Systems and methods for precision dose delivery and packaging of medical devices

Abstract

A drug delivery device that includes a body storing a VEGF antagonist, a plunger rod contacting a stopper inside the body, and a flange coupled to the body. The body is silicone-free. The plunger rod includes protrusions and the flange includes a proximal collar and slots positioned along the proximal collar. The flange is configured such that when the protrusions and slots are misaligned, distal movement of the plunger rod relative to the body is limited upon the protrusions contacting the proximal collar to prime the drug delivery device. The flange is configured such that when the protrusions and slots are aligned, distal movement of the plunger rod relative to the body is limited upon the protrusions extending into the slots to deliver the VEGF antagonist.

Description

Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304SYSTEMS AND METHODS FOR PRECISION DOSE DELIVERY, STERILIZATION, AND PACKAGING OF MEDICAL DEVICESCross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 696,350, filed September 18, 2024, and U.S. Provisional Application No. 63 / 796,227, filed April 28, 2025, each of which is incorporated by reference herein in their entireties.Field of Disclosure

[0002] Aspects of the present disclosure relate to devices, systems, and methods for priming or otherwise configuring a dose delivery device, e.g., a syringe, to promote precision dose delivery, along with systems and methods for sterilizing and / or packaging such dose delivery devices. More specifically, embodiments of the present disclosure relate to devices and methods for loading, storing, transporting, and / or delivering precise doses of a drug substance or other fluid substance. Some embodiments of the present disclosure relate to systems and methods for chemical sterilization (e.g., moist chemical sterilization), including terminal sterilization of dose delivery devices using vaporized sterilant, such as vaporized hydrogen peroxide. Additionally, embodiments of the present disclosure relate to a blister packaging for housing the dose delivery device.

[0003] Various embodiments of the present disclosure further relate to sterilization systems and methods for sterilization. More specifically, some embodiments of the present disclosure relate to systems and methods for chemical sterilization (e.g., moist chemical sterilization) of medical products, including terminal sterilization of drug delivery devices (e.g., pre-filled and packaged syringes) using vaporized sterilant. Additionally, embodiments of the present disclosure relate to systems and methods for monitoring and controlling environments and / or conditions within a sterilization apparatus or process.IntroductionDose Delivery Device and Medicament

[0004] Drug products including fluid drug substances may be deliverable to patients in a variety of ways, including via injection. In many cases, the precision and accuracy of a liquid drug product’s volume is crucial. For example, medical professionals may have an interest in ensuring that an approved or prescribed volume of a drug substance is consistentlyClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 delivered to each patient requiring the drug. Additionally, over- or under-dosing a patient with a drug substance, even slightly, may have an undesired (or even negative) clinical impact on the patient. Moreover, some drug products are prescribed at low volumes (e.g., under 100 pL). At low volumes, human error in preparing and delivering an accurate dose of a drug substance for injection may impact the drug’s efficacy in a patient and the subsequent clinical effect on the patient.

[0005] Additional aspects of fluid drug delivery can complicate the goal of accurate dose delivery via injection. For example, for a correct dose of a drug substance to be dispensed from a device (e.g., a syringe), a corresponding accurate volume of the substance must be loaded into the device. Furthermore, handling, storage, packaging, and / or transportation of loaded devices must not result in inadvertent expulsion of drug substance from the devices. Additionally, prior to administration of a drug substance from a device, the device may need to be primed, e.g., to remove air bubbles and excess drug substance from within the device’s needle and barrel. Incorrectly priming a device may result in expulsion of too much or too little drug substance from the device, which likewise may result in a decreased dose being delivered to a patient, or air bubbles being injected from the device into the patient.

[0006] The present disclosure also addresses needs unmet by prior publications WO 2018 / 232408, published on December 20, 2018; WO 2018 / 224640, published on December 13, 2018; and WO 2018 / 224644, published on December 13, 2018. Further, at least some embodiments of the present disclosure include features that are different than those features disclosed in publication WO 2019 / 118588, published on June 20, 2019. Some features include, for example, a plunger rod including one or more extensions extending distally from an actuation portion of the plunger rod and having hook or clip shaped parts for receipt with side openings of a flange piece. The plunger rod may include a neck having three or more sections, each having a different cross-sectional profile and / or shape relative to one another. Further features may include, for example, a flange piece including a collar having one or more internal grooves for receiving the hook or clip shaped parts of the one or more extensions, thereby allowing the extensions to flex radially-outward from a compressed configuration to an expanded configuration. The flange piece may include an opening configured to receive each of the three or more sections of the neck based on, for example, a rotational arrangement of the plunger rod relative to the flange piece.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0007] A flange piece of the present disclosure may further include one or more movable ribs and / or one or more movable tabs for engaging a syringe body to couple the flange piece to the syringe body. For example, one or more movable ribs may be positioned proximal to a lip and lateral opening of the flange piece for receiving a top flange of the syringe body. The movable ribs may move, deflect, and / or deform in response to receiving the top flange through the lateral opening, and may be configured to apply a distally-directed force onto the top flange to secure the syringe body to the flange piece. By way of further example, the one or more movable tabs may be positioned distal to the lip and lateral opening. The movable tabs may move, deflect, and / or deform in response to the flange piece receiving the syringe body, and may be configured to apply a radially-directed force onto the syringe body to secure the syringe body to the flange piece. It should be appreciated that embodiments of the present disclosure include various other features shown and described herein that are different than those features disclosed in publication WO2019 / 118588.Methods of Treatment & Administration of Medicament

[0008] Neovascular (wet) AMD (nAMD) is a major health issue in aging populations globally. Vision loss in nAMD results from the abnormal growth and leakage of blood vessels in the macula. In elderly patients affected by nAMD, vision loss frequently has an even greater impact, as it substantially reduces the visual compensation of functional impairment by other age-related comorbidities, such as arthritis and osteoporosis. Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macular edema (DME), a manifestation of diabetic retinopathy, is the primary cause of vision loss and blindness in subjects with diabetes and the most frequent cause of blindness in young and middle-aged adults. If left untreated, approximately half of subjects with DME will lose 2 or more lines of visual acuity (VA) within 2 years. Among subjects with diabetes, the prevalence of clinically significant macular edema (CSME) ranges from 2.77% to 7.6%.

[0009] Intravitreally (IVT) administered anti-vascular endothelial growth factor (VEGF) therapies like EYLEA® inhibit neovascular vessel growth and leakage in the retina, and they are currently the standard-of-care for patients with nAMD or DME. They not only maintain visual function but also provide clinically meaningful visual gains. Treatment of nAMD and / or DME is chronic and life-long in most patients to suppress retinal edema and recurrences of choroidal neovascularization (CNV). Although the currently approved IVT anti-VEGF therapies are efficacious and well-tolerated, the need for IVT injections every 4 toClient Ref. 11518WO01Attorney Docket No. 00166-0178-003048 weeks, specifically in the initial phase and during maintenance of treatment, represents a significant burden to physicians, patients, and caregivers. While the procedure is straightforward and relatively easy to perform, capacity issues for ensuring an appropriate injection frequency in order to achieve patient outcomes similar to those seen in the pivotal studies represent an increasing challenge to individual practices and the healthcare system, overall. Moreover, high frequency dosing leads to increased burdens on patients, e.g., to find transportation and miss work. A secondary effect of this burden is a lower probability of non- compliance with the prescribed treatment regimen.

[0010] While the efficacy and safety of currently approved VEGF antagonist therapies have been established for the treatment of nAMD and / or DME, there remains an unmet medical need for the development of therapies with the potential to reduce treatment burden while providing at least similar or even improved visual outcomes over currently available standard-of-care.

[0011] Increasing the molar concentration of VEGF antagonist therapeutic protein in the dosing formulation is a potential way to bring further benefits to subjects with chorioretinal vascular diseases, including DME. A higher dose of aflibercept administered IVT has the potential to prolong the drug’s therapeutic effects. The resulting extension of treatment intervals early after the initiation of treatment to every 12 weeks or 16 weeks would reduce the number of injections in the first treatment year. A potential decrease in injection- related treatment burden and safety events with fewer injections could be a significant contribution to subject care and healthcare services.

[0012] EYLEA (2 mg dose, administered at a concentration of 40 mg / mL, also called intravitreal aflibercept injection [IAI]) is currently approved in the United States (US) for the treatment of nAMD, and is also approved for the treatment of macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR).Packaging of Dose Delivery Device

[0013] Many medical devices are packaged for distribution to healthcare facilities and / or for storage, for example. Once a healthcare provider is ready to use the medical device, the medical device is removed from the packaging and prepped, if necessary, for use on a patient. In order to remove medical devices from packaging, users often need to directly handle the devices and to push, pull, lift, slide, or otherwise directly touch the medical deviceClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 with their hands. In some instances, it may not be desirable to handle the medical devices too much, e.g., for reasons of sterility or to inhibit damage to the medical devices, when removing the medical devices from their packaging.

[0014] For example, syringes, especially pre-filled syringes, may be contaminated when they are handled during removal of packaging, which may j eopardize the sterility of the syringe body, needle, needle attachment, and / or any medicament or other fluid contained within. If the pre-filled syringe is an ophthalmic syringe, handling during removal from packaging may lead to contamination of the syringe and / or medicament or other fluid contained within, which may in turn lead to infectious inflammation of the eye, e.g., intraocular infections, such as post-injection endophthalmitis.

[0015] Additionally, in the case of pre-filled syringes, handling of the syringe may jeopardize dose accuracy, e.g., if the syringe plunger is bumped during removal from the packaging. With ophthalmic syringes, dose accuracy may be more important, because the dose size may be relatively small, e.g., less than or equal to 20 ml, less than or equal to 15 ml, less than or equal to 10 ml, less than or equal to 0.5 ml, or less than or equal to 1 ml. For example, the dose may be less than or equal to 200 pl, less than or equal to 150 pl, or less than or equal to 100 pl. Accordingly, there exists a need for medical device packaging that decreases the amount of direct handling of the medical device, particularly pre-filled ophthalmic syringes, during removal from the packaging and / or provides easier removal of the medical device from the packaging.Systems & Methods of Sterilization

[0016] Chemical sterilization processes, such as processes using ethylene oxide, vaporized hydrogen peroxide, vaporized peracetic acid, and the like, offer many advantages, such as the ability to sterilize a load at relatively low temperatures (e.g., at less than 50 °C), and without the need to enter a deep vacuum (e.g., without decreasing a pressure to below 100 millibars). Such sterilization processes may be particularly useful in the sterilization of medical devices and medical products that are sensitive to extreme temperatures and / or pressures.

[0017] Processes using chemical sterilants include steps to ensure that the sterilant reaches all parts of a load that need to be sterilized, and that after sterilization has taken place, the sterilant is removed from the load to a degree that ensures the safety and efficacy of any products that were sterilized. Removing sterilant from the load may be referred to as aeratingClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 the load. Additionally, sterilization processes may benefit from improvements that reduce the time and resources required to sterilize and aerate / dry a load.

[0018] In particular, the use of vaporized chemicals, such as vaporized hydrogen peroxide, may raise certain challenges. The distribution of vaporized sterilant in a sterilization system, its behavior (e.g., condensation, evaporation, etc.), and its interaction with a sterilization load (e.g., adsorption to materials of the load), may affect its efficacy and how easily it may be removed from the load. Conventional sterilization processes may be less effective for some sterilization loads. For example, material and physical properties of a sterilization load may impact the distribution and movement of vaporized sterilant.Summary

[0019] Disclosed herein are drug delivery devices, methods for treatment and administration using drug delivery devices, packaging for drug delivery devices, and systems and methods for sterilizing packaged drug delivery devices. In some aspects, the techniques described herein relate to a drug delivery device, including: a body storing a medicament, wherein the body is silicone-free; a plunger rod having a proximal portion, a distal portion contacting a stopper inside the body, and a pair of protrusions extending outwards from the proximal portion; and a flange coupled to the body, the flange including a proximal collar and a pair of slots positioned along the proximal collar; wherein the flange is configured such that when the pair of protrusions and the pair of slots are misaligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions contacting the proximal collar to prime the drug delivery device by expelling air or at least a portion of the medicament stored in the body; and wherein the flange is configured such that when the pair of protrusions and the pair of slots are aligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions extending into the pair of slots to deliver the medicament from the body.

[0020] In some aspects, the techniques described herein relate to a drug delivery device, wherein the plunger rod includes a pair of extensions extending distally from the proximal portion, and the flange includes a channel defined by an interior surface and a pair of grooves formed on the interior surface.

[0021] In some aspects, the techniques described herein relate to a drug delivery device, wherein the flange is configured such that the pair of extensions are misaligned withClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 the pair of grooves when the pair of protrusions and the pair of slots are misaligned with one another.

[0022] In some aspects, the techniques described herein relate to a drug delivery device, wherein the interior surface is configured to engage the pair of extensions when the pair of protrusions and the pair of slots are misaligned and the plunger rod translates distally through the channel via a first stroke; and wherein the pair of grooves is configured to receive the pair of extensions when the pair of protrusions and the pair of slots are aligned and the plunger rod translates distally through the channel via a second stroke.

[0023] In some aspects, the techniques described herein relate to a drug delivery device, wherein the flange is configured to compress the pair of extensions radially inwards relative to the proximal portion of the plunger rod upon the interior surface engaging the pair of extensions as the plunger rod translates distally relative to the flange by the first stroke while the pair of protrusions and the pair of slots are misaligned.

[0024] In some aspects, the techniques described herein relate to a drug delivery device, wherein the flange is configured to receive the pair of extensions in the pair of grooves upon the plunger rod rotating relative to the flange to align the pair of protrusions with the pair of slots.

[0025] In some aspects, the techniques described herein relate to a drug delivery device, wherein the pair of extensions are configured to expand radially outwards relative to the proximal portion upon the pair of grooves receiving the pair of extensions as the plunger rod rotates relative to the flange to align the pair of protrusions with the pair of slots.

[0026] In some aspects, the techniques described herein relate to a drug delivery device, wherein the pair of extensions are configured to translate distally through the pair of grooves in response to the plunger rod translating distally relative to the flange by the second stroke to position the pair of protrusions into the pair of slots.

[0027] In some aspects, the techniques described herein relate to a drug delivery device, wherein the flange includes a pair of openings formed in the proximal collar, the pair of openings are configured to at least partially receive the pair of extensions when the plunger rod is coupled to the flange prior to the pair of protrusions contacting the proximal collar to prime the drug delivery device.

[0028] In some aspects, the techniques described herein relate to a drug delivery device, wherein the flange is configured to inhibit proximal and rotational movement of the plunger rod relative to the body while the pair of extensions are received within the pair ofClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 openings; and wherein the pair of extensions are configured to exit the pair of openings upon distal movement of the plunger rod relative to the body to prime the drug delivery device.

[0029] In some aspects, the techniques described herein relate to a drug delivery device, wherein the body and the stopper are silicone-free such that an interior surface of the body and an exterior surface of the stopper each excludes a coating layer that includes silicone.

[0030] In some aspects, the techniques described herein relate to a drug delivery device, wherein the distal portion of the plunger rod includes a neck and a stem that is positioned distally of the neck, the plunger rod includes a cross-sectional shape that varies along a longitudinal length of the neck; and wherein the flange includes an opening that is configured to interface with the neck and the stem to control longitudinal and rotational movement of the plunger rod relative to the flange.

[0031] In some aspects, the techniques described herein relate to a drug delivery device, wherein the neck includes a first portion having a first cross-sectional shape that is configured to permit distal movement of the plunger rod relative to the flange and inhibit rotational movement of the plunger rod relative to the flange when the first portion is received within the opening.

[0032] In some aspects, the techniques described herein relate to a drug delivery device, wherein the neck includes a second portion that is positioned distally relative to the first portion, the second portion having a second cross-sectional shape that is configured to permit distal movement and rotational movement of the plunger rod relative to the flange when the second portion is received within the opening.

[0033] In some aspects, the techniques described herein relate to a drug delivery device, wherein the neck includes a third portion that is positioned distally relative to the second portion, the third portion having a third cross-sectional shape that is configured to permit distal movement of the plunger rod relative to the flange when the third portion is received within the opening and inhibit proximal movement of the plunger rod relative to the flange when the third portion is rotatably misaligned with the opening.

[0034] In some aspects, the techniques described herein relate to a drug delivery device, including: a body containing an aqueous pharmaceutical formulation comprising a VEGF antagonist; a plunger rod having a proximal end, a distal end contacting a stopper inside the body, and a pair of protrusions extending outwards from the proximal end; and a flange coupled to the body, the flange including a proximal collar and a pair of slotsClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 positioned along the proximal collar; wherein the flange is configured such that when the pair of protrusions and the pair of slots are misaligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions contacting the proximal collar to prime the drug delivery device by expelling air or at least a portion of the aqueous pharmaceutical formulation in the body; and wherein the flange is configured such that when the pair of protrusions and the pair of slots are aligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions extending into the pair of slots to deliver the VEGF antagonist from the body.

[0035] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF antagonist includes ranibizumab, bevacizumab, conbercept, pegaptanib, brolucizumab, aflibercept.

[0036] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF antagonist is aflibercept in a concentration of aflibercept of about 114.3 mg / mL.

[0037] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF antagonist is aflibercept and the aqueous pharmaceutical formulation further comprises a stabilizing agent and a buffering agent.

[0038] In some aspects, the techniques described herein relate to a drug delivery device, wherein the stabilizing agent includes one of arginine monohydrochloride, Sucrose, and Polysorbate 20; and wherein the buffering agent includes histidine.

[0039] In some aspects, the techniques described herein relate to a drug delivery device, wherein the body is configured to store a predetermined volume of the VEGF antagonist in a volume from about 150 pL to about 250 pL.

[0040] In some aspects, the techniques described herein relate to a drug delivery device, wherein the aqueous pharmaceutical formulation includes: about 100 mg / ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant.

[0041] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF receptor fusion protein includes two polypeptides that each includes an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0042] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species.

[0043] In some aspects, the techniques described herein relate to a drug delivery device, wherein the aqueous pharmaceutical formulation has a pH of about 5.0 to about 6.8.

[0044] In some aspects, the techniques described herein relate to a drug delivery device, wherein the aqueous pharmaceutical formulation comprises a VEGF receptor fusion protein having a mass ranging between about 2 mg to about 8 mg.

[0045] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF receptor fusion protein includes aflibercept.

[0046] In some aspects, the techniques described herein relate to a drug delivery device, wherein the aqueous pharmaceutical formulation comprises about 114.3 mg / ml of a VEGF receptor fusion protein as the VEGF antagonist, about 50 mM arginine monohydrochloride as the stabilizing agent, and about 10 mM histidine as the buffering agent.

[0047] In some aspects, the techniques described herein relate to a drug delivery device, wherein the aqueous pharmaceutical formulation includes: about 40 mg / ml VEGF receptor fusion protein; about 10 mM sodium phosphate; about 40 mM NaCl; about 0.03% polysorbate 20; about 5% sucrose; and a pH of about 6.2.

[0048] In some aspects, the techniques described herein relate to a drug delivery device, wherein the VEGF antagonist is prefilled within the body during an assembly of the body, the stopper, the plunger rod, and the flange of the drug delivery device such that the drug delivery device is a pre-filled syringe.

[0049] In some aspects, the techniques described herein relate to a packaging for housing a drug delivery device, including: a flexible tray and a removable cover adhered to the flexible tray, wherein the flexible tray includes: an opening; a cavity including a plurality of cavity portions; a plurality of sidewalls at least partially defining the cavity; a base at least partially defining the cavity; and a lip surrounding the opening and extending radially outwards from the cavity to define a periphery of the flexible tray, wherein the removable cover is adhered to the lip; wherein the flexible tray is configured to house the drug delivery device in the cavity with at least a portion of the drug delivery device contained within each of the plurality of cavity portions; and wherein the drug delivery device is a pre-filled syringeClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 including an aqueous pharmaceutical formulation comprising a single dose of about 8 mg or more of a VEGF antagonist.

[0050] In some aspects, the techniques described herein relate to a packaging, wherein the plurality of cavity portions are connected to one another by narrowed portions, and each of the narrowed portions includes a first sidewall, a second sidewall, and a base that are collectively configured to receive at least a portion of a body of the drug delivery device.

[0051] In some aspects, the techniques described herein relate to a packaging, wherein one of the first sidewall, the second sidewall, or the base of each of the narrowed portions includes a geometric feature extending away from the first sidewall, the second sidewall, and the base and projecting into the narrowed portion.

[0052] In some aspects, the techniques described herein relate to a packaging, wherein the geometric feature is configured to abut against the portion of the body of the drug delivery device that is contained within the narrowed portion to position the body away from the first sidewall, the second sidewall, and the base of the narrowed portion.

[0053] In some aspects, the techniques described herein relate to a packaging, wherein the geometric feature is configured to suspend the body of the drug delivery device within the cavity, thereby forming a gap between an exterior of the body and the plurality of sidewalls and the base of the flexible tray.

[0054] In some aspects, the techniques described herein relate to a packaging, wherein the drug delivery device includes a body, a plunger rod, and a flange that are securely disposed inside the plurality of cavity portions and sealed inside the flexible tray by the removable cover closing the opening; and wherein the packaging and the drug delivery device are sterilized.

[0055] In some aspects, the techniques described herein relate to a packaging, wherein the removable cover is permeable to a gaseous sterilant that is configured to sterilize the flexible tray and the drug delivery device disposed inside the cavity during a sterilization of the packaging.

[0056] In some aspects, the techniques described herein relate to a packaging, wherein the flexible tray includes a projection positioned along the base and aligned with one of the plurality of cavity portions, wherein the projection extends outwards from the flexible tray in a direction opposite from the cavity.

[0057] In some aspects, the techniques described herein relate to a packaging, wherein the projection is hollow and open towards the cavity of the flexible tray.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0058] In some aspects, the techniques described herein relate to a packaging, wherein the projection is configurable to be at least partially deformable in response to an application of force on the projection.

[0059] In some aspects, the techniques described herein relate to a packaging, wherein the projection is configured to flex the flexible tray in response to an application of force on the projection, thereby at least partially deforming one or more of the plurality of cavity portions and partially decoupling the drug delivery device from the cavity.

[0060] In some aspects, the techniques described herein relate to a packaging, wherein the projection is dome-shaped and a height of the projection from an apex of the projection to a base of the projection is greater than a distance between the base of the projection and the drug delivery device contained within the cavity and overlying the projection.

[0061] In some aspects, the techniques described herein relate to a packaging, wherein the projection includes a bulbous shape, and a diameter of the projection defines a widest portion of the bulbous shape where the projection meets the base of the flexible tray.

[0062] In some aspects, the techniques described herein relate to a packaging, wherein the projection includes a dome having a widest diameter at the base of the flexible tray, wherein the projection extends directly outwards from the base of the flexible tray such that the widest diameter of the dome is connected at the base.

[0063] In some aspects, the techniques described herein relate to a packaging, wherein the VEGF antagonist that is pre-filled in the drug delivery device includes aflibercept with a concentration of about 114.3 mg / mL.

[0064] In some aspects, the techniques described herein relate to a method of assembling a drug delivery device, including: filling a body of the drug delivery device with a substance; inserting a stopper of the drug delivery device into the body to fluidly seal the substance inside the body; coupling the body with a finger flange of the drug delivery device by inserting a proximal flange of the body into a lateral slot of the finger flange; inserting a plunger rod of the drug delivery device through the finger flange and into the body to an extent such that the plunger rod contacts the stopper; and coupling the plunger rod to the finger flange by inserting an extension of the plunger rod into a lateral opening of the finger flange.

[0065] In some aspects, the techniques described herein relate to a method, wherein filling the body with the substance includes: filling the body to a maximum target fill volume,Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 wherein the maximum target fill volume includes a single dose having a predetermined volume that is less than the maximum target fill volume.

[0066] In some aspects, the techniques described herein relate to a method, wherein inserting the stopper into the body includes: forming a space within the body between the stopper and the substance as the stopper is inserted into the body, wherein the space defines an air pocket.

[0067] In some aspects, the techniques described herein relate to a method, wherein the space includes a headspace volume such that the maximum target fill volume of the substance and the headspace volume of the air pocket are collectively disposed between a distal end of the body and the stopper.

[0068] In some aspects, the techniques described herein relate to a method, wherein the substance includes a VEGF antagonist, the maximum target fill volume is between about 180 pL and about 250 pL, the predetermined volume of the single dose delivered from the drug delivery device is about 90 pL or less, and the body and the stopper are silicone-free.

[0069] In some aspects, the techniques described herein relate to a method, wherein inserting the stopper into the body includes: positioning the stopper near a proximal portion of the body that is adjacent to the proximal flange; and generating a vacuum pressure within the body to reposition the stopper from the proximal portion of the body towards a distal portion of the body that contains the substance, thereby sealing the substance in the body with the stopper.

[0070] In some aspects, the techniques described herein relate to a method, wherein the vacuum pressure generated within the body is to an extent such that the stopper is repositioned to a predetermined location within the distal portion of the body to maintain a maximum target fill volume of the substance that is pre-filled within the body.

[0071] In some aspects, the techniques described herein relate to a method, wherein coupling the body and the finger flange includes: engaging an upper surface of the proximal flange with a pair of ribs of the finger flange and a lower surface of the proximal flange with a lip of the finger flange as the proximal flange is inserted into the lateral slot.

[0072] In some aspects, the techniques described herein relate to a method, wherein the pair of ribs are at least partially deflectable in response to engaging the proximal flange, the pair of ribs being positioned inside the lateral slot of the finger flange.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0073] In some aspects, the techniques described herein relate to a method, wherein coupling the body and the finger flange includes: engaging a side surface of the body with a pair of movable tabs of the finger flange as the proximal flange is inserted into the lateral slot.

[0074] In some aspects, the techniques described herein relate to a method, wherein the pair of movable tabs are at least partially deflectable in response to engaging the body, the pair of movable tabs being positioned outside the lateral slot of the finger flange.

[0075] In some aspects, the techniques described herein relate to a method, wherein inserting the plunger rod through the finger flange and into the body includes: applying an insertion force of about 15 N or less to the plunger rod for positioning a distal end of the plunger rod within the body adjacent to the stopper.

[0076] In some aspects, the techniques described herein relate to a method, wherein inserting the plunger rod through the finger flange and into the body includes: abutting a distal end of the plunger rod against a proximal end of the stopper without coupling the plunger rod to the stopper.

[0077] In some aspects, the techniques described herein relate to a method, wherein inserting the plunger rod through the finger flange and into the body includes: inserting a distal end of the plunger rod into a proximal end of the stopper without coupling the plunger rod to the stopper.

[0078] In some aspects, the techniques described herein relate to a method, wherein coupling the plunger rod to the finger flange includes: deflecting the extension of the plunger rod laterally inwards upon engaging a proximal edge of the finger flange as the plunger rod is inserted distally through the finger flange; and deflecting the extension laterally outwards upon entering the lateral opening of the finger flange as the plunger rod is inserted further distally through the finger flange.

[0079] In some aspects, the techniques described herein relate to a method of sterilizing a packaging assembly housing a drug delivery device, the method including: positioning the packaging assembly inside a sterilization chamber, wherein the drug delivery device housed within the packaging assembly is pre-filled with a VEGF antagonist; sterilizing the packaging assembly by conducting: (a) a primary sterilant exposure that includes: (i) adjusting a pressure in the sterilization chamber to a first sterilization pressure;(ii) injecting at least a first amount of a gaseous sterilant into the sterilization chamber; and(iii) injecting a first amount of a distribution gas into the sterilization chamber to raise the pressure in the sterilization chamber to a first transition pressure that is greater than the firstClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 sterilization pressure; (b) a secondary sterilant exposure that includes: (i) adjusting the pressure in the sterilization chamber to a second sterilization pressure; (ii) injecting at least a second amount of the gaseous sterilant into the sterilization chamber; and (iii) injecting a second amount of the distribution gas into the sterilization chamber to raise the pressure in the sterilization chamber to a second transition pressure that is greater than the second sterilization pressure.

[0080] In some aspects, the techniques described herein relate to a method, wherein each of the primary sterilant exposure and the secondary sterilant exposure comprises: directing the gaseous sterilant through a removable cover of the packaging assembly and into a cavity of the packaging assembly that houses the drug delivery device, wherein the drug delivery device includes a body that is silicone-free and stores the VEGF antagonist.

[0081] In some aspects, the techniques described herein relate to a method, wherein the first sterilization pressure and the second sterilization pressure each includes at least about 500 millibars, and the first transition pressure and the second transition pressure each include at least about 900 millibars.

[0082] In some aspects, the techniques described herein relate to a method, wherein the gaseous sterilant includes vaporized hydrogen peroxide; and wherein the first amount of the gaseous sterilant includes between about 125 grams to about 150 grams of the vaporized hydrogen peroxide, and the second amount of the gaseous sterilant includes between about 50 grams to about 75 grams of the vaporized hydrogen peroxide.

[0083] In some aspects, the techniques described herein relate to a method, wherein prior to sterilizing the packaging assembly, the method includes: conditioning the sterilization chamber by: (i) adjusting the pressure in the sterilization chamber to a conditioning pressure; and (ii) adding a conditioning gas into the sterilization chamber to raise the pressure in the sterilization chamber to at least about 150 millibar greater than the conditioning pressure.

[0084] In some aspects, the techniques described herein relate to a method, wherein the conditioning pressure is between about 450 millibars to about 650 millibars.

[0085] In some aspects, the techniques described herein relate to a method, wherein conditioning the sterilization chamber includes one of a plurality of conditioning pulses.

[0086] In some aspects, the techniques described herein relate to a method, wherein the first transition pressure is at least about 400 millibar greater than the first sterilization pressure, and the second transition pressure is at least about 400 millibar greater than the second sterilization pressure.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0087] In some aspects, the techniques described herein relate to a method, further including: aerating the sterilization chamber by: (i) adjusting the pressure within the sterilization chamber to a first aeration pressure that is less than or equal to the first sterilization pressure; and (ii) adding an aeration gas into the sterilization chamber to raise the pressure in the sterilization chamber to an exhaust pressure that is greater than the first sterilization pressure.

[0088] In some aspects, the techniques described herein relate to a method, wherein the first aeration pressure includes between about 400 millibars to about 500 millibars, and the exhaust pressure includes between about 700 millibars to about 1000 millibars.

[0089] In some aspects, the techniques described herein relate to a method, wherein aerating the sterilization chamber further includes: adjusting the pressure within the sterilization chamber to a second aeration pressure over an exhaust time, wherein the second aeration pressure is equal to or greater than the first aeration pressure.

[0090] In some aspects, the techniques described herein relate to a method, wherein the second aeration pressure is at least 900 millibar, and the exhaust time is at least about 25 minutes.

[0091] In some aspects, the techniques described herein relate to a method, further including: sterilizing the packaging assembly by conducting a tertiary sterilant exposure that includes: (i) adjusting the pressure in the sterilization chamber to a third sterilization pressure; (ii) injecting at least a third amount of the gaseous sterilant into the sterilization chamber; and (iii) injecting a third amount of the distribution gas into the sterilization chamber to raise the pressure in the sterilization chamber to a third transition pressure that is greater than the second sterilization pressure.

[0092] In some aspects, the techniques described herein relate to a method, wherein the third transition pressure is at least about 400 millibar greater than the third sterilization pressure.

[0093] In some aspects, the techniques described herein relate to a method, wherein a total amount of the gaseous sterilant injected into the sterilization chamber during the primary sterilant exposure, the secondary sterilant exposure, and the tertiary sterilant exposure is greater than or equal to about 800 grams.

[0094] In some aspects, the techniques described herein relate to a method of treating or preventing an angiogenic eye disorder, including: administering a single initial dose of about 8 mg or more of a VEGF antagonist that is pre-filled in a first drug deliveryClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 device to an eye of a patient; administering one or more secondary doses of about 8 mg or more of the VEGF antagonist to the eye of the patient by one or more second drug delivery devices that are pre-filled with the VEGF antagonist; and administering one or more tertiary doses of about 8 mg or more of the VEGF antagonist to the eye of the patient by one or more third drug delivery devices that are pre-filled with the VEGF antagonist; wherein the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices each include a body storing the VEGF antagonist, a finger flange coupled to the body, and a plunger rod movably coupled to the finger flange for priming the body prior to administering the single initial dose, the one or more secondary doses, and the one or more tertiary doses.

[0095] In some aspects, the techniques described herein relate to a method, wherein the plunger rod of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices includes a protrusion extending outwards from a proximal end of the plunger rod; and wherein the finger flange of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices includes a proximal collar and a slot extending distally from the proximal collar.

[0096] In some aspects, the techniques described herein relate to a method, wherein the protrusion is configured to abut against the proximal collar upon the plunger rod moving distally relative to the finger flange to prime the body; and wherein the protrusion is configured to abut against the slot upon the plunger rod moving distally relative to the finger flange to administer the single initial dose, the one or more secondary doses, and the one or more tertiary doses.

[0097] In some aspects, the techniques described herein relate to a method, wherein the body of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices is silicone-free.

[0098] In some aspects, the techniques described herein relate to a method, wherein the body of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices is a syringe having a maximum volume of 0.5 mL or 1.0 mL.

[0099] In some aspects, the techniques described herein relate to a method, wherein the body of each of the first drug delivery device, the one or more second drug deliveryClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 devices, and the one or more third drug delivery devices includes a stopper that is silicone- free.

[0100] In some aspects, the techniques described herein relate to a method, wherein administering the one or more secondary doses includes: administering each of the one or more secondary doses about 2 weeks to about 4 weeks after an immediately preceding dose from the one or more secondary doses.

[0101] In some aspects, the techniques described herein relate to a method, wherein a time interval for administering each of the one or more secondary doses is based on an indication of the angiogenic eye disorder.

[0102] In some aspects, the techniques described herein relate to a method, wherein administering the one or more tertiary doses includes: administering each of the one or more tertiary doses about 4 weeks, about 8 weeks, or about 12 weeks after an immediately preceding dose from the one or more tertiary doses.

[0103] In some aspects, the techniques described herein relate to a method, wherein the VEGF antagonist includes afhbercept and the single initial dose, the one or more secondary doses, and the one or more tertiary doses have a volume of about 100 pL or less.

[0104] In some aspects, the techniques described herein relate to a method, wherein the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices are each configured to treat or prevent the angiogenic eye disorder by administering doses of aflibercept at an interval and a quantity whereby a clearance of free aflibercept from an ocular compartment in the eye is about 0.3 mL / day to about 0.46 mL / day after intravitreal injection of aflibercept to the eye.

[0105] In some aspects, the techniques described herein relate to a method, wherein a time for the clearance for free aflibercept to reach a lower limit of quantitation (LLOQ) in the ocular compartment of the eye after said intravitreal injection of aflibercept is about 15 weeks.

[0106] In some aspects, the techniques described herein relate to a method, wherein a time for free aflibercept to reach a lower limit of quantitation (LLOQ) in a plasma of the eye after said intravitreal injection of aflibercept is about 3.5 weeks to about 3.8 weeks.

[0107] In some aspects, the techniques described herein relate to a method, further including: administering one or more non-scheduled doses of the VEGF antagonists to the eye of the patient by one or more additional drug delivery devices that are pre-filled with the VEGF antagonist on a pro re nata basis in response to anatomic findings from the eye of theClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 patient; wherein the one or more non-scheduled doses are capped at a minimum dosing frequency of one at least every 2 months to 4 months.

[0108] In some aspects, the techniques described herein relate to a method, wherein the angiogenic eye disorder includes one of age-related macular degeneration (AMD), macular edema (ME), retinal vein occlusion (RVO), diabetic macular edema (DME), neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), pannus, pterygium, vascular retinopathy, and diabetic retinopathy.Brief Description of the Drawings

[0109] The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate various exemplary embodiments and, together with the description, serve to explain principles of the disclosed embodiments. The drawings show different aspects of the present disclosure and, where appropriate, reference numerals illustrating like structures, components, materials, and / or elements in different figures are labeled similarly. It is understood that various combinations of the structures, components, and / or elements in various embodiments, other than those specifically shown, are contemplated and are within the scope of the present disclosure.

[0110] There are many embodiments described and illustrated herein. The described devices and methods are neither limited to any single aspect nor embodiment thereof, nor to any combinations and / or permutations of such aspects and / or embodiments. Moreover, each of the aspects of the described inventions, and / or embodiments thereof, may be employed alone or in combination with one or more of the other aspects of the described inventions and / or embodiments thereof. For the sake of brevity, certain permutations and combinations are not discussed and / or illustrated separately herein.

[0111] FIGS. 1 A-1E depict an exemplary delivery device and components thereof, according to some embodiments of the present disclosure.

[0112] FIGS. 1F-2T depict additional aspects and embodiments of the exemplary delivery device of FIGS. 1A-1E.

[0113] FIGS. 3A and 3B depict an exemplary method of assembling the delivery device depicted in FIGS. 1 A-1E, according to aspects of the present disclosure.

[0114] FIGS. 3C-3F depict an exemplary method of assembling an embodiment of the delivery device depicted in FIGS. 1 A-1E, according to aspects of the present disclosure.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0115] FIGS. 4A-4F depict an exemplary method of using the delivery device depicted in FIGS. 1 A-1E, according to aspects of the present disclosure.

[0116] FIGS. 4G-4J depict an exemplary method of using an embodiment of the delivery device depicted in FIGS. 1 A-1E, according to aspects of the present disclosure.

[0117] FIGS. 4K-4S depict exemplary aspects of plunger rods for use in embodiments of the delivery device depicted in FIGS. 1 A-1E.

[0118] FIGS. 4T-4X depict views of an exemplary neck portion of a plunger rod and opening of a flange piece in embodiments of the delivery device depicted in FIGS. 1 A-1E.

[0119] FIGS. 4Y-4Z depict exemplary aspects of plunger rods for use in embodiments of the delivery device depicted in FIGS. 1 A-1E.

[0120] FIGS. 5A-5C depict another exemplary delivery device according to additional embodiments of the present disclosure.

[0121] FIGS. 6A-6E depict a further exemplary delivery device according to additional embodiments of the present disclosure.

[0122] FIGS. 7A-7F depict an exemplary method of using the delivery device depicted in FIGS. 6A-6E, according to aspects of the present disclosure.

[0123] FIGS. 8A-8E depict a further exemplary delivery device according to embodiments of the present disclosure.

[0124] FIGS. 8F and 8G depict a blocking component of the delivery device depicted in FIGS. 8A-8E according to embodiments of the present disclosure.

[0125] FIGS. 9A-9E depict an exemplary method of using the delivery device depicted in FIGS. 8A-8E, according to aspects of the present disclosure.

[0126] FIGS. 10A-10C depict an exemplary method of assembling the delivery device depicted in FIGS. 8A-8E, according to aspects of the present disclosure.

[0127] FIGS. 10D-10G depict another exemplary method of assembling a variation of the delivery device depicted in FIGS. 8A-8E, according to aspects of the present disclosure.

[0128] FIGS. 11 A-l IE depict an exemplary method of using the delivery device depicted in FIGS. 10D-10G according to aspects of the present disclosure.

[0129] FIGS. 12A-12D depict a close-up view of aspects of the exemplary method depicted in FIGS. 11 A-l IE.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0130] FIGS. 13A and 13B depict a further exemplary delivery device and method of assembling said delivery device, according to additional embodiments of the present disclosure.

[0131] FIG. 14A-14F depict a method of using the delivery device depicted in FIGS. 12A and 12B.

[0132] FIGS. 15A-15B, and 16A-16B depict exemplary plunger rod dials according to further embodiments of the present disclosure.

[0133] FIG. 17 depicts an exemplary plunger rod and dial according to further embodiments of the present disclosure.

[0134] FIGS. 18A and 18B depict a further exemplary plunger rod and dial according to additional embodiments of the present disclosure.

[0135] FIGS. 19A and 19B depict an exemplary rotation lock mechanism according to additional embodiments of the present disclosure.

[0136] FIG. 20 depicts an exemplary plunger rod snap feature according to additional embodiments of the present disclosure.

[0137] FIG. 21 depicts an exemplary plunger rod with a bump feature according to additional embodiments of the present disclosure.

[0138] FIG. 22 depicts exemplary visual feedback features according to some embodiments of the present disclosure.

[0139] FIGS. 23A-23C depict a further exemplary delivery device according to aspects of the present disclosure.

[0140] FIGS. 24A-24E depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.

[0141] FIGS. 25A-25E depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.

[0142] FIGS. 26A-26G depict further exemplary delivery devices and a method of using one such delivery device, according to aspects of the present disclosure.

[0143] FIGS. 27A-27H depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.

[0144] FIGS. 28A-28Z depict further exemplary delivery devices and methods of using said delivery devices, according to aspects of the present disclosure.

[0145] FIGS. 29A-29C depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0146] FIGS. 30-31 depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.

[0147] FIGS. 32-33 depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.

[0148] FIGS. 34-40C depict a further exemplary delivery device and method of using said delivery device, according to aspects of the present disclosure.

[0149] FIGS. 41 A-41D depict exemplary flange pieces according to further embodiments of the present disclosure.

[0150] FIGS. 42A-42C depict an exemplary method of assembling the delivery device depicted in FIGS. 34-40C, according to aspects of the present disclosure.

[0151] FIG. 43 illustrates Mean Change from Baseline (BL) in Central Retinal Thickness (CRT; micrometers) over time through Week 44. Syringes on the X-axis indicate scheduled dose visits. Week 16 data for patients receiving treatment at week 16 are carried forward. LOCF: Patients receiving treatment at week 16 were considered not dry from week 16 onward. Inset box shows changes in CRT between weeks 12 and 20; 24 and 32; or 36 and 44 in the HD and I Al groups.

[0152] FIG. 44 illustrates Median Change from Baseline (BL) in Central Retinal Thickness (CRT; micrometers) over time through Week 44. Syringes on the X-axis indicate scheduled dose visit. LOCF: Patients receiving treatment at week 16 were considered not dry from week 16 onward.

[0153] FIG. 45 illustrates Mean Change from Baseline (BL) in Best Corrected Visual Acuity (BCVA; ETDRS letters) over time through Week 44. Syringes on the X-axis indicate scheduled dose visit. LOCF: Patients receiving treatment at week 16 were considered not dry from week 16 onward.

[0154] FIG. 46 depicts Ocular Treatment Emergent Adverse Events (TEAEs) in the Study Eye Occurring in > 2% of Patients (Pts). Percentages and number of patients out of 53 (n / 53) in HD and IAI groups are shown.

[0155] FIG. 47 depicts Ocular Serious Treatment Emergent Adverse Events (TEAEs) in the Study Eye. Percentages and number of patients out of 53 (n / 53) in HD and IAI groups are shown.

[0156] FIG. 48 depicts a Summary of Intraocular Pressure Events in the HD and IAI Study Groups. Safety analysis set. Percentages are calculated based on N. Percentages and number of patients out of 53 (n / 53) in HD and IAI groups are shown.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0157] FIG. 49 depicts Non-Ocular Treatment Emergent Adverse Events (TEAEs) Occurring in > 2% of Patients. Percentages and number of patients out of 53 (n / 53) in HD and I Al groups are shown.

[0158] FIG. 50 depicts Non-Ocular Serious Treatment Emergent Adverse Events (TEAEs) in the HD and IAI study groups. Percentages and number of patients out of 53 (n / 53) are shown.

[0159] FIG. 51 depicts Hypertension Treatment Emergent Adverse Events (TEAEs) in the HD and IAI study groups. Percentages and number of patients out of 53 (n / 53) in HD and IAI groups are shown.

[0160] FIG. 52 depicts a dosing schedule and does regimen modification (DRM) criteria of PHOTON clinical trial.

[0161] FIG. 53 depicts criteria for dose regimen modifications of PHOTON clinical trial.

[0162] FIG. 54 depicts a CANDELA Clinical Trial Plan and Dosing Schedule according to embodiments of the present disclosure.

[0163] FIG. 55 depicts Proportion of Patients Losing and Gaining Vision (ETDRS letters) from Baseline (BL) at Week 44. Percentages and number of patients out of 53 (n / 53) are shown.

[0164] FIG. 56 depicts Intraocular Inflammation Treatment Emergent Adverse Events (TEAEs) in the Study Eye. Percentages and number of patients out of 53 (n / 53) in HD and IAI groups are shown.

[0165] FIG. 57 depicts Mean Pre-Dose Intraocular Pressure, Change from Baseline in the HD and IAI study groups over time (mmHg). Safety analysis set.

[0166] FIG. 58 provides a perspective view of exemplary packaging, according to an embodiment of the present disclosure.

[0167] FIG. 59 provides a bottom view of exemplary packaging containing a syringe, according to an embodiment of the present disclosure.

[0168] FIG. 60A provides a cross-sectional view of the packaging of FIG. 59 containing a syringe, according to an embodiment of the present disclosure.

[0169] FIG. 60B provides a cross-sectional view of the packaging of FIG. 59 containing a partially ejected syringe while in a flexed configuration, according to an embodiment of the present disclosure.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0170] FIG. 61 provides a top view of exemplary packaging, according to an embodiment of the present disclosure.

[0171] FIG. 62 provides a perspective view of exemplary packaging, according to an embodiment of the present disclosure.

[0172] FIG. 63 provides a bottom view of exemplary packaging containing a syringe, according to an embodiment of the present disclosure.

[0173] FIG. 64 provides a perspective view of exemplary packaging, according to an embodiment of the present disclosure.

[0174] FIG. 65 provides a bottom view of exemplary packaging containing a syringe, according to an embodiment of the present disclosure.

[0175] FIG. 66 provides a bottom view of exemplary packaging containing syringes that are printed according to an embodiment of the present disclosure.

[0176] FIG. 67 provides a top view of exemplary packaging, according to an embodiment of the present disclosure.

[0177] FIG. 68 provides a bottom view of exemplary packaging, according to an embodiment of the present disclosure.

[0178] FIG. 69 provides a perspective view of exemplary packaging, according to an embodiment of the present disclosure.

[0179] FIG. 70 provides a side view of an exemplary packaging, according to an embodiment of the present disclosure. The dashed line identifies the cross-sectional view shown in FIG. 71.

[0180] FIG. 71 provides a cross-sectional view of exemplary packaging, according to an embodiment of the present disclosure. The cross-sectional view is taken from the dashed line shown in FIG. 70.

[0181] FIG. 72 provides a top view of exemplary packaging according to an embodiment of the present disclosure.

[0182] FIG. 73 provides a bottom view of exemplary packaging, according to an embodiment of the present disclosure.

[0183] FIG. 74 provides a perspective view of exemplary packaging according to an embodiment of the present disclosure.

[0184] FIG. 75 provides a side view of an exemplary packaging, according to an embodiment of the present disclosure. The dashed line identifies the cross-sectional view shown in FIG. 76.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0185] FIG. 76 provides a cross-sectional view of an exemplary packaging, according to an embodiment of the present disclosure. The cross-sectional view is taken from the dashed line shown in FIG. 75.

[0186] FIGS. 77A-77B provide perspective views of exemplary packaging according to embodiments of the present disclosure.

[0187] FIG. 78 A is a schematic drawing of an exemplary sterilization system that may be used for sterilization of medical products, such as the exemplary delivery devices according to aspects of the present disclosure.

[0188] FIG. 78B is another schematic drawing of an exemplary sterilization system that may be used for sterilization of medical products, such as the exemplary delivery devices according to aspects of the present disclosure.

[0189] FIG. 78C is a schematic drawing showing an expanded view of a portion of the system shown in FIG. 78A.

[0190] FIGS. 79A-79B are flow diagrams of steps in an exemplary method of sterilizing medical products using vaporized chemicals.

[0191] FIGS. 80A-80B are flow diagrams of steps in an exemplary method of performing a sterilization phase.

[0192] FIG. 81 is a flow diagram of steps in an exemplary method of performing an aeration phase.

[0193] FIG. 82 is a flow diagram of steps in an exemplary method of performing another aeration phase.

[0194] FIG. 83 is a flow diagram of steps in an exemplary method of sterilizing medical products using vaporized chemicals, according to aspects of the present disclosure.

[0195] FIG. 84 is a flow diagram of steps in an exemplary method of conditioning a sterilization apparatus, according to aspects of the present disclosure.

[0196] FIGS. 85A-85B are flow diagrams of steps in an exemplary method of exposing a sterilization load to vaporized sterilant, according to aspects of the present disclosure.

[0197] FIG. 86 is a flow diagram of steps in an exemplary method of aerating a sterilization apparatus, according to aspects of the present disclosure.

[0198] FIGS. 87-90B show sterilization chamber pressure and load temperatures during exemplary sterilization methods.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0199] FIG. 91 is a plot showing a relationship between pressure and movement of a plunger in a prefilled syringe, according to aspects of the present disclosure.

[0200] FIG. 92 is a plot of pressure and temperature within an exemplary sterilization chamber during an exemplary sterilization method, according to aspects of the present disclosure.

[0201] There are many embodiments described and illustrated herein. The present disclosure is neither limited to any single aspect nor embodiment thereof, nor to any combinations and / or permutations of such aspects and / or embodiments. Each of the aspects of the present disclosure, and / or embodiments thereof, may be employed alone or in combination with one or more of the other aspects of the present disclosure and / or embodiments thereof. For the sake of brevity, many of those combinations and permutations are not discussed separately herein.Detailed Description

[0202] Embodiments of the present disclosure may be used in addition to and / or in combination with aspects of International Application No. PCT / US2018 / 021013, filed March 6, 2018; International Application No. PCT / US2018 / 065192, filed December 12, 2018; International Application No. PCT / US2020 / 036200, filed June 4, 2020; International Application No. PCT / US2022 / 071436, filed March 30, 2022; International Application No. PCT / US2022 / 029462, filed May 16, 2022; International Application No. PCT / US2023 / 061946, filed February 3, 2023; International Application No.PCT / US2023 / 015223, filed March 14, 2023; and U.S. Provisional Application No. 63 / 796,157, filed April 28, 2025; each of which is incorporated by reference in its entirety herein.

[0203] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements, but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. The term “exemplary” is used in the sense of “example,” rather than “ideal.” Notably, an embodiment or implementation described herein as an “example” or “exemplary” is not to be construed as preferred or advantageous, for example, over other embodiments or implementations; rather, it is intended reflect or indicate the embodiment(s) is / are one “example,” rather than “ideal.” In addition, the terms “first,”Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304“second,” and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish an element, a structure, a step or a process from another. Moreover, the terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of one or more of the referenced items. Similarly, terms of relative orientation, such as “front side, “top side,” “back side,” “bottom side,” “upper,” “lower,” etc. are referenced relative to the described figures. Additionally, the terms “about,” “approximately,” “substantially,” and the like, when used in describing a numerical value, denote a variation of + / - 10% of that value, unless specified otherwise. It is completed that the terms “about,” “approximately,” “substantially,” and the like, are used interchangeably herein and intended to convey a similar numerical value and / or range of numerical values.

[0204] As used in the present disclosure, the term “sterilization” refers to achieving a level of sterility appropriate for a formulated drug substance or drug product for commercial distribution and use. Such a level of sterility may be defined in, for example, regulatory guidelines or regulations, such as guidelines released by the U.S. Food and Drug Administration. In some embodiments, such a level of sterility may include, for example, a 6- log, 9-log, and / or 12-log reduction in microbial populations of biological indicators placed on an outside or inside surface of a drug product (e.g., an outside surface of a syringe or an inside surface of a blister pack). In other embodiments, such a level of sterility may include, for example, a 9-log or 12-log reduction in microbial populations of biological indicators. Sterilization refers to achieving such an appropriate level of sterility while also achieving a sufficiently low level of residual sterilizing chemicals (e.g., vaporized hydrogen peroxide, ethylene oxide, etc.) for commercial distribution and use. Such a low level of residual sterilizing chemical may also be defined in regulatory guidelines or regulations.

[0205] As used in the present disclosure, the terms “terminal sterilization” and “external sterilization” refer to the sterilization of a drug product and / or drug delivery device in a container or packaging, such as in a primary packaging component, or in both primary and secondary packaging components, suitable for commercial distribution and use.

[0206] As used in the present disclosure, the term “medical product” refers to a product for medical use on a living animal. The term “medical product” includes, for example, drug products, formulated drug substances, medical implants, medical instruments, dose delivery devices, drug delivery devices, or combinations thereof. For example, the term “medical product” may refer to a syringe containing a formulated drug substance, such as a parenteral or an ophthalmic syringe. Other exemplary medical products include, e.g.,Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 suppository applicators and medication, transdermal drug delivery devices, medical implants, needles, cannulas, medical instruments, and any other product requiring sterilization prior to an intended medical use. In some examples, the term “medical product” may refer to one or more of the exemplary dose delivery devices and / or drug delivery devices depicted and described in the present disclosure.

[0207] As used in the present disclosure, the term “formulated drug substance” refers to a composition containing at least one active ingredient (e.g., a small molecule, a protein, a nucleic acid, or a gene therapy medicament) and an excipient, prepared for medical distribution and use. A formulated drug substance may include fillers, coloring agents, and other active or inactive ingredients.

[0208] As used in the present disclosure, the term “drug product” refers to a dosage form that contains a formulated drug substance, such as a finished dosage form for an active ingredient. A drug product may include packaging for commercial distribution or use, such as a bottle, vial, or syringe.

[0209] As used in the present disclosure, the term “vaporized chemical” refers to a chemical that has been converted into a substance that may be diffused or suspended in air. In some instances, a vaporized chemical may be a chemical that has been combined with water and then converted into a substance that may be diffused or suspended in air.

[0210] As used in the present disclosure, the term “fluid” refers to a liquid, semiliquid, vapor, or gas including oxygen, hydrogen, nitrogen, or a combination thereof.

[0211] Embodiments of the present disclosure may be used with any type of fluidcontaining products, such as liquid drug substances, liquid placebos, or other liquids that may be dispensed in a dose form. As used herein, the term “drug substance” may refer to a formulated substance including an active ingredient or ingredients, such as, e.g., small or large molecules, such as pain medications, steroids, or biologies. As used herein, the term “biologic” may refer to a large molecule (e.g., having a size greater than 15 kDa, greater than 30kDa, greater than 50kDa, greater than 75 kDa, or greater than 100 kDa) created in a living system such as a cell. Biologies may include proteins (e.g., antibodies), nucleic acids, large sugars, etc. Unlike small molecules that may have well-defined chemical structures, biologies may have highly complex structures that cannot be easily quantified by laboratory methods. As used herein, the term “drug product” may refer to a volume of a drug substance apportioned into a primary packaging component for packaging, transportation, delivery, and / or administration to a patient.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0212] The term “primary packaging component” refers to a packaging component for a drug product, such as a drug container, that is designed and manufactured to be in direct physical contact with the formulated drug substance. (See, for example, Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologies, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologies Evaluation and Research (May 1999), which is incorporated by reference herein.) Examples of primary packaging components include pre-fillable syringes, Luer syringes, cartridges, and vials made of glass, plastic, other polymers or co-polymers, and / or other materials. In further examples, the primary packaging components may be made of a hybrid configuration in which one or more materials may be combined with one another, including but not limited to, a combination of glass and plastic.

[0213] As used herein, the terms “distal” and “distally” refer to a location (or portion of a device) relatively closer to, or in the direction of, a patient delivery site, and the terms “proximal” and “proximally” refer to a location (or portion of a device) relatively closer to, or in the direction of, a user end opposite a distal location / portion of a device.

[0214] As used herein, the term “body,” when used in reference to a part of a device, may refer to a component of the device suitable for containing a volume of a drug substance. A body may include, e.g., a barrel (such as a syringe barrel), tube, cylinder, or other containing portion of a device. In some embodiments, a body may also include a distal end portion having a nozzle, needle, needle attachment site, and / or distal cap.Dose Delivery Device & Medicament

[0215] Embodiments of the present disclosure may be used with products typically having small dose volumes, such as, e.g., ophthalmic drug products, vaccinations, insulin, etc.. In some embodiments, devices of the present disclosure may be used with drug products including a large molecule, e.g., a molecular weight of 30 kDA or greater. In some embodiments, devices of the present disclosure may be used with drug products including a fragment of a large molecule. For example, in some embodiments, devices of the present disclosure may be used with drug products including an antigen-binding molecule. In some aspects, the antigen-binding molecule may be an antibody or antigen-binding fragment. In some embodiments, devices of the present disclosure may be suitable for use with drug products including ingredients such as, e.g., aflibercept, alirocumab, abicipar pegol, bevacizumab, brolucizumab, conbercept, dupilumab, evolocumab, tocilizumab, certolizumab,Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 abatacept, rituximab, infliximab, ranibizumab, sarilumab, adalimumab, anakinra, trastuzumab, pegfilgrastim, interferon beta- la, insulin glargine [rDNA origin], epoetin alpha, darbepoetin, filigrastim, golimumab, etanercept, antigen-binding fragments of any of the above, or combinations of such binding domains, such as a bispecific antibody to VEGF or angiopoietin-2, among others.

[0216] In some embodiments, devices and aspects of the present disclosure can be used with any therapies for ophthalmic diseases, including for the treatment of patients with Diabetic Eye Disease, post-injection noninfectious Endophthalmitis, Neovascular (Wet) Age- related Macular Degeneration (AMD), Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR). In addition, in some embodiments, devices and aspects of the present disclosure can be used with various other therapies other than ophthalmic diseases including, but not limited to, vaccines, insulin, small dose treatments, or a combination thereof. In particular, large molecule and small molecule antagonists of VEGF and / or ANG-2, such as aflibercept, ranibizumab, bevacizumab, conbercept, OPT-302, RTH258 (brolocizumab), abicipar pegol (a pegylated designed ankyrin repeating protein (DARPin)), RG7716, or fragments thereof and in any concentration. Intravitreal (IVT) administration of therapeutic agents may be an effective treatment for such eye disorders (e.g., macular degeneration, retinal vein occlusion, macular edema, retinopathy, etc.), however, IVT administration includes various challenges such as drug product development, administration procedure and adverse events. For example, providing accurate and precise delivery of small volumes (10-100 pL) requires precise design of container components. Accordingly, inaccuracies in a dosage delivery (e.g., over or underdosing) may provide undesired adverse events or lack of efficacy resulting in unpredictable and variable clinical responses.

[0217] In some embodiments, the medicament or drug substance stored within a drug delivery device of the present disclosure may conform to the US Pharmacopeia (USP) standard 789 (USP789) for particles within a solution.

[0218] In some embodiments, the drug product manufacturing process may include one or more of the following steps: (1) quality control inspection of drug product; (2) identity testing of drug product; (3) storage of drug product in a controlled environment (e.g., at a temperature of less than or equal to approximately 80 degrees Celsius); (4) thawing of drug product; (5) pooling and mixing of thawed formulated drug substance; (6) bioburden reduction filtration; (7) sterilizing filtration; (8) aseptic filling and stoppering of dose deliveryClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 device; (9) visual inspection; (10) time limits; and / or (11) shipping of dose delivery device. It should be appreciated that the manufacturing process may include additional and / or fewer steps than those described above without departing from a scope of this disclosure. Thawing the drug product may include removing one or more bottles from a freezer and thawing the bottles at room temperature. A thaw check may be performed throughout the thawing process as instructed by batch records. Thawing will be complete until no ice is visually present. A thaw time may be measured from when the bottles are removed from the freezer or other storage unit until thawing is complete. Thawed drug products may be held between approximately 2 degrees Celsius and 8 degrees Celsius until further processing and / or use. The thaw duration may be less than or equal to approximately 16 hours. The drug product may be transferred to cold storage (e.g., 2-8°C) after thawing for a hold time until removal from the cold storage before pooling, such as for less than or equal to approximately 36 hours.

[0219] Pooling and mixing of the thawed formulation drug substance may take place within an environment that is under high efficiency particulate air (HEP A) filtered (unidirectional) airflow. Controls for pooling and mixing may include a pooled weight of approximately 9.8 kg to 31.8kg, a mixing duration of approximately 30 minutes + / - 10 minutes, and a mixing speed of approximately 250 rpm + / - 20 rpm. The pooling hold time at ambient storage conditions may include approximately less than or equal to 24 hours from when the drug substance is removed from cold storage before pooling to the start of pooling.

[0220] The bioburden reduction filtration may be performed in an environment under HEPA filtered (unidirectional) airflow in which a pooled drug substance may be filtered using a 0.22 pm filter into a pre-sterilized single-use holding bag. Exemplary time limits for bioburden reduction filtration may include a filter flush volume (weight) of greater than or equal to approximately 90 mL (95.31 g); a flow rate of less than or equal to approximately 0.75 L / min; and a product-filter contact time for bioburden reduction and sterile filtration of less than or equal to approximately 53 hours. Exemplary performance parameters for bioburden reduction filtration may include a pre-BBR (“bioburden reduction”) filtration bioburden of approximately less than or equal to 10 CFU / 100 mL, a pre-use FIT (“filter integrity test”) passing a threshold of greater than or equal to approximately 50 psi, and a post-use FIT passing a threshold of greater than or equal to approximately 50 psi.

[0221] The sterilization filtration may be performed using a redundant sterilizing filer assembly consisting of two 0.22 pm filters. Exemplary process parameters for sterilizingClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 filtration may include a filter flush volume (weight) of greater than or equal to approximately 180 mL per filter to 190 mL per filter (190 g per filter to 95 g per filter); a flow rate of less than or equal to approximately 0.75 L / min (30 rpm); and a product-filter contact time for bioburden reduction and sterile filtration of less than or equal to approximately 53 hours. Exemplary performance parameters may include a pre-sterile filtration bioburden of less than or equal to approximately 10 CFU / 100 mL; a pre-sterile filtration endotoxin of less than or equal to approximately 0.2 EU / mL; a filtration pressure of less than or equal to approximately 25 psi; a post-sterile filtration FIT (bubble point) passing a threshold of greater than or equal to approximately 50 psi; and a pre-sterile filtration solution temperature of greater than or equal to approximately 15 °C. A pre-sterile filtration FIT, the upstream and downstream filters, may be measured for passing a threshold of greater than or equal to approximately 50 psi.

[0222] Aseptic time pressure filing of syringes may be performed in an enclosed / isolated environment under HEPA filtered (unidirectional) airflow. One or more exemplary fill machines may pick up a nest of approximately 100 dose delivery devices (e.g., syringes) from each tub of one or more tubs for placement on a table that is transported through the fill machine for filling and stoppering the syringes. Each of the syringes may be filled with a sterile filtered product and a weight check may be performed by the filling machine, such as for a minimum of approximately 2% of the filled syringes. Any syringes with fill weights outside of a segregation limit may be segregated and rejected for use. Consecutive weight checks may be performed for numerous syringes and the corresponding fill weights may be selectively adjusted until a predetermined number (e.g., at least three) are obtained. After the syringes are filled, stoppers may be inserted into the syringes via vacuum stopper insertion at a predetermined depth to allow for sufficient headspace disposed within the syringes. Once syringe filing, weight check, and stoppering is completed, the syringes may be set aside for visual inspection. The control parameters for aseptic filling and stoppering may include a fill weight between approximately 0.17 g to approximately 0.19 g, a fill duration of less than or equal to approximately 49 hours, and a stopper position within a body of the syringe of approximately 29.0 mm + / - 10.0 mm. As described herein, the filling machine may be configured and operable to selectively locate the stopper within the body of the syringe at the predetermined position noted above by, for example, inserting the stopper into the syringe body via an insertion rod and generating a vacuum pressure within the syringe body to further move the stopper into position during the stoppering process.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0223] As discussed above, a 100% visual inspection may be performed for each of the filled syringes, such as for identifying any defects relating to the particles, container closure, the drug product, and process handling. In some embodiments, a performance parameter that may be used for the visual inspection is in accordance with ASNI / ASQ Z1.4 (acceptance quality limit). Following visual inspection, the syringes may be bulk packaged and stored at approximately 2 degrees Celsius to 8 degrees Celsius prior to shipment for assembly, labeling, and secondary packaging.

[0224] Time limitations may be placed on the drug product manufacturing process, such as a duration from the end of thawing the drug product until the commencement of storage after filling, including after inspection and packaging, which may be referred to herein as a time out of refrigeration (“TOR”). For example, such time limit controls may include a total filter contact time of less than or equal to approximately 53 hours; a bulk TOR (e.g., end of thaw to start of storage) of less than or equal to approximately 139 hours; a DP TOR (e.g., end of thaw to start of storage after inspection) of less than or equal to approximately 201 hours; a post-thaw bulk between 2 °C to 8 °C of less than or equal to 36 hours; and a post-BBR filtration bulk between 2 °C to 8 °C of less than or equal to 36 hours.

[0225] Shipping procedures for packaging and labeling bulk drug products may include various measures, including but not limited to certain transportation modes (e.g., ground transportation via temperature-controlled truck), shipping temperatures between 2 °C to 8 °C, and a maximum shipping duration of approximately 120 hours of continuous movement, such as when consistent shipping temperatures are not maintained. A load configuration during shipping may include a minimum load and a maximum load with respect to a number of bulk PFS contained within each tub, a number of tubs shipped per each shipper, and a total quantity of bulk PFS being transported. For example, a minimum load may include approximately 100 bulk PFS per tub, with approximately 8 tubs per shipper, and a total of approximately 800 bulk PFS. A maximum load may include 100 bulk PFS per tub, with approximately 8 tubs per shipper, and a total of approximately 12,800 bulk PFS.

[0226] In some embodiments, devices and aspects of the present disclosure may provide accurate dose delivery while also providing a container closure system for maintaining the agent in a sterile, stable, and safe condition to increase an intended shelf-life and efficacy of the agent. IVT drug products are primarily presented in glass vials, however, pre-filled syringes offer a more convenient administration by reducing the number of steps required for dose preparation. Preassembling the agent in the devices of the present disclosureClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 may minimize the steps necessary for preparing a dose for delivery to a patient. Product development studies may focus on primary container component characterization, material compatibility with the formulation, formulation stability, fill volume determination, extractable / leachable and terminal sterilization.

[0227] Additionally, careful selection of ancillary components such as disposable syringes and needles, and a detailed administration procedure that includes dosing instructions can ensure successful administration of the product. Despite significant efforts in improving the drug product and administration procedures, ocular safety concerns such as endophthalmitis, increased intraocular pressure and presence of silicone floaters have been reported. Devices and aspects of the present disclosure may provide detailed administration procedures (e.g., priming instructions, dosing instructions, etc.) to ensure successful administration of the agent to a patient to minimize such ocular safety concerns. In some embodiments, devices and aspects of the present disclosure can also be used for cosmetic applications or medical dermatology, such as treatment or diagnosis of allergic responses.

[0228] In some embodiments, devices and aspects of the present disclosure can be used to perform various eye injection procedures, such as, for example, intraocular treatments and surgeries involving an intravitreal injection of a drug product. Devices and aspects of the present disclosure may be used to dispense drug products of varying protein concentration and / or viscosity, including, for example, drug products having a viscosity ranging from about 1 centipoise to about 10 centipoise, from about 2 centipose to about 9 centipose, from about 3 centipose to about 8 centipose, from about 4 centipose to about 7 centipose, or from about 5 centipose to about 6 centipose. Drug products having still other viscosities also are contemplated. Providing a precise dose with a device of the present disclosure may be important given a possible variability in protein concentration or viscosity of a drug product being delivered to a patient. Devices and aspects of the present disclosure may be further used to dispense varying volumes and / or quantities of a drug product, such as, for example, volumes ranging from about 1 pL to about 200 pL, from about 10 pL to about 190 pL, from about 50 pL to about 150 pL, from about 75 pL to about 125 pL, from about 90 pL to about 110 pL, or about 100 pL. Devices of the present disclosure may be configured and operable to require application of a minimum force exceeding a threshold for performing one or more procedures, such as, for example, priming a device, delivering a dosage, and the like. By requiring application of the minimum force, devices of the present disclosure may promote control in administering a consistent dose of a drug product, and promote safety byClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 minimizing inadvertent movement of the device’s components, thereby potentially reducing pain, discomfort, and injury to a patient.

[0229] In some embodiments, once the syringe is filled with the medicament, a stopper may be positioned within the syringe. For example, once the syringe is filled with the medicament, the stopper may be positioned approximately 29.0 mm + / - 10.0 mm from the proximal end of the syringe. In other examples, the stopper may be positioned in a range of about 28.0 mm to about 31.0 mm + / - 10.0 mm from the proximal end of the syringe. As described herein, a position of the stopper relative to the syringe body may be predetermined and / or selectively adjusted using a vacuum pressure that is generated within the syringe body after filling the medicament within the syringe body and prior to assembling of one or more of a plunger rod and a flange piece onto the syringe body.

[0230] As an example, a pre-filled 0.5 mL silicone-free syringe may include a nominal target placement of the stopper within the syringe body (i.e., the stopper height) of approximately 29.0 mm + / - approximately 10.0 mm relative to a proximal end of the syringe body, and a target fill weight for the fluid disposed therein ranging from approximately 0.15 g to approximately 0.25 g, such as, for example, approximately 0.18 g (0.17 mL). A measurement of the stopper placement may be performed during assembly of the pre-filled syringe with an insertion rod moving distally into the syringe body to a depth position ranging between approximately 430 mm to approximately 480 mm, such as, for example, approximately 456 mm + / - 5.0 mm (i.e., in the z-direction), such as with a vacuum pressurization generated inside the syringe body within a range between approximately 50 mbar to approximately 100 mbar, such as, for example, approximately 80 mbar + / - 5 mbar. In other words, vacuum assisted stoppering may be performed during assembly of the pre-filled syringe, in conjunction with the insertion rod advancing the stopper into the syringe body, to accurately position the stopper within the syringe body. In the example, the 0.5 mL silicone- free syringe may include a 0.5 mL silicone-free stopper with the target fill weight of approximately 0.18 g. In some examples, the 0.5 mL silicone-free syringe may include a 0.5 mL long luer lock cap, such as a TELC ® Tip Cap or V-OVS ®. It should be appreciated that a luer lock cap may be configured to twist off a body of the silicone-free syringe, and a tip cap may be configured to snap off the body of a syringe. In the embodiments, the silicone- free syringe includes a luer lock cap. It should be appreciated that the height of the stopper disposed within the syringe body is measured from a proximal (top) end of the syringe, suchClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 as adjacent to a proximal flange of the syringe body, towards the proximal end (i.e., the nondrug product contacting side) of the stopper.

[0231] In some embodiments, the maximum injection force of the syringe may be less than approximately 28 N, such as, for example, in a range between approximately 8 N to approximately 18 N, and by further example in a range from approximately 10 N to approximately U N. The contents of the device may be considered sterile when the sterility of the container is found to meet USP and / or Ph. Eur. Requirements. The endotoxin content may be in the range from less than approximately 0.05 EU / mL to less than 0.15 EU / mL.

[0232] In some embodiments, devices according to the present disclosure may be manufactured and / or otherwise prepared to be completely silicone free, such that a body (e.g., a vial, a syringe, a cartridge, etc.) storing a substance (e.g., a drug, a medicament, etc.) may not include any amounts of silicone, such as along an interior surface defining a lumen of the body. In other embodiments, devices according to the present disclosure may be manufactured and / or otherwise prepared to be substantially (e.g., 90% or greater) silicone free. In further embodiments, devices according to the present disclosure may be manufactured and / or otherwise prepared to include plasma-cured silicone oil or baked-on silicone, such as along the interior surface defining the lumen of the body. In such instances, it should be appreciated that an amount of baked-on silicone is relatively minimal.

[0233] In further embodiments, a maximum injection force of the pre-filled silicone- free syringe with approximately 8 mg of a drug substance, such as a VEGF antagonist (e.g., aflibercept), may include a minimum of approximately 13 N to approximately 14 N, a maximum of approximately 17 N to approximately 18 N, and an average of approximately 15 N to approximately 16 N with a standard deviation of approximately 0.8 N.

[0234] In other embodiments, a delivered volume from the pre-filled silicone-free syringe may include an average delivered volume ranging from approximately 0.08 mL to 0.09 mL with a standard deviation ranging from approximately 0.001 mL to approximately 0.002 mL. In some examples, the silicone-free syringe may be pre-filled with approximately 8 mg of a drug product, such as a VEGF antagonist, with a stoppering pressure ranging from approximately 40 mbar to approximately 50 mbar.

[0235] In further embodiments, a finger flange of the pre-filled silicone-free syringe may be configured to receive a maximum force during assembly with the syringe body. For example, a flange of a syringe body by Gerresheimer (GH) may be configured to receive an average maximum force ranging from approximately 51 N to approximately 53 N with aClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 standard deviation of approximately 4 N. As a further example, a flange of a syringe body by Ompi may be configured to receive an average maximum force of approximately 42 N to approximately 44 N with a standard deviation of approximately 6 N.

[0236] In further embodiments, a tip cap (e.g., needle attachment portion, such as TELC ® Tip Cap) of the pre-filled silicone-free syringe may be configured to receive a torque, such as by twisting / rotating at a rate of approximately 19 rev / minute to approximately 23 rev / minute, for detaching the tip cap from the syringe body during use. For example, a minimum tip cap torque may range between approximately 6 N*cm to approximately 7 N*cm, a maximum tip cap torque may range between approximately 9 N*cm to approximately 10 N*cm, and an average tip cap torque may range between approximately 7 N*cm to approximately 8 N*cm with a standard deviation of approximately 0.5 N*cm.

[0237] In other embodiments, the pre-filled silicone-free syringe may include a dead volume distribution disposed inside the syringe body between a distal end (fluid contacting side) of the stopper and a distal end of the syringe body. For example, a minimum dead volume distribution included within the body of the pre-filled silicone-free syringe may be approximately 0.01 mL, a maximum dead volume distribution may be approximately 0.05 mL, and an average dead volume distribution may be approximately 0.03 mL with a standard deviation of approximately 0.01 mL. Numerous volumes may collectively define the dead volume distribution, including but not limited to, a fill volume, an expelled volume, a total dead volume, a needle dead volume, and a syringe dead volume. In this instance, exemplary volumes measured inside the syringe body may include, for example, a fill volume of approximately 0.17 mL with a standard deviation of approximately 0.001 mL, an expelled volume of approximately 0.13 mL with a standard deviation of approximately 0.01 mL, a total dead volume of approximately 0.03 mL with a standard deviation of approximately 0.11 mL, a needle dead volume of approximately 0.01 mL with a standard deviation of approximately 0.01 mL, and a syringe dead volume of approximately 0.02 mL with a standard deviation of approximately 0.01 mL.

[0238] In some embodiments, a measurement of the stopper and a delivered volume of drug product (e.g., VEGF antagonist) from the pre-filled silicone-free syringe may be selectively determined such that the delivered volume of a dose is relatively independent of a fill volume. For example, when the silicone-free syringe is pre-filled with approximately 174 pL of 8 mg of the drug product (e.g., aflibercept), an average delivered volume may beClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 approximately 0.08 mL with a standard deviation of approximately 0.003 mL. In another example, the average delivered volume may be approximately 0.09 mL with a standard deviation of approximately 0.002 mL. A distribution of the stopper position within the syringe body may include a minimum position ranging between approximately 27 mm to approximately 29 mm, a maximum position ranging between approximately 29 mm to approximately 31 mm, and an average position ranging between approximately 29 mm to approximately 30 mm with a standard deviation of approximately 0.4 mm. A distribution of the delivered volume from the syringe body may include a minimum volume of approximately 0.07 mL, a maximum volume of approximately 0.09 mL, and an average volume of approximately 0.08 mL with a standard deviation of approximately 0.003 mL.

[0239] In some embodiments, a compressed length of the stopper and a delivered volume of the pre-filled silicone-free syringe may be selectively determined and / or adjusted. For example, the pre-filled silicone-free syringe may include a target fill of approximately 0.2 g + / - approximately 0.01 g and a target position of the stopper within the syringe body of approximately 29.0 mm + / - approximately 10.0 mm. In the example, the compressed length of the stopper may include a minimum length of approximately 7.4 mm + / - approximately 0.5 mm, a maximum length of approximately 7.5 mm + / - approximately 0.5 mm, and an average length of approximately 7.5 mm + / - approximately 0.5 mm with a standard deviation of approximately 0.03 mm. The position of the stopper within the syringe body may include a minimum position of approximately 28 mm + / - approximately 10 mm, a maximum position of approximately 30 mm + / - approximately 10 mm, and an average position of approximately 29 mm + / - approximately 10 mm with a standard deviation of approximately 0.1 mm. The deliverable mass of the drug product stored in the syringe body may include a minimum mass of approximately 0.08 g + / - approximately 0.05 g, a maximum mass of approximately 0.09 g + / - approximately 0.05 g, and an average mass of approximately 0.084 g with a standard deviation of approximately 0.002 g.

[0240] In some embodiments, an axial pull-off force for decoupling a luer lock adapter collar from the pre-filled silicone-free syringe may be selectively determined, in which the tip cap (e.g., TELC ® Tip Cap) is coupled to the luer lock adapter collar. In this instance, an instrument (e.g., a chuck) may be inserted between the luer lock adapter collar and a body of the pre-filled silicone-free syringe to remove the luer lock adapter collar from the body. For example, a minimum axial pull-off force may range from approximately 70 N to approximately 100 N, a maximum axial pull-off force may range from approximately 140Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304N to 170 N, and an average axial pull-off force may range from approximately 120 N with a standard deviation of approximately 10 N to approximately 140 N with a standard deviation of approximately 8 N.

[0241] In further embodiments, a fill height of the drug product stored in the prefilled silicone-free syringe may be selectively determined relative to the proximal (top) end of the syringe flange to a bottom of the meniscus. For example, a minimum fill height may be approximately 37.34 mL, a maximum fill height may be approximately 39.22 mL, and an average fill height may be approximately 38.53 mL with a standard deviation of approximately 0.43 mL.

[0242] In further embodiments, the pre-filled silicone-free syringe may be configured to include a seal integrity between the syringe body and the stopper. In this instance, the syringe body may be filled with the drug product (e.g., VEGF antagonist) to a nominal capacity that requires expelling at least a portion of air disposed therein. For example, an axial force applied to the plunger rod may force the stopper distally to generate a pressure of approximately 300 kPa and maintain such pressure for approximately 30 seconds. A minimum force during such application may range from approximately 5 N to approximately 7 N for approximately 30 seconds to approximately 40 seconds, with a maximum force of approximately 5 N for approximately 40 seconds.

[0243] In additional embodiments, a position of the stopper relative to the syringe body of the pre-filled silicone-free syringe and a delivered mass from the syringe body may be selectively determined and / or adjusted relative to one another. In this instance, the position of the stopper within the syringe body may be measured from a proximal end of the syringe flange to the proximal (top) end of the stopper. For example, the position of the stopper may include a minimum position of approximately 27.7 mm, a maximum position of approximately 29.4 mm, and an average position of approximately 28.7 mm with a standard deviation of approximately 0.4 mm. By further example, the delivered mass may include a minimum mass of approximately 0.07 g, a maximum mass of approximately 0.09 g, and an average mass of approximately 0.08 g with a standard deviation of approximately 0.002 g.

[0244] In additional embodiments, a delivered volume of the drug product (e.g., VEGF antagonist) from the pre-filled silicone-free syringe having a target fill volume of approximately 174 pL may include a minimum volume of approximately 0.07 mL, a maximum volume of approximately 0.09 mL, and an average volume of approximately 0.08 mL with a standard deviation of approximately 0.002 mL.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0245] In some embodiments, 0.5 mL pre-filled silicone-free syringes may be packaged in a 100-count nest configuration, as described in detail above. An exemplary syringe filling machine may utilize 0.5 mL standard change parts to handle the 0.5 mL standard nest configuration. In some examples, each of the 0.5 mL syringes may include an inner diameter ranging between approximately 4.5 mm to approximately 4.8 mm, an outer diameter ranging between approximately 6.7 mm to approximately 7.0 mm, and a total length ranging between approximately 66 mm to approximately 69 mm (max). The 0.5 mL stoppers may include a total height ranging between approximately 5.7 mm to approximately 6.3 mm and an outer neck diameter ranging between approximately 4.8 mm to approximately 5.2 mm. It should be appreciated that the outer neck diameter may correspond to a diameter of the stopper at an outer rib of the stopper.

[0246] Dose delivery devices available on the market, such as pre-filled syringes or syringes for use with vials, may not necessarily assist with accurately loading a desired volume of a substance, priming the devices, expelling an excessive volume of drug substance from the devices, and / or removing air bubbles from the devices. In dose delivery devices containing a small volume of a drug substance in particular (e.g., about 500 pL or less, about 300 pL or less, about 250 pL or less, about 200 pL or less, about 150 pL or less, about 100 pL or less, about 50 pL or less, or about 25 pL or less, such as between about 25 pL and about 50 pL, between about 50 pL and about 100 pL, between about 25 pL and about 100 pL, between about 50 pL and about 150 pL, between about 100 pL and about 250 pL, between about 100 pL and about 150 pL, between about 150 pL and about 250 pL, between about 200 pL and about 250 pL, between about 200 pL and about 500 pL, or between about 250 pL and about 500 pL), it may also be difficult to confirm the presence of the correct dose of a drug substance in the device with the naked eye. Currently in the dose delivery device market, and specifically in the syringe market, there is a need for mechanisms that allow a user to set precisely for delivery a small volume of a product in a syringe (e.g., a pre-filled or fillable / refillable syringe), prime the syringe, remove air bubbles from the syringe, and / or confirm or be assured that the dose volume in the syringe is correct. Embodiments of the present disclosure may assist manufacturers, drug product providers, medical professionals, and / or patients with accurately making, filling, or otherwise preparing a dose administration device, priming the device, removing bubbles from the device, confirming the dose, and / or administering a dose from the device to a patient. Moreover, embodiments of the present disclosure may assist in preventing or mitigating errors or variation in device manufacture orClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 use, such as errors or variation in placement of dose lines on devices, variation in device geometry (e.g., variation in syringe neck geometry), variations in component manufacturing tolerance, and / or variation or errors in setting a dose line prior to delivery of a product.

[0247] In some instances, embodiments of the present disclosure may be of particular assistance to individuals who may have difficulty setting doses with precision and accuracy. For example, embodiments of the present disclosure may assist elderly individuals, young children, or persons with physical or mental disabilities in setting accurate doses.

[0248] Described herein are various embodiments of dose delivery devices, and in particular, for syringes. In some instances, embodiments or aspects of embodiments disclosed herein may be used in conjunction with existing syringe body parts to modify off- the-shelf products, which may reduce the development and manufacturing time for the dose delivery devices. In other instances, embodiments or aspects of embodiments disclosed herein may be included in devices during their manufacture. The syringes described herein may be pre-filled or may be fillable / refillable.

[0249] Embodiments of the present disclosure may include syringes having rotating parts, threaded parts, springs, gears, detents, channels, grooves, and the like, that may allow a user to precisely control the movement of priming and dosage delivery elements such as, e.g., plungers and / or stoppers. Such parts may be intended to reduce human error and / or increase accuracy.

[0250] In some embodiments, visualization devices, such as magnifiers, may be provided with, attached to, or otherwise disposed on, delivery devices, in order to help enhance visibility of dose measurement markers on the devices. It is contemplated that aspects of one embodiment (such as sleeves, channels, blocking components, protrusions, detents, threaded parts, grips, visual, tactile, or auditory indicators, etc.) may be combined with aspects of one or more other embodiments, to create various combinations and permutations of features in a single device.

[0251] In some embodiments, devices according to the present disclosure may be depicted as including one type of plunger rod and plunger, or as including a general schematic representation of a plunger rod and plunger. For example, some devices according to the present disclosure may be depicted or described as including, e.g., a plunger rod having a ball-tipped end (e.g., non-threaded), which engages with a stopper such that the plunger rod and the stopper may be attached together. It is contemplated that multiple and / or different configurations of plunger rods and stoppers may be appropriate for each of the embodimentsClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 disclosed herein. For example, in some cases, the aforementioned ball-tipped plunger rod may be used with embodiments disclosed herein. In some embodiments, a plunger rod may not be affixed to a stopper, and instead may be disposed near, next to, or flush against a stopper such that pressure from the plunger rod towards the stopper may push the stopper, but withdrawal, twisting, or other movement of the plunger rod may not cause the stopper to likewise be withdrawn, twisted, or otherwise moved. As another example, in some embodiments, a plunger rod may be affixed to a stopper by threads, a clip, or an adhesive, or may be of a single piece with a stopper (e.g., may have been manufactured in a single mold with a stopper).

[0252] In some embodiments, devices according to the present disclosure may include various cosmetic features relevant to intended users of the devices. For example, devices according to the present disclosure may be manufactured and sold for use with pediatric, elderly, or differently-abled patients. In such cases, devices according to the present disclosure may include child-friendly coloring, cartoon images, or other cosmetic features to appeal to children, or high-contrast coloring, textured surfaces, or other features to enhance ease of identification and / or use. In some cases, devices according to the present disclosure may include lettering, labeling, or other features designed to be easily recognized by the intended users. For example, lettering on a pediatric device or a device for use by a disabled or differently-abled person or an elderly person may have larger, more accessible labeling so that it may be more easily recognized and read by the user(s) of the device. In some embodiments, lettering or labeling may be raised, molded, or embossed. In some embodiments, the drug delivery device (DDD), includes a body; a plunger rod disposed partially inside the body; a protrusion extending from the plunger rod; and a blocking component coupled to a proximal end portion of the body, wherein the blocking component is a flange piece, wherein, when the protrusion is in a first position relative to the blocking component, the blocking component restricts distal movement of the plunger rod to a first stopping point, and when the protrusion is in a second position relative to the blocking component, the blocking component restricts distal movement of the plunger rod to a second stopping point. In an embodiment of the invention, the DDD further includes: a stopper disposed in the body, wherein distal movement of the plunger rod distally moves the stopper; and a drug substance disposed in the body in between the stopper and a distal end of the body, wherein distal movement of the plunger rod to the first stopping point primes the drugClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 delivery device, and distal movement of the plunger rod to the second stopping point dispenses a predetermined volume of the drug substance from a distal end of the device.

[0253] In some instances, moving the protrusion from the first position to the second position includes twisting the plunger rod relative to the blocking component. In an embodiment of the invention, the DDD further includes: a cavity in a proximal side of the blocking component, the cavity sized and configured to receive a portion of the protrusion, wherein when the protrusion is in the second position relative to the blocking component, the protrusion is positioned proximally from the cavity, such that distal movement of the plunger rod moves the protrusion into the cavity; e.g., wherein the cavity is a first cavity, and further includes: a second cavity in a proximal side of the blocking component, the second cavity sized and configured to receive a portion of the protrusion, wherein the first and second cavity are located on opposite sides of a central longitudinal axis of the drug delivery device. In an embodiment of the invention, the plunger rod passes through an opening in the blocking component.

[0254] In some instances, the DDD further includes an actuation portion at a proximal end portion of the plunger rod, wherein the protrusion extends from the actuation portion, e.g., wherein the actuation portion includes a generally cylindrical shape having a diameter greater than a width of the remainder of the plunger rod, wherein the protrusion extends from a side of the generally cylindrical shape, and wherein the actuation portion further comprises: a thumb pad on a proximal end of the actuation portion; and a ring on an exterior surface on the side of the generally cylindrical shape; e.g., further including a proximal collar on the blocking component, wherein the actuation portion partially fits inside the proximal collar; e.g., wherein the plunger rod further includes a pair of extensions protruding distally from the actuation portion and the blocking component (e.g., which includes one or more indents formed along a bottom wall of the blocking component; and wherein a portion of each extension is configured to be received by the one or more indents upon distal movement of the plunger rod relative to the blocking component to allow distal movement of the plunger rod to the second stopping point; or, which includes one or more indents formed along a bottom wall of the blocking component.

[0255] In some instances, a portion of each extension is configured to be received by the one or more indents upon distal movement of the plunger rod relative to the blocking component to allow distal movement of the plunger rod to the second stopping point; or, which includes a pair of internal grooves formed along a sidewall of the blocking component;Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 and wherein a portion of each extension is configured to be received by at least one of the pair of internal grooves upon rotation of the plunger rod relative to the blocking component to expand the extensions radially-outward from a compressed state to a relaxed state) includes a pair of openings; and wherein a portion of each extension is configured to be received by one of the pair of openings in the first stopping point.

[0256] In some instances, the protrusion is a first protrusion, and further includes a second protrusion extending from the plunger rod in a direction opposite to the first protrusion. In an embodiment of the invention, the blocking component is slidably coupled to the body and includes a third cavity and a pair of ribs that extend into the third cavity, wherein the body includes a top flange and the pair of ribs are configured to engage the top flange received in the third cavity; wherein the pair of internal ribs are configured to apply a distally-directed force onto the top flange. In an embodiment of the invention, the blocking component is slidably coupled to the body and includes a pair of movable tabs that are configured to engage the body; and the pair of movable tabs are laterally deflectable upon receiving the body in the blocking component and are configured to apply a radially -inward directed force onto the body. In some instances, the blocking component further includes a pair of finger flanges, and each of the finger flanges includes a textured surface having a predefined pattern that increases a grip of the blocking component.

[0257] In further embodiments, a drug delivery device (DDD) includes a body; a plunger rod having a distal end contacting a stopper inside the body, and a proximal end including an actuation portion with a thumb pad; a plurality of protrusions extending from the actuation portion; and a blocking component disposed on the body, the blocking component including a proximal collar having a plurality of slots.

[0258] In some instances, when the protrusions and the slots are in a first configuration relative to one another, the blocking component restricts distal movement of the plunger rod to a first stopping point, and when the protrusions and the slots are in a second configuration, the blocking component restricts distal movement of the plunger rod to a second stopping point, wherein, in the second configuration, the slots are configured to receive the protrusions upon distal movement of the plunger rod. In some instances, the protrusions and the slots are movable from the first configuration to the second configuration by rotation of the actuation portion about a longitudinal axis in relation to the blocking component, and wherein when the protrusions and the slots are in the second configuration, the protrusions and the slots are not movable to the first configuration; and / or a differenceClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 between the first stopping point and the second stopping point is equivalent to a distance that the stopper must travel to expel a predetermined volume of a drug product from a distal end of the body, wherein the plunger rod is prevented from moving from the second stopping point to the first stopping point.

[0259] In some instances, the plurality of protrusions includes two protrusions disposed symmetrically about the actuation portion; and / or the blocking component further comprises a pair of finger flanges; and / or the drug delivery device is a pre-filled syringe; and / or the drug delivery device is changeable: (a) from a pre-use state to a primed state, by longitudinally moving the plunger rod (e.g., wherein the plunger rod includes a neck disposed distally from the actuation portion, wherein the neck interfaces with an opening in the blocking component to prevent proximal movement of the plunger rod, for example, wherein the neck further interfaces with the opening in the blocking component to prevent movement of the drug delivery device from the delivery state to the primed state) until the plunger rod reaches the first stopping point; (b) from the primed state to a delivery state by rotating the plunger rod in relation to the blocking component until the protrusions and the blocking component are in the second configuration; and (c) from a delivery state to a used state by longitudinally moving the plunger rod until the plunger reaches the second stopping point, wherein the drug delivery device is not changeable from the used state to the delivery state, from the delivery state to the primed state, or from the primed state to the pre-use state. In some instances, when the plunger rod is at the second stopping point, the stopper does not contact a distal end of the body.

[0260] In further embodiments, a drug delivery device includes a body; a plunger rod, including a distal portion contacting a stopper inside the body; a proximal end including a generally cylindrical actuation portion disposed outside of the body; and two protrusions extending from opposite sides of the actuation portion in a symmetrical configuration; and a blocking component coupled to the body, the blocking component including a collar configured to accept a distal part of the actuation portion; and two cavities in the collar having proximally-facing openings, wherein each cavity is configured to accept a distal portion of one of the two protrusions.

[0261] In some instances, the plunger rod is longitudinally movable and rotatable about a longitudinal axis relative to the blocking component, and when the drug delivery device is in a pre-use state, the protrusions and the cavity openings are not longitudinally aligned, and when the drug delivery device is in a delivery state, the protrusions and theClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 cavity openings are longitudinally aligned. In some instances, the blocking component further includes a finger flange, and further includes a ribbed surface on a side of the actuation portion. In some instances, the plunger rod further includes: two extensions protruding distally from the actuation portion; and a plurality of openings in the collar of the blocking component, wherein a portion of each extension is configured to be received by one of the plurality of openings upon distal movement of the plunger rod relative to the blocking component.

[0262] In some embodiments, a substance may be dispensed using a DDD having a plunger rod and a body, by a method including (a) advancing the plunger rod by a predetermined distance into the body until advancement of the plunger rod is resisted by a stop; (b) rotating the plunger rod about a longitudinal axis; and (c) actuating the plunger rod to dispense a predetermined volume of the substance, wherein none of steps (a), (b), and (c) are reversible.

[0263] In some embodiments, the DDD further includes a flange piece having a collar, and advancing the plunger rod and actuating the plunger rod comprise pressing an actuation portion of the plunger rod into the collar of the flange piece; for example, wherein the plunger rod comprises a protrusion, and wherein the collar of the flange piece abuts against the protrusion to resist advancement of the plunger rod. For example, in an embodiment of the invention, wherein rotating the plunger rod comprises twisting an actuation portion of the plunger rod relative to the flange piece, until a protrusion on the plunger rod becomes longitudinally aligned with a cavity in the collar of the flange piece, which may further include advancing the protrusion into the cavity until the protrusion abuts a distal side of the cavity, wherein the predetermined volume of the substance is dispensed when the protrusion abuts the distal side of the cavity. See International patent application publication no. WO2020 / 247686.

[0264] Referring now to FIGS. 1 A-1E, views of a delivery device 1050 and component parts are depicted. Device 1050 includes a body 1060, and a blocking component in the form of a flange piece 1070 with a proximal collar 1072 surrounding an opening 1073 (shown in, e.g., FIGS. 4B-4E), through which a plunger rod 1080 may pass into body 1060. Plunger rod 1080 includes an actuation portion 1082 which may be actuated (e.g., pushed or twisted) to rotate plunger rod 1080, or to move plunger rod 1080 longitudinally into body 1060. Actuation portion 1082 may be sized and configured to fit (e.g., nest or otherwise fit) inside proximal collar 1072.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0265] Device 1050 may be, for example, an injection device, such as a syringe, for dispensing a predetermined volume of a formulated drug substance. In some embodiments, device 1050 may be a pre-filled syringe. For example, a user may receive an assembled and packaged device 1050 ready for use, with a volume of formulated drug substance already disposed between a stopper 1062 in body 1060 and an expulsion end 1064 of body 1060. In some embodiments, an air bubble (not shown) may also be disposed between stopper 1062 and expulsion end 1064. In further embodiments, device 1050 may be a fillable syringe.

[0266] Body 1060 may be any suitable body configured for holding and expelling a predetermined volume of a formulated drug substance. In some embodiments, body 1060 may have, e.g., a hollow cylindrical portion. Body 1060 may be configured to hold any suitable volume of a formulated drug substance for delivering to, e.g., a patient, and (together with other components of device 1050) to expel a predetermined amount of the held volume through, e.g., expulsion end 1064 in a priming step and / or delivery step. In some embodiments, body 1060 may be configured to hold and (together with other components of device 1050) expel a relatively small volume of formulated drug substance (e.g., less than about 100 pl, such as less than about 80 pl, less than about 60 pl, less than about 40 pl, less than about 20 pl, less than about 10 pl, about 95 pl, about 90 pl, about 85 pl, about 80 pl, about 75 pl, about 70 pl, about 65 pl, about 60 pl, about 55 pl, about 50 pl, about 45 pl, about 40 pl, about 35 pl, about 30 pl, about 25 pl, about 20 pl, about 15 pl, about 10 pl, or about 5 pl). Device 1050, together with its other components, may be further configured to minimize a residual volume of the formulated drug substance remaining in body 1060 after delivering the predetermined small volume to the patient. In some embodiments, body 1060 may be prefilled (e.g., prior to completed assembly, packaging, sterilization and / or shipment of device 1050 to users). In some embodiments, stopper 1062 may be configured to hold a predetermined volume of a formulated drug substance inside a cavity of body 1060.

[0267] Flange piece 1070 may be of any suitable size and / or shape to serve as a blocking component in delivery device 1050, to close, partially close, cover, or partially cover an end of body 1060 opposite expulsion end 1064, and / or to support and hold plunger rod 1080 in place inside body 1060. In some embodiments, flange piece 1070 may include a distal collar 1075 configured to engage with body 1060 and hold flange piece 1070 in place in relation to body 1060. For example, distal collar 1075 may include a lip 1071 that may slide under or otherwise in relation to a body flange 1061, to hold flange piece 1070 in place (e.g., to slidably couple flange piece 1070 to body 1060). In alternative embodiments, lipClient Ref. 11518WO01Attorney Docket No. 00166-0178-003041071 of distal collar 1075 may be made of a flexible or semi-flexible material, so that it may snap in place over body flange 1061. In further embodiments, distal collar 1075 or another portion of flange piece 1070 may be adhered to, molded to, or otherwise affixed to, body 1060, or may engage with body 1060 via a friction fit.

[0268] Flange piece 1070 may be or include a blocking component; i.e., part or all of flange piece 1070 may be sized and configured to control movement of plunger rod 1080 by blocking movement of plunger rod 1080 when plunger rod 1080 is in certain configurations relative to flange piece 1070. For example, flange piece 1070 may be configured to control rotational and longitudinal movement of plunger rod 1080, e.g., via opening 1073 (see, e.g., FIGS. 4B-4E) that complements the size and shape of parts of plunger rod 1080 (e.g., neck 1084 and actuation portion 1082, and / or other portions of plunger rod 1080 as shown in FIGS. 4K and 40). As described in further detail herein, flange piece 1070 may be formed of various materials having a minimum strength and / or rigidity which may provide further control of a rotational or longitudinal movement of plunger rod 1080. For example, flange piece 1070 may be configured to resist proximal movement (or “pull back”) of plunger rod 1080 (e.g., to inhibit disassembly of device 1050 by retracting plunger rod 1080) up to a predetermined force based at least in part on a material composition of flange piece 1070. It should be appreciated that flange piece 1070 may be configured such that applying a force exceeding the predetermined force may cause one or more of flange piece 1070 and plunger rod 1080 to break, thereby rendering device 1050 inoperable.

[0269] By way of further example, flange piece 1070 may be configured to resist rotational movement of plunger rod 1080 (e.g., to inhibit inadvertent rotation) up to a predetermined force based at least in part on a material composition of flange piece 1070. Additionally and / or alternatively, flange piece 1070 may be configured to resist distal movement of plunger rod 1080 to control a rate of dosage delivery (e.g., to inhibit inadvertent delivery) based at least in part on a material composition of flange piece 1070. Various other components of device 1050 other than flange piece 1070 may include a material composition providing a frictional interference to inhibit disassembly of device 1050, inadvertent rotation of plunger rod 1080, and / or inadvertent dosage delivery.

[0270] Proximal collar 1072 of flange piece 1070 may be sized and configured to accept part of actuation portion 1082 of plunger rod 1080, while blocking protrusions 1086 of plunger rod 1080 from moving distally past a predetermined point until plunger rod 1080 isClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 rotated to a particular position. As shown in FIGS. 1 A and IB, collar 1072 may be cylindrical; in alternate embodiments, collar 1072 may have any suitable size or shape compatible with actuation portion 1082. Collar 1072 may also include cavities, e.g., slots 1074 into which protrusions 1086 of plunger rod 1080 may be received. Slots 1074 may have proximally-facing openings and may have a depth dimension parallel to a longitudinal axis of device 1050. A number and configuration of slots 1074 may correspond to a number and configuration of protrusions 1086 on plunger rod 1080. In some embodiments, slots 1074 may be disposed about a perimeter of collar 1072 in a radially symmetrical configuration. In further embodiments, collar 1072 may include only one slot 1074. The depth of slots 1074 may correspond to a distance plunger rod 1080 must move in order to push stopper 1062 towards expulsion end 1064, and dispense a predetermined volume of formulated drug substance from body 1060 through expulsion end 1064. Advantageously, the predetermined volume of formulated drug substance that is to be dispensed from body 1060 may be controlled during manufacturing, by, e.g., selecting a particular depth of slots 1074. In some embodiments, device 1050 may be configured such that normal variations in manufacturing of other parts of device 1050 (e.g., body 1060 or plunger rod 1080) may not cause variations in the volume of formulated drug substance that is to be dispensed from body 1060. As such, the predetermined volume may be controlled by simply varying manufacture of flange piece 1070.

[0271] In some embodiments, flange piece 1070 may include one or more flanges 1076, which may be sized and configured to aid a user in holding device 1050 and / or expelling a formulated drug substance from device 1050. In some embodiments, as depicted in FIGS. 1 A-1E, flange piece 1070 may include two flanges 1076 opposite to one another and extending perpendicularly from a longitudinal dimension of device 1050. In some embodiments, flange piece 1070 may include other arrangements of a flange or flanges, such as four flanges, or one circumferential flange extending radially outward from a central longitudinal axis of device 1050. In some embodiments, flange piece 1070 may extend radially outward from a central longitudinal axis of device 1050 farther than a circumference of body 1060. In such embodiments, flange piece 1070 may support device 1050 if device 1050 is placed on a surface, may prevent device 1050 from rolling on a flat surface, and / or may allow device 1050 to be picked up more easily. In still further embodiments, blocking component aspects of flange piece 1070 (e.g., collar 1072) may be separate from flange pieceClient Ref. 11518WO01Attorney Docket No. 00166-0178-003041070, such that delivery device 1050 includes a separate flange piece and blocking component.

[0272] Plunger rod 1080 in general may be rotatable about a central longitudinal axis (e.g., in one direction or in both directions). In some embodiments, rotation of plunger rod 1080 may be accomplished by grasping and / or twisting actuation portion 1082 relative to flange piece 1070 and / or body 1060. In some embodiments, protrusions 1086 may assist a user in grasping and / or twisting actuation portion 1082 relative to flange piece 1070 and / or body 1060, by providing additional surface area that a user may grasp and / or push against to twist actuation portion 1082. In some embodiments, only a part or parts of plunger rod 1080 (e.g., actuation portion 1082 and / or a neck 1084) may be rotatable relative to flange piece 1070 and / or body 1060. In some embodiments, plunger rod 1080 may be configured to rotate relative to flange piece 1070 in response to applying a predetermined twisting force onto actuation portion 1082. A material composition of flange piece 1070 may be determinative of the predetermined twisting force required to rotate plunger rod 1080 relative to flange piece 1070. For example, flange piece 1070 may be formed of various materials having a predetermined rigidity that may generate frictional resistance against plunger rod 1080 to control rotational movement of plunger rod 1080 up to the predetermined force (e.g., to inhibit inadvertent rotation / acci dental twisting of plunger rod 1080). Further, a material composition of flange piece 1070 may provide a frictional tolerance to control a distal translation of plunger rod 1080 up to a predetermined force (e.g., to inhibit inadvertent dosage delivery by device 1050).

[0273] A stem 1081 of plunger rod 1080 may have any thickness and cross-sectional shape suitable for fitting into body 1060, while maintaining sturdiness. For example, in some embodiments, stem 1081 may have as great a thickness, along at least one dimension, as can fit and slide into body 1060. Advantageously, such a thickness may help in preventing unwanted wobbling of plunger rod 1080 relative to the other components of device 1050. In further embodiments, stem 1081 may have a smaller thickness while still maintaining sturdiness (e.g., not bending, breaking, or warping during assembly and / or use of device 1050). In some embodiments, portions of stem 1081 may be configured to allow for plunger rod 1080 to rotate relative to flange piece 1070, whereas other portions of stem 1081 may not (see, e.g., FIGS. 4K-4S).

[0274] Plunger rod 1080 may also include a distal tip 1083 (see, e.g., FIG. ID) sized and configured to push, attach to, or otherwise interface with stopper 1062. Tip 1083 mayClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 have any size or shape suitable to achieve this purpose. In some embodiments, for example, tip 1083 may be sized and configured to clip to stopper 1062 via an opening in stopper 1062. In further embodiments, tip 1083 may have a ball-shape configured to fit into an opening in stopper 1062. In yet further embodiments, tip 1083 may present a flat surface parallel to a proximal surface of stopper 1062, and may be configured to push stopper 1062 distally without attaching to stopper 1062. In further embodiments, tip 1083 may have any shaped surface suitable for pushing stopper 1062 distally.

[0275] In some embodiments, neck 1084 of plunger rod 1080 and opening 1073 of flange piece 1070 may have complementary geometries that restrict the extent and direction that plunger rod 1080 (or a part thereof) may rotate, depending on the specific longitudinal and / or rotational position of plunger rod 1080 relative to flange piece 1070. In some embodiments, actuation portion 1082 of plunger rod 1080 and collar 1072 may also include complementary geometries that control the extent and direction that plunger rod 1080 may move relative to flange piece 1070. For example, rotation and / or longitudinal movement of plunger rod 1080 may be restricted based on priming, preparing, and / or drug delivery steps of a method of using device 1050 (see, e.g., the method described with respect to FIGS. 4A-4F and the additional / al ternative method described with respect to FIGS. 4G-4H and 4I-4J), and the corresponding position of plunger rod 1080 with respect to each step in such methods. For example, plunger rod 1080 may be restricted from being moved out of flange piece 1070 in a proximal direction (e.g., falling out or being pulled out) once device 1050 is assembled. Moreover, plunger rod 1080 may be restricted from rotation about a longitudinal axis before device 1050 is in a “primed” state, and / or after device 1050 is in a “delivery” state. Additionally, longitudinal movement of plunger rod 1080 in the proximal direction (e.g., to “back out” plunger rod 1080), may be restricted after device 1050 is in a “primed” and / or “delivery” state by complementary geometries of neck 1084 of plunger rod 1080 and opening 1073 of flange piece 1070 and / or of actuation portion 1082 of plunger rod 1080 and collar 1072 of flange piece 1070. Advantageously, this may prevent unwanted plunger rod back out in cases where plunger rod 1080 is not held inside body 1060 by, e.g., being affixed to stopper 1062. For example, in some embodiments, plunger rod 1080 may be configured to simply contact or rest against stopper 1062, such that proximal movement of plunger rod 1080 does not move stopper 1062 proximally. In such cases, proximal movement of plunger rod 1080 may be prevented by interaction between complementary geometries of plunger rod 1080 and flange piece 1070. Moreover, interaction between actuation portion 1082 ofClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 plunger rod 1080 and collar 1072 of flange piece 1070 may restrict longitudinal movement of plunger rod 1080 in a distal direction. As an example, plunger rod 1080 may be restricted from moving distally after the “primed” state but before the “delivery” state.

[0276] Upon being moved to the “delivery” state, protrusions 1086 on actuation portion 1082 may be longitudinally aligned with slots 1074 of collar 1072, allowing for distal movement of plunger rod 1080 to dispense a desired volume of a drug substance from body 1060. As such, plunger rod 1080 may include a number and configuration of protrusions 1086 such that each protrusion 1086 may move distally into a slot 1074 when plunger rod 1080 is in a particular position (e.g., a “delivery” state). In some embodiments, one, two, three, or more protrusions 1086 may extend from actuation portion 1082, corresponding to one, two, three, or more slots 1074, respectively. For example, as depicted, two protrusions 1086 may extend from the sides of actuation portion 1082 in a radially symmetrical configuration (corresponding to two slots 1074 in collar 1072). In some embodiments, radial symmetry of multiple protrusions 1086 (and slots 1074) may advantageously allow for protrusions 1086 to fit into slots 1074 in multiple configurations (e.g., depending on whether actuation portion 1082 is twisted in one direction or another). In such embodiments, actuation portion 1082 may be twisted in either direction based on, e.g., user preference, right-handedness or left-handedness, or other factors. In some embodiments, plunger rod 1080 may not be pulled proximally or backed out of body 1060 (e.g., towards actuation portion 1082) after plunger rod 1080 is in a “primed” state and / or after a desired volume of formulated drug substance has been delivered from device 1050 by depression of plunger rod 1080 into body 1060 (e.g., due to a geometry of neck 1084 and / or opening 1073).

[0277] In some embodiments, device 1050 may be configured for ease of use, and may include one or more features that aid a user by providing tactile or visual feedback. For example, one, two, or more components of device 1050 may have contrasting colors or textures. In some embodiments, for example, flange piece 1070 may have a different coloring than plunger rod 1080. As a further example, a single component of device 1050 may have two or more colors or textures. In some embodiments, for example, actuation portion 1082 may include a first color on a distal part of actuation portion 1082, that becomes covered by collar 1072 when device 1050 is primed, and a second color on a second portion of actuation portion 1082, that moves adjacent to collar 1072 when device 1050 is primed, to help indicate to a user that device 1050 has been properly primed. As a further example, in some embodiments, flange piece 1070 may have a different tactile feel than plunger rod 1080Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 and / or body 1060. For example, flange piece 1070 may be relatively rougher or smoother than plunger rod 1080 and / or body 1060. As yet another example, one or more components of device 1050 may have textures that aid in holding, gripping, identifying, or using device 1050. For example, flange piece 1070 may have a slightly rough or raised texture to aid a user in gripping flanges 1076, and / or to prevent a user’s fingers from slipping off of the flanges 1076 during use. In some embodiments, some or all of flange piece 1070 may have a smooth -feeling surface. As another example, actuation portion 1082 of plunger rod 1080 may include a rough or raised texture to aid in gripping and rotating plunger rod 1080. For example, as depicted in FIGS. 1A-1I, 3A-3C, 3E, and 4A-4I, actuation portion 1082 may include circumferential ribbing on its side(s). Actuation portion 1082 may have any suitable number of ribs on its side(s) to provide texture. In further embodiments, actuation portion 1082 may have no ribbing on its side(s).

[0278] In some embodiments, device 1050 or one or more of its components may include colors, labels or markers, which may indicate contents or a status of device 1050, and / or which may direct or provide instructions to a user of device 1050. Examples include one or more labels to indicate a priming position versus a dosage delivery position of the plunger rod, one or more labels to indicate directions in which to rotate or otherwise move plunger rod 1080, and / or one or more labels to indicate an amount of formulated drug substance included in device 1050 (e.g., linear markings on body 1060). Labels may be, e.g., adhered or printed on components of device 1050, or may be embossed on, or molded as a part of, components of device 1050. In some embodiments, one or more textured labels (e.g., embossed or molded on device 1050) may also serve as a textured, rough, or raised surface to aid a user in gripping or using device 1050. One or more exemplary labels may include words, numerals, indicators, and / or symbols (e.g., lines, padlocks, arrows, diagrams, etc.).

[0279] In some embodiments, device 1050 may be configured to make one or more sounds and / or include haptics, such as audible cues, during its use. For example, device 1050 may make a “clicking” noise upon completion of a priming step, or upon rotation of the plunger rod to a position suitable for dispensing a predetermined volume of a formulated drug substance. A “clicking” noise may be produced by, e.g., friction between two or more components (e.g., plunger rod 1080 and flange piece 1070), or a portion of one component contacting another portion (e.g., neck 1084 of plunger rod 1080 contacting opening 1073 of flange piece 1070). In some embodiments, device 1050 may include one or more detents or protrusions on adjacent surfaces of, e.g., plunger rod 1080 and flange piece 1070, which mayClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 produce a clicking sound when contacting one another (e.g., wings 1089 on neck 1084 contacting detents 1078 surrounding opening 1073, as shown in FIGS. 4T-4X). Such sounds may serve as auditory feedback to indicate that a user has reached a particular step in the use of device 1050.

[0280] In some embodiments, device 1050 may include additional features or components to control movement of plunger rod 1080 relative to body 1060. For example, as shown in FIG. IF, flange piece 1070 may include an opening 1079 through which a pin 1077 may be disposed. Pin 1077 may be sized and configured to interface with actuation portion 1082 of plunger rod 1080 (e.g., to slide into an opening (not shown) in actuation portion 1082), such that when pin 1077 is inserted so as to engage actuation portion 1082, plunger rod 1080 may not be moved proximally or distally relative to body 1060 and flange piece 1070. In some embodiments, pin 1077 may also prevent rotational movement of plunger rod 1080 relative to flange piece 1070. Pin 1077 may be inserted upon filling and assembly of a device (e.g., device 1050 shown in FIGS. 1 A and IB), to prevent unwanted movement of plunger rod 1080 prior to its use. In some embodiments, pin 1077 may remain inserted during packaging, transportation, and delivery of device 1050. Before use of device 1050, pin 1077 may be removed or otherwise positioned so that it does not engage actuation portion 1082.

[0281] As shown in FIGS. 1G and 1H, in some embodiments, a protrusion 1093 may be disposed at a distal portion of actuation portion 1082, which may be located inside flange piece 1070 upon assembly of device 1050. An inward lip 1091 of flange piece 1070 may overhang protrusion 1093, such that actuation portion 1082 may not be pulled proximally out of flange piece 1070. In some embodiments, either protrusion 1093, lip 1091, or both may be disposed circumferentially about actuation portion 1082, such that lip 1091 blocks protrusion 1093 regardless of a rotational position of actuation portion 1082 relative to flange piece 1070. Protrusion 1093 and lip 1091 may have squared-off cross-sectional profiles, as shown in FIG. 1G, angled cross-sectional profiles, as shown in FIG. 1H, or any other suitable cross-sectional profiles. In some embodiments, a cross-sectional profile of protrusion 1093, lip 1091, or both may be selected to improve ease of manufacturing (e.g., machining or molding the shape of protrusion 1093 or lip 1091), or may be selected to improve assembly (e.g., insertion of plunger rod 1080 into and partially through flange piece 1070).Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0282] As shown in FIG. II, in some embodiments, actuation portion 1082 may include one or more projections 1096 extending radially outward from an exterior perimeter of protrusion 1093. For example, protrusion 1093 may include a pair of projections 1096 disposed about protrusion 1093 at opposite locations relative to one another. Projections 1096 may include various suitable sizes, shapes, and / or cross-sectional profiles. In some embodiments, projections 1096 may have a circular shape with a rounded exterior profile to facilitate movement of protrusion 1093 within flange piece 1070.

[0283] In the present example, projections 1096 may be positioned along a side of protrusion 1093 that longitudinally aligned with a corresponding side of actuation portion 1082 including protrusions 1086. In other examples, projections 1096 may be positioned along a side of protrusion 1093 that is offset (e.g., not in longitudinal alignment) with the side of actuation portion 1082 including protrusions 1086. Projections 1096 may be formed of various flexible materials, including, for example, a polymer such as plastic, rubber, etc. It should be appreciated that plunger rod 1080 may include additional and / or fewer projections1096 on protrusion 1093, or other portions of actuation portion 1082, than those shown and described herein without departing from this disclosure.

[0284] FIG. 1J depicts a distal end portion of flange piece 1070 including one or more recesses 1097 along an interior surface. Recesses 1097 may be sized and shaped to receive projections 1096 when protrusion 1093 is received within flange piece 1070 and positioned adjacent and / or in contact with lip 1091. It should be appreciated that lip 1091 may be configured to require application of a hydrodynamic force onto plunger rod 1080 to receive projections 1096 and protrusion 1093 distally of lip 1091 and into flange piece 1070, thereby priming device 1050 and inhibiting retraction (e.g., proximal movement) of plunger rod 1080 relative to flange piece 1070. It should be appreciated that by inhibiting removal of plunger rod 1080 after an initial assembly into flange piece 1070, device 1050 may be configured to prevent reuse of device 1050 after an initial use, and / or to prevent inadvertent air intake forming bubbles within device 1050. In the present example, flange piece 1070 may include a plurality of recesses 1097 disposed about the distal end portion in an annular array relative to one another. The plurality of recesses 1097 may be spaced apart from one another about a circumference of flange piece 1070. In some embodiments, flange piece 1070 may include recesses 1097 having varying sizes and / or shapes relative to one another.

[0285] As described in further detail below, a subset of the plurality of recesses1097 may be sized and shaped to receive and allow passage of projections 1096 therethroughClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 upon movement of protrusion 1093 relative to flange piece 1070. A second subset of the plurality of recesses 1097 may be sized and shaped to receive and inhibit passage of projections 1096 therethrough such that protrusion 1093 is restricted from further movement relative to flange piece 1070, as explained in further detail below.

[0286] For example, as shown in FIG. IK, flange piece 1070 includes a pair of widened recesses 1097a positioned about opening 1073 (with plunger rod 1080 received therethrough) at opposite locations relative to one another (e.g., spaced about 180 degrees apart from one another). Flange piece 1070 further includes a pair of narrowed recesses 1097b positioned about opening 1073 at opposite locations relative to one another (e.g., about 180 degrees from one another). A recess 1097a may be positioned about 90 degrees apart from an adjacent recess 1097b, along the circumference of flange piece 1070. Widened recesses 1097a may include a center wall transverse (e.g., perpendicular) to a longitudinal length of flanges 1076 and sidewalls that are angled relative to the center wall. Narrowed recesses 1097b may include a center wall parallel to the longitudinal length of flanges 1076 and sidewalls that are perpendicular to the center wall. It should be appreciated that widened recesses 1097a may form a larger opening for receiving projections 1096 relative to narrowed recesses 1097b. It should further be understood that sidewalls of recesses 1097a, 1097b may have a height that is parallel to a longitudinal length of device 1050.

[0287] In a first configuration seen in FIG. IK, plunger rod 1080 is received through flange piece 1070 and protrusion 1093 is oriented relative to opening 1073 such that projections 1096 are received within widened recesses 1097a. The angled sidewalls of widened recesses 1097a may provide clearance to facilitate movement of projections 1096 out of widened recesses 1097a in response to a rotation of plunger rod 1080 relative to flange piece 1070. In this instance, projections 1096 may move along the angled sidewalls of widened recesses 1097a as protrusion 1093 rotates relative to opening 1073.

[0288] As seen in FIG. IL, projections 1096 may abut against the interior surface of flange piece 1070 defining opening 1073 as protrusion 1093 rotates. Projections 1096 may generate a frictional interference against flange piece 1070 while moving between adjacent recesses 1097. FIG. IM shows protrusion 1093 positioned relative to opening 1073 with projections 1096 aligned with and received in narrowed recesses 1097b. In this instance, plunger rod 1080 may be configured to generate an audible and / or tactile feedback in response to narrowed recesses 1097b receiving projections 1096. For example, a “click” or “snap” noise may be generated in response to a release of pressure applied to projectionsClient Ref. 11518WO01Attorney Docket No. 00166-0178-003041096 by the interior surface of flange piece 1070 when projections 1096 are received in narrowed recesses 1097b. Additionally and / or alternatively, an audible feedback may be produced in response to projections 1096 expanding and striking one or more walls defining narrowed recesses 1097b when received therein.

[0289] It should be appreciated that a frictional interference between projections 1096 and flange piece 1070 may be removed upon receipt of projections 1096 within narrowed recesses 1097b. The sidewalls of narrowed recesses 1097b may provide a physical restriction that inhibits further movement of projections 1096. In this instance, plunger rod 1080 may be fixed relative to flange piece 1070 such that protrusion 1093 is inhibited from further rotation relative to opening 1073 when projections 1096 are received within narrowed recesses 1097b.

[0290] As shown in FIGS. 1N-1P, in some embodiments, plunger rod 1080 may additionally or alternatively include a protrusion 1085 on stem 1081, which may be configured to interact with opening 1073 of flange piece 1070, such that protrusion 1085 may only move distally through opening 1073. A side 1092 of opening 1073 may be angled to allow for distal passage of protrusion 1085, and to block proximal passage of protrusion 1085, as stem 1081 moves through opening 1073. Protrusion 1085 and / or side 1092 may have any suitable shape or configuration to achieve this purpose. In some embodiments, a shape or configuration of protrusion 1085 and / or side 1092 may be selected to improve ease of manufacturing (e.g., machining or molding the shape of protrusion 1085 and / or flange piece 1070).

[0291] In other embodiments, flange piece 1070 may include a movable lever 1071a as seen in FIGS. 1Q-1T. Movable lever 1071a may include a first end 1071b extending outwardly from collar 1072 and a second end 1071c disposed within collar 1072. Movable lever 1071a may be movable (e.g., pivotable) about a rotation pin 1071 d. Second end 1071c may be positioned within opening 1073 such that movable lever 1071a is configured to interact with protrusion 1085 upon receipt of plunger rod 1080 in flange piece 1070. Referring initially to FIG. IQ, plunger rod 1080 may be configured to prime device 1050 by translating stem 1081 distally through flange piece 1070 until encountering movable lever 1071a.

[0292] As seen in FIG. 1R, second end 1071c may abut against protrusion 1085 when movable lever 1071a is in an obstructing position. Second end 1071c may be configured to inhibit translation of plunger rod 1080 relative to flange piece 1070 whenClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 plunger rod 1080 is in a primed position. It should be appreciated that a distance between second end 1071c and protrusion 1085 may define a priming distance for moving plunger rod 1080 to prime device 1050. Movable lever 1071a may be configured to move (e.g., pivot) relative to collar 1072 and about rotation pin 107 Id to displace second end 1071c from the obstruction position. The pivoting axis, along which rotation pin 107 Id extends, may be substantially perpendicular to the longitudinal axis along which plunger rod 1080 extends.

[0293] For example, as seen in FIG. IS, movable lever 1071a may be actuated in response to moving first end 1071b distally toward flange 1076 and about rotation pin 107 Id. In some embodiments, first end 1071b may be actuated in response to receiving a distally- directed force applied thereto by, for example, a user of device 1050. Second end 1071c may be moved in a proximal direction away from flange 1076 and relative to rotation pin 107 Id in response to first end 1071b moving distally, thereby causing second end 1071c to disengage protrusion 1085.

[0294] Accordingly, as shown in FIG. IT, movable lever 1071a may allow plunger rod 1080 to translate relative to flange piece 1070 until protrusion 1085 encounters an abutment 1072a positioned at a distal end of opening 1073. Abutment 1072a may cause plunger rod 1080 to settle into a dose completion position of plunger rod 1080 when protrusion 1085 is engaged thereto. It should be appreciated that a distance between second end 1071c and abutment 1072a may define a dosage delivery distance for moving plunger rod 1080 to dispense a controlled volume of substance from device 1050.

[0295] As shown in FIGS. 1U and IV, in some embodiments, actuation portion 1082 of plunger rod 1080 may additionally or alternatively include one or more extensions 1087 configured to interface with side openings 1094, 1095 in collar 1072 of flange piece 1070. Extensions 1087 may extend distally from actuation portion 1082, and may have an angled or rounded distal portion sized and configured to be pushed inward toward a central axis of plunger rod 1080 when actuation portion 1082 is pushed distally into collar 1072. The angled or rounded distal portion of each extension 1087 may include a hook or clip shaped part 1087a. Extensions 1087 may additionally be made of a flexible material, allowing them to be pushed inward into collar 1072 and spring back outwards when no longer being restricted by a side of collar 1072. Side openings 1094, 1095 in collar 1072 may be sized and configured to receive hook or clip shaped part 1087a of an extension 1087, such that once an extension 1087 reaches a side opening 1094 or 1095, a hook or clip shaped part 1087a may spring outward into the side opening 1094 or 1095 and thereafter preventClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 proximal movement of plunger rod 1080. A number of extensions 1087 may coincide with a number of each of side openings 1094 and side openings 1095, such that each extension 1087 may be received in a corresponding side opening 1094 or 1095 simultaneously as plunger rod 1080 moves distally relative to flange piece 1070.

[0296] Specifically, first side openings 1094 may be configured to receive hook or clip shaped parts 1087a of extensions 1087 upon assembly of device 1050, to prevent proximal movement of plunger rod 1080 once plunger rod 1080 is inserted to a ready -to-use position. As hook or clip shaped part 1087a of each extension 1087 is received in first side openings 1094, it may make a “clicking” sound as it interfaces with collar 1072, thereby providing auditory and / or tactile feedback, indicating that the device is in a ready-to-use position. In some embodiments, first side openings 1094 may each extend around a partial circumference of collar 1072, such that the hook or clip shaped parts 1087a of extensions 1087 may be received in side openings 1094 in a range of rotational positions of plunger rod 1080 relative to flange piece 1070. Second side openings 1095 may be configured to receive hook or clip shaped parts 1087a of extensions 1087 once device 1050 is in a “delivery” configuration (e.g., after priming and additional rotation of actuation portion 1082 to align protrusions 1086 with slots 1074). In the embodiment depicted in FIGS. 1U and IV, extensions 1087 are longitudinally aligned with protrusions 1086, and, as depicted in FIGS. 3C-3F, side openings 1095 are likewise longitudinally aligned with slots 1074, to allow for distal movement of actuation portion 1082 further into collar 1072 when device is in the “delivery” configuration. It should be appreciated that device may be transitioned to the “delivery” configuration in response to applying a distally-directed force onto actuation portion 1082, to overcome an engagement of side openings 1094 with extensions 1087, and a rotative force to overcome a frictional force between an interior of collar 1072 and extensions 1087. However, in other embodiments, it is contemplated that extensions 1087 and side openings 1094, 1095 may be in any suitable complementary configuration to assist in controlling proximal movement of plunger rod 1080.

[0297] In other embodiments, as shown in FIG. 1W, side openings 1094 may be positioned along collar 1072 in longitudinal alignment with side openings 1095. Device 1050 may be primed upon receiving hook or clip shaped parts 1087a of extensions 1087, initially positioned proximally of side openings 1094, within side openings 1094. In some instances, a feedback (e.g., tactile, auditory, etc.) may be generated in response to extensions 1087 being received within side openings 1094. It should be understood that a proximal end of collarClient Ref. 11518WO01Attorney Docket No. 00166-0178-003041072 may resist distal advancement of plunger rod 1080 relative to flange piece 1070 in response to hook or clip shaped parts 1087a being engaged to collar 1072 at side openings 1094. Applying a distally-directed force onto plunger rod 1080 may cause extensions 1087 to be released from side openings 1094 and translated distally through collar 1072 until received within side openings 1095.

[0298] It should be appreciated that the distally-directed force required to deflect extensions 1087 inwardly and to release hook or clip shaped parts 1087a from side openings 1094 may correspond to a minimum priming and hydrodynamic force. Accordingly, plunger rod 1080 may be maintained in a constant radial orientation during a priming step and delivery step of device 1050. In other embodiments, additional and / or fewer side openings may be included along a circumferential wall of collar 1072 in longitudinal alignment and / or offset (e.g., not longitudinally aligned) with side openings 1094, 1095.

[0299] As seen in FIG. IX, flange piece 1070 may alternatively include one or more inner projections 1095' in lieu of side openings 1095 shown and described above. In this instance, plunger rod 1080 may be preassembled into flange piece 1070 with extensions 1087 (FIG. IV) squeezed into collar 1072 and positioned relatively proximal to side openings 1094. Device 1050 may be primed by pushing plunger rod 1080 distally through flange piece 1070 until extensions 1087 are received within side openings 1094. In some instances, a feedback (e.g., tactile, auditory, etc.) may be generated in response to extensions 1087 being received within side openings 1095. In further embodiments, side openings 1094 may be flared and / or extensions 1087 may have a distally-tapering profile to facilitate further distal advancement of plunger rod 1080 from a primed position to a dose completion position.

[0300] Further translation of plunger rod 1080 relative to flange piece 1070 may cause extensions 1087 to bend radially -inward toward one another, thereby allowing plunger rod 1080 to translate distally to deliver a dose from device 1050. Plunger rod 1080 may continue to translate distally relative to collar 1072 until hook or clip shaped parts 1087a (FIG. IV) encounter inner projections 1095’. Inner projections 1095’ may be configured to contact extensions 1087 and fix plunger rod 1080 to the dose completion position, and / or prevent further distal movement of plunger rod 1080 relative to flange piece 1070. Accordingly, further movement (e.g., proximal and / or distal) of plunger rod 1080 relative to flange piece 1070 may be inhibited by inner projections 1095’ engaging hook or clip shaped parts 1087a within collar 1072. Inner projections 1095’ may include complimentary hooks or clip-shaped parts that are sized and / or shaped to interact with hook or clip shaped parts 1087aClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 or extensions 1087. It should be appreciated that a distance between side openings 1094 and inner projections 1095’ may define a dosage delivery distance to dispense a controlled volume of substance from device 1050.

[0301] In other embodiments, as shown in FIGS. 2A-2C, flange piece 1070 may include a fixed sleeve 1072P extending proximally from collar 1072. Fixed sleeve 1072P may have a circular cross-section defining an inner channel with an opening at each terminal end of the fixed sleeve 1072P. The inner channel of fixed sleeve 1072P may extend through a longitudinal length of fixed sleeve 1072P and may be longitudinally aligned with opening 1073 (FIG. 10) such that a respective longitudinal axis of the inner channel and opening 1073 are coaxial with one another. Fixed sleeve 1072P may be sized, shaped, and configured to receive stem 1081. In some embodiments, fixed sleeve 1072P may be integral with collar 1072, while in other embodiments fixed sleeve 1072P may be a separate component assembled onto flange piece 1070.

[0302] Fixed sleeve 1072P may include a plurality of openings that are sized and shaped to receive protrusion 1085. For example, fixed sleeve 1072P may include a pair of proximal openings 1072Q and a pair of distal openings 1072R longitudinally spaced apart from one another by an offset distance. Further, the pair of proximal openings 1072Q are located at the same longitudinal position as one another, and the pair of distal openings 1072R are located at the same longitudinal position as one another. As described in further detail below, the longitudinal offset between proximal openings 1072Q and distal openings 1072R may define a dosage delivery distance for moving plunger rod 1080 to dispense a controlled volume of substance from device 1050. Alternatively, the longitudinal offset between openings 1072Q, 1072R may define a priming distance of device 1050 such that protrusion 1085 may be initially received within proximal openings 1072Q during an assembly of device 1050 to inhibit proximal retraction of plunger rod 1080. In this instance, a dosage delivery distance may correspond to a longitudinal offset between a distal end of actuation portion 1082 and a bottom surface of collar 1072 when protrusion 1085 is received within distal opening 1072R. Although not shown, it should be appreciated that an additional set of openings may be included on fixed sleeve 1072P (e.g., proximal of proximal openings 1072Q, distal of proximal openings 1072Q, and / or distal of distal openings 1072R) to further define a priming distance and / or dosage delivery distance.

[0303] A proximal end of fixed sleeve 1072P may include an angled interface 107 IP defining a proximal opening of fixed sleeve 1072P. Angled interface 107 IP may beClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 tapered radially-inward toward the inner channel of fixed sleeve 1072P and configured to guide stem 1081 and protrusion 1085 into the inner channel. In the present example, protrusion 1085 may extend radially outward from stem 1081 in opposing lateral directions and may be compressible and / or formed of a flexible / deformable material, such that protrusion 1085 is configured to retract or deform radially inward into and / or toward stem 1081 in response to a force being applied thereto. In other embodiments, protrusion 1085 may be configured to at least partially deform fixed sleeve 1072P to facilitate movement of protrusion 1085 toward and / or between openings 1072Q, 1072R. In this instance, fixed sleeve 1072P may be formed of a flexible material operable to flex radially-outward when applying a distally-directed force onto stem 1081, thereby causing protrusion 1085 to apply a radial force onto fixed sleeve 1072P.

[0304] Still referring to FIG. 2 A, fixed sleeve 1072P may be configured to receive plunger rod 1080 through the inner channel and allow stem 1081 to pass through collar 1072 to prime device 1050. Protrusion 1085 may be received within fixed sleeve 1072P in response to encountering angled interface 107 IP and compressing radially inward relative to stem 1081 until plunger rod 1080 is moved distally enough so that protrusion 1085 is received by proximal openings 1072Q. As shown in FIG. 2B, protrusion 1085 may be configured to expand radially outward (decompress) when longitudinally aligned with proximal openings 1072Q to lock stem 1081 relative to flange piece 1070. In this instance, device 1050 may be in a primed position such that further translation of stem 1081 distally relative to fixed sleeve 1072P and flange piece 1070 may deliver a dose from device 1050. Alternatively, device 1050 may be preassembled with protrusion 1085 received in proximal openings 1072Q such that translation of stem 1081 distally relative to fixed sleeve 1072P may prime device 1050 until protrusion 1085 is received within distal openings 1072R.

[0305] As seen in FIG. 2C, while protrusion 1085 is positioned within proximal openings 1072Q applying a distally-directed force onto stem 1081 may cause fixed sleeve 1072P to compress (or deform) protrusion 1085 radially inward, thereby allowing stem 1081 to translate distally relative to fixed sleeve 1072P. Alternatively, protrusion 1085 may be manually compressed (or deformed) by applying a radially inward-directed force through proximal openings 1072Q. Protrusion 1085 may move distally through an inner channel of fixed sleeve 1072P and may be received by distal openings 1072R. As stem 1081 translates distally relative to collar 1072, device 1050 may transition from the primed position to a doseClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 completion position when protrusions 1085 are received within distal openings 1072R, thus delivering the dose.

[0306] It should be appreciated that a volume of the dose delivered by device 1050 may be controlled based on the longitudinal offset distance between proximal openings 1072Q and distal openings 1072R. In some embodiments, fixed sleeve 1072P may include additional openings for receiving protrusion 1085 after priming and delivering a dose to inhibit proximal retraction of stem 1081 (e.g., pull back of plunger rod 1080) relative to flange piece 1070. For example, protrusion 1085 may be received within proximal openings 1072Q during an assembly of device 1050 at a manufacturing stage such that distal openings 1072R may define a priming position and a third set of openings (not shown) distal to distal opening 1072R may define a dosage delivery position. Alternatively, a bottom, interior surface of flange piece 1070 distal to distal opening 1072R may define the dosage delivery position of plunger rod 1080.

[0307] In some embodiments, as seen in FIGS. 2D-2G, flange piece 1070 may include a movable sleeve 1072S extending distally and proximally from collar 1072. Movable sleeve 1072S may have a circular cross-section defining an inner channel with an opening at each terminal end of movable sleeve 1072S. The inner channel of movable sleeve 1072S may extend through a longitudinal length of movable sleeve 1072S. Movable sleeve 1072S may be sized, shaped, and configured to be received through opening 1073, and the inner channel of movable sleeve 1072S may be sized to receive stem 1081. Movable sleeve 1072S may be fixed relative to collar 1072 when in an preassembled configuration and may be movable relative to collar 1072 upon engagement with plunger rod 1080.

[0308] Movable sleeve 1072S may include a plurality of openings that are sized and shaped to receive protrusion 1085. For example, movable sleeve 1072S may include a proximal opening 1072U at a proximal end of movable sleeve 1072S and a distal opening 1072T at a distal end of movable sleeve 1072S. A proximal end of movable sleeve 1072S may further include an angled interface 107 IS defining a proximal opening of movable sleeve 1072S. Angled interface 107 IS may be tapered radially -inward toward the inner channel of movable sleeve 1072S and configured to guide stem 1081 and protrusion 1085 into the inner channel of movable sleeve 1072S. In some embodiments, protrusion 1085 may extend radially outward from stem 1081 in opposite directions and may be compressible such that protrusion 1085 is configured to compress into and / or toward stem 1081 in response to a force being applied thereto.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0309] Still referring to FIG. 2D, the proximal end of movable sleeve 1072S may be positioned adjacent to a proximal end of collar 1072 and a distal end of movable sleeve 1072S may be positioned adjacent to a distal end of collar 1072 when in the preassembled position. Plunger rod 1080 may be received through the inner channel of movable sleeve 1072S with stem 1081 extending through collar 1072. Protrusion 1085 may be received within distal opening 1072T such that plunger rod 1080 may be fixed to movable sleeve 1072S. Protrusion 1085 may be configured to exit distal opening 1072T and expand laterally outward in response to plunger rod 1080 translating relative to movable sleeve 1072S.

[0310] For example, as shown in FIG. 2E, applying a distally-directed force onto actuation portion 1082 may cause protrusion 1085 to compress radially inward, thereby allowing stem 1081 to translate distally relative to movable sleeve 1072S. In this instance, protrusion 1085 may exit distal opening 1072T and expand upon translating distally from a distal end of movable sleeve 1072S. Device 1050 may transition from a preassembled state to a primed state, in response to stem 1081 translating distally relative to collar 1072, until actuation portion 1082 abuts against a proximal end of movable sleeve 1072S. In this instance, device 1050 may be in a primed state and further translation of stem 1081 relative to collar 1072 may be inhibited by the presence of movable sleeve 1072S.

[0311] Referring now to FIG. 2F, plunger rod 1080 may couple to movable sleeve 1072S in response to proximal translation of stem 1081 relative to collar 1072 until protrusion 1085 engages proximal opening 1072U. It should be understood that protrusion 1085 may be in a compressed state when translating through an inner channel of movable sleeve 1072S and may expand into proximal opening 1072U upon longitudinal alignment therewith. With protrusion 1085 engaged to proximal opening 1072U, a distal translation of plunger rod 1080 relative to flange piece 1070 may provide a simultaneous movement of movable sleeve 1072S relative to collar 1072. It should be appreciated that a collective length of movable sleeve 1072S and plunger rod 1080 may be greater than a longitudinal length of plunger rod 1080 alone.

[0312] As seen in FIG. 2G, plunger rod 1080 may be configured to move movable sleeve 1072S through a channel of flange piece 1070 by a predetermined distance until actuation portion 1082 encounters a proximal end of collar 1072. Plunger rod 1080 may be configured to deliver a dose from device 1050 in response to translating movable sleeve 1072S distally relative to collar 1072. It should be appreciated that the dosage delivered by device 1050 may be controlled based on the predetermined distance between actuationClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 portion 1082 and collar 1072 when protrusion 1085 is received within proximal opening 1072U. In some embodiments, flange piece 1070 may be configured to inhibit proximal movement of movable sleeve 1072S relative to collar 1072 when protrusion 1085 is received within proximal opening 1072U. Although not shown, flange piece 1070 may include one or more blocking components operable to restrict proximal retraction of movable sleeve 1072S from opening 1073.

[0313] In other embodiments, as seen in FIGS. 2H-2M, plunger rod 1080 may include at least one protrusion 1085W positioned on actuation portion 1082. In the example, protrusion 1085W may be positioned at or adjacent a distal end of actuation portion 1082 such that protrusion 1085W may be received within flange piece 1070 in response to translation of plunger rod 1080 into collar 1072.

[0314] As seen in FIG. 2K, flange piece 1070 may include one or more channels formed along an inner surface of collar 1072. In particular, collar 1072 may include a first (proximal) helical channel 1071W formed along an interior of collar 1072 and having a first curvature, and a second (distal) helical channel 1072W formed along the interior of collar 1072 and having a different and / or opposite curvature than the first helical channel 1071W. For example, when viewed from the proximal end of actuation portion 1082, first helical channel 1071W may be concave, while second helical channel 1072W may be convex when viewed from the same vantage point. Or, first helical channel 1071W may be convex when viewed from the proximal end of actuation portion 1082, while second helical channel 1072W is concave from the same vantage point. Further, second helical channel 1072W may be longitudinally spaced apart from first helical channel 1071W. First helical channel 1071W may be connected with second helical channel 1072W by an intermediate, third channel 1073W extending therebetween.

[0315] Third channel 1073W may extend along or substantially parallel to a longitudinal axis of collar 1072. It should be understood that a size, shape, and / or orientations of the one or more channels on collar 1072 are merely exemplary such that other suitable configurations may be included without departing from a scope of this disclosure. As described in detail below, the plurality of channels on collar 1072 are configured to receive protrusion 1085W. In some embodiments, first helical channel 1071W and second helical channel 1072W may be threaded and configured to mesh with a corresponding component of plunger rod 1080 (e.g., protrusion 1085W). Opposite rotational movement may be required for protrusion 1085W to traverse through first helical channel 1071W and second helicalClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 channel 1072W. For example, a first rotational movement of actuation portion (e.g., clockwise) may cause protrusion 1085W to traverse first helical channel 1071W, while an opposing rotational movement (e.g., counterclockwise) may cause protrusion 1085W to traverse through second helical channel 1072W.

[0316] Referring to FIG. 2H, with plunger rod 1080 in a ready position, protrusion 1085W may be received within collar 1072 in response to a distal translation of actuation portion 1082 toward flange piece 1070. As seen in FIG. 21, protrusion 1085W may be received within first helical channel 1071W and moved therethrough in response to a rotation of plunger rod 1080 (e.g., in a first direction) relative to flange piece 1070. It should be appreciated that plunger rod 1080 may be configured to translate axially in a distal direction relative to flange piece 1070 as plunger rod 1080 rotates within collar 1072, due to the curvature of first helical channel 1071W. For example, plunger rod 1080 may translate a first distance defined by a configuration of first helical channel 1071W until reaching a terminal end of first helical channel 1071W. The first distance may correspond to a priming step of device 1050 such that device 1050 may be at least partially primed upon protrusion 1085W moving through first helical channel 1071W.

[0317] Referring now to FIG. 2J, protrusion 1085W may be positioned at a terminal end of first helical channel 1071W and a proximal (e.g., top) end of third channel 1073W. In some embodiments, plunger rod 1080 may experience a tactile feedback formed by the terminal end of first helical channel 1071W. Plunger rod 1080 may be translated distally through third channel 1073W to complete a priming step of device 1050, as shown in FIG. 2K. It should be understood that first helical channel 1071W and third channel 1073W may collectively define a priming distance of device 1050 such that plunger rod 1080 is in a primed position when protrusion 1085W translates through third channel 1073W.

[0318] With protrusion 1085W received within second helical channel 1072W, plunger rod 1080 may be rotated in the second direction (opposite of the first direction) to translate plunger rod 1080 distally by a second distance that is defined by a configuration of second helical channel 1072W. The second distance may be less than, greater than, and / or substantially equal to the longitudinal dimension of second helical channel 1072W, depending on the particular application and need. Plunger rod 1080 may be rotated in the second direction and translated by the second distance until reaching a terminal end of second helical channel 1072W to deliver a dose from device 1050. It should be understood that the second distance may correspond to a dosage delivery step of device 1050 such that deviceClient Ref. 11518WO01Attorney Docket No. 00166-0178-003041050 may deliver the dose upon protrusion 1085W moving through second helical channel 1072W and arriving at a dose completion position.

[0319] In other embodiments, as seen in FIGS. 2L-2O, plunger rod 1080 may include a protrusion, a knob, and / or a thread 1085X positioned on actuation portion 1082. In the example, thread 1085X may be positioned about a circumference of actuation portion 1082 and along a distal end such that thread 1085X may be received within flange piece 1070 in response to translation of plunger rod 1080 into collar 1072.

[0320] Flange piece 1070 may further include a threaded portion 1072X disposed within opening 1073 and forming a helical path that is configured to receive thread 1085X. In the example, threaded portion 1072X may be positioned along a proximal portion of opening 1073 such that a distal portion of opening 1073 may include a non-threaded portion 1071X. As described in further detail herein, threaded portion 1072X may define a longitudinal distance corresponding to a priming step of device 1050 and non-threaded portion 1071X may define a distance corresponding to a dosage delivery step of device 1050.

[0321] For example, as seen in FIG. 2L, actuation portion 1082 may be translated distally toward flange piece 1070 until thread 1085X encounters a distal end of collar 1072. Rotation of plunger rod 1080 in a first direction (e.g., clockwise or counter clockwise) may cause thread 1085X to engage threaded portion 1072X. As shown in FIG. 2M, rotation of plunger rod 1080 may provide axial / longitudinal translation of actuation portion 1082 into collar 1072 as thread 1085X moves through the helical path of threaded portion 1072X. It should be appreciated that rotation and translation of thread 1085X through threaded portion 1072X may transition device 1050 from a ready position (FIG. 2L) to a primed position (FIG. 2N). With thread 1085X disengaged from threaded portion 1072X and positioned along nonthreaded portion 1071X, device 1050 may be in the primed position. In some instances, a feedback (e.g., tactile, auditory, etc.) may be generated in response to thread 1085X exiting threaded portion 1072X and / or entering non-threaded portion 1071X.

[0322] In this instance, as shown in FIG. 20, actuation portion 1082 may be translated distally relative to flange piece 1070 to deliver a dose from device 1050 by application of a distally-directed force against actuation portion 1082. Thread 1085X may move through the distal portion of opening 1073 when thread 1085X is positioned within non-threaded portion 107 IX. A longitudinal length of non-threaded portion 107 IX defined between a distal end of threaded portion 1072X and a distal end of opening 1073 may control a dosage delivery of device 1050. Device 1050 may complete delivery of a dose whenClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 actuation portion 1082 engages a proximally-facing and distal surface of collar 1072 and plunger rod 1080 arrives at the dose completion position.

[0323] FIGS. 2P-2T illustrate further embodiments of a flange piece that may be configured and operable similar to flange piece 1070 shown and described above except for the differences explicitly noted herein. It should be understood that like reference numerals are used to identify like components and the flange pieces described below may be readily incorporated with one or more components of device 1050 shown and described above.

[0324] For example, referring initially to FIG. 2P, a flange piece 1070A may include one or more flanges 1076A that may be sized and configured to aid a user in holding device 1050 and / or expelling a formulated drug substance from device 1050. Flanges 1076A may be further sized and / or shaped to allow a user to hold device 1050 with a plurality of hand / grip positions, arrangements, and / or orientations. By way of illustrative example, flanges 1076A may be sized and / or shaped such that flange piece 1070A may be held similar to a writing instrument (e.g., pencil, pen, etc.) without requiring use of flanges 1076A, or sized in accordance with the example shown in FIG. 24A such that flanges 1076A may abut against one or more fingers of a user. Flange piece 1070A may include a pair of flanges 1076A extending radially outwardly from collar 1072 in opposite radial directions relative to one another. Flanges 1076A may extend transversely from collar 1072 (e.g., flanges 1076A may include an angled surface that is sloped radially-inward in a distal direction) and configured to inhibit a user’s fingers from slipping off of flange piece 1070A during use of device 1050.

[0325] Flanges 1076A may be coupled to one another to form a semi-circular profile with a minimal radius relative to collar 1072. Accordingly, flanges 1076A may form a slim profile to facilitate visualization of a target treatment site at a distal end of device 1050 (not shown) when using device 1050 from a perspective proximal of flange piece 1070A. It should be understood that flange piece 1070A may include various other quantities and / or arrangements of flange pieces 1070A than those shown and described herein without departing from a scope of this disclosure. In other embodiments, flanges 1076 may include various other suitable sizes and / or shapes.

[0326] Flange piece 1070A may further include a distal collar 1075A extending distally from collar 1072 and configured to engage body 1060 to hold flange piece 1070A in a fixed position relative to body 1060. Distal collar 1075A may be adhered to, molded, or otherwise affixed to body 1060, or may engage body 1060 via a friction fit. In the example,Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 distal collar 1075A includes a longitudinal length that is generally less than a longitudinal length of collar 1072. In some embodiments, distal collar 1075A may be sized sufficiently small enough to facilitate adequate exposure of body 1060 for user grasp and / or manipulation during use of device 1050. Additionally, distal collar 1075A may include a material composition that is similar to and / or different from collar 1072. For example, distal collar 1075 A may be formed of a flexible material such that distal collar 1075 A may be configured to flex radially -outward when receiving body 1060 into flange piece 1070A and flex radially- inward once body 1060 is fully received to facilitate a snap-fit connection (without breaking distal collar 1075A). It should be appreciated that, in other embodiments, flange piece 1070A may omit distal collar 1075A entirely.

[0327] In other embodiments, as seen in FIG. 2Q, a flange piece 1070B may include a distal collar 1075B that is substantially longer than distal collars 1075, 1075A shown and described above. For example, distal collar 1075B may be enlarged with a longitudinal length that is greater than a longitudinal length of collar 1072. In the example, distal collar 1075 A may be sized sufficiently large enough to encompass a substantial length of body 1060. In this instance, an exterior surface of distal collar 1075B may provide an interface for a user to grasp and / or manipulate during use of device 1050. Additionally, distal collar 1075B may include an expanded diameter that exceeds a diameter of body 1060 to provide an enhanced surface area for grasping flange piece 1070B. Stated differently, distal collar 1075B may have a widened size and / or shape to facilitate ease in gripping and / or manipulating device 1050. In the present example, distal collar 1075B may have a barrel-shape with a convex outer surface when viewed from an exterior of device flange piece 1070B.

[0328] Alternatively, as seen in FIG. 2R, a flange piece 1070C may include a distal collar 1075C that is substantially similar to distal collar 1075B and includes a longitudinal length that is greater than a longitudinal length of collar 1072. In the example, an exterior surface of distal collar 1075C may be configured to provide an interface for a user to grasp and / or manipulate during use of device 1050. Distal collar 1075C may include a slim profile with a diameter that is greater than a diameter of body 1060 such that distal collar 1075C does not substantially increase a profile of body 1060. Stated differently, distal collar 1075C may have a narrowed size relative to distal collar 1075B. In some embodiments, distal collar 1075C may include a terminal lip 1077C that extends radially outward at a distal end. Terminal lip 1077C may be sized, shaped, and configured to enhance gripping and / or manipulation of distal collar 1075C. In the present example, distal collar 1075C may have aClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 flared-shape with a concave outer surface when viewed from an exterior of device flange piece 1070C.

[0329] In other embodiments shown in FIGS. 2S-2T, a flange piece 1070D may include a collar 1072D having a proximal lip 1074D. Proximal lip 1074D may define an irregular surface configured to interface with plunger rod 1080 when actuation portion 1082 is received by collar 1072D. For example, proximal lip 1074D may include a pair of recessed surfaces 1075D positioned along opposing sides from one another along proximal lip 1074D. In other words, recessed surfaces 1075D may be separated from one another by surfaces and / or portions of proximal lip 1074D that are not recessed. In the example, recessed surfaces 1075D may be positioned adjacent to slots 1074 and may define a pathway for moving plunger rod 1080 relative to collar 1072D for priming and delivering a dose from device 1050. In some embodiments, recessed surfaces 1075D may include a spiral configuration (e.g., have a distally-directed slope) such that recessed surfaces 1075D may be tapered in a distal direction between a first ledge 1073D and a second ledge 1076D.

[0330] In some embodiments, flange piece 1070D may include visualization mechanisms, such as, for example, one or more labels or markings disposed on collar 1072D to provide instructions to a user of device 1050. For example, the one or more labels (e.g., numbering) may indicate directions in which to rotate or otherwise move plunger rod 1080 relative to flange piece 1070D to prime and deliver a dosage from device 1050. By way of example, the one or more labels may include markings that indicate a start position (e.g., “1”), a priming position (e.g., “2”), and a dosage delivery position (e.g., “3”) of protrusions 1086 relative to proximal lip 1074D. The one or more labels may be adhered, printed, embossed, and / or molded onto collar 1072D.

[0331] As described in greater detail herein, flange piece 1070D may be configured to allow movement of plunger rod 1080 in a single direction when priming and delivering a dosage from device 1050. In exemplary use, plunger rod 1080 (not shown) may initially be received through flange piece 1070D and actuation portion 1082 may be positioned against collar 1072D with protrusions 1086 positioned along a first end of recessed surfaces 1075D at marking “1” and opposite of slot 1074. Protrusions 1086 may only be rotated in a single direction along recessed surface 1075D, toward marking “2,” due to first ledge 1073D inhibiting protrusions 1086 from moving in an opposite direction away from marking “2”.

[0332] When protrusions 1086 are received along recessed surfaces 1075D at marking “2,” second ledge 1076D may further prevent protrusions 1086 from moving pastClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 slots 1074 and passing by marking “3”. It should be appreciated that a configuration of proximal lip 1074D is exemplary such that flange piece 1070D may include various other sizes, shapes, and / or configurations of proximal lip 1074D and / or recessed surfaces 1075D than those shown and described herein to facilitate movement of plunger rod 1080 during use of device 1050.

[0333] In other embodiments, the components of device 1050 may include one or more color indicators in lieu of and / or in addition to the markings described above to provide instructions to a user of device 1050. For example, device 1050 may include colors, symbols (e.g., arrows), and the like indicating a direction in which to rotate or otherwise move plunger rod 1080 relative to flange piece 1070D to prime and deliver a dosage. In one embodiment, an exterior surface of plunger rod 1080 may be provided with different colors along various portions of actuation portion 1082 to indicate a respective start position (e.g., green), priming position (e.g., yellow), and dosage delivery position (e.g., red) of plunger rod 1080 relative to collar 1072D. The one or more color indicators may be printed or molded onto plunger rod 1080. In other embodiments, the various portions of plunger rod 1080 may include different textures in lieu of and / or in addition to the color indicators described above to provide instructions to a user of device 1050.

[0334] Components of device 1050, and / or any other device described herein, may be made of any suitable material, and each component may be made from the same or different materials as other components. It should be appreciated that, in some embodiments, one or more components of device 1050 (e.g., flange piece 1070, proximal collar 1072, plunger rod 1080, actuation portion 1082, and more) may be formed of a flexible material having sufficient flexibility to prevent breakage during flexing. In some embodiments, the one or more components of device 1050 may be rigid and have enough strength to maintain shape and provide support. In other embodiments, one or more components of device 1050 (or at least a portion of a component) may having a varying rigidity along a longitudinal length or lateral width such that the component may have a variable flexibility. In still further embodiments, the one or more components of device 1050 may have sufficient flexibility to prevent breakage during flexing while also having sufficient rigidity and strength to maintain shape and provide support. In some embodiments, such features may further provide a user feedback (e.g., tactile, audible, visual, etc.) when flexing and / or interacting with other components of device 1050. For example, each of body 1060, flange piece 1070, and plunger rod 1080 may be made of a material including a polymer, such as a plastic. In someClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 embodiments, one or more of body 1060, flange piece 1070, and plunger rod 1080 may include multiple different materials (e.g., glass, rubber, and / or plastic). In some embodiments, for example, the cylindrical portion of body 1060 may be made of glass, Plexiglas, or any other suitable polymer (e.g., cyclic olefin polymer or cyclic olefin copolymer) or other material, and stopper 1062 may be made of, e.g., plastic, rubber, or other polymer or copolymer. Body 1060 may be configured to include an interior volume of approximately 0.4 mL, 0.5 mL, or 0.6 mL. In some embodiments, stopper 1062 may be separated from plunger rod 1080 to ensure that stopper 1062 can be moved distally through body 1060 and / or prevent stopper 1062 from moving proximally through body 1060. It should be appreciated that stopper 1222 of delivery device 1050, 2800 may be similarly positioned within body 1220 relative to plunger rod 1080. By way of further example, flange piece 1070, 2870 may include polycarbonate / acrylonitrile butadiene styrene, polypropylene homopolymer, an ABS (Acrylonitrile, Butadiene, and Styrene) polymer, ABS polycarbonate blend, and other suitable materials. In some embodiments, plunger rod 1080 may include an ABS polycarbonate blend. In some embodiments, plunger rod 1080, 2880 may be formed of one or more materials, including polycarbonate / acrylonitrile butadiene styrene, polypropylene homopolymer, an ABS (Acrylonitrile, Butadiene, and Styrene) polymer, ABS polycarbonate blend, and other suitable materials. Body 1220 may be formed of Type 1 borosilicate glass. Stopper 1222 may be formed of bromobutyl rubber. A tip cap of the delivery device may be formed of polyisoprene. In further embodiments, one or more components of the delivery device may be evaluated for one or more of cytotoxicity, sensitization, irritation or intracutaneous reactivity, material mediated pyrogenicity, acute system toxicity, and / or hemocompatability.

[0335] Such materials may provide greater tolerances for manufacturing (e.g., injection molding) flange piece 1070 and / or plunger rod 1080, or facilitate an increased reproducibility of said components of device 1050. As described in greater detail above, in some embodiments, one or more components of device 1050 may be formed of a flexible and / or deformable material composition providing greater tolerances for flexing or deforming said components (e.g., without breaking) when priming or delivering a dose from device 1050.

[0336] In some embodiments, a portion of body 1060 configured to contain a formulated drug substance may be made of a transparent or translucent material. In some embodiments, flange piece 1070 and plunger rod 1080 may be made of the same, similar, orClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 different materials, such as similar or different plastics (e.g., each having a similar or different hardness). In some embodiments, parts of device 1050 may include elastic materials. For example, parts of device 1050 may include rubber or plastic configured to allow a user to better grip device 1050, or to create an airtight or otherwise sealing fit between two components of device 1050 (e.g., between body 1060 and stopper 1062). In some embodiments, some or all of plunger rod 1080 (e.g., actuation portion 1082 and / or extensions 1087, or alternately the entirety of plunger rod 1080) may be made of a material having some flexibility, e.g., to allow for bending of extensions 1087. One or more of the materials listed above (e.g., plastic, rubber, polymers, or copolymers) may have such characteristics. In some embodiments, some or all of device 1050 may be suitable for sterilization, e.g., heat or chemical sterilization.

[0337] FIGS. 3A and 3B depict an exemplary method of assembling the delivery device depicted in FIGS. 1 A-1E. Flange piece 1070 may be assembled to body 1060, as shown in FIG. 3 A. The assembly of flange piece 1070 to body 1060 may include sliding, snapping, adhering, or otherwise affixing the two components together. As depicted in FIG. 3 A, flange piece 1070 may be slid onto body 1060, e.g., such that lip 1071 of flange piece 1070 engages with body flange 1061. Plunger rod 1080 may be inserted through the assembled flange piece 1070 and body 1060, such that a distal end of plunger rod 1080 contacts stopper 1062. The assembled device 1050 may then be in a configuration suitable for packaging, sterilization, and / or use.

[0338] FIGS. 3C-3F depict an exemplary method of assembling device 1050 in which actuation portion 1082 includes extensions 1087 and collar 1072 includes side openings 1094. In such an embodiment, plunger rod 1080 may be inserted through flange piece 1070 until the hook or clip portions of extensions 1087 are received within side openings 1094, at which point the assembled device 1050 may be in a configuration suitable for packaging, sterilization, and / or use. It should be appreciated that side openings 1094 may be configured to inhibit a proximal retraction of plunger rod 1080 relative to flange piece 1070 once the hook or clip portions of extensions 1087 are received therein. Side openings 1094 may function as a first lock when device 1050 is placed into an initial assembly state to prevent disassembly of device 1050.

[0339] As described in further detail herein (see FIGS. 4G-4J), side openings 1095 may be configured to inhibit a proximal retraction of plunger rod 1080 once the hook or clip portions of extensions 1087 are received therein. Side openings 1095 may function as aClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 second lock when device 1050 is placed in a dosage delivery state to prevent extracting patient fluid after completion of drug / medicament delivery. It should be appreciated that side openings 1094, 1095 may generate a feedback indicating a relative position of plunger rod 1080 to flange piece 1070, such as, for example, an audible feedback, a tactile feedback, and the like. In some embodiments, device 1050 may include additional and / or fewer side openings 1094, 1095 than those shown and described herein to increase and / or decrease a quantity of locks on device 1050.

[0340] In some embodiments, assembling device 1050 may include pre-filling body 1060 before combining it with flange piece 1070 and stopper 1062; for example, a predetermined amount of drug substance may be disposed in body 1060 between stopper 1062 and expulsion end 1064. In some embodiments, an alternate order of assembly of the components of device 1050 may be employed, depending on contemplated variations in the structures of components of device 1050. For example, in an embodiment (not shown) in which flange piece 1070 is configured to be assembled to body 1060 using a snap-fit interface, plunger rod 1080 may be first inserted through flange piece 1070, and the combined flange piece 1070 and plunger rod 1080 may be assembled to body 1060, e.g., such that flange piece 1070 snaps over a proximal body flange 1061 of body 1060 and plunger rod 1080 is inserted into body 1060.

[0341] FIGS. 4A-4F depict an exemplary method of using device 1050, according to aspects of the present disclosure. In a pre-use configuration depicted in FIG. 4A, device 1050 may hold a volume of a drug substance in between stopper 1062 and expulsion end 1064. A priming distance p may exist between protrusions 1086 and a proximal end of proximal collar 1072, and protrusions 1086 may be non-aligned with slots 1074. In a priming step depicted in FIG. 4B, plunger rod 1080 may be moved longitudinally further into body 1060. For example, a user may press actuation portion 1082 partially into proximal collar 1072 of flange piece 1070. In some embodiments, device 1050 may be held in an inverted position during this step, to ensure that air trapped in body 1060 may be expelled via expulsion end 1064, as stopper 1062 is pushed distally by plunger rod 1080. In the pre-use configuration of FIG. 4 A and during the priming step shown in FIG. 4B, plunger rod 1080 may be prevented from rotating about the longitudinal axis of the syringe, due to the geometries of opening 1073 in flange piece 1070, and neck 1084 of plunger rod 1080 (as shown in the top cross- sectional view in FIG. 4B). As shown in FIG. 4C, the priming step may be stopped when protrusions 1086 of plunger rod 1080 abut a proximal end of proximal collar 1072. When theClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 priming step is completed, neck 1084 of plunger rod 1080 may be positioned longitudinally with respect to opening 1073 of flange piece 1070, such that it may now be rotatable with respect to flange piece 1070. For example, when the priming step is completed, a narrower portion of neck 1084 may be disposed inside opening 1073 than when device was in a pre-use configuration.

[0342] As depicted in FIG. 4D, device 1050 may be in a primed configuration. In a dispensing preparation step depicted in FIG. 4E, plunger rod 1080 may be rotated about a longitudinal axis to align protrusions 1086 with slots 1074. To do so, a user may grasp and twist actuation portion 1082. In some embodiments, as has been described elsewhere, it may be possible to twist actuation portion 1082 in either direction to align protrusions 1086 and slots 1074. In other embodiments, actuation portion 1082 may be rotatable only in one direction. In some embodiments, once protrusions 1086 are aligned with slots 1074, further rotation of plunger rod 1080 relative to flange piece 1070 may be stopped by, e.g., contact between the geometries of neck 1084 and opening 1073. Thus, aligning protrusions 1086 and slots 1074 may lock device 1050 in a ready -to-dispense configuration. In some embodiments, rotation of actuation portion 1082 may align protrusions 1086 with slots 1074, and may allow plunger rod 1080 to remain longitudinally stationary relative to flange piece 1070 (e.g., no proximal or distal movement of plunger rod 1080 is caused by rotation of actuation portion 1082). As depicted in FIG. 4F, in a dispensing step, plunger rod 1080 may be moved longitudinally further into body 1060. For example, a user may press actuation portion 1082 distally into proximal collar 1072 of flange piece 1070, such that protrusions 1086 slide into slots 1074. Once protrusion 1086 abut distal ends of slots 1074, further distal movement of plunger rod 1080 is stopped. The dispensing step may ensure that a predetermined volume of a drug substance inside body 1060 is dispensed from device 1050. In some embodiments, when protrusions 1086 abut distal ends of slots 1074, stopper 1062 does not “bottom out” or abut an interior of expulsion end 1064 in body 1060. Advantageously, by ensuring that a predetermined volume of a drug substance inside body 1060 is dispensed from device 1050 before stopper 1062 can bottom out, any variations in the manufacture of expulsion end 1064 (e.g., altering the exact size or shape of expulsion end 1064) are less likely to affect the predetermined volume of drug substance that is delivered from device 1050. Indeed, in some embodiments, the predetermined volume of drug substance that is delivered from device 1050 may not be affected by typical variations in manufacturing of any component of device 1050, particularly in any component except forClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 flange piece 1070. Advantageously, this may allow for the existence of different or larger tolerances in manufacturing variation in several components of device 1050 (e.g., variations in formation of a glass body 1060 or other glass components), without affecting the predetermined volume of drug substance to be delivered from device 1050.

[0343] In some embodiments, after one or more steps in the use of device 1050, a user may be prevented from re-doing a step, and / or from reversing one or more steps. For example, geometries of, e.g., plunger rod neck 1084 and opening 1073 may prevent a user from pulling plunger rod 1080 proximally (e.g., out of) body 1060, from rotating plunger rod 1080 preemptively (e.g., before the priming step shown in FIG. 4C), and / or from overrotating plunger rod 1080 during a dispensing preparation step (e.g., shown in FIG. 4E). In particular, FIGS. 4G-4J depict steps in the use of an embodiment of device 1050 having extensions 1087 on actuation portion 1082 and corresponding side openings 1094, 1095 in collar 1072 of flange piece 1070. FIGS. 4G and 4H depicts device 1050 as actuation portion 1082 is being pushed distally into collar 1072. Due to their angled distal portions, extensions 1087 are pushed inward into collar 1072. Once plunger rod 1080 has been rotated to a “delivery” position and actuation portion 1082 is further pushed distally into collar 1072 to deliver a predetermined volume of drug substance from device 1050, extensions 1087 may be received into side openings 1095 (shown in FIGS. 41 and 4 J), thereafter restricting proximal movement of plunger rod 1080. Advantageously, restricting proximal movement of plunger rod 1080 may prevent inadvertent withdrawal of material into device 1050 from, e.g., a site into which a drug substance is delivered. In some embodiments, device 1050 may include either side openings 1094, or side openings 1095. In other embodiments, as shown in FIGS. 4G-4J, device 1050 may include both side openings 1094 and side openings 1095.

[0344] FIGS. 4K and 40 depicts in further detail exemplary aspects of a geometry of neck 1084, which may help to control movement of plunger rod 1080. For example, a proximal -most portion a of neck 1084 and stem 1081 (indicated by section d in FIG. 4K) may both have a first cross-sectional shape, as shown in FIG. 4L. This shape may allow for corresponding portions of plunger rod 1080 to move proximally / distally through an opening (e.g., opening 1073) of a blocking component (e.g., flange piece 1070), but may prevent rotation of plunger rod 1080 about a longitudinal axis. A narrow portion b of neck 1084 may have a smaller cross-sectional shape, as shown in FIG. 4M. This shape, when disposed in an opening (e.g., opening 1073) of a blocking component (e.g., flange piece 1070) may allow for unidirectional or bidirectional rotation of plunger rod 1080 about a longitudinal axis. ItClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 should be appreciated that the respective portion of neck 1084 allowing for transitional rotation of plunger rod 1080 (e.g., at narrow portion Z>) may have a geometry with the smallest cross-sectional shape to allow greater space for such movement, relative to the cross- sectional shapes of other portions of plunger rod 1080. A third portion c of neck 1084 may have a larger cross-sectional shape, as shown in FIG. 4N, which may correspond directly with the size and shape of an opening (e.g., opening 1073) of a blocking component (e.g., flange piece 1070). As such, proximal or distal movement of this portion of neck 1084 through opening 1073 may only be possible when plunger rod 1080 is in a specific rotational orientation relative to flange piece 1070. Moreover, plunger rod 1080 will not be rotatable while portion c of neck 1084 is disposed within opening 1073. This may ensure that, e.g., plunger rod 1080 is in a desirable position relative to flange piece 1070 (e.g., priming is complete and portion c is no longer disposed within opening 1073) before plunger rod 1080 may be rotated. Together, the various cross-sectional shapes of neck 1084 and the size and shape of opening 1073 may combine to create a specific sequence of movements of plunger rod 1080 needed to prime and deliver a drug substance from device 1050. In the example, a distal portion of opening 1073 may have the greatest cross-sectional profile relative to an intermediate and / or proximal portion of opening 1073 to accommodate the varying geometries of plunger rod 1080 therethrough (e.g., neck 1084, stem 1081, etc.).

[0345] In a further embodiment depicted in FIG. 40, a proximal-most portion e of neck 1084 and a majority portion h of stem 1081 may both have a first cross-sectional shape, as shown in FIG. 4P. This shape may allow for corresponding portions of plunger rod 1080 to move proximally / distally through an opening (e.g., opening 1073) of a blocking component (e.g., flange piece 1070), but may prevent rotation of plunger rod 1080 about a longitudinal axis. A narrow portion f of neck 1084 may have a smaller winged (or arrow-shaped) cross- sectional shape, as shown in FIG. 4Q (in a pre-rotation configuration relative to flange piece 1070) and FIG. 4R (in a post-rotation configuration relative to flange piece 1070). This “winged” shape, when disposed in an opening (e.g., opening 1073) of a blocking component (e.g., flange piece 1070) may allow for unidirectional or bidirectional rotation of plunger rod 1080 about a longitudinal axis, and may restrict or resist “backwards” rotation of plunger rod 1080 in the opposite direction after rotation has been completed (as described further with respect to FIGS. 4T-4X). Portions g and I of plunger rod 1080 may have a larger cross- sectional shape, as shown in FIG. 4S, which may correspond directly with the size and shape of an opening (e.g., opening 1073) of a blocking component (e.g., flange piece 1070). AsClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 such, proximal or distal movement of these portions of plunger rod 1080 through opening 1073 may only be possible when plunger rod 1080 is in a specific rotational orientation relative to flange piece 1070. Moreover, plunger rod 1080 will not be rotatable while portions g or / of plunger rod 1080 are disposed within opening 1073. This may ensure that, e.g., plunger rod 1080 is in a desirable position relative to flange piece 1070 at certain steps during assembly and use of device 1050, allowing for precise assembly and use of device 1050. Additionally, the “larger” cross sectional area of portions g and I may assist in preventing plunger rod “back-out”, as they will not be able to move proximally through opening 1073 unless in a particular rotational position relative to flange piece 1070. For example, after rotation of plunger rod 1080 from a “primed” position to a “delivery” position, portion g of plunger rod 1080 may not be able to move through opening 1073, thus preventing plunger rod “back-out” at that stage of use of device 1050. Together, the various cross-sectional shapes of plunger rod 1080 and the size and shape of opening 1073 may combine to create a specific sequence of movements of plunger rod 1080 needed to assemble, prime, and deliver a drug substance from device 1050.

[0346] FIGS. 4T-4X depict in further detail specific interactions between a wingshaped part of neck 1084 and opening 1073 in flange piece 1070. Flange piece 1070 may include detents 1078 either adjacent to or within opening 1073, which may interface with wings 1089 on neck 1084. FIG. 4T depicts a cross-sectional view of neck 1084 inside opening 1073 in a pre-rotation configuration (e.g., after device 1050 has been primed but before plunger rod 1080 has been rotated to a “delivery” configuration relative to flange piece 1070). FIG. 4U depicts that, as plunger rod 1080 is rotated about a longitudinal axis, one of wings 1089 may contact one of detents 1078 (depending on the direction of rotation). As rotation continues, one of detents 1078 may cause one of wings 1089 to be compressed towards the remainder of neck 1084. When rotation is complete, the one of wings 1089 has passed the one of detents 1078 and has expanded. This expansion of a wing 1089 past detent 1078 may cause an auditory “click” feedback and / or a tactile feedback to indicate that rotation is complete, and may thereafter prevent “backwards” rotation of plunger rod 1080 relative to flange piece 1070. Wings 1089 and detents 1078 may be configured to interact in a similar fashion regardless of whether plunger rod 1080 is rotated in a clockwise or counterclockwise direction, thereby allowing for bidirectional rotation of plunger rod 1080 to move plunger rod 1080 from a “primed” position to a “delivery” position. As shown in further detail in FIG. 4X, each wing 1089 may have a rounded shape to allow for ease ofClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 rotation in one direction, and the expansion of a wing 1089 past a detent 1078 may place the wing 1089 in a position relative to detent 1078 that greatly resists or otherwise prohibits rotation in the opposite direction. Detent 1078 may have any suitable contour configured to assist unidirectional movement of a wing 1089 past detent 1078.

[0347] Advantageously, the various configurations of plunger rod 1080 described herein may allow for modeling, molding, and / or manufacturing one piece (e.g., plunger rod 1080) or two pieces (e.g., plunger rod 1080 and flange piece 1070) in order to achieve several goals — e.g., control desired plunger rod movement and assembly, reduce user error, prevent plunger rod back-out, and minimize a number of disparate parts needing to be manufactured and handled in order to assemble device 1050.

[0348] In some embodiments, as seen in FIGS. 4Y-4Z, device 1050 may include a pair of plunger rods in one kit, interchangeable with a single actuation portion 1082, or coupled to separate actuation portions 1082. For example, referring initially to FIG. 4Y, device 1050 may include a first plunger rod 1080A that is substantially similar to plunger rod 1080 shown and described above except for the differences explicitly noted herein. First plunger rod 1080 A may include a stem 1081 A having a longitudinal length A defined between a distal end of actuation portion 1082 and a tip 1083 A. As described in detail below, longitudinal length A may define a priming distance for moving plunger rod 1080A relative to flange piece 1070 for priming device 1050. Tip 1083 A may have a flat and / or planar interface that may be configured to inhibit engagement of stopper 1062 when first plunger rod 1080A is received within body 1060.

[0349] Referring now to FIG. 4Z, device 1050 may further include a second plunger rod 1080B that is substantially similar to plunger rod 1080. Second plunger rod 1080B may include a stem 108 IB extending distally from actuation portion 1082 and having a longitudinal length B defined between a distal end of actuation portion 1082 and a tip 1083B. Tip 1083B is substantially similar to tip 1083 A described above. Longitudinal length B of stem 1081B is relatively greater than longitudinal length A of stem 1081 A and may define a dosage delivery distance for moving plunger rod 1080A relative to flange piece 1070 to deliver a dose from device 1050.

[0350] First plunger rod 1080A may be configured to prime device 1050 in response to translating stem 1081 A through collar 1072 and into body 1060 (see FIGS. 1 A-1B). In this instance, tip 1083 A may contact and push stopper 1062 distally by the priming distance. It should be understood that the priming distance of device 1050 may be controlled based on aClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 size of longitudinal length A of first plunger rod 1080A. Upon priming device 1050, first plunger rod 1080 A may be removed from body 1060 and flange piece 1070 without retracting stopper 1062 due to a flattened-interface of tip 1083 A. Accordingly, stopper 1062 may remain at a fixed position relative to body 1060 upon retraction of first plunger rod 1080A.

[0351] Second plunger rod 1080B may be configured to deliver a dose from device 1050 in response to translating stem 108 IB through collar 1072 and into body 1060 (see FIGS. 1 A-1B), after the priming step described above using stem 1081 A. In this instance, tip 1083B may contact and push stopper 1062 distally by the dosage delivery distance. It should be understood that the dosage delivery distance of device 1050 may be controlled based on a size of longitudinal length B of second plunger rod 1080B. The dosage delivery distance may be substantially equal to the difference in length between stem 1081B and stem 1081A.

[0352] FIGS. 5A-5C depict another exemplary delivery device 1200 according to additional embodiments of the present disclosure. Device 1200 includes a body 1220, and a flange piece 1240 with a proximal collar 1242, in which an inner collar 1260 may be disposed. Together, proximal collar 1242 and inner collar 1260 may form a blocking component for device 1200. A plunger rod 1280 (also referred to herein as “stem” or “plunger rod stem”) may pass through inner collar 1260 and flange piece 1240, into body 1060. Plunger rod 1280 may share a longitudinal axis with a central axis of proximal collar 1242 and inner collar 1260, and may have an actuation portion 1282 sized and configured to fit (e.g., nest or otherwise fit) inside inner collar 1260.

[0353] Device 1200 may be, for example, an injection device, such as a syringe, for dispensing a predetermined volume of a formulated drug substance. Generally, device 1200 may share size, capacity, material, preparation, assembly, manufacturing, operation, or use characteristics with device 1050, or with other delivery devices disclosed herein. As with device 1050, device 1200 may be configured for ease of use and may include one or more features that aid a user by providing tactile, auditory, or visual feedback (e.g., using any of the features described elsewhere herein).

[0354] Body 1220 may have any or all of the same characteristics as, e.g., body 1060 of device 1050, or as any syringe body known in the art. For example, in some embodiments, body 1220 may be pre-fillable or pre-filled (e.g., fillable or filled with a drug substance prior to completed assembly, packaging, sterilization and / or shipment of device 1200 to users). In some embodiments, a stopper 1222 may be configured to be inserted intoClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 body 1220 and may be configured to hold a predetermined volume of a formulated drug substance inside body 1220, between stopper 1222 and an expulsion end 1224.

[0355] Flange piece 1240 may be of any suitable size and / or shape to close, partially close, cover, or partially cover an end of body 1220 opposite expulsion end 1224, and / or to support and hold plunger rod 1280 in place inside body 1220. In some embodiments, flange piece 1240 may share some characteristics with flange piece 1070 of device 1050. For example, flange piece 1240 may include a distal collar 1244 configured to engage with body 1220 and hold flange piece 1240 in place in relation to body 1220. For example, distal collar 1244 may include a lip 1245 that may slide over a body flange 1226, to hold flange piece 1240 in place. In alternative embodiments, lip 1245 of distal collar 1244 may be made of a flexible or semi-flexible material, so that it may snap in place over body flange 1226. In further embodiments, distal collar 1244 or another portion of flange piece 1240 may be adhered to, molded to, or otherwise affixed to, body 1220, or may engage with body 1220 via a friction fit.

[0356] In some embodiments, flange piece 1240 may include one or more flanges 1246, which may be sized and configured to aid a user in holding device 1200 and / or expelling a formulated drug substance from device 1200. In some embodiments, as depicted in FIGS. 1 A-1E, flange piece 1240 may include two flanges 1246 opposite to one another and extending perpendicularly from a longitudinal dimension of device 1200. In some embodiments, flange piece 1240 may include other arrangements of a flange or flanges, such as four flanges, or one circumferential flange extending radially outward from a central longitudinal axis of device 1200. In some embodiments, flange piece 1240 may extend radially outward from a central longitudinal axis of device 1200 farther than a circumference of body 1220. In such embodiments, flange piece 1240 may support device 1200 if device 1200 is placed on a surface, may prevent device 1200 from rolling on a flat surface, and / or may allow device 1200 to be picked up more easily.

[0357] In some embodiments, flange piece 1240 and inner collar 1260 may be sized and configured to serve as a blocking component in device 1200, e.g., by limiting and / or directing rotational and longitudinal movement of plunger rod 1280. Proximal collar 1242 of flange piece 1240 may be sized and configured to accept part of inner collar 1260, while blocking protrusions 1262 from moving distally until inner collar 1260 is rotated to a particular position. In turn, inner collar 1260 may be sized and configured to receive part or all of an actuation portion 1282 of plunger rod 1280. As shown in FIGS. 5A-5C, proximalClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 collar 1242, inner collar 1260, and actuation portion 1282 may all have generally cylindrical shapes; in alternate embodiments, each of proximal collar 1242, inner collar 1260, and actuation portion 1282 may have any suitable size or shape that allows for actuation portion 1282 to fit (e.g., nest) within inner collar 1260, and inner collar 1260 to fit within proximal collar 1242.

[0358] Plunger rod 1280 and inner collar 1260 may be in general rotatable about a shared central longitudinal axis (e.g., in one direction or in both directions). Moreover, both plunger rod 1280 and inner collar 1260 may be movable along the central longitudinal axis, e.g., in a distal direction to prime device 1200 and / or deliver a volume of drug substance from expulsion end 1224 of body 1220. Actuation portion 1282 of plunger rod 1280 may include a distal geometry which, when actuation portion 1282 is moved distally into inner collar 1260, interfaces with inner collar 1260 to prevent proximal movement (e.g., back-out) of plunger rod 1280 from inner collar 1260. For example, actuation portion 1282 may include a wedge-shaped distal portion that, when it passes a distal portion of inner collar 1260, expands distally from inner collar 1260 so that actuation portion 1282 can no longer move freely in relation to inner collar 1260.

[0359] Flange piece 1240 may include cavities, such as slots 1248, into which protrusions 1262 of inner collar 1260 may slide when inner collar 1260 is rotated to a particular position. As with slots 1074 of device 1050, slots 1248 may have a depth dimension parallel to a longitudinal axis of device 1200, and the depth of slots 1248 may correspond to a distance plunger rod 1280 must move distally in order to push stopper 1222 towards expulsion end 1224, and dispense a predetermined volume of formulated drug substance from body 1220 through expulsion end 1224.

[0360] In some embodiments, device 1200 may have additional features. For example, in some embodiments, a neck of plunger rod 1280 may have a geometry complementary to an opening of flange piece 1240 that restricts the extent and direction that plunger rod 1280 may rotate or move longitudinally, similar to neck 1084 and opening 1073 of device 1050. For example, rotation and / or longitudinal movement of plunger rod 1280 may be restricted based on priming, preparing, and / or drug delivery steps during use of device 1200. As another example, plunger rod 1280 may be prevented from being pulled or backed out of body 1220 at any point during preparation or use of device 1200.

[0361] In a contemplated method of use of device 1200, device 1200 may be filled with a predetermined volume of drug substance. The predetermined volume of drugClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 substance may be greater than a volume of drug substance suitable for delivery to a patient. In some embodiments, device 1200 (e.g., body 1220) may contain both a predetermined volume of drug substance and an air bubble (not shown) that should be removed prior to delivery of the drug substance to a patient. In some embodiments, device 1200 may be a prefilled syringe. In order to prime device 1200 (e.g., removing an air bubble if any and ensuring that a suitable volume of the drug substance will be delivered to a patient), a user may push actuation portion 1282 of plunger rod 1280 into inner collar 1260. A geometry of actuation portion 1282 may interact with inner collar 1260 (e.g., a distal wedge or clip of actuation portion 1282 may expand on a distal side of inner collar 1260) to secure actuation portion 1282 in and / or to inner collar 1260 and to prevent back-out of plunger rod 1280. At this point, device 1200 may be in a “primed” state. Subsequently, inner collar 1260 may be rotated about a longitudinal axis, until protrusions 1262 become longitudinally aligned with slots 1248. At this point, device 1200 may be in a “delivery” state. To deliver a predetermined volume of drug substance from device 1200, inner collar 1260, together with actuation portion 1282 and plunger rod 1280, may then be moved distally until protrusions 1262 abut a distal end of slots 1248. The distance traveled by plunger rod 1280 in this step may push stopper 1222 distally by a distance required to dispense the predetermined volume of drug substance from expulsion end 1224 of device 1200.

[0362] Referring now to FIGS. 6A-6E, views of a delivery device 1300 and component parts are depicted. Delivery device 1300 includes a blocking component comprising a distal flange piece 1340 and a proximal flange piece 1360, a plunger rod 1380, and a body 1320. Distal flange piece 1340 and proximal flange piece 1360 each include flanges (1346 and 1366, respectively). The flanges 1366 of proximal flange piece 1360 optionally may include a texture 1365. Distal flange piece 1340 includes a channel 1341 which may allow for distal flange piece 1340 and body 1320 to be slidably assembled. Proximal flange piece 1360 includes a clip 1364 which may allow for proximal flange piece 1360 and distal flange piece 1340 to be movably affixed to one another, such that they may still be rotatable relative to one another about a longitudinal axis of delivery device 1300 (see, e.g., FIGS. 6D and 6E). Proximal flange piece 1360 includes clips 1362 bordering a central opening 1368 through which plunger rod 1380 may pass. Plunger rod 1380 includes an actuation portion 1382, which optionally may include a texture 1381. Plunger rod 1380 further includes a distal neck portion 1384, a proximal neck portion 1387, and a proximal stop 1386 having a cavity 1385, all of which are configured to interface with distal flangeClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 piece 1340 and proximal flange piece 1360 in a plurality of configurations to allow for controlled priming and delivery of a predetermined volume of a drug substance using delivery device 1300. Plunger rod 1380 further includes a distal tip 1383 at a distal end of a stem 1389, where tip 1383 is configured to interface with stopper 1322. Tip 1383 may have any suitable size, shape, and mode of attaching to, affixing to, or pushing stopper 1322 as has been described with respect to, e.g., tip 1083 of plunger rod 1080. As with stem 1081, stem 1389 may have any size and configuration suitable to fit inside body 1320. In some embodiments, stem 1389 may be sized and configured to provide sufficient size (e.g., thickness), stability and / or rigidity to reduce a likelihood of undesirable bending, wobbling, or breaking.

[0363] Body 1320 (depicted in FIGS. 6D and 6E) may have any or all of the same characteristics as, e.g., body 1060 of device 1050, or as any syringe body known in the art. For example, in some embodiments, body 1320 may be pre-fillable or pre-filled. A stopper 1322 may be configured to be inserted into body 1320 and may be configured to hold a predetermined volume of a formulated drug substance inside body 1320, between stopper 1322 and an expulsion end 1324.

[0364] Delivery device 1300 may be, for example, an injection device, such as a syringe, for dispensing a predetermined volume of a formulated drug substance. Generally, delivery device 1300 may share size, capacity, material, preparation, assembly, or manufacturing characteristics with device 1050, device 1200, or with other delivery devices disclosed herein. As with devices 1050 and 1200, delivery device 1300 may be configured for ease of use and may include one or more features that aid a user by providing tactile, auditory, or visual feedback (e.g., textures 1365, 1381, other textures, labels, colors, or tactile or auditory feedback, or using any of the other features described elsewhere herein). As with devices 1050 and 1200, such features are optional, and one or more such features may be combined to improve ease of use.

[0365] Proximal flange piece 1360 and distal flange piece 1340 may be of any suitable size and / or shape to serve as a blocking component in delivery device 1300, to close, partially close, cover, or partially cover an end of body 1320 opposite expulsion end 1324, and / or to support and hold plunger rod 1380 in place inside body 1320. In some embodiments, proximal flange piece 1360 and distal flange piece 1340 may each include one or more flanges, which may be sized and configured to aid a user in holding device 1300 and / or expelling a formulated drug substance from expulsion end 1324. In someClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 embodiments, as depicted in FIGS. 6A-6E, flange pieces 1360, 1340 may each include two flanges 1366, 1346 respectively, where each pair of flanges is opposite to one another and extending perpendicularly from a longitudinal dimension of device 1300. In general, other arrangements of a flange or flanges, such as one flange on each of flange pieces 1360, 1340, are possible. Each of flange pieces 1340, 1360 may extend radially outward from a central longitudinal axis of device 1300 farther than a circumference of body 1320, to, e.g., support device 1300 if device 1300 is placed on a surface, prevent device 1300 from rolling on a flat surface, and / or allow device 1300 to be picked up more easily.

[0366] Flange pieces 1360 and 1340 may, in combination, form a central opening having a changeable size and / or shape depending on a relative position of proximal flange piece 1360 and distal flange piece 1340. For example, in the configuration depicted in FIG. 6D, proximal flange piece 1360 and distal flange piece 1340 may combine to form an opening sized and configured to allow for distal passage of distal neck portion 1384 of plunger rod 1380, but to block passage of proximal neck portion 1387. In the second configuration depicted in FIG. 6E (e.g., where flanges 1346 and 1366 are in alignment), the central opening formed by flange pieces 1360 and 1340 may be sized and configured to allow for distal passage of proximal neck portion 1387. Proximal stop 1386 may be of a size and shape that is too large to pass through the central opening formed by flange pieces 1360 and 1340 in any combination. In some embodiments, distal flange piece 1340 may be assembled with body 1320 and plunger rod 1380 such that distal flange piece 1340 is not movable relative to body 1320 and not rotatable relative to plunger rod 1380. Proximal flange piece 1360 may, in contrast, be assembled to distal flange piece 1340 (and body 1320) such that it is rotatable about a longitudinal axis in relation to distal flange piece 1340, body 1320, and plunger rod 1380, which may pass through central opening 1368. Specifically, proximal flange piece 1360 may be rotatable relative to distal flange piece 1340 from a first configuration in which flanges 1346, 1366 are offset from one another (see FIG. 6D), to a second configuration in which flanges 1346, 1366 overlay one another (see FIG. 6E). One of ordinary skill in the art will understand that in alternate embodiments, distal flange piece 1340 may be rotatable in relation to other parts of device 1300, while proximal flange piece 1360 may not be rotatable. In yet further embodiments, both proximal flange piece 1360 and distal flange piece 1340 may be assembled with body 1320 and plunger rod 1380 such that they are both rotatable relative to other components of device 1300.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0367] Clips 1362 of proximal flange piece 1360 may overhang and be biased towards opening 1368. In a pre-use configuration (depicted in FIG. 6D), clips 1362 may be compressed by plunger rod 1380. They may be positioned on proximal flange piece 1360 such that, upon distal movement of plunger rod 1380 such that distal neck portion 1384 passes through opening 1368, they expand inward to abut the sides of distal neck portion 1384. Once clips 1362 expand in this manner, they may block proximal movement of plunger rod 1380, e.g., to prevent plunger rod back-out (see, e.g., FIG. 7C). A cavity 1385 may be positioned on proximal stop 1386 for each clip 1362, such that when plunger rod 1380 is moved distally into body 1320 to a fullest desired extent, each clip 1362 may fit into a cavity 1385.

[0368] FIGS. 7A-7F depict an exemplary method of using device 1300, according to aspects of the present disclosure. In a pre-use configuration depicted in FIG. 7A, device 1300 may hold a volume of a drug substance in between stopper 1322 and expulsion end 1324. Flange pieces 1340 and 1360 may be in a pre-use configuration, in which flanges 1346, 1366 are offset from one another. Plunger rod 1380, which may abut or be assembled to stopper 1322, may be partially inserted into body 1320 through flange pieces 1340, 1360. Proximal flange piece 1360 may be prevented from rotating about the longitudinal axis of the syringe, due to the geometries of plunger rod 1380 and flange piece 1360. In a priming step depicted in FIG. 7B, plunger rod 1380 may be moved longitudinally further into body 1320, until distal movement is blocked by the abutment of proximal neck portion 1387 against a surface of proximal flange piece 1360. For example, a user may press actuation portion 1382 towards proximal flange piece 1360. In some embodiments, device 1300 may be held in an inverted position during this step, to ensure that air trapped in body 1320 may be expelled via expulsion end 1324, as stopper 1322 is pushed distally by plunger rod 1380. In the “primed” configuration, distal neck portion 1384 may be disposed in opening 1368 of proximal flange piece 1360. Moreover, as depicted in FIG. 7C, once the priming step is stopped, clips 1362 may be released from their compressed configuration such that they may expand inwards and abut a side of distal neck portion 1384. As distal neck portion 1384 may be comparatively narrower than the part of plunger rod 1380 previously disposed in opening 1368, the expansion of clips 1362 may prevent proximal movement (e.g., back-out) of plunger rod 1380.

[0369] As depicted in FIG. 7D, device 1300 may be in a primed configuration. In a dispensing preparation step depicted in FIG. 7E, proximal flange piece 1360 may be rotatedClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 about a longitudinal axis to align flanges 1366 and flanges 1346, and to change (e.g., enlarge) a shape of the central opening formed by the combined openings of proximal flange piece 1360 and distal flange piece 1340. To do so, a user may grasp and twist proximal flange piece 1360. In some embodiments, it may be possible to twist proximal flange piece in either direction to align flanges 1366 and flanges 1346. In other embodiments, proximal flange piece 1360 may be rotatable only in one direction. In some embodiments, once flanges 1366 and flanges 1346 are aligned (as shown in, e.g., FIG. 7E), further rotation of plunger rod 1080 relative to flange piece 1070 may be stopped by, e.g., clip 1362 abutting against flange 1346. Thus, device 1300 may be locked in a ready -to-dispense configuration. As depicted in FIG. 7F, in a dispensing step, plunger rod 1380 may be moved longitudinally further into body 1320. For example, a user may press actuation portion 1382 distally, until each of clips 1362 enter a cavity 1385 in a proximal stop 1386, and / or until proximal stop 1386 abuts a proximal surface of proximal flange piece 1360. The dispensing step may ensure that a predetermined volume of a drug substance inside body 1320 is dispensed from device 1300.

[0370] In some embodiments, after each successive step in the use of device 1300, a user may be prevented from re-doing a step, and / or from reversing one or more steps. For example, geometries of, e.g., plunger rod 1380 and the combined openings of proximal flange piece 1360 and distal flange piece 1340 may prevent a user from pulling plunger rod 1380 proximally (e.g., out of) body 1320, from rotating plunger rod 1380, from rotating proximal flange piece 1360 preemptively (e.g., before completion of the priming step shown in FIGS. 7B and 7C), and / or from over-rotating flange piece 1360 during a dispensing preparation step (e.g., shown in FIG. 7E).

[0371] FIGS. 8A-8G depict a further exemplary delivery device 1400 and component parts Delivery device 1400 includes a plunger rod 1480, a blocking component 1460, a flange piece 1440, and a body 1420. Plunger rod 1480 includes an actuation portion 1482 and a protrusion 1484. Blocking component 1460 may be a rotatable alignment component that is configured to partially or fully surround plunger rod 1480, and includes three connected channels 1462, 1464, 1468 sized and configured to allow for passage of protrusion 1484. Flange piece 1440 includes a proximal collar 1442 having a channel 1447 into which tabs 1461 of blocking component 1460 may slidably fit, a distal collar 1444 including a channel 1445 into which a flange 1421 of body 1420 may fit (e.g., may be slidably assembled), and flanges 1446.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0372] Body 1420 (depicted in FIGS. 8D and 8E) may have any or all of the same characteristics as, e.g., body 1060 of device 1050, or as any syringe body known in the art. For example, in some embodiments, body 1420 may be pre-fillable or pre-filled. A stopper 1422 may be configured to be inserted into body 1420 and may be configured to hold a predetermined volume of a formulated drug substance inside body 1420, between stopper 1422 and an expulsion end 1424.

[0373] Delivery device 1400 may be, for example, an injection device, such as a syringe, for dispensing a predetermined volume of a formulated drug substance. Generally, delivery device 1400 may share size, capacity, material, preparation, assembly, or manufacturing characteristics with device 1050, device 1200, device 1300, or with other delivery devices disclosed herein. As with other devices disclosed herein, delivery device 1400 may be configured for ease of use and may include one or more features that aid a user by providing tactile, auditory, or visual feedback, using any of the features described elsewhere herein.

[0374] Blocking component 1460 may be of any suitable size and / or shape to assist in controlling proximal and distal movement of plunger rod 1480 in device 1400.

[0375] Flange piece 1440 may be of any suitable size and shape to close, partially close, cover, or partially cover an end of body 1420 opposite expulsion end 1424, and / or to support and hold blocking component 1460 and plunger rod 1480 in relation to body 1420. For example, proximal collar 1442 and channel 1447 may be sized and configured to hold blocking component 1460, and distal collar 1444 and channel 1445 may be sized and configured to hold a flange 1421 of body 1420, such that blocking component 1460 is held stationary in relation to body 1420. Further, blocking component 1460 may be sized and configured to plunger rod 1480 inside body 1420, and to limit movement of plunger rod 1480 with respect to body 1420. Flange piece 1440 may include one or more flanges 1446, which may be sized and configured to aid a user in holding device 1400 and / or expelling a formulated drug substance from expulsion end 1424. In some embodiments, as depicted in FIGS. 8A-8E, flange piece 1440 may include two flanges 1446, opposite to one another. In general, other arrangements of a flange or flanges, such as one flange or three flanges, are possible. Flange piece 1440 may extend radially outward from a central longitudinal axis of device 1400 farther than a circumference of body 1420, to, e.g., support device 1400 if device 1400 is placed on a surface, prevent device 1400 from rolling on a flat surface, and / or allow device 1400 to be picked up more easily.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0376] Channels 1462, 1464, 1468 in blocking component 1460 together form a path through which protrusion 1484 may travel, to allow for controlled movement of plunger rod 1480. A first channel 1462 may allow for sufficient distal movement of plunger rod 1480 to prime device 1400. A second channel 1464 may allow for movement of the plunger rod between a “primed” state and a “delivery” state. Channel 1464 may have a path requiring rotation of plunger rod 1480 about a longitudinal axis of device 1400 (as opposed to distal movement of plunger rod 1480), such that the likelihood of plunger rod 1480 being accidentally or unintentionally moved to a “delivery” state may be reduced. Channel 1464 may provide a path of any suitable length (corresponding to any suitable angle of rotation of plunger rod 1480) to ensure adequate separation between the “primed” state and the “delivery” state. A third channel 1468 may allow for sufficient distal movement of plunger rod 1480 to dispense a predetermined volume of drug substance from device 1400.

[0377] One or more of each channel 1462, 1464, 1468 may include one or more detents, as shown in FIGS. 8F and 8G. For example, a cross sectional view of blocking component 1460 in FIG. 8F shows an interior of channel 1464 having a small detent 1491 disposed on one side. FIG. 8G depicts two larger detents 1492, 1493 in channels 1462, 1464, respectively. Each detent may provide resistance to the movement of protrusion 1484 through channels 1462, 1464, and / or 1468 to provide auditory feedback and / or to prevent unintended movement of protrusion 1484. In some embodiments, detents 1491, 1492, 1493 may be angled on one side, to allow for passage of protrusions 1484 in one direction, but not in the other direction. Detents such as those shown in FIGS. 8F and 8G may be suitable for inclusion in any device disclosed herein, as well as in device 1400.

[0378] FIGS. 9A-9E depict an exemplary method of using device 1400, according to aspects of the present disclosure. In a pre-use configuration depicted in FIG. 9A, device 1400 may hold a volume of a drug substance in between stopper 1422 and expulsion end 1424. Plunger rod 1480 may be partially inserted into body 1420 such that protrusion 1484 of plunger rod 1480 is disposed in a proximal end portion of channel 1462. In a priming step depicted in FIG. 9B, plunger rod 1480 may be moved longitudinally further into body 1420, until distal movement is blocked by the abutment of protrusion 1484 against a distal end of channel 1462. For example, a user may press actuation portion 1482 distally through blocking component 1460. In some embodiments, device 1400 may be held in an inverted position during this step, to ensure that air trapped in body 1420 may be expelled, as stopperClient Ref. 11518WO01Attorney Docket No. 00166-0178-003041422 is pushed distally by plunger rod 1480. In the “primed” configuration, depicted in FIG. 9C, protrusion 1484 of plunger rod 1480 may be disposed at a first end of channel 1464.

[0379] In a dispensing preparation step depicted in FIG. 9D, plunger rod 1480 may be rotated about a longitudinal axis such that protrusion 1484 is moved from a first end of channel 1464 to a second end of channel 1464. For example, a user may grasp and twist actuation portion 1482 of plunger rod 1480. Device 1400 may then be in a ready -to-dispense configuration, wherein protrusion 1484 is disposed at a proximal end of channel 1468. As depicted in FIG. 9E, in a dispensing step, plunger rod 1480 may be moved longitudinally further into body 1420. For example, a user may press actuation portion 1482 distally, until protrusion 1484 abuts a distal end of channel 1468. The dispensing step may ensure that a predetermined volume of a drug substance inside body 1420 is dispensed from device 1400.

[0380] In some embodiments, after each successive step in the use of device 1050, a user may be prevented from re-doing a step, and / or from reversing one or more steps. For example, geometries of, e.g., plunger rod 1480, protrusion 1484, and / or channels 1462, 1464, 1468 may prevent a user from pulling plunger rod 1480 proximally (e.g., out of) body 1420.

[0381] FIGS. 10A-10C depict an exemplary method of assembly of device 1400. As depicted in FIG. 10 A, flange piece 1440 may be slidably assembled to body 1420 such that flange 1421 fits into channel 1445 and collar 1444 partially surrounds body 1420. As depicted in FIG. 10B, blocking component 1460 may be slidably assembled to flange piece 1440, such that tabs 1461 rest within channels 1447 and blocking component 1460 abuts proximal collar 1442. As depicted in FIG. 10C, plunger rod 1480 may then be inserted into the combined blocking component 1460, flange piece 1440, and body 1420, such that protrusion 1484 is disposed within channel 1462 of body 1420.

[0382] FIGS. 10D-10G, 11 A-l IE, and 12A-12D depict a variation on a configuration and method of use of device 1400, and to avoid redundancy will not be described in great detail. FIGS. 10D-10G depict an alternate method of assembly of device 1400, where blocking component 1460 includes an opening 1463 through which plunger rod 1480 may fit. In this embodiment, the channels within blocking component 1460 (e.g., channels 1462, 1468) may be closed on a proximal and distal end, to prevent back-out or over-insertion of plunger rod 1480 relative to body 1420. As depicted in FIG. 10E, plunger rod 1480 may be partially inserted into body 1420, and flange piece 1440 may be slidably assembled to body 1420 such that flange 1421 fits into channel 1445 and collar 1444 partially surrounds body 1420. As depicted in FIG. 10F, blocking component 1460 may be assembledClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 to plunger rod 1480, such that protrusion 1484 is disposed within one of the channels in blocking component 1460. As depicted in FIG. 10G, blocking component 1460 may then be assembled to flange piece 1440 such that it is disposed in channel 1447. Blocking component may be affixed to flange piece 1440 in any suitable manner (e.g., using clips, adhesive, a friction fit, a dovetail connection, etc.). FIGS. 12A-12D depict a close-up view of protrusion 1484 moving through the channels of blocking component 1460, per the method of use shown in FIGS. 11 A- HE.

[0383] FIGS. 13A and 13B depict a further exemplary delivery device 1500, and a method of assembling said delivery device, according to additional embodiments of the present disclosure. Device 1500 includes a plunger rod 1580, a blocking component in the form of flange piece 1540, and a body 1520. To assemble device 1500, plunger rod may be inserted into body 1520 (e.g., as shown in FIG. 13A), such that it abuts or attaches to a stopper 1522 in body 1520, and flange piece 1540 may be slidably assembled to 1521, e.g., by sliding a channel 1541 on to a flange 1521 of body 1520 (e.g., as shown in FIG. 13B). An opening 1543 may allow for flange piece 1540 to be assembled to body 1520 around plunger rod 1580. It is contemplated that, depending on the size, shape, and structure of each component of device 1500, alternate methods of assembly are possible.

[0384] Delivery device 1500 may be, for example, an injection device, such as a syringe, for dispensing a predetermined volume of a formulated drug substance. Generally, delivery device 1500 may share size, capacity, material, preparation, assembly, or manufacturing characteristics with device 1050, device 1200, device 1300, or with other delivery devices disclosed herein. As with other devices disclosed herein, delivery device 1500 may be configured for ease of use and may include one or more features that aid a user by providing tactile, auditory, or visual feedback, using any of the features described elsewhere herein.

[0385] FIG. 14A-14F depict a further view of device 1500 and a method of using device 1500. As shown in FIG. 14A, plunger rod 1580 may include an actuation portion 1582, a proximal stop 1588, a proximal neck portion 1586, and a distal neck portion 1584. Body 1520 may have any or all of the same characteristics as, e.g., body 1060 of device 1050, or as any syringe body known in the art. For example, in some embodiments, body 1520 may be pre-fillable or pre-filled. Stopper 1522 may be configured to be inserted into body 1520 and may be configured to hold a predetermined volume of a formulated drug substance inside body 1520, between stopper 1522 and an expulsion end 1524.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0386] Flange piece 1540 may be of any suitable size and shape to partially close, cover, or partially cover an end of body 1520 opposite expulsion end 1524, and / or to support and hold plunger rod 1580 in body 1520. An opening 1542 may have a size and shape configured to allow passage of plunger rod 1580 in two different configurations. Distal neck portion 1584 and proximal neck portion 1586 may have similar shapes, but may be rotationally offset from one another (e.g., such that once distal neck portion 1584 passes through opening 1542, plunger rod 1580 must be rotated about a longitudinal axis to allow proximal neck portion 1587 to pass. Distal neck portion 1584 may include, e.g., a tapered distal side, which may assist in orienting plunger rod 1580 such that distal neck portion 1584 may pass through opening 1542. This may increase the ease of, e.g., a priming step.

[0387] FIG. 14A depicts a pre-use configuration of device 1500. In such a configuration, device 1500 may hold a volume of a drug substance in between stopper 1522 and expulsion end 1524. Plunger rod 1580 may be partially inserted into body 1520 such that distal neck portion 1584 is positioned proximally from flange piece 1540. In a priming step depicted in FIG. 14B, plunger rod 1580 may be moved longitudinally further into body 1520, until distal movement is blocked by the abutment of proximal neck portion 1586 against opening 1542 (as shown in FIG. 14C). For example, a user may press actuation portion 1582 until distal neck portion passes through opening 1542. In some embodiments, device 1500 may be held in an inverted position during this step, to ensure that air trapped in body 1520 may be expelled, as stopper 1522 is pushed distally by plunger rod 1580. In the “primed” state, depicted in FIG. 14D, proximal neck portion 1586 may be disposed against a surface of flange piece 1540.

[0388] In a dispensing preparation step depicted in FIG. 14D, plunger rod 1580 may be rotated about a longitudinal axis such that the shape of proximal neck portion 1586 aligns with opening 1542. For example, a user may grasp and twist actuation portion 1582 of plunger rod 1580. Device 1500 may then be in a ready -to-dispense configuration. As depicted in FIG. 14E, in a dispensing step, plunger rod 1580 may be moved longitudinally further into body 1520. For example, a user may press actuation portion 1582 distally, until proximal stop 1588 abuts a surface of flange piece 1540. The dispensing step may ensure that a predetermined volume of a drug substance inside body 1520 is dispensed from device 1500.

[0389] In some embodiments, after each successive step in the use of device 1500, a user may be prevented from re-doing a step, and / or from reversing one or more steps. ForClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 example, geometries of, e.g., plunger rod 1580, distal neck portion 1584, proximal neck portion 1586, and opening 1542 may interface with one another to prevent a user from pulling plunger rod 1580 proximally (e.g., out of) body 1520.

[0390] Additional variations on blocking components, dosage control components, and the like will now be described. FIGS. 15A-23C depict exemplary plunger rod dials according to further embodiments of the present disclosure. For example, FIG. 15A depicts a plunger rod 1600 having an actuation portion 1610. Actuation portion 1610 may have a shape generally corresponding to a flange piece 1640. Plunger rod 1600 may be rotatable with respect to flange piece 1640 and / or a body of the device. A device may be in a configuration suitable for delivery of a desired amount of a drug substance when, e.g., a shape of plunger rod 1600 is generally aligned with shape of 1640 (as shown in, e.g., the top view of FIG. 15 A). As another example, FIG. 15B depicts an actuation portion 1610’ with a ridged side, to allow for ease of rotation of plunger rod 1600’ with respect to flange piece 1640 and / or a remainder of the syringe. FIG. 16A depicts an actuation portion 1610” with a ribbed side, again to allow for ease of rotation of plunger rod 1600. FIG. 16B depicts an exemplary combination of actuation portion 1610” with device 1500. One of ordinary skill in the art will understand that any of the actuation portions or other features described herein may be combined with devices described herein.

[0391] FIG. 17 depicts an exemplary plunger rod and dial according to further embodiments of the present disclosure. An actuation portion 1612 may be sized and configured to fit into a collar 1642 of a flange piece 1640’ in only a particular configuration. A depth of collar 1642 may correspond to, e.g., a distance that plunger rod 1600 must travel to dispense a predetermined volume of a drug substance from a drug delivery device. In one embodiment, actuation portion 1612 may be moved distally until it abuts collar 1642, and then may be rotated until its shape corresponds with the shape of collar 1642 so that it may be pushed into collar 1642 in a dispensing step. FIGS 18A and 18B depict a further exemplary plunger rod and dial, which combine exemplary features that allow for precision dose delivery. The plunger rod may include, e.g., protrusions 1684 and 1682, which may each fit through an opening 1641’ in a flange piece 1680 in a particular configuration. Each of protrusions 1682 and 1684 may correspond to a distance required to deliver a desired volume of a drug substance from a device and / or prime the device. Actuation portion 1650 may include a raised portion 1652, which may aid a user in twisting the plunger rod in relation to flange piece 1680.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0392] FIGS. 19A and 19B depict a top view of a flange piece 1740 and a plunger rod 1720. Flange piece 1740 and plunger rod 1720 may have a cross-sectional shape allowing for limited rotation of plunger rod 1720 relative to flange piece 1740 in a single direction. For example, flange piece 1740 may have inner protrusions that may interact with an irregular cross-sectional shape of plunger rod 1720 to resist a first portion of plunger rod 1720 as it rotates past the inner protrusions, and to stop a second portion of plunger rod 1720 when it abuts the inner protrusions.

[0393] FIG. 20 depicts an exemplary flange piece 1750 with a well 1760 having clips 1762. A plunger rod actuation portion 1780 may be pushed distally into well 1760 until clips 1762 overlay actuation portion 1780, to hold actuation portion 1780 in place and, e.g., prevent back-out of the plunger rod. The plunger rod includes a distal protrusion 1781 and a proximal protrusion 1783, each of which is sized to fit through an opening 1764 when the plunger rod is rotated to a particular position. Distal protrusion 1781 includes a tapered distal side, which may assist in orienting the plunger rod into the position required to advance the plunger rod distally such that distal protrusion 1781 passes through opening 1764. This may increase the ease of, e.g., a priming step. In some embodiments, a height of well 1760 and / or actuation portion 1780 may correspond to a height that a plunger rod must travel to dispense a predetermined volume of a drug substance. Thus, a device may be primed when actuation portion 1780 abuts a proximal side of well 1760, and may deliver a predetermined volume of a drug substance as actuation portion 1780 travels distally into well 1760.

[0394] FIG. 21 depicts an exemplary device 1800 with a plunger rod 1820 and a complementary flange piece 1840. Plunger rod 1820 may include, e.g., protrusions 1844, 1846 having an angled or wedge shape, corresponding to a shape of one or more openings 1842 in flange piece 1840. The wedge or angled shapes of protrusions 1844, 1846 and openings 1842 may suffice to resist distal movement of plunger rod 1820 when a protrusion 1844 or 1846 abuts a side of opening 1842, but may be able to move past one another given enough force. The resistance provided by the abutment of protrusions 1844, 1846 against the sides of openings 1842 may suffice to indicate to a user that a particular step in the use of device 1800 is completed. A user may then apply enough force to move plunger rod 1820 past the resistance and continue to a next step (e.g., from a completed priming step to a delivery-ready step).

[0395] As has been described elsewhere, any of the devices disclosed herein may be combined with labels, auditory feedback, and / or tactical feedback in the form of symbolsClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304(e.g., in FIG. 22 depicted as lock and unlock symbols 1850, 1852, chevrons 1856 on actuation portion 1854). Rotation of a plunger rod also may be accompanied by a “clicking” sound.

[0396] FIGS. 23A-23C depict a further exemplary combination of components in a delivery device. For example, a plunger rod actuation portion 1650 may include, e.g., ribbed sides and a raised portion 1652, to assist in twisting the actuation portion. A device with these characteristics may include, e.g., openings 1842 and corresponding angled protrusions 1844, 1846 (described with respect to FIG. 21).

[0397] FIGS. 24A-24E depict a further exemplary delivery device 1900 and a method of using device 1900. Device 1900 may include an actuation portion 1940 and a blocking component 1980 depicted on a plunger rod 1920. Plunger rod 1920 may abut a stopper 1912 in a body 1910. Blocking component 1980 may be rotatable relative to plunger rod 1920. In a pre-use configuration depicted in FIG. 24B, blocking component 1980 may be in a first position with respect to plunger rod 1920 and flange piece 1960. In a priming step depicted in FIG. 24C, plunger rod 1920 may be moved longitudinally further into body 1910, until distal movement is blocked by the abutment of blocking component 1980 against a recess 1962 in flange piece 1960. For example, a user may press actuation portion 1940 distally towards flange piece 1960. In a dispensing preparation step depicted in FIG. 24D, blocking component 1980 may be rotated such that a shorter dimension of blocking component 1980 faces flange piece 1960. Recess 1962 may be curved to allow for ease of rotation of blocking component 1980. A distance between blocking component 1980 and flange piece 1960 after blocking component 1980 is rotated may correspond to a distance that plunger rod 1920 may move to dispense a predetermined volume of a drug substance from device 1900. As depicted in FIG. 24E, in a dispensing step, plunger rod 1920 may be moved longitudinally further into body 1910, until the rotated blocking component 1980 abuts flange piece 1960 in a second position. For example, a user may press actuation portion 1940 distally, until protrusion blocking component abuts flange piece 1960. The dispensing step may ensure that a predetermined volume of a drug substance inside body 1910 is dispensed from device 1900.

[0398] FIGS. 25A-25E depict a further exemplary delivery device 2000, and a method of using delivery device 2000. A plunger rod 2080 of device 2000 may include threads 2100, corresponding to inner threads (not pictured) in a flange piece 2062. As depicted in FIG. 25 A, plunger rod 2080 may be rotatable relative to other portions of deviceClient Ref. 11518WO01Attorney Docket No. 00166-0178-003042000. Plunger rod 2080 may also include a protrusion 2082 located proximally from threads 2100 (see, e.g., FIG. 25B), which may correspond to an opening in a flange piece 2062, such that plunger rod 2080 must be in a particular configuration and position to allow protrusion 2082 to pass into and / or through flange piece 2060. In a pre-use configuration depicted in FIG. 25C, threads 2100 and protrusion 2082 may be positioned proximally to flange piece 2060. In a priming step, plunger rod 2080 may be rotated with respect to the inner threads of flange piece 2060 until threads 2100 pass through flange piece 2060 and / or protrusion 2082 prevents further rotation or distal movement of plunger rod 2080. In a dispensing preparation step, protrusion 2082 may be moved towards opening in flange piece 2062. In a dispensing step, protrusion 2082 may be moved through opening in flange piece 2062 to further advance plunger rod 2080, and to dispense a predetermined volume of a drug substance inside the body of device 2000.

[0399] FIGS. 26A-26E depict a delivery device 2200 having further variations on dosage control components. For example, device 2200 includes a plunger rod 2280 with one or more clips 2284, each of which may be configured to slide distally into a channel 2242 of a flange piece 2240 and, once having slid distally, to resist sliding proximally out of channel 2242 (e.g., to prevent or resist back-out of plunger rod 2280). Flange piece 2240 may further have a second channel 2244 and a third channel 2246, through which each of clips 2284 may slide in delivery preparation and dosage delivery steps, as has been previously described. Alternately, as shown in FIG. 26B, channel 2242’ may have an open proximal end through which a protrusion 2284’ may move, allowing for proximal and / or distal movement of a plunger rod 2280 relative to flange piece 2240’. As depicted in FIG. 26C, in a pre-use configuration, clips 2284 may be disposed proximally to channels 2242 of flange piece 2240. In a priming step, plunger rod 2280 may be moved distally into a body of device 2200, until clips 2284 move into channels 2242 and abut a distal end of channels 2242. In a dispensing preparation step, plunger rod 2280 may be rotated relative to flange piece 2240. In a dispensing step, plunger rod 2280 may be moved further distally into a body of device 2200 to dispense a predetermined volume of the drug substance from device 2200.

[0400] In other embodiments, as shown in FIGS. 26F-26G, a flange piece 2240" may include one or more projections 2246" disposed within a collar 2242". In the present example, collar 2242" may include a pair of projections 2246" extending radially inward from an interior surface of collar 2242" and in opposite directions relative to another. For example, projections 2246” may be disposed approximately 180 degrees away from one another. ItClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 should be appreciated that flange piece 2240" may include additional and / or fewer projections 2246" than those shown and described herein without departing from a scope of this disclosure. Flange piece 2240" may be configured to engage a plunger rod 2080" in response to plunger rod 2280" receiving projections 2246".

[0401] As seen in FIG. 26G, a plunger rod 2280" may include an actuation member 2284" defined by a proximal end 2282" and a distal end 2283". Plunger rod 2280" may include a series of channels along opposing sides of actuation member 2284", such as, for example, a first channel 2286", a second channel 2288", and a third channel 2290" positioned between proximal end 2282" and distal end 2283". First channel 2286" is offset from third channel 2290" and connected to third channel 2290" by second channel 2288" positioned therebetween. As described in detail below, first channel 2286" may define a longitudinal and axial priming path of plunger rod 2280", second channel 2288" may define a circumferential path of plunger rod 2280", and third channel 2290" may define a longitudinal and axial dose completion path. It should be appreciated that an opposing surface and / or side of actuation member 2284" (not shown) includes a substantially similar series of interconnected first channel 2286", second channel 2288", and third channel 2290" as seen in FIG. 26G. In the present example, first channel 2286" and third channel 2290" may be aligned parallel relative to one another.

[0402] First channels 2286", second channels 2288", and third channels 2290" may be sized, shaped, and configured to receive at least one of the pair of projections 2246". With plunger rod 2280" coupled to flange piece 2240", projections 2246" may protrude and slide through first channels 2286", second channels 2288", and third channels 2290" to prime and deliver a dosage from device 2200 (FIG. 26A) as described in detail above. In some embodiments, first channels 2286" may have an open end at proximal end 2282" through which projections 2246" may be received in. In some embodiments, first channels 2286" may have a closed proximal end and projections 2246" may be at least partially flexible and / or deformable such that projections 2246" may be configured to flex radially-outward when being received at the proximal end of first channels 2286". In other embodiments, first channels 2286" may have a sloped, chamfered, and / or tapered end to facilitate guiding projections 2246" toward second channels 2288". In this instance, the sloped end may inhibit retraction (e.g., proximal movement) of plunger rod 2280" relative to flange piece 2240". A longitudinal length of first channels 2286" may define an axial priming path (e.g., an amount or extent priming) that is configured to facilitate proximal and / or distal movement of plungerClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 rod 2280" relative to flange piece 2240". For example, projections 2246" may be disposed at a proximal end of first channels 2286" and proximally of second channels 2288" when device 2200 is in an assembly state. In a priming step, plunger rod 2280" may move distally relative to flange piece 2240" until projections 2246" are positioned within second channels 2288" and at a distal end of first channels 2286". Second channels 2288" may define a circumferential path of plunger rod 2280".

[0403] In a dispensing preparation step, plunger rod 2280" may be rotated relative to flange piece 2240" to translate projections 2246" laterally through the circumferential path of second channels 2288" and toward a dose completion path defined by third channels 2290". In some embodiments, plunger rod 2280" and / or flange piece 2240" may be configured to generate a user feedback (e.g., tactile, audible, visual, etc.) when device 1050 is in the dispensing preparation step. In a dispensing step, plunger rod 2280" may move distally into a body of device 2200 to dispense a controlled volume of substance by translating projections 2246" through third channels 2290". A longitudinal length of third channels 2290" may define a dosage delivery path (e.g., a dosage amount). It should be appreciated that the axial priming path (length of first channels 2286") may vary relative to the dosage delivery path (length of third channels 2290"). In other embodiments, plunger rod 2280" may include additional and / or fewer channels along actuation member 2284" (e.g., corresponding to a quantity of projections 2246" on flange piece 2240"), or have various other relative channel configurations, than those shown and described herein.

[0404] FIGS. 27A-27H depict an exemplary delivery device 2300 and method of using delivery device 2300. An actuation portion 2350 may also serve as a blocking component of device 2300. Actuation portion 2350 may be slidably coupled to plunger rod 2380 in two configurations, via a channel 2352. As depicted in FIG. 27B, one side of actuation portion 2350 may include a channel 2354. A depth of channel 2354 may correspond to a distance that a plunger rod may move to dispense a predetermined volume of a drug substance once device 2300 has been primed. As depicted in FIG. 27C and FIG. 27D, in a pre-use configuration, actuation portion 2350 may be assembled onto plunger rod 2380 such that a flat side of actuation portion 2350 faces a collar 2360 of device 2300. In a priming step, actuation portion 2350 may be used to move plunger rod 2380 distally until the flat side 2356 of actuation portion 2350 abuts a proximal side of collar 2360. To prepare for a dosage delivery step, actuation portion 2350 may be removed from plunger rod 2380, and may be rotated or flipped and reassembled with plunger rod 2380 such that channel 2354Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 faces collar 2360, as depicted in FIGS. 27F and 27G. In a dosage delivery step, actuation portion 2350 may be used to push plunger rod 2380 further distally, until a proximal end of collar 2360 abuts an inner end of channel 2354. This movement of plunger rod 2380 may be sufficient to dispense a predetermined dose of a drug substance from device 2300.

[0405] FIGS. 28A-28C depict an exemplary delivery device 2400 and method of using delivery device 2400. Delivery device 2400 may include substantially similar features as those shown and described above such that like reference numerals are used to identify like components. As shown in FIG. 28A, delivery device 2400 may include a removable clip 2402 coupled to body 1060 at a position distal to flange piece 1070. Removable clip 2402 may be an obstruction and / or blocking component configured to inhibit movement of flange piece 1070 relative to body 1060. Removable clip 2402 is selectively removable such that removable clip 2402 may be configured to disengage body 1060 in response to manual actuation of removable clip 2402.

[0406] By way of illustrative example, removable clip 2402 may have a body that wraps about an exterior of body 1060 and is configured to selectively deform (e.g., break, tear, etc.) upon application of a force thereto to decouple removable clip 2402 from body 1060. In other examples, removable clip 2402 may have a flexible body that is configured to bend in response to a radially-outward force being applied thereto, thereby disengaging removable clip 2402 from body 1060. By way of further example, removable clip 2402 may have a body that is configured to selectively transition between a closed configuration encapsulating a circumference of body 1060 therein and an open configuration permitting removal of body 1060 from the body of removable clip 2402. Removable clip 2402 may include various other suitable sizes, shapes, and / or configurations than those shown and described herein without departing from a scope of the present disclosure.

[0407] Delivery device 2400 may include a radial wall 1063 extending laterally outward from an exterior of body 1060, thereby forming an obstruction along body 1060. As seen in FIG. 28 A, radial wall 1063 may be configured to inhibit distal translation of removable clip 2402 along body 1060. In some embodiments, radial wall 1063 may be an add-component attached to body 1060, while in other embodiments, radial wall 1063 may be integrally formed onto body 1060. Referring now to FIG. 28B, flange piece 1070 and plunger rod 1080 may be configured to translate distally along body 1060 to prime delivery device 2400 upon removal of removable clip 2402 from body 1060. In this instance, plunger rod 1080 may remain stationary relative to flange piece 1070, as the combined assembly ofClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 flange piece 1070 and plunger rod 1080 moves relative to body 1060. In other embodiments, plunger rod 1080 may remain stationary as flange piece 1070 translates distally along body 1060 to prime delivery device 2400. For example, at least a portion of flange piece 1070 may extend into body 1060 (e.g., and behind stopper 1062) when priming device 2400. In this instance, plunger rod 1080 may be translated separately to deliver a dosage from delivery device 2400.

[0408] With flange piece 1070 translated from a proximal position (FIG. 28 A) to a distal position (FIG. 28B), delivery device 2400 may be in a primed position. It should be appreciated that body 1060 may be configured to limit movement by flange piece 1070 to a defined distance based on a location of radial wall 1063, which may correspond to a priming distance of delivery device 2400. Accordingly, a priming distance of delivery device 2400 may be controlled by adjusting a range of movement of flange piece 1070 along body 1060.

[0409] As seen in FIG. 28C, plunger rod 1080 may be translated distally relative to body 1060 in response to applying a distally-directed force onto actuation portion 1082. In this instance, stem 1081 may move relative to flange piece 1070, thereby causing stopper 1062 to move within body 1060 to deliver a dose. It should be appreciated that an extent that plunger rod 1080 translates relative to flange piece 1070 may define a dosage delivery distance of delivery device 2400. The dosage delivery distance may be controlled based on a gap formed between collar 1072 and actuation portion 1082.

[0410] In other embodiments, as seen in FIGS. 28D-28F, delivery device 2400 may further include a locking component, such as, for example, a removable rod 2404 coupled to flange piece 1070. Referring specifically to FIG. 28D, removable rod 2404 may be received through a proximal end of collar 1072, such as, for example, through one or more lateral apertures (not shown) formed through collar 1072. Removable rod 2404 may be configured to inhibit movement of plunger rod 1080 relative to flange piece 1070, such as, for example, preventing receipt of actuation portion 1082 into collar 1072. Removable rod 2404 may be selectively removable and configured to disengage collar 1072 upon manual actuation of removable rod 2404. It should be appreciated that delivery device 2400 may include various other locking components in addition to and / or in lieu of removable rod 2404, such as, for example, a pin, a tab, a bar, and the like.

[0411] For example, referring now to FIG. 28E, flange piece 1070 and plunger rod 1080 (e.g., stem 1081 and actuation portion 1082) may be configured to translate distally along body 1060 to prime delivery device 2400 in response to removal of removable clipClient Ref. 11518WO01Attorney Docket No. 00166-0178-003042402 from body 1060. Plunger rod 1080 may remain stationary relative to flange piece 1070 as the assembly of flange piece 1070 and plunger rod 1080 moves relative to body 1060. With flange piece 1070 translated from a proximal position (FIG. 28D) to a distal position (FIG. 28E), delivery device 2400 may be in a primed position. It should be appreciated that body 1060 may be configured to limit movement by flange piece 1070 to a defined distance based on a location of radial wall 1063 along body 1060, which may correspond to a priming distance of delivery device 2400.

[0412] As seen in FIG. 28F, removable rod 2404 may be disengaged from collar 1072 such that plunger rod 1080 is no longer inhibited from moving distally relative to flange piece 1070. Actuation portion 1082 may be translated into collar 1072 to move stem 1081 and stopper 1062 within body 1060 to deliver a dose. An extent that plunger rod 1080 translates relative to flange piece 1070 may define a dosage delivery distance of delivery device 2400.

[0413] In other embodiments, as seen in FIGS. 28G-28I, removable clip 2402 may be omitted entirely such that delivery device 2400 may include a single obstruction and / or blocking component, i.e., rod 2404. In this instance, flange piece 1070 may be fixed relative to body 1060. With actuation portion 1082 positioned proximally of rod 2404, delivery device 2400 may be primed in response to plunger rod 1080 translating distally toward flange piece 1070 until encountering rod 2404. It should be appreciated that flange piece 1070 and / or rod 2404 may be configured to inhibit distal translation of plunger rod 1080 relative thereto absent an application of a distally-directed force thereto. In other examples, delivery device 2400 may include a blocking component positioned between actuation portion 1082 and rod 2404 (e.g., removable clip 2402) to inhibit distal movement of plunger rod 1080.

[0414] Accordingly, a priming distance of delivery device 2400 may be defined by a distance between the distal end of actuation portion 1082 and rod 2404 when delivery device 2400 is in an assembled, pre-primed state (FIG. 28G). With actuation portion 1082 engaged against rod 2404, as seen in FIG. 28H, delivery device 2400 may be in a primed state. Rod 2404 may be removed from collar 1072 to thereby allow further translation of plunger rod 1080 distally relative to flange piece 1070. As shown in FIG. 281, a dose may be delivered from delivery device 2400 in response to collar 1072 receiving actuation portion 1082. It should be appreciated that a longitudinal offset of a distal end of actuation portion 1082 and an inner surface of collar 1072 may be determinative to a dosage delivery distance. Accordingly, an extent (e.g., the dosage delivery distance) that plunger rod 1080 translatesClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 relative to flange piece 1070 may define a volume of dosage delivered by delivery device 2400.

[0415] In further embodiments, as shown in FIGS. 28J-28L, delivery device 2400 may include a fixed clip 2406 attached to body 1060 at a location relatively distal of removable clip 2402. Fixed clip 2406 may be an obstruction and / or blocking component positioned in contact with removable clip 2402 such that fixed clip 2406 may be configured to inhibit movement of removable clip 2402 along body 1060. With flange piece 1070 positioned proximally of removable clip 2402, fixed clip 2406 may be further configured to inhibit movement of flange piece 1070 when removable clip 2402 is positioned therebetween.

[0416] Referring now to FIG. 28K, flange piece 1070 may be configured to translate distally along body 1060 to prime delivery device 2400 upon removing removable clip 2402 from body 1060. In this instance, plunger rod 1080 may remain stationary relative to flange piece 1070 as the assembly of plunger rod 1080 and flange piece 1070 moves toward fixed clip 2406. With flange piece 1070 translated from a proximal position (FIG. 28 J) to a distal position (FIG. 28K) engaged against fixed clip 2406, delivery device 2400 may be in a primed position. It should be appreciated that body 1060 may be configured to limit movement by flange piece 1070 to a defined distance, which may correspond to a priming distance of delivery device 2400.

[0417] As seen in FIG. 28L, plunger rod 1080 may be translated distally relative to body 1060 in response to applying a distally-directed force onto actuation portion 1082. Stem 1081 may move relative to flange piece 1070, causing stopper 1062 to move within body 1060 to deliver a dose. It should be appreciated that an extent that plunger rod 1080 translates relative to flange piece 1070 may define a dosage delivery distance of delivery device 2400. The dosage delivery distance may be controlled based on a position of fixed clip 2406 along body 1060.

[0418] In further embodiments, delivery device 2400 may include a sleeve 2408 extending distally from flange piece 1070, as shown in FIG. 28M. Sleeve 2408 may be attached to a distal end of flange piece 1070 and / or be integral with flange piece 1070, thereby forming a unitary structure. Sleeve 2408 may be disposed within body 1060 and include a distal end 2410. Sleeve 2408 may define a lumen that is sized and shaped to receive stem 1081 when plunger rod 1080 is coupled to flange piece 1070. As described in further detail herein, sleeve 2408 may be configured to move within a lumen of body 1060 in response to flange piece 1070 translating along an exterior of body 1060.Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0419] Sleeve 2408 may further include a locking component, such as, for example, a second protrusion 2412 formed along an interior surface of sleeve 2408 such that second protrusion 2412 extends at least partially into the lumen defined by sleeve 2408. In the embodiment, second protrusion 2412 is positioned relatively proximal of distal end 2410. In other embodiments, sleeve 2408 may include various other suitable locking components in lieu of second protrusion 2412, such as, for example, an opening sized, shaped, and configured to receive protrusion 1085.

[0420] Referring specifically to FIG. 28M, protrusion 1085 may extend radially outward from stem 1081 and positioned proximally relative to second protrusion 2412 when plunger rod 1080 is received through flange piece 1070 and sleeve 2408. To prime delivery device 2400, plunger rod 1080 may be translated distally relative to flange piece 1070 and sleeve 2408 until protrusion 1085 contacts second protrusion 2412. It should be appreciated that an extent that plunger rod 1080 translates relative to sleeve 2408 may define a priming distance of delivery device 2400. The priming distance may be controlled based on a position of protrusion 1085 and second protrusion 2412 relative to one another.

[0421] With protrusion 1085 engaged against second protrusion 2412 and a distal end of actuation portion 1082 received against an inner surface of collar 1072, plunger rod 1080 may be coupled to sleeve 2408 and delivery device 2400 may be in a primed state, as shown in FIG. 28N. Actuation portion 1082 may be fully received within collar 1072 and stem 1081 may be locked onto sleeve 2408. Accordingly, further translation of plunger rod 1080 may provide translation of flange piece 1070 and sleeve 2408 relative to body 1060. For example, as seen in FIG. 280, plunger rod 1080 and flange piece 1070 may be translated distally relative to body 1060 in response to applying a distally-directed force onto actuation portion 1082. Stem 1081 may move relative to body 1060, causing stopper 1062 to move within body 1060 to deliver a dose.

[0422] Distal end 2410 may translate toward expulsion end 1064 as plunger rod 1080 and flange piece 1070 move distally until encountering fixed clip 2406. It should be appreciated that an extent that plunger rod 1080 and flange piece 1070 translate may define a dosage delivery distance of delivery device 2400. The dosage delivery distance may be controlled based on a position of fixed clip 2406 along body 1060.

[0423] In other embodiments, as seen in FIGS. 28P-28Q, delivery device 2400 may include an obstruction and / or blocking component in the form of a pull tab 2420. Pull tab 2420 may include a body 2422 having a circular-cross section defining a center openingClient Ref. 11518WO01Attorney Docket No. 00166-0178-003042424. Body 2422 may be formed of various flexible materials, including, for example, plastic, rubber, and the like. As described in further detail herein, pull tab 2420 may be frangible and / or deformable in response to an application of force onto body 2422. Pull tab 2420 may further include a graspable feature 2426 extending outwardly from body 2422 and configured to facilitate manual actuation of pull tab 2420. As seen in FIG. 28P, graspable feature 2426 may be integrally formed with body 2422 such that applying a radially-outward force (e.g., a pulling force) onto graspable feature 2426 may cause body 2422 to deform (e.g., tear, break, etc.), as shown in FIG. 28Q.

[0424] Referring now to FIG. 28R, pull tab 2420 may be secured to flange piece 1070 along a proximal end of collar 1072. Pull tab 2420 may be disposed over collar 1072 such that flange piece 1070 is separated from actuation portion 1082 by pull tab 2420 positioned therebetween. Stem 1081 may be received through center opening 2424 and into collar 1072 when body 2422 is attached to collar 1072. Pull tab 2420 may be configured to inhibit translation of actuation portion 1082 into collar 1072. A thickness and / or width of body 2422 may be sized such that a diameter of center opening 2424 is smaller than a diameter of actuation portion 1082 to block actuation portion 1082 from passing through pull tab 2420.

[0425] Delivery device 2400 may be primed in response to translating plunger rod 1080 distally relative to flange piece 1070 until encountering body 2422, as seen in FIG. 28S. It should be appreciated that an extent plunger rod 1080 translates relative to flange piece 1070 may correspond to a priming distance of delivery device 2400. The priming distance may be controlled based on a thickness of body 2422, thereby varying a relative distance between actuation portion 1082 and collar 1072. With actuation portion 1082 engaged against body 2422, graspable feature 2426 may be actuated to remove (e.g., break, tear, pull, etc.) pull tab 2420 from collar 1072. In this instance, body 2422 may be deformed (see FIG. 28Q) and disengaged from flange piece 1070, thereby permitting further translation of plunger rod 1080 distally relative to flange piece 1070.

[0426] As seen in FIG. 28T, actuation portion 1082 may be received within collar 1072 in response to applying a distally-directed force onto actuation portion 1082. Stem 1081 may move relative to body 1060, causing stopper 1062 to move within body 1060 to deliver a dose. It should be appreciated that an extent that plunger rod 1080 translates relative to collar 1072 may correspond to a dosage delivery distance of delivery device 2400. The dosage delivery distance may be controlled based on a thickness of pull tab 2420, thereby varying aClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 relative distance between actuation portion 1082 and a distal (e.g., bottom) end of collar 1072.

[0427] In further embodiments, as shown in FIGS. 28U-28X, delivery device 2400 may include a removable cap 2430 coupled to plunger rod 1080. Removable cap 2430 may include a body 2432 defining a cavity 2434 that is sized and shaped to receive at least a portion of plunger rod 1080 therein (e.g., actuation portion 1082). Removable cap 2430 may include an opening along a bottom (e.g., distal) wall of body 2342 for receiving stem 1081. In some embodiments, removable cap 2430 may be attached to actuation portion 1082, while in other embodiments body 2342 may be directly coupled to stem 1081. Removable cap 2430 may be an obstruction and / or blocking component configured to increase a cross-sectional profile of actuation portion 1082 to inhibit movement of plunger rod 1080 relative to flange piece 1070, and more specifically to prevent translation of actuation portion 1082 into collar 1072.

[0428] Referring now to FIG. 28V, plunger rod 1080 may be configured to translate distally relative to flange piece 1070 to prime delivery device 2400 until a bottom wall of body 2432 encounters a proximal end of collar 1072. Removable cap 2430 may inhibit actuation portion 1082 from being received within collar 1072 due to at least a portion of body 2342 being disposed between actuation portion 1082 and collar 1072. With plunger rod 1080 translated from a proximal position (FIG. 28U) to a distal position (FIG. 28V) with body 2432 engaged against collar 1072, delivery device 2400 may be in a primed position. It should be appreciated that an extent that plunger rod 1080 translates relative to flange piece 1070 may correspond to a priming distance of delivery device 2400. The priming distance may be controlled based on a size of removable cap 2430 and / or a position of removable cap 2430 relative to plunger rod 1080. For example, in other embodiments, a bottom wall of body 2432 may be secured to a proximal portion of stem 1081 positioned relatively distal of actuation portion 1082. In this instance, a priming distance of delivery device 2400 may be reduced relative to that shown and described herein as body 2432 may be positioned in closer proximity to collar 1072. Accordingly, plunger rod 1080 may be required to move a smaller distance for removable cap 2430 to encounter collar 1072.

[0429] As seen in FIG. 28X, removable cap 2430 may be detached from plunger rod 1080 such that actuation portion 1082 may be exposed from body 2432. Plunger rod 1080 may be translated distally relative to body 1060 and received within collar 1072 in response to applying a distally-directed force onto actuation portion 1082. Stem 1081 may moveClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 relative to flange piece 1070, causing stopper 1062 to move within body 1060 to deliver a dose. It should be appreciated that an extent that plunger rod 1080 translates relative to flange piece 1070 may correspond to a dosage delivery distance of delivery device 2400. The dosage delivery distance may be controlled based on an attachment of removable cap 2430 relative to actuation portion 1082 and / or stem 1081 as described above. Further, a depth of collar 1072 may be determinative of the dosage delivery distance such that a size of collar 1072 may be adjusted accordingly to form various suitable dosage delivery distances.

[0430] For example, attaching removable cap 2430 such that a distal wall of removable cap 2430 is positioned flush against a distal end of actuation portion 1082 may increase a relative priming distance of delivery device 2400 by providing a longer separation between removable cap 2430 and collar 1072. Accordingly, the attachment position of removable cap 2430 may correspond to a smaller dosage delivery distance upon translating actuation portion 1082 into collar 1072 after removal of removable cap 2430. Alternatively, attaching removable cap 2430 such that the distal wall of removable cap 2430 is positioned distally from the distal end of actuation portion 1082 may decrease a relative priming distance, thereby providing a greater dosage delivery distance as actuation portion 1082 may require further longitudinal translation to be fully received within collar 1072. It should be appreciated that a size and / or shape of removable cap 2430 may vary to accommodate the various attachment positions described above.

[0431] In some embodiments, as shown in FIGS. 28W-28Z, delivery device 2400 may include one or more tabs 2440 secured to plunger rod 1080, such as, for example, along actuation portion 1082, stem 1081, and / or various other portions of plunger rod 1080. In the example, delivery device 2400 includes a pair of tabs 2440 extending radially outward from a distal end of actuation portion 1082. Tabs 2440 may be an obstruction and / or blocking component configured to increase a cross-sectional profile of actuation portion 1082 to inhibit movement of plunger rod 1080 relative to flange piece 1070, and more specifically to inhibit translation of actuation portion 1082 into collar 1072. In some embodiments, tabs 2440 may be selectively removable from actuation portion 1082 upon an application of force thereto. In other embodiments, tabs 2440 may be compressible and configured to be pushed into actuation portion 1082 in response to an application of force thereto. In either instance, tabs 2440 may be configured to transition actuation portion 1082 from an expanded profile (FIGS. 28W-28Y) to a compressed profile (FIG. 28Z).Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304

[0432] Referring now to FIG. 28 Y, plunger rod 1080 may be configured to translate distally relative to flange piece 1070 to prime delivery device 2400 until tabs 2440 encounter a proximal end of collar 1072. Tabs 2440 may inhibit collar 1072 receiving actuation portion 1082 therein. With plunger rod 1080 translated from a proximal position (FIG. 28W) to a distal position (FIG. 28 Y) with tabs 2440 engaged against collar 1072, delivery device 2400 may be in a primed position. It should be appreciated that an extent that plunger rod 1080 translates relative to flange piece 1070 may correspond to a priming distance of delivery device 2400.

[0433] The priming distance may be controlled based on a size (e.g., thickness, width, height, etc.) of tabs 2440 and / or a position of tabs 2440 relative to plunger rod 1080. For example, in other embodiments, the pair of tabs 2440 may be secured to an intermediate and / or proximal portion of actuation portion 1082, or alternatively along stem 1081. In this instance, a priming distance of delivery device 2400 may be increased and / or decreased, respectively, relative to that shown and described herein.

[0434] As seen in FIG. 28Z, tabs 2440 may be compressed into actuation portion 1082 by collar 1072 applying an inward, pushing force thereto (or alternatively decoupled from actuation portion 1082 by applying an outward, pulling force, a rotating snapping force, or the like) such that actuation portion 1082 may form a smaller cross-sectional profile. Plunger rod 1080 may be translated distally relative to body 1060 and received within collar 1072 in response to applying a distally-directed force onto actuation portion 1082. Stem 1081 may move relative to flange piece 1070, causing stopper 1062 to move within body 1060 to deliver a dose. It should be appreciated that an extent that plunger rod 1080 translates relative to flange piece 1070 may correspond to a dosage delivery distance of delivery device 2400. As described above, the dosage delivery distance may be controlled based on a position of tabs 2440 relative to actuation portion 1082, a size (e.g., longitudinal depth) of collar 1072, and the like. For example, a relative position of tabs 2440 that increases a priming distance of delivery device 2400 may correspond to a smaller dosage delivery distance, and a position of tabs 2440 that corresponds to a reduced priming distance may provide a greater dosage delivery distance. In other examples, plunger rod 1080 may include a second set of tabs (not shown) along actuation portion 1082 which may define a dosage delivery distance based on a relative position of the tabs relative to tabs 2440.

[0435] FIGS. 29A-29C depict an exemplary delivery device 2500 and method of using delivery device 2500. Delivery device 2500 may include substantially similar featuresClient Ref. 11518WO01Attorney Docket No. 00166-0178-00304 as those shown and described above such that like reference numerals are used to identify like components. As shown in FIG. 29A, delivery device 2500 may include a plunger rod 2580 comprising a first actuation portion 2502, a second actuation portion 2504, and a cam lever 2510. First actuation portion 2502 may be coupled to second actuation portion 2504 by one or more arms 2506. In the example, a pair of arms 2506 may be fixed to first actuation portion 2502 along a first end of arms 2506, and arms 2506 may be further coupled to second actuation portion 2504 at a second end of arms 2506 that is opposite of the first end. Second actuation portion 2504 may be a rotatable element including a proximal end 2505 and an opposing distal end having a joint 2508. The pair of arms 2506 may be coupled to the distal end of second actuation portion 2504 at joint 2508.

[0436] It should be understood that, when in a ready position as seen in FIG. 29 A, second actuation portion 2504 may be oriented such that joint 2508 is positioned proximate to first actuation portion 2502 relative to proximal end 2505. A proximal end 1088 of stem 1081 may be positioned adjacent to joint 2508 at a distal end of second actuation portion 2504. For example, proximal end 1088 may be in contact with and / or abut against the distal end of second actuation portion 2504. In some embodiments, stem 1081 may extend through a center of first actuation portion 2502 and / or be positioned alongside first actuation portion 2502. Second actuation portion 2504 may be configured to move relative to first actuation portion 2502 and about joint 2508. Cam lever 2510 may be coupled to second actuation portion 2504 at joint 2508 and configured to move (e.g., rotate, pivot, translate, etc.) second actuation portion 2504 relative to first actuation portion 2502. Accordingly, it should be appreciated that second actuation portion 2504 may be configured to move stem 1081 relative to body 1060 in response to ...

Claims

Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304What is claimed is:

1. A drug delivery device, comprising: a body storing a medicament, wherein the body is silicone-free; a plunger rod having a proximal end, a distal end contacting a stopper inside the body, and a pair of protrusions extending outwards from the proximal end; and a flange coupled to the body, the flange including a proximal collar and a pair of slots positioned along the proximal collar; wherein the flange is configured such that when the pair of protrusions and the pair of slots are misaligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions contacting the proximal collar to prime the drug delivery device by expelling air or at least a portion of the medicament stored in the body; and wherein the flange is configured such that when the pair of protrusions and the pair of slots are aligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions extending into the pair of slots to deliver the medicament from the body.

2. The drug delivery device of claim 1, wherein the plunger rod includes a pair of extensions extending distally from the proximal end, and the flange includes a channel defined by an interior surface and a pair of grooves formed on the interior surface.

3. The drug delivery device of claim 2, wherein the flange is configured such that the pair of extensions are misaligned with the pair of grooves when the pair of protrusions and the pair of slots are misaligned with one another.

4. The drug delivery device of claim 2, wherein the interior surface is configured to engage the pair of extensions when the pair of protrusions and the pair of slots are misaligned and the plunger rod translates distally through the channel via a first stroke; and wherein the pair of grooves is configured to receive the pair of extensions when the pair of protrusions and the pair of slots are aligned and the plunger rod translates distally through the channel via a second stroke.Client Ref. 11518WO01Attorney Docket No. 00166-0178-003045. The drug delivery device of claim 4, wherein the flange is configured to compress the pair of extensions radially inwards relative to the proximal end of the plunger rod upon the interior surface engaging the pair of extensions as the plunger rod translates distally relative to the flange by the first stroke while the pair of protrusions and the pair of slots are misaligned.

6. The drug delivery device of claim 4, wherein the flange is configured to receive the pair of extensions in the pair of grooves upon the plunger rod rotating relative to the flange to align the pair of protrusions with the pair of slots.

7. The drug delivery device of claim 5, wherein the pair of extensions are configured to expand radially outwards relative to the proximal end upon the pair of grooves receiving the pair of extensions as the plunger rod rotates relative to the flange to align the pair of protrusions with the pair of slots.

8. The drug delivery device of claim 5, wherein the pair of extensions are configured to translate distally through the pair of grooves in response to the plunger rod translating distally relative to the flange by the second stroke to position the pair of protrusions into the pair of slots.

9. The drug delivery device of claim 2, wherein the flange includes a pair of openings formed in the proximal collar, the pair of openings are configured to at least partially receive the pair of extensions when the plunger rod is coupled to the flange prior to the pair of protrusions contacting the proximal collar to prime the drug delivery device.

10. The drug delivery device of claim 9, wherein the flange is configured to inhibit proximal and rotational movement of the plunger rod relative to the body while the pair of extensions are received within the pair of openings; and wherein the pair of extensions are configured to exit the pair of openings upon distal movement of the plunger rod relative to the body to prime the drug delivery device.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030411. The drug delivery device of claim 1, wherein the body and the stopper are silicone-free such that an interior surface of the body and an exterior surface of the stopper each excludes a coating layer that includes silicone.

12. The drug delivery device of claim 1, wherein the distal portion of the plunger rod includes a neck and a stem that is positioned distally of the neck, the plunger rod includes a cross-sectional shape that varies along a longitudinal length of the neck; and wherein the flange includes an opening that is configured to interface with the neck and the stem to control longitudinal and rotational movement of the plunger rod relative to the flange.

13. The drug delivery device of claim 12, wherein the neck includes a first portion having a first cross-sectional shape that is configured to permit distal movement of the plunger rod relative to the flange and inhibit rotational movement of the plunger rod relative to the flange when the first portion is received within the opening.

14. The drug delivery device of claim 13, wherein the neck includes a second portion that is positioned distally relative to the first portion, the second portion having a second cross-sectional shape that is configured to permit distal movement and rotational movement of the plunger rod relative to the flange when the second portion is received within the opening.

15. The drug delivery device of claim 14, wherein the neck includes a third portion that is positioned distally relative to the second portion, the third portion having a third cross-sectional shape that is configured to permit distal movement of the plunger rod relative to the flange when the third portion is received within the opening and inhibit proximal movement of the plunger rod relative to the flange when the third portion is rotatably misaligned with the opening.

16. A drug delivery device, comprising: a body containing an aqueous pharmaceutical formulation comprising a VEGF antagonist;Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 a plunger rod having a proximal end, a distal end contacting a stopper inside the body, and a pair of protrusions extending outwards from the proximal end; and a flange coupled to the body, the flange including a proximal collar and a pair of slots positioned along the proximal collar; wherein the flange is configured such that when the pair of protrusions and the pair of slots are misaligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions contacting the proximal collar to prime the drug delivery device by expelling air or at least a portion of the aqueous pharmaceutical formulation in the body; and wherein the flange is configured such that when the pair of protrusions and the pair of slots are aligned with one another, distal movement of the plunger rod relative to the body is limited upon the pair of protrusions extending into the pair of slots to deliver the VEGF antagonist from the body.

17. The drug delivery device of claim 16, wherein the VEGF antagonist includes ranibizumab, bevacizumab, conbercept, pegaptanib, brolucizumab, aflibercept.

18. The drug delivery device of claim 17, wherein the VEGF antagonist is aflibercept in a concentration of about 114.3 mg / mL.

19. The drug delivery device of claim 16, wherein the VEGF antagonist is aflibercept and the aqueous pharmaceutical formulation further comprises a stabilizing agent and a buffering agent.

20. The drug delivery device of claim 19, wherein the stabilizing agent includes one of arginine monohydrochloride, Sucrose, and Polysorbate 20; and wherein the buffering agent includes histidine.

21. The drug delivery device of claim 16, wherein the body is configured to store a predetermined volume of the VEGF antagonist in a volume from about 150 pL to about 250 pL.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030422. The drug delivery device of claim 16, wherein the aqueous pharmaceutical formulation includes: about 100 mg / ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant.

23. The drug delivery device of claim 22, wherein the VEGF receptor fusion protein includes two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component.

24. The drug delivery device of claim 23, wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species.

25. The drug delivery device of claim 22, wherein the aqueous pharmaceutical formulation has a pH of about 5.0 to about 6.8.

26. The drug delivery device of claim 16, wherein the aqueous pharmaceutical formulation comprises a VEGF receptor fusion protein having a mass ranging between about 2 mg to about 8 mg.

27. The drug delivery device of claim 26, wherein the VEGF receptor fusion protein includes aflibercept.

28. The drug delivery device of claim 16, wherein the aqueous pharmaceutical formulation comprises about 114.3 mg / ml of a VEGF receptor fusion protein as the VEGF antagonist, about 50 mM arginine monohydrochloride as the stabilizing agent, and about 10 mM histidine as the buffering agent.

29. The drug delivery device of claim 16, wherein the aqueous pharmaceutical formulation comprises: about 40 mg / ml VEGF receptor fusion protein;Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 about 10 mM sodium phosphate; about 40 mM NaCl; about 0.03% polysorbate 20; about 5% sucrose; and a pH of about 6.2.

30. The drug delivery device of claim 16, wherein the VEGF antagonist is prefilled within the body during an assembly of the body, the stopper, the plunger rod, and the flange of the drug delivery device such that the drug delivery device is a pre-filled syringe.

31. A packaging for housing a drug delivery device, comprising: a flexible tray and a removable cover adhered to the flexible tray, wherein the flexible tray includes: an opening; a cavity including a plurality of cavity portions; a plurality of sidewalls at least partially defining the cavity; a base at least partially defining the cavity; and a lip surrounding the opening and extending radially outwards from the cavity to define a periphery of the flexible tray, wherein the removable cover is adhered to the lip; wherein the flexible tray is configured to house the drug delivery device in the cavity with at least a portion of the drug delivery device contained within each of the plurality of cavity portions; and wherein the drug delivery device is a pre-filled syringe including an aqueous pharmaceutical formulation comprising a single dose of about 8 mg or more of a VEGF antagonist.

32. The packaging of claim 31, wherein the plurality of cavity portions are connected to one another by narrowed portions, and each of the narrowed portions includes a first sidewall, a second sidewall, and a base that are collectively configured to receive at least a portion of a body of the drug delivery device.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030433. The packaging of claim 32, wherein one of the first sidewall, the second sidewall, or the base of each of the narrowed portions includes a geometric feature extending away from the first sidewall, the second sidewall, and the base and projecting into the narrowed portion.

34. The packaging of claim 33, wherein the geometric feature is configured to abut against the portion of the body of the drug delivery device that is contained within the narrowed portion to position the body away from the first sidewall, the second sidewall, and the base of the narrowed portion.

35. The packaging of claim 34, wherein the geometric feature is configured to suspend the body of the drug delivery device within the cavity, thereby forming a gap between an exterior of the body and the plurality of sidewalls and the base of the flexible tray.

36. The packaging of claim 31, wherein the drug delivery device includes a body, a plunger rod, and a flange that are securely disposed inside the plurality of cavity portions and sealed inside the flexible tray by the removable cover closing the opening; and wherein the packaging and the drug delivery device are sterilized.

37. The packaging of claim 31, wherein the removable cover is permeable to a gaseous sterilant that is configured to sterilize the flexible tray and the drug delivery device disposed inside the cavity during a sterilization of the packaging.

38. The packaging of claim 31, wherein the flexible tray includes a projection positioned along the base and aligned with one of the plurality of cavity portions, wherein the projection extends outwards from the flexible tray in a direction opposite from the cavity.

39. The packaging of claim 38, wherein the projection is hollow and open towards the cavity of the flexible tray.

40. The packaging of claim 38, wherein the projection is configurable to be at least partially deformable in response to an application of force on the projection.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030441. The packaging of claim 38, wherein the projection is configured to flex the flexible tray in response to an application of force on the projection, thereby at least partially deforming one or more of the plurality of cavity portions and partially decoupling the drug delivery device from the cavity.

42. The packaging of claim 38, wherein the projection is dome-shaped and a height of the projection from an apex of the projection to a base of the projection is greater than a distance between the base of the projection and the drug delivery device contained within the cavity and overlying the projection.

43. The packaging of claim 38, wherein the projection includes a bulbous shape, and a diameter of the projection defines a widest portion of the bulbous shape where the projection meets the base of the flexible tray.

44. The packaging of claim 38, wherein the projection includes a dome having a widest diameter at the base of the flexible tray, wherein the projection extends directly outwards from the base of the flexible tray such that the widest diameter of the dome is connected at the base.

45. The packaging of claim 38, wherein the VEGF antagonist that is pre-filled in the drug delivery device includes aflibercept with a concentration of about 114.3 mg / mL.

46. A method of assembling a drug delivery device, comprising: filling a body of the drug delivery device with a substance; inserting a stopper of the drug delivery device into the body to fluidly seal the substance inside the body; coupling the body with a finger flange of the drug delivery device by inserting a proximal flange of the body into a lateral slot of the finger flange; inserting a plunger rod of the drug delivery device through the finger flange and into the body to an extent such that the plunger rod contacts the stopper; and coupling the plunger rod to the finger flange by inserting an extension of the plunger rod into a lateral opening of the finger flange.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030447. The method of claim 46, wherein filling the body with the substance comprises: filling the body to a maximum target fill volume, wherein the maximum target fill volume includes a single dose having a predetermined volume that is less than the maximum target fill volume.

48. The method of claim 47, wherein inserting the stopper into the body comprises: forming a space within the body between the stopper and the substance as the stopper is inserted into the body, wherein the space defines an air pocket.

49. The method of claim 48, wherein the space includes a headspace volume such that the maximum target fill volume of the substance and the headspace volume of the air pocket are collectively disposed between a distal end of the body and the stopper.

50. The method of claim 49, wherein the substance includes a VEGF antagonist, the maximum target fill volume is between about 180 pL and about 250 pL, the predetermined volume of the single dose delivered from the drug delivery device is about 90 pL or less, and the body and the stopper are silicone-free.

51. The method of claim 46, wherein inserting the stopper into the body comprises: positioning the stopper near a proximal portion of the body that is adjacent to the proximal flange; and generating a vacuum pressure within the body to reposition the stopper from the proximal portion of the body towards a distal portion of the body that contains the substance, thereby sealing the substance in the body with the stopper.

52. The method of claim 51, wherein the vacuum pressure generated within the body is to an extent such that the stopper is repositioned to a predetermined location within the distal portion of the body to maintain a maximum target fill volume of the substance that is pre-filled within the body.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030453. The method of claim 46, wherein coupling the body and the finger flange comprises: engaging an upper surface of the proximal flange with a pair of ribs of the finger flange and a lower surface of the proximal flange with a lip of the finger flange as the proximal flange is inserted into the lateral slot.

54. The method of claim 53, wherein the pair of ribs are at least partially deflectable in response to engaging the proximal flange, the pair of ribs being positioned inside the lateral slot of the finger flange.

55. The method of claim 46, wherein coupling the body and the finger flange comprises: engaging a side surface of the body with a pair of movable tabs of the finger flange as the proximal flange is inserted into the lateral slot.

56. The method of claim 55, wherein the pair of movable tabs are at least partially deflectable in response to engaging the body, the pair of movable tabs being positioned outside the lateral slot of the finger flange.

57. The method of claim 46, wherein inserting the plunger rod through the finger flange and into the body comprises: applying an insertion force of less than about 15 N to the plunger rod for positioning a distal end of the plunger rod within the body adjacent to the stopper.

58. The method of claim 57, wherein inserting the plunger rod through the finger flange and into the body comprises: abutting a distal end of the plunger rod against a proximal end of the stopper without coupling the plunger rod to the stopper.

59. The method of claim 57, wherein inserting the plunger rod through the finger flange and into the body comprises:Client Ref. 11518WO01Attorney Docket No. 00166-0178-00304 inserting a distal end of the plunger rod into a proximal end of the stopper without coupling the plunger rod to the stopper.

60. The method of claim 46, wherein coupling the plunger rod to the finger flange comprises: deflecting the extension of the plunger rod laterally inwards upon engaging a proximal edge of the finger flange as the plunger rod is inserted distally through the finger flange; and deflecting the extension laterally outwards upon entering the lateral opening of the finger flange as the plunger rod is inserted further distally through the finger flange.

61. A method of treating or preventing an angiogenic eye disorder, comprising: administering a single initial dose of about 8 mg or more of a VEGF antagonist that is pre-filled in a first drug delivery device to an eye of a patient; administering one or more secondary doses of about 8 mg or more of the VEGF antagonist to the eye of the patient by one or more second drug delivery devices that are prefilled with the VEGF antagonist; and administering one or more tertiary doses of about 8 mg or more of the VEGF antagonist to the eye of the patient by one or more third drug delivery devices that are prefilled with the VEGF antagonist; wherein the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices each include a body storing the VEGF antagonist, a finger flange coupled to the body, and a plunger rod movably coupled to the finger flange for priming the body prior to administering the single initial dose, the one or more secondary doses, and the one or more tertiary doses.

62. The method of claim 61, wherein the plunger rod of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices includes a protrusion extending outwards from a proximal end of the plunger rod; and wherein the finger flange of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices includes a proximal collar and a slot extending distally from the proximal collar.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030463. The method of claim 62, wherein the protrusion is configured to abut against the proximal collar upon the plunger rod moving distally relative to the finger flange to prime the body; and wherein the protrusion is configured to abut against the slot upon the plunger rod moving distally relative to the finger flange to administer the single initial dose, the one or more secondary doses, and the one or more tertiary doses.

64. The method of claim 61, wherein the body of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices is silicone-free.

65. The method of claim 64, wherein the body of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices is a syringe having a maximum volume of 0.5 mL or 1.0 mL.

66. The method of claim 61, wherein the body of each of the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices includes a stopper that is silicone-free.

67. The method of claim 61, wherein administering the one or more secondary doses comprises: administering each of the one or more secondary doses about 2 weeks to about 4 weeks after an immediately preceding dose from the one or more secondary doses.

68. The method of claim 67, wherein a time interval for administering each of the one or more secondary doses is based on an indication of the angiogenic eye disorder.

69. The method of claim 61, wherein administering the one or more tertiary doses comprises: administering each of the one or more tertiary doses about 4 weeks, about 8 weeks, or about 12 weeks after an immediately preceding dose from the one or more tertiary doses.Client Ref. 11518WO01Attorney Docket No. 00166-0178-0030470. The method of claim 61, wherein the VEGF antagonist includes aflibercept and the single initial dose, the one or more secondary doses, and the one or more tertiary doses have a volume of about 100 pL or less.

71. The method of claim 70, wherein the first drug delivery device, the one or more second drug delivery devices, and the one or more third drug delivery devices are each configured to treat or prevent the angiogenic eye disorder by administering doses of aflibercept at an interval and a quantity whereby a clearance of free aflibercept from an ocular compartment in the eye is about 0.3 mL / day to about 0.46 mL / day after intravitreal injection of aflibercept to the eye.

72. The method of claim 71, wherein a time for the clearance for free aflibercept to reach a lower limit of quantitation (LLOQ) in the ocular compartment of the eye after said intravitreal injection of aflibercept is about 15 weeks.

73. The method of claim 71, wherein a time for free aflibercept to reach a lower limit of quantitation (LLOQ) in a plasma of the eye after said intravitreal injection of aflibercept is about 3.5 weeks to about 3.8 weeks.

74. The method of claim 61, further comprising: administering one or more non-scheduled doses of the VEGF antagonist to the eye of the patient by one or more additional drug delivery devices that are pre-filled with the VEGF antagonist on a pro re nata basis in response to anatomic findings from the eye of the patient; wherein the one or more non-scheduled doses are capped at a minimum dosing frequency of one at least every 2 months to 4 months.

75. The method of claim 61, wherein the angiogenic eye disorder includes one of age-related macular degeneration (AMD), macular edema (ME), retinal vein occlusion (RVO), diabetic macular edema (DME), neovascularization, neovascular glaucoma, post- surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), pannus, pterygium, vascular retinopathy, and diabetic retinopathy.

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