WO2011083055A1

WO2011083055A1 - Method for forming collapsible reservoir

Info

Publication number: WO2011083055A1
Application number: PCT/EP2010/070618
Authority: WO
Inventors: Kristian GLEJBØL; Martin VON BÜLOW; Niels Berg Madsen
Original assignee: Novo Nordisk A/S
Priority date: 2010-01-05
Filing date: 2010-12-23
Publication date: 2011-07-14

Abstract

A method for manufacturing a reservoir comprising the steps of (a) providing a generally rigid reservoir member in which a first generally concave cavity with a peripheral portion is formed, (b) providing a generally planar flexible foil member, (c) sealing the rigid reservoir member and the flexible foil member to each other corresponding to the peripheral portion 5 thereby forming a reservoir cavity, and (d) moving the flexible foil member into contact with the first concave cavity to thereby form a second generally concave cavity in the flexible foil member.

Description

METHOD FOR FORMING COLLAPSIBLE RESERVOIR

The present invention generally relates to medical devices adapted for administration of a fluid drug as well as components for use in such devices. In specific embodiments the invention relates to medical delivery devices and components and methods therefore adapted to provide ease of use in a cost-effective way.

BACKGROUND OF THE INVENTION

In the disclosure of the present invention reference is mostly made to the treatment of diabetes by delivery of insulin, however, this is only an exemplary use of the present invention.

Medical injection devices are used to deliver selected doses of medication to patients. Some medication, such as insulin is self-administered. The typical diabetes patient will require injections of insulin several times during the course of the day. In order to prevent infections it is recommended to use a sterile needle assembly for each injection. Needle assemblies are often delivered in magazines where each magazine contains only one needle assembly in a sterile compartment. Such a magazine is described in US 5,971 ,966. Using a needle assembly of this kind requires the patient to open the magazine and to fasten the needle assembly on to the injection device prior to each injection. The storage of sterile needle assemblies of this type and the final disposal of used needle assemblies present a problem since new ster- ile needle assemblies are often carried loosely in purses or briefcases. Furthermore, used needle assemblies are often disposed of unsafely.

To overcome these problems needle magazines for storing and dispensing a plurality of needle assemblies has been proposed. A first type of needle magazine is adapted to be used with a traditional pen-formed injection device as an add-on instead of traditional single needles.

For example, in US 5,829,589 a needle magazine is provided as a container having a plurality of cavities each accommodating a needle assembly. A cover is rotatably mounted on top of the container. When aligning a slot in the cover with one of the cavities, the user can access the cavity. The needle assembly is connected to the injection device by forcing the tip of the injection device into the cavity where the needle assembly is force fitted, e.g. by a well- known luer coupling, onto the distal end of the injection device. The needle assembly can then be detached from the magazine. When the used needle is to be returned to the maga- zine the user has to conduct a reverse procedure. The above prior art needle magazine is attached to the injection device by fitting the entire magazine into an open end of the remov- able cap of a pen-shaped injection device. Due to the dimensions of a pencil-shaped injection device only five needle assemblies can be contained in the magazine. An ordinary disposable injection device usually contains 300 IU of insulin. For many diabetes patients this is sufficient for 10 to 20 injections, therefore one magazine of needle assemblies are not enough for the lifetime of one disposable injection device, which is very inconvenient.

US 2002/0020646 discloses another needle magazine which is intended to be mounted onto the dispensing distal end portion of an injection device. The needle magazine includes a ro- tatable cassette holding a plurality of needles in a circular array configuration. By sequentially rotating the cassette, each of the needles can be brought into alignment with the distal end of the injection device. By moving the injection device in the distal direction, the back needle of the particular selected needle penetrates a septum in the cartridge. Further distal movement causes the front needle to penetrate a seal in a distal face of the needle container to bring the selected needle into an injection position. Even though the needle magazine according to US 2002/0020646 may include a large number of needles, this needle magazine is rather bulky and takes up much space in the plane which includes the array. If the needle magazine is dimensioned to hold several needles, the circular array extends quite far in a direction transverse to the needle which is aligned with the cartridge, particular in the direction which intersects the centre axis of the circular array. Thus, the geometric form of the needle maga- zine according to US 2002/0020646 is practically not adaptable to all kinds of injection devices, in particular not to injection devices of the pen-shaped form factor. From US 2008/0312604 is known a pen-formed injection device provided with a relative compact needle magazine. Thus, as appears, it is difficult to provide a pen-shaped device with a needle magazine which comprises a relatively large number of needles and at the same time fits the general pen- shaped form-factor of a traditional drug injection device.

A second type of needle magazine is not adapted to be used as an add-on to a traditional pen-shaped injection device but is provided as part of a drug delivery system specifically designed for use only with a custom-designed needle magazine.

Such a system is known from WO 2005/097237 which discloses a computer controlled and motor actuated drug injection apparatus comprising a needle cassette, and from WO 2008/150715 disclosing a needle cassette. Such an apparatus is relatively expensive and would not be suitable as a pre-filled device. When providing a drug delivery device having a non-pen-shaped configuration it may be desirable to use a reservoir having an alternative form-factor different from the traditional cylindrical cartridge used in most pen-shaped devices, this providing a higher degree of freedom for both the outer form and the interior mechanical design. One such alternative type of reservoir is represented by a collapsible reservoir made fully or in part of a flexible foil material.

For example, EP 1 002 512 discloses a manufacturing process for a flexible reservoir in which first and second pre-formed polymeric sheets are superimposed and sealed together at their peripheries to form a reservoir. Similar reservoirs are shown in US 2008/097318, WO 2009/ 013733. Alternatively the flexible reservoir may be formed by a rigid concave portion in combination with a collapsible portion attached at the periphery to form a cavity, see e.g. US 4,559,053, WO 93/17940 and EP 1 486 258. Having regard to the above, it is an object of the present invention to provide a drug delivery device providing an alternative configuration to the traditional pen-shaped delivery device, the device being convenient to carry and operate, yet allowing for cost-effective manufacturing. In order to provide a drug delivery device with a compact and pocket-friendly form-factor it is a further object of the present invention to provide components and methods of manufacture of components for a drug delivery device which allows for a compact and cost-effective design without relying on a pre-determined outer form factor as may be the case if the injection device would be based on traditional dose setting and dose expelling principles and mecha- nisms used in prior art pen-shaped devices.

DISCLOSURE OF THE INVENTION

In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.

Thus, in a first aspect of the invention a method for manufacturing a reservoir is provided, the reservoir being of the type comprising a generally rigid reservoir member in which a first generally concave cavity is formed, a flexible foil member forming a second generally con- cave cavity, wherein the first and second members are sealed to each other corresponding to the peripheries of the concave portions, the portion of the flexible foil member forming the second concave cavity being moveable relative to the first concave cavity thereby providing a variable-volume reservoir. The method for forming such a reservoir comprises the steps of (a) providing a generally rigid reservoir member in which a first generally concave cavity with a peripheral portion is formed, (b) providing a generally planar flexible foil member, (c) seal- ing the rigid reservoir member and the flexible foil member to each other corresponding to the peripheral portion thereby forming a reservoir cavity, and (d) moving the flexible foil member into contact with the first concave cavity to thereby permanently form a second generally concave cavity in the flexible foil member. To allow the deformed foil member to keep its new form until the reservoir is subsequently filled (see below) the forming should be based sub- stantially on non-elastic (plastic) deformation.

As appears, in this way a collapsed reservoir is formed which ideally has an initial volume of zero and, ideally, also a residual volume of zero after having been filled and expanded with a fluid and subsequently emptied and collapsed. Indeed, under normal manufacturing and use circumstances both the initial volume and the residual will be larger than zero. As emptying of the reservoir is based merely on reversing the flexible foil portion between an expanded convex state (when seen from the outside) and a collapsed concave state (when seen from the outside) only a relative low suction force is needed to provide an almost complete emptying of the reservoir. The reservoir may be formed as a reservoir per se for e.g. subsequent placement in a given device or it may be formed as an integral part of a given device, e.g. the generally rigid reservoir member may be in the form of a member making up a smaller or larger part of the given device.

The flexible foil member may be cold-formed into its concave shape or the method may comprise the further step of heating the relevant portion of the flexible foil member before moving the flexible foil member into contact with the first concave cavity, e.g. by use of radiation and/or heated fluid. The flexible foil member may be moved into contact with the concave cavity by means of a relative vacuum applied to the reservoir cavity or it may be moved by applying positive pressure on the outside, e.g. using a tool member having a form corre- sponding to the first generally concave cavity. Depending on the method of deforming the flexible foil a small amount of elastic deformation may take place, e.g. when using cold- forming.

The formed reservoir may be utilized in different ways. For example, the reservoir may be sealed in its fully collapsed state after having been formed, this preventing the reservoir to start expand due to e.g. elastic properties of the formed flexible portion. The collapsed reser- voir may be filled prior to delivery to a user or it may be filled by the user, the reservoir being provided with an appropriate seal or valve arrangement allowing fluid transfer in and out of the reservoir, e.g. a needle-penetratable membrane. During filling the formed portion of the flexible foil member will be forced into a reversed concave shape relative to the shape of the first concave cavity of the reservoir member, i.e. a convex shape when seen from the outside. Alternatively, the method may comprise the further step of introducing a fluid into the reservoir cavity before the cavity is sealed. Indeed, in case the foil has been heated it should not be filled before it has been cooled to a temperature preventing deformation during filling. By providing an initially virtually fully collapsed reservoir it would be possible to fill the reser- voir virtually without the trapping of air bubbles.

The flexible foil may be of any suitable type allowing the foil to be attached to the rigid reservoir portion, e.g. by welding or adhesive means, and subsequently permanently deformed into the desired concave configuration. For example, the foil may be in the form of a lami- nate, the different layers of the laminate providing the desired properties, e.g. allowing welding between the foil and the rigid member, preventing diffusion of components of an enclosed fluid (e.g. drug formulation) out of the reservoir, and providing an inner surface not reacting with components of the enclosed fluid. The foil may be transparent or non-transparent. In case a non-transparent foil is used inspection of the enclosed fluid, e.g. an insulin formula- tion, may be provided by the rigid member comprising a transparent portion. A suitable laminated foil for e.g. an insulin formulation is described in US 2006/0134358 which is hereby incorporated by reference.

In the above different aspects of the invention have been described individually, however, it will be appreciated that the features corresponding to the individual aspects can be combined, e.g. the features of the dosing mechanism, the reservoir, the needle actuation, and the needle magazine.

As used herein, the term "drug" is meant to encompass any drug-containing flowable medi- cine capable of being passed through a delivery means such as a cannula or hollow needle in a controlled manner, such as a liquid, solution, gel or fine suspension. Representative drugs include pharmaceuticals such as peptides, proteins, and hormones, biologically derived or active agents, hormonal and gene based agents, nutritional formulas and other substances in both solid (dispensed) or liquid form. In the description of the exemplary embodi- ments reference will be made to the use of insulin. Correspondingly, the term "subcutaneous" infusion is meant to encompass any method of transcutaneous delivery to a subject. BRIEF DESCRIPTION OF THE DRAWINGS

In the following the invention will be further described with reference to the drawings, wherein fig. 1 shows a drug delivery unit and a thereto attachable needle magazine,

fig. 2 shows the drug delivery unit and the needle magazine attached to each other, fig. 3 shows an exploded view of the drug delivery unit seen from above,

fig. 4 shows an exploded view of the drug delivery unit seen from below,

fig. 5 shows a rubber band,

fig. 6 shows the expelling mechanism of fig. 3 assembled in an assembled state,

fig. 7 shows a cross-sectional view of the expelling mechanism of fig. 6,

fig. 8 shows an exploded view of the needle magazine seen from above,

fig. 9 shows an exploded view of the needle magazine seen from below,

fig. 10 shows a cross-section view of a needle unit in an initial position,

fig. 1 1 shows a cross-section view of a needle unit in an actuated position,

figs. 12A and 12B show schematic cross-sectional views of a drug reservoir in a filled respectively collapsed state, and

figs. 13A - 13D show different steps of a process for manufacturing a reservoir. In the figures like structures are mainly identified by like reference numerals. DESCRIPTION OF EXEMPLARY EMBODIMENTS

When in the following terms such as "upper" and "lower", "right" and "left", "horizontal" and "vertical" or similar relative expressions are used, these only refer to the appended figures and not to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as there relative dimensions are intended to serve illustrative purposes only. In the below described embodiment the lower planar surface is described as being arranged horizontally for the purpose of description only.

Fig. 1 shows an embodiment of a drug infusion device 1 comprising a generally cylindrical drug delivery unit 10 and a thereto attachable ring-formed needle magazine or needle storage unit 20 in which a plurality of needles are mounted. When assembled as seen in fig. 2 the device has a general flat and oval configuration providing a "pocket friendly" form for the user. As will be explained in greater detail below, the assembled device comprises a dose- setting dial, a priming button, a combined needle insertion and drug expelling button, as well as a needle advancing button.

With reference to figs. 3-7 the structure and functionality of the drug delivery unit 10 will be described. More specifically, the drug delivery unit comprises a generally circular base member 100 in which a piston 200 and a piston stop member 300 are slidingly received, a valve member 190 mounted in the base member, a piston ring 290 mounted on the piston, a circular dose setting member 400 rotationally arranged relative to the base member, a coupling member 500 rotationally arranged relative to both the dose setting member and the base member, a priming button 490 arranged axially moveable relative to the base member, and an end-of-content (EOC) indicator 590 arranged between the dose setting member 400 and the coupling member 500. A rubber band 280 is attached between the piston, the piston stop member and the base member. A ring-formed drug unit housing 600 (see fig. 1 ) is attached to the base member, thereby enclosing and holding together the different components of the drug delivery unit.

Turning to the individual components, the base member 100 comprises a generally circular base plate portion 1 10 with a peripheral edge 1 1 1 and a generally planer lower surface 1 12, first and second cavities 120, 130 surrounded by half moon-shaped outer walls 121 , 132, a central space 140 being formed between the two cavities. In the first cavity a reservoir 125 is arranged, the reservoir comprising a half moon-shaped wall 126 and an upper opening closed by a flexible foil (shown in fig. 12A). The outer wall 121 may be provided with a cutout window 124 allowing inspection of the drug in the reservoir (which indeed would require the reservoir wall to be transparent). The second cavity is intended for use by optional com- ponents such as an electronic module. Between the two cavities a dose cylinder portion150 is arranged, the dose cylinder having a bore 154 with a distal opening 151 , in which a valve member 190 is arranged, and a proximal opening 152 receiving the piston 200, thereby creating a dose (or metering) chamber 129 between the valve member and the piston. A channel 128 connects the reservoir and the distal end of the dose cylinder. On top of the dose cyl- inder a flexible locking finger 155 with a detent 156 is arranged, as well as a short axle 157 having a central bore 158 in communication with the bore of the cylinder. Opposite (or behind) the dose cylinder portion the two opposed walls 121 , 131 are provided with a pair of guiding grooves 122, 132 adapted to slidingly engage the piston 200 and the piston stop member 300. The valve member 190 comprises a distal head portion 191 serving as a needle penetratable septum between the exterior and the dose cylinder, as well as proximal cylindrical and flexible skirt portion 192 serving as a flap valve for controlling a flow of fluid through channel 128 into the dose chamber. Further details for the design and functions of the valve member can be found below.

The piston comprises a partly hollow body 210 adapted to receive and lock a distal end of the rubber band 280, a distal end with a cylindrical projection 220 onto which the piston ring 290 is mounted, a proximal end 230 with two feet 231 , 232 adapted to engage the guiding grooves 122, 132, and an upper flexible locking finger 240 with a free end adapted to engage the central bore 158. The two feet also serve as a stop against the proximal end of the cylinder portion.

The piston stop member 300 comprises a body portion 310 adapted to be slidingly received in a groove 160 between the cylinder portion and the wall 131 of the second cavity, a proximal portion 330 comprising two feet 331 , 332 adapted to engage the guiding grooves 122, 132, and a notch 335 adapted to receive and lock a middle portion of the rubber band 280. The distal-facing surface of the foot 331 also serves to engage the proximal-facing surfaces of the piston feet. The body portion comprises an upper toothed rack 31 1 and a lower groove 312 adapted to receive a portion of the rubber band 280. The groove is provided with a distal notch 161 adapted to lock a proximal portion of the rubber band 280.

The dose setting member 400 has a general disc form with an upper and lower surface and a central bore. The upper surface has a stepped configuration with a thinner peripheral portion 410 and a raised central portion 420 adapted to be received in an upper opening 610 of the drug unit housing 600. The central portion has an upwardly protruding central tubular portion 430 adapted to receive the button 490, as well as four gripping flanges 431 allowing a user to set a dose by turning the dose setting member. Between the peripheral and central portion a detent 421 is provided serving as both a pointer for the set dose and a stop for rotation rela- tive to the housing. The lower surface comprises a downwardly protruding central tubular portion 440 with a bore 447 adapted to receive the axle 157 in rotational engagement. The lower outer surface of the tubular portion is in the form of a pinion 441 adapted to engage the rack 31 1 , rotation of the dose setting member thereby moving the piston stop member 300 linearly. Around the upper outer surface of the tubular portion four locking detents 442 are arranged for engagement with the central bore 510 of the coupling member 500. The peripheral portion of the lower surface is provided with a circular band 450 of teeth having ramp shaped surfaces, the distance between the teeth corresponding to one increment of dose as also indicated by indices on the housing, see below. Radially across the lower surface a linear guiding groove 460 for the EOC indicator 590 is arranged. The coupling member 500 is in the form of a generally circular disc with an upper and lower surface and a central bore 510 adapted to be mounted around the downwardly protruding central tubular portion 440 of the dose setting member and held axially in place by the locking detents 442. The peripheral portion of the upper surface is provided with a number of teeth 530 having ramp shaped surfaces and adapted to engage the circular band 450 of teeth on the dose setting member. Between the bore and the periphery the upper surface is provided with a spiral groove 560 in which a guide projection 591 of the EOC indicator is slid- ingly arranged. The peripheral portion of the lower surface is provided with a circular band of teeth 540, the spaces 541 between the teeth being adapted to engage the detent 156 of the flexible locking finger.

The lock between the dose setting member and the coupling member, as well as the flexibility of the latter, is designed to slightly force the members against each other. By this arrangement a bi-directional coupling is provided between the dose setting member and the coupling member, the engaging peripheral portions being forced against each other with the ramp shaped surfaces of the teeth on one surface abutting the ramp shaped surfaces of the teeth on the other surface. When the dose setting member is rotated in either direction, i.e. setting or adjusting a dose size, the teeth on the coupling parts will slide with their ramp shaped parts over each other, whereby essentially the coupling member is axially displaced against the force of the spring provided by the central part of the coupling member and will jump back each time a top of the teeth is reached. Each jump back may be heard and/or sensed by the operator, and the pitch of the teeth may be chosen so that a jump back takes place each time the dose setting is increased by say one unit. The two coupling surfaces could be provided by any suitable combination of materials and surface configurations providing the desired functionality. To prevent a user to set and infuse a too large dose the dose setting mechanism may be provided with a settable stop allowing a maximum dose to be set, e.g. 20 units of insulin.

In its initial position as supplied to the user the EOC indicator 590 is arranged at the inner end of the linear guiding groove 460. As the EOC indicator is guided by both the linear guid- ing groove and the spiral groove 560 rotational movement between the dose setting member and the coupling member will result in the EOC indicator being moved outwardly or inwardly when the dose setting member is dialled up respectively dialled down. In this way the EOC indicator will serve to summarize the relative movement of the two members in the "dial up" direction, i.e. corresponding to the doses set and later expelled by the user, whereby the indicator will positioned in its outer-most position when the reservoir is empty. When the EOC indicator reaches the outer end of the spiral groove the dose setting member cannot be rotated further relative to the coupling member, this indicating EOC to the user. Indeed, in order to allow a user to observe the position of the EOC indicator the dose setting member or a portion thereof has to be made from a transparent material. The priming button 490 is arranged axially moveable relative to the dose member by means of two locking legs 491 engaging the bore 447, this allowing the button to move between an initial upper and an actuated lower position. A spring (not shown) is arranged between the two parts biasing the button towards its initial position. The priming button further comprises a central projection 492 adapted to engage the flexible locking finger 240 via the central bore 158.

To drive the expelling mechanism, i.e. the piston 200 and the piston stop member 300, a single elastic rubber band member 280 is used, the rubber band comprising a distal connector portion 281 adapted to engage the piston body 210, an intermediate connector portion 282 adapted to engage the notch 335 of the piston stop member, a proximal connector portion 283 adapted to engage the notch, as well as distal and proximal drive portions 284, 285. The proximal extension 286 is for manufacturing purposes only and is cut off later. Fig. 6 shows the rubber band in its mounted position corresponding to the state in which a dose has been set but before priming (see below). Fig. 6 does not show the inspection window 124.

The above-described components of the drug delivery unit is enclosed in a cavity formed between the ring-formed drug unit housing 600 and the base plate portion 1 10, thereby enclosing and holding together the different components of the drug delivery unit. The housing comprises an upper opening 610 with an inner edge and is as described above adapted to receive the central portion of the dose setting member 420, the inner edge comprises an inwardly protruding portion 61 1 having first and second stop surfaces 612, 613 adapted to engage the pointer detent 421 and thereby serve as rotational stops. Arranged on the upper surface 620 are indices (not shown) serving as a dose setting guide for the user like on an egg timer. In the shown embodiment the pointer can be moved 300 degrees between its two stops which may correspond to a maximum of 50 units of drug which can be set and subsequently expelled. The drug unit housing further comprises a cut-out portion 630 allowing structures of the dose setting and expelling mechanism to engage with the needle storage unit 20. As can be seen in fig. 1 the opening allows access to the free end of the flexible locking finger 155 as well as the valve member 190 arranged distally in the dose cylinder. The upper outer wall of the housing is provided with a number of projections 631 adapted to re- leasably engage the needle storage unit. Facing away in fig. 1 , the outer wall of the housing is provided with an opening allowing inspection of the reservoir through window 124.

With reference to figs. 8 and 9 the structure and functionality of the needle storage unit 20 will be described. More specifically, the needle storage unit comprises a generally ring- formed housing 700 in which a needle insertion and release button 790 as well as a needle- forwarding member 780 are arranged and guided, a ring-formed magazine member 800 rota- tionally arranged in the housing, and a plurality of needle units 900 arranged in the needle magazine, each needle unit comprising a body member 910 and a U-formed needle 920 having downwardly facing pointed distal and proximal ends 921 , 922. A ring-formed paper mem- brane (not shown) is attached to the lower planar surface of the magazine member.

Turning to the individual components, the housing 700 comprises a ring-formed cavity formed between a full outer wall 710 and a partial inner wall, the latter comprising three flexible portions 71 1 serving as locking members to hold the magazine in place, yet allows it to rotate. Between the upper surface 715 of the housing and the inner wall a number of cut-out portions 712 are arranged and adapted to releasably engage the projections 631 on the drug unit housing. The housing further comprises a "nose-formed" extension 720 and an associated cut-out 721 in the upper surface adapted to receive an inner radial extension of the button 790, as well as on oppositely arranged and outwardly protruding housing portion 730 with an upper slit-formed opening 731 adapted to receive the member 780. The nose portion is provided with a cross-formed guide opening 722 adapted to receive a corresponding cross- formed guide member 792 on the needle insertion and release button. The inner side of the outer cavity wall is corresponding to the nose portion provided with a pair of horizontally arranged flexible arms 718 with distal hook portions 719 adapted to engage corresponding locking grooves 819 in the outer wall 810 of needle magazine. The hooks and grooves are designed to allow uni-directional rotation of the needle magazine only.

The needle insertion and release button 790 comprises the above-described cross-formed guide member 792, a pair of opposed locking hooks 793 engaging corresponding edges 723 on the on the housing, this allowing the button to move between an initial upper and an actuated lower position. A spring (not shown) is arranged between the two parts biasing the but- ton towards its initial position. The button further comprises a user actuatable portion 799 allowing a finger of a user to fully actuate the button, as well as an inner radial extension 791 adapted to be received in the housing cut-out 721 and having on its lower surface a pair of guide members 797, 798 adapted to receive a guide portion of a needle unit. By providing an inwardly directed extension to actuate both a needle unit and release the dosing mechanism, the button per se can be arranged peripherally in relation to the circular needle magazine, this providing a pocket-friendly flat design.

The needle magazine 800 comprises a ring-formed body portion 810 having a plurality of vertical bores 81 1 with upper and lower openings, and an outer wall 810 with a corresponding number of locking grooves 819. Between each bore a vertical tower 815 is arranged, each pair of towers (i.e. two towers arranged on each side of a bore) comprising a pair of guide flanges 816 for engaging and vertically guiding a needle unit. Each needle unit 900 comprises a body member 910 having an upper generally flat guide portion 915 with a pair of opposed vertical guide grooves 916 adapted to engage a pair of guide flanges 816. The flat guide portion has inner and outer edges 918, 919 adapted to be received in the guide members 797, 798 of the button extension 791 . From the lower surface of the guide portion an outer long 91 1 and an inner short 912 tubular portion extend. Each tubular portion comprises a bore which is connected to each other by an open groove 917 in the upper surface of the guide portion. A U-formed needle 920 is mounted in the body member with a leg projecting from each tubular portion with the connecting needle portion arranged in the groove 918. The needle and its method of manufacture are described in greater detail in applicants co-pending application EP 08168817.8. In an initial position (see fig. 10) the outer tubular portion 912 is positioned in sealing and sliding engagement with a circumferential sealing lip in the proximal end 812 of a bore 81 1 , the distal opening 813 of the bore being closed and sealed by a membrane 814 (see fig. 10), e.g. made from Tyvek ® paper allowing a sterilizing gas to penetrate, thereby creating a sterile chamber 818 for the distal needle end between the tubular portion and the membrane. To fully enclose the U-formed needle in a sterile state a collapsible closed membrane 817, e.g. made from silicone rubber, is arranged around the proximal end of the needle. When all the needle units are mounted in the needle magazine the guide portions create an upper circular surface adapted to slide through the guide members 797, 798 of the button 790. As appears from figs. 8 and 9, one needle unit is "missing", however, this allows the needle storage unit 20 to be assembled as otherwise the release button could not be "threaded" onto the circular row of needle unit guide portions. When supplied to the user the needle magazine may be positioned corre- sponding to the empty position which would necessitate the user to "prime" the needle magazine by forwarding a first new needle to the actuatable position. Further, the needle magazine may advantageously be provided with a stop preventing more than one full rotation and thus unintended re-use of needles.

The needle-forwarding member 780 comprises a body portion with a horizontally arranged flexible arm 781 with a distal hook portion 782 adapted to engage the corresponding locking grooves 81 1 in the needle magazine, as well as a button part 785 projecting through opening 731. The member 780 can be moved back and forth with the hook and grooves serving as a uni-directional coupling allowing the hook 782 to slide backwards on the wall 810 (with the needle magazine being held in place by the oppositely arranged hooks 719), whereas full forwards movement of the needle-forwarding member will result in the hook 782 pushing the needle magazine an increment corresponding to the distance between to needle units. With the needle insertion and release button in its upper position, this will result in an "old" needle being moved out of engagement with guide members 797, 798 of the radial extension 791 , and a "new" needle being moved into engagement with the guide members. In this "active" position up- and downwards movement of the needle insertion and release button will result in the active needle unit being moved up and down and thereby the distal needle end in and out of the needle magazine. The needle magazine may advantageously be designed to allow only one rotation of the needle magazine in order to prevent re-using a previously used needle.

Next a situation of use of the above-described drug infusion device 1 will be explained. The device will only work when the two units are assembled, however, they can be exchanged independently of each other, e.g. when either the reservoir or the number of needles is exhausted.

To set (or "dial") a dose the user will rotate the dose setting member clockwise until the pointer 421 points at the desired amount of drug as indicated be indices on the upper hous- ing surface 620, e.g. 20 units of insulin. As the coupling member 500 initially is locked to the base member 100 via locking finger 155 the dose setting member can be rotated bi- directionally relative to the remaining device, with the coupling 450, 530 between the dose setting member and the coupling member preventing the dose setting member to be rotated backwards by the spring (see below) and at the same time providing a clicking sound with each click corresponding to one increment of dose. As the pinion 441 engages the rack 31 1 the rotation of the dose setting member moves the piston stop member 300 linearly back and forth corresponding to the set dose. As the piston 200 initially is locked in place by the locking finger 240 engaging the central bore 158, backwards movement of the piston stop member will result in stretching of both the distal and proximal drive portions 284, 285 of the rubber band, this as shown in fig. 6. Indeed, the same couplings preventing rotation of the dose setting member during dose setting will also prevent movement of the piston stop member. In addition to the piston stop member also the EOC indicator is moved radially outwards in its guide groove 460 corresponding to the set dose.

When the user has positioned the pointer 421 at the desired dose (and thereby the piston stop member in a corresponding position), the user pushes down the priming button 490 which via the central projection 492 pushes the flexible locking finger 240 out of engagement with the central bore 158, this allowing the piston to be pulled backwards into engagement with the piston stop member by the distal rubber band drive portion 284, whereby fluid drug will be sucked from the reservoir, through the channel and past the valve member into the dose chamber, this as shown in fig. 7.

Next the user positions the "nose portion" of the lower surface 1 12 on a skin surface corresponding to the desired location of injection and pushes the needle insertion and release button 790 down until in its fully actuated position, this providing that a needle is inserted subcu- taneously and the set dose infused.

More specifically and as illustrated in figs. 9 and 10, initial movement of the button 790 moves the distal end 921 of the "active" needle out of its sterile compartment and into subcu- tis of the user as well as the proximal end 922 of the needle towards the valve member 190. Before the needle penetrates the valve member the radial button extension 791 moves the free end of the flexible locking finger 155 downwards and thereby out of engagement with the teeth 540 of the coupling member, this allowing the coupling member, and the thereto coupled dose setting member 400, to rotate relative to the base member 100. As the pinion 441 is part of the dose setting member, the piston stop member is no longer locked in its set posi- tion via the rack 31 1 and can thus move distally pulled by the proximal drive portion 284 of the rubber band, this resulting in the piston 200 being forced distally by the piston stop member. At this point in time the dose chamber is closed such that the force acting on the piston via the piston stop member merely will pressurize the fluid in the dose chamber. However, shortly after the dose chamber has been pressurized the proximal end 922 of the needle will penetrate the valve member 190 and thus establish a flow communication between the dose chamber and the distal subcutaneously arranged end of the needle, this resulting in subcuta- neous infusion of the fluid drug contained in the dose chamber. Before the proximal end of the needle is inserted into the valve member it will penetrate the collapsing flexible enclosure 817 arranged around the needle to ensure sterility. By pressurizing the dose chamber before connection is established with the needle, it is prevented that body fluids at a slightly ele- vated pressure can flow into and contaminate the dose chamber. At the same time the piston stop member is pulled forwards by the rubber band the dose setting member 400 is via the rack and pinion rotated anti-clockwise into its initial position, i.e. with the pointer 421 in abutment with the stop 612. Finally the user removes pressure from the needle insertion and release button 790 whereby the active needle unit 900 will be returned to its initial position, this providing that the distal needle end is retracted into the device and the proximal needle end is withdrawn from the valve member. By actuating the forwarding member 780 a new needle unit is rotated into place and the device is ready for a new dose to be set and infused.

In the above description of the device the valve member has been described during its nor- mal use, i.e. serving as a flap valve controlling flow from the reservoir as well as a needle penetratable septum for the proximal needle end. However, the valve member also serves to control diffusion prior to and during use. During storage it is essential that components of the drug, e.g. insulin preservatives such as cresol, will not diffuse out of the reservoir. To prevent this, the reservoir is made from materials having diffusion properties preventing loss of e.g. preservatives, however, the preservatives may also diffuse from the reservoir through the channel 128 for which reason the valve member during storage should prevent diffusion. For this purpose a material as e.g. brome-butyl rubber could be used, this material also being used to seal conventional insulin cartridges. However, as a needle has to be inserted into the dose chamber during emptying thereof, it follows that a small amount of drug will be standing in the dose chamber after a set dose has been expelled. As the drug in the dose chamber is in contact with different surfaces (e.g. the cylinder bore, the piston end, and the piston ring), preservatives may be absorbed by these surfaces and would thus change the properties of the drug remaining in the dose chamber. If the next set dose is small this may result in a drug being infused having undesired properties. To compensate for this absorption it would be de- sirable to replenish preservatives from the much larger reservoir by allowing diffusion through the channel 128 and the valve member. Correspondingly, a composite valve member is provided having a distal portion preventing diffusion and a proximal skirt portion allowing diffusion, whereby the distal portion will cover the channel during storage and the proximal portion will cover the channel during the period of use. A corresponding valve member may be configured as shown in fig. 10 with a proximal skirt portion 195 made of e.g. silicone rubber having a high permeability for insulin preservatives such as cresol, and a ring-formed distal portion 196 made of e.g. brome-butyl rubber having a low permeability for insulin preservatives such as cresol. During storage the valve member will be positioned in a proximal position with the ring-formed distal portion covering the reservoir channel. Indeed, this position will result in the piston and thus the piston stop member being displaced proximally with the proximal portion 285 of the rubber band slightly stretched. Correspondingly, when supplied to the user the dose setting member is not positioned in its "zero" position but with the pointer at e.g. five units of insulin. Although the rubber band will tend to rotate the dose setting member via the rack and pinion, this is prevented by the coupling to the coupling member which is firmly locked in place. Thus, before using the device, the user will rotate the dose setting member to its zero position which will move the piston and thus the valve member to its forward-most position in which the reservoir channel is covered by the proximal skirt portion. By this design it is also assured that the valve function is improved as e.g. silicone rubber is a better material for this function than brome-butyl rubber. The above-described reservoir is of a semi-flexible design comprising a cavity 125 formed integrally with the relatively rigid base member 100 and an upper opening closed by a flexible foil 127 as shown in fig. 12A. The foil is configured to be collapsible into the rigid cavity as shown in fig. 12B (e.g. formed by attaching a planar foil to the upper edge of the rigid reservoir wall, thermoforming the foil into the cavity, and then fill and expand the reservoir), this providing a variable volume reservoir. A method of manufacturing the disclosed semi-flexible reservoir is described below. Alternatively, the reservoir may also be formed entirely from flexible foils. To ensure that visual inspection of the drug is possible the rigid part of the semi- flexible reservoir is made from a transparent material having desired optical properties (e.g. as part of a base member made entirely in a transparent material). For this design a non- transparent foil can be used allowing for use of many more grades of foil (i.e. non- transparent foils), hence allowing for a more optimal design. The non-transparent sheet can be marked or coloured on the side facing the drug hereby allowing for a better drug inspection. In the above-described embodiment a window is provided on the side surface of the drug unit 10, this allowing the window to be covered by the needle magazine 20. In this way a user can inspect the drug in the reservoir when a new drug unit is taken use, whereas the window will be covered by the needle magazine during normal use. As the needle magazine easily disconnects from the drug unit the user can inspect the reservoir when desired. In case the base member is made fully from a transparent material it would also be possible to inspect the reservoir through the lower surface of the reservoir cavity, however, this may result in undesired exposure of the drug to light for a much longer time, e.g. if the device was left on a table with the lower surface upwards. Correspondingly, a lower transparent surface would be covered by a non-transparent foil, e.g. a sticker with data relating to the contents of the drug reservoir. Alternatively, the bottom surface of the device may be provided with a window as well as means protecting the drug against decomposition, e.g. a material that absorbs UV light to protect the drug, or a door that may be opened (e.g. by sliding) to allow the drug reservoir and its contents to be inspected.

In the above-described embodiment the needle magazine has a ring-formed configuration in the form of a general circular configuration, however, alternatively the ring could have other configurations such as square (e.g. as a boxing ring) or other closed configurations. To provide for non-circular needle magazine forms the needles (or needle units) could be arranged in a flexible conveyer belt adapted to be moved "around corners" or just along a non-circular path.

In the above-described embodiment the needle magazine is forwarded fully manually by the user, however, alternatively the needle magazine may be configured so it has to be forwarded before the needle insertion and release button 790 can be actuated again, this ensuring that the user can use a given needle only once. Such a mechanism could essentially comprise two basic components: (i) a blocking element associated with the button mechanism which has to be in an "activated" position to allow button actuation, and (ii) an element associated with the needle magazine and configured to activate the blocking element. Depending on the market it may be desirable to offer devices in which the needle can be used only once as well as devices in which a given needle can be used a number of times by the user. By designing the blocking element in such a way that a small change of form in a single component would turn on an off the blocking functionality, it would be possible in a simple way to provide both alternatives which then may be offered on relevant markets.

In the above-described embodiment the needle magazine is forwarded manually by the user, however, alternatively the needle magazine may be forwarded automatically, e.g. energy stored during actuation of the needle insertion and release button 790 may be used to forward the needle magazine when the button is returned to its new position, this ensuring that a new and sterile needle is used for each injection. Such a mechanism would essentially comprise two basic components: (i) an element associated with the button mechanism and "pushing" the needle magazine forwards, and (ii) an element associated with the needle magazine and being pushed by the actuator element. Depending on the market it may also here be desirable to offer devices in which the needle can be used only once by setting the "automatic forward" option to "on" as well as devices in which a given needle can be used a number of times by the user by setting the "automatic forward" option to "off". In the above-described embodiment an EOC mechanism is provided ensuring that a user cannot set a dose larger than the "calculated" remaining amount of drug, i.e. if full movement of the EOC indicator to its stop will allow setting and expelling doses of e.g. 300 IU of insulin, then a position of the EOC indicator corresponding to 280 expelled IU would allow setting a dose of 20 IU before reaching the stop. However, flexible reservoirs for injection devices have to be overfilled to ensure there is drug until the pre-specified amount has been injected and the device is blocked. To make sure there is enough drug the reservoir needs to be filled with the pre-specified amount plus an amount for all the tolerances in the delivery system and filling system. This often adds up to an overfilling at 10-20 % which is left in the device when it locks and are therefore waste for the costumer as well as the manufacturer. Thus, instead of using a blocking EOC mechanism it would be desirable to allow a user to fully utilize the amount of drug in a flexible reservoir, yet preventing that a too large dose is set. As described above, drug is drawn from the flexible reservoir into a piston-based variable volume dosing chamber. When there is no more drug in the reservoir further withdrawal of the piston will result in the creation of a relative vacuum in the dosing chamber. Thus, if a dose higher than what is left in the reservoir is chosen, the piston will be forced to the corresponding position but when the user let go of the setting button, the vacuum created in front of the piston will then serve to return the piston to the position that corresponds to the amount of drug drawn into the dosing chamber. Indeed, to allow such a mechanism to work properly it should be ensured that the "vacuum forces" created will be sufficiently high to overcome fric- tion in the dosing mechanism and thus be able to turn back the dose setting member.

In the above-described embodiment of a drug delivery device a semi-flexible reservoir is used, the reservoir comprising a generally rigid reservoir member 126 in which a first generally concave cavity is formed, a flexible foil member 127 forming a second generally concave cavity, wherein the first and second members are sealed to each other corresponding to the peripheries of the concave portions, the portion of the flexible foil member forming the second concave cavity being moveable relative to the first concave cavity thereby providing a variable-volume reservoir 125. As shown in figs. 12A and 12B emptying of the reservoir is based on reversing the flexible but basically non-distensible foil portion between its raised expanded and its inverted collapsed state by suction. Such a reservoir may be manufactured using any desirable method, however, in the following an exemplary general method of manufacturing a semi-flexible reservoir will be described.

The method comprises the steps of providing a generally rigid reservoir member 1900 in which a first generally concave cavity 1901 with a peripheral portion 1902 is formed, the reservoir member further having an opening 1903 allowing a vacuum source to be connected. Next a generally planar flexible foil member 1910 is positioned over the first cavity (fig. 13A) and by means of a welding tool 1920 sealed to the rigid reservoir member corresponding to the peripheral portion 1902 thereby forming a reservoir cavity 1930 (fig. 13B), after which the foil is heated to make it easily distensible. Finally a vacuum source 1905 is connected to the opening 1903 whereby ambient pressure 1904 (fig. 13C) will force the flexible foil member into contact with the first concave cavity to thereby form a second generally concave cavity (191 1 ) in the flexible foil member (fig. 13D), this creating an initially fully collapsed reservoir. When the foil has cooled to set the vacuum is released and the reservoir may be either sealed for subsequent filling or filled and then sealed as part of the manufacturing process.

In the above description of the preferred embodiment, the different structures and means providing the described functionality for the different components have been described to a degree to which the concept of the present invention will be apparent to the skilled reader. The detailed construction and specification for the different components are considered the object of a normal design procedure performed by the skilled person along the lines set out in the present specification.

Claims

1. A method for manufacturing a reservoir (125), the reservoir comprising:

a generally rigid reservoir member (126) in which a first generally concave cavity (1901 ) is formed, and

- a flexible foil member (127) forming a second generally concave cavity,

wherein the first and second members are sealed to each other corresponding to the peripheries of the concave portions, the portion of the flexible foil member forming the second concave cavity being moveable relative to the first concave cavity thereby providing a variable-volume reservoir (125),

the method comprising the steps of:

providing a generally rigid reservoir member (1900) in which a first generally concave cavity (1901 ) with a peripheral portion is formed (1902),

providing a generally planar flexible foil member (1910),

sealing the rigid reservoir member and the flexible foil member to each other corre- sponding to the peripheral portion thereby forming a reservoir cavity (1930), and

moving by substantially plastic deformation the flexible foil member into contact with the first concave cavity to thereby form a second generally concave cavity (191 1 ) in the flexible foil member.

2. A method as in claim 1 , comprising the further step of:

heating the flexible foil member before moving the flexible foil member into contact with the first concave cavity.

3. A method as in claim 2, wherein the flexible foil member is moved into contact with the concave cavity by means of a relative vacuum applied to the reservoir cavity.

4. A method as in any of the previous claims, comprising the further step of introducing a fluid into the reservoir cavity to thereby force the formed portion of the flexible foil member into a reversed concave shape relative to the shape of the first concave cavity of the reser- voir member.

5. A method as in claim 1 , wherein the flexible foil member is cold-formed into its concave shape.

6. A method as in any of the previous claims, comprising the further step of sealing reservoir cavity. *****