Drug delivery device with dose delivery clicker

Abstract

An assembly for a drug delivery device is provided comprising a housing, and a lead screw having a longitudinal axis, a distal end and a proximal end, the lead screw being rotatably fixed during dose setting and dose delivery and axially movable in a distal direction relative to the housing, the lead screw further including a thread. The assembly further comprises a drive nut threadedly engaged with and screwable along the lead screw thread and a dial link connected with the drive nut and axially movable and rotatably fixed relative to the drive nut, where the dial link comprises a first portion of a feedback ratchet. The assembly is configured such that, during dose delivery, the assembly generates a feedback signal.

Claims

1. An assembly for a drug delivery device, the assembly comprising: a housing; a lead screw rotatably fixed during dose setting and dose delivery and axially movable relative to the housing; a drive nut screwable along a thread of the lead screw; a dial link connected with the drive nut, the dial link being axially movable and rotatably fixed relative to the drive nut, the dial link comprising a ratchet arm, wherein the dial link is movable relative to the housing a first axial distance from a home position during the dose setting and movable relative to the housing back toward the home position, and the drive nut is movable along the thread of the lead screw a second axial distance during the dose setting and movable axially with the lead screw during the dose delivery; and a feedback ratchet comprising a first portion and a second portion, the first portion of the feedback ratchet formed by the ratchet arm of the dial link, and the second portion formed by the thread of the lead screw, wherein the first portion of the feedback ratchet and the second portion of the feedback ratchet are configured to contact one another to generate a feedback signal.

2. The assembly of claim 1, where the ratchet arm is configured to engage the second portion of the feedback ratchet.

3. The assembly of claim 1, wherein the feedback ratchet is configured such that at least one of an onset or a duration of the feedback signal is varied based on an axial position of the lead screw relative to the housing.

4. The assembly of claim 1, wherein the feedback signal is a first feedback signal generated during the dose delivery, and the first portion of the feedback ratchet and the second portion of the feedback ratchet are configured to contact one another to generate a second feedback signal separate from the first feedback signal during the dose setting.

5. The assembly of claim 1, wherein the feedback signal is configured to be generated as the ratchet arm snaps over the thread of the lead screw.

6. The assembly of claim 1, wherein the ratchet arm is configured to move axially beyond an end of the lead screw during the dose setting.

7. The assembly of claim 1, wherein the ratchet arm is positioned on a distal portion of the dial link and extends longitudinally along the lead screw.

8. The assembly of claim 1, wherein the dial link is connected to a dose setting knob operable by a user to set the dose and to inject the set dose.

9. The assembly of claim 8, wherein the dial link is rotationally fixed to the dose setting knob.

10. The assembly of claim 1, wherein the dial link comprises a plurality of ratchet arms comprising the ratchet arm and at least one other ratchet arm, each of the plurality of ratchet arms configured to contact the thread of the lead screw.

11. The assembly of claim 1, wherein the ratchet arm comprises a portion extending radially inwardly to engage the thread of the lead screw.

12. The assembly of claim 1, further comprising an inner sleeve, wherein the inner sleeve is axially fixed relative to the drive nut and is rotatably fixed with respect to the housing.

13. The assembly of claim 12, wherein the assembly is configured such that the drive nut is rotatable with respect to the inner sleeve.

14. The assembly of claim 12, comprising a number sleeve threadedly engaged with the housing, wherein the dial link is configured to be rotatably fixed with the number sleeve during the dose setting when the dial link and the number sleeve are in a first axial arrangement, and the number sleeve is rotatable relative to the dial link when the dial link and the number sleeve are in a second axial arrangement during the dose delivery.

15. The assembly of claim 14, wherein the inner sleeve is threadedly engaged with the number sleeve, and the inner sleeve is configured to advance the drive nut axially during the dose delivery.

16. A drug delivery device comprising: a housing; a cartridge holder within the housing, the cartridge holder configured to receive a cartridge containing medicament to be delivered from the drug delivery device; a lead screw rotatably fixed during dose setting and dose delivery and axially movable relative to the housing; a drive nut screwable along a thread of the lead screw; a dial link connected with the drive nut, the dial link being axially movable and rotatably fixed relative to the drive nut, the dial link comprising a ratchet arm, wherein the dial link is movable relative to the housing a first axial distance from a home position during the dose setting and movable relative to the housing back toward the home position, and the drive nut is movable along the thread of the lead screw a second axial distance during the dose setting and movable axially with the lead screw during the dose delivery; and a feedback ratchet comprising a first portion and a second portion, the first portion of the feedback ratchet formed by the ratchet arm of the dial link, and the second portion formed by the thread of the lead screw, wherein the first portion of the feedback ratchet and the second portion of the feedback ratchet are configured to contact one another to generate a feedback signal.

17. The drug delivery device of claim 16, where the ratchet arm is configured to engage the second portion of the feedback ratchet.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Exemplary embodiments are described herein with reference to the drawings, in which:

(2) FIG. 1 is an illustration of one embodiment of the present invention showing the assembled pen type medication dispensing apparatus where the cap has been removed to reveal the cartridge container affixed to the dose setting mechanism;

(3) FIG. 2 is close up view of the cartridge container and the pen needle that is attached to the cartridge container for injection of the medicament;

(4) FIG. 3 is an exploded view of the embodiment from FIG. 1 showing each of the individual parts arranged relative to each other as they exist in the fully assembled device;

(5) FIG. 4 is a cross-sectional view of one embodiment of the invention where the dial link includes a ratchet arm to engage the threads on the lead screw during both dose setting and dose delivery;

(6) FIG. 5 is a perspective view of showing the interaction of the dial link and lead screw from the embodiment shown in FIG. 4;

(7) FIG. 6 is a close-up cross-sectional view of the interaction of the dial link and lead screw from the embodiment shown in FIG. 4;

(8) FIG. 7 is a perspective view of the dial link and drive nut from another embodiment of the invention; and

(9) FIG. 8 is a side view of the embodiment shown in FIG. 7 illustrating the interaction of the flexible arm on the dial link with the linear arrangement of ratchet teeth on the drive nut.

(10) Corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent embodiments of the present invention, the drawings are not necessarily to scale, and certain features may be exaggerated or omitted in some of the drawings in order to better illustrate and explain the present invention.

DETAILED DESCRIPTION

(11) Referring first to FIGS. 1 to 3, there is shown a drug delivery device 1 as an injector pen, which pen has an elongated, substantially writing instrument-like form, although other forms are within the scope of the invention. The drug delivery device 1 may be a pen-type device. The drug delivery device 1 comprises a housing having a cartridge holder 2, and main (exterior) body or housing 4. The numeral 1 may as well indicate an assembly or parts thereof, wherein single or all of the parts or components of the device may relate or be comprised by the assembly. Reference to the injector or device may actually additionally or alternatively relate to the assembly for said device.

(12) The drug delivery device 1 and the housing have a distal end and a proximal end. The term “distal end” designates that end of the drug delivery device 1 or a component thereof which is or is to be arranged closest to a dispensing end of the drug delivery device 1. The term “proximal end” designates that end of the device 1 or a component thereof which is or is to be arranged furthest away from the dispensing end of the device 1. The distal end and the proximal end are spaced apart from one another in the direction of an axis. The axis may be the longitudinal axis or rotational axis of the device 1.

(13) The proximal end of the cartridge holder 2 and the distal end of the main housing 4 are secured together by appropriate retaining features depending on whether the pen injector is designed as a reusable device or as a disposable device. In the latter case, the retaining feature would be permanent using the connection means described below. If the device is reusable, the retaining meaning would be a screw-type connection, a Luerlok, snap fit, bayonet, or the like type or combination of fittings that allow the user to easily disassemble the device to replace the empty cartridge with a fresh new cartridge. In this illustrated arrangement, the cartridge holder 2 is secured within the proximal end of the main body 4.

(14) A cartridge 8 from which a number of doses of a medicinal product may be dispensed is provided in the cartridge holder 2. Preferably, the cartridge 8 contains a type of medicament that must be administered often, such as once or more times a day. One such medicament is insulin. A piston 10 shown in FIG. 2 is initially retained in the proximal end of the cartridge 8 and as each injection is completed gradually moves distally to the empty cartridge position. A removable cap 14 is releasably retained connected to the main body 4 covering the cartridge holder 2.

(15) The dose setting mechanism or the assembly of or for the drug delivery device illustrated in FIGS. 1-3 may be utilized as or for either a disposable or reusable drug delivery device. Where the drug delivery device 1 comprises or exhibits a disposable drug delivery device, the cartridge 8 cannot be removed from the device 1 without destroying the device. In a disposable device, the proximal end of the cartridge holder can be fixedly mounted or secured, via adhesives, ultrasonic welding or in another suitable manner, to the dose setting mechanism housing when the injector pen is assembled by the manufacturer. Alternatively, where the drug delivery device comprises or exhibits a reusable drug delivery device, the cartridge is removable and may be removed from the device without destroying the device. In the drug delivery device 1 illustrated in FIGS. 1-3, the device is illustrated as a disposable drug delivery device. However, those of ordinary skill in the art will recognize that the dose setting mechanism could also be used on reusable drug delivery devices as well, while in the case of a reusable pen, wherein the cartridge holder 2 may be reusable, such that the proximal end can be removably mounted or secured, for example via a threaded, bayonet, or snap fit connection, to a reusable dose setting mechanism having a resettable lead screw.

(16) The previously mentioned removable or replaceable cap 14 is used to cover the cartridge holder 2 extending from the main housing 4. Preferably, the outer dimensions of the replaceable cap 14 are similar to or identical to the outer dimensions of the main housing 4 so as to provide an impression of a unitary whole part when the replaceable cap 14 is in position covering the cartridge holder 2. In use, the removable cap 14 is removed and a pen needle 16 assembly comprising a double-ended needle mounted in a hub may be screwed or pushed onto the distal end of the cartridge holder or alternatively may be snapped onto this distal end.

(17) Cartridge 8 is of conventional design and defines a medicine-filled reservoir that is closed at its proximal end by the piston 10 that is axially slidably and sealably engaged with the cartridge interior wall to hold the fluid medication within the reservoir. The distal, outlet end of the cartridge reservoir is sealed by a septum 11 held by a cap 13 that is secured to a stepped-down diameter neck portion 15 of the cartridge 8. When pen needle assembly 16 is mounted on the distal end of the cartridge holder 2, the proximal point of injection needle 16 passes through a central opening in the distal end of the cartridge holder 2, an opening in the cap 13, and penetrates the cartridge septum 11 to provide a fluid flow outlet by which medicine within the cartridge reservoir can be dispensed from the distal needle tip during operations of injector pen 1. The fluid medicine cartridge 2 shown and described above is illustrative and not intended to be limiting as other constructions may be employed within the scope of this invention.

(18) Main body 4 of injector pen 1 houses an axially advanceable lead screw 22, a drive nut 23, an inner sleeve 29, a dial link 25, a number sleeve 24, a clutch 26, and a compression spring 27. A dose knob 28 is connected to the dial link 25 and is used to set the dose and then to inject the set dose. Housing or main body 4 is formed from a lightweight material, such as injection molded plastic. The housing 4 may be molded as a single, tubular piece for robustness. A window 51 in the housing near its proximal end can be filled with a magnifying lens that snaps fits to the housing and allows dosage indicating markings (not shown) on the number sleeve 24 to be readily visible during use.

(19) Near the interior distal end of the housing 4 is mounted a mid-body 20 that is formed with an central opening having an inward facing anti-rotation mechanism formed from a pair of diametrically opposed elements or tabs 31 having squared off inward ends that each slidably fit within longitudinal keyways 32 in the lead screw 22. In alternate embodiments, features other than tabs and keyways, for instance a lead screw with flats that fits within a complementarily shaped hole in a collar, may be used to prevent rotation. Tabs 31 prevent the lead screw 22 from rotating within the housing 4 during pen use, but permit the lead screw 22 to be shifted longitudinally, such as in the distal direction toward the cartridge. A snap fit or sonic welding connection of the mid-body 20 to the tubular housing 4 can be used to prevent axial and rotational relative motion of the mid-body to the housing.

(20) The lead screw 22 is in the form of a screw that is axially translatable and rotatably fixed during dosing and injecting. The term “rotatably fixed” shall mean in this context that the lead screw 22 is prevented from rotation during dosing and injecting. The lead screw 22 includes a shaft with a helical threading 33 along its length, which threading 33 is interrupted by the longitudinally extending keyways or grooves 32. A thread stop 34 shown at the proximal end of the threading 33 is provided and is used in preventing the pen from being set by a user to deliver a dose of medicine larger than remains in cartridge 2. Other forms of stopping the screw motion may be substituted within the scope of the invention, for example, the threading at the proximal screw end could stop near the proximal end where it cannot be cammed in, and such solid screw with thread stop better ensures the nut 23 will not be torqued off the screw during dose setting. The distal end of lead screw 22 includes an enlarged, disc-shaped foot or bearing 21 to distribute loading on the cartridge piston 10 that the bearing contacts and thereby directly engages during piston advancing. The separate bearing foot 21 can be attached, such as with a snap fit 20 that may permit relative rotation, to the lead screw 22. The lead screw 22 is shown as being a one-piece plastic injection molding, but alternate materials of construction and multiple pieces are possible.

(21) FIGS. 4-6 show one embodiment of the invention where at least one of the dial link fingers 43 has been modified with at least one ratchet arm 80 to engage the threads or threading 33 of the lead screw 22. The ratchet arm 80 is configured to extend radially inward such that it engages the threads 33 to ride up and over each individual thread or winding as the dial link moves axially relative to the lead screw during dose setting and dose injection. As the dial link 25 moves relative to the lead screw 22 during dialing and dispensing, the ratchet arm 80 will snap over the thread 33 of the lead screw 22 generating a clicking sound. The ratchet arm 80 is positioned in a way that it is always in contact with the lead screw thread 33. One such design includes more than one ratchet arm, for example one arm on each of the dial link fingers 43 could be used. As the lead screw 22 moves forward in the distal direction after each subsequent dosing the less and less medicament will remain in the cartridge 8. As the lead screw 22 moves further and further distally into the cartridge 8 there will be less threads available for the ratchet arm 80 to contact during dose dialing and dose dispense. As such, the clicking sound will not be generated over the entire dose setting and dose dispensing sequences. This is related to the relative movement of the lead screw 22 to the dial link 25 during usage of the pen. Meaning that at the end of the use cycle (a lot of drug is already expelled) the lead screw 22 has moved in distal direction. So the ratchet arm 80 will run over and off the end of the lead screw 22 during dose setting and therefore no longer create the sound. During dispensing the first part of the dosing sequence will run without sound because there is no engagement of the ratchet arm 80 with the lead screw threads 33. However, as the dial link 25 is further advanced distally it will eventually catch up to the remaining threads on the lead screw 22 and the ratchet arm 80 will once again contact or engage the lead screw threads 33 creating the clicking. So the more empty the cartridge 8 is, the more advanced is the lead screw 22 and the shorter is the sound during dose setting and dose dispensing. This gap in the sound (or lack of clicking) works as a signal to the user that the medicament in the cartridge 8 is almost at an end and that a new full cartridge will soon be needed. In other words, the positioning of the ratchet arm 80 along the longitudinal length of the dial link 25 can be selectively chosen so as to customize the audible cartridge fill level or replacement advice feedback signal.

(22) Yet another embodiment of the invention is shown in FIGS. 7-8. Drive nut fingers 36 include a linear row of teeth 82 that run parallel to the longitudinal axis of the drug delivery device. These teeth 82 engage a flexible arm 81 located on the distal end of dial link fingers 43. As the dial link 25 and drive nut 25 move relative to each other during dose setting and injection the flexible arm 81 with run up and down each tooth 82 generating a ratchet sound (clicking) between the drive nut 23 and dial link 25. The ratchet arm 80 is located one the contact surface between both parts. Although the flexible arm 81 is illustrated being on the dial link fingers 43 the reverse could be possible where the teeth are on the dial link and the flexible arm is on the drive nut fingers 36. Another possible configuration of this embodiment would be where there is only one click at the end of the injection providing feed back to the user that the injection was complete. In such a design there would be only one ratchet tooth located in a most distal end of the drive nut finger.

(23) Flexible arms 81 and ratchet arm 80 can be integral with the dial link fingers or they can be a separate component. The configuration of both the arms and ratchet teeth are such that the user hears a noticeable and audible “CLICK” as the arm rides up and over the teeth. Preferably, the design also provides that the user feels or senses a tactile feedback indicating that a dose setting or dose delivery is in progress. The arms can be fabricated from either plastic or metal.

(24) The dial link 25 may comprise a first portion. Said first portion may belong to a feedback ratchet, e.g. to the herein described feedback functionality. The first portion may comprise the ratchet arm 80. Accordingly, the lead screw 22 may comprise a second portion of the feedback ratchet. The thread 33 of the lead screw 22 may be comprised by said second portion (portions not explicitly indicated).

(25) Alternatively, the drive nut 23 may comprise the second portion, wherein the teeth 82 may be comprised by the second portion, wherein either the first portion comprises a ratchet arm and the second portion comprises a, e.g., a single tooth or a linear row of ratchet teeth or the second portion comprises a ratchet arm and the first portion comprises a single tooth or a linear row of ratchet teeth.

(26) Although this is not explicitly indicated, also the inner sleeve 29 may comprises the second portion of the feedback ratchet.

(27) The drive nut 23 includes a cylindrical, tube-shaped body with flexible fingers 36 and clicker teeth 35. The distal region of the drive nut 23 is formed with an internal threading 37 that threadedly engages in a friction locking fashion the threading 33 on the lead screw 22. Threadings 33 and 37 are shown as a double start threading but may be differently formed while still providing suitable friction locking capabilities, such as a single start threading or another multiple start threading. The drive nut 23 is located within the inner sleeve 29 and is axially, but not rotationally fixed, to the inner sleeve 29. In the original commercial design as drive nut 23 is rotated relative to inner sleeve 29 during dose setting, clicker teeth 35 engage in a ratchet fashion flexible arms 38 that project radially on the inside of the inner sleeve 29. As the drive nut 23 rotates the flexible arms 38 ride over the teeth 35 creating an audible clicking noise. Thereby, a setting feedback clicker may be established. The teeth are configured so that each click is equal to one dose volume being set. As few as one flexible clicker arm 38 may be provided, but the use of four equally angularly spaced arms 38 aids in centering drive nut 23 within the inner sleeve 29. However, with our present configuration where a ratchet arm engages the threads on the lead screw or where a flexible arm on one of the dial link and drive nut engage teeth on the other, there is no need to have flexible arms 38 or clicker teeth 35. The hollow interior of drive nut body 23 located proximally of the threading 37 allows free passage of the proximal end of lead screw 22. The exterior surface of drive nut 23 is designed to cooperatively engage with dial link 25 so that the drive link 25 is axially free and rotatably fixed relative to drive nut 23. Thus, during use the dial link 25 is axially moveable relative to, but rotatably locked with, the threaded drive nut. This connection is possible because of the cooperation of the proximally extending fingers 36 on drive nut 23 and the distally extending fingers of the dial link 25. These two sets of fingers 36, 43 move axially relative to each other but engage each other rotationally during dose setting when the dial link 25 is rotated by turning dose knob 28, which is fixed to the dial link 25. The drive nut 23 is shown as being a one-piece plastic injection molding, but other constructions are within the scope of the invention.

(28) In the shown embodiment, the dial link 25 is formed in one piece of an injection molded plastic and which fits within the body 4. A flange 40 that rings a central region of the dial link body includes splines or teeth 39 that extend from the distal face of the flange 40, and teeth 41 that extend from the proximal face of the flange 40. A stepped-down portion of the proximal end of the dial link 25 forms an axially and proximally extending stem 42. The distal end of the dial link body includes the pair of fingers 43 that fit with the fingers 36 of the drive nut 23 to allow axial motion but not rotational motion of the drive nut 23 relative to the dial link 25, thereby rotationally locking the pieces together within the same annular space. Fingers 36 and 43 extend sufficiently axially to ensure they do not disengage during the setting of the maximum pen dose for injection.

(29) An injection molded plastic dose knob 28 with a proximal face, and having a distally facing and centrally located bearing collar and alignment post 55 is provided. Dose knob skirt 50 distally extends from the radial periphery of the dose knob distal face to serve as a grip portion for a user during dose setting. Stem 42 of the of the dial link 25 receives the dose knob alignment post and can be ultrasonically welded within the bearing collar during manufacturing assembly, so as to axially and rotatably fix together the dose knob 28 and dial link 25. The term “rotatably fix” shall mean in this context that any relative rotational movement between the dose knob 28 and the dial link 25 is prevented.

(30) Coaxially mounted around the dial link 25 is the number sleeve 24. The number sleeve 24 has a cylindrical exterior surface 30 with a threading 52 formed as a helical groove that engages a corresponding threading 62 formed on the interior surface of body 4 to threadedly engage the number sleeve 24 to the pen housing. Threadings 52 and 62 are shown as a single start threading but may be differently formed. The threading 62 abuts the end 63 of threading 52 on the number sleeve 24 at the maximum pen dose, assuming the cartridge 8 is sufficiently full for such a maximum dose. A stop surface 64 on the distal end of the outer surface of the number sleeve 24 is positioned in slightly spaced apart relationship with a projecting stop at the zero dose position, and another stop surface is to be abutted by the stop if a user attempts to manually screw the screw element below a zero dose position. A hollow interior 65 of the number sleeve 24 is defined by a cylindrical interior surface provided with a helical threading 67.

(31) The outside diameter of number sleeve 24 is selected such that it can fit inside the dose knob 28. The proximal end region of the number sleeve 24 includes a number of notches 70 and corresponding windows 71 that are alternately spaced around the circumference. The number sleeve 24 includes around its exterior surface 30 suitable indicia of therapeutic dose size as visible through body 4 opening 51. A clutch 26 fits within the open proximal end of the number sleeve 24. Ears 72 on the clutch fit within the notches 70 and the assembly fingers 73 snap lock into windows 71 to axially and rotatably lock the number sleeve 24 and the clutch 26 together during manufacturing of the assembly. A ring of axially extending teeth 54 on the clutch 26 formed in the interior surface of the flange cooperate with the dial link teeth 41 proximally facing on dial link 25.

(32) Disposed between the clutch 26 and the inside portion of the dose knob is the compression or biasing spring 27 that urges the clutch 26 to engage the teeth 41 on the dial link 25. During injection, when a user manually applies a plunging force onto the proximal face of dose knob 28, the spring 27 is elastically compressed, thus disengaging the clutch 26 and the number sleeve 24 from the dial link. The flange teeth 41 on the dial link 25 and clutch teeth 54 mesh when the spring 27 has biased the clutch 26 and the attached the number sleeve 24 to the dose knob 28 and the dial link 25. The dose knob 28 and dial link 25 are not meshed with the clutch 26 and the number sleeve 28 when the spring 27 has been sufficiently compressed during injecting. While a helically coiled metal wire spring is shown, other forms of commonly known biasing elements may be substituted.

(33) The inner sleeve 29 is injection molded from plastic and includes a tubular body that fits into the hollow 65 of the number sleeve 24. The inner sleeve 29 has a helical threading 75 on its outer surface that engages the internal threading 67 on the inside surface of the number sleeve 24. Threadings 67 and 75 are shown as a single start threading, but may be differently formed. The proximal most portion of the end of inner sleeve 24, which end is partially helically shaped corresponding to the threading, is notched to form a partial ring of axially projecting teeth 76 that, when meshed with dial link distally facing teeth 39, serve to rotatably lock together the dial link 25 and the inner sleeve 29. The inner sleeve 29 is keyed to the pen body 4 through the intermediate mid-body 20 that is axially and rotationally fixed to the body 4. The distal end of the inner sleeve 29 has a pair of ridge-defined slots 77 on the periphery of the inner sleeve 24 which axially, slidably receive the lugs 78 radially inwardly projecting from the mid-body 20.

(34) Openings molded into the inner sleeve 29 define four resilient fingers 38 having radially inwardly projecting teeth that are axially oriented and shaped to project into a recess in the distal end of the drive nut 23 that has radially projecting teeth or ridges 35 such that the inwardly projecting teeth click over, in either rotational direction, teeth 35 during dose setting. The fingers 38 with teeth cooperate with the recess on the drive nut 23 to hinder the nut 23 from coming off the inner sleeve 29 after being assembled thereto during manufacture.

(35) To facilitate back-driving during dose delivery, the threaded connections of the number sleeve 24 and the body 4, and the number sleeve 24 and the inner sleeve 29, are non-binding and provided by projecting 60° face angle threads that slide within correspondingly designed recessed grooves. With these threadings, it is preferred that the mechanical advantage is 3.4 or greater, and the screw lead of the drive member or drive nut is 0.108 inch.

(36) The operation of the above described embodiment will now be explained. The pen 1 with a needle 16 attached should first be primed to remove any trap air in the cartridge 8 and to ensure the bearing 21 is in contact with the proximal end of the cartridge stopper or piston 10. In particular, typically while clutching the pen body 4 in one hand, a user manually grips the dose knob skirt 50 and then begins to turn the knob 28 relative to the body 4. At the zero dose arrangement, and as long as knob 28 is not also being plunged which is improper, the knob 28 can only be rotated in a dose increasing direction due to the number sleeve 24 not being further movable distally. A user stops the rotating after a short amount of number sleeve travel that is associated with a small delivery volume, such as one or two units, which is indicated by markings visible through a window 51. Then, and after removing the cap 14 and any other needle cap present, and while pointing the needle tip upward, the user applies a plunging force on the dose knob 28 to drive it distally until the number sleeve 24 returns to the zero dose position, at which the number sleeve threading 52 has reached the distal end of the body threading 62, during which plunging action the piston 10 is shifted forward within cartridge 8. If a user sees that the piston movement has caused liquid to reach the needle distal tip, the priming process is complete. If no liquid is visible at the needle tip, the priming steps are repeated as needed. After priming, the pen 1 is ready to be used for an actual injection.

(37) First, a user prepares the pen by setting the desired dose, as visible in window 51, by turning of knob 28. If the user dials up too large of a dose, and without expelling any medicine, the user can rotate down the dial by turning the knob 28 in the opposite direction, all the way back to zero if desired. To set a dose, the knob 28 is turned in a clockwise direction. Because the dose knob 28 and dial link 25 are fixed rotationally, the dial link 25 is rotated causing the distally facing fingers 43 to engage the proximally facing fingers 36 of the drive nut to thereby turn the drive nut in same direction. Rotation of the drive nut 23 causes the nut 23 to rotate relative to the stationary lead screw 22 whereby the nut 23 moves or climbs up the lead screw 22 in the proximal direction. The drive nut 23 rotates relative to the inner sleeve 29 that is held rotationally fixed relative to the body 4 through the splined connection to the mid-body 20. Because drive nut and inner sleeve are axially fixed, proximal axial movement of the drive nut 23 causes the inner sleeve 29 to slide proximally relative to the mid-body 20. Because the clutch 26 is rotationally fixed with the dial link 25 the clutch 26 rotates causing the number sleeve 24 to rotate and to spin out proximally away from body 4. Because the pitch of the threads on the number sleeve 24 are greater than the pitch of the threads on the inner sleeve 29, the number sleeve 24 and the dial link 25 will translate a larger axially distance compared to the inner sleeve 29 and the drive nut 23.

(38) To inject the dose, after pen 1 is manipulated so the injection needle distal tip properly penetrates, for example, a user's skin, an axial, distal plunging force is applied to the knob face 53 to force the dial link 25 axially in the distal direction toward the body 4, such as with a thumb or index finger of the hand which grasps the housing 4. Initially during injecting, the dial link 25 is shifted axially, which shifting motion compresses the biasing spring 27 to close the gap between the knob surface and the proximal end of the number sleeve 24. The biasing spring 27 is designed to compress prior to the number sleeve 24 moving relative to the body 4. When dial link 25 shifts relative to the number sleeve 24 to the axial arrangement of the drive nut 23, the clutch teeth 54 and dial link teeth 42 disengage to allow a backdriving rotation of the number sleeve 24 relative to the dial ink 25. During the axial movement of the dial link 25, drive nut 23 does not move axially or rotationally. When the number sleeve 24 and the clutch 26 rotatably uncouples from the dial link 25, as the dial link 25 is continued to be axially plunged without rotation by the user by the plunging of the knob 28, the number sleeve 24 screws into the body 4 as it spins relative to the knob 28 and the dose markings on the number sleeve 24 that indicate the amount still remaining to be injected is visible through window 51.

(39) As it screws down, the number sleeve 24 causes inner sleeve 29 to in essence screw up the internal thread inside of the number sleeve threading as the inner sleeve 29 advances distally a lesser distance than the number sleeve 24. The advancement of the inner sleeve 29, due to the abutting or direct engagement with the distal end of the drive nut 23, advances drive nut 23 without rotation, which due to its threaded connection with the lead screw 22 advances the lead screw 22 axially without rotation, which lead screw advancement shifts cartridge piston 10 to expel medication from the cartridge reservoir. The injection is completed when the number sleeve threading 52 has reached the distal end of the body 4, at which time pen 1 is once again arranged in the ready state or zero dose position.

(40) Pen 1 can continue to be used to deliver any desired dose until the medicine remaining in the cartridge 8 is insufficient for a proper dosing. This insufficiency is indicated to the user by the inability to fully set the desired dose due to drive nut threading 37 abutting the thread stop 34 of the lead screw 22, at which time the drive nut 23 and dial link 25 cannot be rotated proximally any farther. When insufficient medicine remains, the pen 1 is to be disposed of and replaced with a similar but entirely new pen.

(41) The terms “medicament” or “medicinal product”, as used herein, mean a pharmaceutical formulation containing at least one pharmaceutically active compound,

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

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

(44) wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,

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

(46) Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, 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.

(47) Insulin derivates 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-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.

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

(49) Exendin-4 derivatives are for example selected from the following list of compounds:

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

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

(52) des Pro36 Exendin-4(1-39),

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(69) wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; or an Exendin-4 derivative of the sequence

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

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

(72) des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,

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

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

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

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

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

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

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

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

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

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

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

(84) H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,

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

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

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

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

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

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

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

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

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

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

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

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

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

(98) or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.

(99) Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.

(100) A polysaccharide is for example 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, 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.

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

(102) The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.

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

(104) Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.

(105) In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.

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

(107) An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).

(108) Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, 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 described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.

(109) Pharmaceutically acceptable solvates are for example hydrates.

(110) While this invention has been shown and described as having various designs, the present invention may be modified within the spirit and scope of this disclosure. For example, to deliver a fixed dose, the pen would preferably be modified such that the maximum that the dial could be screwed out to prepare the pen for injection would correspond to the fixed dose. Such a fixed dose pen could eliminate numerical dosage indicating marking, and instead provide user cues in the form of, for example, instructions and a graphical dosing indicator. This disclosure is therefore intended to cover any variations, uses or adaptations of the invention using its general principles. Further, this disclosure is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains.