Drug delivery device with plunger rod having nonuniform stopper interface

Abstract

To provide a drug delivery device having means for reducing the force required to set one or more pistons or stoppers in motion.SOLUTION: The present invention provides a drug delivery device 1 comprising: a drug reservoir 20 comprising a reservoir body 21 extending along a reference axis and an elastomeric stopper 30 arranged in the reservoir body 21, the elastomeric stopper comprising a stopper body, the stopper body extending between a front stopper end and a rear stopper end 34 and having a plurality of axially spaced circumferential ribs for sealing interaction with an interior wall of the reservoir body; and a plunger rod structure 10 for displacing the elastomeric stopper relatively to the interior wall, the plunger rod structure extending along the reference axis and comprising a distal end face adapted to interface with the rear stopper end.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to medical devices, and more particularly to medication delivery devices with a reservoir having a volume that can be reduced by displacement of a piston or stopper. [Background technology]

[0002] Within some medical therapeutic areas, combination therapy involving the co-administration of at least two agents is advantageous due to synergistic or additive effects. For example, in diabetes care, in the management of type 2 diabetes, the simultaneous use of certain insulin and glp-1 products has been shown to increase HbA 1c It has been shown to reduce levels, thereby improving glycemic control.

[0003] Many drugs must be administered parenterally to be effective in the body, and some of these, such as insulin and GLP-1, may require one or more doses to be delivered subcutaneously daily. Subcutaneous drug delivery is often associated with discomfort, as many people dislike the idea of ​​inserting a needle through the skin. An unknown number of people even suffer from needle phobia, and these people have a strong desire to escape, especially from multiple daily injection therapy.

[0004] Therefore, one attractive scenario is to reduce the number of skin penetrations required by administering drugs simultaneously or substantially simultaneously through a single injection needle.In some cases, this can be achieved by co-formulation of active ingredients, and the co-formulated product is administered using a conventional injection device.In other cases, for example, when the active ingredients are not suitable for co-formulation, the individual substances are stored in separate chambers of a dual-chamber or multi-chamber storage device, which can be simultaneously or sequentially expressed through a single injection needle by using a dedicated expression means.

[0005] US Patent No. 5,399,633 discloses an embodiment of a dual chamber storage device in the form of an autoinjector having a cartridge with a fixedly attached hypodermic needle. In the pre-use state of the device, the cartridge holds a forward liquid medicament in the forward chamber and a rearward liquid medicament in the rearward chamber. The two liquids are separated by an intermediate piston, and the rearward chamber is sealed proximally by the rearward piston. In use, in response to the release of the stressed spring, it urges the plunger forward, pushing the rearward piston and pressurizing the rearward liquid medicament to transmit the movement of the rearward piston to the intermediate piston. Eventually, as the spring continues to provide a forward bias to the plunger, this results in the ejection of the forward liquid medicament through the hypodermic needle and then the ejection of the rearward liquid medicament through a distally disposed bypass section.

[0006] US Patent No. 5,399,633 discloses an embodiment of a dual chamber storage device in the form of a manually operated mixing device with a piston coupling arrangement that allows for an aspiration procedure to ensure proper insertion of an associated IV infusion needle. In the pre-use state of the device, a dry drug or liquid is held in the front chamber and a liquid is held in the rear chamber. The two substances are separated by a front piston, and the rear chamber is sealed proximally by a rear piston through which the piston rod extends. In use, the piston rod is manually advanced, disconnecting the rear piston and pressurizing the rear chamber liquid to transfer the movement of the rear piston to the front piston. As the user continues to push the piston rod forward, the front piston enters the bypass section and becomes stuck as pressure forces the rear chamber liquid into the bypass, past the front piston and into the front chamber. In the front chamber, the two substances mix as the rear chamber compresses. When the rear piston finally reaches the front piston and the substances are completely mixed, the user can expel the mixed substance by continued advancement of the piston rod.

[0007] A common drawback of such devices is the fact that over time during storage, the piston material tends to adhere to the reservoir material, meaning that significant static friction must be overcome to initiate drug mixing and / or ejection. Due to the incompressibility of the liquid in the rear chamber, the two pistons move simultaneously until the front piston reaches the bypass section. As a result, the force required to overcome this static friction is actually the sum of the forces required to release the individual pistons.

[0008] In the case of a manually driven piston rod, the sudden shift from static to kinetic friction when the piston is released is likely to cause a sudden forward movement of the piston as the user attempts to compensate for the sudden acceleration by drastically reducing the force input. Not only is this an unpleasant user experience, but it may actually lead to an excessively rapid transfer of rear chamber liquid to the front chamber. If the front chamber is reconstituted carrying a dry powder, the transfer process may even lead to undesirable foaming.

[0009] In the context of spring-driven injection devices, such as the auto-injector of US Pat. No. 5,999,633, the spring needs to be relatively strong to ensure availability of sufficient release force. The drawback of this is that when friction becomes dynamic, the power available for actual drug ejection can be very high, leading to uncomfortably fast delivery. Furthermore, a strong spring requires stronger mating injection device parts to avoid creep or breakage during potential medium or long-term storage periods in a preloaded state, increasing both the cost and weight of the injection device.

[0010] Although only one piston needs to be mobilized and the required release force is relatively small, the described adhesion of the piston material to the reservoir material may in practice be a challenge even for single chamber reservoirs. Thus, problems associated with overcoming stiction and controlling delivery rate are also relevant to devices such as conventional syringes and autoinjector pens that employ conventional drug cartridges. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 4,394,863 (Survival Technology, Inc.) [Patent Document 2] WO 2010 / 139793 (Novo Nordisk A / S) Summary of the Invention

[0012] It is an object of the present invention to obviate or reduce at least one disadvantage of the prior art, or to provide a useful alternative to the prior art solutions.

[0013] In particular, it is an object of the present invention to provide a medication delivery device having means for reducing the force required to operate one or more pistons or stoppers.

[0014] It is a further object of the present invention to provide a drug delivery device having a means for allowing a more uniform piston displacement force throughout the drug administration procedure.

[0015] In the present disclosure, aspects and embodiments are described that address one or more of the above objectives and / or that address objectives that are apparent from the following text.

[0016] In one aspect, the present invention provides a drug delivery device as claimed in claim 1.

[0017] Thus, there is provided a drug delivery device comprising a drug reservoir comprising a reservoir body extending along a reference axis and an elastic stopper disposed within the reservoir body. The elastic stopper comprises a stopper body extending between a front stopper end and a rear stopper end and having a plurality of axially spaced circumferential ribs for sealing interaction with an inner wall of the reservoir body, as specified in, for example, ISO 11040-5 (2012) Prefilled syringes-part 5: Plunger stoppers for injectables. The drug delivery device further comprises a plunger rod structure for displacing the elastic stopper against the inner wall. The plunger rod structure comprises a distal end face adapted to interface with the rear stopper end. The distal end face comprises a first force transmission portion and a second force transmission portion. The first force transmission portion is positioned distal to the second force transmission portion and adapted to interact with a peripheral portion of the rear stopper end. In the present context, a "peripheral portion" of a structure having a given lateral extent away from a central axis is a portion of that structure in which more than half of the given lateral extent is located away from the central axis.

[0018] Thus, the first force transmission portion leads the second force transmission portion as the plunger rod structure moves distally along the reference axis to displace the elastic stopper. This exerts a non-uniform pressure on the rear stopper end, where a non-zero pressure is exerted on the peripheral portion first and zero pressure on the remaining portion of the rear stopper end. The pressure on the peripheral portion creates a localized breakage of the rear stopper material from the inner wall, so that when the second force transmission portion reaches the rear stopper end, the displacement of the bulk stopper is more easily achieved because some of the adhesion has already been overcome. As a result of the sequential separation of the peripheral ribs from the reservoir body, the maximum force required to activate the elastic stopper is reduced and the overall force profile for a complete drug ejection interaction with the drug delivery device is more homogenous.

[0019] The distal end surface may be designed in various ways to achieve the desired effect, but generally the effect is a function of the location and configuration of the first force transmission portion. For example, if the rear stop end is circular with a center, the first force transmission portion may be arranged to abut an area of ​​the rear stop end located at a radial distance from the center that is greater than half or two-thirds of the radius of the circle that the rear stop end intersects. The closer the contact area between the first force transmission portion and the rear stop end is to the inner wall of the reservoir body, the greater the effect of the pressure provided by the first force transmission portion relative to the intended reduction in the release force. Similarly, for example, the peripheral portion may be sized smaller than a semicircle to maximize the localized pressure effect.

[0020] In exemplary embodiments of the invention, the first force transmission portion has a radial extent in the range of [1 mm, 2 mm]. In certain of these embodiments, the first force transmission portion has a radial extent of 2 mm or about 2 mm.

[0021] The first and second force transmission portions may have a cumulative surface area substantially equal to a total surface area of ​​the rear stopper end, whereby the resilient stopper is supported during displacement over the entire or substantially the entire rear stopper end.

[0022] The second force transmission portion may be orthogonal to the reference axis and the first force transmission portion may form part of a stud member projecting distally from the second force transmission portion such that a surface of the plunger rod structure that interacts with a majority of the rear stopper end conforms thereto, ensuring that the elastomeric stopper does not tilt during bulk advancement in the medicament reservoir.

[0023] The stud may be adapted to abut the rear stop end at an interface between one of the plurality of axially spaced circumferential ribs and the inner wall to maximize the effect of the initial pressure provided by the first force transfer portion.

[0024] In an exemplary embodiment of the invention, the studs have an axial dimension in the range [1mm, 2mm].

[0025] The distal end face may alternatively present a wavy profile with a wave crest at a peripheral portion of the distal end face, which then constitutes a first force transmission portion and axially leads the remaining portion of the distal end face, which constitutes a second force transmission portion.

[0026] The distal end face may alternatively exhibit a parabolic profile, in which case the first force transmission portion is adapted to apply pressure on diametrically opposing peripheral portions of the rear stopper end, thereby initially causing localized release of the stopper material from the inner wall of the reservoir body at two distinct locations.

[0027] In an exemplary embodiment of the invention, the medication delivery device further comprises a housing, the plunger rod structure comprising a hollow interior adapted to accommodate a releasable compression spring element to displace the plunger rod structure distally relative to the housing.

[0028] The drug reservoir may further comprise a second elastic stopper disposed distal to the elastic stopper and a bypass section for allowing fluid flow past the second elastic stopper during displacement of the elastic stopper against the inner wall. In that case, the drug reservoir is of the dual chamber type described above, which usually exhibits a relatively large release force as a result of the fact that two elastic stoppers must be mobilized simultaneously. With a plunger rod structure of the type defined herein, the maximum input force for performing the expulsion action of the drug may be significantly reduced.

[0029] In another aspect, the present invention provides a plunger rod structure for displacing an elastomeric stopper of the type comprising a stopper body extending axially between a front stopper end and a rear stopper end and having a plurality of axially spaced peripheral sealing ribs along a wall of a drug reservoir, the plunger rod structure comprising a distal end face adapted to mate with the rear stopper end, wherein the distal end face comprises a first force transmission portion and a second force transmission portion, the first force transmission portion axially leading the second force transmission portion around the distal end face.

[0030] Such a plunger rod structure engages with and applies an axial force to a peripheral portion of the rear stopper end before interacting with the remainder of the rear stopper end, which in turn provides separation of the sealing rib from the wall of the drug reservoir, and as a result requires a lower axial input force to operate the elastomeric stopper. The plunger rod structure may be specifically configured as described above.

[0031] It should be noted that the elastic stopper as described in connection with the present invention may be made entirely or partially of an elastic material, and although its outer surface interfaces with the reservoir, it is elastic in nature to obtain the desired sealing effect.

[0032] For the avoidance of any doubt, in this context, the term "medicament" refers to an agent used in the treatment, prevention, or diagnosis of a condition, i.e. includes an agent that has a therapeutic or metabolic effect in the body. Furthermore, the terms "distal" and "proximal" refer to a location on or a direction along a drug delivery device, drug reservoir, or needle unit, with "distal" referring to the drug exit end and "proximal" referring to the end opposite the drug exit end.

[0033] Reference herein to a particular aspect or embodiment (e.g., "one aspect," "first aspect," "one embodiment," "exemplary embodiment," etc.) indicates that the particular feature, structure, or characteristic described in connection with each aspect or embodiment is included or inherent in at least that aspect or embodiment of the invention, but not necessarily in or inherent in all aspects or embodiments of the invention. However, it is emphasized that any combination of the various features, structures, and / or characteristics described in connection with the invention is encompassed by the invention, unless expressly stated herein or clearly contradicted by context.

[0034] The use of any and all examples or exemplary language (such as, for example, etc.) in the text is intended merely to better clarify the invention and does not limit the scope of the invention unless otherwise claimed. Moreover, no language or phraseology in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0035] In the following the invention is further explained with reference to the drawings. [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 is a perspective view of a plunger rod structure according to an exemplary embodiment of the present invention. [Diagram 2] FIG. 2 is a longitudinal cross-sectional view of a drug delivery device according to an exemplary embodiment of the invention, including the plunger rod structure of FIG. [Diagram 3] FIG. 3 is a side view of a distal portion of a plunger rod structure interacting with an elastomeric stopper in a drug delivery device. [Figure 4] FIG. 4 is a diagram of the initial deformation of a resilient stopper resulting from interaction with a plunger rod structure. [Diagram 5]FIG. 5 is a side view of a distal portion of a plunger rod structure according to another exemplary embodiment of the present invention. [Figure 6] FIG. 6 is a side view of a distal portion of a plunger rod structure according to a further exemplary embodiment of the present invention.

[0037] In the drawings, like structures are primarily identified by like reference numbers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] When / if relative expressions such as "up" and "down", "left" and "right", "horizontal" and "vertical", "clockwise" and "counterclockwise" are used below, they refer to the attached figures and do not necessarily refer to actual usage situations. The figures shown are schematic and therefore their relative dimensions as well as the configuration of different structures are intended to serve illustrative purposes only.

[0039] Figure 1 is a perspective view of a plunger rod 10 for use in a drug delivery device according to one embodiment of the present invention. The plunger rod 10 comprises a hollow elongated shaft 11 extending along a longitudinal axis. At its front end, the plunger rod 10 is provided with an abutment surface 12 adapted to abut a stopper in a drug reservoir during a drug dispensing action, as will be explained in more detail below. A peripheral stud 13 projects distally from the abutment surface 12 and has a leading end 14 for arranging for movement of the stopper, as will also be explained below. The plunger rod 10 is further provided with a pair of diametrically opposed notches 15.

[0040] 2 is a longitudinal cross-sectional view of an injection device 1 according to an exemplary embodiment of the invention employing a plunger rod 10. The injection device 1 comprises a housing 2 containing a syringe 20 having a barrel 21 extending along a general axis coinciding with the longitudinal axis of the plunger rod 10. The barrel 21 is generally circularly cylindrical, but has a distal bulge forming a bypass channel 25 and a narrow distal end portion that holds an injection needle 35. A front stopper 40 is disposed proximal to the bypass channel 25 and provides a proximal seal for a front chamber 29 that holds a first liquid substance, and a rear stopper 30 is disposed proximal to and axially spaced from the front stopper 40, thereby providing a proximal seal for a rear chamber 28 that holds a second liquid substance.

[0041] In the illustrated pre-use state of the injection device 1, the leading end 14 of the stud 13 abuts the proximal end 34 of the rear stopper 30, but the abutment surface 12 is spaced from the rear stopper 30. A pre-constrained drive spring 80 is disposed within the hollow of the plunger rod 10 and abuts proximally against the inner surface of the end wall 3 of the housing 2. A pair of radially flexible arms 4 extend distally from the end wall 3, and the plunger rod 10 is held in place by a detent 5 on each arm 4 that is anchored in one of the notches 15, and each detent 5 is radially restrained by a retaining edge 52 of a needle shield 50 extending axially between the syringe 20 and the housing 2.

[0042] The needle shield 50 is biased distally by a shield spring 90 and is axially displaceable along the syringe 20 against this bias to expose the injection needle 35. The final product provided by the manufacturer includes a needle cap 60 attached to the housing 2 for covering the needle shield 50, the needle cap 60 carrying an inner cover 65 for dedicated protection of the injection needle 35.

[0043] To perform a medication administration, the user simply removes the needle cap 60, places the needle shield 50 against the skin surface and presses the housing 2 toward the skin, thereby compressing the shield spring 90 and displacing the needle shield 50 to allow the injection needle 35 to enter the desired injection site.

[0044] Thus, as the needle shield 50 is displaced, the retention edge 52 slides past the pawl 5, allowing the arm 4 to deflect radially. As a result, the force from the pre-constrained drive spring 80 immediately urges the pawl 5 radially out of the notch 15, thereby unlatching the plunger rod 10 and releasing the drive spring 80.

[0045] 3 illustrates the initial interaction between the plunger rod 10 and the rear stopper 30 upon release of the drive spring 80. The rear stopper 30 comprises a resilient stopper body 31 extending between a distal end 32 and a proximal end 34 and having four axially spaced circumferential ribs 33 which provide a fluid-tight sealing interface with the inner wall 22 of the barrel 21.

[0046] To operate the rear stopper 30, the static friction between the outer peripheral rib 33 and the inner wall 22 must be overcome. Once the static friction is overcome and the rear stopper 30 starts to move across the interface between the stopper body 31 and the barrel 21, a dynamic friction that is smaller than the static friction is exhibited. Thus, the effort required to perform the drug administration action is highly dependent on the size of the so-called release force.

[0047] Compared to a corresponding single chamber injection device, the release force of the injection device 1 is twice as high as the rear stopper 30 and the front stopper 40 operate simultaneously due to the incompressibility of the second liquid substance in the rear chamber 28. A solution that can reduce the release force therefore allows the manufacturer of the injection device 1 to incorporate a less powerful drive spring, thereby reducing the risk of mating components deforming under the load from a pre-constrained spring during shelving.

[0048] The solution provided by this embodiment of the invention is the addition of studs 13 to the peripheral portion of the abutment surface 12, which provide a leading interface that interacts with the peripheral portion of the proximal end 34 of the rear stopper 30 before the abutment surface 12 interacts with the remainder of the proximal end 34. In FIG. 3, the relative dimensions of the studs 13 are exaggerated to show their effect more clearly. As the plunger rod 10 advances towards the distal end of the syringe 20, the leading end 14 first exerts pressure on the peripheral portion of the proximal end 34, while the abutment surface 12 approaches the rear stopper 30. This causes the peripheral portion of the proximal end 34 to deform, eventually resulting in localized release of the rear stopper 30 material from the barrel 21 at the interface between the proximal-most portion of the circumferential rib 33 and the inner wall 22.

[0049] Thus, when the abutment surface 12 subsequently contacts the proximal end 34, the penetration of the stud 13 into the resilient stopper body 31 will have already displaced part of the periphery of the rear stopper 30 relative to the inner wall 22. This is illustrated in Figure 4, where a cluster of solid lines on the exterior of the barrel 21 represents the location of each circumferential rib 33 along the inner wall 22. It can be seen that the proximal-most circumferential rib sketched by contact line 33d is locally deflected in the distal direction, the circumferential rib adjacent to the proximal-most circumferential rib sketched by contact line 33c is only slightly deflected, one rib adjacent to it sketched by contact line 33b is slightly deflected, and the distal-most circumferential rib sketched by contact line 33a is still unaffected.

[0050] The localized initial deflection of the circumferential ribs 33, facilitated by the relatively high local pressure provided by the leading end 14, contributes positively to a reduction in the release force required to mobilize the rear and front stops 30, 40 within the barrel 21. The sequential detachment of the circumferential ribs 33 from the inner wall 22 increases the effectiveness of the drive spring 80, since not all contact points between the two stops and the inner wall 22 need to be broken simultaneously.

[0051] To ensure that the rear stop 30 does not tilt within the barrel 21, as this could result in leakage, the axial dimension of the stud 13 should be limited relative to the axial dimension of the rear stop 30. In this case, the axial dimension of the stud 13 is 2 mm. Thereby, following the initial actuation by the leading end 14, the abutment surface 12 takes over and provides stable and uniform support for the progression of the rear stop 30 as the drive spring 80 continues to release energy.

[0052] The level of reduction in release force depends on the friction of the barrel / stopper interface. Naturally, the effect of the stud 13 is greater in high friction systems. For example, in a simulation using a friction coefficient of approximately 0.3, the release force is reduced to approximately 1 / 3 of that of a conventional plunger rod design.

[0053] As the bulk of the rear stopper 30 sets in motion and advances through the barrel 21, similar to the conventional mode of operation of a dual chamber injection device, the second liquid substance pushes the front stopper 40 towards and eventually into the bypass channel 25, while forcing a volume of the first liquid substance through the injection needle 35. Once the front stopper 40 reaches the bypass channel 25, the continued advancement of the rear stopper 30 causes the second liquid substance to pass through the front stopper 40 and into the front chamber 29, where it mixes with the remaining volume of the first liquid substance and is therewith flowed through the injection needle 35.

[0054] 5 is a side view of a distal portion of a plunger rod 110 according to another embodiment of the present invention. The plunger rod 110 comprises an elongate shaft 111 extending along a longitudinal axis and provided at its front end with a wavy abutment surface 112 for interaction with a stopper in a drug reservoir. The abutment surface 112 is shaped to provide a wave crest 114 at a peripheral portion of the shaft 111. The wave crest 114 axially leads the remaining portion of the abutment surface 112, thus having a similar effect to the leading end 14 of the stud 13 on the plunger rod 10 described above. The shaft 111 may be hollow, in which case the plunger rod 110 may be employed in the injection device 1 as an alternative to the plunger rod 10, or may be solid.

[0055] 6 is a side view of a distal portion of a plunger rod 210 according to a further embodiment of the invention. The plunger rod 210 comprises an elongate shaft 211 extending along a longitudinal axis and having an abutment surface 212 at its front end for interaction with a stopper in a drug reservoir. The abutment surface 212 has a parabolic profile and provides two protruding portions 214 at diametrically opposed peripheral portions of the shaft 211. Each of the protruding portions 214 has an effect similar to the leading end 14 of the stud 13 on the plunger rod 10 described above, whereby initially a local disengagement of the stopper material from two circumferentially spaced apart internal portions of the drug reservoir is obtained. The shaft 211 may be hollow, in which case the plunger rod 210 may be employed in the injection device 1 as an alternative to the plunger rod 10, or may be solid.

Claims

1. A drug delivery device (1), comprising: a drug reservoir (20) comprising a reservoir body (21) extending along a reference axis and an elastic stopper (30) disposed within said reservoir body (21), said elastic stopper (30) extending between a front stopper end (32) and a rear stopper end (34) and having a plurality of axially spaced circumferential ribs (33) for sealing interaction with an inner wall (22) of said reservoir body (21); a plunger rod structure (10) for displacing said elastic stopper (30) relative to said inner wall (22), said plunger rod structure (10) extending along said reference axis and comprising a distal end face (12, 14) adapted to join with said rear stopper end (34); A drug delivery device (1), wherein the distal end face (12, 14) comprises a first force transmission portion (14) and a second force transmission portion (12), the first force transmission portion (14) axially leading the second force transmission portion (12) and adapted to interact with a peripheral portion of the rear stopper end (34).

2. 2. The medication delivery device of claim 1, wherein the peripheral portion of the rear stop end (34) is less than a semicircle.

3. 3. A drug delivery device as described in claim 1 or 2, wherein the second force transmission portion (12) is perpendicular to the reference axis and the first force transmission portion (14) forms part of a stud (13) protruding distally from the second force transmission portion (12).

4. 4. A drug delivery device as claimed in claim 3, wherein the stud (13) has an axial dimension in the range [1mm, 2mm].

5. 5. A drug delivery device according to claim 3 or 4, wherein the stud (13) has a maximum radial dimension of 2 mm.

6. A drug delivery device as claimed in any one of claims 3 to 5, wherein the stud (13) is adapted to abut the rear stop end (34) at an interface between one of the plurality of axially spaced peripheral ribs (33) and the inner wall (22).

7. 7. The medication delivery device of claim 1, further comprising a housing (2), wherein the plunger rod structure (10) comprises a hollow interior adapted to accommodate a releasable compression spring element (80) to displace the plunger rod structure (10) distally relative to the housing (2).

8. The drug delivery device of any one of claims 1 to 7, wherein the drug reservoir (20) further comprises a second elastic stopper (40) disposed distal to the elastic stopper (30) and a bypass section (25) for allowing fluid flow through the second elastic stopper (40) during displacement of the elastic stopper (30) relative to the inner wall (22).

Images