pharmaceutical Technology.

[0119] Pharmaceutically acceptable solvates are, for example, hydrates.

[0120] It will be further apparent to those skilled in the art that various modifications and variations can be made to the invention without departing from the true scope of this disclosure. Furthermore, it should be noted that any reference numerals used in the appended claims should not be construed as limiting the scope of the injection device. Attached Figure Description

[0121] In the following sections, several examples of containers and injection devices will be described in detail with reference to the accompanying drawings, wherein:

[0122] Figure 1 An example of an injection device is shown.

[0123] Figure 2 A schematic diagram is shown. Figure 1 The proximal part of the injection device,

[0124] Figure 3 This is an explanatory diagram of the piston rod of the injection device.

[0125] Figure 4 yes Figure 3 An enlarged view of the piston rod.

[0126] Figure 5 This is a schematic cross-sectional view of an example of an injection device.

[0127] Figure 6 This is a schematic cross-sectional view of another example of the injection device.

[0128] Figure 7 The proximal end face of the injection device is shown schematically.

[0129] Figure 8 It schematically shows along the path based on Figure 5 The cross section of AA,

[0130] Figure 9 It schematically shows along the path based on Figure 6 The cross section of BB, and

[0131] Figure 10 It schematically shows along the path based on Figure 6 The cross section of CC. Detailed Implementation

[0132] Figure 1 A cross-sectional view of an injection device 30 configured as a pen-type syringe and including a drive mechanism 32 is shown. The drive mechanism 32 is arranged in a body 1 or a housing having a distal end 2 and a proximal end 3. A piston rod 5 is arranged along the axis 4 of the device. The thread 6 of the piston rod 5 is engaged with a drive feature of the piston rod nut 7 to guide the piston rod 5 in a helical motion about the piston rod nut 7. In a further embodiment, the thread and drive feature may be reversed, such that the piston rod has a separate drive feature and the piston rod nut has a helical thread. The piston rod nut 7 is locked to the body 1 in rotation.

[0133] Figure 1 and Figure 2Examples include an actuator 8, which can be operated by a user via a button 9 located at the proximal end 3 and protruding beyond the body 1. The actuator 8 is connected or engaged with a piston rod 5. This is achieved by means of a thread 18 in the actuator 8 and a flexible guiding feature 15 in the piston rod 5. The actuator 8 can in particular be a substantially cylindrical drive sleeve, the axis of which is arranged parallel to the axis 4 of the device. The piston rod 5 can be arranged to enter the actuator 8.

[0134] A removable and attachable portion 11 of the main body 1 can be configured as a cartridge holder. When this portion 11 is removed from the remainder of the main body 1, a cartridge 12 can be inserted. When the portion 11 is attached to the main body 1, a piston rod 5 contacts a piston 13 configured to expel medication from the cartridge 12. A bearing 14 can be arranged between the piston rod 5 and the piston 13 to prevent any damage that may result from relative movement between the piston rod 5 and the piston 13. The piston rod 5 serves as a lead screw to advance the piston 13 in a distal direction 22. A puncturable seal 34 is provided at the distal end of the cartridge 12, the puncturable seal being configured to be punctured by a double-pointed injection needle configured to attach to the distal end of the attachable portion 11 or the cartridge holder. The glass cartridge 33 is generally translucent to allow visual inspection of the medication located inside the cartridge 12.

[0135] During delivery, the piston rod 5 helically moves about the body 1 in the distal direction 22. The piston rod 5 is guided by a piston rod nut 7 that engages with the piston rod 5's thread 6. A stop feature, described below, is provided in the piston rod 5's thread 6 to enable a dose setting operation, by which a fixed dose to be dispensed can be preset. For this purpose, the actuator 8 is pulled relative to the body 1 and relative to the piston rod 5 in the proximal direction 23. The actuator 8 is connected to the piston rod 5. Figure 1 and 2 In the embodiment shown, the connection is achieved through the thread 18 of the driver 8 and the flexible guide feature 15 of the piston rod 5.

[0136] During the dosage setting operation, the piston rod 5 must not be moved. Therefore, during the setting operation, the engagement between the actuator 8 and the piston rod 5 is temporarily released. This can be achieved by deforming the flexible guide feature 15 to override the threads 18 of the actuator 8. Although the actuator 8 is engaged with the piston rod 5, the actuator 8 can therefore move without rotation, while the piston rod 5 remains stationary relative to the body. The flexible guide feature 15, which can be bent toward the central axis 4, facilitates the override of the engagement between the actuator 8 and the piston rod 5. Rotation of the actuator 8 relative to the body 1 can be prevented by the guide feature 10, which can be, for example, a protruding element of the body 1 that engages with an axial groove in the outer surface of the actuator 8.

[0137] After the actuator 8 has moved a certain distance corresponding to the pitch of the thread 18 of the actuator 8, the flexible guide feature 15 of the piston rod 5 re-engages the thread 18 of the actuator 8, and the user can advance the piston rod 5 by pushing the actuator 8 backward in the distal direction 22. This method of operation, which involves disengaging and re-engaging the piston rod 5 with the actuator 8, relies entirely on keeping the piston rod 5 substantially stationary during the setting operation. If the piston rod 5 rotates or moves axially during the setting operation, the actuator 8 will likely fail to re-engage the piston rod 5 properly, thus causing inaccurate dosing. Therefore, at least during the dispensing operation, the piston rod nut 7, which guides the helical movement of the piston rod 5 about the body 1, is locked to the body 1 in direction, and furthermore, the piston rod 5 is provided with a stop feature that interferes with the rotation of the piston rod 5 in such a way that rotation of the piston rod 5 at the position obtained after drug delivery and before setting a new dose is inhibited.

[0138] Therefore, the rotation of piston rod 5 is locked with respect to piston rod nut 7, preventing piston rod nut 7 from rotating relative to body 1. Thus, when actuator 8 is pulled in the proximal direction 23, the relative linear movement between actuator 8 and piston rod 5 causes the engagement between actuator 8 and stationary piston rod 5 to be overridden, and thus the engagement between actuator 8 and piston rod 5 is released. Therefore, a stop feature is arranged at least on the distal sidewall of the thread 6 of piston rod 5, while the thread 6 can be smooth on its proximal sidewall, forming a helix. When actuator 8 is pushed in the distal direction, the guide of piston rod nut 7 engaging with the thread 6 of piston rod 5 remains in contact with the smooth proximal sidewall of thread 6, thereby enabling piston rod 5 to achieve a smooth helical movement sliding through the opening of piston rod nut 7. Therefore, during dispensing operations, the stop feature does not interfere with the relative movement of piston rod 5 with respect to piston rod nut 7.

[0139] The stopping feature can be provided, in particular, by a recess in the helical groove forming the thread 6 of the piston rod 5. The recess can have a contact surface arranged transversely to the axis 4, and the contact surface interrupts the smooth helix of the corresponding sidewall of the groove forming the thread 6. The contact surface can be, in particular, a flat portion that is substantially perpendicular to the axis 4 or at least has a zero helix angle, but may have a rake angle in the radial direction. The drive feature of the piston rod nut 7 can be formed such that it enters the recess and stops at the contact surface. When the drive feature of the piston rod nut 7 contacts one of the flat portions, the guidance of the helical movement of the piston rod 5 about the body 1 caused by the generally perpendicular orientation of the flat portion about the axis 4 is stopped. It may be advantageous if the drive feature of the piston rod nut 7 engaging with the thread 6 of the piston rod 5 and stopping in the recess consists of one or more individual drive features and is not formed by completely continuous drive features.

[0140] The stop features are arranged in such a way that, after a dose of medication has been fully delivered and the device is ready to set the next dose, when the actuator 8 is pulled in the proximal direction, one of the stop features is in a position ready to stop the rotation of the piston rod 5. The axial load applied to the piston rod 5 is then compensated by the engagement of the drive feature of the piston rod nut 7 with the associated stop feature, particularly by contact with the substantially flat portion of the associated recess. This serves to lock the rotation of the piston rod 5 rather than rotate it, because the piston rod nut 7 is locked to the body 1 in direction, at least during the dose setting and dispensing operations. Essentially, the flat surface on the thread 6 is designed to prevent the piston rod 5 from being driven backward during the setting operation. The movement of the piston rod 5 can then be restricted in the distal direction.

[0141] Figure 3An enlarged perspective view of an embodiment of the piston rod 5 is shown. 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 features with separate inlets at or near the distal end of the piston rod 5. The thread 18 of the actuator 8 may also have two independent coaxial helical features intertwined. The shape of the flexible guide feature 15 at the proximal end of the piston rod 5 is adapted for the thread 18 of the actuator 8. The flexible guide feature 15 may specifically include two coaxial helical external thread features configured to engage helical grooves that can form the thread 18 of the actuator 8. If the thread 18 has two coaxial helical features, the flexible guide feature 15 may have two separate portions, each of which engages with one of the helical features. The flexible guide feature 15 can deform and thus disengage from the thread 18 of the actuator 8. This allows the connection between the piston rod 5 and the actuator 8 to be temporarily overridden when the actuator 8 is pulled in the proximal direction 23.

[0142] The piston rod 5 is provided with spike features or spline features 25 arranged in a regular sequence. Figure 3 In this example, the three rows 20 of spline feature 25 are arranged parallel to axis 4. Spline feature 25 is mainly located in the region of threads 6, 16 at the distal end of piston rod 5. The rows 20 are spaced 120° apart from each other around the circumference of piston rod 5. The spacing can be varied alternatively, or there can be an additional number of rows 20 of spline feature 25. Spline feature 25 is configured to interact with stop feature 19 on the inner surface of actuator 8 facing piston rod 5.

[0143] The stop feature 19 may be a single protruding element, or alternatively may include two or more separate elements. When the dosage is applied, the stop feature 19 helps prevent rotation of the piston rod 5. Each row 20 of the spline features 25 may include a series of positive protrusions located between the helical grooves of the threads 6, 16. Therefore, gaps exist between the spline features 25. Each second gap between the spline features 25 is large enough to allow the corresponding stop feature 19 on the inner surface of the actuator 8 to pass through during dosage dispensing. The spline features 25 also serve a further function: at the transition between the helical thread section and the stop feature 17 of the threads 6, 16, they extend the contact line between the piston rod 5 and the piston rod nut 7. This reduces the risk of deformation, especially of the piston rod nut 7, in this area under high dispensing loads.

[0144] Figure 4A magnified detailed view of the distal end of piston rod 5 is shown. In this embodiment, piston rod 5 includes interlocking threads 6 and further threads 16, each having a separate inlet (“double-start” thread). Piston rod nut 7 engages the threads 6 and 16 of piston rod 5. The stop features 17 of threads 6 and 16 can be arranged such that their proximal surfaces continuously extend into at least one of the spline features 25 in rows 20 of spline features 25, as shown from... Figure 4 Visible in the image. Threads 6 and 16 can be arranged at intervals corresponding to different gaps between subsequent spline features 25. Spline features 25 can therefore be arranged adjacent to the grooves of threads 6 and 16, and in particular, can be integrally formed with the stop feature 17 of threads 6 and 16. Conversely, only one thread 6 or more threads can be provided on the piston rod 5. In this case, spline features 25 are arranged along row 20, wherein the gaps between subsequent spline features 25 alternately decrease and increase, regardless of the position of the helical grooves of the threads.

[0145] A larger gap is provided to allow the stop feature 19 of the actuator 8 to pass through during drug dispensing, and the piston rod 5 to move helically relative to the actuator 8. A smaller gap is provided to prevent the stop feature 19 of the actuator 8 from passing through when the actuator 8 is pulled in the proximal direction to set the dosage. In this case, the spline feature 25 slides along the stop feature 19 of the actuator 8. This helps prevent the piston rod 5 from rotating relative to the actuator 8, which is locked in direction with the body 1 and the piston rod nut 7. Therefore, the piston rod 5 also does not rotate relative to the body 1 and the piston rod nut 7.

[0146] Figure 2 The arrangement of piston rod 5 and actuator 8 is shown, in which the actuator is a drive sleeve surrounding piston rod 5. The distal end of piston rod 5 protrudes from actuator 8. A stop feature 19 is located on the inner wall of actuator 8 and may be, for example, a protruding element or two or more separate protruding elements. Stop feature 19 is preferably integral with actuator 8 and formed in the inner wall. The axial dimension of each element of stop feature 19 is small enough to allow the element to pass between two adjacent spline features 25 (if the gap between them is large). After the dose has been dispensed, in the resting position occupied by actuator 8 with respect to piston rod 5, stop feature 19 is located near the two spline features 25 separated by a smaller gap.

[0147] If the next dose is to be set and the actuator 8 is pulled proximally relative to the body 1, rotation of the piston rod 5 is prevented by the stop feature 17 of the thread 6, which engages with the drive feature of the piston rod nut 7. Therefore, the stop feature 19 of the actuator 8 moves axially to a position adjacent to, in contact with, and slides along the spline feature 25, while the actuator 8 moves further proximally relative to the piston rod 5. The spline feature 25 prevents the stop feature 19 of the actuator 8 from moving transversely to the axis 4 about the circumference of the piston rod 5, and thus prevents rotation of the piston rod 5 relative to the actuator 8. As the stop feature 19 passes the first spline feature 25, it slides axially in the same manner along the next spline feature 25 of the same row 20, because the gaps between the spline features 25 are small and do not allow the stop feature 19 to pass between them. After the dosage has been set, when the actuator 8 is pushed in the distal direction and the piston rod 5 is helicaled, the stop feature 19 of the actuator 8 is positioned where it enters a position with a larger gap between adjacent spline features 25. It is preferred to arrange multiple spline features 25 along the piston rod 5 because it always provides adjacent spline features 25 for the purposes described above, regardless of the position of the piston rod 5, which advances further in the distal direction with each dose dispensing.

[0148] The design of spline feature 25 can deviate from the shape shown by example in the figure. The arrangement of spline feature 25 depends on its purpose, which is to either prevent the piston rod 5 from rotating or to enable the piston rod 5 to move helically. The embodiment shown in the figure has the advantage that the arrangement of the spline features is adapted to the location of the helical grooves and facilitates the manufacture of the device components.

[0149] exist Figure 5 and Figure 7 The image shows an example of an injection device equipped with a dose adjuster. For example, the drive mechanism 32 of the injection device 30 is based on the one described above. Figures 1 to 4 The same working principle is described. The dose size regulator described herein can also be applied to other drive mechanisms in fixed-dose devices.

[0150] like Figure 5 As shown, the piston rod 5 is hollow and includes a hollow sleeve. The piston rod 5 includes a hollow cavity 44 in which a rod extension 50 is disposed. 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. It is axially displaceable relative to the piston rod 5. In this example, the rod extension 50 and the piston rod 5 are threadedly engaged. For this purpose, the rod extension 50 includes an external thread 51 that engages with the internal thread 26 of the piston rod 5.

[0151] Due to the threaded engagement of the rod extension 50 and the piston rod 5, the rod assembly 58 can have a variable longitudinal length. The rod extension 50 includes a shank 52 projecting in the distal direction 22. The shank 52 forms or constitutes the distal end of the rod extension 50. The shank 52 supports the bearing 14 in the steering direction, the bearing being... Figure 5 and Figure 6 Not specifically shown. The rod extension 50 is longitudinally displaceable relative to the piston rod 5 by rotation relative to the piston rod 5. For this purpose, the rod extension 50 is operatively engaged with the adjuster 70. The adjuster 70 is arranged on or in the actuator 8.

[0152] 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 to a driver 8. The button 9 and the driver 8 may be integrally formed. The proximal section 73 is provided with a radially widening head 75, which is disposed in a receiver 40 of the button 9. The button 40 includes a through-hole 41 extending from the receiver 40 in a distal direction 22. The through-hole 41 extends axially through a radially narrowing neck 42 of the button 9. In particular, the proximal end face of the neck 42 of the button 9 axially engages with the distal end face of the radially widening head 75 of the regulator 70. The regulator also includes a sleeve section 76 extending in the distal direction 22. The sleeve section 76 extends distally from the radially widening 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 widening head is axially confined in the receiver 40 of the button 9. In this way, the regulator 70 is axially connected or axially engaged with the button 9.

[0153] Adjuster 70 engages or locks to lever extension 50 on steering. For example... Figure 5 As shown, the sleeve section 76 of the regulator 70 radially overlaps with the rod section 56 of the rod extension 50. The sleeve section 76 may form the distal section 71 of the regulator 70, and the rod section 56 may overlap with 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 inside the hollow piston rod 5. The sleeve section 76 and the rod section 56 are in a spline engagement. The spline engagement forms a rotational interlock between the regulator 70 and the rod extension 50, but allows the regulator 70 to slide longitudinally relative to the rod extension 50. In this way, the regulator 70 slides freely relative to the rod extension 50 in the proximal direction 23 as the dose is set and when the button 9 is pulled in the proximal direction 23.

[0154] The spline engagement between the rod extension 50 and the adjuster 70 is formed by corresponding spline features 54 and 74 of the rod extension 50 and the adjuster 70, respectively. Here, at least one of the spline features 54 and 74 includes a radial protrusion that slides into a corresponding or complementary radial recess of the other spline feature 54 or spline feature 74. In this example, and as... Figure 8 As shown, the rod extension 50 includes a radially outwardly projecting spline feature 54 that rotatably engages with a corresponding shaped spline feature 74 of the adjuster 70. The spline feature 54 includes a radially outwardly extending protrusion on the outer surface of the rod extension 50, particularly in the outward-facing portion of the rod section 56. The spline feature 74 is a radially recessed portion provided on the inward-facing sidewall section of the sleeve-type adjuster 70.

[0155] Spline feature 74 typically includes an elongated groove on the inner surface of the sleeve section 76. As the adjuster 70 undergoes longitudinal displacement relative to the body 1 and therefore relative to the housing, the corresponding spline features 54, 74 remain engaged. This allows torque to be transmitted from the adjuster 70 to the rod extension 50, regardless of the axial position of the adjuster 70 (i.e., for each axial position of the adjuster 70). The dosage can be adjusted before or after setting the dosage, and of course, before dispensing or discharging the dosage.

[0156] As in Figure 5 As shown, the rod section 56 of the rod extension is located inside the cavity 72 of the adjuster 70, and therefore inside the cavity 72 of the sleeve section 25. In such a way... Figure 5 In the idle configuration or initial setup shown, the adjuster 70 can be rotated, for example, by means of a screwdriver or tightening tool, to engage with the recess 78 formed as a threaded slot at the proximal end face 77 of the adjuster 70. The proximal end face 77 of the adjuster 70 can be located distal to the proximal end face 43 of the button 9. In this way, the adjuster 70 can be rotated and actuated using only a suitable tightening tool. This prevents unauthorized dose adjustment.

[0157] To adjust the dosage, the regulator 70 rotates clockwise or counterclockwise relative to the button 9. Clockwise or counterclockwise rotation causes a corresponding rotation of the lever extension 50 relative to the piston rod 5. Figure 7In the example shown, the regulator 70 can be rotated clockwise in a first rotation direction or direction to increase the dose. The regulator 70 can be rotated counterclockwise in a second rotation direction opposite to the first rotation direction to decrease the dose. When the regulator 70 is rotated in the second rotation direction, the corresponding turning motion of the regulator 70 is transmitted equally to the rod extension 50. Due to the threaded engagement of the rod extension 50 with the piston rod 5, the rod extension 50 undergoes proximal directional displacement relative to the piston rod 5. Here, the bearing 14 may lose contact with the stopper of the cartridge 12 or the proximal side of the piston 13.

[0158] When the adjuster 70 is turned or rotated in the first rotation direction (e.g., clockwise), the rod extension 50 is displaced relative to the piston rod 5 in the distal direction 22. Here, the entire drive mechanism 32 can be pre-tensioned or prestressed, and any final mechanical play or geometric tolerance can be eliminated. The intention is that the adjuster 70 can only be rotated within a range along the first rotation direction such that the distal directional force applied to the stopper or piston 13 is always lower than the separation force required to drive the piston 13 in the distal direction 22.

[0159] To enable the regulator 70 to rotate 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 can include a one-way coupling engagement or a one-way ratchet engagement that limits the unidirectional rotation of the regulator 70 relative to the piston rod 5. The mechanical engagement between the regulator 70 and the piston rod can be configured to support only the dose-decreasing rotation of the regulator 70 and can prevent the dose-increasing adjustment movement of the regulator 70.

[0160] In this way, patients can be offered the option of reducing a fixed dose without ever increasing it. This avoids the potential dangers of overdose.

[0161] Using other examples and as shown herein, the mechanical engagement between the regulator 70 and the piston rod 5 is of a bidirectional type. Here, the regulator 70 can rotate or move relative to the piston rod 5 in opposite directions of rotation or in a reverse rotational sensing manner. This allows for increasing or decreasing the magnitude of a fixed, predefined dose.

[0162] In such Figure 5In the example shown, 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. To rotate the regulator 70 relative to the piston rod 5, a torque higher than a predefined regulating torque must be applied to the regulator 70. The regulating torque is typically greater than the driving torque required to shift the piston rod 5 in the distal direction 22 during dose dispensing, i.e., the torque required to push the piston 13 in the distal direction 22 relative to the cartridge body 33 of the cartridge 12. In this way, it provides that during the dose dispensing process, as the piston rod undergoes rotation relative to the body 1, the rod extension 50 and the regulator 70 remain locked in direction to the piston rod 5.

[0163] exist Figure 6 , Figure 9 and Figure 10 Another example of the injection device 30 is shown in the image. Figure 6 The example further includes an intermediate component 60. The intermediate component 60 includes a sleeve 61 that is radially sandwiched between a sleeve section 76 of the adjuster 70 and a rod section 56 of the rod extension 50. For example... Figure 9 As shown, the intermediate member 60 is splinedly engaged with both the rod extension 50 and the adjuster 70. For this purpose, the intermediate member 60 includes a spline feature 64 that engages with the spline feature 74 of the adjuster 70. The intermediate member 60 further includes a further spline feature 66 that splinely engages with the spline feature 54 of the rod extension. In this way, the adjuster 70 slides freely relative to the intermediate member 60 in the longitudinal direction while remaining locked to the intermediate member 60 in steering.

[0164] In the same manner, the rod extension 50 slides freely relative to the intermediate member 60 in the longitudinal or axial direction, while remaining locked to and connected to the intermediate member 60 in the steering direction. The adjusting torque applied by the user to the adjuster 70 can be transmitted to the rod extension 50 through the intermediate member 62, thereby causing a change in the total elongation of the rod assembly 58.

[0165] As from Figure 6 and Figure 10 As is evident, the intermediate member 60 is permanently ratchetedly engaged with the piston rod 5. For this purpose, the piston rod 5 includes a ratchet feature 45 on its inner sidewall. The ratchet feature 45 includes a toothed ring extending along the inner circumference of the hollow piston rod 5. The toothed ring includes a plurality of radially inwardly projecting teeth 47. The correspondingly formed ratchet feature 65 of the intermediate member 60 includes at least one radially outwardly extending tooth 67 that ratchetly engages with the continuous teeth 47 of the ratchet feature 45.

[0166] like Figure 10As shown, the intermediate member 60 includes two opposing ratchet features 65. The ratchet features 65 may be located on one or more flexible arms configured to bend or deflect radially inward as the intermediate member 60 rotates relative to the piston rod 5. Two or more arms with ratchet features 65 may be arranged oppositely or equidistantly. In this way, the process torque can be distributed among the individual teeth 67 of the ratchet features 65. The ratchet engagement of the intermediate member 60 with the piston rod 5 defines the process torque and prevents self-actuated or automatic rotation of the rod extension 50 relative to the piston rod 5 during dose dispensing.

[0167] To adjust the dosage, an adjusting torque must be applied to the regulator 70 and thus to the intermediate member 60, wherein the adjusting torque is greater than the holding torque. Therefore, the ratchet feature 65 will undergo a radially inward directional movement, which allows and supports a clearly defined, gradual rotation of the intermediate member 60 and therefore the rod extension 50 relative to the piston rod 5. To set the dosage, the piston rod 5 is prevented from rotating due to the interaction described above with the stop features 17, 19 and due to the threaded engagement with the actuator 8.

[0168] List of reference numerals

[0169] 1. Main Body

[0170] 2. Remote

[0171] 3 Proximal

[0172] 4 axis

[0173] 5. Piston rod

[0174] 6 threads

[0175] 7 nuts

[0176] 8 drives

[0177] 9 buttons

[0178] 10 Guiding Features

[0179] 11 Attachable parts

[0180] 12 medicine cartridges

[0181] 13 Pistons

[0182] 14 bearings

[0183] 15 Flexible guidance features

[0184] 16 thread

[0185] 17. Stopping characteristics

[0186] 18 thread

[0187] 19. Stopping characteristics

[0188] 20 lines

[0189] 22 Distal direction

[0190] 23. Proximal direction

[0191] 25 Spline Features

[0192] 26 thread

[0193] 30 Injection Device

[0194] 32 Drive mechanism

[0195] 33. Cylinder

[0196] 34. Pierceable seals

[0197] 35 medicines

[0198] 40 Receiver

[0199] 41. Port

[0200] 42 Neck

[0201] 43 End face

[0202] 44 cavities

[0203] 45. Ratchet characteristics

[0204] 47 teeth

[0205] 50-bar extension

[0206] 51 thread

[0207] 52 handles

[0208] 54 Spline Features

[0209] 56 pole section

[0210] 58-bar assembly

[0211] 60 Middleware

[0212] 61 Sleeve

[0213] 64 Spline Features

[0214] 65. Ratchet characteristics

[0215] 66 Spline features

[0216] 67 teeth

[0217] 70 Regulator

[0218] 71 Distal Section

[0219] 72 cavities

[0220] 73 Proximal segment

[0221] 74 Spline Features

[0222] 75 head

[0223] 76 Sleeve Section

[0224] 77 End Face

[0225] 78 recess

[0226] 79 Proximal

Claims

1. An injection device (30) configured to dispense a dose of medication, said injection device (30) comprising: - An elongated shell (1) that extends in the longitudinal direction - A piston rod (5) that is movable relative to the housing (1) in a longitudinal distal direction (22) to apply dispensing pressure to the stopper (13) of a cartridge (12) that is at least partially filled with an injectable drug (35). - A rod extension (50), which is movably disposed above or in the distal end of the piston rod (5) and threadedly engaged with the distal end of the piston rod (5). - A driver (8), which is operatively engaged with the piston rod (5) and movable relative to the housing (1) in the longitudinal proximal direction (23) for setting the dose, and movable relative to the housing (1) in the longitudinal distal direction (22) for dispensing the dose. - A regulator (70) disposed above or in the actuator (8) and locked in direction to the rod extension (50), wherein the regulator is rotatable in a first direction for causing a distally oriented displacement of the rod extension relative to the piston rod to increase the dose, and wherein the regulator is rotatable in a second direction opposite to the first direction for causing a proximally oriented displacement of the rod extension relative to the piston rod to decrease the dose.

2. The injection device according to claim 1, wherein, The adjuster (70) is user-operable and allows the rod extension (50) to be moved longitudinally relative to the piston rod (5) independently.

3. The injection device according to claim 1 or 2, wherein, The drive (8) is locked to the housing (1) in steering and slides freely along the longitudinal direction of the housing (1).

4. The injection device according to claim 1 or 2, wherein, The driver (8) is threadedly engaged with the piston rod (5).

5. The injection device according to claim 1 or 2, wherein, The piston rod (5) includes at least one flexible guide feature (15) that threadedly engages with the thread (18) of the actuator (8).

6. The injection device according to claim 1 or 2, wherein, The regulator (70) is axially engaged with the driver (8).

7. The injection device according to claim 1 or 2, wherein, The adjuster (70) is longitudinally slidably engaged with the rod extension (50).

8. The injection device according to claim 1 or 2, wherein, The piston rod (5) is hollow and includes a hollow cavity (44).

9. The injection device according to claim 8, wherein, The rod extension (50) is located within the hollow cavity (44) of the piston rod (5).

10. The injection device according to claim 1 or 2, wherein, when an adjusting torque higher than a predefined holding torque is applied to the adjuster (70), the adjuster (70) is rotatable relative to the piston rod (5), wherein, The holding torque is greater than the driving torque required to shift the piston rod (5) in the distal direction (22) during the dispensing of the agent.

11. The injection device according to claim 10, further comprising at least one of frictional engagement and ratchet engagement between the regulator (70) and the piston rod (5), wherein, At least one of the friction engagement and the ratchet engagement defines the predefined holding torque.

12. The injection device according to claim 1 or 2, further comprising an intermediate member (60) disposed between the rod extension (50) and the adjuster (70), wherein, The intermediate component (60) is locked to the rod extension (50) in steering and to the adjuster (70) in steering.

13. The injection device according to claim 12, wherein, The intermediate member (60) is longitudinally slidably engaged with at least one of the rod extension (50) and the adjuster (70), wherein the intermediate member (60) is in rotational ratchet engagement with the piston rod (5).

14. The injection device according to claim 1 or 2, wherein, The regulator (70) includes a distal section (71) and a proximal section (73), wherein the distal section (71) is operatively engaged with the rod extension (50), and wherein the proximal section (73) of the regulator (70) is supported in the interior of the drive (8) for steering.

15. The injection device according to claim 1 or 2, further comprising a button (9) axially engaged with the driver (8), and wherein, The proximal end (79) of the regulator (70) is arranged in the receiver (40) of the proximal end face (43) of the button (9).

16. The injection device according to claim 15, wherein, The regulator (70) includes a longitudinally extending sleeve section (76) and a head (75), wherein the head (75) is radially wider than the sleeve section (76), wherein the head (75) is located at the proximal end of the sleeve section (76), and wherein the head (75) forms the proximal end (79) of the regulator (70).

17. The injection device according to claim 16, wherein, The head (75) includes a proximal surface (77) located distal to the proximal surface (43) of the button (9).

18. The injection device according to claim 1 or 2, further comprising the cartridge (12) disposed inside the housing (1).

19. The injection device according to claim 1 or 2, wherein, The piston rod (5) is threadedly engaged with the housing (1).

20. The injection device according to claim 1 or 2, wherein, The regulator (70) includes a sleeve section (76), wherein the rod extension (50) includes a rod section (56), and wherein the rod section (56) and the sleeve section (76) are located inside the hollow cavity (44) of the piston rod (5).

21. The injection device according to claim 1 or 2, further comprising a rod assembly (58) of variable length, the rod assembly (58) comprising the piston rod (5) and the rod extension (50) connected to the piston rod, wherein the length of the rod assembly (58) depends on the longitudinal or axial position of the rod extension (50) relative to the piston rod (5).

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