Patent ID: 12186540

Corresponding parts are marked with the same reference symbols in all figures.

DETAILED DESCRIPTION

FIG.1is a perspective view of an exemplary embodiment of an auto-injector1. The auto-injector1comprises a case2comprising a sleeve shaped front case2.1and a rear case2.2. A cap11is attached at a distal end of the case2. A sleeve-shaped needle shroud7is telescoped within the case2. The case2is adapted to receive a medicament container3, such as a syringe3, for example a glass syringe. The medicament container is referred to hereinafter as the “syringe3”. The syringe3may be a pre-filled syringe containing a medicament M and having a needle4arranged at a distal end of the syringe3. In another exemplary embodiment, the medicament container3may be a cartridge which includes the medicament M and engages a removable needle (e.g., by threads, snaps, friction, etc.) When the auto-injector1or the syringe3is assembled, a protective needle sheath5is attached to the needle4. A stopper6is arranged for sealing the syringe3proximally and for displacing a liquid medicament M contained in the syringe3through the hollow needle4. The syringe3is held in the case2and supported at its proximal end therein.

The protective needle sheath5may be coupled to the cap11so that when the cap11is removed, the protective needle sheath5is also removed from the needle4. The cap11may comprise grip features for facilitating removal of the cap11.

The sleeve-shaped needle shroud7is telescoped in the distal end of the case2. A control spring8is arranged to bias the needle shroud7in a distal direction D against the case2.

A drive spring9in the shape of a compression spring is arranged within a proximal part of the case2. A plunger10serves for forwarding the force of the drive spring9to the stopper6. In an exemplary embodiment, the plunger10is hollow and the drive spring9is arranged within the plunger10, biasing the plunger10in the distal direction D against the rear case2.2.

The auto-injector1may be divided in two subassemblies, a control subassembly1.1and a drive subassembly1.2. This allows for improving flexibility as to the time and location of manufacture of the subassemblies1.1,1.2and final assembly with the syringe3.

FIG.2is a perspective view of the control subassembly1.1.FIG.3is a perspective exploded view of the control subassembly1.1. The control subassembly1.1comprises all parts and mechanisms which control access to the needle4and the forces a user will feel when they use the auto-injector1. The control subassembly1.1comprises the cap11, the needle shroud7and the front case2.1.

FIG.4is a perspective view of the drive subassembly1.2.FIG.5is a perspective exploded view of the drive subassembly1.2. The drive subassembly1.2comprises the components required to deliver the medicament M. If the viscosity or volume of the medicament M in the syringe3is varied, only parts of the drive subassembly1.2may need to be changed. The drive subassembly1.2comprises the plunger10, the drive spring9, the rear case2.2, the control spring8and a sleeve shaped collar14which will be explained in more detail below.

FIG.6is a schematic exploded view of the auto-injector1during assembly. In order to assemble the auto-injector1, a syringe3with an attached needle4and a protective needle sheath (not illustrated) is inserted into the control subassembly1.1in the distal direction D. Afterwards, the drive subassembly1.2is inserted into the control subassembly1.1in the distal direction D.

A plunger release mechanism12is schematically illustrated in four different states inFIGS.7A to7D. The plunger release mechanism12is arranged for preventing release of the plunger10prior to depression of the needle shroud7and for releasing the plunger10once the needle shroud7is sufficiently depressed.

The plunger release mechanism12is adapted to control the automated activation of syringe emptying. The plunger release mechanism12is activated immediately prior to full needle insertion. The plunger release mechanism12comprises the plunger10, a longitudinal inner rib2.3on the rear case2.2and the collar14. The needle shroud7, not represented inFIGS.7A to7D, is coupled to the collar14and adapted to push the collar14in a proximal direction P.

The needle shroud7, the rear case2.2and its inner rib2.3, and the collar14are configured to move only in an axial direction, i.e. in the distal direction D and the proximal direction P, whereas the plunger10can both move rotationally in rotational directions R1, R2and axially in the distal direction D and the proximal direction P. In an exemplary embodiment, there may be no compliant part in the plunger release mechanism12, i.e. the parts may be all rigid and move as a whole with no relative deformation within a part.

FIG.7Ashows the plunger release mechanism12in a pre-assembly or pre-use state with the plunger10in a proximal position P1. The configuration of the plunger release mechanism12does not change when transitioning from the pre-assembly state to the pre-use state, i.e. assembling the control sub-assembly1.1and the drive sub-assembly1.2does not impact the plunger release mechanism12.

In the pre-assembly or pre-use state, a rib10.1on the plunger10is slid in an opening2.4within the rear case2.2. The opening2.4has an angled surface2.5so that when a force in the distal direction D is applied to the plunger10, e.g. by the drive spring9, the rib10.1abuts the angled surface2.5and the plunger10attempts to rotate in the rotational direction R1. The rib10.1is prevented to move along the angled surface2.5of the opening2.4by a first collar rib14.1on the collar14. The collar14is prevented from rotating in the rotational direction R1by the inner rib2.3on the rear case2.2.

FIG.7Bshows the plunger release mechanism12in a state during extension of the injection needle4. The needle shroud7is moved in the proximal direction P into the front case2.1, e.g. by a user pressing the shroud against an injection site, thereby inserting the needle4into the injection site. As the needle shroud7is coupled to the collar14, the collar14moves in the proximal direction P as well. The first collar rib14.1moves in the proximal direction P accordingly, beginning to clear the way for the rib10.1of the plunger10.

FIG.7Cshows the plunger release mechanism12in a state during extension of the injection needle4immediately prior to the needle4reaching full insertion depth. The first collar rib14.1has been moved further in the proximal direction P and disengages the rib10.1on the plunger10so that the plunger10is no longer prevented from rotating in the rotational direction R1. The rib10.1on the plunger10is free to slide along the angled surface2.5of the opening2.4in the rear case2.2.

FIG.7Dshows the plunger release mechanism12in a state at the beginning of an injection. The rib10.1on the plunger10finishes its course along the angled surface2.5of the opening2.4in the rear case2.2, thus becoming able to move in the distal direction D without being further rotated. Under the action of the drive spring9, the plunger10pushes on the stopper6and starts to empty the content of the syringe3.

A feedback mechanism13is arranged for enabling emission of an audible and/or tactile feedback indicating the completion of medicament delivery. The feedback mechanism13is schematically illustrated in six different states inFIGS.8A to8F.

The feedback mechanism13comprises the plunger10, the rear case2.2, the needle shroud7, the collar14and the control spring8.

FIG.8Ashows the feedback mechanism13in the pre-assembly state. Only the drive sub-assembly1.2is represented in this state. The control spring8is compressed between two second collar ribs14.2on the collar14and a proximal end2.6of the rear case2.2. The plunger10is arranged within the collar14between inner protrusions14.4of first snap-fit joints14.3on the collar14. Consequently, the first snap-fit joints14.3cannot deflect inward under the force of the control spring8pushing in the distal direction D.

FIG.8Bshows the feedback mechanism13in the pre-use state. The control subassembly1.1is pushed into the drive sub-assembly1.2. The front case2.1and the rear case2.2may be coupled by two clips on the front case2.1getting caught within openings in the rear case2.2(not represented) or vice versa. The needle shroud7is inserted and proximal arms7.1on the needle shroud7axially abut the first snap-fit joints14.3.

FIG.8Cshows the feedback mechanism13in a state with the needle4at full insertion depth. The needle shroud7has been fully moved in the proximal direction P, e.g. by pushing it against an injection site, and has dragged along the collar14in the proximal direction P, compressing the control spring8. As the plunger10is arranged within the collar14between the inner protrusions14.4of the first snap-fit joints14.3, the first snap-fit joints14.3cannot deflect inward under the force of the control spring8pushing in the distal direction D.

FIG.8Dshows the feedback mechanism13in a state when the feedback is triggered near the end of medicament dispense. The plunger10, approaching the end of its travel with the stopper6having nearly bottomed out in the syringe3, slides down inward angled surfaces14.5on the inner protrusions14.4allowing for inward deflection of the first snap-fit joints14.3. Due to a ramp engagement between the first snap-fit joints14.3and the proximal ends of the proximal arms7.1of the collar14, the first snap-fit joints14.3are inwardly deflected driven by the control spring8disengaging them from their axial abutment with the proximal arms7.1, moving them between the proximal arms7.1.

FIG.8Eshows the feedback mechanism13in a state at the end of dose prior to generating the feedback. The plunger10at least almost finishes emptying the syringe3and is completely removed from between the first snap-fit joints14.3. In the meantime, the collar14has travelled further in the distal direction D along the proximal arms7.1and the two first snap-fit joints14.3have arrived at respective openings7.2in the proximal arms7.1, allowing the first snap-fit joints14.3to relax and straighten back to their initial shape within and engage within the openings7.2in the proximal arms7.1.

FIG.8Fshows the feedback mechanism13in a state at the end of dose F after having generated the feedback. Due to the relaxed first snap-fit joints14.3being engaged within the openings7.2whose longitudinal extension allows for some free travel of the first snap-fit joints14.3, the friction acting against the control spring8is reduced and the control spring8can now expand and drive the collar14in the distal direction D along the proximal arms7.1of the needle shroud7until two third collar ribs14.6on the collar14axially hit the proximal arms7.1of the needle shroud7, thus creating an audible and/or tactile feedback which indicates that the dose is complete.

FIGS.9A to9Dshow schematic views of a shroud lock mechanism15in four different states. The shroud lock mechanism15is arranged to lock the needle shroud7after removal of the auto-injector1from an injection site post-use and consequent translation of the needle shroud7in the distal direction D relative the case2.

The shroud lock mechanism15comprises the rear case2.2and the collar14.

FIG.9Ashows the shroud lock mechanism15in a state prior to needle insertion, i.e. in a preassembly state or pre-use state. Two second snap-fit joints14.7are arranged on the collar14and rest in two openings2.8in distal arms2.9on the rear case2.2.

FIG.9Bshows the shroud lock mechanism15in a state between the beginning of the injection and the release of the feedback mechanism13(both states included). The needle shroud7and the collar14moved in the proximal direction P as the needle shroud7was pushed against the injection site. The two second snap-fit joints14.7move in the proximal direction P accordingly, travelling up the openings2.8whose axial extension allows for some free travel.

FIG.9Cshows the shroud lock mechanism15in a state at the end of dose after release of the feedback mechanism13. As the feedback mechanism13is released, the collar14moves in the distal direction D (cf.FIG.8F). The two second snap-fit joints14.7move in the distal direction D accordingly, travelling down the openings2.8in the distal arms2.9of the rear case2.2.

FIG.9Dshows the shroud lock mechanism15in a post-use state. Once the medicament injection is complete, the user pulls the auto-injector1away from the injection site and the needle shroud7is forced out of the case2in the distal direction D by the control spring8, enveloping the needle4and thus acting as a protective shell around it (not represented). The collar14is arranged between the needle shroud7and the control spring8. Following the motion of the needle shroud7, the collar14moves in the distal direction D as well. The two second snap-fit joints14.7move accordingly and are deflected inward within the rear case2.2as angled surfaces14.8on the second snap-fit joints14.7engage the distal ends of the openings2.8. As the second snap-fit joints14.7travel further beyond the distal ends of the distal arms2.9on the rear case2.2, they are allowed to relax and straighten back outwards to their initial shape. The collar14is in an advanced position A and the needle shroud7, coupled to the collar14, is in its distal position S1. If it is attempted to push the needle shroud7in the proximal direction P again, transversal proximal surfaces14.9on the second snap-fit joints14.7proximally abut the distal arms2.9of the rear case2.2preventing further depression of the needle shroud7and re-exposure of the needle4.

A sequence of operation of the auto-injector1is as follows:

The auto-injector1is initially in the state as shown inFIG.1. The plunger release mechanism12is in the pre-use state as shown inFIG.7A. The feedback mechanism13is in the pre-use state as illustrated inFIG.8B. The shroud lock mechanism15is in the pre-use state as illustrated inFIG.9A.

The user removes the cap11pulling it in the distal direction D away from the case2. The protective needle sheath5may be coupled to the cap11so that when the cap11is removed, the protective needle sheath5is also removed from the needle4.FIG.10is a perspective longitudinal section of the auto-injector1with the cap11removed. The needle shroud7is in a distal position S1.

FIG.11is a perspective longitudinal section of the auto-injector1with the needle shroud7being moved in the proximal direction P, e.g. by placing it against the injection site and sliding the case2forwards. The control spring8is held between the collar14and the rear case2.2and is further compressed when the case2moves forwards relative to the needle shroud7. Except for the needle shroud7and the collar14, all components of the auto-injector1move with the case2. The needle shroud7and the collar14, axially coupled as shown inFIG.8B, move in the proximal direction P in comparison to the rest of the parts of the auto-injector1, thus initiating the plunger release mechanism12. The plunger release mechanism12thus arrives in the state as illustrated inFIG.7B. The feedback mechanism13transitions from the pre-use state shown inFIG.8Bto the state as illustrated inFIG.8C. The shroud lock mechanism15transitions from the pre-use state ofFIG.9Ato the state as illustrated inFIG.9B.

FIG.12is a perspective longitudinal section of the auto-injector1with the needle shroud7being fully moved in the proximal direction P into a proximal position S2such that the needle4has reached the insertion depth in the injection site. Once the needle shroud7is fully depressed, the plunger10releases as shown inFIG.7Dand medicament delivery begins. The drive spring9begins to expand, pushing the plunger10in the distal direction D to inject the medicament M. The feedback mechanism13is in the state as illustrated inFIG.8C. The shroud lock mechanism15is in the state as illustrated inFIG.9B.

FIG.13is a perspective longitudinal section of the auto-injector1during delivery of the medicament M after release of the feedback mechanism13. As the delivery of the medicament M progresses with the plunger10moving down the syringe3barrel, the feedback mechanism13activates. Up to this point, the collar14was resting on the needle shroud7, the needle shroud7preventing the collar14from moving further in the distal direction D. Prior to the end of the dose, the plunger10clears the inside of the collar14, leaving the two first snap-fit joints14.3free to deflect inward. Under the force of the control spring8, the collar14moves in the distal direction D, forcing its way in between the proximal arms7.1on the needle shroud7. The two first snap fit joints14.3are deflected inward within the needle shroud7. The feedback mechanism13arrives in the state as illustrated inFIG.8D. The shroud lock mechanism15is in the state as illustrated inFIG.9B.

FIG.14is a perspective longitudinal section of the auto-injector1at the end of dose prior to generation of the audible feedback. The plunger10has fully advanced the stopper6within the syringe3barrel and arrived at a distal position P2. Pursuing its course, the collar14brings the two first snap-fit joints14.3down to the opening7.2in the needle shroud7, where the first snap-fit joints14.3straighten back to their initial shape. The feedback mechanism13arrives in the state as illustrated inFIG.8E.

FIG.15is a perspective longitudinal section of the auto-injector1at the end of dose after generation of the audible feedback. The injection is complete and an audible and/or tactile feedback is emitted through the collar14hitting the needle shroud7as the feedback mechanism13operates. With reduced friction, the collar14is propelled by the control spring8and the two third collar ribs14.6hit the needle shroud7, creating the noise indicating that the dose is complete. The feedback mechanism13arrives in the state as illustrated inFIG.8F. The shroud lock mechanism15is in the state as illustrated inFIG.9C.

FIG.16is a perspective longitudinal section of the auto-injector1post-use with the needle shroud7extended from the case2. As the auto-injector1is moved away from the injection site, the needle shroud7and the collar14, which are axially coupled as shown inFIG.8F, advance, driven by the control spring8. The needle shroud7returns to its pre-use position. However, the position of the collar14has evolved since the pre-use state. The two second snap-fit joints14.7, which were so far travelling within the opening2.8in the rear case2.2, move further in the distal direction D and take position just beneath the distal arms2.9of the rear case2.2. This suppresses the axial degree of freedom of the collar14and the needle shroud7, which are both still axially coupled. The collar14is locked and prevents any further axial motion of the needle shroud7, rendering the auto-injector1needle safe in its post-use state. The shroud lock mechanism15is in the state as illustrated inFIG.9D.

The case2may comprise a viewing window (not illustrated) allowing the user to examine the medicament M for clarity, observe the advancing plunger10for allowing to estimate the progress of the medicament delivery, and helping the user differentiate between a used and an un-used auto-injector1.

In an exemplary embodiment, a tamper strip may be arranged between the cap11and the front case2.1when the control subassembly1.1is assembled.

The auto-injector1may be placed against the injection site multiple times without any adverse effect to the mechanism. The force to depress the needle shroud7may be less than 6 N.

The syringe3used in the auto-injector1may for example be a 1 ml syringe3.

The auto-injector1is always needle safe as the needle can be retracted before the delivery of the medicament M is complete.

As only the plunger10and the rear case2.2are subjected to the relatively high force of the drive spring9, the other components of the auto-injector1are not affected, so reliability and shelf life are increased.

The auto-injector1is suited to be used as a platform as the drive spring9can be swapped to deliver different viscosity drugs without affecting the insertion or retraction functions. This is particularly advantageous for high viscosity fluids.

The terms “drug” or “medicament” are used herein to describe one or more pharmaceutically active compounds. As described below, a drug or medicament can include at least one small or large molecule, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Exemplary pharmaceutically active compounds may include small molecules; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more of these drugs are also contemplated.

The term “drug delivery device” shall encompass any type of device or system configured to dispense a drug into a human or animal body. Without limitation, a drug delivery device may be an injection device (e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for intraocular, subcutaneous, intramuscular, or intravascular delivery), skin patch (e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal or pulmonary), implantable (e.g., coated stent, capsule), or feeding systems for the gastro-intestinal tract. The presently described drugs may be particularly useful with injection devices that include a needle, e.g., a small gauge needle.

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

The drug delivery devices and drugs described herein can be used for the treatment and/or prophylaxis of many different types of disorders. Exemplary disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further exemplary disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis.

Exemplary drugs for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the term “derivative” refers to any substance which is sufficiently structurally similar to the original substance so as to have substantially similar functionality or activity (e.g., therapeutic effectiveness).

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

Exemplary insulin derivatives 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-gamma-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. Exemplary GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, for example: Lixisenatide/AVE0010/ZP10/Lyxumia, Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993 (a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-Xten.

An exemplary oligonucleotide is, for example: mipomersen/Kynamro, a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia.

Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.

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

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

The term “antibody”, as used herein, refers to an immunoglobulin molecule or an antigen-binding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab′) 2 fragments, which retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region.

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

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

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

The compounds described herein may be used in pharmaceutical formulations comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may also be used in pharmaceutical formulations that include one or more other active pharmaceutical ingredients or in pharmaceutical formulations in which the present compound or a pharmaceutically acceptable salt thereof is the only active ingredient. Accordingly, the pharmaceutical formulations of the present disclosure encompass any formulation made by admixing a compound described herein and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable salts of any drug described herein are also contemplated for use in drug delivery devices. Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from an alkali or alkaline earth metal, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: 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. Further examples of pharmaceutically acceptable salts are known to those of skill in the arts.

Pharmaceutically acceptable solvates are for example hydrates or alkanolates such as methanolates or ethanolates.

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

LIST OF REFERENCES

1auto-injector1.1control subassembly1.2drive subassembly2case2.1front case2.2rear case2.3inner rib2.4opening2.5angled surface2.6proximal end2.8opening2.9distal arm3syringe4injection needle5protective needle sheath6stopper7needle shroud7.1proximal arm7.2opening8control spring9drive spring10plunger10.1rib11cap12plunger release mechanism13feedback mechanism14collar14.1first collar rib14.2second collar rib14.3first snap-fit joint14.4inner protrusion14.5angled surface14.6third collar rib14.7second snap-fit joint14.8angled surface14.9proximal surface15shroud lock mechanismA advanced positionD distal directionM medicamentP proximal directionP1proximal positionP2distal positionR1rotational directionR2rotational directionS1distal positionS2proximal position