Drug delivery device and assembly method for a drug delivery device.

Abstract

Drug delivery device and method of assembly for a drug delivery device. The present invention relates to a drug delivery device comprising a housing (5, 10) with an opening (12), a piston rod (11) having a proximal end and a distal end, at least one part with an interface (14) adapted to engage in the opening (12) to guide the piston rod (11) during a distal or proximal movement of the piston rod (11) relative to the housing (5, 10) and at least one first fastening element (15) located at the distal end; and a bearing (16) with at least one second fastening element (17, 18) for rotary fastening of the bearing (16) at the distal end of the piston rod (11).at least one first fastening element (15) and / or at least one second fastening element (17, 18) is elastically deformable in a radial direction for engagement of the piston rod (11) and bearing (5, 10). The opening (12) comprises at least one part having a contour adapted to receive at least one first fastening element (15) and at least one second fastening element (17, 18) if fastened to each other, but preventing the disengagement of at least one first fastening element (15) and at least one second fastening element (17, 18) if received in the opening (12). Furthermore, the present invention relates to a mounting method for a drug delivery device.

Description

[001] The present invention is generally directed to a drug delivery device, for example, an injection device for selecting and delivering a variable number of user doses of a drug. The invention is further directed to a method of assembling a drug delivery device.

[002] Pen-type drug delivery devices have applications where regular injections are performed by people without formal medical training. This may be increasingly common among patients with diabetes, where self-treatment allows these patients to conduct effective management of their disease. In practice, such a drug delivery device allows a user to individually select and administer a series of variable user doses of a medication. The present invention is further directed to so-called fixed-dose devices that allow only the administration of a predefined dose without the possibility of increasing or decreasing the established dose.

[003] There are basically two types of drug delivery devices: resettable (i.e., reusable) and non-resettable (i.e., disposable) devices. For example, disposable pen administration devices are supplied as stand-alone devices. These stand-alone devices do not have removable pre-filled cartridges. Instead, the pre-filled cartridges cannot be removed and replaced from these devices without destroying the device itself. Consequently, such disposable devices do not need to have a resettable dose adjustment mechanism. The present invention is applicable to both types of devices, i.e., to disposable devices and also to reusable devices. Petition 870250052998, dated 06 / 24 / 2025, page 7 / 68 2 / 23

[004] These types of pen-type administration devices (so called because they generally resemble an enlarged fountain pen) generally comprise three main elements: a cartridge section that includes a cartridge usually contained in a housing or holder; a needle assembly connected to one end of the cartridge section; and a dose adjustment section connected to the other end of the cartridge section. A cartridge (often referred to as an ampoule) typically includes a reservoir that is filled with a medication (e.g., insulin), a movable rubber stopper or cap located at one end of the cartridge reservoir, and a top with a puncture-capable rubber seal located at the other end, usually necked downwards. A corrugated ring-shaped metal band is typically used to hold the rubber seal in place.Although cartridge casings are typically made of plastic, cartridge reservoirs have historically been made of glass.

[005] The needle assembly is typically a replaceable double-ended needle assembly. Before an injection, a replaceable double-ended needle assembly is connected to one end of the cartridge assembly, a dose is set, and then the set dose is administered. Such removable needle assemblies may be threaded or pushed (i.e., fitted) into the puncture-capable sealing end of the cartridge assembly.

[006] The dose adjustment section or dose adjustment mechanism is typically the part of the pen device that is used to set (select) a dose. During an injection, a spindle or piston rod contained in the dose adjustment mechanism presses against the cap or stopper of the cartridge. This force causes the medication contained in the cartridge to be injected through an attached needle assembly. After an injection, as generally recommended by most of the Petition 870250052998, dated 06 / 24 / 2025, page 8 / 68 3 / 23 manufacturers and suppliers of drug delivery devices and / or needle sets, the needle set is removed and discarded.

[007] Another differentiation of drug delivery device types refers to the actuation mechanism: There are devices that are manually actuated, for example, by a user applying force to an injection button, devices that are actuated by a spring or similar, and devices that combine these two concepts, i.e., spring-assisted devices that still require a user to exert an injection force. Spring-type devices involve springs that are pre-loaded and springs that are charged by the user during dose selection. Some stored-energy devices use a combination of spring pre-loading and additional energy supplied by the user, for example, during dose adjustment.

[008] Known drug delivery devices typically comprise a housing with an opening and a piston rod having a proximal end and a distal end, wherein at least one part of the piston rod is provided with an interface adapted to engage the opening to guide the piston rod during a distal or proximal movement of the piston rod relative to the housing and at least one first fastening element located at the distal end. A bearing may be provided with at least one second fastening element for rotary fastening of the bearing at the distal end of the piston rod. An example of drug delivery devices comprising a pressure foot or bearing located at the distal end of the piston rod or spindle is shown in EP 2 437 821 B1, wherein the bearing is arranged to abut one end of the cartridge or plug piston.

[009] Document EP 2 437 827 B1 describes a combination Petition 870250052998, dated 06 / 24 / 2025, page 9 / 68 4 / 23 spindle and bearing comprising a rotating spindle having a distal end and a disc-shaped bearing coupled to the distal end of the spindle through a first connection comprising a web that securely fastens the bearing to the spindle to prevent independent movement of the bearing relative to the spindle. This first connection is replaced during assembly by a second connection that is created when the web is cut (trimmed) and the web is disconnected from the bearing. The second connection is a rotary joint connection, i.e., one where the spindle can rotate freely.

[010] The assembly of such drug delivery devices may include an initial sequence of assembly steps to provide a sub-assembly of the mechanism that may undergo final assembly by combining the mechanism sub-assembly with a cartridge. Final assembly may occur at a location remote from where the mechanism sub-assembly is produced. This may involve transporting and storing the mechanism sub-assembly with the bearing and piston rod.

[011] In some drug delivery devices, the piston rod must be mounted from the proximal end (button) of the device through, for example, the threaded opening in the housing. This requires that the diameter of any fitting connection feature for the bearing be smaller than the inside diameter of the threaded hole in the housing. This diameter is, for example, only 3 mm, and this makes a robust fitting connection more challenging to design.

[012] The axial load of the piston rod during administration must be transferred to the bearing using a contact surface as close as possible to a contact point. This is to reduce the effects of friction when the piston rod rotates during administration relative to the bearing. This contact point must be on the axis of the Petition 870250052998, dated 06 / 24 / 2025, page 10 / 68 5 / 23 device, so that as the piston rod rotates on this axis, the contact point does not move off the axis.

[013] Furthermore, the features used to connect the bearing to the piston rod must be formable without adding any further complication to the design of the forming tools that make these two parts. Essentially, this means that the features must be formable with simple open and close tool construction whenever possible, and at most two slides if necessary.

[014] Once connected, it should be difficult to pull the bearing off the end of the piston rod. This is to ensure that, during transport of the mechanism subassembly before final assembly, the bearing does not fall out. After final assembly of the disposable pen, the bearing is secured between the mechanism and the cartridge, and therefore the risk of it falling out at this point is minimal. Furthermore, once partially administered, this bearing retention is not necessary, as the bearing is inside the cartridge and is prevented from moving axially.

[015] It is therefore an object of the present invention to provide a drug delivery device comprising a bearing, preferably with a point of contact with the piston rod, which is easy to assemble but is securely retained in the sub-assembled condition before final assembly in the complete device.

[016] This objective is solved by a drug delivery device as defined in claim 1 and an assembly method as defined in claim 13.

[017] In a drug delivery device according to the present invention, at least one first fastening element and / or at least one second fastening element is elastically deformable in a radial direction for engagement of the piston rod and bearing. Furthermore, the opening comprises at least Petition 870250052998, dated 06 / 24 / 2025, page 11 / 68 6 / 23 a part having a contour adapted to receive at least one first fastening element and at least one second fastening element if fastened to each other. On the other hand, the contour of the opening is adapted to the fastening elements so that the opening prevents or at least impedes the disengagement of at least one first fastening element and at least one second fastening element if received in the opening. For example, the opening part may be adapted to receive or enclose the first and second fastening elements with a clearance fit or an interference fit allowing axial movement of the bearing and piston rod, preferably without friction due to contact with the inside of the opening. The clearance or interference fit may be chosen so that the elastic deformation of the fastening element(s) required for disengagement is blocked by the opening.

[018] The present invention is based on the idea of ​​fixing the bearing to the piston rod, for example, in a disposable injection pen, so that the bearing is locked in the transport position to reduce the risk of falling out before final assembly. The present invention relates preferably to, but is not limited to, disposable pen-type devices where good bearing retention is required only for the purpose of transporting the mechanism before final assembly in a device.

[019] A drug delivery device according to the present invention may have a very simple design, wherein the piston rod may be operated directly by a user by pulling, pushing and / or rotating the piston rod during use, for example, for dose administration. Alternatively, the drug delivery device may further comprise at least one drive element operatively coupled to the piston rod to displace the piston rod in the distal direction during administration of Petition 870250052998, dated 06 / 24 / 2025, page 12 / 68 7 / 23 dose and / or a dose-defining element operatively coupled to the carcass to select a dose.

[020] In order to lock the bearing in the transport position during the assembly of the drug delivery device, the piston rod can be axially movable between a distal mounting position in which at least one first fastening element and at least one second fastening element are located distally from the opening and a proximal transport position in which at least one first fastening element and at least one second fastening element are received in the opening. In other words, with the piston rod in the distal mounting position, the bearing is secured by allowing radial expansion of the respective fastening element(s), since the opening does not interfere with such expansion.On the other hand, with the piston rod retracted into its proximal transport position, the opening of the housing or the respective part of the opening prevents the enlargement of the respective fastening element(s) at least in such a way that the disengagement of the piston rod bearing is prevented, thus locking the bearing onto the piston rod.

[021] In one example of the present invention, the opening is provided with an internal thread wherein the interface adapted for engaging the opening to guide the piston rod during a distal or proximal movement of the piston rod relative to the housing comprises an external thread. In this case, at least one part having a contour adapted to receive at least one first fastening element and at least one second fastening element may comprise the internal thread. Thus, the axial movement of the piston rod normally involves a combined rotation and displacement along a helical path. However, although the overall engagement of the piston rod and housing for dose administration may be in the form of a threaded interface, a pure axial displacement for a distance Petition 870250052998, dated 06 / 24 / 2025, page 13 / 68 8 / 23 short distances, for example, between the distal mounting position and the proximal transport position, may be allowed without rotation.

[022] Alternatively, the opening is provided with a non-circular cross-section wherein the interface adapted for engaging the opening to guide the piston rod during a distal or proximal movement of the piston rod relative to the housing comprises a corresponding non-circular cross-section, for example, in the form of a groove, a slot, a rib and / or a flattening. In this case, at least one part having a contour adapted to receive at least one first fastening element and at least one second fastening element may comprise a protrusion.

[023] According to an example of the invention, the bearing may comprise a disc for abutting a cartridge plug and at least one second bearing fastening element may comprise a shoulder or rod extending proximally from the near side of the disc. The shoulder may be provided with at least one radial recess allowing engagement by snap-fit ​​with the piston rod. In this case, at least one first piston rod fastening element may comprise at least one pressure hook adapted for engagement in at least one radial recess of the bearing. This design is similar to the design of existing products on the market, which facilitates the implementation of this feature in production and assembly. In other words, in this configuration the bearing has a male shoulder that connects to female snap-fit ​​features on the piston rod.However, similarly, the piston rod can house the shoulder and bearing fitting features, for example, at least one pressure hook, although for low-friction operation, the domed end of the shoulder is preferably shaped without a dividing line. The piston rod can be mounted in either way (end to end) and a shoulder with a domed end can be shaped. Petition 870250052998, dated 06 / 24 / 2025, page 14 / 68 9 / 23 at both ends, this would require two additional slides, making the tooling for this part more complex with fewer cavities per tool, when compared to molding the dome in the bearing.

[024] With respect to the present invention, the term housing is not limited to an external body or housing of the device. Instead, the housing may be an internal component of the housing or an insert. Such an internal housing component or insert may be a separate component part or may be a unitary part of an external body or housing of the device.

[025] For a drug delivery device comprising at least one housing with an opening, a piston rod having a proximal end and a distal end and at least one first fastening element located at its distal end and a bearing with at least one second fastening element for rotary attachment of the bearing to the distal end of the piston rod, a method of assembly according to the present invention comprises the steps of introducing the piston rod, for example, in the distal direction, into the housing so that the distal end of the piston rod projects distally through the opening, then securing the bearing to the piston rod by engaging at least one first fastening element and at least one second fastening element and then,By retracting the piston rod in the proximal direction until at least one first fastening element and at least one second fastening element are at least partially engaged in the compartment opening. This retraction of the piston rod serves to block the fastening elements, for example, the fittings, from radially outward deflection and therefore prevents the bearing from loosening without a considerable force being applied.

[026] Steps for introducing the piston rod in the distal direction Petition 870250052998, dated 06 / 24 / 2025, page 15 / 68 10 / 23 in the housing and / or retraction of the piston rod in the proximal direction may involve a combined rotation and translation of the piston rod, for example, along a helical path. Furthermore, the step of securing the bearing to the piston rod may involve elastically deforming at least one first fastening element and / or at least one second fastening element in a radial direction.

[027] The injection device normally comprises a cartridge containing a drug. Thus, the assembly method may further comprise the step of attaching a cartridge holder containing a drug cartridge to the housing so that the bearing rests against a plug in the cartridge.

[028] The term medicine, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,

[029] wherein in one embodiment the pharmaceutically active compound has a molecular weight of up to 1500 Da and / or is a peptide, a protein, a polysaccharide, a vaccine, DNA, RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the pharmaceutically active compound mentioned above,

[030] wherein, in another embodiment, the pharmaceutically active compound is useful for the treatment and / or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus, such as diabetic retinopathy, thromboembolic disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis;

[031] wherein, in another embodiment, the pharmaceutically active compound comprises at least one peptide for the treatment and / or prophylaxis of diabetes mellitus or complications associated with Petition 870250052998, dated 06 / 24 / 2025, page 16 / 68 11 / 23 diabetes mellitus, such as diabetic retinopathy;

[032] wherein, in another embodiment, the pharmaceutically active compound comprises at least one human insulin or an analogue or derivative of human insulin, a glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.

[033] Insulin analogues are, for example, human insulin Human insulin Lys (B3), Glu (B29); Human insulin Lys (B28), Pro (B29); Human insulin Asp (B28); human insulin, wherein proline at position B28 is replaced by Asp, Lys, Leu, Vai or Ala and wherein at position B29 Lys can be replaced by Pro; Human insulin Ala (B26); Human insulin Des (B28-B30); Human insulin Des (B27) and human insulin Des (B30).

[034] Insulin derivatives are, for example, human insulin B29-N-myristoyl-des (B30); Human insulin B29-N-palmitoyl-des (B30); B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; Human insulin B28-N-myristoyl LysB28ProB29; Human insulin B28-Npalmitoyl-LysB28ProB29; Human insulin B30-N-myristoylThrB29LysB30; Human insulin B30-N-palmitoyl-ThrB29LysB30; Human insulin B29-N-(N-palmitoyl-Y-glutamyl)-des (B30); Human insulin B29-N-(N-lithocholyl-Y-glutamyl)-des (B30); Human insulin B29N- (co-carboxyheptadecanoyl)-des (B30) and human insulin B29-N- (cocarboxyheptadecanoyl).

[035] Exendin-4, for example, means Exendin-4 (1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-LeuSer-Lys-GIn-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-LeuLys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

[036] Exendin-4 derivatives are, for example, selected from the following list of compounds:

[037] H- (Lys) 4-des Pro36, des Pro37 Exendin-4 (1-39) -NH2, Petition 870250052998, dated 06 / 24 / 2025, page 17 / 68 12 / 23

[038] H- (Lys) 5-des Pro36, des Pro37 Exendin-4 (1-39) -NH2,

[039] des Pro36 Exendin-4 (1-39),

[040] des Pro36[Asp28] Exendin-4 (1-39),

[041] des Pro36[lsoAsp28] Exendin-4 (1-39),

[042] des Pro36 [Met (O) 14, Asp28] Exendin-4 (1-39),

[043] des Pro36 [Met (O) 14, lsoAsp28] Exendin-4 (1-39),

[044] des Pro36 [Trp (O2) 25, Asp28] Exendin-4 (1-39),

[045] des Pro36 [Trp (O2) 25, lsoAsp28] Exendin-4 (1-39),

[046] des Pro36 [Met (O) 14 Trp (O2) 25, Asp28] Exendin-4 (139),

[047] des Pro36 [Met (O) 14 Trp (O2) 25, lsoAsp28] Exendina-4 (139); or

[048] des Pro36[Asp28] Exendin-4 (1-39),

[049] des Pro36[lsoAsp28] Exendin-4 (1-39),

[050] des Pro36 [Met (O) 14, Asp28] Exendin-4 (1-39),

[051] des Pro36 [Met (O) 14, lsoAsp28] Exendin-4 (1-39),

[052] des Pro36 [Trp (O2) 25, Asp28] Exendin-4 (1-39),

[053] des Pro36 [Trp (O2) 25, lsoAsp28] Exendin-4 (1-39),

[054] des Pro36 [Met (O) 14 Trp (O2) 25, Asp28] Exendin-4 (139),

[055] des Pro36 [Met (O) 14 Trp (O2) 25, lsoAsp28] Exendina-4 (139.

[056] In which the -Lys6-NH2 group can be attached to the C-terminal of the Exendin-4 derivative;

[057] Or an Exendin-4 derivative of the sequence;

[058] des Pro36 Exendin-4 (1-39) -Lys6-NH2 (AVE0010),

[059] H- (Lys) 6-des Pro36 [Asp28] Exendin-4 (1-39) -Lys6-NH2,

[060] des Asp28 Pro36, Pro37, Pro38Exendin-4 (1-39) -NH2,

[061] H- (Lys) 6-des Pro36, Pro38 [Asp28] Exendin-4 (1-39) NH2, Petition 870250052998, dated 06 / 24 / 2025, p. 18 / 68 13 / 23

[062] H-Asn- (Glu) 5des Pro36, Pro37, Pro38 [Asp28] Exendin-4 (1-39)-NH2,

[063] des Pro36, Pro37, Pro38 [Asp28] Exendin-4 (1-39) - (Lys) 6-NH2,

[064] H- (Lys) 6-des Pro36, Pro37, Pro38 [Asp28] Exendina-4 (139) - (Lys) 6-NH2, H-Asn- (Glu) 5-des Pro36, Pro37, Pro38 [Asp28] Exendina-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-des Pro36 [Trp (O2) 25, Asp28] Exendina-4 (1-39) -Lys6-NH2, H-des Asp28 Pro36, Pro37, Pro38 [Trp (O2) 25] Exendina-4 (1-39) -NH2, H- (Lys) 6-des Pro36, Pro37, Pro38 [Trp (O2) 25, Asp28] Exendina-4 (1-39) -NH2, H-Asn(Glu) 5-des Pro36, Pro37, Pro38 [Trp (O2) 25, Asp28] Exendina-4 (1-39) -NH2, des Pro36, Pro37, Pro38 [Trp (O2) 25, Asp28] Exendina-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-des Pro36, Pro37, Pro38 [Trp (O2) 25, Asp28] Exendina-4 (1 -39) - (Lys) 6-NH2, H-Asn- (Glu) 5-des Pro36, Pro37, Pro38 [Trp (O2) 25, Asp28] Exendina-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6des Pro36 [Met (0) 14, Asp28] Exendina-4 (1-39) -Lys6-NH2, des Met (0) 14 Asp28 Pro36, Pro37, Pro38 Exendina-4 (1- 39) -NH2, H- (Lys) 6desPro36, Pro37, Pro38 [Met (0) 14, Asp28] Exendina-4 (1-39) -NH2, HAsn- (Glu) 5-des Pro36, Pro37, Pro38 [Met (0) 14,Asp28] Exendin-4 (1-39) -NH2, des Pro36, Pro37, Pro38 [Met (0) 14, Asp28] Exendin-4 (1-39) - (Lys) six -NH2, H- (L ys) 6-des Pro36, Pro37, Pro38 [Met (0) 14, Asp28] Exendin-4 (1-39) - (Lys) 6-NH2, H-Asn- (Glu) 5 des Pro36, Pro37, Pro38 [Met (0) 14, Asp28] Exendin-4 (1-39) - (Lys) 6-NH2, HLys6-des Pro36 [Met (0) 14, Trp (O2) 25, Asp28] Exendin-4 (1 -39) Lys6-NH2, H-des Asp28 Pro36, Pro37, Pro38 [Met (0) 14, Trp (O2) 25] Exendin-4 (1-39) -NH2, H- (Lys) 6-des Pro36, Pro37, Pro38 [Met (0) 14, Asp28] Exendin-4 (1-39) -NH2, H-Asn- (Glu) 5-des Pro36, Pro37, Pro38 [Met (0) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39) -NH2, des Pro36, Pro37, Pro38 [Met (0) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39) - (Lys)6- NH2, H- (Lys) 6-des Pro36, Pro37, Pro38 [Met (0) 14, Trp (O2), Petition 870250052998, dated 06 / 24 / 2025, page 19 / 68 14 / 23 25, Asp28] Exendin-4 (S1-39) - (Lys) 6- NH2, H-Asn- (Glu) 5-des Pro36, Pro37, Pro38 [Met (0) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39) - (Lys) 6-NH2;

[065] Or a pharmaceutically acceptable salt or solvate of any of the Exendin-4 derivatives mentioned above.

[066] Hormones are, for example, pituitary hormones or hypothalamic hormones or active regulatory peptides and their antagonists, as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropin (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropin (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.

[067] A polysaccharide is, for example, a glycosaminoglycan, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra-low molecular weight heparin or a derivative thereof, or a sulfated form, for example, a polysulfated form of the polysaccharides mentioned above and / or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a low molecular weight polysulfated heparin is enoxaparin sodium.

[068] Antibodies are globular plasma proteins (~150 kDa), also known as immunoglobulins, that share a basic structure. Because they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units as with teleost fish IgM, or pentameric with five Ig units as with mammalian IgM.

[069] The Ig monomer is a Y-shaped molecule consisting of four polypeptide chains; two heavy chains Petition 870250052998, dated 06 / 24 / 2025, page 20 / 68 15 / 23 identical cysteines and two identical light chains connected by disulfide bonds between cysteine ​​residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Each of the heavy and light chains contains intra-chain disulfide bonds that stabilize its folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (e.g., variable or V and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β-sheets create a sandwich shape, held together by interactions between conserved cysteines and other charged amino acids.

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

[071] Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε contain approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In a species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. The γ, α, and δ heavy chains have a constant region composed of three tandem Ig domains and a hinge region for greater flexibility; the μ and ε heavy chains have a constant region composed 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. The variable region of each heavy chain is approximately 110 Petition 870250052998, dated 06 / 24 / 2025, page 21 / 68 16 / 23 amino acids in length and is composed of a single Ig domain.

[072] In mammals, there are two types of immunoglobulin light chains denoted by λ and k. A light chain has two successive 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 light chains that are always identical; only one type of light chain, k or λ, is present per antibody in mammals.

[073] Although the overall structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable regions (V), as detailed above. More specifically, variable loops, three of each in the light chain (VL) and three in the heavy chain (VH), are responsible for antigen binding, that is, for its antigen specificity. These loops are called Complementarity-Determining Regions (CDRs). Because the CDRs of both the VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and light chains, and not alone, that determines the final antigen specificity.

[074] 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 proteolytic digestion with papain splits the Ig prototype into three fragments. Two identical amino-terminal fragments, each containing an entire L chain and about half of an H chain, are the antigen-binding fragments (Fab). The third fragment, similar in size but containing the carboxyl-terminal half of both heavy chains with their inter-chain disulfide bond, is the crystallizable fragment (Fc). The Fc contains carbohydrates, complement-binding sites, and FcR-binding sites. Limited pepsin digestion yields a single F(ab') fragment. Petition 870250052998, dated 06 / 24 / 2025, page 22 / 68 17 / 23 containing both Fab fragments and the articulation region, including the inter-chain disulfide linkage HH. F(ab')2 is divalent for antigen binding. The disulfide linkage of F(ab')2 can be cleaved to obtain Fab'. In addition, the variable regions of the heavy and light chains can be fused together to form a single-chain variable fragment (scFv).

[075] Pharmaceutically acceptable salts are, for example, acid addition salts and basic salts. Acid addition salts are, for example, salts of HCl or HBr. Basic salts are, for example, salts with a cation selected from an alkali or alkaline, for example, Na+, or K+, or Ca2+, or an ammonium ion N+ (R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other means: hydrogen, an optionally substituted alkyl-C1-C6 group, an optionally substituted alkenyl-C2-C6 group, an optionally substituted aryl-C6-C10 group, or an optionally substituted heteroaryl-C6-C10 group. Other examples of pharmaceutically acceptable salts are described in Remington's Pharmaceutical Sciences 17th ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., USA, 1985 and in Encyclopedia of Pharmaceutical Technology.

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

[077] Non-limiting exemplary embodiments of the invention will now be described with reference to the accompanying drawings, in which:

[078] Figure 1 shows a drug delivery device with a dose-setting mechanism according to an aspect of the present invention;

[079] Figure 2 shows the drug delivery device in Figure 1 with a cap removed and showing a cartridge holder;

[080] Figure 3 shows a cross-sectional view of an embodiment. Petition 870250052998, dated 06 / 24 / 2025, p. 23 / 68 18 / 23 of the drug delivery device according to the invention before mounting a bearing; and

[081] Figure 4 shows a cross-sectional view of the realization of Figure 1 after the bearing assembly.

[082] With reference to Figure 1, a drug delivery device 1 is shown according to an exemplary arrangement. The drug delivery device 1 comprises a distally disposed cartridge retention part 2 and a proximally disposed dose setting mechanism 3. The drug delivery device may be a resettable drug delivery device (i.e., a reusable device) or, alternatively, a non-resettable drug delivery device (i.e., a non-reusable device). The cartridge retention part 2 and the dose setting mechanism 3 are fastened together by connecting features. For non-resettable devices, these connecting features would be permanent and irreversible. For resettable devices, these connecting features would be releaseable.

[083] In this illustrated arrangement, the cartridge retention part 2 is fixed within the dose adjustment mechanism 3. A removable cover 4 is removablely retained over the cartridge retention part 2. The dose adjustment mechanism 3 is surrounded by an outer housing 5 and comprises a dose dimmer 6 and a window or lens 7. A dose scale arrangement 8 is visible through the window or lens 7.

[084] To set a dose of medication contained in the drug delivery device 1, a user rotates the dose regulator 6 relative to the outer housing 5 so that a marked dose becomes visible in the window or lens 7 by means of the dose scale arrangement 8. Dose adjustment may involve a proximal movement of the dose regulator 6 relative to the outer housing 5, as shown in Figure 2. Petition 870250052998, dated 06 / 24 / 2025, p. 24 / 68 19 / 23 Administering the dose may involve pushing the dose regulator back in a distal direction.

[085] Figure 2 illustrates the drug delivery device of Figure 1 with the cap 4 removed from a distal end of the device 1. This removal exposes a cartridge holder 9. A cartridge (not shown) from which a series of doses of a drug can be administered is provided in the cartridge holder 9. The cartridge comprises a stopper or cork (not illustrated in Figure 2) which is retained near a proximal end of the cartridge.

[086] The drug delivery device, in particular the dose setting mechanism 3, may also comprise an inner housing 10 or insert which may be a separate component part, as shown in Figure 3, or may be an integral part of the outer housing 5. The drug delivery device further comprises a piston rod 11 or a spindle having a distal end facing the cartridge retention part 2 and an opposite proximal end.

[087] In the embodiment shown in Figure 3, the inner housing 10 is provided with a central opening 12 that receives the piston rod 11. As an alternative to the embodiment shown, the opening 12 can be provided directly in the outer housing 5. The opening 12 is provided with an internal thread 13 interacting with an external thread 14 of the piston rod 11. Thus, rotation of the piston rod 11 relative to the inner housing 10 results in an axial displacement of the piston rod 11 relative to the inner housing 10. The distal end of the piston rod 11 is provided with a female fitting feature, for example, comprising two flexible hooks 15. The hooks 15 are designed so that they can be elastically deformed in a radial direction, thus widening the female fitting feature.

[088] The dimensions of the central opening 12 with its internal thread Petition 870250052998, dated 06 / 24 / 2025, page 25 / 68 20 / 23 and for the flexible hooks 15 are chosen so that the central opening 12 and the internal thread 13 do not interfere with the flexible hooks 15 in the untensioned (at rest) condition of the hooks as shown in Figures 3 and 4. However, the central opening 12 with its internal thread 13 substantially prevents the widening of the flexible hooks 15 in the radial direction. At least one flexible hook 15 constitutes a first fastening element.

[089] The drug delivery device further comprises a bearing 16 which is shown in Figure 3 before attachment to the piston rod 11. The bearing 16 is substantially disc-shaped and comprises a protrusion 17 or rod extending in the proximal direction. The protrusion 17 is provided with an annular recess 18 or groove disposed between the proximal end of the tip 17 and the disc-shaped part of the bearing 16. The protrusion 17 with its recess 18 constitutes a second fastening element. The dimensions of the protrusion 17 and the recess 18 are adapted to the dimensions of the female fitting features, i.e., the flexible hooks 15, of the piston rod 11 so that the bearing 16 can be fixed to the distal end of the piston rod 11 by a fitting engagement of the protrusion 17 within the flexible hooks 15.

[090] As an alternative to the concretizations represented in Figures 3 and 4, the shoulder with the recess can be provided on the piston rod 11 and the female fitting features can be provided on the bearing 16.

[091] Figures 3 and 4 illustrate two steps during the assembly of the drug delivery device 1, especially the fixing of the bearing 16 to the piston rod 11. Figure 3 shows the piston rod 11 advanced through the thread 13 of the inner housing 10 to a distal mounting position and ready to join the bearing 16. To secure the piston rod 11 to the bearing 16, the bearing can be Petition 870250052998, dated 06 / 24 / 2025, page 26 / 68 21 / 23 pushed to the right (as seen in Figure 3) or the piston rod 11 can be advanced by rotating it through the threaded opening in the inner housing 10 by an amount equal to that required to fully assemble the snap-fit ​​connection.

[092] In Figure 4, the piston rod 11 was clamped in the bearing and then the piston rod 11 was rotated back so that it moves to the right (as seen in Figure 4) axially and pulls the bearing 16 back into the threaded region 13 of the inner housing 10. This retraction of the piston rod 11 serves to lock the fittings (hooks 15) of the radial deflection outwards and therefore prevents the bearing 16 from coming loose without a considerable force being applied.

[093] In the example shown in the Figures, the inner housing 10 is provided with a substantially cylindrical coupling part 19 that extends in the distal direction relative to the opening 12. The coupling part 19 can be adapted to rigidly constrain the inner housing 10 to the outer housing 5.

[094] In the exemplary embodiment of Figures 3 and 4, the drug delivery device also comprises the actuator 20 interacting with the piston rod 11, for example, by means of a splined coupling. The actuator 20 may be provided with an external thread engaging a nut 21 which may limit the maximum amount of drug that may be administered from the drug delivery device 1. Figures 3 and 4 further show a portion of the dose adjustment sleeve 22 which may be an integral part of the dose regulator 6 and / or the dose scale arrangement 8. Alternatively, the dose adjustment sleeve 22 may be coupled to the dose regulator 6 and / or the dose scale arrangement 8 and / or the actuator 20.

[095] For example, dose adjustment may involve rotating the dose adjustment sleeve 22 in a first direction by means of the dose regulator 6. This rotation may be a rotation relative to the housing. Petition 870250052998, dated 06 / 24 / 2025, page 27 / 68 22 / 23 external 5 and to the internal housing 10 and / or a rotation in relation to the actuator 20.

[096] Dose administration may involve rotating the dose adjustment sleeve 22 in a second direction that is opposite to the first direction. During dose administration, the actuator 20 may be rotationally coupled to the dose adjustment sleeve 22. The rotation of the actuator 20 may be transferred to the piston rod 11 which, due to the threaded engagement with the inner housing 10, moves in the distal direction after rotation. This distal movement of the piston rod 11 with the bearing 16 may push the cartridge cap in the distal direction to administer a dose of the medication.

[097] Alternatively, rotating the dose adjustment sleeve 22 during dose administration may involve an axial or helical movement of the actuator 20, which may be transferred via a threaded interface to the piston rod 11. This may result in a pure axial or combined axial and rotational movement of the piston rod 11 with the bearing 16 to push the cartridge cap in the distal direction to administer a dose of the medication. Reference numbers for drug delivery device, cartridge holder, housing, dose adjustment mechanism, cap, dose regulator, window / lens, dose scale arrangement, cartridge holder, inner housing, piston rod. Petition 870250052998, dated 06 / 24 / 2025, page 28 / 68 23 / 23 opening internal thread external thread hook / female coupling feature (first fastening element) recess coupling part actuator nut dose adjustment sleeve

Claims

1. Drug administration device, comprising a housing (5, 10) with an opening (12); a piston rod (11) having a proximal end and a distal end, at least one part with an interface (14) adapted to engage in the opening (12) to guide the piston rod (11) during a distal or proximal movement of the piston rod (11) relative to the housing (5, 10) and at least one first fastening element (15) located at the distal end; and a bearing (16) with at least one second fastening element (17, 18) for rotary fastening of the bearing (16) at the distal end of the piston rod (11); wherein at least one first fastening element (15) is elastically deformable in a radial direction for engagement of the piston rod (11) and the bearing (16).characterized in that the opening (12) comprises at least one part having a contour adapted to receive at least one first fastening element (15) and at least one second fastening element (17, 18) if fastened to each other, but preventing the disengagement of at least one first fastening element (15) and at least one second fastening element (17, 18) if received in the opening (12) by preventing the at least one first fastening element (15) from deflecting radially outwards.

2. Drug delivery device, according to claim 1, characterized in that, during the assembly of the drug delivery device, the piston rod (11) can be axially movable between a distal mounting position in which at least one first fastening element (15) and at least one second fastening element (17, 18) are located distally from the opening (12) and a proximal transport position in which at least one first fastening element (15) and at least one second fastening element (17, 18) are received in the opening (12).

3. Drug administration device, according to claim 1 or 2, characterized in that the opening is provided with an internal thread and, wherein the interface (14) adapted to engage in the opening (12) to guide the piston rod (11) during a distal or proximal movement of the piston rod (11) relative to the housing (5, 10) comprises an external thread (14).

4. Drug delivery device according to claim 3, characterized in that at least one part having a contour adapted to receive at least one first fastening element (15) and at least one second fastening element (17, 18) comprises the internal thread (13).

5. Drug delivery device, according to claim 1 or 2, characterized in that the opening is provided with a non-circular cross-section and, wherein the interface adapted to engage in the opening (12) to guide the piston rod (11) during a distal or proximal movement of the piston rod (11) relative to the housing (5, 10) comprises a corresponding non-circular cross-section.

6. Drug delivery device according to claim 5, characterized in that at least one part having a contour adapted to receive at least one first fastening element (15) and at least one second fastening element (17, 18) comprises a protrusion.

7. Drug delivery device, according to any of the preceding claims, characterized in that the bearing (16) comprises a disc for abutting a cartridge stopper and in which at least one second fastening element Petition 870250052998, dated 06 / 24 / 2025, page 31 / 68 3 / 5 (17, 18) comprises a protrusion (17) extending proximally from the near side of the disc, in which the protrusion (17) comprises at least one radial recess (18).

8. Drug delivery device according to claim 7, characterized in that at least one first fastening element (15) of the piston rod (11) comprises at least one pressure hook (15) adapted to engage in at least one radial recess (18) of the bearing (16).

9. Drug delivery device, according to any one of claims 1 to 6, characterized in that at least one first piston rod fastening element (11) comprises a tip at its distal end, wherein the tip comprises at least one radial recess.

10. Drug delivery device according to claim 9, characterized in that the bearing (16) comprises a disc for abutting a cartridge stopper and at least one second fastening element comprises at least one pressure hook extending proximally from the proximal side of the disc and adapted for engaging in at least one radial recess of the piston rod (11).

11. Drug administration device, according to any of the preceding claims, characterized in that it further comprises a drive element (20) operatively coupled to the piston rod (11) for displacing the piston rod (11) in the distal direction and / or a dose adjustment element (6, 8, 22) operatively coupled to the housing (5, 10) for selecting a dose and / or a cartridge holder (9) fixed to the housing (5, 10) and bearing a cartridge containing a drug.

12. Drug administration device, according to any of the preceding claims, characterized by Petition 870250052998, dated 06 / 24 / 2025, page 32 / 68 4 / 5 in that the opening (12) comprises at least one part with a contour adapted to receive at least one first fastening element (15) and at least one second fastening element (17, 18), wherein said contour further provides a clearance fit or an interference fit permitting axial movement of the bearing (16) and the piston rod (11) if fixed to each other, but blocking the elastic deformation of at least one of the fastening elements (15) necessary for the disengagement of at least one first fastening element (15) and at least one second fastening element (17, 18) if received in the opening (12).

13. A method of assembling a drug delivery device, comprising at least one housing (5, 10) with an opening (12), a piston rod (11) having a proximal end and a distal end and at least one first fastening element (15) located at the distal end and a bearing (16) with at least one second fastening element (17, 18) for rotary fastening of the bearing (16) at the distal end of the piston rod (11), the method comprising the steps of: introducing the piston rod (11) into the housing (5, 10) so that the distal end of the piston rod (11) projects distally through the opening (12), then securing the bearing (16) to the piston rod (11) by engaging at least one first fastening element (15) and at least one second fastening element (17, 18),characterized by the fact that after retracting the piston rod (11) in the proximal direction until at least one first fastening element (15) and at least one second fastening element (17, 18) is at least partially received in the opening (12) of the housing (5, 10) thus preventing at least one first fastening element (15) from deflecting radially outwards.

14. Assembly method according to claim 13, Petition 870250052998, dated 06 / 24 / 2025, page 33 / 68 5 / 5 characterized in that the steps of introducing the piston rod (11) in the distal direction into the housing (5, 10) and / or retracting the piston rod (11) in the proximal direction may involve a combined rotation and translation of the piston rod (11).

15. Assembly method according to claim 13 or 14, characterized in that the step of attaching the bearing (16) to the piston rod (11) may involve elastically deforming at least one first fastening element (15) and / or at least one second fastening element (16, 17) in a radial direction.

16. Assembly method, according to any one of claims 13 to 15, characterized in that it further comprises the step of attaching a cartridge holder (9) containing a cartridge containing a medicine to the housing (5, 10) so that the bearing (16) rests on a plug in the cartridge.

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