Patent Publication Number: US-2021178080-A1

Title: Accurate, precise microliter dosing syringe

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. Provisional Application Ser. No. 62/323,341, filed Apr. 15, 2016, titled “Accurate, Precise Microliter Dosing Syringe,” which is hereby incorporated by reference in its entirety. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to syringes and, more specifically, to syringes that can deliver microliter-sized doses. 
     BACKGROUND OF THE INVENTION 
     Studies have shown that a number of factors contribute towards inability of standard syringes to deliver accurate and precise microliter sized doses. Most conventional syringes, which include components such as a cylindrical barrel, a plunger rod, and a plunger seal, are designed to deliver milliliter doses and are unable to deliver an accurate and precise dose. Variation in delivering microliter-sized doses using a conventional syringe are often caused by the inability of the user to precisely control the distance of travel by the plunger rod. Travel distance is controlled by setting the start of the dose and the end of the dose. Studies have shown that providing a better defined start and end of the dose can improve accuracy of delivering a microliter dose. However, this is insufficient to ensure precision. Imprecision can be due to variability from one user to another and to inherent human limitations in establishing limits and resolution of the travel distance. Studies have shown that this variation could be as much as 20% of the intended dose. Further, manufacturing issues may cause variations when establishing visual references and markings that define plunger travel. These variations are negligible when delivering milliliter sized doses, but are significant source of variation when delivering microliter sized doses. 
     Many clinical and non-clinical applications require that a microliter sized dose be delivered. Applications for microliter delivery include injectable drug delivery into or onto the eye, intracellular delivery, delivery of radioactive agents, chemotherapy, etc. Both accuracy and precision are important with drugs that have a small therapeutic window, and where inadequate accuracy and precision would put the amount of injected drug outside of its therapeutic window. In some cases, inaccuracy and imprecision can cause alterations in biophysical properties at the injected site, such as increase in pressure, rupture of cell walls, etc. In the case of microliter delivery of drugs, systems that are not compatible with either standard pharmaceutical fill-finish systems or standard prefillable syringe components may be unsuitable. Studies have shown that used of microliter delivery systems for intravitreous administration with only conventional prefillable syringe components results in a suboptimal outcome. 
     Irrespective of whether an injectable substance or drug is prefilled or user-filled, a microliter dosing syringe should be able to prime the needle or any other delivery conduit to ensure that any air is expelled before delivery. Priming is important to ensure that once the dose is set, an accurate dose is dispensed. In instances where the drug is prefilled (i.e. not filled by the end user), the ability to prime is critical to ensuring that the accuracy of the administered dose is independent of the accuracy of the drug fill. 
     There is a need for accurate, precise microliter dose setting and delivery mechanisms adaptable to conventional, commercially available syringes—thereby enabling a conventional syringe to deliver accurate, precise microliter volumes. 
     SUMMARY OF THE INVENTION 
     According to some embodiments, accurate and precise dosing mechanisms can be configured with a number of syringe configurations, including: prefilled (with pre-attached needle, with user-attached needle, with a retractable needle, etc.) and user filled. According to some embodiments, a system includes a dosing mechanism that is manufactured and partly assembled independent of the syringe and then coupled to the syringe to provide the plunger rod functionality. As such, the functioning of the accurate dosing mechanism may include features analogous to those of a plunger rod in a conventional syringe but with improved resolution of dose setting for accurate and precise microliter dose delivery. 
     According to some embodiments, the system may include a plunger rod with lugs and teeth. The lugs on the plunger rod may mechanically interact with internal threads within the thumb nut. The teeth of the plunger rod may mesh with a set of teeth of a gear of a gear train. Axial advancement of the plunger rod may generate a torsional force that causes rotation of the gear. The gear may be coupled with one or more additional gears. The teeth of one of the additional gears may mesh with the teeth of a drive rod. The drive rod may be placed within a prefilled syringe barrel and may abut a plunger adapter. The plunger adapter may be screwed into the back of a plunger seal. The thumb nut and gear train are all placed within a housing. The gear may be attached to the housing by way of a pin at its geometric center. The flange of the syringe barrel may be placed within the housing and a cover may mate with the housing to couple the dosing mechanism to the syringe. 
     According to some embodiments, a plunger rod assembly for a syringe includes a first plunger rod component comprising a first linear gear, a second plunger rod component comprising a second linear gear, a first rotational gear having a plurality of gear teeth for engaging the first linear gear, and a second rotational gear having a second plurality of gear teeth for engaging the second linear gear, wherein the first rotational gear is coupled to the second rotational gear such that translation of the first plunger rod component causes translation of the second plunger rod component. 
     In any of these embodiments, translation of the first plunger rod component a first amount may cause translation of the second plunger rod component a second amount that is less than the first amount. In any of these embodiments, the first rotational gear and the second rotational gear may be portions of a compound gear. 
     In any of these embodiments, the first rotational gear may be spaced from the second rotational gear. In any of these embodiments, the first and second rotational gears may be spaced by a third rotational gear. In any of these embodiments, the second and third rotational gears may be compound gears. 
     In any of these embodiments, the first set of gear teeth may have a first pitch diameter and the second set of gear teeth may have a second pitch diameter that is different from the first pitch diameter. In any of these embodiments, the first pitch diameter may be greater than the second pitch diameter. 
     In any of these embodiments, at least one of the first and second sets of gear teeth may include involute gear teeth. In any of these embodiments, the first and second plunger rod components may be configured for at least partial insertion into a barrel of a syringe. In any of these embodiments, at least a portion of the first plunger rod component may include a semicircular cross section and at least a portion of the second plunger rod component may include a complimentary semicircular cross section. In any of these embodiments, the first plunger rod component may include at least one protrusion and the assembly may further include a rotational component for engaging the at least one protrusion. 
     In any of these embodiments, the first plunger rod component may be configured to axially translate in response to rotation of the rotational component when the rotational component is engaged with at least one of the at least one protrusion. In any of these embodiments, the first plunger rod component may be configured to axially translate in response to a force having an axial component applied directly to the first plunger rod component after the rotational component disengages from the at least one protrusion. 
     In any of these embodiments, the rotational component may include an internal thread for engaging the at least one protrusion. In any of these embodiments, the rotational component may include at least one stop that engages one of the at least one protrusion when the plunger rod component reaches an axial position relative to the rotational component. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component is prevented from rotating in one direction. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component rotates more freely in a first direction than in a second direction. 
     In any of these embodiments, the assembly may include a housing for mounting on an end of a syringe barrel. In any of these embodiments, the assembly may include a retainer for engaging with the housing and the end of the syringe barrel for affixing the plunger rod assembly to the end of the syringe barrel. In any of these embodiments, the retainer may affix to the housing. In any of these embodiments, the retainer may engage with an internal thread or groove in the recess of the housing. In any of these embodiments, the first plunger rod component may extend through an aperture in the housing, and the perimeter of the aperture may engage with the first plunger rod component to prevent rotation of the first plunger rod component. 
     According to some embodiments, a syringe may include a barrel; a delivery conduit; an elastomeric or elastomer containing plunger seal disposed within the barrel; and a plunger rod assembly affixed to an end of the barrel, the plunger rod assembly including a first plunger rod component comprising a first linear gear, a second plunger rod component disposed at least partially in the barrel and engaged with the plunger seal, wherein the second plunger rod component comprises a second linear gear, a first rotational gear having a plurality of gear teeth for engaging the first linear gear, and a second rotational gear having a second plurality of gear teeth for engaging the second linear gear, wherein the first rotational gear is coupled to the second rotational gear such that translation of the first plunger rod component causes translation of the second plunger rod component. 
     In any of these embodiments, axial translation of the first plunger rod component a first amount may cause axial translation of the second plunger rod component a second amount that is less than the first amount. In any of these embodiments, the first rotational gear and the second rotational gear may be portions of a compound gear. In any of these embodiments, the first rotational gear may be spaced from the second rotational gear. 
     In any of these embodiments, the first and second rotational gears may be spaced by a third rotational gear. In any of these embodiments, the second and third rotational gears may be compound gears. In any of these embodiments, the first set of gear teeth may have a first pitch diameter and the second set of gear teeth may have a second pitch diameter that is different from the first pitch diameter. In any of these embodiments, the first pitch diameter may be greater than the second pitch diameter. In any of these embodiments, at least one of the first and second sets of gear teeth may include involute gear teeth. In any of these embodiments, the first and second plunger rod components may be configured for at least partial insertion into a barrel of a syringe. 
     In any of these embodiments, at least a portion of the first plunger rod component may include a semicircular cross section and at least a portion of the second plunger rod component may include a complimentary semicircular cross section. In any of these embodiments, the first plunger rod component may include at least one protrusion and the assembly may further include a rotational component for engaging the at least one protrusion. 
     In any of these embodiments, the first plunger rod component may be configured to axially translate in response to rotation of the rotational component when the second rotational component is engaged with at least one of the at least one protrusion. In any of these embodiments, the first plunger rod component may be configured to axially translate in response to a force having an axial component applied directly to the first plunger rod component after the rotational component disengages from the at least one protrusion. 
     In any of these embodiments, the rotational component may include an internal thread for engaging the at least one protrusion. In any of these embodiments, the rotational component may include at least one stop that engages one of the at least one protrusion when the plunger rod component reaches an axial position relative to the rotational component. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component is prevented from rotating in one direction. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component rotates more freely in a first direction than in a second direction. In any of these embodiments, the assembly may include a housing mounted on an end of the barrel. 
     In any of these embodiments, the assembly may include a retainer that is engaged with the housing and the end of the barrel to affix the plunger rod assembly to the end of the syringe barrel. In any of these embodiments, the retainer may affix to the housing. In any of these embodiments, the retainer may engage with an internal thread or groove in the recess of the housing. In any of these embodiments, the first plunger rod component may extend through an aperture in the housing, and the perimeter of the aperture may engage with the first plunger rod component to prevent rotation of the first plunger rod component. In any of these embodiments, the syringe may be a prefilled or a prefillable syringe. 
     In any of these embodiments, the delivery conduit may include an attached needle, an attachable needle, an IV connector, an attachable tubing connector, or an attachable microneedle array. In any of these embodiments, the plunger seal may include an adapter for engagement with the second plunger rod component. 
     According to some embodiments, a plunger rod assembly for a syringe includes a first plunger rod component; and a second plunger rod component configured to translate relative to the first plunger rod component, wherein the second plunger rod component engages with the first plunger rod component such that the second plunger rod component translates in response to translation of the first plunger rod component. 
     In any of these embodiments, the second plunger rod component may engage with the first plunger rod component through at least one rotational gear. In any of these embodiments, the first plunger rod component may include a first linear gear; the second plunger rod component may include a second linear gear; and the at least one rotational gear may include a first gear having a first set of gear teeth for engaging the first linear gear and a second gear having a second set of gear teeth for engaging the second linear gear. 
     In any of these embodiments, the first gear and the second gear may be portions of a compound gear. In any of these embodiments, the first gear may be spaced from the second gear. In any of these embodiments, the assembly may further include a rotational component configured to engage with the first plunger rod component such that rotation of the rotational component causes axial translation of the first plunger rod component. 
     In any of these embodiments, the rotational component may include an internal thread for engaging one or more protrusions on the first plunger rod component. In any of these embodiments, the second plunger rod component engages with the first plunger rod component such that the second plunger rod component axially translates a first amount in response to axial translation of the first plunger rod component a second amount that is greater than the first amount. 
     In any of these embodiments, the assembly may include at least one ratchet or ratchet-like component that is engaged with the rotational component such that the rotational component is prevented from rotating in one direction. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component rotates more freely in a first direction than in a second direction. In any of these embodiments, the assembly may include a housing for mounting on a non-patient end of a syringe barrel. In any of these embodiments, the assembly may include a retainer for engaging with the housing and the non-patient end of the syringe barrel for affixing the plunger rod assembly to the non-patient end of the syringe barrel. 
     In any of these embodiments, the first plunger rod component may extend through an aperture in the housing, and the perimeter of the aperture may be shaped to prevent rotation of the first plunger rod component. 
     According to some embodiments, a syringe includes a barrel; a delivery conduit; a plunger seal disposed within the barrel; and a plunger rod assembly affixed to an end of the barrel, the plunger rod assembly including a first plunger rod component; and a second plunger rod component disposed at least partially in the barrel and engaged with the plunger seal, wherein the second plunger rod component is configured to axially translate relative to the first plunger rod component and engages with the first plunger rod component such that the second plunger rod component axially translates in response to translation of the first plunger rod component. 
     In any of these embodiments, the second plunger rod component may engage with the first plunger rod component through at least one rotational gear. In any of these embodiments, the first plunger rod component may include a first linear gear; the second plunger rod component may include a second linear gear; and the at least one rotational gear may include a first gear having a first set of gear teeth for engaging the first linear gear and a second gear having a second set of gear teeth for engaging the second linear gear. 
     In any of these embodiments, the first gear and the second gear may be portions of a compound gear. In any of these embodiments, the first gear may be spaced from the second gear. In any of these embodiments, the syringe may further include a rotational component configured to engage with the first plunger rod component such that rotation of the rotational component causes axial translation of the first plunger rod component. In any of these embodiments, the rotational component may include an internal thread for engaging one or more protrusions on the first plunger rod component. 
     In any of these embodiments, the second plunger rod component may engage with the first plunger rod component such that the second plunger rod component translates a first amount in response to translation of the first plunger rod component a second amount that is greater than the first amount. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component is prevented from rotating in one direction. In any of these embodiments, the assembly may include at least one ratchet component that is engaged with the rotational component such that the rotational component rotates more freely in a first direction than in a second direction. 
     In any of these embodiments, the assembly may include a housing mounted on an end of the barrel. In any of these embodiments, the assembly may include a retainer that is engaged with the housing and the end of the barrel to affix the plunger rod assembly to the end of the syringe barrel. In any of these embodiments, the first plunger rod component may extend through an aperture in the housing, and the perimeter of the aperture may be shaped to prevent rotation of the first plunger rod component. In any of these embodiments, the syringe may be a prefilled syringe. 
     In any of these embodiments, the delivery conduit may include an attached needle, an attachable needle, an attachable tubing connector, or an attachable microneedle array. In any of these embodiments, the plunger seal may include an adapter for engagement with the second plunger rod component. 
     According to some embodiments, a blister pack includes a pre-filled syringe according to any of the above embodiments, wherein the syringe has been sterilized using EtO, H2O2, NO2 or Vaporized Peracetic Acid. 
     In any of these embodiments, the outer surface of the syringe may have at most 1 ppm EtO, H2O2, NO2 or Vaporized Peracetic Acid. In any of these embodiments, the total EtO, H2O2, NO2 or Vaporized Peracetic Acid residue on the outside of the syringe and inside of the blister pack may be at most 0.1 mg. In any of these embodiments, the syringe may have been sterilized with a Sterility Assurance Level of at least 10 −6 . 
     According to some embodiments, a method of delivering a dosage using a syringe according to any of the above embodiments includes while pointing the delivery conduit of the syringe upwards with respect to the barrel, advancing the plunger seal within the barrel by rotating the rotational component; setting a dosage by continuing to rotate the rotational component until the rotational component disengages from the first plunger rod; and after the rotational component disengages from the first plunger rod, delivering the dosage by applying a user force directly to an end of the first plunger rod to advance the plunger seal. 
     In any of these embodiments, the method may include attaching a needle to the syringe prior to advancing the plunger seal within the barrel by rotating the second rotational component. In any of these embodiments, the syringe may be a prefilled syringe. 
     In any of these embodiments, the prefilled syringe may be filled with a drug used for ophthalmic applications. In any of these embodiments, the number of 10 micrometer or larger sized sub-visible particulates may be less than 50 per milliliter of drug solution. In any of these embodiments, the number of 25 micrometer or larger sized sub-visible particulates may be less than 5 per milliliter of the drug solution. In any of these embodiments, the number of 50 micrometer or larger sized sub-visible particulates may be less than 2 per milliliter of the drug solution. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention will now be described, by way of example only, with reference to the accompanying drawings, in which: 
         FIG. 1  is a side view of a dosing syringe system, according to a first embodiment; 
         FIG. 2  is a cross-sectional view of the system of  FIG. 1 ; 
         FIG. 3  is an exploded view of the system of  FIG. 1 ; 
         FIG. 4  is a perspective view of a dosing mechanism, according to an embodiment; 
         FIG. 5  is a side view of a plunger rod, according to an embodiment; 
         FIG. 6  is a perspective view of a compound gear, according to an embodiment; 
         FIGS. 7A and 7B  are perspective and cross-sectional views, respectively, of a thumb nut, according to an embodiment; 
         FIGS. 8A and 8B  are perspective and side views, respectively, of a drive rod, according to an embodiment; 
         FIGS. 9A-9D  are perspective, perspective cross-sectional, cross-sectional, and bottom views of a housing, according to one embodiment; 
         FIGS. 10A and 10B  are cross-sectional views illustrating the dose set configuration of a system, according to an embodiment; 
         FIGS. 11A and 11B  are cross-sectional views illustrating the dose delivered configuration of the system of  FIGS. 10A and 10B ; 
         FIG. 12  is a perspective view of a dosing syringe system according to a second embodiment; 
         FIG. 13  is a side view of the system of  FIG. 12 ; 
         FIGS. 14A and 14B  are side views of the dosing system of  FIG. 12  in a dose set configuration and a dose delivered configuration, respectively; 
         FIG. 15  is a perspective view illustrating the coupling of a dosing mechanism to a syringe barrel, according to an embodiment; 
         FIGS. 16A and 16B  are perspective and side views, respectively, illustrating a gear train, according to an embodiment; 
         FIGS. 17A-17C  are cross-sectional views illustrating a dose setting and dose delivery process; 
         FIGS. 18A-18C  illustrate the engagement of a thumb nut and plunger rod, according to an embodiment; 
         FIG. 19  illustrates a ratchet, according to an embodiment; 
         FIG. 20A  illustrates a plunger rod, according to an embodiment; 
         FIGS. 20B and 20C  illustrate a drive rod, according to an embodiment; and 
         FIGS. 21A and 21B  are exploded views illustrating aspects of an assembly process of a plunger rod subassembly, according to some embodiments. 
     
    
    
     DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS 
     Described herein are accurate and precise dosing mechanisms and systems incorporating the mechanisms with conventional (or custom) syringe bodies to provide an accurate and precise dosing syringe. According to some embodiments, the dosing mechanism translates user action into precisely controlled movements of a multi-component plunger rod. A gear train may couple plunger rod components such that the axial distance travelled by the plunger rod component that pushes on a syringe plunger seal is reduced relative to the axial distance travelled by the plunger rod component with which the user directly engages. A thumb nut engages with one of the plunger rod components to precisely control the travel distances of the plunger rod components. The dosing mechanism can include one or more features for coupling the mechanism to the plunger seal end of a conventional syringe. 
     The below description is provided to assist in an understanding of exemplary embodiments of the present disclosure with reference to the accompanying figures. Accordingly, those of ordinary skill in the art will recognize that various changes to and modifications of the exemplary embodiments described herein can be made without departing from the scope of the claimed invention. Also, descriptions of generally well-known functions and constructions are omitted for conciseness. 
     As used herein to describe the mechanism to deliver an accurate, precise dose, drug delivery syringes, or any of the relative positions of the components of the present invention, the terms “axial” or “axially” refer generally to a longitudinal axis “A” around which the mechanisms and syringes may be positioned, although not necessarily symmetrically. The term “radial” refers generally to all directions orthogonal to axis “A”. The term user end refers generally to the end marked “U”, and the patient end refers generally to the end marked “P.” As used herein, the term “glass” should be understood to include other similarly chemically inert materials suitable for use in a pharmaceutical grade application that would normally require type I borosilicate glass, quartz, including but not limited to certain non-reactive polymers such as cyclic olefin copolymers (COC), cyclic olefin polymers (COP), and the like used in pharmaceutical prefillable syringes. These syringes may involve additional treatments such removal of subvisible particulates to make them appropriate for ophthalmic drugs. Plastic also refers to polymers such as polypropylene, polycarbonate and the like used in hypodermic syringes. The term “elastomer,” “elastomeric” or “elastomeric materials commonly used in the manufacture of plunger seals in syringes. This also includes plunger seals that may be coated to afford chemical inertness for certain pharmaceutical applications. “Fluid” refers primarily to water, but can also refer to solutions such as polyethylene glycol, solids suspended in solution, immiscible substances in solution and refers to Newtonian as well as non-Newtonian liquids; all of these are injectable using a syringe. A system with needle safety can refer to safety implemented either with a retractable needle mechanism or an external sheath/cover for the needle. When a needle used is for administration, the needle is typically made of stainless steel; needles also include microneedles and microneedle arrays. Needle size used could range from 21G through 40G in diameter and up to 1″ in length. Administration could be subcutaneous, intravenous, intradermal, intravitreal, intraocular, suprachoroidal, sub-conjunctival, intra-tumoral, intracellular, topical, etc. 
     Embodiments of a mechanism to set and deliver an accurate, precise injectable dose and embodiments of drug delivery syringe(s) that could incorporate such mechanisms are described below. Such devices can be safe and easy to use, aesthetically appealing, and designed per ergonomic considerations of their users, which may include researchers, veterinary health practitioners, and other clinical practitioners. Ergonomic features may be included that enable activation, operation, and disposal of devices with minimal or no training. Embodiments of dose control mechanisms, fluid delivery syringes, and respective components are described further herein with reference to the accompanying figures. 
       FIGS. 1-3  illustrate a syringe-based system  100  incorporating an accurate, precise dose delivery mechanism, according to a first embodiment. System  100  includes plunger rod subassembly  101 , prefillable syringe  102 , plunger seal adapter  103 , and cover  104 . Cover  104  is affixed to plunger rod subassembly  101  by the engagement of external threads  105  on cover  104  with internal threads  107  on the barrel opening end of housing  106 . In other embodiments, cover  104  may be affixed to housing  106  using other means, including press fitting, snap-on features, fasteners, etc. According to some embodiments, the prefillable syringe may include a luer lock adapter  108  or a staked/pre-attached needle. In some embodiments, a cartridge may be used instead of a syringe. In some embodiments, a delivery adapter may be used that enables topical delivery or intranasal delivery. The prefillable syringe  102  may be sprayed on the inside of the syringe barrel  109  with silicone oil such as Dow Corning 360 to provide lubrication. Alternatively, a siliconization emulsion such as Dow CORNING 365 may be sprayed. The syringes may be baked at a high temperature to bake the silicone onto the inside of the syringe barrel  109 . 
     According to some embodiments, the plunger rod subassembly  101 , an embodiment of which is shown separately in  FIG. 4 , includes a multi-component plunger rod that includes plunger rod  110  and drive rod  112 . Plunger rod subassembly  101  also includes housing  106 , gear  111 , drive rod  112 , thumb nut  113 , and a spring  114 . 
     Plunger rod  110  includes a set of linear gear teeth  128  along a portion of its length ( FIG. 5 ). Teeth  128  mesh with a first set of larger pitch gear teeth  118  on gear  111 . Gear  111  is pinned to the housing such that it can rotate but it cannot translate. Thus, linear movement of plunger rod  110  causes gear  111  to rotate. Gear  111  is a compound gear ( FIG. 6 ) with a second set of smaller pitch gear teeth  120  that engage with a set of linear gear teeth  124  on drive rod  112 . Thus, rotation of gear  111  causes axial advancement of drive rod  112  in the patient “P” direction, pushing the non-patient surface of the plunger adapter  136 . This, in turn, pushes the filled fluid  133 , dispensing it through the tip of the needle  139  (or other component). Due to the difference in pitch between the two sets of teeth of the compound gear, the drive rod  112  advances a smaller amount than the plunger rod  110  and a mechanical advantage is provided such that less user force is required than would be required to directly push plunger seal  132 . In other embodiments, the configuration of gear  111  may be reversed such that the smaller pitch gear teeth interface with the plunger rod and the larger pitch gear teeth interface with the drive rod. 
     Plunger rod  110  also includes a plurality of dosing pegs  129  that engage with an internal thread  131  of thumb nut  113  ( FIGS. 7A-7B ). At least a portion of plunger rod  110  may include a non-circular cross-section that fits within a complimentary aperture in the housing, which prevents rotation of plunger rod  110 . With plunger rod  110  constrained against rotation, the rotation of thumb nut  113  causes axial movement of plunger rod  110 . The engagement of dosing pegs  129  with internal thread  131  also prevents a user from pushing plunger rod  110  to axially advance plunger rod  110 . Continued axial advancement of the plunger rod  110  via turning of thumb nut  113  will result in a rearmost dosing peg  142  (the dosing peg nearest the user end of the plunger rod  110 ) escaping the internal thread  131  of thumb nut  113 . Once it has escaped, the thumb nut  113  no longer prevents a user from directly advancing plunger rod  110  by pushing on plunger rod  110 . According to some embodiments, lugs  130  are provided on the plunger rod  110  to help maintain orientation of the plunger rod  110  inside the syringe barrel  109 . 
     Assembly of the plunger rod subassembly  101  may include placing the spring  114  in seat  115 , which is cavity in thumb nut  113 . The gear  111  may be attached to the housing  106  using a cylindrical pin  116  such that the back surface  117  of the larger pitch teeth  118  abut housing  106 . There may be interference between the pin  116  and two holes  122 ,  123  in the housing  106  ensuring that there is no rotational slip. The gear  111  may rotate freely about the axis of the pin  116 . 
     Spring  114  inside the thumb nut  113  may then be slid inside housing  106  as an assembly through opening  126  such that the open side of the spring  114  is facing the patient end “P” of the system. Spring  114  may preload the thumb nut  113  against the housing to reduce any axial play that may arise from component tolerances. The drive rod  112  may be inserted from the patient end P such that teeth  124  on drive rod  112  interact with smaller pitch teeth  120 . The drive rod  112  may be pushed all the way until a hard stop when the shoulder  125  on the drive rod ( FIGS. 8A and 8B ) touches the surface of the housing  106 . The plunger rod  110  may then be inserted through the dorsal cavity  127  (see  FIG. 9A-9D ) in the housing  106  such that teeth  128  are pointed away from the user end “U” and in a manner that they interact with the larger pitch teeth  118 . The pegs or lugs  129  on the plunger rod  110  interfere with the internal thread  131  on the thumb nut  113  such that rotation of the thumb nut  113  in one direction advances the plunger rod  110  in the direction of the patient end “P”. The shape of dorsal cavity  127  of the housing  106  is matched with the cross-section of the plunger rod  110 , and is designed such that it would prevent any rotation of the plunger rod  110 . The plunger rod subassembly  101  is now assembled. 
     To assemble a prefilled syringe, according to some embodiments, the fluid  133  may be filled from the non-patient end of the syringe and then a substantially elastomeric plunger seal  132  is inserted from the non-patient end towards the patient end. This is now a filled syringe. A plunger adapter  136  may be screwed into the back of the plunger seal  132  with matching, complementary threads  137 . In order to attach the plunger rod subassembly  101  to this prefilled syringe, the patient end “P” of the plunger rod subassembly  101  may be inserted from the user end “U” of prefilled syringe inside the syringe barrel  109 . The cover  104  with its threads  105  oriented towards the user end “U” may then be slid across the length of the syringe barrel  109  until it mates with the threads  107  on the housing. The cover may be turned until tightened. The accurate, precise dosing syringe-based system  100  is now completely assembled. This assembled system is ready for use by the user, ready for secondary packaging, and/or ready for terminal sterilization as required for certain applications. 
     In this embodiment, when ready to use, the user can attach a needle  139  by twisting and turning on the luer lock adapter  108  of the syringe. By pointing the patient end “P” of the syringe upwards, the user rotates thumb nut  113  to set the dose. Striated features  140  may be provided on the outer curved surface of the thumb nut  113  to allow for better grip and tactile feel. Markings  141  on the dorsal surface of the thumb nut  113  may provide a visual cue to the user of the direction of rotation of the thumb nut  113  for dose setting. As the thumb nut  113  is rotated, the internal threads  131  act as a guide for pegs or lugs  129  on the plunger rod  110 , thereby advancing the plunger rod  110 . 
     As the user continues to rotate the thumb nut  113 , the plunger rod  110  is axially advanced in direction “P” until the dose set peg  142  (the last peg) exits from the thread  131  inside the thumb nut  113 . After this point, subsequent rotation of the thumb nut  113  does not cause any axial translation of the plunger rod  110 , and thus, does not cause any more fluid to be dispensed. The dose is now “set.” This configuration is illustrated in  FIGS. 10A and 10B . The user then inserts the needle into the target site for delivery and pushes the thumb rest  138  on the plunger rod  110  until the underside  143  of thumb rest  138  contacts the surface  144  of the housing  106 . This configuration is illustrated in  FIGS. 11A and 11B . An accurate, precise dose is now delivered and system  100  can be safely discarded. 
       FIGS. 12-15  illustrate a syringe-based system  1000  incorporating an accurate, precise dose delivery mechanism, according to a second embodiment. System  1000  includes plunger rod subassembly  1001  coupled to a prefillable syringe  1002 . Prefillable syringe  1002  may include luer lock adapter  1008  and a plunger seal  1032 . Prefillable syringe  1002  is shown with a cap in  FIG. 12  and with a needle in  FIG. 13 , for illustration purposes. A plunger seal adapter  1003  may be provided in the prefillable syringe  1002  to serve as the interface between the plunger seal  1032  and the plunger rod subassembly  1001 . 
     The plunger rod subassembly  1001  is affixed to the user end of the prefillable syringe. The plunger rod subassembly  1001  includes drive rod  1012 , which drives the plunger seal  1032  (e.g., via plunger seal adapter  1003 ) during dose delivery, and plunger rod  1010 , which is driven by a user press during dose delivery. Plunger rod subassembly  1001  also includes housing  1006 , housing clip  1004  and thumb nut  1013 . The operation of system  1000  is similar to that of system  100  in that a user rotates thumb nut  1013  to set the dose and then presses on plunger rod  1010  to deliver the dose. Housing  1006  may include an indicator  1040  for indicating the direction of rotation of thumb nut  1013  for dose setting. Rotation of thumb nut  1013  causes plunger rod  1010  to advance via the engagement of an internal thread on thumb nut  1013  with dosing lugs  1029  on the plunger rod  1010 . Advancement of plunger rod  1010  causes advancement of drive rod  1012  via a gear train that couples the movements of the plunger rod and the drive rod. Once the dosing lugs  1029  have cleared the internal thread on the thumb nut  1013 , the dose is set, and a user press on the user end of plunger rod  1010  causes plunger rod  1010  to fully advance, which in turn, causes drive rod  1012  to push plunger seal  1032  to expel the set dose. 
       FIG. 14A  shows system  1000  in the dose set configuration. The plunger rod  1010  has advanced within housing  1006  to the point that the dosing lugs  1029  have cleared the internal thread on the thumb nut  1013 . In the illustrated embodiment, a dose indication  1042  (“20”) can be seen through a window  1044  on the side of housing  1006  to indicate that the dose has been set and/or the amount of the dose that has been set.  FIG. 14B  shows system  1000  in the dose delivered configuration. A user press on the thumb rest  1038  of plunger rod  1010  has advanced plunger rod  1010  to its fully depressed position, against housing  1006 . The patient end of plunger rod  1010  has advanced within syringe barrel  1009 . The drive rod  1012 , plunger seal adapter  1003 , and plunger seal  1032  have also advanced within syringe barrel  1009  to a lesser degree than plunger rod  1010  due to the gear reduction of the gear train, as will be discussed in more detail below. Thus, the plunger rod travel “X” is greater than the drive rod travel “Y”. In the embodiment shown, the dose indication  1042  shown through window  1044  is “0” to indicate that the set dose has been fully dispensed. 
       FIG. 15  illustrates the assembly of plunger rod subassembly  1001  onto syringe barrel  1009 , according to some embodiments. The patient end of the plunger rod subassembly  1001  may be inserted from the user end of syringe barrel  1009 . Clip  1004  is positioned around syringe barrel  1009 . Clip  1004  may be formed of two pieces that may register to one another with one or more pegs or other registering features. In some embodiments, the pieces snap together, for example, via an interference fit of registering features. The clip pieces may be screwed together, glued together, or otherwise affixed to one another using any suitable method. In some embodiments, clip  1004  is a unitary piece, such as cover  104  of system  100 . Once clip  1004  is positioned around syringe barrel  1009 , clip  1004  is slid toward the user end of syringe barrel  1009  to interface with the patent end of housing  1006 . Clip  1004  may include one or more tabs  1046  that engage with an inner-facing groove  1048  in the patient end of housing  1006  such that turning clip  1004  once the tabs  1046  are engaged in groove  1048  (for example, a quarter turn) locks the housing  1006 , syringe barrel  1009 , and clip  1004  together. In some embodiments, clip  1004  includes an external thread that mates with an internal thread on the housing (for example, similar to system  100  described above). In some embodiments, clip  1004  includes one or more recesses for insertion of a tool, such as a spanner wrench, to turn clip  1004  in housing  1006 . In some embodiments, compliance in one or more of clip  1004  and housing  1006  (for example, compliance of tabs  1046 ) results in preloading of the housing, cover, and syringe barrel once clip  1004  is tightened into housing  1006 , which eliminates free play between the components. In some embodiments, a compliance component (such as a wave spring, coil spring, gasket, etc.) is included to preload the syringe barrel-to-housing engagement 
       FIGS. 16A and 16B  show a gear train  1011  that couples plunger rod  1010  and drive rod  1012 , according to some embodiments. The gear train  1011  includes rotor gear  1060 , lower force gear  1062 , and higher force gear  1064 . Lower force gear  1062  and higher force gear  1064  are both compound gears, each having two sets of gear teeth. Rotor gear  1060  is pinned to the housing through its axis of rotation and includes teeth that engage a set of teeth on plunger rod  1010  such that linear movement of plunger rod  1010  causes rotational movement of rotor gear  1060 . The teeth on rotor gear  1060  also engage a first set of teeth  1062 A on lower force gear  1062 , which is also pinned to the housing, such that rotation of rotor gear  1060  causes rotation of lower force gear  1062 . Lower force gear  1062  includes a second set of gear teeth  1062 B on the other side (see  FIG. 17A ). The second set of gear teeth  1062 B engage a first set of gear teeth  1064 A on higher force gear  1064 , which is pinned to housing  1006 , such that rotation of lower force gear  1062  causes rotation of higher force gear  1064 . Higher force gear  1064  includes a second set of gear teeth  1064 B on the other side (see  FIG. 17A ). The second set of gear teeth  1064 B engage a set of linear gear teeth  1024  on drive rod  1012  such that rotation of higher force gear  1064  causes linear movement of drive rod  1012 . Thus, gear train  1011  converts linear motion of plunger rod  1010  to linear motion of drive rod  1012 . 
     The gear train may be configured to provide a stroke reduction of the drive rod relative to the plunger rod and a mechanical advantage through the configuration of the gears. As illustrated, the pitch of the first set of teeth  1062 A on lower force gear  1062  may be greater than the pitch of the teeth on rotor gear  1060  such that lower force gear  1062  rotates less than rotor gear  1060 . The pitch of the second set of gear teeth  1062 B may be less than the pitch of the first set of teeth  1062 A. The pitch of the first set of gear teeth  1064 A on higher force gear  1064  may be greater than the pitch of the second set of teeth  1062 A and the pitch of the second set of gear teeth  1064 B on higher force gear  1064  may be less than that of the first set of gear teeth  1064 A. This configuration results in the drive rod  1012  moving a fraction of the amount that plunger rod  1010  moves and results in a mechanical advantage such that the force required to depress the plunger rod  1010  is less than it would be if no gear train were provided. 
     One of skill in the art will readily understand that a gear train may be configured with any suitable combination of gears to achieve design requirements, such as gear reduction, mechanical advantage, compactness, etc. For example, according to some embodiments, the gear train may include just a single compound gear, such as gear  101  of system  100  described above. A gear train may include two gears or four or more gears. Any of the gears may include just a single tooth pitch or may include two or more tooth pitches. A gear train may include idler gears, epicyclic gears, or any other suitable gears or gear arrangements. Further, embodiments may be configured to reverse the gear reduction described above such that axial movement of the drive rod is greater than axial movement of the plunger rod. 
       FIG. 17A-C  are cross-sectional views illustrating the dose setting and dose delivery configurations of system  1000 , according to some embodiments.  FIG. 17A  shows system  1000  in an “as-delivered” state, prior to the dose being set. In this state, the plunger rod  1010  cannot be pushed in by a user press because of the engagement of at least one dosing lug  1029  on plunger rod  1010  with the internal thread of thumb nut  1013 . To set the dose, the user turns thumb nut  1013  in the dose setting direction (for example, as indicated by indicator  1040 ), causing dosing lugs  1029  (and, thus, plunger rod  1010 ) to be advanced by the internal thread of thumb nut  1013 . 
     System  1000  is shown in the dose set state in  FIG. 17B . As shown, plunger rod  1010  has moved toward the patient end but the thumb rest  1038  is still spaced from the housing. Through action of the gear train  1011 , the drive rod  1012  has advanced within the syringe barrel  1009 , though to a lesser degree due to the gear reduction of the gear train  1011  described above. Although not shown in  FIG. 17B , all of the dosing lugs  1029  have escaped the internal thread of thumb nut  1013  such that further turning of thumb nut  1013  in the dose setting direction causes no further advancement of plunger rod  1010 . In some embodiments, thumb nut  1013  includes one or more stops that engage with dosing lugs  1029  to prevent further turning of thumb nut  1013  in the dose setting direction, as will be described in more detail below, which can provide an indication to the user that the dose is set and can provide precise positioning of the plunger rod  1010 . The system  1000  is now ready for dispensing the set dose.  FIG. 17C  illustrates system  1000  in the dispensed configuration. Plunger rod  1010  has been advance fully to the point that its thumb rest  1038  abuts the user end of housing  1006 . As illustrated, the drive rod  1012 , plunger seal adapter  1003 , and plunger seal  1032  have advanced within syringe barrel  1009 , expelling the set dose. As is readily apparent, the dosage delivered is proportional to the stroke of the drive rod  1010  during the dose delivery process. The stroke of the drive rod  1012  during dose delivery is controlled by the gear train configuration and by the distance between the rearmost dosing lugs  1029  and the underside of the thumb rest  1038 , which determines the dose delivery stroke of the plunger rod. Thus, the drive rod stroke can be tailored for specific applications by the dosing lug configuration and the gear train configuration. 
       FIG. 18A-C  illustrate the engagement between plunger rod  1010  and thumb nut  1013 , according to some embodiments.  FIG. 18A  shows plunger rod  1010  and thumb nut  1013  in their relative positions when the system is in the dose set position. Plunger rod  1010  includes dosing lugs  1029  on two sides, which provides balanced loading on plunger rod  1010 . In this embodiment, the second side includes fewer lugs than the first side. The rearmost lugs  1050 A and  1050 B have both emerged from the groove  1031  within thumb nut  1013  ( FIG. 18B ) and are abutting stops  1054 A and  1054 B at ends of groove  1031 . These stops prevent thumb nut from being turned in the dose setting direction (the direction indicated by the arrow of  FIG. 18A ). By providing stops, the relative position of the lugs with respect to the thumb nut can be precisely controlled, allowing for precise control of the axial position of plunger rod  1010 . 
     Plunger rod  1010 , according to the illustrated embodiment, includes dosage indications  1042  on the side, which may show through window  1044  on the side of housing  1006  to indicate to the user conformation that the dose is set and that the dose delivery is complete. For example, once the dose is set ( FIG. 17B ), the number “20” (in this embodiment) may show through window  1044  to indicate to the user that the dose has been properly set. After the dose has been set and the plunger rod  1010  advances further within the housing  1006  during dosage delivery, the “20” marker moves axially out of window  1044  and the “0” marker moves axially into window  1044 . Alignment of the “0” marker within window  1044  may indicate to the user that the dose has been completely delivered. 
       FIG. 19  illustrates a ratchet engagement between a pawl  1056  on the housing  1006  and grooves  1058  on the side of thumb nut  1013 . This ratchet engagement serves dual purposes of preventing the thumb nut  1013  from being rotated in the direction opposite to the dose setting direction and providing an aural and/or tactile indication of the dose setting process. The ratchet engagement may also serve to urge thumb nut  1013  against the housing to control the axial positioning of the thumb nut. The pawl  1056  is configured such that it is urged into the grooves  1058  of the thumb nut  1013 . One face of the pawl is configured such that the pawl rides out of a respective groove  1058  as the thumb nut  1013  is rotated in the dose setting direction. The pawl then snaps back into the next groove  1058 , providing an aural and/or tactile indication of the movement of thumb nut  1013 . In some embodiments, the opposite face of pawl  1056  is configured such that the pawl remains in the groove  1058  and prevents the thumb nut  1013  from being rotated in the counter direction such that the plunger rod  1010  can only be advanced in the dose-setting direction. In some embodiments, the opposite face of pawl  1056  is configured such that the pawl resists rotation of the thumb nut  1013  in the counter direction but can rise out of the groove  1058  if enough rotational force is applied to the thumb nut. In this way, the thumb nut can be counter rotated but the effort required to counter rotate the thumb nut is greater than the effort required to rotate the thumb nut in the dose-setting direction. In some embodiments, the opposite face of pawl  1056  is configured such that the pawl does not resist rotation of the thumb nut  1013  or, at most, resists counter rotation to the same degree as it resists rotation in the dose-setting direction. In this way, the ratchet provides aural and/or tactile feedback but does not generally favor rotation in one direction or the other. 
       FIG. 20A  is a perspective view of a plunger rod  1010 , according to some embodiments. Plunger rod  1010  includes spacing pegs  1030  for maintaining the lateral position of plunger rod  1010  within syringe barrel  1009 , as discussed above. Plunger rod  1010  includes a longitudinal groove  1070  along a portion of the shaft nearest the thumb rest  1038 . Portions of the low and high force gears are located within this groove when the plunger rod subassembly is assembled. Plunger rod  1010  includes a cutout  1072  such that a cross section perpendicular to the longitudinal axis of plunger rod  1010  is semicircular. Cutout  1072  provides a bearing surface for a portion of drive rod  1012 , which has a complimentary semicircular cross section, to slide along. Drive rod  1012 , according to some embodiments, is shown in  FIGS. 20B-C . Drive rod  1012  includes a set of linear gear teeth  1024 , which engage the second set of teeth  1064 B of higher force gear  1064 . The cross-sectional profile of a portion of drive rod  1012  is configured to fit with and slide along the cutout  1072  of plunger rod  1010 , providing a large bearing surface interface that can ensure smooth relative axial motion between the plunger rod and drive rod and reduced lateral play. Drive rod  1012  can include a cylindrical end portion to help concentrically locate drive rod  1012  in syringe barrel  1009 . 
       FIGS. 21A-B  are exploded views illustrating aspects of the assembly process of plunger rod subassembly  1001 , according to some embodiments. In the illustrated embodiment, housing  1006  includes four components—main body  1080 A, back cover  1080 B, front cover  1080 C, and top cover  1080 D. Pins  1082  in front cover  1080 C fit into corresponding bores  1083  in back cover  1080 B to assemble the front and back covers to the main body. Main body  1080 A includes a plurality of holes into which gear pins  1084  are inserted. Gear pins  1084  provide shafts for the gears of the gear train  1011 . Main body  1080 A also includes grooves into which window  1044  slides. Top cover  1080 D includes pins that fit into corresponding bores in the user end of main body  1080 A. Top cover  1080 D includes a cavity  1027  shaped to match the cross-sectional profile of plunger rod  1010 , which can prevent rotation of plunger rod  1010 , such that plunger rod  1010  can translate but not rotate. In some embodiments, a preloading ring  1086  may be provided to preload the engagement of plunger rod subassembly  1001  with the syringe barrel  1009 . Preloading ring  1086  may be a coil spring, a wave spring, a ring of compliant material, such as plastic, foam, or rubber, or any other suitable component for preloading the engagement. 
     Following is a description of an assembly process for plunger rod subassembly  1001 , according to some embodiments. The following process is intended to be exemplary only. Steps may be conducted in a different order, one or more of the steps may be omitted, and/or one or more additional steps may be included depending on the configuration of the various components of the particular embodiment. In a first step, top cover  1080 D is seated and press-fit into main body  1080 A, for example, using an arbor press. Next, the three gear pins  1084  are press-fit into the main body  1080 A. Then, the thumb nut  1013  is inserted into the corresponding portion of main body  1080 A, the back cover  1080 B is seated onto the back side of the housing, and the preloading ring  1086  is inserted into the barrel opening of the housing. Next, the higher force gear  1064  is installed on the corresponding gear pin  1084 —the gear pin farthest from the thumb nut  1013 . The lower force gear  1062  is then installed onto the center gear pin  1084  and aligned such that its second set of gear teeth  1062 B engage with the first set of gear teeth  1064 A on higher force gear  1064 . The drive rod  1012  is then inserted through the barrel opening in the housing  1006 , aligned with alignment features of the housing, and pushed such that its teeth  1024  engage the second set of teeth  1064 B on higher force gear  1064 . The drive rod  1012  is inserted into the housing to a specified depth, which may depend on the particular application and which may be controlled using tooling. 
     In the next step, the plunger rod  1010  is inserted through the top cover  1080 D and through the thumb nut  1013  until the lowest-most dosing lug  1029  prevents further insertion. The rotor gear  1060  is then installed onto the remaining gear pin  1084  and aligned for engagement with both the first set of teeth  1062 A of the lower force gear  1062  and the teeth  1028  on plunger rod  1010 . The thumb nut  1013  is rotated in the dose setting direction to engage the dosing lugs  1029  on plunger rod  1010  with the internal thread of thumb nut  1013 . Plunger rod  1010  is translated further into the housing  1006  through continued rotation of thumb nut  1013  in the dose setting direction until plunger rod  1010  reaches a predetermined depth. 
     Next, window  1044  may be inserted into the corresponding groove in main body  1080 A. The front cover  1080 C is then aligned with features on the main body  1080 A and/or features on back cover  1080 B and press fit into place. This completes assembly of plunger rod subassembly  1001 , according to some embodiments. The assembled plunger rod subassembly  1001  may then be assembled to a prefilled syringe or packaged, for example, for storage and/or shipment to the syringe filler for final assembly of a prefilled accurate and precise dosing syringe system. 
     Embodiments of the present invention may provide configurations which allow the use of standard, commercially-available components, thereby reducing overall manufacturing costs, streamlining assembly processes, and avoiding regulatory concerns often associated with non-standard materials and components. For example, syringe barrels may be made of plastic, glass, or any other material commonly used for medical grade products. One or more components may be made of any suitable plastic, such as polycarbonate (including those sold under the trade name “LEXAN” by SABIC Innovative Plastics of Pittsfield, Mass.) and the like. Any suitable elastomeric polymers or rubbers may be utilized (such as the rubber products sold under the trade name “HELVOET” by Datwyler Pharma Packaging USA Inc. of Pennsauken, N.J.) for components such as the plunger seal. Various medical grade metals, such as stainless steel, may be utilized for one or more components, such as the plunger rod, drive rod, gear pins, gears, thumb nut, etc., as will be appreciated by an ordinarily skilled artisan. Any of the components described herein may be shaped or sized in any configuration to meet desired parameters. Any of the components described herein may be formed as singular components or may comprise multiple sub-components. Components may be built and/or assembled by any suitable process, including using glues or welding methods such as ultrasonic welding. 
     A person of skill in the art will appreciate that dosing mechanisms, syringes, syringe systems, etc., according to the principles and features described herein, can generally be configured for any application including, injectable drug delivery into or onto the eye, intracellular delivery, delivery of radioactive agents, delivery of chemotherapy, etc. 
     The foregoing description, for the purpose of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the techniques and their practical applications. Others skilled in the art are thereby enabled to best utilize the techniques and various embodiments with various modifications as are suited to the particular use contemplated. 
     Although the disclosure and examples have been fully described with reference to the accompanying figures, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications are to be understood as being included within the scope of the disclosure and examples as defined by the claims. Finally, the entire disclosure of the patents and publications referred to in this application are hereby incorporated herein by reference.