Variable dose syringes

Abstract

A syringe comprises a dose setter operably coupled to a plunger rod and comprising a rotatable body comprising a set of one or more stops for engaging the set of one or more projections of the plunger rod at least in accordance with a rotational position of the set of one or more stops relative to the set of one or more projections, wherein a first rotational adjustment device associated with the dose setter is configured to set a first dose increment by adjusting a relative axial position between the rotatable body and the plunger rod, and a second rotational adjustment device associated with the dose setting assembly is configured to set a second dose increment greater than the first dose increment by adjusting a relative rotational alignment between the set of one or more stops and the set of one or more projections.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 935,193, filed on November 14, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates generally to drug delivery devices and, more particularly, to dosing systems for prefilled syringes. Background Art

[0004] Syringes are commonly used to administer injectable therapeutic agents or fluids. Syringes are usually composed of a cylindrical barrel, and the inner surface of the barrel is lubricated to enable the elastic plunger stop to be axially manipulated with the plunger rod. Considering the intended application, several types of syringes are designed. Some syringes can also be used to store injectable drugs within a few months; these involve special construction materials of syringes, including syringes without lubricants. Syringes designed for storing drugs are called prefillable syringes (PFS). Some syringes have injection needles pre-attached to the syringe barrel, while some other syringes have a Luer lock feature to connect to other delivery catheters, such as catheters, injection ports, etc. Dose marks are printed on the outer surface of some syringe barrels as a reference for users to set doses; this is conventional dose metering.

[0005] Dosage metering allows different amounts of a drug (e.g., drug doses) to be administered by simply changing the volume of the drug for a given concentration of the drug. The need to administer different drug doses (i.e., dosage metering) is driven by many factors; for example, in tumor treatment, dosage metering helps administer a certain amount of drug based on the patient's weight. Another illustrative example is the injection of insulin, where the amount of insulin injected is based on the patient's blood glucose level.

[0006] Most drugs have a therapeutic window that maximizes drug efficacy. The amount of drug administered at a level below the therapeutic window can result in suboptimal efficacy of the drug, and conversely, the amount of drug administered at a level exceeding the limit of the therapeutic window can expose the patient to the toxic effects of the drug. The accuracy and precision of drug dose delivery are important for ensuring the best therapeutic outcome for a given drug. For sub-milliliter injection volumes, the accuracy and precision of drug delivery are more challenging. In the case of applications involving treatment of pediatric patients, injection of highly effective therapeutic agents (e.g., insulin, tumor agents, immunotherapy, etc.), targeted organ delivery (e.g., eyes, brain, inner ear, etc.), injection of sub-milliliter volumes is relevant.

[0007] Consistent with the need for accurate, precise drug delivery, there is a need to minimize the number of SKUs (stock keeping units) that drug manufacturers must maintain in order to simplify the supply chain logistics of drugs that need to be metered for the reasons mentioned above. Each drug SKU has overhead associated with formulation development, regulatory approval, testing, manufacturing, storage, customer support, etc. Maintaining multiple SKUs of the same drug will have inherent redundancy, which results in increased costs to provide the drug to patients.

[0008] Conventional dose metering using current syringes has limitations on the volume range of a given syringe and is inaccurate and imprecise for administering microliter-sized volumes. Conventional syringes are also limited in the availability of features that maximize the safety of drug administration, e.g., needle stick prevention, counterfeit prevention, prevention of abuse of unused drugs, etc.

[0009] Injection devices also need to incorporate needle safety to mitigate the risk of needle stick injuries in order to comply with regulations or ensure suitability for administration in a home setting. Activation of the needle safety should be independent of the dose volume injected. Moreover, it is important to prevent premature activation of the needle safety mechanism which could result in non-therapeutic or underdosing.

[0010] Pen injectors have been widely used to inject insulin. Pen injectors allow the user to select a dose (injection volume) and self-administer the drug. There are some limitations to the widespread applicability of pen injectors - a) pen injectors include a cartridge (rather than a syringe), b) they require a dedicated injection needle, c) are designed for multiple uses, d) the maximum injection volume that can actually be delivered is about 1 mL, e) needle safety is not included.

[0011] In any injectable dose delivery system including a cylindrical barrel (syringe or cartridge), the volume of the injected dose is defined by the difference between the dose start position of the plunger stop and the dose end position of the plunger stop (see Figure 1). The error in the dose volume is caused by the variability when setting the above-mentioned dose start position and / or the variability caused by the dose end position. This variability ultimately translates into inaccuracy and imprecision in the final dose volume delivered. The sources of this variability include user error and / or tolerances of delivery system components.

[0012] Manually operated traditional dose delivery systems can deliver a certain range of volumes. All manually operated traditional injectable dose delivery systems use the same volume resolution to set the dose volume, regardless of whether the dose volume is selected at the lower end of the delivery volume range or the upper end of the delivery volume range. This results in limiting the maximum deliverable volume of the device (e.g., pen-type syringe) with higher injection volume resolution, or causes the inaccuracy and imprecise (e.g., traditional subcutaneous syringe and prefilled syringe) of low volume (microliter range). Simply increasing the volume range of the above-mentioned higher resolution device will cause the overall size of the device to be increased to a degree that makes it impractical. Similarly, large volume devices (e.g., 5 milliliters of maximum volume syringes) will not be suitable for delivering small volumes (e.g., 10 microliter doses). When used, there is a compromise between dose volume resolution and volume range in the prior art of manually operated drug delivery systems.

[0013] The outer diameter of the elastic plunger stop is slightly oversized relative to the inner diameter of the syringe - this helps to form a seal in pre-filled syringes and non-pre-filled syringes. After the plunger stop is inserted into the syringe, and during storage, the plunger stop continues to apply a radially outward force to the inner diameter of the syringe barrel, thereby generating "static friction". After long-term storage of such pre-filled syringes, additional effort is required to overcome the static friction in order to loosen the plunger stop from its original position. The user force applied axially is generally referred to as the "loosening" force. Overcoming static friction with the loosening force causes the user to temporarily lose control of the plunger rod stroke. If a priming step is required before injection, the consequences of this loss of control are particularly serious. Priming is important to ensure the patency of the delivery catheter (e.g., needle). Priming will help minimize the risk of air being delivered as part of the injection, and therefore minimize underdosing. Over-priming results in exceeding the minimum volume required to perform the priming step, which can lead to potential underdosing of the maximum dose and / or drug waste. Overcoming the static friction of the plunger stop is uncomfortable for the user. Summary of the invention

[0014] According to various embodiments, a plunger rod assembly for a syringe includes fine and coarse dose setting capabilities. The syringe may include one or more dials for achieving fine dose setting and for achieving coarse dose setting. According to various embodiments, the dose delivery starting position of the plunger rod of the plunger rod assembly that pushes the stopper in the syringe barrel to deliver the dose is the same, regardless of the dose setting, and the dose setting end point for controlling the stop position of the plunger rod is different for different doses. According to various embodiments, one or more rotational inputs can achieve fine dose setting and coarse dose setting. In some embodiments, different dials are used as user inputs for fine and coarse dose settings, while in other embodiments, the same dial is used as user input for fine and coarse dose settings.

[0015] According to various embodiments, a plunger rod assembly for a syringe includes: a body; a plunger rod, which is at least partially received in the body and includes a set of one or more protrusions; and a dose setter, which is operably coupled to the plunger rod and includes a rotatable body, the rotatable body including a set of one or more stops for engaging the set of one or more protrusions of the plunger rod at least according to a rotational position of the set of one or more stops relative to the set of one or more protrusions, wherein a first rotational adjustment device associated with the dose setter is configured to set a first dose increment by adjusting the relative axial position between the rotatable body and the plunger rod, and a second rotational adjustment device associated with the dose setting assembly is configured to set a second dose increment greater than the first dose increment by adjusting the relative rotational alignment between the set of one or more stops and the set of one or more protrusions.

[0016] In any of these embodiments, the first rotation adjustment device may include a rotatable dial that engages the rotatable body and can rotate relative to the rotatable body to axially translate the rotatable body relative to the main body. In any of these embodiments, the rotatable dial may include threads that engage threads of the rotatable body.

[0017] In any of these embodiments, the second rotation adjustment device may include a dial for rotating the rotatable body. In any of these embodiments, the rotatable body may translate relative to the dial. In any of these embodiments, the rotatable body and the dial may be fixed relative to each other.

[0018] In any of these embodiments, the first rotation adjustment device can adjust the axial position of the rotatable body relative to the main body.

[0019] In any of these embodiments, the first rotational adjustment device can adjust the axial position of the plunger rod relative to the body.

[0020] In any of these embodiments, the plunger rod may be rotationally fixed.

[0021] In any of these embodiments, the rotatable body may be laterally offset relative to the plunger rod.

[0022] In any of these embodiments, the rotational axis of the rotatable body may intersect the plunger rod.

[0023] In any of these embodiments, the set of one or more protrusions may include a single protrusion and the set of one or more stops may include a plurality of stops.

[0024] In any of these embodiments, the set of one or more protrusions may include a plurality of protrusions and the set of one or more stops may include a single stop.

[0025] In any of these embodiments, the first rotation adjustment device may include a slot in the rotatable body that receives a portion of the plunger rod, and the slot includes an inclined surface that axially pushes the portion of the plunger rod received in the slot when the rotatable body rotates. In any of these embodiments, the set of one or more protrusions may include a single protrusion, and the portion of the plunger rod is a single protrusion. In any of these embodiments, the portion of the plunger rod can be disengaged from one circumferential end of the slot so that continued rotation of the rotatable body does not cause further axial translation of the plunger rod relative to the rotatable body.

[0026] According to various embodiments, a plunger rod assembly includes: a body; a plunger rod at least partially received in the body and including one or more protrusions; and a dose setter including a rotatable body including one or more first stops aligned with the one or more protrusions to define a dose delivery end position of the plunger rod, wherein different alignments of the one or more first stops with the one or more first protrusions define different dose settings, and a second stop engaging the one or more protrusions of the plunger rod to define a dose delivery start position of the plunger rod, wherein the dose delivery start position of the plunger rod is the same for different dose settings.

[0027] In any of these embodiments, the one or more protrusions of the plunger rod may include a first protrusion, and wherein engagement between the first protrusion and the second stop defines a dose delivery start position, and engagement between the first protrusion and the one or more first stops defines a dose delivery end position.

[0028] In any of these embodiments, the one or more protrusions of the plunger rod may include a first protrusion and a second protrusion, and wherein engagement between the first protrusion and the second stop defines a dose delivery start position, and engagement between the second protrusion and the one or more first stoppers defines a dose delivery end position.

[0029] In any of these embodiments, the second stop can include a slot that receives a first protrusion of the one or more protrusions.

[0030] In any of these embodiments, the slot may include an inclined surface that pushes the first protrusion received in the slot when the rotatable body rotates in the rotational direction.

[0031] In any of these embodiments, the first protrusion may disengage from the slot as the rotatable body continues to rotate in the rotational direction.

[0032] In any of these embodiments, the dose setter may include a rotatable dial that engages the rotatable body and is rotatable relative to the rotatable body to axially translate the rotatable body relative to the main body.

[0033] In any of these embodiments, the rotatable dial may include threads that engage threads of the rotatable body.

[0034] In any of these embodiments, the dose setter may include a dial for rotating the rotatable body.

[0035] In any of these embodiments, the rotatable body can translate relative to the dial.

[0036] In any of these embodiments, the rotatable body and the dial may be fixed relative to each other.

[0037] In any of these embodiments, the rotatable body is translatable relative to the main body to define an end-dose delivery position of the plunger rod.

[0038] In any of these embodiments, translation of the rotatable body may provide a first resolution of dose setting and rotation of the rotatable body may define a second resolution of dose setting.

[0039] In any of these embodiments, the plunger rod may be rotationally fixed.

[0040] In any of these embodiments, the rotatable body may be laterally offset relative to the plunger rod.

[0041] In any of these embodiments, the rotational axis of the rotatable body may intersect the plunger rod.

[0042] In any of these embodiments, the rotatable body may include a second stop.

[0043] In any of these embodiments, the assembly may include a locking mechanism to rotationally constrain the dose setting dial in the end-dose delivery position of the plunger rod.

[0044] According to various embodiments, the syringe includes any of the plunger rod assemblies described above.

[0045] In any of these embodiments, the syringe can be a pre-filled syringe.

[0046] In any of these embodiments, the syringe may be a disposable syringe used to inject only one dose.

[0047] In any of these embodiments, the syringe may include a retractable needle cover that locks in the extended position at the end of dose delivery.

[0048] According to various embodiments, a method of setting and delivering a dose using a prefilled syringe includes: applying a first rotational input to a dose setter of the syringe to adjust the relative axial position between at least a portion of the dose setter and a plunger rod of the syringe to set a first dose increment; applying a second rotational input to the dose setter of the syringe to adjust the rotational position of at least a portion of the dose setter to set a second dose increment, wherein the second dose increment is greater than the first dose increment; and axially advancing the plunger rod to deliver a dose from a dose-independent dose starting position.

[0049] In any of these embodiments, the first rotational input may be applied to a dial that is rotatable relative to at least a portion of the dose setter.

[0050] In any of these embodiments, the second rotational input may be applied to a second dial rotatably coupled to at least a portion of the dose setter.

[0051] In any of these embodiments, at least a portion of the dose setter is axially translatable relative to the second dial.

[0052] In any of these embodiments, at least a portion of the dose setter is axially translatable relative to the first dial.

[0053] In any of these embodiments, the first and second rotational inputs may be applied to a dial of at least a portion of the dose setter.

[0054] In any of these embodiments, applying the first rotational input may axially advance the plunger rod relative to the syringe barrel.

[0055] In any of these embodiments, applying the first rotational input may axially advance at least a portion of the dose setter relative to the syringe barrel.

[0056] In any of these embodiments, at least a portion of the dose setter may include at least one stop, the plunger rod may include at least one protrusion, and adjusting the rotational position of at least a portion of the dose setter may include aligning the at least one stop with the at least one protrusion.

[0057] In any of these embodiments, the second rotational input may be applied after the first rotational input is completed.

[0058] In any of these embodiments, the method may further include constraining the dose setter after delivering the dose.

[0059] According to various embodiments, a method of setting and delivering a dose using a prefilled syringe includes adjusting a relative axial position between at least a portion of a dose setter of a syringe and a plunger rod of the syringe; rotating at least a portion of the dose setter to align at least one stop of at least a portion of the dose setter with at least one protrusion of the plunger rod; and axially translating the plunger rod to deliver the dose until at least one protrusion of the plunger rod engages at least one stop of at least a portion of the dose setter.

[0060] In any of these embodiments, adjusting the relative axial position between at least a portion of the dose setter and the plunger rod comprises adjusting the axial position of at least a portion of the dose setter relative to the syringe barrel.

[0061] In any of these embodiments, adjusting the relative axial position between at least a portion of the dose setter and the plunger rod may include adjusting the axial position of the plunger rod relative to the syringe barrel.

[0062] In any of these embodiments, adjusting the relative axial position between at least a portion of the dose setter and the plunger rod may include a user applying a rotational input to the dose setter.

[0063] In any of these embodiments, a rotational input may be applied to a dial of the dose setter, which rotates relative to at least a portion of the dose setter and may engage at least a portion of the dose setter such that at least a portion of the dose setter is axially translated by rotation of the dial.

[0064] In any of these embodiments, the rotational input may be applied to a dial that is translationally fixed relative to at least a portion of the dose setter.

[0065] In any of these embodiments, rotating at least a portion of the dose setter can include a user-applied rotational input.

[0066] In any of these embodiments, the plunger rod may remain translationally fixed while at least a portion of the dose setter is rotated.

[0067] In any of these embodiments, at least a portion of the dose setter may remain translationally fixed while at least a portion of the dose setter is rotated.

[0068] In any of these embodiments, the method may further include axially restraining the plunger rod at the end of dose delivery.

[0069] According to various embodiments, a method of delivering a dose using a prefilled syringe includes setting a dose of the syringe by setting an end of travel of a plunger rod of the syringe; axially translating the plunger rod of the syringe to deliver the dose from a dose-independent starting position; and displaying a dose delivery completion indication at the end of travel of the plunger rod.

[0070] In any of these embodiments, the method may further include generating an audible indication of dose delivery completion at the end of travel of the plunger rod.

[0071] In any of these embodiments, the method may further include locking a dose setter of the syringe device at the end of travel of the plunger rod.

[0072] In any of these embodiments, the method may further include withdrawing the syringe from the injection site and locking the needle shield in place after dose delivery is complete.

[0073] In any of these embodiments, after dose delivery is complete, a portion of the dose corresponding to the difference between the total dose and the delivered dose may remain in the syringe.

[0074] It should be understood that any variations, aspects, features and options described with regard to apparatus and components are also applicable to methods, and vice versa. It will also be clear that any one or more of the above variations, aspects, features and options can be combined. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] The present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0076] FIG1 shows a conventional syringe;

[0077] FIG. 2 illustrates a syringe according to various embodiments;

[0078] Figure 3 is an exploded view of various aspects of the syringe of FIG. 2 according to various embodiments;

[0079] Figure 4a and 4b Various aspects of a dose stop according to various embodiments are shown;

[0080] Figure 5 and 6 are examples of dose setting dials according to various embodiments;

[0081] FIG. 7 illustrates a plunger rod according to various embodiments;

[0082] FIG8 illustrates a housing of a plunger rod assembly according to various embodiments;

[0083] FIG. 9 illustrates various features for retaining the plunger rod assembly on the syringe body according to various embodiments;

[0084] FIG. 10 illustrates a dose setter according to various embodiments;

[0085] 11a-c illustrate various dosage settings according to various embodiments;

[0086] FIG. 11a ′ shows the position of the plunger rod relative to the groove according to various embodiments;

[0087] FIG. 12 illustrates a process for setting and delivering a dose according to various embodiments;

[0088] FIG. 13 illustrates locking of a dose setting dial at the end of dose delivery according to various embodiments;

[0089] FIG. 14 illustrates an exemplary plunger stopping force according to various embodiments;

[0090] FIG. 15 illustrates a syringe according to various embodiments;

[0091] FIG. 16 illustrates a plunger rod according to various embodiments;

[0092] FIG. 17 illustrates a housing according to various embodiments;

[0093] FIG. 18 illustrates a latch according to various embodiments;

[0094] 19 and 20 illustrate aspects of a dose setter according to various embodiments;

[0095] 21 and 22 illustrate a cover according to various embodiments;

[0096] FIG. 23 illustrates a process for setting and delivering a dose according to various embodiments;

[0097] FIG. 24 illustrates a process for setting and delivering a dose according to various embodiments;

[0098] FIG25 illustrates fine resolution plunger rod travel according to various embodiments;

[0099] FIG. 26 illustrates plunger rod travel for two different dose settings according to various embodiments;

[0100] 27 and 28 illustrate syringe covers according to various embodiments;

[0101] FIG. 29 illustrates a syringe according to various embodiments;

[0102] FIG. 30 illustrates a plunger rod according to various embodiments;

[0103] FIG. 31 illustrates a plunger rod according to various embodiments;

[0104] 32 and 33 illustrate a dose setter according to various embodiments;

[0105] FIG. 34 illustrates a cover according to various embodiments;

[0106] FIG. 35 illustrates a housing according to various embodiments;

[0107] FIG. 36 illustrates an end-of-dose indication according to various embodiments;

[0108] FIG. 37 illustrates a disk for preventing the plunger rod from rotating according to various embodiments;

[0109] FIG. 38 illustrates a window covering according to various embodiments;

[0110] FIG. 39 illustrates a syringe according to various embodiments;

[0111] 40-42 illustrate various dose settings and dose deliveries according to various embodiments; and

[0112] FIG. 43 illustrates a syringe with a needle shield according to various embodiments. DETAILED DESCRIPTION

[0113] According to various embodiments, the devices and methods described herein relate to controlled dose delivery, such as using a syringe or cartridge. In order to provide appropriate resolution when setting a low volume (less than 100 microliters) or a higher volume (>100 microliters to milliliters) dose, various embodiments include separate features for higher volume and low volume dose settings - hereinafter generally referred to as coarse and fine dose settings, respectively. The combination of these two settings provides a wide range of dose setting options from low microliters to milliliters in a compact configuration that is practical to use. Separating the coarse and fine injection dose volume settings avoids the redundancy of having microliter level resolution for milliliter dose volumes, but provides the necessary resolution for injection microliter volumes.

[0114] According to various embodiments, the controlled dose delivery device may include a syringe, a plunger stop, a plunger rod, a dose stop, one or more dose setting dials, which may include a fine dose setting dial and a coarse dose setting dial or a single dial that can control fine and coarse dose settings. According to various embodiments, the syringe may be a pre-filled syringe with an elastic plunger stop translated by a plunger rod. The plunger rod moves axially to distribute the injectable drug filled in the syringe. The amount of the plunger rod axial stroke defines the volume of the injected dose. The plunger rod translates axially until the design feature on the plunger rod abuts against the "stop" feature of the dose stop.

[0115] According to various embodiments, the dose stop may have one or more radially arranged "stop" features, and the plunger rod may have one or more radially arranged protrusions, and the corresponding alignment between the stop features and the protrusions corresponds to the dose setting. The "stop" features and / or the protrusions may be arranged at different longitudinal / axial positions. For example, the dose stop may include multiple stop features at different axial and circumferential positions, and rotation of the dose stop may align a specific stop feature with the protrusion of the plunger rod to set a dose corresponding to the specific stop feature. Aligning different stop features with the protrusions will set different doses.

[0116] According to various embodiments, the fine dose setting dial may engage with the dose stop such that rotation of the fine dose setting dial causes axial translation of the dose stop, which axially translates one or more stop features of the dose stop to provide fine adjustment of the dose setting. The dose stop and / or the dial may have threads, and the thread angle and pitch may define the resolution of the fine dose adjustment. The selectivity of the alignment of a particular stop feature with a particular protrusion may provide coarse dose setting adjustability, while the axial / longitudinal position of the dose stop may provide fine dose setting adjustability. Thus, the user may select the amount of the dose by a combination of the fine dose setting dial and the coarse dose setting dial.

[0117] According to various embodiments, the higher resolution of the plunger rod stroke is reserved for a portion of the entire plunger rod stroke, for example, for micro-advancing the plunger rod to prime the syringe in a controlled manner and / or to help overcome the static friction of the plunger stop. According to various embodiments, a single dose setting dial combines features of high resolution and coarse resolution for axial translation of the plunger rod. As described above, one or more stop features corresponding to the amount of various user-selectable doses can be incorporated into the dose setting dial or the plunger rod. The plunger rod may include one or more radially extending protrusions, one or more of which may be used for dual purposes, namely interacting with one or more stop features on the dose setting dial and enabling the plunger rod to be micro-advanced (high resolution stroke) by a partial rotation of the dose setting dial. The plunger rod may include features that provide audible and visual end-of-dose indications, as well as tactile end-of-dose indications generated by the protrusions on the plunger rod abutting against the stop features on the dose setting dial at the end of the dose. Visual and audible end-of-dose indications are important for providing the user with confirmation that the injection process is completed in the system, wherein the end-of-dose position of the plunger rod varies according to the dose selected by the user.

[0118] According to various embodiments, according to various embodiments, stop features corresponding to the amount of various user-selectable doses are incorporated into the plunger rod. Depending on the selected dose volume, one of these stop features can translate until it reaches the stop feature of the dose stop to define the end of delivery of the intended dose (dose end). According to some embodiments, simultaneous with the end of the dose is an audible and / or visual dose end indication to the user. The visual dose end indication may include a dose end barrel that translates axially toward the injection end stroke, wherein the colored features of the marking are visible to the user when approaching the injection end stroke.

[0119] According to various embodiments, the syringe is a pre-filled disposable syringe for injecting only one dose. According to various embodiments, in the absence of administration of the maximum possible volume of the drug in the syringe, the undelivered drug remaining in the syringe is considered a biohazard. In order to minimize the possibility of misusing such unused drug by reusing the device, the plunger rod and dose setting dial can be locked in place.

[0120] According to various embodiments, the drug delivery device may include one or more needle safety features for embodiments in which the needle is pre-attached (fixed) to the syringe barrel in any of the above-described device embodiments. According to various embodiments, the needle safety device is actuated independently of the dosing mechanism. According to other embodiments, the needle safety device is actuated by the injection stroke, such as near the end of the dose. The actuation of the needle safety device can disable the injection device. Therefore, according to various embodiments, the actuation of the needle safety device by completing the injection can disable the injection device and ensure that the needle safety device is only actuated when the dose selected by the user is delivered.

[0121] According to various embodiments, the prefillable syringe may have a flange, such as circular or having diametrically opposed flat surfaces, and one or more features on an element incorporated into the syringe retaining component of the device minimize rotation of the syringe, regardless of the design of the syringe flange.

[0122] In the following description of the present disclosure and embodiments, reference is made to the accompanying drawings, in which specific embodiments that can be implemented are shown by way of illustration. It should be understood that other embodiments and examples can be implemented, and changes can be made, without departing from the scope of the present disclosure.

[0123] Furthermore, it should be understood that the singular forms "a", "an" and "the" used in the following description are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and / or" as used herein refers to and encompasses any and all possible combinations of one or more of the relevant listed items. It should be further understood that the terms "includes", "including", "comprises" and / or "comprising" when used herein specify the presence of stated features, integers, steps, operations, elements, parts and / or units, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, parts, units and / or groups thereof.

[0124] Fig. 1 shows a conventional delivery system based on a syringe, which includes a cylindrical barrel 1, the inner surface of which can be lubricated so that an elastic plunger stopper 2 can be translated along the barrel axis by a standard plunger rod 3. The user can select a dose by aligning the tip of the stopper with a dose volume mark 4 printed on the outer surface of the barrel 1. This will be the dose starting position. The user then inserts a delivery catheter (e.g., a needle, catheter, etc. connected to or pre-attached to the syringe) into the injection site and axially depresses the plunger rod 3 until the plunger stopper bottoms out. The above-mentioned dose mark 4 provides the same resolution for dose setting, regardless of whether the user selects a dose at the low or high end of the volume range. In the example shown in Fig. 1, if the expected dose is less than 0.1 ml, it is desirable to have a higher resolution to ensure accurate and precise delivery. On the contrary, in the example shown, the resolution required for accurately and precisely delivering a 0.9 ml dose is sufficient. In addition, if a pre-filled syringe (filled with 1ml of drug by the drug manufacturer) is needed to administer a low volume (e.g., 0.1ml in the current example of FIG. 1), the user will have to spray out 0.9ml of drug before administering the injection. In the case of effective drugs such as chemotherapeutics, oncolytic viruses, gene therapies, etc., exposing the wasted drug to the user may be harmful to the user, caregivers, and family members. This situation is unique to all drug delivery device solutions based on non-pen syringes in the prior art. If a portion of the entire drug encapsulated in the syringe is to be delivered, it is desired to administer only the expected dose and retain the remaining dose in the syringe. Used syringes with undelivered drugs can be safely disposed of without unnecessary exposure to drugs.

[0125] According to various embodiments, variable dose syringe 100 is shown in Fig. 2, and it is configured to provide the user with the control of dosage setting resolution, so that the user can select injection volume and prevent unnecessary exposure to excessive medicine. Variable dose syringe embodiment provides the separate fine and rough setting of expected dose volume. Shown embodiment is intended to deliver at most 1 milliliter with setting dose resolution 0.1 milliliter or 0.01 milliliter (that is, 10 microlitres), and this depends on the expected volume to be injected. Therefore, 100 dosage volume levels (0.01 milliliter minimum dose to 1 milliliter maximum dose, increment is 0.01 milliliter) can be realized by variable dose syringe shown in this article. Figure 3 Components of a variable dose syringe 100 according to various embodiments are shown. For example, a standard prefillable syringe 9 with a maximum fill volume of 1 ml can be used, with a needle pre-attached (fixed) therein, but it should be understood that the apparatus, methods and principles described herein can be used with any syringe size and any syringe configuration.

[0126] The variable dose syringe 100 includes a plunger rod assembly, which can be attached to the proximal end of the syringe 9, for example, by a clip 14 and an X-ring 15. The plunger rod assembly can include a housing 16 (also referred to herein as a body), a plunger rod 10, a dose setter including a rotatable body 13 (hereinafter also referred to as a "dose stop") and one or more dials (diales 11 and 12 are shown). The syringe 9 can be filled with an injectable drug 8 and include an elastic plunger stop 7. According to various embodiments, fine and coarse dose volume settings are facilitated by a fine dose setting dial 11 and a coarse dose setting dial 12, respectively. The device includes a dose stop 13. The above components are supported or contained in the housing 16. The prefillable syringe 9 is retained on the housing 16 by a clip 14 and an elastic X-ring 15.

[0127] Pre-filled syringes with pre-attached (or fixed) needles are typically provided to the user in a ready-to-inject form. Similarly, according to various embodiments, the variable dose syringe 100 may have a pre-filled syringe 9 in which the axial position of the plunger rod 10 is in a dose start position provided to the end user. The dose end position may be defined by a dose stop 13. Embodiments of the dose stop 13 are Figure 4a As shown in Figure 4aAs shown, the end of dose is facilitated by a stop surface 18 on the dose stop 13. Each stop surface 18 is arranged circumferentially and each corresponds to a coarse dose volume that can be set. The axial position of each stop surface 18 is defined by the dose volume amount on the coarse dose setting dial 12. The dose stop 13 comprises four spline segments 19, each having the same length, arranged at the same axial position on the dose stop 13 and arranged at 90 degrees relative to each other. These spline segments 19 interact with the coarse dose setting dial 12. The dose stop 13 also comprises a thread 20, which interacts with the fine dose setting dial 11. In Figure 4b 1 shows a partial expansion of the dose stop surfaces of the cylindrical dose stop 13, the stop surface 18a corresponds to the lowest volume on the coarse dose setting dial 12, and the stop surface 18j corresponds to the highest volume on the coarse dose setting dial 12. The end-of-dose position of the plunger rod 10 is determined by one of the stop surfaces 18, the axial position of which is a combination of the coarse dose setting and the axial advancement of the dose stop 13 mediated by the rotation of the fine dose setting dial 11. The resolution of the fine dose setting is determined by the angle of the internal thread 20.

[0128] Figure 5 An example of a fine dose setting dial 11 is shown, which includes an outer thread 21 to match the pitch and thread angle of the inner thread 20. Indicia 22 corresponding to fine dose levels providing finer resolution of dose setting are printed on the cylindrical surface of the fine dose setting dial 11. Radial grooves 23f are located on the bottom surface. Each groove 23f is spaced apart at an angle defined by the amount of rotation of the fine dose setting dial 11 so that the axial translation of the dose stop 13 corresponds to the dose volume resolution provided by the fine dose setting dial 11. The grooves 23f help to fix the rotational position of the fine dose setting dial 11. The dose stop 13 is arranged in the cavity 24. The longitudinal grooves 27f on the cylindrical surface of the fine dose setting dial 11 are separated by the same angle as 23f; these longitudinal grooves play a role in locking the fine dose setting dial at the end of the injection. The friction between the mating threads 20 and 21 axially constrains the dose stop 13.

[0129] An example of a coarse dose setting dial 12 is shown in FIG6 , which includes an axial keyway 25 which aligns with and accommodates a spline segment 19 on a dose stop 13. A radial groove 23c is located on the top surface. The groove 23c helps to fix the rotational position of the coarse dose setting dial 12. Each groove 23f is spaced at the same angle as the angle between the stop surfaces 18, and the number of grooves 23c is one more than the number of stop surfaces 18. Longitudinal grooves 27c on the cylindrical surface of the coarse dose setting dial 12 are spaced at the same angle as 23c; these longitudinal grooves act to lock the fine dose setting dial at the end of an injection. The dose stop 13 is disposed within a cavity 28. Indicia 26 corresponding to a coarse dose level providing a coarse resolution of the dose setting are printed on the cylindrical surface of the fine dose setting dial 12.

[0130] According to various embodiments, features of the plunger rod 10 are shown in FIG7 . The locking blade 29 and the low dose locking blade 30 are longitudinally disposed but axially separated from each other and from the dose stop mark 31 . The user performs an injection by pushing the finger seat 32 , which helps to axially translate the plunger 10 until the dose stop mark travel is interrupted by the stop surface 18 on the dose stop 11 ; the stop surface and its axial distance from the start of the injection are defined by the fine dose setting dial 11 and the coarse dose setting dial 12 . The distal end 43 of the plunger rod meets the side of the plunger stop 7 opposite to the drug contact side. In some applications, the distal end 43 may be adapted to cooperate with the plunger stop 7 .

[0131] Features of the housing 16 are shown in FIG8 . The axial cavities 33 and 34 contain the dose stop 13 and the plunger rod 10, respectively. The fine dose setting dial 11 is placed in the side slot 35, while the coarse dose setting dial 12 is placed in the side slot 36. Along the axis of the device, the side slot 35 is bounded by a hollow circular beam with a marking tip 17f. When located in the groove of the radial groove 23f, the tip of 17f helps to record the dose setting position of the fine dose setting dial 11. Along the axis of the device, the side slot 36 is also bounded by a hollow circular beam with a marking tip 17c. When located in the groove of the radial groove 23c, the tip of 17c helps to record the dose setting position of the coarse dose setting dial 12. The deflection of the two circular beams is sufficient to rotate the fine and coarse dose setting dials. The fine and coarse dose setting dials are axially constrained by the housing 16 and radially constrained by the dose stop 13. The syringe is attached to the housing 16 by placing it in the cavity 38.

[0132] The clip 14 and x-ring 15 can be used to attach the pre-filled syringe 9 to the housing 16 (see FIG. 9 ). The x-ring is placed in the cavity 38. To attach the syringe 9 to the housing 16, the syringe flange 41 is placed between the clip 14 and the housing 16 when inserted into the cavity 38, so that the tabs 39 on the clip 14 are aligned with the axial keyways on the housing 16 until the inclined slot 37 is reached. Using a torque wrench with an adapter to engage the slot 39, the clip is turned along the ramp defined by the slot 37 until it is tight. The pre-filled syringe is now secured to the housing 16, and therefore to the device.

[0133] The mating features 19 and 25 can be used to enable the coarse dose setting dial 12 to be rotationally keyed to the dose stop 13, and to enable the coarse dose setting dial 12 to slide axially relative to the dose stop 13. The stop surface 18 on the dose stop 13 defines the end-dose position of the plunger rod dose stop mark 31. Rotation of the fine dose setting dial 11 causes an axial translation of the dose stop 13. The end-dose position is defined by the axial position of the stop surface 18, which in turn depends on the combination of the volume selected on the coarse dose setting dial 12 and the volume selected on the fine dose setting dial 11. Manipulation of the fine dose setting dial 11 adjusts the axial position of the stop surface 18 corresponding to each setting of the coarse dose setting dial 12. Therefore, the user can selectively adopt a higher resolution dose setting or a coarse resolution dose setting or a combination thereof to effectively set the dose volume to be injected. Compared with variable dose systems such as pen-type injectors in the prior art, another dose setting advantage is that the user does not have to set the target dose volume through all dose levels. For example, to set a 0.2 ml dose, the user only needs to rotate the coarse dose setting dial 12 to set a 0.2 ml dose without having to go through 0.01 ml increments up to 0.2 ml.

[0134] FIG. 11a shows the positions of the coarse dose setting dial 12 and the fine dose setting dial 11 before the user operates to set the dose according to various embodiments. According to various embodiments, the dose starting position of the plunger rod 10 is defined by the abutment between the locking blade 29 of the plunger rod 10 and the proximal end of the dial 11, which prevents the plunger rod 10 from being advanced by the user. The marks 17c and 17f on the circular beam on the housing 16 provide a visual reference for the user to set the dose volume based on the marks 22 and 26 on the fine and coarse setting dials, respectively. The dose volumes set to 0.000, 0.460 and 1.000 ml injection are shown in the examples of FIGS. 11a, 11b and 11c. Corresponding to when the dose volume is 0.000, the locking blade 29 of the plunger rod 10 is longitudinally misaligned with the groove 27f, as shown in 11a'. The dose setting causes the locking blade to be longitudinally aligned with the groove 27f. The plunger rod 10 is now in the dose starting position.

[0135] FIG. 12 shows various aspects of the internal mechanism for dose setting and end of dose for an exemplary 0.440 ml injection according to various embodiments. The internal mechanism including the fine dose setting dial 11, the coarse dose setting dial 12, the dose stop 13 and the plunger rod 10 corresponding to the device state received by the user is shown in "a". Rotating the fine dose setting dial to align the "40" mark with the mark 17f on the housing 16, and rotating the coarse dose setting dial to align the "0.4" mark with the mark 17c on the housing 16 helps to rotationally align and axially position the stop surface 18 on the dose stop 13; this is shown in "b". "c" shown is after the user depresses the plunger rod 10 causing the plunger rod 10 to translate axially until the end of dose mark 31 abuts the stop surface 18; this also provides tactile feedback to the user that the intended dose has been delivered. The above-mentioned total axial travel is the injection stroke 42.

[0136] It may be advantageous to lock the dose setting dial after the injection is complete; this option is shown in Figure 13. For the same 0.440 ml example above, "b" in Figure 13 shows the internal mechanism when the user sets a dose. After the injection stroke 42 is completed, the locking blade 29 is axially translated within the grooves 27c and 27f of the coarse dose setting dial 12 and the fine dose setting dial 11. The presence of the locking blade 29 prevents further rotation of the fine dose setting dial 11 or the coarse dose setting dial. This makes the device unable to be used to deliver any undelivered drug in the syringe 9 after the intended dose is completed. Only for low dose volumes, the low dose locking blade 30 comes into play to lock the coarse dose setting dial.

[0137] In embodiments involving pre-filled syringes or pre-filled cartridges, after aseptic filling of the drug, the syringe (or cartridge) is stopped with an elastic plunger stop. The plunger stop is radially oversized relative to the inner diameter of the syringe (or cartridge) to provide and maintain a sterile barrier. Over time and during the storage of the pre-filled drug, the elastic plunger stop will produce an inertia called static friction to the motion, wherein the plunger stop must be loosened before its axial translation. Figure 14 shows an exemplary injection force curve illustrating this phenomenon. Static friction has several practical meanings. The increase in the axial application force 5 that overcomes static friction can cause the user to lose control of the plunger stop stroke (due to momentum). This loss of user control will eventually lead to a waste of medicine. The increase in force 5 can also trigger a blocking alarm in an automatic delivery system such as an infusion pump. In addition, Figure 14 shows that the amount of the plunger stop stroke corresponding to when static friction begins to work is very small relative to the total expected stroke of the plunger stop to administer the expected drug volume. It is desirable to be able to controllably advance the plunger stop to overcome static friction before demonstrating that drug can be advanced with a predictable force 6 .

[0138] In view of the above, in the drug delivery application based on pre-filled syringe (or cartridge), it is desirable to have a plunger stopper stroke with higher resolution to overcome static friction, that is, to retain a higher resolution for the plunger stopper stroke amount only for overcoming the plunger stopper static friction. A rougher resolution can then be provided for other preset dose volumes. Only when the various doses of a given injectable drug 8 are known in advance, it is possible to pre-set the dose level. Figure 15 shows a variable dose syringe 43 according to various embodiments, which can overcome the plunger stopper static friction and provide fine and rough resolution. Syringe 43 can be used for example to deliver a minimum of 0.2 ml and a maximum of 2.0 ml (that is, 10 dose volume levels-0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0 ml) with an increment of 0.2 ml. It should be understood that these delivery amounts and increments are merely exemplary, and syringe 43 can be configured to deliver any suitable amount and increment.

[0139] The syringe 43 includes a plunger rod assembly that can be assembled to the syringe 9. The plunger rod assembly may include a plunger rod 44, a housing 45, a cap 46 and a dose setting device 47 (also referred to herein as a dose setting dial 47). The embodiment shown includes a pre-filled syringe 9 containing an injectable drug 8 stopped by a plunger stop 7. Similar to the syringe 100 of FIG. 2, the pre-filled syringe 9 is fixed to the housing 45 using a clip 14 and an elastic x-ring.

[0140] The plunger rod 44 according to various embodiments is shown in FIG. 16 . The patient end of the plunger rod 44 includes a disc 48 to allow the user to manually advance the plunger rod 44 after setting the dose. The cylindrical patient end 49 abuts the plunger stop 7 when assembled. The end 49 can also be modified to have a thread that interlocks with the axial non-drug contact side of the plunger stop 7. A traction latch 47 can be used to provide control of the axial plunger rod 44 stroke. The plunger rod 44 includes four longitudinal ribs 50, which together with the features on the housing 45 and the cover 46 help prevent the plunger rod 44 from rotating during device operation. The marking 51 includes a high-resolution drive surface 52 on the non-patient end and a stop surface 53 on the patient end. The plunger rod 44 also includes a beam 54, which helps to provide an audible end-of-dose indication and axially locks the plunger rod 44 once the selected dose is fully delivered (dose end). The plunger rod 44 also includes a flat surface with a dose end mark 55 corresponding to various deliverable dose volumes. The intervals of the dose volume markings correspond to injection strokes of the respective dose volume.

[0141] The housing 45 according to various embodiments is shown in FIG. 17 . It includes a dose setting latch ratchet 56 . A flange portion 57 is provided for the user to grip the device during injection. A cavity 58 radially constrains the plunger rod 44 . A side slot 59 is provided to allow the user to access the dose setting dial 47 . An axial slot 60 provides alignment for inserting the tab 40 on the clip 14 during insertion of the syringe 9 before attachment. The slot 61 provides an inclined slot for the tab 40 to securely attach the syringe 9 to the housing 45 when the clip 14 is rotated. The latch 56 according to various embodiments is shown in detail in FIG. 18 , and consists of a hemispherical pin 63 and a latch 62 . The height of the hemispherical pin is slightly greater than the height of the latch 62 . The latch 56 provides tactile and audible feedback to the user during dose setting, and interacts with features on the dose setting dial 47 housed within a recessed cylindrical portion 66 of the housing 45 . The surfaces 64 and 65 help to axially constrain the dose setting dial 47 .

[0142] A dose setting dial 47 according to various embodiments is shown in FIG. 19 . The dose setting dial 47 comprises a rotatable body having a plurality of dose stops 76 which engage the markings 51 of the plunger rod 44 to stop the axial travel of the plunger rod 44, thereby controlling the end of dose delivery. A portion 67 of the dose setting dial 47 is contained within a portion 66 of the housing 45 . Dose markings 68 are printed to enable the user to select an injection volume (dose setting). A portion of the markings 69 comprises a “→” marking indicating to the user the initial rotation direction of the dose setting dial 47 . Only one of these markings 68 is visible to the user through the cover 46 . The surface 69 abuts against the surface 64 of the housing 45 axially constraining the dose setting dial 47 towards the patient end. The surface 70 is constrained by the surface 65 of the housing 45 , thereby constraining the dose setting dial 47 in the non-patient end direction. The dose setting dial 47 consists of a plurality of longitudinal splines 71 . The markings 51 of the plunger rod 44 are constrained within these splines 71 . The longitudinal groove 72 on the portion 67 of the surface of the dose setting dial 47 interacts with the pegs 62 and 63 of the latch 56. Among them, the grooves 72a, 72b and 72c are longer than the other grooves to accommodate the pegs 62 and 63. The rest of the groove 72 accommodates only the peg 63. When not in use, the pegs 62 and 63 are located in the groove 72a. The shape of the groove 72a ensures that the dose setting dial 47 is rotated only in the direction indicated by the "→" part of the mark 68. After rotating the dose setting dial 47 by an angle corresponding to 74°, and when reaching the groove 72b, the dose volume is set to 0.2 ml. The shape of the groove 72b (same as the shape of 72a) prevents the user from returning to "→"; this groove 72 accommodates the pegs 62 and 63. Continuous rotation towards the other hemispherical groove 72 only engages the hemispherical peg 63. The hemispherical shape of the other groove 72 allows bidirectional rotation of the dose setting dial 47, except in the positions corresponding to 0.2 and 2.0 ml. This arrangement prevents transition from 2.0 ml to the "→" position or from 0.2 ml to the "→" position, but at the same time allows the user to flexibly move back and forth between other dose levels before injection. The side slot 73 provides and defines the high resolution of this embodiment. The slot constrains the mark 51 of the plunger rod 44. When the device is not in use, the mark 51 is located at position 75a. The surface 52 of the mark 51 contacts the surface 73a. When the dose setting dial 47 is rotated, the mark 51 axially translates a distance 75 to a position 75b. Once the mark 51 reaches 75b, there is more axial constraint on the stop surface 53 on the plunger rod 44. For any dose volume that can be set in this embodiment, the plunger rod 44 is in the axial dose starting position. In this example, the dose setting at this rotational position of the dose setting dial 47 is 0.2 ml. Distance 75 is a fine resolution of the axial translation of the plunger rod 44, which helps to overcome the static friction of the plunger stop 7 and in some cases also helps to irrigate the delivery catheter, such as an injection needle.The end-of-dose position is defined by surfaces 76 that are axially separated based on an injection stroke corresponding to a dose volume selected by the user by rotating the dose setting dial 47. The surface 76 corresponding to the user-set dose volume is longitudinally aligned with the stop surface 53 on the plunger rod 44. The plunger rod 44 is contained within a cavity 78.

[0143] FIG. 20 provides a cross-sectional view of features on the dose setting dial 47. Surface 77 engages the tip of beam 54 of the plunger rod 44. At the end of the dose, the beam 54 strikes the surface 77 to provide an audible end-of-dose indication. Surface 79 engages the beam 54, thereby axially locking the plunger rod 44 in the non-patient direction at the end of the dose. Thus, at the end of the dose, the plunger rod is axially locked in the patient direction by the engagement of surfaces 53 and 76, and axially locked in the non-patient direction by the interaction of beam 54 and surface 79. The user interface 80 on the dose setting dial 47 for rotating it may include stripes or textures for gripping. Unlike the previous embodiment shown in FIG. 2, the fine resolution travel and dose stops are encoded onto the dose setting dial 47.

[0144] The interaction between surfaces 73a and 52 is similar to a portion of the fine resolution travel adjustment between threads 21 and 20 in syringe 100 in Figure 2. The coarse dose setting interaction between surfaces 53 and 76 is similar to features 18 and 31 of the embodiment of Figure 2.

[0145] The device cover 46 according to various embodiments is shown in FIG. 21 . It includes the other half of the flange 57 and the slot 59 for the dose setting dial 47 . The surfaces 64 and 65 together with the surfaces within the housing 45 provide axial constraint to the dose setting dial 47 internally. The slot 81 on the top surface engages to constrain the rib 50 of the plunger rod 44 in rotation. Since the plunger rod 44 is axially locked when the end of the dose is reached, the rotational locking of the plunger rod 44 by the slot 81 prevents the rotation of the dose setting dial 47 because its spline 71 is rotationally keyed with the marking 51 of the plunger rod 44. Therefore, at the end of the dose, in addition to the plunger rod 44 being axially locked, the dose setting dial 47 is rotationally locked, thereby disabling the device and preventing reuse, even if some amount of undelivered drug 8 remains in the syringe 9 contained in the device 43. At the end of the dose, the window 82 provides visibility for the marking 55 corresponding to the injected dose volume. During dose setting, only the marking 68 corresponding to the dose volume setting is visible to the user through the window 83. Upon receiving the device 43, the user sees "→" in the window 83. The pinhole 85 is used during assembly, as shown in FIG22. A locating pin 85 that is slightly oversized (radially) relative to the pinhole 85 is used to assemble the cover 46 to the housing 45. The locating pin 85 can also be incorporated as a post and molded into the cover 46 or housing 45.

[0146] The operation of the device for setting and delivering a 0.2 ml dose is shown in FIG. 23 . The device received by the user is shown as “a”. “→” is visible in window 83. The corresponding plunger rod 44 axial position is shown as “86”. The user rotates the dial 47 in the direction indicated by the “→” mark 68. Once the dose setting dial is rotated by angle 74, the dose volume is now set to “0.2” ml (depicted in “b”). The corresponding plunger rod 44 axial position 87 is the dose start position. Once the delivery catheter, such as a needle, is at the injection site, the user uses the disk 48 to depress the plunger rod 44 until the plunger rod 44 cannot translate further; this is the dose end position depicted by 88. In this position, the mark 55 is also visible in the window 82, thereby providing a visual dose end indication to the user. At the end of the dose, the marks 68 and 55 are the same dose volume amount. The position of the patient end 49 of the plunger rod 44 at the dose start 87 'and the dose end 88 'is also shown. The axial position difference between 88 and 87 and between 88' and 87' is the same and represents the injection stroke of the dose set by the user, in this case 0.2 ml. The distance traveled between the plunger rod 44 position 86 and position 87 is a fine resolution stroke that helps overcome the static friction of the plunger stop 7. This stroke is the same as 75 shown in Figure 19. In some cases, this fine resolution stroke can also help to priming the delivery catheter to minimize the risk of underdosing.

[0147] FIG. 24 illustrates the operation of the device for setting and delivering a 2.0 ml dose according to various embodiments. Even when the dose is set to 2.0 ml, the corresponding dose start position 87 is the same as when the 0.2 ml dose is set; this is also true for all other dose volumes in between. The dose end position corresponding to the 2.0 ml dose is indicated by 89, and the corresponding position of the patient end of the plunger rod is 89'. The axial difference between 89 and 87 and 89' and 87' is the injection stroke of the 2.0 ml dose in the syringe 9.

[0148] Figure 25 also shows the fine resolution travel to overcome the stiction (and potential priming) of the plunger stop 7. The front and rear views (housing not shown) show how rotation of the dose setting dial 47 moves the marking 51 from 75a to 75b, resulting in a higher resolution of the axial travel 75 (as shown in Figure 19).

[0149] The cross-sectional view in Figure 26 shows the device operation (dose start and dose end) of delivering exemplary 0.2 ml dose and 2.0 ml dose according to various embodiments. When setting a 0.2 ml dose, the plunger rod 44 mark 51 and the beam 54 are longitudinally aligned with the dose end position 76 corresponding to the 0.2 ml dose volume. The plunger rod 44 position is 87 here. When the user presses the plunger rod 44, the plunger rod 44 is axially translated until the stop surface 53 reaches the dose end position 76. At the same time, the beam 54 deflects onto the surface 79. The surface 90 of the beam 54 is axially constrained by the surface 78 in the non-patient direction. The user rotates the dose setting dial 47 to set a 2.0 ml dose until the rotational position corresponding to the dose end position 76 of the 2.0 ml dose is longitudinally aligned with the stop surface 53 of the plunger rod 44.

[0150] In order to protect the syringe 9 incorporated into the device, it may be necessary to include a cover. In addition, in order to minimize the risk of needle stick injuries and comply with regulations (or facilitate injection at home), it is desirable to incorporate a safety mechanism to protect the needle after use. Figure 27 shows an exemplary cover 91. The syringe cover 91 can be an extension of the housing 45, with a diametrically opposed window 94 to enable the user to check the medicine in the syringe 9 before injection. The needle safety clip 92 pivots around the hinge 95. When the user receives the device with the enclosed medicine, the needle safety clip is aligned as shown in "a". When the cap 93 is removed (as shown in "b"), the elastic beam 98 moves the needle safety clip 92 along the direction 99. Surface 96 ensures that the insertion angle of the needle 97 is perpendicular to the injection site to ensure the correct depth of the exposed needle insertion. Once the injection is fully applied and the device is removed from the injection site, the user can push the needle safety clip 92 along the direction 99' until it is locked with the needle 97 (shown in "c"). The tip of the needle 97 is now fully loaded in the safety clip 92. The latch 100 shown in FIG. 28 captures the needle 97 to prevent exposure to a used needle 97 .

[0151] Different from the syringe 100 shown in Fig. 2, syringe 43 comprises the sequential deployment of fine resolution and coarse resolution.The syringe 43 described in the text first relates to higher resolution, and then is the various dosage levels (coarse resolution) limited by dosage end position 76.Syringe 43 is also illustrated as having 10 dosage volume levels in this article.Yet, comprise being less than 10 or be more than 10 dosage levels and be included in the scope of the present disclosure.

[0152] According to various embodiments, the coarse resolution can be deployed before the fine resolution of the plunger rod 44 travels. This is relevant in applications where the delivery catheter has a large dead zone, for example, for delivery using a catheter tube, the dose volume is very small relative to the volume required to irrigate the catheter. In this case, when the dose setting dial, such as 47, is set to the irrigating position, the dose end position 76 (whose distance corresponds to the stroke required for the irrigating volume) is longitudinally aligned with the stop surface 53 of the plunger rod 44. This irrigating stroke is a coarse resolution. At the end of the irrigating stroke, the beam 54 is not locked. There is also no spline 71, allowing the dose dial 47 to be rotated at the end of the irrigating to set the desired dose volume. The axial position of the dose end position 76 for small doses provides fine resolution.

[0153] Likewise, embodiments are envisioned where it is desired to deliver several equal or unequal volumes sequentially. This can be achieved by removing the splines 71 in the dose setting dial 47 in the syringe 43, which are removed to enable sequential delivery of several equal or unequal volumes.

[0154] The various embodiments described above have fine and coarse resolutions encoded into the dose setting dial 47. According to various embodiments, a syringe 101 is shown in FIG. 29 where fine and coarse resolutions are encoded onto the plunger rod 102 and the stop surface opposite to embodiment 43 is on the dose setting dial 103.

[0155] The syringes 100 and 43 discussed above can have fine and coarse resolutions for dose volume and plunger rod stroke encoded on the dose setting dial. Alternatively, fine and coarse resolutions for dose volume and plunger rod stroke can be encoded on the plunger rod, as described below with respect to the syringe 101 shown in Figure 29. The syringe 101 may include a plunger rod assembly attached to the syringe 9. The plunger rod assembly may include a plunger rod 102, a dose setter 103 (also referred to herein as a dose setting dial 103), a cover 104, a housing 105, a dose end barrel 106, a disk 107, and a window cover 108. The embodiment shown includes a pre-filled syringe 9 filled with an injectable drug 8, which is closed by an elastic plunger stop 7. The syringe has a pre-attached (fixed) needle 97 as a delivery conduit. The filled syringe is fixed to the device using a clip 14 and an elastic x-ring 15. Embodiment 101 shows delivery of a minimum of 0.2 ml and a maximum of 2.0 ml in 0.2 ml increments for a total of 10 dose volume levels.

[0156] The plunger rod 102 of the embodiment in FIG. 29 includes a patient end 111p and a non-patient end 111np (see FIG. 30 ). The user axially depresses the disc 111np to administer the dose. The plunger rod 102 includes a cylindrical fine resolution plug 109 and a plurality of plugs 110 corresponding to different dose volumes that can be set and injected using the device 101. Plug 110a corresponds to the lowest deliverable dose volume, and plug 110c corresponds to the highest deliverable dose volume. Axial slots 112d and 112a are also shown in FIG. 30 , both of which help prevent the plunger rod 102 from rotating during device operation. Slots 112b and 112c help improve the manufacturability of the plunger rod 102. The surface 110s of the plug 110 is related to the end of the dose. The surface 100l of the plug 110 is related to the axial locking of the plunger rod 102 in the non-patient direction after the end of the dose. FIG. 31 shows a modification of the plunger rod 102 within the scope of the device 101. The fine resolution peg 109a may have a flat surface, and the patient end 111p-a of the plunger rod 102 may have a flat surface that contacts the plunger stop 7 (as shown in FIG. 31 ) compared to 111p on the plunger rod 102. This end of the plunger rod may have other modifications to engage the plunger stop 7.

[0157] According to various embodiments, features of the dose setting dial 103 are detailed in FIG. 32 . The dose setting dial 103 comprises a rotatable body comprising a first stopper having a surface 118a defining a dose delivery start position of the plunger rod 102 and a second stopper having a surface 122a defining a dose delivery end position of the plunger rod 102. The dose setting dial 103 may comprise three sections - user contact and dose setting 113, dose volume reference 114 and end of dose device 115. Indicia 116 are printed on the cylindrical portion 114 to provide a visual aid to the user of the dose volume to be set. The dose setting dial 103 has an axial cavity 117 in which the plunger rod 102 is placed. The end of dose device 115 comprises a portion of a cylinder 114s having features on the cylindrical surface extending radially towards the axis of the dose setting dial 103. Through side slots 118 and 119 are present on the cylinder 114s. Slot 118 engages the fine resolution peg 109 (or 109a). Surface 118a contacts the surface on the peg 109 on its non-patient side. Slot 119 is divided by beam 120 into a primary end-of-dose slot 121e, a dose start slot 121s and a secondary end-of-dose slot 122. When the user selects and sets a dose volume for injection, the peg 110 corresponding to the selected dose volume on the plunger rod 102 is longitudinally aligned with the slot 121e. Except for the lowest dose volume setting and in all other dose volumes set by the user, the peg 110 corresponding to the dose just below the user-selected dose is longitudinally aligned with the secondary end-of-dose slot 122. At the end of delivery of the aforementioned user-selected dose volume, the aforementioned peg corresponding to the immediately lower volume is contained and constrained within the secondary end-of-dose slot 122 and is axially constrained by surface 122a. An audible end-of-dose indication is provided by deflecting the beam 120 by a latch corresponding to the selected dose volume just before the dose ends, and then returning to the position shown in FIG. 32 . The user is able to rotate the dose setting dial 103 by manipulating the user contact and dose setting segment 113 . The bottom of the dose setting dial 103 has features for controlling and aligning the dose setting dial. The rectangular groove segments 124 each correspond to a different dose volume that can be set using this embodiment; there is also a rectangular groove segment 124a corresponding to the “→” mark 116 . Groove 124b corresponds to the lowest injection volume (0.2 ml), while groove 124c corresponds to the highest injection volume (2.0 ml) that can be set in the embodiment 101 shown here. The circular groove segment 123 covers the cumulative rotation angle of the dose setting dial 103 between the lowest dose volume and the highest dose volume, i.e., the angle between 123b and 123c. 123a corresponds to the position of the “→” mark 116. The slope 125 enables the beam 138 on the housing 105 to traverse from the inside of the groove starting at 123a to the outside of the groove.The interaction between surfaces 118 and 109 is similar to a portion of the fine resolution travel adjustment between threads 21 and 20 in the embodiment of Figure 2. The coarse dose setting interaction between peg 110 and surface 122a is similar to features 18 and 31 of the embodiment of Figure 2.

[0158] Various views of the beam 120 through the multiple parts forming the dose setting dial 103 are shown in FIG. 33. Surface 120a contacts the plunger rod 102. The protrusion 120-1 on the beam 120 helps to axially constrain the bolt 110 (and therefore the plunger rod 102), which corresponds to the dose volume setting for injection in the non-patient direction. At the end of dose delivery, the bolt 110 corresponding to the dose volume setting and the beam 140 of the dose end barrel 106 are constrained together between the surfaces 120b and 121a. Before the dose is about to end, the ramp feature on 120-1 enables the beam 140 to deflect the beam 120 from "b" to "a". After the bolt 110 corresponding to the dose volume setting has reached the dose end position, the beam 120 relaxes back to the position "a", and the surface 120b locks the retraction of the plunger rod 102. This also produces an audible sound indicating the end of the dose. For all dose volumes except the lowest dose volume, the peg 110 corresponding to the volume just below the set volume is axially constrained between surfaces 120c and 122a at the end of the dose. For all dose volume levels except the lowest settable volume, the peg 110 also deflects the beam 120 from "d" to "c" just before the end of the dose. Once the end of the dose is reached, the peg 110 disengages from the beam 120, allowing it to relax back to position "d", which also produces an audible indication of the end of the dose.

[0159] The cover 104 according to various embodiments is shown in FIG. 34 . The cutout 126 on the cover 104 provides a window only for the dose markings 116 corresponding to the dose volume set by the user. Other markings are obscured by the rest of the cover 104 . The slot 127c provides the user with access to the segment 114 of the dose setting dial 103 , which enables the user to rotate the dose setting dial 103 in order to set the dose volume. To facilitate attachment to the housing 105 , the cover 104 has a plurality of cylindrical posts 128p . The slot 129c allows placement and axial restraint of the disc 107 together with the same slot 129h in the housing 105 . The anti-rotation feature 112a plunger rod tilted slot 131c is used to engage the tab 40 of the clip 14 for attaching the syringe 9 in the same manner as the previously disclosed embodiment. 132c is used to engage the features in the dose end barrel 106 . The dose end barrel is visible through the slot 133 . A semi-circular transverse slot 134c is also incorporated into the cover 104 to aid in attaching a needle shield device.

[0160] The housing 105 according to various embodiments is shown in FIG. 35 . The slot 129h is complementary to the slot 129c to ensure the placement and axial constraint of the disc 107. Similar to the slot 131c, 131h is used to engage one of the tabs 40 of the clip 14 used in the attachment of the syringe 9. During assembly, the tabs 40 of the clip 14 are axially aligned with the axial keyway 135 until they reach the slots 131h and 131c. The clip 14 is twisted until the syringe 9 is tightly fixed to the housing 105. The slot 132h is identical and complementary to the slot 132c on the cover 104. The semicircular transverse slot 134h can help attach the needle shield device. The housing 105 also includes two symmetrical slots 136 that cross each other radially to allow the user to check the drug 8 in the syringe 9 before injection. Features 136a and 136b are formed by the intersection of the slot 136 and the axial keyway 135. The latch beam 137 interacts with the rectangular groove segment 124 on the dose setting dial 103. The surfaces 137a and 137c are angled so that they can transition in and out of the rectangular groove segment 124 depending on the rotation direction of the dose setting dial 103. Each time the latch beam 137 transitions into the rectangular groove segment 124, the user hears an audible sound and provides tactile feedback to the user. When the latch beam 137 is contained within the rectangular groove segment, the user can see the corresponding dose marking 116 through the cutout 126 on the cover 104. For example, when the latch beam 137 is contained within the rectangular groove segment 124a, "→" is visible through the cutout 126. In addition, when the latch beam 137 is contained within the rectangular groove segment 124b, "0.2" is visible through the cutout 126. In addition, in this example, when the latch beam 137 is contained within the rectangular groove segment 124c, "2.0" is visible through the cutout 126. The latch beam 138 is disposed within the circular groove segment 123. Upon first receipt by a user, the latch beam 138 is positioned so that the surface 138a contacts the edge 123a; at the same time, the "→" marking 116 is visible through the cutout 126. The surface 138a ensures that the user's rotational input to the dose setting dial 103 can be applied only in the direction of the ramp 125 to 123b by deflecting the latch beam 138. Once the surface 138a is located at 123b, the "0.2" portion of the marking 116 is visible through the cutout 126. Once located at 123b, the latch beam returns to its undeflected state and the surface 138a prevents the dose setting dial 103 from rotating in the direction 125. The rotation angle between 123a and 123b is the same as the rotation angle between the "→" and "0.2" markings 116. Therefore, the surface 138b prevents the dose setting dial 103 from transitioning from "0.2" to "→". After the transition from “→” to “0.2”, the dose setting dial 103 is allowed to continue to rotate until the surface 138 c contacts 123 c , at which point the “2.0” (maximum deliverable dose for the illustrated embodiment) marking 116 is visible through the cutout 126 .The dose setting dial 103 can be rotated in either direction except when the latch beam 138 is at 123b and 123c. The interaction between the surface 138c and the surface through the edge 123c prevents the transition from the "2.0" to the "→" marking 116 on the dose setting dial 103.

[0161] The end of dose barrel 106 is shown in FIG36 . It comprises two flexible beams 141 with hemispherical pegs which facilitate its rotation within slots 132c and 132h of the cover 104 and housing 105 respectively. A coloured band 139 is printed on the outer cylindrical surface of the end of dose barrel 106; this band 139 provides a visible end of dose indication to the user and is visible to the user through the slot 133 on the cover 104 at the end of the dose. The inner diameter of the end of dose barrel 106 defining the cavity 117 is slightly larger than the segment 115 on the dose setting dial 103 and its outer diameter is smaller than the diameter of the segment 114 of the dose setting dial 103. The end of dose barrel 106 is placed coaxially with the dose setting dial 103. The radially inwardly directed beam 140 is disposed within the slot 121s of the dose setting dial 103 at the start of a dose; this rotatably keys the end of dose barrel 106 to the dose setting dial 103. When the patient-facing side of the plug 110 corresponding to the dose volume set by the user is axially advanced toward 121a of the dose setting dial 103 to deliver the dose, the beam 140 is advanced from the slot 121s to the slot 121e. At the end of the dose, the beam 140 is located between the plug 110 and the surface 121a. This axial translation causes the hemispherical plug on the beam 141 to be released from the slots 132c, 132h and makes the colored band 139 visible to the user through the slot 133 on the cover 104 at the end of the dose. This method of indicating the end of the dose to the user is the same regardless of the injection volume. This provides consistency in conveying information to the user. It is conceivable that the end of dose barrel 106 may alternatively be a portion of a cylinder.

[0162] FIG. 37 shows a disc 107 that can be placed in 129c and 129h. It includes a radially inwardly directed protrusion 143 that is placed in the slot 112d of the plunger rod 102. The protrusion 143 helps prevent rotation of the plunger rod 102. The X-ring 15 is placed around the cylindrical feature 142. When assembled, the plunger rod 102 is placed in the cavity 117.

[0163] 38 are shown with two optically clear window covers 108 attached to slots 136. The window covers 108 are attached to the housing 105 by first placing feature 143 into 136a of the housing 105 and then placing clip 142 into 136b, locking it and covering the slots 136.

[0164] According to various embodiments, in FIG. 39 , the assembled syringe 101 without its cap 104 is shown as 101 ′.

[0165] According to various embodiments, a partial external view of a dose setting using embodiment 101 is shown in FIG. 40 . "a" corresponds to the view when the user receives the embodiment. The axial position of the plunger rod 102 is marked as 144. When the user rotates the dose setting dial 103 to obtain "b" (0.2ml), "c" (0.4ml), "d" (0.8ml), "e" (1.0ml), "f" (1.8ml) or "g" (2.0ml), the axial position of the plunger rod 102 changes to 145. However, this axial position 145 is the same regardless of the dose volume setting for "b", "c", "d", "e" or "f". The axial translation from 144 to 145 is a fine resolution of the plunger rod 102 stroke, followed by a coarse resolution of the plunger rod 102 stroke.

[0166] The relative positions of the plunger rod 102 and the dose setting dial 103 after the initial translation facilitated by the fine resolution stroke are shown in FIG. 41 . The fine resolution stroke is completed when the surface 118a axially advances the peg 109a to the position shown in b'. B' corresponds to a 0.2 ml dose volume starting dose in the illustrated embodiment. Upon further rotation of the dose setting dial 103 as shown in c', the peg 109a is placed behind the maximum inner diameter of the segment 114, but at the same axial position as b'. Continuous rotation of the dose setting dial 103 produces views d', e', f' and g', in which the peg 109a is positioned in its axial position shown in b' and c'.

[0167] Dose setting and dose delivery for 0.2 and 2.0 ml dose volumes are illustrated in FIG. 42 , showing the interaction between the dose setting dial 103 and the plunger rod 102 . The position of the dose setting dial 103 relative to the plunger rod 102 prior to dose setting is shown by “a”. Once the dose setting dial 103 is rotated to set a dose volume of 0.2 ml (shown in “b”), the plunger rod 102 advances from axial position 144 to position 145; this is a fine resolution stroke that helps overcome the static friction of the plunger stop 7 in a controlled manner. At the same time, the peg 110a on the plunger rod 102 is longitudinally aligned with the stop surface 121a. After the user axially advances the plunger rod 102 to administer a 0.2 ml set dose as shown in “c”, the axial position 146 of the plunger rod 102 is the end-of-dose position. Simultaneously with this end-of-dose position 146, the peg 110a is in 121e. Between the patient-facing side of the plug 110a and the stop surface 121a is the beam 140 of the dose end barrel 106 (not shown here for visibility). "d" describes the configuration when a 2.0 ml dose (the maximum dose of the illustrated embodiment) is set. The axial position 145 of the plunger rod 102 at the start of the dose is the same in "d" as in "b". The plugs 110c and 110b on the plunger rod are longitudinally aligned with the stop surfaces 121a and 122a of the dose setting dial 103, respectively. After the user axially advances the plunger rod 102 to administer a 2.0 ml set dose as shown in "e", the axial position 147 of the plunger rod 102 is the dose end position. Simultaneously with this dose end position 147, the plug 110c is in 121e. Between the patient-facing side of the plug 110c and the stop surface 121a is the beam 140 of the dose end barrel 106 (not shown here for visibility). Also, at this point, the plug 110b is axially constrained within the cavity 122 and contacts the surface 122a. The cavity 122 is empty only at the lowest dose volume (0.2 ml in the example shown). For all other doses, the cavity 122 constrains the plug 110 on the plunger rod axially and rotationally, which corresponds to a volume just below the level set for injection.

[0168] In some applications it may be desirable to shield the view of the needle before and after an injection. Embodiment 148 shows one such example in which a needle shield 149 shields the view of the injection needle 97. The needle shield 149 is guided into the track 135 of the housing 105. An end-of-process indicator barrel is contained within the needle shield 149. When the needle shield 149 is pressed against the injection site to insert the shielded needle 97, the needle shield 149 rotates a slide 150 when retracted into the housing 105, which includes a track for guiding features on the needle shield 149. The slide 150 is axially constrained within the slots 134c and 134h. After the injection process is completed, the spring 152 pushes the needle shield 149 to cover the needle 97 and axially locks the needle shield 149 due to the locking features on the slide 150.

[0169] For the purpose of explanation, the above description has been described with reference to specific embodiments. However, the above illustrative discussion is not intended to be exhaustive or to limit the invention to the precise form disclosed. In view of the above teachings, many modifications and variations are possible. The embodiments are selected and described in order to best explain the principles of the technology and its practical application. Thus, other persons skilled in the art can best utilize the technology and various embodiments with various modifications suitable for the intended specific use.

[0170] Although the present disclosure and examples have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art. These changes and modifications should be understood to be included within the scope of the present disclosure and examples defined by the claims. Finally, the entire disclosures of the patents and publications mentioned in this application are incorporated herein by reference.

Claims

1. A plunger rod assembly for a syringe, comprising: main body; a plunger rod at least partially received in the body and including a set of one or more protrusions; as well as A dose setter operably coupled to the plunger rod and comprising a rotatable body comprising a set of one or more stops for engaging the set of one or more projections of the plunger rod at least in accordance with a rotational position of the set of one or more stops relative to the set of one or more projections, wherein a first rotational adjustment device associated with the dose setter is configured to set a first dose increment by adjusting a relative axial position between the rotatable body and the plunger rod, and a second rotational adjustment device associated with the dose setting assembly is configured to set a second dose increment greater than the first dose increment by adjusting a relative rotational alignment between the set of one or more stops and the set of one or more projections.

2. The plunger rod assembly of claim 1, wherein the first rotational adjustment device comprises a rotatable dial that engages the rotatable body and is rotatable relative to the rotatable body to axially translate the rotatable body relative to the main body. 3 . The plunger rod assembly of claim 2 , wherein the rotatable dial includes threads that engage threads of the rotatable body.

4. The plunger rod assembly according to any one of claims 1 to 3, wherein the second rotation adjustment device comprises a second dial for rotating the rotatable body.

5. The plunger rod assembly of claim 4, wherein the rotatable body is translatable relative to the second dial.

6. The plunger rod assembly of claim 4, wherein the rotatable body and the second dial are fixed relative to each other.

7. The plunger rod assembly according to any one of claims 1 to 3, wherein the first rotation adjustment device adjusts the axial position of the rotatable body relative to the main body.

8. The plunger rod assembly according to any one of claims 1 to 3, wherein the first rotation adjustment device adjusts the axial position of the plunger rod relative to the body.

9. The plunger rod assembly of any one of claims 1-3, wherein the plunger rod is rotationally fixed.

10. The plunger rod assembly of any one of claims 1-3, wherein the rotatable body is laterally offset relative to the plunger rod.

11. The plunger rod assembly according to any one of claims 1-3, wherein the rotation axis of the rotatable body intersects the plunger rod.

12. The plunger rod assembly of any one of claims 1-3, wherein the set of one or more protrusions comprises a single protrusion and the set of one or more stops comprises a plurality of stops.

13. The plunger rod assembly of any one of claims 1-3, wherein the set of one or more protrusions comprises a plurality of protrusions and the set of one or more stops comprises a single stop.

14. The plunger rod assembly according to any one of claims 1-3, wherein the first rotational adjustment device includes a narrow slot in the rotatable body that receives a portion of the plunger rod, and the narrow slot includes an inclined surface that axially pushes the portion of the plunger rod received in the narrow slot when the rotatable body rotates.

15. The plunger rod assembly of claim 14, wherein the set of one or more protrusions comprises a single protrusion, and the portion of the plunger rod is the single protrusion.

16. The plunger rod assembly of claim 14, wherein the portion of the plunger rod is disengageable from one circumferential end of the slot such that continued rotation of the rotatable body does not cause further axial translation of the plunger rod relative to the rotatable body.

17. A method of defining a fluid volume using a pre-filled syringe, wherein the pre-filled syringe comprises a plunger rod assembly according to any one of claims 1-16, the method comprising: applying a first rotational input to the dose setter to adjust a relative axial position between at least a portion of the dose setter and the plunger rod to set a first dose increment; as well as A second rotational input is applied to the dose setter to adjust the rotational position of the at least a portion of the dose setter to set a second dose increment, wherein the second dose increment is greater than the first dose increment, wherein the start of the dose axial position of the plunger rod is the same for different dose settings.

18. The method of claim 17, wherein the first rotational input is applied to a rotatable dial that is rotatable and translatable relative to the plunger rod.

19. The method of claim 18, wherein the second rotational input is applied to a second dial that is translationally fixed relative to the plunger rod and rotationally coupled to the at least a portion of the dose setter.

20. The method of claim 17, wherein the first and second rotational inputs are applied to a second dial of the at least a portion of the dose setter.

21. The method of any one of claims 17-20, wherein applying the first rotational input advances the plunger rod axially relative to the barrel of the syringe.

22. The method of any one of claims 17-20, wherein the second rotational input is applied after the first rotational input is completed.

23. The method of any one of claims 17-20, further comprising constraining the dose setter after delivering the dose.

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