RU2794029C2 - Drug delivery device and assembly method for drug delivery device - Google Patents

Abstract

FIELD: medical equipment.

SUBSTANCE: 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 a part with a mating device (14) adapted to engage with the opening (12) for guiding the piston rod (11) during the distal or proximal movement of the piston rod (11) relative to the housing (5, 10), and at least one first fastener (15) located on the distal end, and a support (16) with at least one second fastener (17, 18) for rotatably attaching the support (16) to the distal end of the piston rod (11). Moreover at least one first fastening element (15) and/or at least one second fastening element (17, 18) is elastically deformable in the radial direction for snapping engagement of the piston rod (11) and support (5, 10). In this case, the opening (12) contains at least one part having a contour adapted to accommodate at least one first fastener element (15) and at least one second fastener element (17, 18), when connected to each other, however preventing separation of at least one first fastener (15) and at least one second fastener (17, 18) when placed in the opening (12).

EFFECT: method for assembling a drug delivery device.

16 cl, 4 dwg

Description

The present invention is generally directed to a drug delivery device, such as an injection device, for selecting and dispensing a number of variable user doses of a drug. The present invention is further directed to an assembly method for a drug delivery device.

Pen-type drug delivery devices are used when regular injections are carried out by persons without appropriate medical training. This may be increasingly common among diabetic patients, where self-medication allows such patients to effectively control their disease. In practice, such a drug delivery device allows the user to individually select and dispense a certain number of variable user doses of drug. The present invention is further directed to so-called fixed dose devices which allow the delivery of only a given dose without the possibility of increasing or decreasing the set dose.

There are basically two types of drug delivery devices: reusable (i.e., reusable) and disposable (i.e., disposable) devices. For example, disposable pen-type delivery devices are supplied as self-contained devices. These self-contained devices do not have removable pre-filled cartridges. Rather, pre-filled cartridges cannot be removed and replaced from these devices without destroying the device itself. Therefore, such disposable devices should not have a resettable dose setting mechanism. The present invention is applicable to both types of devices, ie disposable devices as well as reusable devices.

These types of pen-type delivery devices (so called because they often resemble an oversized fountain pen) generally contain three main elements: a cartridge portion that contains the cartridge, often contained within a housing or holder; a needle assembly connected to one end of the cartridge compartment; and a dispensing section connected to the other end of the cartridge section. A cartridge (often referred to as an ampoule) typically contains a reservoir that is filled with medication (such as insulin), a removable rubber stopper or plug located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often narrowed end. A crimp ring metal band is typically used to hold the rubber seal in place. While the cartridge body can generally be made from plastic, cartridge reservoirs are always made from glass.

The needle assembly is typically a replaceable reversible needle assembly. Prior to injection, a replaceable reversible needle assembly is attached to one end of the cartridge assembly, the dose is set, and then the set dose is administered. Such removable needle assemblies may be screwed on or inserted (ie, snapped) onto the pierceable seal end of the cartridge assembly.

The dosing site or dose setting mechanism is typically part of a pen-type device that is used to set (select) a dose. During the injection, the spindle or piston rod contained within the dose setting mechanism is pressed against the stopper or plug of the cartridge. This force causes the drug contained within the cartridge to be injected through the attached needle assembly. After injection, as generally recommended by most manufacturers and suppliers of drug delivery devices and/or needle assemblies, the needle assembly is removed and discarded.

An additional differentiation in the types of drug delivery devices relates to the drive mechanism. There are devices that are manually actuated, such as by the user applying force to an injection button, devices that are actuated by a spring or the like, and devices that combine these two principles, i.e. spring devices, which still require the user to applied the necessary force for the injection. Spring type devices include springs that are preloaded and springs that are loaded by the user during dose selection. Some stored energy devices use a combination of spring preload and additional energy provided by the user, such as during dose setting.

Known drug delivery devices typically comprise an apertured body and a piston rod having a proximal end and a distal end, wherein at least a portion of the piston rod is provided with a mating device adapted to engage with the aperture to guide the piston rod during distal or proximal displacement of the piston rod relative to the body, and at least one first fastener located at the distal end. The support may be provided with at least one second fastener for rotatably attaching the support to the distal end of the piston rod. One example of drug delivery devices comprising a presser foot or support located at the distal end of a piston rod or spindle is shown in EP 2 437 821 B1, with the support positioned adjacent to the end of the cartridge piston or stopper.

Document EP 2 437 827 B1 describes a combination of a spindle and an anvil which comprises a rotatable spindle having a distal end and a disk-shaped anvil attached to the distal end of the spindle via a first connection comprising a septum which fixedly attaches the anvil to the spindle to prevent independent movement of the anvil. regarding the spindle. This first connection is replaced during assembly by a second connection, which is formed when the baffle is torn (cut off) and the baffle is detached from the support. The second connection is a rotatable nodal connection, i.e. one where the spindle can rotate freely.

The assembly of such drug delivery devices may include a first sequence of assembly steps to provide a mechanism subassembly that can be final assembled by combining the mechanism subassembly with a cartridge. The final assembly may take place at a location that is remote from the location where the mechanism subassembly was manufactured. This may include transportation and storage of the mechanism subassembly with support and piston rod.

In some drug delivery devices, the piston rod must be assembled at the proximal (button) end of the device through a hole, such as a threaded hole, in the housing. This requires that the diameter of any of the snap-fit elements for the support be smaller than the internal diameter of the thread form in the housing. This diameter is only 3 mm, for example, and this makes a strong snap connection more difficult to develop.

The axial load from the piston rod during dispensing must be transferred to the support by means of the contact surface, i.e. as close as possible to the point contact. That is, to reduce the effect of friction when the piston rod rotates relative to the support during dispensing. Such a point contact must be on the axis of the device, so that when the piston rod rotates on this axis, the point contact does not leave the axis.

In addition, the elements that are used to connect the support to the piston rod must be moldable without adding any additional complexity to the design of the mold that creates these two parts. Essentially, this means that the elements must be moldable with a simple injection mold design, capable of being opened and closed where possible, and with a maximum of two movable molding parts if required.

Once secured, it should be difficult to pull the support out of the end of the piston rod. This is to ensure that during transport of the mechanism subassembly before final assembly, the support does not fall out. After the final assembly of the disposable pen, the support is limited between the mechanism and the cartridge, and therefore the risk of falling out at this point is minimal. In addition, after partial dispensing, this support support is not required because the support is then inside the cartridge and axial movement is prevented.

Therefore, it is an object of the present invention to provide a drug delivery device comprising a support, preferably in point contact with a piston rod, that is easily assembled but securely held in subassembly prior to final assembly into a complete device.

This task is solved by means of a drug delivery device as defined in paragraph 1 and an assembly method as defined in paragraph 13.

In the drug delivery device of the present invention, at least one first fastener and/or at least one second fastener is resiliently deformable in the radial direction to snap-engage the piston rod and the support. In addition, the opening contains at least one part having a contour adapted to receive at least one first fastener element and at least one second fastener element when fastened to each other. On the other hand, the contour of the opening is adapted to the fasteners so that the opening prevents or at least prevents the separation of at least one first fastener and at least one second fastener when placed in the opening. For example, a portion of the opening may be adapted to receive or insert the first and second fasteners with a clearance or interference fit, allowing the support and piston rod to move axially, preferably without friction from contact with the inside of the opening. A clearance fit or an interference fit may be chosen such that the elastic deformation of the fastener(s) required for release is blocked by the opening.

The present invention is based on the idea of attaching a support to a piston rod, for example in a disposable pen type injector, in such a way that the support is locked in the transport position to reduce the risk of it falling out prior to final assembly. The present invention preferably relates, inter alia, to disposable pen type devices where good retention of the support is required only for the purpose of transporting the mechanism to final assembly in the device.

The drug delivery device of the present invention may be of a very simple design, where the piston rod can be used directly by the user by pulling, depressing and/or rotating the piston rod during use, for example to dispense a dose. Alternatively, the drug delivery device may further comprise at least an actuating element operatively connected to the piston rod to distally displace the piston rod during dose delivery and/or a dose setting element operatively connected to the dose selection housing.

To lock the support in the transport position, during assembly of the drug delivery device, the piston rod can be moved in the axial direction between the distal installation position, in which at least one first fastener and at least one second fastener are placed distally from the opening, and a proximal transport position in which at least one first fastener and at least one second fastener are placed in the opening. In other words, when the piston rod is in the installation position, the attachment of the support is possible by allowing the corresponding fastening element(s) to expand radially, as long as the opening does not prevent such expansion. On the other hand, when the piston rod is retracted to its proximal transport position, the opening of the housing or the corresponding part of the opening prevents the corresponding fastener (s) from expanding at least so that the support is difficult to detach from the piston rod, thereby fixing the support on the piston rod.

In one example of the present invention, the opening is internally threaded, wherein a mating device adapted to engage with the opening to guide the piston rod during distal or proximal movement of the piston rod relative to the housing has an external thread. In this case, at least one part having a contour adapted to receive at least one first fastener and at least one second fastener may have an internal thread. Thus, axial movement of a piston rod typically involves a combination of rotation and displacement along a helical path. However, when the common engagement of the piston rod and the dose dispensing housing can be in the form of a threaded interface, a short distance net axial displacement, for example between the distal mounting position and the proximal transport position, can be achieved without rotation.

Alternatively, the opening is provided with a non-circular cross section, wherein the mating device adapted to engage with the opening to guide the piston rod during distal or proximal movement of the piston rod relative to the housing has a corresponding non-circular cross section, e.g., in the form of a groove, splines, rib and/or flattening. In this case, at least one part having a contour adapted to receive at least one first fastener and at least one second fastener may have a protrusion.

According to one example of the present invention, the support may include a disk for abutting against the cartridge stopper, and at least one second fastening element of the support may include a male element or shank extending proximally from the proximal side of the disk. In this case, the male element can be provided with at least one radial recess, which provides snap-fit engagement with the piston rod. In this case, at least one first fastening element of the piston rod may include at least one snap hook adapted to engage at least one radial recess of the support. This design is similar to that of existing products on the market, making this feature easier to manufacture and assemble. In other words, in this configuration, the support has a male element that is attached to the female snap elements on the piston rod. While the piston rod can accommodate the male member and support with snap-in features, such as at least one snap-hook, for low friction movement, the domed end of the male member is preferably molded without a split line. The piston rod can be assembled in any way (end to end) and when forming a male element with a domed end at both ends, this will require two additional movable forming parts, which will make the injection molds for this part more complex with fewer part cavities per mold, as compared to molding a dome on a support.

With respect to the present invention, the term housing is not limited to the outer body or shell of the device. Rather, the housing may be an internal component of the housing or an insert. Such an internal housing component or insert may be part of a separate component, or may be an integral part of the outer body or shell of the device.

For a drug delivery device comprising at least a housing with an opening, a piston rod having a proximal end and a distal end and at least one first fastener located at its distal end, and a support with at least one second fastener for fastening with the possibility of rotation of the support on the distal end of the piston rod, the assembly method according to the present invention includes the steps of inserting the piston rod, for example, in the distal direction, into the housing so that the distal end of the piston rod protrudes distally through the opening, then attaching the support to the piston rod by engagement with snapping at least one first fastener and at least one second fastener, and then pulling the piston rod in the proximal direction until at least one first fastener and at least one second fastener at least partially will be placed in the opening of the hull. This retraction of the piston rod serves to lock the fasteners, such as a latch, preventing radial outward deflection, and therefore prevents the support from detaching without applying significant force.

The steps of inserting the piston rod distally into the housing and/or retracting the piston rod proximally may include combined rotation and linear movement of the piston rod, such as along a helical path. In addition, the step of attaching the support to the piston rod may include elastic deformation of at least one first fastener and/or at least one second fastener in the radial direction.

The injection device typically contains a cartridge containing a drug. Thus, the assembly method may further include the step of attaching a cartridge holder containing a medicament-containing cartridge to the body such that the support abuts a stopper in the cartridge.

The term "drug" as used herein means a pharmaceutical composition containing at least one pharmaceutically active compound,

wherein 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 fragment thereof, hormone, or oligonucleotide, or a mixture of the above pharmaceutically active connections,

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

wherein in an additional embodiment, the pharmaceutically active compound contains at least one peptide for the treatment and/or prevention of diabetes mellitus or complications associated with diabetes mellitus, such as diabetic retinopathy,

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

Insulin analogues are, 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 in which 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.

Derivatives of insulin are, 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; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Υ-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Υ-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin; and B29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4, for example, means exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu- Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

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

H-(Lys)4-des Pro36, des Pro37 exendin-4(1-39)-NH2,

H-(Lys)5-des Pro36, des Pro37 exendin-4(1-39)-NH2,

des Pro36 exendin-4(1-39),

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

des Pro36 [IsoAsp28] exendin-4(1-39),

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

des Pro36 [Met(O)14, IsoAsp28] exendin-4(1-39),

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

des Pro36 [Trp(O2)25, IsoAsp28] exendin-4(1-39),

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

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

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

des Pro36 [IsoAsp28] exendin-4(1-39),

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

des Pro36 [Met(O)14, IsoAsp28] exendin-4(1-39),

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

des Pro36 [Trp(O2)25, IsoAsp28] exendin-4(1-39),

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

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

while the -Lys6-NH2 group may be linked to the C-terminus of the exendin-4 derivative;

or a derivative of exendin-4 sequence

des Pro36 exendin-4(1-39)-Lys6-NH2 (AVE0010),

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

des Asp28 Pro36, Pro37, Pro38 exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro38 [Asp28] exendin-4(1-39)-NH2,

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

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

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

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

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

H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] exendin-4(1-39)-NH2,

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

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

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

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

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

H-(Lys)6-des Pro36 [Met(O)14, Asp28] exendin-4(1-39)-Lys6-NH2,

des Met(O)14 Asp28 Pro36, Pro37, Pro38 exendin-4(1-39)-NH2,

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

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

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

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

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

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt or solvate of any of the aforementioned exendin-4 derivatives.

Hormones are, for example, pituitary hormones, or hypothalamic hormones, or regulating active peptides and their antagonists, as described in Rote Liste, ed. 2008, chapter 50, such as gonadotropin (follitropin, lutropin, human chorionic gonadotropin, menotropin), somatropin (somatotropin), desmopressin, terlipressin, gonadorelin, triptorelin, leuprorelin, buserelin, nafarelin, goserelin.

The polysaccharide is, for example, glycosaminoglycan, hyaluronic acid, heparin, low molecular weight heparin, or ultra-low molecular weight heparin, or a derivative or sulfated, for example polysulfated, form of the aforementioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of polysulphated low molecular weight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (~150 kDa), which are also known as immunoglobulins, having a common 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.

The Ig monomer is a Y-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains linked by disulfide bonds between cysteine residues. Each heavy chain is approximately 440 amino acids long; each light chain is approximately 220 amino acids long. Each heavy and light chain contains intrachain disulfide bonds that stabilize their folding. Each chain is made up of structural domains called Ig domains. These domains contain approximately 70-110 amino acids and are classified into different categories (eg variable or V and constant or C) according to their size and function. They have a characteristic immunoglobulin chain folding feature in which two β-sheets create a "sandwich" shape, held together by an interaction between stable cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain, designated α, δ, ε, γ, and μ. The type of heavy chain present determines the isotype of the antibody; these chains can be found in IgA, IgD, IgE, IgG and IgM antibodies, respectively.

Individual heavy chains differ in size and composition; α and γ are approximately 450 amino acids and δ are approximately 500 amino acids while μ and ε are approximately 550 amino acids. Each heavy chain has two regions, a constant region (CH) and a variable region (VH). In one view, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region consisting of three tandem Ig domains and a hinge region for added flexibility; μ and ε heavy chains have a constant region consisting of four immunoglobulin domains. The heavy chain variable region 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 amino acids long and consists of a single Ig domain.

Mammals have two types of immunoglobulin light chain, designated λ and κ. The light chain has two consecutive domains: one constant domain (CL) and one variable domain (VL). The approximate length of the light chain is 211-217 amino acids. Each antibody contains two light chains that are always identical; however, only one type of light chain, κ or λ, is present in a mammalian antibody.

Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, the variable loops, three on each light (VL) and three on the heavy (VH) chain, are responsible for antigen binding, ie for their antigen specificity. These loops are called hypervariable regions (CDRs). Because the CDRs from both the VH and VL domains contribute to the antigen-binding site of an antibody, it is the combination of the heavy and light chains, not the two alone, that determines the ultimate antigen specificity.

The term "antibody fragment" encompasses at least one antigen-binding fragment as defined above and exhibits substantially the same function and specificity as the complete antibody from which the fragment is derived. Limited proteolytic cleavage with papain cleaves the prototype Ig into three fragments. Two identical amino-terminal fragments, each containing one full L-chain and approximately half of the H-chain, are antigen-binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystallizable fragment (Fc). Fc contains carbohydrates, complement binding and FcR binding sites. Limited pepsin digestion yields a single F(ab')2 fragment containing both Fab moieties and the hinge, including the H-H interchain disulfide bond. F(ab')2 is divalent for antigen binding. The F(ab')2 disulfide bond can be cleaved to give Fab'. In addition, the heavy and light chain variable regions can be fused together to form a single chain variable fragment (scFv).

Pharmaceutically 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 with a cation selected from alkalis or alkaline compounds, for example Na+ or K+ or Ca2+ or the ammonium ion N+(R1)(R2)(R3)(R4) where R1-R4 are independently from the other means: hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C6-C10 aryl group or an optionally substituted C6-C10 heteroaryl group. Additional examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences" 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 and in Encyclopedia of Pharmaceutical Technology.

Pharmaceutically acceptable solvates are, for example, hydrates.

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

in fig. 1 shows a drug delivery device with a dose setting mechanism in accordance with one aspect of the present invention;

in fig. 2 shows the drug delivery device of FIG. 1 with cap removed and cartridge holder shown;

in fig. 3 is a cross-sectional view of one embodiment of a drug delivery device according to the present invention prior to assembly of the support; And

in fig. 4 is a sectional view of the embodiment of FIG. 1 after assembly of the support.

With reference to FIG. 1 shows a drug delivery device 1 according to one exemplary arrangement. The drug delivery device 1 comprises a distally located cartridge holding part 2 and a proximally located dose setting mechanism 3. The drug delivery device may be a reusable drug delivery device (i.e., a reusable device) or alternatively a single-use drug delivery device (i.e., a disposable device). The cartridge holding part 2 and the dose setting mechanism 3 are fastened together by connecting members. For disposable devices, these connectors will be permanent and irreversible. For reusable devices, these connectors will be releasable.

In this exemplary arrangement, the cartridge holding portion 2 is attached within the dose setting mechanism 3. The removable cap 4 is held detachably over the cartridge holding portion 2. The dose setting mechanism 3 is surrounded by an outer housing 5 and includes a handle 6 for dialing the dose and a window or lens 7. A device 8 with a dose scale can be seen through the window or lens 7.

In order to set the dose of the drug contained in the drug delivery device 1, the user rotates the dial knob 6 relative to the outer housing 5 so that the dialed dose becomes visible in the window or lens 7 through the dose scale device 8. Dose setting may include proximal movement of the dose dialing handle 6 relative to the outer housing 5 as shown in FIG. 2. Dose delivery may include pushing the handle to dial the dose in a backward distal direction.

In FIG. 2 shows the drug delivery device 1 of FIG. 1 with the cap 4 removed from the distal end of the device 1. This removal exposes the cartridge holder 9. A cartridge (not shown) from which a number of doses of the medical product can be dispensed is provided in the cartridge holder 9. The cartridge contains a plug or plug (not shown in FIG. 2) that is held near the proximal end of the cartridge.

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

In the embodiment shown in FIG. 3, the inner body 10 is provided with a central opening 12 accommodating the piston rod 11. As an alternative to the embodiments shown, the opening 12 may be provided directly in the outer body 5. The opening 12 is provided with an internal thread 13 cooperating with the external thread 14 of the piston rod 11. Hence , the rotation of the piston rod 11 relative to the inner housing 10 leads to an axial displacement of the piston rod 11 relative to the inner housing 10. direction, thereby expanding the female snap-in member.

The dimensions of the central opening 12 with its internal thread 13 and up to the elastic hooks 15 are chosen so that the central opening 12 and the internal thread 13 do not interfere with the elastic hooks 15 in the relaxed state (at rest) of the hooks, as shown in FIG. 3 and 4. However, the central opening 12, with its internal threads 13, essentially prevents the resilient hooks 15 from expanding in the radial direction. At least one resilient hook 15 constitutes the first fastening element.

The drug delivery device further comprises a support 16 as shown in FIG. 3 prior to attachment to the piston rod 11. The support 16 is essentially disc-shaped and includes a male element 17 or shank extending in the proximal direction. The male element 17 is provided with an annular recess 18 or groove located between the proximal end of the male element 17 and the disc-shaped part of the support 16. The male element 17 with its recess 18 constitutes the second fastening element. The dimensions of the male element 17 and the recess 18 are adapted to the dimensions of the female snap-in elements, i.e. the elastic hooks 15, of the piston rod 11 so that the support 16 can be attached to the distal end of the piston rod 11 by snapping the male element 17 between the elastic hooks 15 .

As an alternative to the embodiments shown in FIG. 3 and 4, a recessed male member may be provided on the piston rod 11 and female snap-on members may be provided on the support 16.

In FIG. 3 and 4 show two steps during the assembly of the drug delivery device 1, in particular the attachment of the support 16 to the piston rod 11. FIG. 3 shows the piston rod 11 passing through the threads 13 of the inner body 10 into the distal mounting position and ready to be secured in the support 16. To secure the piston rod 11 in the support 16, either the support can be pushed to the right (as shown in Fig. 3) or the piston rod 11 can be moved by turning it through the threaded hole in the inner housing 10 by an amount equal to the amount required to fully assemble the snap-on connection.

In FIG. 4, the piston rod 11 was fixed in the support, and then the piston rod 11 was rotated in the reverse direction so that it moves to the right (as shown in Fig. 4) in the axial direction and pulls the support 16 back into the region of the form 13 of the threads of the inner body 10. Such the retraction of the piston rod 11 serves to fix the latches (hooks 15) preventing radial outward deflection, and therefore prevents the support 16 from detaching without applying significant force.

In the example shown in the figures, the inner body 10 is provided with a substantially cylindrical fitting 19 extending distally with respect to the opening 12. The connecting part 19 may be adapted to rigidly fasten the inner housing 10 to the outer housing 5.

In the exemplary embodiment of FIG. 3 and 4, the drug delivery device further comprises an actuator 20 cooperating with the piston rod 11, for example by means of a splined engagement. The actuator 20 may be provided with an external thread that engages with the nut 21, which may limit the maximum amount of drug that can be dispensed from the drug delivery device 1. In FIG. 3 and 4 additionally show a portion of the dose setting sleeve 22, which may be an integral part of the dose dial handle 6 and/or the dose dial device 8. Alternatively, the dose setting sleeve 22 can be connected to the dose dial 6 and/or the dose scale tool 8 and/or the drive 20.

For example, setting the dose may include rotating the sleeve 22 to set the dose in the first direction through the handle 6 to set the dose. This rotation may be rotation relative to the outer housing 5 and the inner housing 10 and/or rotation relative to the actuator 20.

Dose delivery may include rotating sleeve 22 to set the dose in a second direction that is opposite to the first direction. During the delivery of the dose, the actuator 20 can be rotated attached to the sleeve 22 to set the dose. The rotation of the actuator 20 can be transmitted to the piston rod 11, which, due to the threaded connection with the inner housing 10, moves in the distal direction after rotation. Such distal movement of piston rod 11 with support 16 can push the plug in the cartridge in a distal direction to dispense a dose of medication.

Alternatively, the rotation of the dose-setting sleeve 22 during dose delivery may include axial or helical movement of the actuator 20, which may be transmitted through a threaded interface to the piston rod 11. This may result in pure axial or a combination of axial and rotational movement of the piston rod. 11 with a support 16 for pushing the stopper in the cartridge distally to dispense a dose of medication.

Reference positions

1 Drug delivery device

2 Cartridge holder

3 Corps

4 Dose setting mechanism

5 cap

6 Dose handle

7 Window/lens

8 Device with dose scale

9 Cartridge holder

10 Inner case

11 Piston rod

12 opening

13 Internal thread

14 External thread

15 Hook/female snap-on element (first fastener)

16 Support

17 Male element (second fastener)

18 Recess

19 Connecting part

20 Drive

21 Nut

22 Coupling for setting the dose.

Claims (28)

1. A drug delivery device, containing: body (5, 10) with opening (12), piston rod (11) having a proximal end and a distal end, at least part with a mating device (14) adapted to engage with an opening (12) for guiding the piston rod (11) during distal or proximal movement of the piston rod (11) relative to the body (5, 10), and at least one first fastener (15) located at the distal end, and a support (16) with at least one second fastening element (17, 18) for fastening with the possibility of rotation of the support (16) on the distal end of the piston rod (11), wherein at least one first fastening element (15) and/or at least one second fastening element (17, 18) is resiliently deformable in the radial direction for snapping engagement of the piston rod (11) and support (5, 10), while the opening (12) contains at least one part having a contour adapted to accommodate at least one first fastener (15) and at least one second fastener (17, 18), when connected to each other, however preventing separation of at least one first fastener (15) and at least one second fastener (17, 18) when placed in the opening (12). 2. The drug delivery device according to claim 1, characterized in that during the assembly of the drug delivery device, the piston rod (11) can move in the axial direction between the distal position of the installation, in which at least one first fastening element (15) and at least one second fastener (17, 18) is placed distally from the opening (12), and the proximal transport position, in which at least one first fastener (15) and at least one second fastener (17, 18) placed in the opening (12). 3. The drug delivery device according to claim. 1 or 2, characterized in that the opening is provided with an internal thread, and at the same time a mating device (14) adapted to engage with the opening (12) to guide the piston rod (11) during distal or proximal movement of the piston rod (11) relative to the housing (5, 10), contains an external thread (14). 4. The drug delivery device according to claim 3, characterized in that at least one part having a contour adapted to accommodate at least one first fastener (15) and at least one second fastener (17, 18) , contains an internal thread (13). 5. The drug delivery device according to claim. 1 or 2, characterized in that the opening is given a non-circular cross-section, and at the same time a mating device adapted to engage with the opening (12) to guide the piston rod (11) during distal or proximal movement piston rod (11) relative to the housing (5, 10) has a corresponding non-circular cross section. 6. The drug delivery device according to claim 5, characterized in that at least one part having a contour adapted to accommodate at least one first fastener (15) and at least one second fastener (17, 18) , contains an overhang. 7. The drug delivery device according to any one of the preceding claims, characterized in that the support (16) contains a disc for adjoining the cartridge stopper, and at least one second fastener (17, 18) contains a male element (17), passing proximally from the proximal side of the disk, while the male element (17) contains at least one radial recess (18). 8. The drug delivery device according to claim 7, characterized in that at least one first fastener (15) of the piston rod (11) provides at least one hook (15) with a latch adapted to engage with at least one radial recess (18) of the support (16). 9. The drug delivery device according to any one of paragraphs. 1-6, characterized in that at least one first fastening element of the piston rod (11) contains a male element at its distal end, while the male element contains at least one radial recess. 10. The drug delivery device according to claim 9, characterized in that the support (16) contains a disk for adjoining the cartridge stopper, and at the same time at least one second fastener contains at least one snap hook extending proximally from the proximal side of the disc and adapted to engage with at least one radial recess of the piston rod (11). 11. The drug delivery device according to any of the preceding claims, characterized in that it further comprises a drive element (20) operably connected to the piston rod (11) to displace the piston rod (11) in the distal direction, and/or the element (6, 8, 22) dose setting operably connected to the dose selection housing (5, 10) and/or a cartridge holder (9) attached to the housing (5, 10) and containing a cartridge containing a drug. 12. The drug delivery device according to any of the preceding claims, characterized in that the opening (12) contains at least one part having a contour adapted to accommodate at least one first fastener (15) and at least one second fastener element (17, 18) with a clearance or interference fit, allowing movement of the support (16) and piston rod (11) when fastened together, but blocking the elastic deformation of at least one of the fasteners (15) necessary for separating at least one first fastener (15) and at least one second fastener (17, 18) when placed in the opening (12). 13. A method for assembling a drug delivery device, the device comprising at least body (5, 10) with opening (12), a piston rod (11) having a proximal end and a distal end and at least one first fastener (15) located at the distal end, and a support (16) with at least one second fastening element (17, 18) for fastening with the possibility of rotation of the support (16) on the distal end of the piston rod (11), wherein the method includes the steps: introducing the piston rod (11) into the body (5, 10) in such a way that the distal end of the piston rod (11) protrudes distally through the opening (12), then attaching the support (16) to the piston rod (11) by snapping engagement of at least one first fastener (15) and at least one second fastener (17, 18), then pulling the piston rod (11) in the proximal direction until at least one first fastener (15) and at least one second fastener (17, 18) are at least partially placed in the opening (12) cases (5, 10). 14. Assembly method according to claim 13, characterized in that the steps of inserting the piston rod (11) in the distal direction inside the housing (5, 10) and/or pulling the piston rod (11) in the proximal direction include combined rotation and linear movement of the piston rod (eleven). 15. Assembly method according to claim 13 or 14, characterized in that the step of attaching the support (16) to the piston rod (11) includes elastic deformation of at least one first fastener (15) and/or at least one second fastener (16, 17) in the radial direction. 16. Assembly method according to any one of paragraphs. 13-15, characterized in that it additionally includes the step of attaching the holder (9) of the cartridge containing the cartridge containing the drug to the body (5, 10) in such a way that the support (16) is adjacent to the stopper in the cartridge.

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