WO2024251793A1 - Dispositif d'administration de médicament - Google Patents

Dispositif d'administration de médicament Download PDF

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Publication number
WO2024251793A1
WO2024251793A1 PCT/EP2024/065437 EP2024065437W WO2024251793A1 WO 2024251793 A1 WO2024251793 A1 WO 2024251793A1 EP 2024065437 W EP2024065437 W EP 2024065437W WO 2024251793 A1 WO2024251793 A1 WO 2024251793A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug delivery
delivery device
drug
needle
rotatable member
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2024/065437
Other languages
English (en)
Inventor
Uwe Dasbach
Claus Geiger
Tim GLÄSSER
Moritz KEIM
Bernd Kühn
Matthias Rau
Marc SCHADER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Priority to CN202480037913.2A priority Critical patent/CN121285406A/zh
Publication of WO2024251793A1 publication Critical patent/WO2024251793A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
    • A61M5/2033—Spring-loaded one-shot injectors with or without automatic needle insertion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3205—Apparatus for removing or disposing of used needles or syringes, e.g. containers; Means for protection against accidental injuries from used needles
    • A61M5/321—Means for protection against accidental injuries by used needles
    • A61M5/3243—Means for protection against accidental injuries by used needles being axially-extensible, e.g. protective sleeves coaxially slidable on the syringe barrel
    • A61M5/3271—Means for protection against accidental injuries by used needles being axially-extensible, e.g. protective sleeves coaxially slidable on the syringe barrel with guiding tracks for controlled sliding of needle protective sleeve from needle exposing to needle covering position
    • A61M5/3272—Means for protection against accidental injuries by used needles being axially-extensible, e.g. protective sleeves coaxially slidable on the syringe barrel with guiding tracks for controlled sliding of needle protective sleeve from needle exposing to needle covering position having projections following labyrinth paths
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
    • A61M2005/2006—Having specific accessories
    • A61M2005/2013—Having specific accessories triggering of discharging means by contact of injector with patient body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
    • A61M2005/2073—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically preventing premature release, e.g. by making use of a safety lock
    • A61M2005/208—Release is possible only when device is pushed against the skin, e.g. using a trigger which is blocked or inactive when the device is not pushed against the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
    • A61M2005/31518—Piston or piston-rod constructions, e.g. connection of piston with piston-rod designed to reduce the overall size of an injection device, e.g. using flexible or pivotally connected chain-like rod members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3205—Apparatus for removing or disposing of used needles or syringes, e.g. containers; Means for protection against accidental injuries from used needles
    • A61M5/321—Means for protection against accidental injuries by used needles
    • A61M5/3243—Means for protection against accidental injuries by used needles being axially-extensible, e.g. protective sleeves coaxially slidable on the syringe barrel
    • A61M5/326—Fully automatic sleeve extension, i.e. in which triggering of the sleeve does not require a deliberate action by the user
    • A61M2005/3267—Biased sleeves where the needle is uncovered by insertion of the needle into a patient's body

Definitions

  • the drug delivery device comprises a rotatable member, which is rotatable around the axis and which is coupled to the plunger elements such that the rotatable member rotates the plunger elements around the axis upon rotation of the rotatable member.
  • the rotatable member enables to rotate the plunger elements around the axis and as such to push the stopper in the dispensing direction in a very easy way.
  • the rotatable member comprises a gear wheel and the plunger elements each comprise a toothed portion, with the tooth portion of the plunger elements being configured to engage with the gearwheel, upon rotation of the rotatable member around the axis.
  • the gear wheel which may be rigidly fixed to the rotatable member and which is configured to be rotated together with the rotatable member, easily enables to couple the rotatable member with the plunger elements.
  • the drug delivery device comprises a release mechanism being configured for locking the rotatable member in the initial state and for releasing the rotatable member such that the energy storage member rotates the rotatable member around the axis, upon activation of the release mechanism.
  • the release mechanism may comprise an activation member which may have to be moved relative to the housing in order to enable triggering of the drug delivery operation or to trigger the drug delivery operation.
  • the activation member may be a rod.
  • the needle sleeve may be configured as the activation member. If the needle sleeve is the activation member, the drug delivery operation may be triggered without interacting with, e.g. without pushing, any further activation member, e.g.
  • the drug delivery operation may be triggered by the needle sleeve, e.g. by movement thereof.
  • Enable triggering of the drug delivery operation may comprise that in addition to movement of the activation member another member such as a trigger member has to be actuated, e.g. a button, has to be pressed.
  • the activation member itself may comprise the trigger member, wherein one axial end of the rod may be used as the button.
  • the rod may comprise one or more recesses acting in conjunction with corresponding pins or ribs for arresting or releasing the energy storage member.
  • the rod may extend parallel to the dispensing direction and/or perpendicular to the axis.
  • the direction, in which the rod extends and/or may be moved is not perfectly parallel to the dispensing direction. Therefore, in this description, the direction, in which the rod extends and/or may be moved, is referred to as "basically" the dispensing direction. In other embodiments, the rod may extend perpendicular to the dispensing direction and/or parallel to the axis.
  • the drug delivery device comprises a needle sleeve for protecting the needle, wherein the needle sleeve is operatively coupled to the release mechanism and configured such that an activation of the release mechanism is prevented as long as the needle sleeve protects the needle and that the activation of the release mechanism is enabled, when the needle sleeve exposes the needle.
  • the needle sleeve may be movable relative to the housing. The needle sleeve may block the activation of the release mechanism in a first position of the needle sleeve relative to the housing and may release the activation of the release mechanism in a second position of the needle sleeve relative to the housing.
  • the needle sleeve may be provided to cover the needle, in particular the first needle for piercing the skin.
  • the needle sleeve may be provided to cover the needle before the needle pierces the skin and/or after the needle has been removed from the skin, e.g. after completion of the drug delivery operation.
  • the needle sleeve may protrude from the housing, e.g. to cover the tip of the needle (such as by axially extending beyond the tip of needle, e.g. at least with a contact surface of the needle sleeve).
  • the needle sleeve may be displaced relative to the housing.
  • the needle sleeve may be moved relative to the housing, e.g. to cover the tip of needle and/or into a third position relative to the housing.
  • the drug delivery device may comprise a sleeve spring.
  • the sleeve spring may be operatively couplable to or coupled to the needle sleeve in order to move the needle sleeve, e.g. into the axial direction relative to the housing.
  • the force of the needle sleeve spring may have to be overcome in order to move the needle sleeve into the housing. In a final position, e.g.
  • the needle sleeve may be locked against a further movement with respect to the housing, such as by a locking mechanism. This may contribute to a safe handling of the drug delivery device after its usage by protecting the used needle.
  • the plunger elements of the plunger arrangement are guided by a guide structure of the housing.
  • the guide structure may comprise a groove within the housing.
  • the plunger elements are at least partly arranged within the groove such that they may be rotated around the axis while being guided by the groove.
  • the drug container is a syringe. In other embodiments, the drug container may be a cartridge.
  • the drug container may comprise the needle, e.g. the first or second needle, or may be coupled with the needle, e.g. the first or second needle, manually before using the drug delivery device or automatically when using the drug delivery device.
  • Figure 1 illustrates a top view of an interior of an exemplary embodiment of a drug delivery device.
  • Figure 2 illustrates a side view of the interior of the drug delivery device of figure 1.
  • Figure 3 illustrates an exemplary embodiment of a rotatable member of a drug delivery device.
  • Figure 4 illustrates an exemplary embodiment of an energy storage member of a drug delivery device.
  • Figure 5 illustrates another exemplary embodiment of a rotatable member of a drug delivery device.
  • Figure 6 illustrates another exemplary embodiment of a rotatable member of a drug delivery device.
  • Figure 7 illustrates the drug delivery device of figure 1 in a first state.
  • Figure 8 illustrates the drug delivery device of figure 1 in a second state.
  • Figure 9 illustrates the drug delivery device of figure 1 in a third state.
  • Figure 10 illustrates the drug delivery device of figure 1 in a fourth state.
  • Figures 11 illustrates a side view of another exemplary embodiment of a drug delivery device.
  • Figure 12 illustrates an exemplary embodiment of a needle sleeve and a guide unit in a first state.
  • Figure 13 illustrates the needle sleeve and the guide unit of figure 12 in a second state.
  • Figure 14 illustrates the needle sleeve and the guide unit of figure 12 in a third state.
  • Figure 15 illustrates the needle sleeve and the guide unit of figure 12 in a fourth state.
  • Figure 16 illustrates the needle sleeve and the guide unit of figure 12 in a fifth state.
  • Figure 17 illustrates the needle sleeve and the guide unit of figure 12 in a sixth state.
  • Figure 18 illustrates an exemplary embodiment of a drug container.
  • Figure 19 illustrates an exemplary embodiment of a drug container.
  • Figure 20 illustrates an exemplary embodiment of a drug container.
  • Figure 21 illustrates an expanded structural formula, molecular formula, and molecular weight of fitusiran.
  • Figures 1 and 2 illustrate an embodiment of a drug delivery device 20.
  • Figure 1 illustrates a top view of an interior of an exemplary embodiment of a drug delivery device 20.
  • Figure 2 illustrates a side view of the interior of the drug delivery device 20 of figure 1.
  • figures 1 and 2 show the drug delivery device 100 in an initial or as delivered state.
  • the drug delivery device 20 comprises a housing 22.
  • the housing 22 is provided to retain and/or retains a drug container 24 and a release mechanism of the drug delivery device 20 in its interior.
  • a shape and/or size of the housing 22 may correspond to the shape and, respectively, size of a conventional (computer-)mouse.
  • the drug container 24 comprises a dispensing end 28 and a remote end 30 opposite the dispensing end 28.
  • the drug container 24 comprises a chamber 26.
  • a drug i.e. a medicament, e.g. liquid medicament, may be arranged within the chamber 26.
  • the chamber 26 is fluid-tight closed by a stopper 32.
  • the stopper 32 is movably retained in the drug container 24 and may seal the drug container 24 remotely.
  • the stopper 32 may be displaced towards an outlet of the drug container 24 at the dispensing end 28 to dispense the drug retained within the chamber 26 through the outlet.
  • the stopper 32 may be movable in a dispensing direction 40 towards the dispensing end 28. If the stopper 32 is moved in the dispensing direction 40, the drug is dispensed through the outlet at the dispensing end 28.
  • a drive mechanism provided to drive a drug delivery operation is expediently provided in the housing 22.
  • the drive mechanism comprises a plunger arrangement 34, a rotatable member 42 and an energy storage member 86 (see figure 9).
  • the plunger arrangement 34 comprises several plunger elements, in particular a first plunger element 36, a second plunger element 38, and further corresponding plunger elements, which are not characterized by corresponding reference numerals in the figures for clarity reasons.
  • the first plunger element 36 may be in direct physical contact with the stopper 32 or, before the dispensing operation or delivery operation starts, there may be a gap between the first plunger element 36 and the stopper 32.
  • the second plunger element 38 is in direct physical contact with the first plunger element 36.
  • the first plunger element 36 is arranged between the stopper 32 and the second plunger element 38.
  • the plunger elements 36, 38 may be coupled to each other such that they form a flexible plunger.
  • the plunger elements 36, 38 may be coupled to each other via hinges, in particular film hinges or living hinges.
  • the plunger elements 36, 38 each may comprise a tooth portion 46 at a side of the corresponding plunger element 36, 38 facing inwardly.
  • the rotatable member 42 may comprise a gear wheel 44.
  • the gear wheel 44 may be rigidly coupled to the rest of the rotatable member 42 such that a rotation of the rotatable member 42 corresponds to a rotation of the gear wheel 44.
  • the gear wheel 44 may be configured to engage with the toothed portions 46 of the plunger elements 36, 38, at least upon rotation of the rotatable member 42.
  • the toothed portions 46 may be formed at the sides of the plunger elements 36, 38 facing the axis 45.
  • the plunger elements 36, 38 are coupled to the rotatable member 42 such that a rotation of the rotatable member 42 around an axis 45 may be transferred to a rotation of the plunger elements 36, 38 around the axis 45. If the rotatable member 42 is rotated each of the plunger elements 38 acts on the preceding plunger element 36, 38, wherein the first plunger element 36 acts on the stopper 32.
  • the rotatable member 42 may comprise several protrusions 88 (see figures 5 and 6) and the plunger elements 36, 38 each may comprise an indentation 47, wherein the protrusions 88 may be configured to engage with the indentations 47 such that the rotation of the rotatable member 42 is transferred to the plunger elements 36, 38 via the protrusions 88 and the corresponding indentations 47.
  • the energy storage member 86 is coupled to the rotatable member 42. In an initial state, the energy storage member 86 is loaded, wherein energy is stored in the loaded energy storage member 86. If the energy storage member 86 is released, the energy stored in the energy storage member 86 is released and transferred to the rotatable member 42 such that the rotatable member 42 is rotated. If the rotatable member 42 rotates, the rotation is transferred via the gear wheel 44 and the toothed portions 46 to the plunger elements 36, 38. Then, the plunger elements 36, 38 are introduced into the drug container 22 one after the other pushing the stopper 32 in the dispensing direction 40 and carrying out a drug delivery operation. In particular, the second plunger element 38 pushes the first plunger element 36 against the stopper 32 and the first plunger element 36 pushes the stopper 32 in the dispensing direction 40.
  • the rotatable member 42 may be coupled to the energy storage member 86 such that a locking of the rotatable member 42 corresponds to a locking of the energy storage member 86. So, if the rotatable member 42 is held in its initial state, the energy storage member 86 may be held in its initial state also. To hold the rotatable member 42 in its initial state, the rotatable member 42 may comprise an arrestor rib 48 which is blocked by a rod 50. The rod 50 may act as an activation member for activating the dispensing operation.
  • the rod 50 extends through the housing 22 in a direction perpendicular to the axis 45 and basically parallel to the dispensing direction 40.
  • the rod 50 comprises the first recess 52, a second recess 54 and one or more first engaging features 56.
  • the rod 50 remotely extends through the housing 22 such that the end of the rod 50 being exposed outside the housing 22 may be used as a button for pushing the rod 50 in the direction perpendicular to the axis 45 and basically parallel to the dispensing direction 40.
  • the direction, in which the rod 50 may be moved is not perfectly parallel to the dispensing direction 40. Therefore, in this description, the direction, in which the rod 50 may be moved, is referred to as "basically" the dispensing direction 40.
  • the first recess 52 is arranged for accommodating the arrestor rib 48 of the rotatable member 42 in order to release the rotatable member 42 and as such the energy storage member 86, if the rod 50 is pushed basically in the dispensing direction 40. However, the movement of the rod 50 may be blocked by an arrestor pin 62 of a needle sleeve 60.
  • the needle sleeve 60 is arranged for protecting a needle of the drug delivery device 20, e.g. a first needle 70.
  • the needle sleeve 60 protrudes from the housing 22 in the initial state.
  • the needle sleeve 60 is movable relative to the housing 22 from an initial position or first position to a second position or trigger position.
  • the needle sleeve 60 is movable along an axis that extends parallel to the axis 45.
  • the needle sleeve 60 may be provided to extend beyond a tip of the first needle 70 which may protrude from the bottom of the housing 22 before the drug delivery operation is commenced.
  • the needle sleeve 60 is movably arranged within a guide unit 64.
  • the first needle 70 is exposed and may pierce the skin.
  • the needle 70 may not be movable relative to the housing 22 and/or the drug container 24.
  • the needle 70 may not be able to move in a direction parallel to the axis 45.
  • the drug container 24 may not be movable relative to the housing 22.
  • the needle sleeve 60 may serve as a trigger member of the drug delivery device 20.
  • the needle sleeve 60 as trigger member when displaced from the initial or first position depicted in figures 1 and 2 to the second or trigger position (see figures 3 and 14), may automatically initialize the drug delivery operation, preferably when it is in the second position.
  • the needle sleeve 60 when moved from the first position to the second position and expediently when in the second position, may enable the triggering of the drug delivery operation via releasing the rod 50.
  • the drug delivery operation may be initiated by pressing the trigger button, i.e. the remote end of the rod 50. Operating the trigger button to initiate the drug delivery operation may only be possible when the needle sleeve 60 is in the second position.
  • the arrestor pin 62 may be moved outside of a plane in which the rod 50 is arranged and the rod 50 is not blocked by the arrestor pin 62 anymore. Then, the rod 50 may be pushed basically in the dispensing direction 40. So, the rod 50 may be moved only, if the drug delivery device 20 is positioned on the skin and the needle sleeve 60 exposes the first needle 70. If the rod 50 is pushed in its final position, in which the dispensing operation is completed, the first engaging feature of 56 may interact with one or more second engaging features 58 coupled to the housing 22 such that the rod 50 is held in its final position by the engaging features 56, 58.
  • the needle sleeve 60 may be mechanically and operatively coupled to the rotatable member 42 and/or the energy storage member 60 in order to retain the rotatable member 42 and/or the energy storage member 60 at first and then to release the rotatable member 42 and/or the energy storage member 60.
  • the first needle 70 may communicate with the drug container 24 via a conduit 74 and a second needle 72 of the drug container 24.
  • the outlet of the drug container 24 at the dispensing end 28 may be formed or defined by the second needle 72.
  • the second needle 72 may be an integral part of the drug container 24, e.g. (permanently or releasably) connected to a drug container body or separate from the drug container 24.
  • the drug container 24 may be a syringe.
  • the drug container 24 may be a cartridge.
  • the drug container 24 and the second needle 72 may be fluidly disconnected, and a fluid communication between an interior of the drug container 24 and the second needle 72 may be only established during operation of the drug delivery device 20. Further, instead of the two separate needles 70, 72 only one single needle may be arranged (see figures 18 to 20).
  • the drug delivery device 20 is an autoinjector.
  • the energy for driving the drug delivery operation in an autoinjector may be provided by components integral to the drug delivery device 20 and does not have to be loaded into the drug delivery device 20 by the user during the operation as is the case in many spring driven pen-type variable dose injectors, where, usually, the energy is loaded into a spring by the user during a dose setting procedure.
  • the drug delivery device 20 expediently is a single shot device, i.e. it is provided to dispense only one dose.
  • the drug delivery device 20 may be a disposable drug delivery device 20, that is to say a drug delivery device 20 which is disposed of after its use.
  • the drug container 24 and/or the second needle 72 may be secured within the drug delivery device 20, e.g. within the housing 22. So, the user may have to perform the movement for piercing the skin with the first needle 70 communicating with the second needle 72 by placing the drug delivery device 20 on the skin.
  • Figure 3 illustrates an exemplary embodiment of a rotatable member of a drug delivery device, e.g. the rotatable member 42 of the above drug delivery device 20.
  • the rotatable member 42 comprises the gear wheel 44 and the arrestor rib 48.
  • the rotatable member 42, the gear wheel 44 and the arrestor rib 48 are fixed to each other and rotatable around the same axis 45.
  • a direction of rotation 66 during the dispensing operation is illustrated by a curved arrow.
  • FIG 4 illustrates an exemplary embodiment of an energy storage member of a drug delivery device, e.g. the energy storage member 86 of the above drug delivery device 20.
  • the energy storage member 86 may be arranged at a bottom of the rotatable member 42 or in a recess of the rotatable member 42. So, figure 4 shows a bottom view of the rotatable member 42 shown in figure 3.
  • the energy storage member 86 is a spiral spring, in particular a flat spiral spring.
  • the flat spiral spring comprises a hook 87 at one end of the flat spiral spring.
  • the hook 87 may be hooked into a corresponding hook recess (not shown) of the rotatable member 42 such that the end of the flat spiral spring comprising the hook 87 is fixedly connected to the rotatable member 42.
  • the other end of the flat spiral spring is connected to the axis 45 by a fixation 89.
  • the axis 45 is fixed in this context.
  • the fixation 89 may comprise a soldering or clamping of the flat spiral spring to the fixed axis 45.
  • the energy storage member 86 is loaded and as such the flat spiral spring is biased. If the rotatable member 42 is released, the flat spiral spring rotates the rotatable member 42 in the direction of rotation 66 and the rotatable member 42 rotates the plunger arrangement 34 and pushes the plunger elements 36, 38 in the dispensing direction against the stopper 32.
  • Other potential drive energy sources different from a spring comprise an electrical power cell or battery for driving the plunger arrangement 34 by a motor or a reservoir suitable to provide gas pressure, where the gas pressure can be used to drive the drug delivery operation.
  • Figure 5 illustrates another exemplary embodiment of a rotatable member of a drug delivery device, e.g. the above rotatable member 42.
  • the rotatable member 42 comprises several protrusions 88 at the surface of the rotatable member 42 facing the plunger arrangement 34.
  • the protrusions 88 are formed and arranged such that they act on the indentations 47 of the plunger elements 36, 38, if the rotatable member 42 is rotated.
  • the protrusions 88 engage with the indentations 47 at least in part and push the corresponding plunger elements 36, 38 in the direction of rotation 66.
  • Figure 6 illustrates another exemplary embodiment of a rotatable member of a drug delivery device, e.g. the above rotatable member 42.
  • the rotatable member 42 comprises the protrusions 88 at the surface of the rotatable member 42 facing the plunger arrangement 34.
  • the protrusions 88 are formed and arranged such that they act on the indentations 47 of the plunger elements 36, 38, if the rotatable member 42 is rotated.
  • the protrusions 88 engage with the indentations 47 at least in part and push the corresponding plunger elements 36, 38 in the direction of rotation 66.
  • the rotatable member 42 shown in figure 6 does not comprise the gear wheel 44.
  • the plunger elements 36, 38 do not comprise the tooth portions 46 in this embodiment.
  • Figure 7 illustrates the drug delivery device 20 of figure 1 in a first state.
  • the drug delivery device 20 is arranged on the skin such that the needle sleeve 60 is pushed into the housing 22, that the first needle 70 is exposed and that the arrestor pin 62 (see figure 1 ) is moved out of the plane of the rod 50.
  • the rod 50 may be pushed basically in the dispensing direction 40 by the user.
  • Figure 8 illustrates the drug delivery device 20 of figure 1 in a second state.
  • the rod 50 is pushed basically in the dispensing direction 40 by the user such that the rod 50 is in its final position.
  • the first engaging features 56 engage with the second engaging features 58 and the rod 50 is held in its final position by the engaging features 56, 58.
  • the arrestor rib 48 of the rotatable member 42 overlaps the first recess 52 of the rod 50 and as such is released. Then, the rotatable member 42 may be rotated by the energy storage member 86.
  • Figure 9 illustrates the drug delivery device 20 of figure 1 in a third state.
  • the rotatable member 42 is rotated.
  • the rotatable member 42 rotates the plunger elements 36, 38 of the plunger arrangement 34 around the axis 45 and pushes more and more of the plunger elements 36, 38 into the drug container 24 and against the stopper 32.
  • the stopper 32 is pushed in the dispensing direction 40 by the plunger elements 36, 38 and presses the drug through the outlet of the drug container 24, in particular through the second needle 72, the conduit 74 and the first needle 70.
  • the dispensing operation is carried out and the drug is dispensed.
  • Figure 10 illustrates the drug delivery device 20 of figure 1 in a fourth state.
  • the stopper 32 may not be moved further and no further drug may be dispensed through the needles 70, 72. So, in the fourth state, the dispensing operation is accomplished. Further, in the fourth state, the drug delivery device 20 may be removed from the skin of the user such that the needle sleeve 60 moves out of the housing 22, in particular out of the guide unit 64, and protects the first needle 70, and that the arrestor pin 62 moves into the second recess 54 of the rod 50 within the plane of the rod 50.
  • Figures 11 illustrates a side view of another exemplary embodiment of a drug delivery device 20.
  • the drug delivery device 20 may widely correspond to the above drug delivery device 20. Therefore, only those features of the drug delivery device 20 are explained in the following, in which the drug delivery device 20 shown in figure 11 differs from the above drug delivery device 20.
  • the guide unit 64 of the drug delivery device 20 shown in figure 11 comprises arms 78 for holding the conduit 74.
  • the conduit 74 may comprise a holder 80 which may be held by the arms 78.
  • the arms 78 and the holder 80 are engaged with each other.
  • the drug delivery device 20 may comprise a cap 82.
  • the cap 82 may be arranged at a dispensing end of the first needle 70.
  • the cap 82 is detachably connected to the remainder of the drug delivery device 20, e.g. to the housing 22, the needle sleeve 60, the guide unit 64 and/or another component or member of the drug delivery device 20.
  • the cap 82 may cover an opening of the needle sleeve 60 and/or a tip of the first needle 70.
  • the cap 82 may comprise a needle shield 84, which covers the first needle 70 such that the needle shield 84 may be removed from the first needle 70 together with the cap 82, e.g. when the cap 82 is detached or disconnected from the drug delivery device 20.
  • Figure 12 illustrates an exemplary embodiment of a needle sleeve and a guide unit in a first state, e.g. the above needle sleeve 60 and the above guide unit 64.
  • figure 12 illustrates a side view of the needle sleeve 60 and a cutaway side view of the guide unit 64 in the first state.
  • the drug delivery device 20 is not yet arranged on the skin of the user and the needle sleeve 60 protects the first needle 70.
  • the needle sleeve 60 comprises a guide pin 90, a torsion protection 92, and flexible bars 94.
  • the guide pin 90 protrudes from an outer wall of the needle sleeve 60 outwardly.
  • the flexible bars 94 are separated by through-recesses extending through the wall of the needle sleeve 60. So, the flexible bars 94 and the body of the needle sleeve 60 may be made of one piece.
  • the torsion protection 92 may comprise a bar extending vertically in figure 12.
  • the guide unit 64 comprises a first channel 96 and a second channel 104.
  • the first channel 96 extends firstly with a slide inclination against the vertical direction and then basically verticality towards a bent 98 of the first channel 96 and then back towards a dead end 100 of the first channel 96.
  • the dead end 100 is separated from the rest of the first channel 96 by a barb 102.
  • the guide pin 90 is arranged in a part of the first channel 96 below the dead end 100 and at the beginning of the inclination of the first channel 96.
  • the torsion protection 92 of the needle sleeve 60 is arranged within the second channel 104 and is guided by the second channel 104 during the movement of the needle sleeve 60 relative to the guide unit 64.
  • the second channel 104 is straight and parallel to the axis 45 and as such parallel to the moving direction of the needle sleeve 60.
  • the torsion protection 92 within the second channel 104 serves as a protection of the needle sleeve 60 against a rotation of the needle sleeve 60.
  • Figure 13 illustrates the needle sleeve 60 and the guide unit 64 of figure 12 in a second state.
  • the needle sleeve 60 may be partly arranged within the guide unit 64, e.g. because of the drug delivery device 20 being partly arranged on the skin of the user.
  • the guide pin 90 is moved within the first channel 96 towards the bent 98.
  • Figure 14 illustrates the needle sleeve 60 and the guide unit 64 of figure 12 in a third state.
  • the needle sleeve 60 In the third state of the needle sleeve 60, the needle sleeve 60 is pressed into the guide unit 64 completely, e.g. because of the user arranging the drug delivery device 20 on his/her skin. So, in the third state of the needle sleeve 60, the first needle 70 is exposed by the needle sleeve 60. In this situation, the guide pin 90 has arrived in the bent 98 of the first channel 96 and may be moved perpendicular to the moving direction of the needle sleeve 60 within the bent 98. In the third state of the needle sleeve 60, the biased flexible bars 94 force the guide pin 90 through the bent 98.
  • Figure 15 illustrates the needle sleeve 60 and the guide unit 64 of figure 12 in a fourth state.
  • the flexible bars 94 are released and the guide pin 90 has moved perpendicular to the moving direction of the needle sleeve 60 within the bent 98.
  • Figure 16 illustrates the needle sleeve 60 and the guide unit 64 of figure 12 in a fifth state.
  • the drug delivery device 20 may be partly removed from the skin of the user.
  • the guide pin 90 is forced over the barb 102 of the first channel 100 such that the flexible bars 94 are biased again.
  • the needle sleeve 60 may be pushed out of the housing 22, for example by a conventional needle sleeve spring (not shown) such that the guide pin 90 is forced over the barb.
  • Figure 17 illustrates the needle sleeve 60 and the guide unit 64 of figure 12 in a sixth state.
  • the drug delivery device 20 may be completely removed from the skin of the user.
  • the needle sleeve 60 may completely cover the first needle 70.
  • the guide pin 90 snaps into the dead end 100 of the first channel 96 such that the needle sleeve 60 is fixedly engaged to the guide unit 64.
  • Figure 18 illustrates an exemplary embodiment of a drug container.
  • the drug container 24 of figure 18 may widely correspond to the above drug container 24. Therefore, only those features of the drug container 24 are explained in the following, in which the drug container 24 shown in figure 18 differs from the above drug container 24.
  • the first needle 70 is protected by the cap 82 and a needle shield 84 within the cap 82.
  • the conduit 74 may comprise a ball structure 106 and the needle shield 84 may comprise a corresponding ball recess, in which the ball structure 106 is accommodated.
  • the ball structure 106 is form-fitted within the ball recess. This form-fit provides a predetermined resistance against the needle shield 84 and the cap 82 being removed from the first needle 70.
  • the cap 82 and the needle shield 84 may be configured such that the needle shield 84 is removed from the first needle 70, when the cap 82 is removed.
  • Figure 19 illustrates an exemplary embodiment of a drug container.
  • the drug container 24 of figure 19 may widely correspond to the above drug container 24. Therefore, only those features of the drug container 24 are explained in the following, in which the drug container 24 shown in figure 19 differs from the above drug container 24.
  • the drug container 24 shown in figure 19 comprises one needle, e.g. the first needle 70, only.
  • the needle 70 extends parallel to the axis 45.
  • Figure 20 illustrates an exemplary embodiment of a drug container.
  • the drug container 24 of figure 20 may widely correspond to the drug container 24 of figure 19. Therefore, only those features of the drug container 24 are explained in the following, in which the drug container 24 shown in figure 20 differs from the drug container 24 of figure 19.
  • the drug container 24 shown in figure 20 comprises a gripping structure 108 at the cap 82.
  • the gripping structure 108 enables to comfortably and easily grip and remove the cap 82.
  • the gripping structure 108 may be hingedly coupled to the cap 82.
  • drug or “medicament” are used synonymously herein and describe a pharmaceutical formulation containing one or more active pharmaceutical ingredients or pharmaceutically acceptable salts or solvates thereof, and optionally a pharmaceutically acceptable carrier.
  • An active pharmaceutical ingredient (“API”) in the broadest terms, is a chemical structure that has a biological effect on humans or animals. In pharmacology, a drug or medicament is used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. A drug or medicament may be used for a limited duration, or on a regular basis for chronic disorders.
  • a drug or medicament can include at least one API, or combinations thereof, in various types of pharmaceutical formulations, for the treatment of one or more diseases.
  • API may include small molecules having a molecular weight of 500 Da or less; 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 drugs are also contemplated.
  • the drug or medicament may be contained in a primary package or “drug reservoir” adapted for use with a drug delivery device.
  • the drug reservoir 101a may be, e.g., a cartridge, syringe, reservoir, or other solid or flexible vessel (bag) configured to provide a suitable chamber for storage (e.g., short- or long-term storage) of one or more drugs.
  • the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days).
  • the chamber may be designed to store a drug for about 1 month to about 2 years.
  • analogue and “derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, by deleting and/or exchanging at least one amino acid residue occurring in the naturally occurring peptide and/or by adding at least one amino acid residue.
  • the added and/or exchanged amino acid residue can either be codable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues.
  • Insulin analogues are also referred to as "insulin receptor ligands".
  • insulin analogues examples include Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulin glulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28) human insulin (insulin aspart); human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Vai 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.
  • insulin derivatives are, for example, B29-N-myristoyl-des(B30) human insulin, Lys(B29) (N- tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®); 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-omega- carboxypentadecanoyl-gamma-L-g
  • GLP-1 , GLP-1 analogues and GLP-1 receptor agonists are, for example, Lixisenatide (Lyxumia®), Exenatide (Exendin-4, Byetta®, Bydureon®, a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide (Victoza®), Semaglutide, Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®), rExendin-4, CJC- 1134-PC, PB-1023, TTP-054, Langlenatide / HM-11260C (Efpeglenatide), HM-15211, CM-3, GLP-1 Eligen, ORMD-0901, NN-9423, NN-9709, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1 , CVX-096, ZYOG-1, ZYD-1 , GSK-2
  • oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia or RG012 for the treatment of Alport syndrom.
  • DPP4 inhibitors are Linagliptin, Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.
  • 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.
  • Gonadotropine Follitropin, Lutropin, Choriongonadotropin, Menotropin
  • Somatropine Somatropin
  • Desmopressin Terlipressin
  • Gonadorelin Triptorelin
  • Leuprorelin Buserelin
  • Nafarelin Nafarelin
  • Goserelin Goserelin.
  • 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.
  • 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.
  • antibody refers to an immunoglobulin molecule or an antigenbinding portion thereof.
  • 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.
  • the antibody has effector function and can fix complement.
  • the antibody has reduced or no ability to bind an Fc receptor.
  • 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 term antibody also includes an antigen-binding molecule based on tetravalent bispecific tandem immunoglobulins (TBTI) and/or a dual variable region antibody-like binding protein having cross-over binding region orientation (CODV).
  • TBTI tetravalent bispecific tandem immunoglobulins
  • CODV cross-over binding region orientation
  • fragment refers 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 invention 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, tetraspecific and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), monovalent or multivalent antibody fragments such as bivalent, trivalent, tetravalent and multivalent antibodies, 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.
  • SMIP small modular immunopharmaceuticals
  • CDR complementarity-determining region
  • 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.
  • 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.
  • antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).
  • PCSK-9 mAb e.g., Alirocumab
  • anti IL-6 mAb e.g., Sarilumab
  • anti IL-4 mAb e.g., Dupilumab
  • APIs for the prophylaxis of hemophilia A or B, with or without inhibitors include an siRNA targeting antithrombin.
  • An example of an siRNA targeting antithrombin is fitusiran.
  • prophylaxis and prophylactic treatment are used interchangeably herein
  • Pharmaceutically acceptable salts of any API described herein are also contemplated for use in a drug or medicament in a drug delivery device.
  • Pharmaceutically acceptable salts are for example acid addition salts and basic salts.
  • An example drug delivery device may involve a needle-based injection system as described in Table 1 of section 5.2 of ISO 11608-1 :2014(E). As described in ISO 11608-1 :2014(E), needlebased injection systems may be broadly distinguished into multi-dose container systems and single-dose (with partial or full evacuation) container systems.
  • the container may be a replaceable container or an integrated non-replaceable container.
  • a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).
  • Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).
  • a single-dose container system may involve a needle-based injection device with a replaceable container.
  • each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation).
  • each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).
  • a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container.
  • each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation).
  • each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).
  • Fitusiran is a synthetic, chemically modified double-stranded small interfering RNA (siRNA) oligonucleotide covalently linked to a tri-antennary N-acetyl-galactosamine (GalNAc) ligand targeting AT3 mRNA in the liver, thereby suppressing the synthesis of antithrombin.
  • siRNA small interfering RNA
  • GalNAc tri-antennary N-acetyl-galactosamine
  • the nucleosides in each strand of fitusiran are connected through either 3’-5’ phosphodiester or phosphorothioate linkages, thus forming the sugar-phosphate backbone of the oligonucleotide.
  • the sense strand and the antisense strand contain 21 and 23 nucleotides, respectively.
  • the 3’ end of the sense strand is conjugated to the GalNAc containing moiety (referred to herein as L96) through a phosphodiester linkage.
  • the sense strand contains two consecutive phosphorothioate linkages at its 5’ end.
  • the antisense strand contains four phosphorothioate linkages, two at the 3’ end and two at the 5’ end.
  • the 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs and a two-base overhang at the 3’-end of the antisense strand. See also U.S. Pat. 9,127,274, U.S. Pat. 11,091 ,759, US2020/0163987A1, and WO 2019/014187, the entire contents each of which are expressly incorporated herein by reference.
  • sense strand 5’Gf-ps-Gm-ps-Uf-Um-Af-Am-Cf-Am-Cf-Cf-Af-Um-Uf-Um-Af-Cm-Uf-Um-Cf-Am- Af-L96 3’ (SEQ ID NO:1)
  • antisense strand 5’ Um-ps-Uf-ps-Gm-Af-Am-Gf-Um-Af-Am-Af-Um-Gm-Gm-Uf-Gm-Uf-Um-Af- Am-Cf-Cm-ps-Am-ps-Gm 3’ (SEQ ID NO:2), wherein
  • fitusiran can also be described using the following diagram, wherein the X is O: Fitusiran is shown in Figure 21 in sodium salt form.
  • the device delivers fitusiran in an aqueous solution, wherein fitusiran is at a concentration of about 40 to about 200 mg/mL (e.g., about 50 to about 150 mg/mL, about 80 to about 110 mg/mL, or about 90 to about 110 mg/mL).
  • fitusiran is at a concentration of about 40 to about 200 mg/mL (e.g., about 50 to about 150 mg/mL, about 80 to about 110 mg/mL, or about 90 to about 110 mg/mL).
  • values intermediate to recited ranges and values are also intended to be part of this disclosure.
  • ranges of values using a combination of any of recited values as upper and/or lower limits are intended to be included.
  • the pharmaceutical formulation comprises fitusiran in an aqueous solution at a concentration of about 40, about 50, about 75, about 100, about 125, about 150, or about 200 mg/mL.
  • fitusiran is provided in an aqueous solution at a concentration of about 100
  • delivery is intended to mean “administer,” “administers,” or “administering.”
  • the term “approximately” or “about” refers to a value that is within an acceptable error range for a particular value determined by a person of ordinary skill, a portion of which will depend on how the measurement or determination is made. For example, “approximately” or “about” may mean a range of up to 10% (ie, ⁇ 10%). Therefore, “approximately” or “about” can be understood as greater than or less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1 %, 0.05%, 0.01%, or 0.001%. When a specific value is provided in this disclosure, unless otherwise stated, the meaning of “approximately” or “about” should be assumed to be within an acceptable error range for that specific value.
  • fitusiran dosage weight described herein refers to the weight of fitusiran free acid (active moiety)
  • administration of fitusiran to patients herein refers to administration of fitusiran sodium (drug substance) provided in a pharmaceutically suitable aqueous solution (e.g., a phosphate-buffered saline at a physiological pH).
  • a pharmaceutically suitable aqueous solution e.g., a phosphate-buffered saline at a physiological pH.
  • fitusiran means about 100 mg of fitusiran free acid (equivalent to about 106 mg fitusiran sodium, the drug substance) per mL.
  • a fitusiran weight recited in the present disclosure is the weight of fitusiran free acid (the active moiety).
  • a pharmaceutical formulation in the device comprises fitusiran in a phosphate-buffered saline.
  • the phosphate concentration in the solution may be about 1 to about 10 mM (e.g., about 2, about 3, about 4, about 5, about 6, about 7, about 8, or about 9 mM), with a pH of about 6.0-8.0.
  • the pharmaceutical formulations herein may include a stabilizing agent such as EDTA.
  • the pharmaceutical formulations may be preservative-free.
  • the fitusiran pharmaceutical formulation in the device is preservative-free and comprises, consists of, or consists essentially of about 100 mg of fitusiran per mL of an approximately 5 mM phosphate buffered saline (PBS) solution.
  • PBS phosphate buffered saline
  • the fitusiran pharmaceutical formulation in the device is preservative-free and comprises, consists of, or consists essentially of fitusiran in an approximately 5 mM phosphate buffered saline (PBS) solution.
  • PBS phosphate buffered saline
  • the PBS solution is composed of sodium chloride, dibasic sodium phosphate (heptahydrate), and monobasic sodium phosphate (monohydrate).
  • Sodium hydroxide solution and diluted phosphoric acid may be used to adjust the pH of the pharmaceutical formulation to about 7.0 or about 7.1.
  • the fitusiran pharmaceutical formulation in the device for subcutaneous delivery contains fitusiran in a 5 mM phosphate buffered saline having 0.64 mM Na ⁇ PC , 4.36 mM N32HPO4, and 84 mM NaCI at pH 7.0.
  • the pharmaceutical formulation of fitusiran solution for subcutaneous delivery is shown in Table 1 below:
  • the pharmaceutical formulation of fitusiran solution for subcutaneous delivery with the device can be described as shown in Table 2 below. Table 2. Exemplary Fitusiran Pharmaceutical Formulation
  • the device may be used to deliver a single dose of fitusiran wherein the single dose comprises about 20 to about 80 mg of fitusiran (e.g., about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, or about 80 mg). In some embodiments, the device may be used to deliver single dose of fitusiran, wherein the single dose comprises about 1 to about 30 mg of fitusiran (e.g., about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, or about 30 mg).
  • the single dose comprises about 1 to about 30 mg of fitusiran (e.g., about 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, or about 30 mg).
  • the device may be used to deliver a single dose of about 80 mg of fitusiran.
  • the device may be used to deliver a single dose of about 50 mg of fitusiran.
  • the device may be used to deliver a single dose of about 20 mg of fitusiran.
  • the device may be used to deliver a single dose of about 30 mg of fitusiran.
  • the device may be used to deliver a single dose of about 10 mg of fitusiran.
  • the device may be used to deliver a single dose of about 5 mg of fitusiran. In one embodiment, the device may be used to deliver a single dose of about 2.5 mg of fitusiran. In one embodiment, the device may be used to deliver a single dose of about 1.25 mg of fitusiran.
  • the single dose of fitusiran may be delivered in about 0.5 mL to about 1 mL delivery volumes (e.g., about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL).
  • delivery volumes described herein may also be used.
  • the device may be used to deliver a single dose of about 80 mg of fitusiran in about 0.8 mL (about 100 mg fitusiran/mL). In one embodiment, the device may be used to deliver a single dose of about 50 mg of fitusiran in about 0.5 mL (about 100 mg fitusiran/mL). In one embodiment, the device may be used to deliver a single dose of about 20 mg of fitusiran in about 0.5 mL (about 40 mg fitusiran/mL). In one embodiment, the device may be used to deliver a single dose of about 30 mg of fitusiran in about 0.5 mL (about 60 mg fitusiran/mL).
  • the device may be used to deliver a single dose of about 10 mg of fitusiran in about 0.5 mL (about 20 mg fitusiran/mL). In one embodiment, the device may be used to deliver a single dose of about 5 mg of fitusiran in about 0.5 mL (about 10 mg fitusiran/mL). In one embodiment, the device may be used to deliver a single dose of about 2.5 mg of fitusiran in about 0.5 mL (about 5 mg fitusiran/mL). In one embodiment, the device may be used to deliver a single dose of about 1.25 mg of fitusiran in about 0.5 mL (about 2.5 mg fitusiran/mL).
  • the device delivers fitusiran at a prophylactically effective amount to prophylactically treat hemophilia (e.g., hemophilia A or B, in a patient with or without inhibitors) in a patient in need thereof (e.g., a hemophilia A or B patient, with or without inhibitors).
  • “Prophylactically effective amount” refers to the amount of fitusiran that helps the patient with hemophilia A or B, with or without inhibitors to achieve a desired clinical endpoint such as reducing the Annualized Bleeding Rate (ABR), Annualized Joint Bleeding Rate (AjBR), Annualized Spontaneous Bleeding Rate (AsBR), or the frequency of bleeding episodes.
  • ABR Annualized Bleeding Rate
  • AjBR Annualized Joint Bleeding Rate
  • AsBR Annualized Spontaneous Bleeding Rate
  • the term “treat” “treating,” or “treatment” includes prophylactic treatment of the disease and refers to achievement of a desired clinical
  • a hemophilia A or B patient with inhibitors refers to a patient who has developed alloantibodies to the factor he/she has previously received (e.g., factor VIII for hemophilia A patients or factor IX for hemophilia B patients).
  • a hemophilia A or B patient with inhibitors may become refractory to replacement coagulation factor therapies.
  • a patient without inhibitors refers to a patient who does not have such alloantibodies.
  • the present treatment methods may be beneficial for hemophilia A patients with inhibitors, as well as for hemophilia B patients with inhibitors.
  • a patient refers to a human patient.
  • a patient can also refer to a human subject.
  • the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 50 mg of fitusiran once every two months (or every eight weeks). In other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 50 mg of fitusiran every month (or every four weeks). In yet other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 80 mg of fitusiran every two months (or every eight weeks).
  • the device may be used to prophylactical ly treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 80 mg of fitusiran every month (or every four weeks). In yet other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 20 mg of fitusiran every two months (or every eight weeks). In yet other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 20 mg of fitusiran every month (or every four weeks).
  • the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of about 10 mg of fitusiran every month (or every four weeks). In yet other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of fitusiran at about 30 mg every month (or every four weeks). In yet other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of fitusiran at about 5 mg every month (or every four weeks).
  • the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of fitusiran at about 2.5 mg every month (or every four weeks). In yet other embodiments, the device may be used to prophylactically treat a patient with hemophilia A or B, with or without inhibitors, with a subcutaneous dose of fitusiran at about 1.25 mg every month (or every four weeks).
  • a method of prophylactic treatment of a patient with hemophilia A or hemophilia B, with or without inhibitors comprising subcutaneously delivering with the device a prophylactically effective amount of fitusiran to the patient in need thereof.
  • the prophylactically effective amount of fitusiran may be any dose provided herein, such as about 1 to about 80 mg, about 1 to about 30 mg, or about 20 to about 80 mg.
  • the prophylactically effective amount of fitusiran may be, for example, about 1.25 mg, about 2.5 mg, about 5 mg, about 25 mg, about 30 mg, about 50 mg, or about 80 mg.
  • the prophylactically effective amount of fitusiran may be delivered every month (or every four weeks) or once every two months (or every eight weeks).
  • Fitusiran may be delivered in about 0.5 mL to about 1 mL delivery volumes (e.g., about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL).
  • a method of prophylactic treatment of a patient with hemophilia A or hemophilia B, with or without inhibitors may comprise subcutaneously delivering with the device about 50 mg of fitusiran to the patient in need thereof every month (or every four weeks) or once every two months (or every eight weeks).
  • the about 50 mg of fitusiran may be delivered in about 0.5 mL PBS (at a concentration of about 100 mg fitusiran/mL).
  • a method of reducing the frequency of bleeding episodes in a patient with hemophilia A or B, with or without inhibitors comprising subcutaneously delivering with the device a prophylactically effective amount of fitusiran to the patient in need thereof.
  • the prophylactically effective amount of fitusiran may be any dose provided herein, such as about 1 to about 80 mg, about 1 to about 30 mg, or about 20 to about 80 mg.
  • the prophylactically effective amount of fitusiran may be, for example, about 1.25 mg, about 2.5 mg, about 5 mg, about 25 mg, about 30 mg, about 50 mg, or about 80 mg.
  • the prophylactically effective amount of fitusiran may be delivered every month (or every four weeks) or once every two months (or every eight weeks).
  • Fitusiran may be delivered in about 0.5 mL to about 1 mL delivery volumes (e.g., about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL).
  • a method of reducing the frequency of bleeding episodes in a patient with hemophilia A or B, with or without inhibitors may comprise subcutaneously delivering with the device about 50 mg of fitusiran to the patient in need thereof every month (or every four weeks) or once every two months (or every eight weeks).
  • the about 50 mg of fitusiran may be delivered in about 0.5 mL PBS (at a concentration of about 100 mg fitusiran/mL).
  • a method of reducing the ABR in a patient with hemophilia A or B, with or without inhibitors comprising subcutaneously delivering with the device a prophylactically effective amount of fitusiran to the patient in need thereof.
  • the prophylactically effective amount of fitusiran may be any dose provided herein, such as about 1 to about 80 mg, about 1 to about 30 mg, or about 20 to about 80 mg.
  • the prophylactically effective amount of fitusiran may be, for example, about 1.25 mg, about 2.5 mg, about 5 mg, about 25 mg, about 30 mg, about 50 mg, or about 80 mg.
  • the prophylactically effective amount of fitusiran may be delivered every month (or every four weeks) or once every two months (or every eight weeks).
  • Fitusiran may be delivered in about 0.5 mL to about 1 mL delivery volumes (e.g., about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL).
  • a method of reducing the ABR in a patient with hemophilia A or B, with or without inhibitors may comprise subcutaneously delivering with the device about 50 mg of fitusiran to the patient in need thereof every month (or every four weeks) or once every two months (or every eight weeks).
  • the about 50 mg of fitusiran may be delivered in about 0.5 mL PBS (at a concentration of about 100 mg fitusiran/mL).
  • a method of reducing the AjBR in a patient with hemophilia A or B, with or without inhibitors comprising subcutaneously delivering with the device a prophylactically effective amount of fitusiran to the patient in need thereof.
  • the prophylactically effective amount of fitusiran may be any dose provided herein, such as about 1 to about 80 mg, about 1 to about 30 mg, or about 20 to about 80 mg.
  • the prophylactically effective amount of fitusiran may be, for example, about 1.25 mg, about 2.5 mg, about 5 mg, about 25 mg, about 30 mg, about 50 mg, or about 80 mg.
  • the prophylactically effective amount of fitusiran may be delivered every month (or every four weeks) or once every two months (or every eight weeks).
  • the fitusiran may be delivered in about 0.5 mL to about 1 mL delivery volumes (e.g., about 0.5 ml_, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL).
  • a method of reducing the AjBR in a patient with hemophilia A or B, with or without inhibitors may comprise subcutaneously delivering with the device about 50 mg of fitusiran to the patient in need thereof every month (or every four weeks) or once every two months (or every eight weeks).
  • the about 50 mg of fitusiran may be delivered in about 0.5 mL PBS (at a concentration of about 100 mg fitusiran/mL).
  • a method of reducing the AsBR in a patient with hemophilia A or B, with or without inhibitors comprising subcutaneously delivering with the device a prophylactically effective amount of fitusiran to the patient in need thereof.
  • the prophylactically effective amount of fitusiran may be any dose provided herein, such as about 1 to about 80 mg, about 1 to about 30 mg, or about 20 to about 80 mg.
  • the prophylactically effective amount of fitusiran may be, for example, about 1.25 mg, about 2.5 mg, about 5 mg, about 25 mg, about 30 mg, about 50 mg, or about 80 mg.
  • the prophylactically effective amount of fitusiran may be delivered every month (or every four weeks) or once every two months (or every eight weeks).
  • Fitusiran may be delivered in about 0.5 mL to about 1 mL delivery volumes (e.g., about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL).
  • a method of reducing the AsBR in a patient with hemophilia A or B, with or without inhibitors may comprise subcutaneously delivering with the device about 50 mg of fitusiran to the patient in need thereof every month (or every four weeks) or once every two months (or every eight weeks).
  • the about 50 mg of fitusiran may be delivered in about 0.5 mL PBS (at a concentration of about 100 mg fitusiran/mL).

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Environmental & Geological Engineering (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

L'invention concerne un dispositif d'administration de médicament (20). Le dispositif d'administration de médicament (20) comprend : un boîtier (22) ; un récipient de médicament (24) à l'intérieur du boîtier (22) et ayant une chambre (26), une extrémité de distribution (28), et une extrémité distante (30) opposée à l'extrémité de distribution (28) ; un bouchon (32) à l'intérieur de la chambre (26), le bouchon (32) fermant de manière étanche la chambre (26) du récipient de médicament (24) à distance ; un médicament à l'intérieur de la chambre (26), le médicament étant enfermé par le récipient de médicament (24) et le bouchon (32) ; et un agencement de piston (34) ayant plusieurs éléments de piston (36, 38) pour déplacer le bouchon (32) dans une direction de distribution (40) vers l'extrémité de distribution (28) du récipient de médicament (24), les éléments de piston (36, 38) étant configurés pour être mis en rotation autour d'un axe (45) perpendiculaire à la direction de distribution (40), pour être introduits dans la chambre (26) du récipient de médicament (24) l'un après l'autre et pour pousser le bouchon (32) dans la direction de distribution (40), lors de la rotation des éléments de piston (36, 38) autour de l'axe (45).
PCT/EP2024/065437 2023-06-05 2024-06-05 Dispositif d'administration de médicament Ceased WO2024251793A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202480037913.2A CN121285406A (zh) 2023-06-05 2024-06-05 药物递送装置

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23315228.9 2023-06-05
EP23315228 2023-06-05

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WO2024251793A1 true WO2024251793A1 (fr) 2024-12-12

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Citations (8)

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US9127274B2 (en) 2012-04-26 2015-09-08 Alnylam Pharmaceuticals, Inc. Serpinc1 iRNA compositions and methods of use thereof
US20170340834A1 (en) * 2014-12-08 2017-11-30 Sanofi Drive Mechanism and Drug Delivery Device Herewith
WO2019014187A1 (fr) 2017-07-10 2019-01-17 Genzyme Corporation Procédés et compositions pour le traitement d'un événement de saignement chez un sujet atteint d'hémophilie
US20190328973A1 (en) * 2016-11-18 2019-10-31 Owen Mumford Limited Medicament Delivery Devices
US20210046252A1 (en) * 2013-10-23 2021-02-18 Shl Medical Ag Portable infusion pump
US11091759B2 (en) 2015-12-07 2021-08-17 Genzyme Corporation Methods and compositions for treating a Serpinc1-associated disorder
US20210268192A1 (en) * 2015-10-28 2021-09-02 Amgen Inc. Drug delivery device
US20220347393A1 (en) * 2019-09-02 2022-11-03 Shl Medical Ag Administration mechanism for a medicament delivery device

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9127274B2 (en) 2012-04-26 2015-09-08 Alnylam Pharmaceuticals, Inc. Serpinc1 iRNA compositions and methods of use thereof
US20210046252A1 (en) * 2013-10-23 2021-02-18 Shl Medical Ag Portable infusion pump
US20170340834A1 (en) * 2014-12-08 2017-11-30 Sanofi Drive Mechanism and Drug Delivery Device Herewith
US20210268192A1 (en) * 2015-10-28 2021-09-02 Amgen Inc. Drug delivery device
US11091759B2 (en) 2015-12-07 2021-08-17 Genzyme Corporation Methods and compositions for treating a Serpinc1-associated disorder
US20190328973A1 (en) * 2016-11-18 2019-10-31 Owen Mumford Limited Medicament Delivery Devices
WO2019014187A1 (fr) 2017-07-10 2019-01-17 Genzyme Corporation Procédés et compositions pour le traitement d'un événement de saignement chez un sujet atteint d'hémophilie
US20200163987A1 (en) 2017-07-10 2020-05-28 Genzyme Corporation Methods and compositions for treating a bleeding event in a subject having hemophilia
US20220347393A1 (en) * 2019-09-02 2022-11-03 Shl Medical Ag Administration mechanism for a medicament delivery device

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PASI ET AL., N ENGL J MED, vol. 377, no. 9, 2017, pages 819 - 28

Also Published As

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