WO2017191306A1

WO2017191306A1 - Drug delivery device

Info

Publication number: WO2017191306A1
Application number: PCT/EP2017/060787
Authority: WO
Inventors: Michael Jugl; Axel Teucher
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2016-05-06
Filing date: 2017-05-05
Publication date: 2017-11-09

Abstract

The invention relates to a plunger arrangement (7) for a drug delivery device (1), the plunger arrangement (7) comprising: - a piston rod (8) having a drive surface (9) for being engaged by an energy source (6), - a bearing (10) for abutting a stopper (5) of a drug cartridge (3), and - a weight (11) arranged on the piston rod (8) and movable between a proximal position (P1) at a first distance (D1) to the bearing (10) and a distal position (P2) abutting the bearing (10).

Description

Drug delivery device Technical Field

The invention relates to a drug delivery device.

Background of the Invention

Drug delivery devices typically comprise a drug cartridge having a barrel for retaining a drug and a stopper for displacing the drug from the barrel through a nozzle, e.g. an injection needle which may be removably attached or fixed to the drug cartridge. The drug is displaced from the barrel by moving the stopper. This may be achieved by subjecting the stopper to a force from an energy source transferred through a plunger. The force required to move the stopper depends inter alia on the viscosity of the drug and the diameter of the nozzle. Furthermore, a break loose force may be required to move the stopper in the first place as the stopper will increasingly adhere (stick slip effect) to the wall of the barrel with increasing storage time. The energy source must be dimensioned to overcome these forces. This may also require configuring a housing or case to be robust enough to resolve high static and dynamic spring load.

There remains a need to efficiently subjecting the stopper to relatively high forces. Summary of the Invention

It is an object of the present invention to provide an improved drug delivery device with an arrangement for displacing a stopper. The object is achieved by a drug delivery device according to claim 1 .

Exemplary embodiments of the invention are given in the dependent claims.

According to the invention, a drug delivery device comprises:

- a housing adapted to contain a drug cartridge having a barrel for retaining a drug and a stopper for displacing the drug from the barrel, and

an energy source. a plunger arrangement comprising:

a piston rod having a drive surface for being engaged by an energy source, a bearing for abutting a stopper of a drug cartridge, and

a weight arranged on the piston rod and movable between a proximal position and a distal position, wherein in the proximal position, the weight is arranged at a first distance to the bearing and wherein in the distal position, the weight abuts the bearing.

The weight is in the proximal position prior to activation of the drug delivery device and in the distal position following activation of the drug delivery device. In an initial state, the bearing is arranged at a second distance from the stopper so that there is a gap between the bearing and the stopper.

Typically, in a ready to dispense or prior to use position of a drug delivery device, there is a gap between the bearing and the stopper of the drug cartridge. In this state, the weight is in the proximal position. After activation of the energy source, e.g. a spring, the piston rod with the weight is accelerated and the bearing hits the stopper. Upon this impact, the piston rod is suddenly decelerated while the weight continues moving due to its inertia. Consequently, the weight travels the first distance until it hits the bearing and arrives in the distal position. The impact of the weight on the bearing subjects the bearing and the stopper to an impulse reaction, i.e. a force in addition to the force from the energy source thus reliably moving the stopper and overcoming its break loose force even after prolonged storage periods. The stopper can thus be moved with a relatively weak energy source, e.g. a spring, and the housing can be designed less robust and bulky as it only has to retain a smaller energy source and cope with smaller reaction forces of the spring. As soon as the break loose force has been overcome, the force required to move the stopper further is considerably lower and can be provided by the energy source alone.

The impulse reaction of the weight also reduces shock led into the mechanism. In an exemplary embodiment, the weight comprises a hole, through which the piston rod extends. This allows for a symmetric distribution of the force exerted on the bearing and stopper thus preventing canting.

In an exemplary embodiment, a snap mechanism is arranged to releasably retain the weight on the piston rod in the proximal position. This ensures that the weight is only released when the energy source was activated. In an exemplary embodiment, the snap mechanism is adapted to release the weight from the piston rod upon exceedance of a predetermined force. Typically, the predetermined force may be the force generated as the bearing impacts the stopper driven by the energy source minus a safety margin to ensure that the snap mechanism is released.

In an exemplary embodiment, the piston rod is a lead screw.

In an exemplary embodiment, a second snap mechanism may be arranged to retain the weight on the piston rod in the distal position. This may ensure that the weight does not bounce back after the impact and prevents the weight from rattling on the piston rod after release.

The drug cartridge may be adapted to removably mount an injection needle. Likewise, the cartridge may be arranged as a prefilled syringe having a fixed injection needle.

In an exemplary embodiment, the energy source is a spring, e.g. a compression spring.

Likewise, the energy source may be a torsion spring, a tension spring or an electric motor. In an exemplary embodiment, the spring is dimensioned to accelerate the piston rod and the weight within the second distance such that the predetermined force is exceeded as the bearing abuts the stopper. This ensures release of the snap mechanism is released and impacts the bearing for moving the stopper. In an exemplary embodiment, the drug delivery device further comprises a housing in which the drug cartridge, the energy source and the plunger arrangement are arranged.

In an exemplary embodiment, the energy source is adapted to linearly advance the piston rod. In another exemplary embodiment, the piston rod is a lead screw and the energy source is adapted to rotate the piston rod to advance it.

The drug delivery device can be an auto-injector, an inhaler or an irrigator. In an exemplary embodiment, the drug delivery device comprises a drug cartridge having a barrel that contains a medicament. In an exemplary embodiment, a method for using the drug delivery device comprises:

activating the energy source causing the energy source to accelerate the piston rod with the weight and the bearing such that the bearing travels a distance and hits the stopper so that the piston rod is suddenly decelerated while the weight continues moving a distance and then hits the bearing subjecting the bearing and stopper to an impulse reaction.

Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating exemplary embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Brief Description of the Drawings

The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein: Figure 1 is a schematic view of a drug delivery device having an exemplary

embodiment of a plunger arrangement according to the invention in an initial position, and

Figure 2 is a schematic view of a drug delivery device having an exemplary

embodiment of a plunger arrangement according to the invention during use.

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

Detailed Description

Figure 1 is a schematic view of a drug delivery device 1 comprising a housing 2 containing a drug cartridge 3 having a barrel 4 for retaining a drug and a stopper 5 for displacing the drug from the barrel 4 through a nozzle 13, e.g. an injection needle. Furthermore, the housing 2 contains an energy source 6, e.g. a spring and a plunger arrangement 7 for transferring force from the energy source 6 to the stopper 5. The plunger arrangement 7 comprises a piston rod 8 having a drive surface 9 for being engaged by the energy source 6. A bearing 10 is arranged distally on the piston rod 8 for abutting the stopper 5, and a weight 1 1 is arranged on the piston rod 8 and movable between a proximal position P1 at a first distance D1 to the bearing 10 and a distal position P2 abutting the bearing 10. Figure 1 shows the plunger arrangement 7 with the weight 1 1 in the proximal position P1 in an initial state prior to use. The bearing 10 is arranged at a second distance D2 from the stopper 5 so that there is a gap between the bearing 10 and the stopper 5.

A snap mechanism 12 is arranged to releasably retain the weight 1 1 on the piston rod 8 in the proximal position P1.

In an exemplary embodiment, the weight 1 1 comprises a hole, through which the piston rod 8 extends. Figure 2 is a schematic view of the drug delivery device 1 during use. After activation of the energy source 6, e.g. a spring, the piston rod 8 with the weight 1 1 coupled to it by the snap mechanism 12 is accelerated and the bearing 10 travels the second distance D2 and hits the stopper 5. Upon this impact, the piston rod 8 is suddenly decelerated while the weight 1 1 continues moving due to its inertia. Consequently, the weight 1 1 travels the first distance D1 until it hits the bearing 10 and arrives in the distal position P2. The impact of the weight 1 1 on the bearing 10 subjects the bearing 10 and the stopper 5 to an impulse reaction, i.e. a force in addition to the force from the energy source 6 thus reliably moving the stopper 5 and overcoming any break loose forces even after prolonged storage periods. The stopper 5 can thus be moved with a relatively weak energy source 6, e.g. a spring, and the housing 2 can be designed less robust and bulky as it only has to retain a smaller energy source 6 and cope with smaller reaction forces of the spring. As soon as the break loose force has been overcome, the force required to move the stopper 5 further is considerably lower and can be provided by the energy source 6 alone. In an exemplary embodiment, the snap mechanism 12 is adapted to release the weight 1 1 from the piston rod 8 upon exceedance of a predetermined force. Typically, the predetermined force may be the force generated as the bearing 10 impacts the stopper 5 driven by the energy source 6 minus a safety margin to ensure that the snap mechanism 12 is released. In the illustrated exemplary embodiment, the energy source 6 is adapted to linearly advance the piston rod 8. In another exemplary embodiment (not shown), the piston rod 8 is a lead screw and the energy source 6 is adapted to rotate the piston rod 8 to advance it.

Furthermore, in an exemplary embodiment, a second snap mechanism (not illustrated) may be arranged to retain the weight 1 1 on the piston rod 8 in the distal position P2.

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 gastrointestinal 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-(oo-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(oo-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-1 134-PC, PB- 1023, TTP-054, Langlenatide / HM-1 1260C, 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. HCI 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

1 drug delivery device

housing

3 drug cartridge

barrel

5 stopper

6 energy source

7 plunger arrangement

8 piston rod

9 drive surface

10 bearing

1 1 weight

12 snap mechanism

13 nozzle

D1 first distance

D2 second distance

P1 proximal position

P2 distal position

Claims

1 . Drug delivery device (1 ), comprising:

a housing (2) adapted to contain a drug cartridge (3) having a barrel (4) for retaining a drug and a stopper (5) for displacing the drug from the barrel (4),

- an energy source (6), and

a plunger arrangement (7) comprising:

a piston rod (8) having a drive surface (9) for being engaged by the energy source (6),

a bearing (10) for abutting a stopper (5) of a drug cartridge (3), and - a weight (1 1 ) arranged on the piston rod (8) and movable between a proximal position (P1 ) at a first distance (D1 ) to the bearing (10) and a distal position (P2) abutting the bearing (10), wherein in an initial state the bearing (10) is arranged at a second distance (D2) from the stopper (5), wherein the weight (1 1 ) is in the proximal position (P1 ) prior to activation of the energy source (6), wherein after activation of the energy source (6), the piston rod (8) with the weight (1 1 ) is accelerated and the bearing (10) hits the stopper (5), wherein upon this impact, the piston rod (8) is suddenly decelerated while the weight (1 1 ) continues moving due to its inertia so that the weight (1 1 ) travels the first distance until it hits the bearing (10) and arrives in the distal position (P2).

2. Drug delivery device (1 ) according to claim 1 , wherein the weight (1 1 ) comprises a hole, through which the piston rod (8) extends.

3. Drug delivery device (1 ) according to claim 1 or 2, wherein a snap mechanism (12) is arranged to releasably retain the weight (1 1 ) on the piston rod (8) in the proximal position (P1 ).

4. Drug delivery device (1 ) according to claim 3, wherein the snap mechanism (12) is adapted to release the weight (1 1 ) from the piston rod (8) upon exceedance of a predetermined force.

5. Drug delivery device (1 ) according any one of the preceding claims, wherein the piston rod (8) is a lead screw.

6. Drug delivery device (1 ) according to any one of the preceding claims, wherein a second snap mechanism is arranged to retain the weight (1 1 ) on the piston rod (8) in the distal position (P2).

7. Drug delivery device (1 ) according to any one of the preceding claims, wherein the energy source (6) is a spring.

8. Drug delivery device (1 ) according to claims 4 and 7, wherein the spring is dimensioned to accelerate the piston rod (8) and the weight (1 1 ) within the second distance (D2) such that the predetermined force is exceeded as the bearing (10) abuts the stopper (5).

9. Drug delivery device (1 ) according to any one of the preceding claims, further comprising a housing (2) in which the drug cartridge (3), the energy source (6), and the plunger

arrangement (7) are arranged.

10. Drug delivery device (1 ) according to any one of the preceding claims, wherein the energy source (6) is adapted to linearly advance the piston rod (8).

1 1 . Drug delivery device (1 ) according to any one of the preceding claims, wherein the piston rod (8) is a lead screw and wherein the energy source (6) is adapted to rotate the piston rod (8) to advance it.

12. Drug delivery device (1 ) according to any one of the preceding claims, further comprising a drug cartridge (3) having a barrel (4) that contains a medicament.

13. Method for using a drug delivery device (1 ) according to any one of the preceding claims, comprising:

activating the energy source (6) causing the energy source (6) to accelerate the piston rod (8) with the weight (1 1 ) and the bearing (10) such that the bearing (10) travels a distance (D2) and hits the stopper (5) so that the piston rod (8) is suddenly decelerated while the weight (12) continues moving a distance (D1 ) and then hits the bearing (10) subjecting the bearing (10) and stopper (5) to an impulse reaction.