WO2017139003A1

WO2017139003A1 - Drug delivery device

Info

Publication number: WO2017139003A1
Application number: PCT/US2016/063625
Authority: WO
Inventors: Ian B Hanson; Iv Paul F. Bente; Nicholas J. Ciccarelli; Diane DOUGHTY
Original assignee: Unitract Syringe Pty Ltd.
Priority date: 2016-02-10
Filing date: 2016-11-23
Publication date: 2017-08-17
Also published as: WO2017139573A1

Abstract

Drug delivery devices are provided that are capable of delivering a relatively large dosage form (for example, a 2 mL volume dosage form rather than a 1 mL dosage form) comprising a drug at a controlled rate. Advantageously, these devices deliver the required dose of the drug with a generally acceptable level of pain intensity.

Description

DRUG DELIVERY DEVICE

RELATED APPLICATION

[0001] This application claims priority benefit of U.S. Provisional Patent Application No. 62/293,556, filed 10 February 2016, which is incorporated fully herein for all purposes by this reference.

FIELD

[0002] Thee present disclosure relates to drug delivery devices and use thereof. More particularly, the embodiments described herein provide delivery devices capable of delivering a viscous fluid dosage form to a subject. An aspect of the embodiments provides for subcutaneous (SQ) injection of a large volume dose (e.g., 2 mL to 2.5 mL) of a fairly viscous fluid with a tolerable level of pain to a subject. Specific embodiments provide delivery devices capable of delivering a fluid dosage form (including a large-volume dosage form) comprising an antibody, protein, peptide, or nucleic acid.

BACKGROUND

[0003] There are many therapeutic agents for which the drug product (the active agent as formulated for administration) is a thick or viscous liquid. For example, biologies (including antibodies, portions of antibodies, fusion proteins, proteins, peptides, or nucleic acids), are several magnitudes larger than typical chemical compounds; an antibody has a mass of about 150 kDa while aspirin has a mass of only 180 Da— almost 1000 times less. Other injectable dosage forms include a viscous excipient(s), such as oils or polymers, included in the formulation of the drug product, for example, to deliver sustained release of the active agent(s). Such highly viscous injectable dosage forms may cause challenges for device designers, manufacturers, primary container suppliers, and patients. In particular, delivery of a large volume viscous dosage form can cause an unacceptable level of pain in the subject, particularly when the dosage form is administered at a high rate.

[0004] Injection of 1 mL in a single, self-administered dose has historically been regarded as the upper threshold of acceptability, particularly regarding subcutaneous (SQ) delivery, but single injected dosage forms of up to 2.5 mL may be needed to administer a required dose of active agent(s). In addition to pain or discomfort experienced when administering a large volume viscous dosage form, subjects generally do not want to hold a syringe or auto-injector in place for more than about 15 seconds as is needed for the actual injection process. Additionally, in the case of SQ administration, a high rate of injection can exceed the tissue's physical allowance to accept a large volume dosage form, leading to backpressure leakage from the subject's injection site. These issues can impact patient compliance, adding to the burdens of the healthcare system.

[0005] Additionally, self-administered therapies are becoming increasingly relevant in healthcare. Indeed, there are many situations in which a patient needs a medicament but is not able to reach, or otherwise does not require, a healthcare provider. For example, chronic conditions can require regular but infrequent administrations of large volume viscous dosage forms, perhaps injected weekly, monthly, or even quarterly. Thus, there is a demand for drug delivery devices that are safe and easy to use; and that can be manufactured in a cost-effective manner. In particular, there is a need for a prefilled on-body device that an operator or subject can use safely and effectively for the delivery of a viscous dosage form, including large volume viscous dosage forms of biologies, such as antibodies, proteins, peptides, or nucleic acids.

SUMMARY

[0006] The disclosed embodiments include a drug delivery device that comprises a drive mechanism; a drug container including a plunger seal, a barrel, and a distal seal disposed within the barrel such that the barrel, the plunger seal, and the distal seal define a volume; a fluid conduit; a flow restrictor having a diameter and a length; a fluid pathway connection configured to fluidly couple the volume and the fluid conduit; and a needle insertion mechanism in fluid communication with the fluid conduit, the needle insertion mechanism configured to insert a cannula into a target location for delivery of a dosage form such that the drive mechanism causes translation of the plunger seal within the barrel to deliver the dosage form through the fluid conduit and the cannula for delivery to the target, where the improvement includes, but is not limited to, the diameter of the flow restrictor being between about 0.02 mm and 0.32 mm and a length being between about 10 mm and 38 mm.

[0007] In one embodiment, the drive mechanism of the drug delivery device includes one or more springs configured to exhibit a total spring constant between about 0.25 Newtons per mm and about 4 Newtons per mm. In another embodiment, the one or more springs includes two springs disposed and operating in parallel. In yet another embodiment, the drive mechanism further includes one or more biasing members having an initial length prior to initiation and configured to exhibit a total force in the initial length between about 40 Newtons and about 80 Newtons. In some embodiments, the one or more biasing members are compression springs. And in other embodiments, the initial length is between about 10 mm and about 30 mm. [0008] In an embodiment, the dosage form has a viscosity being between

about 3 centipoise and about 30 centipoise when the temperature of the dosage form is approximately 23 °C.

[0009] In one embodiment, the barrel has an internal diameter between about 10 mm and about 20 mm.

[0010] In another embodiment, the fluid pathway connection of the drug delivery device includes a piercing member configured to pierce the distal seal, the piercing member having a piercing member lumen through which the dosage form may flow, and the piercing member lumen having a diameter between about 0.1 mm and about 0.5 mm and a length between about 10 mm and about 20 mm.

[0011] In yet another embodiment, the needle insertion mechanism of the drug delivery device includes a cannula configured for delivery of the dosage form to the target, the cannula having a cannula lumen having a diameter between about 0.2 mm and about 0.8 mm and a length of between about 3 mm and about 12 mm.

[0012] In some embodiments, the distance between the plunger seal and the distal seal is between about 10 mm and about 20 mm.

[0013] In an embodiment, the fluid conduit includes a tubing section having an inner diameter between about 0.2 mm and about 0.6 mm.

[0014] One embodiment provides a fluid pathway assembly for a drug delivery device that includes a fluid conduit; a fluid pathway connection configured to fluidly couple the fluid conduit to a drug container; and a needle insertion mechanism in fluid communication with the fluid conduit, the needle insertion mechanism configured to insert a cannula into a target location for delivery of a dosage form, where the improvement includes the fluid pathway assembly providing a total geometric flow resistance of between about 0.5xl0¹⁵ m^"3 and about 2xl0¹⁵ m^"3. In another embodiment, this fluid pathway assembly further includes a flow restrictor. In yet another embodiment, the the flow restrictor has a geometric flow resistance of between about 0.75xl0¹⁵ m^"3 and about 1.5xl0¹⁵ m^"3. In some embodiments, the fluid pathway connection includes a piercing needle, the piercing needle having a geometric flow resistance between about lxlO¹³ m^"3 and about lxlO¹⁴ m^"3. In certain embodments, the needle insertion mechanism includes a cannula, the cannula having a geometric flow resistance between about 3xl0¹² m^"3 and about 1.2xl0¹³ m^"3.

[0015] Another embodiment provides a drug delivery device that includes a drive mechanism; a drug container including a plunger seal, a barrel, and a distal seal disposed within the barrel such that the barrel, the plunger seal, and the distal seal define a volume; a fluid conduit; a fluid pathway connection configured to fluidly couple the volume and the fluid conduit; and a needle insertion mechanism in fluid communication with the fluid conduit, the needle insertion mechanism configured to insert a cannula into a target location for delivery of a dosage form such that the drive mechanism causes translation of the plunger seal within the barrel to deliver the dosage form through the fluid conduit and the cannula for delivery to the target, where the improvement includes the drug delivery device providing a total geometric flow resistance between about 0.5xl0¹⁵ m^"3 and about 2xl0¹⁵ m^~3. In an embodiment, this drug delivery device further comprises a flow restrictor. In another embodiment, the flow restrictor has a geometric flow resistance between about 0.75xl0¹⁵ m^"3 and about 1.5xl0¹⁵ m^"3. In an embodiment, the fluid pathway connection of this drug delivery device comprises a piercing needle, the piercing needle having a geometric flow resistance between about lxlO¹³ m^"3 and about lxlO¹⁴ m^"3. In another embodiment, the needle insertion mechanism of this drug delivery device includes a cannula, the cannula having a geometric flow resistance between

about 3xl0¹² m^"3 and about lxlO¹³ m^"3.

[0016] Another embodiment provides a method of assembling a fluid pathway assembly for a drug delivery pump comprising the steps of: connecting a fluid pathway connection to a drug container; fluidly coupling a fluid conduit to the fluid pathway connection; and fluidly coupling a needle insertion mechanism to the fluid conduit; wherein the fluid path provides a total geometric flow resistance between about 0.5xl0¹⁵ m^"3 and about 2xl0¹⁵ m^"3. In an embodiment, this method further comprises the step of fluidly coupling a flow restrictor to the fluid conduit, wherein the geometric flow resistance of the flow restrictor is between about 0.75xl0¹⁵ m^"3 and about 1.5xl0¹⁵ m^"3.

[0017] The embodiments also include drug delivery devices capable of delivering a large volume dosage form (for example, 2 mL to 2.5 mL rather than 1 mL) of a liquid. In some embodiments, the drug delivery devices are capable of delivering a large volume dosage form (for example, 2 mL to 2.5 mL rather than 1 mL) of a viscous liquid. In some embodiments, the drug delivery devices are capable of delivering a large volume dosage form (for example, 2 mL to 2.5 mL rather than 1 mL) of a viscous liquid, with a level of pain intensity that is tolerable to a subject. These devices are advantageous, for example, in administering the large volume viscous dosage form at a rate such that pain does not negatively impact compliance with the prescribed dosing regimen.

[0018] At least one embodiment provides a delivery device comprising a fluid pathway assembly including a fluid conduit, a fluid pathway connection, and a needle insertion mechanism; and a drive mechanism, wherein said device is configured to deliver to a human patient from about 1.0 mL to about 2.5 mL, inclusive, of a viscous dosage form at rate of up to about 12 mL per minute. In certain embodiments, the delivery is subcutaneous (SQ) injection. In at least one embodiment, the drug delivery device is an on-body or wearable device. In particular embodiments, the device is preloaded with a dosage form. In some embodiments, the dosage form comprises a biologic, such as an antibody, or antigen-binding portion thereof. In some embodiments, the dosage form comprises about 50 mg to about 400 mg, inclusive, of a biologic. In some aspects, the drug is administered at a fixed dose. In specific aspects, the drug is administered at a fixed dose selected from about 50 mg to about 400 mg, inclusive; such as a fixed dose of about 50 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 325 mg drug/dose. In some aspects, the drug is administered in two or more doses. In other aspects, the drug is administered weekly, biweekly, or monthly. In certain aspects, the drug is administered biweekly. In some embodiments, the device is configured for SQ delivery of about 2 mL of a dosage form comprising about 300 mg drug. In some embodiments, the device is configured for delivery of the dosage form once-daily, twice a week (semiweekly), once-weekly, biweekly (fortnightly), once monthly, twice monthly

(semimonthly), every two months (bimonthly), or at a frequency determined by a health care professional. In some embodiments, the delivery device is configured to deliver the dosage form at a preselected flow rate from, the rate chosen from a range of about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute. In some embodiments, the device is disposable.

[0019] At least one embodiment provides a drug delivery device comprising means for delivering to a human subject a volume of about 1 mL to about 2.5 mL, inclusive, of a viscous dosage form at a flow rate of up to about 12 mL per minute. In certain embodiments, the delivery is SQ injection. In some embodiments, the dosage form comprises a biologic. The biologic may be an antibody. In some embodiments, the dosage form comprises about 100 mg to about 400 mg, inclusive, of a biologic. In particular embodiments, the device is preloaded with a dosage form comprising a biologic, such as an antibody. In some embodiments, the device is configured for SQ delivery of about 2 mL of a drug. In some embodiments, the device is configured for delivery of the dosage form on a once-daily basis. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate ranging from about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute.

[0020] At least one embodiment provides for a method for administering to a human subject in need thereof a dosage form comprising a viscous pharmaceutical dosage form, comprising contacting a human patient with a drug delivery device configured to deliver from about 1.0 mL to about 2.5 mL, inclusive, of a viscous dosage form at a flow rate of up to about 12 mL per minute, and actuating said device to deliver said dosage form. In certain embodiments, the delivery is SQ injection. In some embodiments, the viscous dosage form comprises a biologic, such as an antibody. In some embodiments, the device is configured for SQ delivery of about 2 mL of a dosage form. In some embodiments, the device is actuated once daily. In some embodiments, the delivery (administration) rate is from a range of about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery rate is about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute.

[0021] At least one embodiment provides a delivery device comprising a fluid pathway assembly having a fluid conduit, a fluid pathway connection, and a needle insertion mechanism; and a drive mechanism, wherein said device is configured to deliver to a human patient about 2 mL of a dosage form comprising a drug at a flow rate of up to about 12 mL per minute. In certain embodiments, the delivery is subcutaneous injection. In particular embodiments, the device is preloaded with a dosage form comprising a drug. In some embodiments, the dosage form comprises about 300 mg of a drug. In some embodiments, the device is configured for delivery of the dosage form comprising a drug on a once-daily basis. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate ranging from about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute.

[0022] At least one embodiment provides for a drug delivery device comprising a means for delivering a dosage form to a human patient of about 2 mL, comprising a drug, at a flow rate of up to about 12 mL per minute. In certain embodiments, the delivery is subcutaneous injection. In some embodiments, the dosage form comprises about 300 mg of a drug. In particular embodiments, the device is preloaded with a dosage form comprising a drug. In some embodiments, the device is configured for delivery of the dosage form comprising a drug on a once-daily basis. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate ranging from about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute.

[0023] At least one embodiment provides for a method for administering to a human patient in need thereof a dosage form comprising a drug comprising contacting a human patient with a drug delivery device configured to deliver about 2 mL of a dosage form comprising a drug at a flow rate of up to about 12 mL per minute, and actuating said device to deliver said dosage form. In certain embodiments, the delivery is subcutaneous injection. In some embodiments, the device is actuated once daily. In some embodiments, the dosage form comprises about 300 mg of a drug. In some embodiments, the device is configured for delivery of the dosage form comprising a drug on a once-daily basis. In some embodiments, the delivery (administration) rates ranges from about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery rate is about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute.

DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 is a graph presenting drive system force profiles as a function of drive assembly force (N) (x-axis) over travel distance (mm) (y-axis).■ indicates minimum;

▲ indicates maximum;♦ indicates nominal.

[0025] FIG. 2 is a bar graph conveying the contribution (%) to delivery time variation of components (x-axis) in Case 4, ambient delivery and viscosity constant, by various groups. Relative contribution, in seconds, is shown as percent on the _y-axis (see also Table 4).

[0026] FIG. 3 is an isometric view of one embodiment of a fluid pathway assembly.

[0027] FIG. 4 is an isometric view of one embodiment of a fluid pathway assembly and drug container.

[0028] FIG. 5A is an isometric view of a drug delivery pump, according to one embodiment with integrated safety insertion mechanism; FIG. 5B is an isometric view of the bottom of the same embodiment; FIG. 5C shows an isometric view of the interior components of the same embodiment of a drug delivery pump. [0029] FIG. 6 shows an isometric view of an insertion mechanism that may be included in a drug delivery device, according to one embodiment.

[0030] FIG. 7A to FIG. 7C show cross-sectional views of an insertion mechanism, according to one embodiment, in a locked and ready to use stage (FIG. 7A); in an unlocked and inserted stage (FIG. 7B); and in a retracted stage for drug delivery (FIG. 7C).

[0031] FIG. 8 A and FIG. 8B are cross-sectional views of another embodiment of a fluid pathway connection attached to a drug container before then after, respectively, activation. FIG. 8C and FIG. 8D are cross-sectional views of yet another embodiment of a fluid pathway connection attached to a drug container before and then after, respectively, activation.

[0032] FIG. 9A shows an isometric view, from the distal perspective, of a connection hub, according to one embodiment; FIG. 9B shows an isometric view, from the proximal perspective, of the same connection hub; and FIG. 9C shows a transparent view of that connection hub.

[0033] FIG. 10A and FIG. 10B are isometric views from the distal perspective and the proximal perspective, respectively, of another embodiment of a connection hub; and FIG. IOC shows a transparent view of the same connection hub. FIG. 10D and FIG. 10E are isometric views from the distal perspective and the proximal perspective, respectively, of another embodiment of a connection hub.

[0034] FIG. 11 A shows an exploded view of the fluid pathway connection, exploded along a longitudinal axis "A," according to at least one embodiment; and FIG. 11B shows a cross-sectional exploded view of the same fluid pathway connection.

[0035] FIG. 12A shows an isometric view of an example drive mechanism in an embodiment of a drug delivery pump having safety integrated insertion; and FIG. 12B is an exploded view of along an axis "A" of that device.

[0036] FIG. 13A to FIG. 13C present cross-sectional views of an example drive mechanism in the initial inactive state (FIG. 13A); in an actuated state (FIG. 13B); and at the completion of the delivery of the drug dosage form (FIG. 13C).

[0037] FIG. 14 is a graph showing mean profile plot of injection site pain by cohort (as-treated population). · indicates Cohort 1 Flow Rate = 6 mL/min; Δ indicates Cohort 2 Flow Rate = 12 mL/min;□ indicates Cohort 3 Flow Rate = 2 mL/min; x indicates Cohort 4 Flow Rate = 0.167 mL/min.

[0038] FIG. 15 is a graph of mean profile plots of injection site pruritus by cohort (as-treated population). · indicates Cohort 1 Flow Rate = 6 mL/min; Δ indicates Cohort 2 Flow Rate = 12 mL/min;□ indicates Cohort 3 Flow Rate = 2 mL/min; x indicates Cohort 4 Flow Rate = 0.167 mL/min. [0039] FIG. 16 is a graph showing incidence of injection site erythema over time for each cohort following injection of a dosage form comprising 300 mg of an exemplary drug (as-treated population).

DETAILED DESCRIPTION

[0040] All patents and other publications identified are incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention, but are not to provide definitions of terms inconsistent with those presented herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.

[0041] As used herein and in the claims, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises" and "comprising" are used inclusively rather than exclusively, so that a stated integer or group of integers may include one or more other non-stated integers or groups of integers. The term "or" is inclusive unless modified, for example, by "either." Other than in the operating examples, or where expressly stated or otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about."

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood to one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. The terms male and female may be used interchangeably to describe corresponding components or complementary aspects thereof and are not a limitation to either particular structure unless context clearly indicates otherwise.

[0043] Headings are provided for convenience only and are not to be construed to limit the invention in any way. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood to one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. In order that the present disclosure can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0044] As used herein, "fluid" refers primarily to liquids, but can also include suspensions of solids dispersed in liquids (dispersions, suspensions, colloidal mixtures), emulsions, liposomal compositions, and gasses dissolved in or otherwise present together within liquids inside the fluid-containing portions of syringes.

[0045] "Glass" should be understood to include other similarly non-reactive materials suitable for use in a pharmaceutical grade application that would normally require glass (e.g., Type I borosilicate glass), including but not limited to certain non-reactive polymers such as cyclic olefin copolymers (COC) and cyclic olefin polymers (COP).

[0046] "Plastic" may include both thermoplastic and thermosetting polymers.

Thermoplastic polymers can be re-softened to their original condition by heat; thermosetting polymers cannot. As used herein, the term "plastic" refers primarily to moldable thermoplastic polymers such as, for example, polyethylene and polypropylene, or an acrylic resin, that also typically contain other ingredients such as curatives, fillers, reinforcing agents, colorants, or plasticizers, etc., and that can be formed or molded under heat and pressure. As used herein, the term "plastic" can include pharmaceutical grade non-reactive polymers or elastomers that are approved for use in applications where they are in direct contact with therapeutic substances, such that the plastics do not interact with the substances contacting the plastic and are not readily susceptible to leaching or gas migration under ambient temperature and pressure.

[0047] The terms "elastomer," "elastomeric material," or "elastomeric" refer primarily to cross-linked thermosetting rubbery polymers that are more easily deformable than resilient plastics, are approved for use with pharmaceutical grade substances, and are not readily susceptible to leaching or gas migration under ambient temperature and pressure. It is appreciated in the art that particular elastomeric polymers are better suited for contact with pharmaceuticals than are some particular plastics, hence the elastomeric material can be a biocompatible material. As used herein, the term "elastomer," "elastomeric," or "elastomeric material" may also include other biocompatible materials, such as styrenic block copolymers (TPE-s), polyolefin blends (TPE-o), elastomeric alloys (TPE-v or TPV), thermoplastic polyurethanes (TPU), thermoplastic copolyesters, or thermoplastic polyamides, among other biocompatible materials which are approved for use with pharmaceutical grade substances, and are not readily susceptible to leaching or gas migration under ambient temperature and pressure.

[0048] References to "prefillable" generally refer to delivery devices comprising components for filling with a substance prior to dispensing the substance (e.g., dosage form) for its intended use. More specifically, in the context of the delivery device embodiments, the term "prefillable" refers to a configuration or state in which a substance may be introduced into the device any time prior to the delivery (dispense) by the device of the substance(s) for their intended use (such as delivery into a subject or patient). A prefillable delivery device thus includes devices described herein as prefilled, fill-at-time-of-use, fill-on-demand, ready-to-use, and the like.

[0049] A "dosage form" or "formulation" refers to a drug or drug product which includes the active agent and may further include inactive substances such as excipients or diluents as are known in the art. The active agent may be a biologic, such as an antibody, protein, peptide or nucleic acid. A container used in conjunction with the drug delivery devices described herein, configured to deliver a selected dose, may include an additional volume of dosage form to account for "loss" in the delivery device.

[0050] As used herein, the term "pump" is intended to include any number of drug delivery systems which are capable of dispensing a fluid to a user upon activation. Such drug delivery systems include, for example, injection systems, infusion pumps, bolus injectors, and the like. FIG. 5A to FIG. 5C show an exemplary drug delivery device according to at least one embodiment of the present invention.

[0051] As used herein, "needle" can refer to a variety of needles including but not limited to conventional hollow needles, such as a rigid hollow steel needles, and solid core needles more commonly referred to as a "trocars." For example, a needle can be a 27-gauge solid core trocar. In other embodiments, the piercing member may be any size needle suitable to insert a cannula for subcutaneous delivery of a dosage form comprising a drug. Various embodiments include a piercing member, which may be the same or a different component from the needle, as describe further herein.

[0052] As used herein, "cannula" can refer to a variety of tubes through which a fluid may pass. Such cannulas may be rigid or flexible and include an interior lumen which, during operation of the device, is placed in fluid communication with the dosage form. The cannulas disclosed here may be constructed of any material.

[0053] With reference to a "biasing member," such as in the context of one or more biasing members for insertion or retraction of the needle, trocar, or cannula, it will be appreciated that a biasing member may be any member that is capable of storing and releasing energy. Non-limiting examples include a spring, such as for example a coiled spring, a compression or extension spring, a torsional spring, and a leaf spring, a resiliently compressible or elastic band, or any other member with similar functions. In at least one embodiment, the biasing member is a compression spring. In the context of biasing members, the terms "series," "in series," or "disposed in series" is to be interpreted as springs disposed and operating as they would when connected end-to-end; and the terms "parallel," "in parallel," or "disposed in parallel" is to be interpreted as springs disposed and operating as they would in a side -by-side relationship.

[0054] A container may be used in conjunction with the drug delivery devices described herein, such as a prefilled container configured to deliver a selected dose; which container may include an additional volume of dosage form to account for "loss" in the delivery device and still deliver the required dose to the subject.

[0055] As used herein, "fluid" refers primarily to liquids, but can also include suspensions of solids dispersed in liquids (dispersions, suspensions, colloidal mixtures), emulsions, liposomal compositions, and gasses dissolved in or otherwise present together within liquids inside the fluid-containing portions of syringes.

[0056] "Viscosity" refers in general to the state of being thick, sticky, and semifluid in consistency, corresponding to the informal concept of "thickness." In particular, however, "viscosity" of a fluid is a measure of its resistance to gradual deformation by shear stress or tensile stress. Viscosity can be expressed as the magnitude of force needed to overcome internal friction, for example, as measured by the force per unit area resisting a flow, in which parallel layers a unit distance apart have a unit speed relative to one another. The viscosity of a

Newtonian fluid is dependent only on temperature, and not on shear rate and time. The viscosity of non-Newtonian fluids, time dependent, depends on temperature, shear rate and time;

depending on how viscosity changes with time the fluid behavior can be characterized as thixotropic (time thinning, i.e., viscosity decreases with time), rheopetic (time thickening, i.e., viscosity increases with time), or rheomaiaxis (time thinning correlates with breakdown of structure). The viscosity of Non-Newtonian fluids, time independent, depends not only on temperature but also on shear rate. Viscosity may be measured as centipoise (cps), in which water is the standard at 1 cps. Blood has an approximate viscosity of 10 cps; maple syrup 150 cps to 200 cps; motor oil SAE60 1000 cps to 2000 cps; ketchup 50,000 cps to 70,000 cps; peanut butter 150,000csp to 250,000 cps; caulking compound 5,000,000 cps to 10,000,000 cps.

[0057] As noted, temperature can be a factor in viscosity fluid mechanics, but for the purposes of the analytical modeling discussed herein, temperature is assumed to be ambient and remain substantially so for the course of drug delivery. Those of skill in the art armed with this specification can adjust configuration of a drug delivery device to control, manage, or harness changes in viscosity attributed to temperature. The viscous liquid as envisioned herein may be in liquid form or reconstituted from lyophilized form. Non- limiting examples of viscous fluids include those with at least about 10 cps or about 100 cps at a shear rate of 0.1/second. An example viscosity can be in the range of from about 80,000 cps to about 300,000 cps, inclusive, or the viscosity be in the range of from about 140,000 cps to about 280,000 cps, inclusive, at a shear rate of 0.1/second at 25 °C, or a viscosity range from about 100 cps to about 1,000 cps, inclusive, at a shear rate 0.1/second at 25°C. Viscosity can be measured by a rheometer.

[0058] The embodiments described herein provide for a drug delivery device capable of SQ delivery of a 2 mL dosage form comprising 300 mg of a drug with acceptable

pharmacokinetics and tolerability. In some embodiments, the pharmacokinetics and tolerability of the 2 mL injection are comparable with two 150 mg drug/1 mL SQ injections. Tolerability factors include local injection site pain and injection site pruritus post-injection; local injection site reactions (e.g., erythema, bleeding, rash, etc.) post-injection; presence of fluid leakage immediately post-injection; and incidence of treatment-emergent adverse events including clinically significant changes in vital signs, physical examinations, and laboratory parameters. Additionally, biomarkers relevant to the mechanism of action of a drug, and the presence of antidrug antibodies may be found acceptable relative to the two-injection regimen. Thus, the present embodiments provide for drug delivery devices that allow for a reduction in the number of injections by the administration of a larger dose volume of a rather viscous dosage form over longer injection times, still satisfying pharmacokinetic requirements as well as patient tolerance of pain.

[0059] In at least one embodiment, the drug delivery device is a drug delivery pump. As used herein, the term "pump" is intended to include any number of drug delivery systems which are capable of dispensing a fluid dosage form to a subject upon activation. The drug delivery pump is capable of delivering a range of dosage forms, such as those of different viscosities and volumes. The delivery device is capable of delivering a dosage form at a controlled flow rate (speed) or of a specified volume. In one embodiment, the dosage form delivery process is controlled by one or more flow restrictors within the fluid pathway connection or the sterile fluid conduit. In other embodiments, other flow rates may be provided by varying the geometry of the fluid conduit or delivery cannula, varying the speed at which a component of the drive mechanism advances into the drug container to dispense the drug therein, varying the forces applied by the drive mechanism, or combinations thereof, as described herein.

[0060] In particular embodiments, a drug delivery pump includes an activation mechanism, a drive mechanism, a fluid pathway connection, and the insertion mechanism. A drug delivery pump may comprise an insertion mechanism that includes an insertion mechanism housing, a manifold guide, at least one insertion biasing member held initially in an energized state, a retraction biasing member, and a hub connected to a proximal end of a needle. The retraction biasing member can be held in the initial energized state between the hub and the manifold guide. The manifold can have a septum and a cannula, wherein the annular space between the septum and the cannula defines a manifold header. In some embodiments, the needle and cannula are inserted into the body by an insertion biasing member(s), then the needle is retracted but the cannula remains inserted for administration of a drug. Retraction of the needle can open a fluid pathway from the manifold header to the body through the cannula. See U.S. Patent Pub. No. 20130060233. In other embodiments, the needle can open a fluid pathway from the manifold header to the body, is inserted into the body, and remains inserted for administration of a drug.

[0061] In at least one embodiment, the delivery device can be a drug delivery pump comprising a drive mechanism having integrated status indication. A drug delivery pump with integrated status indication can include a housing and an assembly platform, upon which can be mounted an activation mechanism, an insertion mechanism, a fluid pathway connection, a power and control system, and a drive mechanism comprising a drug container. In a particular embodiment, the drive mechanism having integrated status indication includes a drive housing, a status switch interconnect, a drive biasing member, a piston, and a drug container having a cap, a distal seal, a barrel, and a plunger seal, in which the drive biasing member is configured to bear upon an interface surface of the piston. The drive mechanism may include an incremental status stem having a stem interconnect, wherein the stem resides within the drive housing and the piston, and wherein the stem has an interconnect that engages one or more contacts on the piston to provide incremental feedback. See U.S. Patent Pub. No. 20130060196.

[0062] An example drive mechanism includes a drive housing, a piston adapted to impart movement to a plunger seal within a drug container, a plurality of biasing members disposed in parallel, and a retainer. The biasing members are disposed to release energy, which release causes the piston to move from a retracted position to an extended position, the piston bearing against the plunger seal to dispense drug from the container. The retainer is configured to maintain the biasing members in the energized position and then release the biasing members to permit the piston to dispense the drug. The drive mechanism may also include an end-of-dose indicator to identify when a sleeve assembly is positioned subjacent a window in the housing, the relative motion of the sleeve assembly with reference to the window or another reference component, the stoppage of such motion, or the rated or change of rate of plunger motion. See U.S. Patent Pub. No. 20140200510.

[0063] An example drug pump drive mechanism, for use in cooperation with a drug container having a plunger seal, includes a drive housing including an axis, a piston disposed for movement from at least a retracted first position to an extended second position along the axis, the piston adapted to impart movement to the plunger seal within the drug container, a plurality of biasing members disposed in parallel and adapted to move from an energized position to a deenergized position, a retainer, the retainer being moveable between a retaining position and a releasing position, the retainer disposed to maintain the biasing members in the energized first position when the retainer is in the retaining first position, and to release the biasing members from the first energized position when the retainer moves to the releasing second position, the biasing members disposed to cause movement of the piston from the retracted first position to the extended second position as the biasing members move from the energized first position to the deenergized second position. See U.S. Patent Pub. No. 20140200510.

[0064] A further example of a drug pump drive mechanism, for use in cooperation with a drug container, includes a plunger seal and a power and control system. The drive mechanism can include a drive housing including an axis, the housing further including at least one window. The drive mechanism can also include a piston disposed for movement from at least a retracted position to an extended position along said axis, the piston adapted to impart movement to the plunger seal within the drug container. The drive mechanism can also include at least one biasing member disposed and adapted to move from an energized position to a deenergized position as a result of the release of energy, the biasing member being positioned to cause movement of the piston from the retracted position to the extended position as the biasing member moves from the energized position to the deenergized position. See U.S. Patent Pub. No. 20140296787. The drive mechanism of this embodiment can include a retainer, the retainer being moveable from a retaining position to a releasing position, the retainer disposed to maintain the biasing member in the energized position when in the retaining position, and to release the biasing member from its energized position when the retainer moves to the releasing position.

[0065] The drive mechanism of this embodiment may also include a sleeve assembly positioned at least partially within the drive housing, in which at least a portion of the sleeve assembly is adapted to move along the axis with the piston. At least a portion of the sleeve assembly is visible through the window in the housing when the piston is in either the retracted position or the extended position, but the sleeve assembly is not visible through the window when the piston is in the other of either the retracted position or the extended position. The drive mechanism can also include an end-of-dose indicator, the end-of-dose indicator including at least one switch interconnect, at least a portion of which is disposed substantially adjacent the window and adapted to identify when the sleeve assembly is disposed subjacent the window, or when the sleeve assembly is not disposed subjacent the window. The drive mechanism can also include a switch interconnect that includes a mechanical trigger adapted to engage the sleeve assembly through the window, the switch interconnect can also be adapted to selectively engage the power and control system as a result of the engagement or disengagement end of the trigger. [0066] In at least one embodiment, the delivery device includes an operator-initiated fluid pathway connection that comprises a connection hub, a piercing member, a sterile sleeve, and a drug container having a cap, a distal seal, a barrel, and a plunger seal. In certain embodiments, the distal seal is a pierceable seal. The piercing member can be retained initially within the sterile sleeve which is located between the connection hub and the pierceable seal of the drug container. The connection hub may surround an internal aperture that functions as a flow restrictor, and the internal aperture can have a piercing member connected to one end and a fluid conduit connected to the other end. The drug delivery pump can include integrated sterility maintenance features, such as a housing upon which are mounted an activation mechanism, an insertion mechanism, a fluid pathway connection, a power and control system, and a drive mechanism connected to a drug container. See U.S. Patent Pub. No. 20130066274.

[0067] An exemplary drug delivery device is shown in FIG. 5A to FIG. 5C. The delivery device 10 includes a pump housing 12 that contains all of the device components and provides a means of removably attaching the device 10 to the skin of the user. The pump housing 12 also provides protection to the interior components of the device against environmental influences. The pump housing 12 is ergonomically and aesthetically designed in size, shape, and related features to facilitate easy packaging, storage, handling, and use by users who may be untrained and/or physically impaired. Furthermore, the external surface of the pump housing 12 may be utilized to provide product labeling, safety instructions, and the like. Pump housing 12 may include one or more housing subcomponents which are fixedly engageable to facilitate easier manufacturing, assembly, and operation of the drug pump. For example, drug delivery pump 10 includes a pump housing 12 which includes an upper housing 12A and a lower housing 12B. The drug delivery pump may further include an activation mechanism 14, a status indicator 16, and a window 18. Window 18 may be any translucent or transmissive surface through which the operation of the drug pump may be viewed. The status indicator 16 and window 18 may provide operation feedback to the operator.

[0068] As shown in FIG. 5C, drug delivery pump 10 further includes assembly platform 20, drive mechanism 100 having drug container 50, power and control system 400, and a fluid pathway assembly having fluid conduit 30, fluid pathway connection 300, and needle insertion mechanism 200. One or more of the components of such drug delivery pump may be modular in that they may be, for example, pre-assembled as separate components and configured during manufacturing into position onto the assembly platform 20 of the drug delivery device 10. In this embodiment, the drug delivery device is configured such that, when an operator (e.g., subject or patient) activates the device by depressing the activation mechanism 14, the device is initiated to: insert a fluid pathway into the user; enable, connect, or open necessary connections between a drug container, a fluid pathway, and a sterile fluid conduit; and deliver the dosage form stored in the drug container through the fluid pathway, fluid conduit, and into the subject.

[0069] One or more optional safety mechanisms may be utilized, for example, to prevent premature activation of the drug pump. For example, an on-body sensor 24 (shown in FIG. 5B) may be provided as a safety feature to ensure that the power and control system 400, or the activation mechanism 14, cannot be engaged unless the drug pump 10 is in contact with the body of the subject. More specifically, the on-body sensor 24 is located on the bottom of lower housing 12B where, in use, it contacts the subject's body. Upon displacement of the on-body sensor 24, depression of the activation mechanism is permitted. In this embodiment, the on-body sensor 24 is a mechanical safety mechanism, such as for example a mechanical lock-out, that prevents triggering of the drug delivery device 10 by the activation mechanism 14 unless the device is in position to administer drug. Alternatively, the on-body sensor may be an electromechanical sensor such as a mechanical lock-out that sends a signal to the power and control system 400 to permit activation. Additionally, the on-body sensor can be electrically based such as, for example, a capacitive- or impedance -based sensor which must detect tissue before permitting activation of the power and control system 400. These concepts are not mutually exclusive and one or more combinations may be utilized within the breadth of the present embodiments to prevent, for example, premature activation of the drug pump function.

[0070] In at least one embodiment, the power and control system 400 includes a power source which provides the energy for various electrical components within the housing: at least one feedback mechanism, a microcontroller, a circuit board, one or more conductive pads, and one or more interconnects. Other components commonly used in such electrical systems may also be included, as would be appreciated by one having ordinary skill in the art. The microcontroller may be, for example, a microprocessor. The power and control system 400 controls several device interactions with the operator, and interfaces with the drive mechanism 100. In one embodiment, the power and control system 400 interfaces with the control arm 40 to identify when the on-body sensor 24 or the activation mechanism 14 have been activated. As such, the control interfaces between the power and control system and the other components of the drug pump are not engaged or connected until activation by the operator as described above. This safety feature prevents accidental operation of the drug pump, and may conserve the energy of the power source during storage, transportation, and the like.

[0071] In at least one embodiment, the power and control system 400 interfaces with the drive mechanism 100 through one or more interconnects to relay status indication, such as activation, drug delivery, and end-of-dose, to the operator. Accordingly, the feedback mechanism(s) may include, for example, audible alarms such as piezo alarms or light indicators such as light emitting diodes (LEDs). Thus, for example, the power and control system 400 may also interface with the status indicator 16 of housing 12, which may be a transmissive or translucent material through which light provides visual feedback to the operator. The power and control system 400 may be configured such that after the on-body sensor or trigger mechanism have been pressed, the power and control system 400 provides a ready-to-start status signal via the status indicator 16 if device start-up checks provide no errors. The insertion mechanism 200 and the fluid pathway connection 300 may be caused to activate directly by user operation of the activation mechanism 14. After providing the ready-to-start status signal, and if the on-body sensor remains in contact with the body of the subject, the power and control system 400 will power the drive mechanism 100 to begin delivery of the drug dosage form through the fluid pathway connection 300 and sterile fluid conduit 30. The power and control system 400 may be configured to provide a dispensing status signal during the drug delivery process, via the status indicator 16. After the dosage form has been administered into the body of the user, and after the end of any additional dwell time to ensure that substantially the entire dose has been delivered to the user, the power and control system 400 may provide an okay-to-remove status signal via the status indicator 16. This may be independently verified by the user by viewing the drive mechanism and drug dose delivery through the window 18 of the pump housing 12.

Additionally, the power and control system 400 may be configured to provide one or more alert signals via the status indicator 16, such as alerts indicative of fault or operation failure situations.

[0072] Other power and control system configurations may be utilized with the drug delivery devices described herein. Such features provide desirable safety integration and ease-of- use parameters to the drug delivery devices. For example, certain activation delays may be used during drug delivery. As mentioned above, one such delay is a dwell time which ensures that substantially the entire dose has been delivered before signaling completion to the user.

Similarly, activation of the device may require a delayed depression (i.e., pushing) of the activation mechanism 14 of the drug pump 10 prior to drug pump activation. An additional safety feature may be integrated into the activation mechanism to prevent partial depression and, therefore, partial activation of the device. Additionally, the system may include a feature permitting the operator to respond to the end-of-dose signals and to deactivate or power-down the drug pump. Such a feature may similarly require a delayed depression of the activation mechanism, to prevent accidental deactivation of the device.

[0073] Referring to FIG. 5C, the fluid pathway connection 300 includes a piercing member, a connection hub, and a sterile sleeve. See also FIG. 9A to FIG. 10E. The fluid pathway connection may further include one or more flow restrictors. Upon activation of the device 10, the fluid pathway connection 300 is enabled to connect the sterile fluid conduit 30 to the drug container of the drive mechanism 100. Such connection may be facilitated by a piercing member (e.g., FIG. 8A-FIG. 9C: piercing member 330; FIG. 10-FIG. IOC: piercing member 3330), such as a needle, penetrating a pierceable seal of the drug container of the drive mechanism 100 (e.g., FIG. 8A-FIG. 8D: pierceable seal 56). The sterility of this connection may be maintained by performing the connection within a flexible sterile sleeve (e.g., FIG. 8A- FIG. 8B: sleeve 320). Upon activation of the insertion mechanism 200 (e.g., FIG. 7A-FIG.7C), the fluid pathway 300 between drug container 50 and insertion mechanism 200 is complete to permit drug delivery into the body of the subject.

[0074] In at least one embodiment, the piercing member of the fluid pathway connection is caused to penetrate the pierceable seal of the drug container of the drive mechanism by direct action of the operator, such as by depression of the activation mechanism by the operator. For example, the activation mechanism itself may bear on the fluid pathway connection such that displacement of the activation mechanism from its original position also causes displacement of the fluid pathway connection. For example, the fluid pathway connection is enabled only when the operator depresses the activation mechanism which thereby drives the piercing member through the pierceable seal; this prevents fluid flow from the drug container until desired by the operator. In such an embodiment, a compressible sterile sleeve may be fixedly attached between the cap of the drug container and the connection hub of the fluid pathway connection. The piercing member may reside within the sterile sleeve until a connection between the fluid pathway connection and the drug container is desired. The sterile sleeve may be sterilized to ensure the sterility of the piercing member and the fluid pathway prior to activation.

[0075] A number of insertion mechanisms may be utilized within the drug pumps disclosed here. In at least one embodiment, the insertion mechanism 200 includes an insertion mechanism housing having one or more lockout windows, and a base for connection to the assembly platform or pump housing, as shown in FIG. 5A and FIG. 5B. See also FIG. 6-FIG. 7C (base 252). The connection of the base to the assembly platform 20 may be, for example, such that the bottom of the base is disposed within a hole in the assembly platform to permit direct contact of the base to the body of the user (e.g., FIG. 7B: opening in base 252A). In such configurations, the bottom of the base may include a sealing membrane 254 that is removable prior to use of the drug pump 10. The insertion mechanism may further include one or more insertion biasing members, a needle, a retraction biasing member, a cannula, and a manifold. The manifold may connect to sterile fluid conduit 30 to permit fluid flow through the manifold, cannula, and into the body of the user during drug delivery. [0076] Accordingly, the insertion mechanism inserts the needle into the body of the subject, which needle may then be withdrawn in favor of a cannula. As noted, the needle may be any needle suitable for inserting the cannula into the subject. A sterile boot may be utilized within the needle insertion mechanism. The sterile boot is a collapsible sterile membrane that is in fixed engagement at a proximal end with the manifold and at a distal end with the base. The sterile boot can be maintained in fixed engagement at a distal end between the base and insertion mechanism housing. The base includes a base opening through which the needle and cannula pass during operation of the insertion mechanism. Sterility of the cannula and needle are maintained by their initial positioning within the sterile portions of the insertion mechanism. Specifically, the needle and cannula are maintained in the sterile environment of the manifold and sterile boot. The base opening of base may be closed from non-sterile environments as well, such as by for example a sealing membrane 254 (shown in FIG. 5B and FIG. 7A).

[0077] According to at least one embodiment, the insertion mechanism 200 is initially locked into a ready-to use-stage by lockout pin(s) that are positioned within lock-out windows of the insertion mechanism housing. In this initial configuration, insertion biasing member and retraction biasing member are each retained in their compressed, energized states. As shown in FIG. 7A, lockout pins 208 may be directly displaced (as in FIG. 7B), by depression of the activation mechanism 14 (see also FIG. 8C: clip 315, clip receiver 310A)). As the operator disengages any safety mechanisms, such as an optional on-body sensor 24 (shown in FIG. 5B), the activation mechanism 14 may be depressed to initiate the drug pump. Depression of the activation mechanism 14 may directly cause translation or displacement of control arm 40 and directly or indirectly cause displacement of lockout pins 208 from their initial position within locking windows 202A of insertion mechanism housing 202. Displacement of the lockout pin(s) 208 permits insertion biasing member to decompress from its initial compressed, energized state. This decompression of the insertion biasing member drives the needle and the cannula through the skin of the subject, as shown in FIG. 7A to FIG. 7C. At the end of the insertion stage, the retraction biasing member is permitted to expand in the proximal direction from its initial energized state. This axial expansion in the proximal direction of the retraction biasing member retracts the needle, while maintaining the cannula in fluid communication with the body of the user, as shown in FIG. 7C.

[0078] More specifically referring to an example embodiment of FIG. 7A, before activation hub ledges 212A hold retraction biasing member 216 in an energized state between hub 212 and manifold guide 220 within inner upper chamber 222A; hub 212 fixedly engages proximal end of needle 214 at hub recess 212B; and pins 208 located in locking groove 202A maintain insertion mechanism 200 in an energized state. Sealing member 254 is then removed and base 252 is contacted with the target injection site before activation. As pin(s) 208 are displaced (directly or indirectly) by the activation mechanism, insertion biasing member 210 expands distally, forcing manifold ring guide 228 to translate distally. Guide protrusions 204, mechanism housing 202, and corresponding pass-throughs 224 maintain the distal translation of manifold guide 220 to push needle 214 and cannula 234 through base opening 252 A and into the body. While manifold guide 220 travels distally, release surfaces 218A of clip 218 remain engaged with hub 212, holding retraction biasing member 216 in an energized state until clip 218 reaches the end of guide protrusions 204, where clip 218 is permitted to flex outwards. FIG. 7B shows a "needle inserted" stage, in which sterile boot 250 collapses as expanded insertion biasing member 210 introduces needle 214 into the body and places cannula 234 into position for drug delivery. As shown in FIG. 7C, after needle 214 and cannula 234 insertion, needle 214 is retracted back into the insertion mechanism housing 202. Specifically, manifold guide 220, clip 218, and guide protrusions 204 are configured so that when manifold 240 reaches its full distal translation toward base 252, clip 218 escapes guide protrusions 204 and flexes outwards to disengage release surfaces 218 A from hub 212. Upon this disengagement, retraction biasing member 216 expands proximally (i.e., away from insertion site). Accordingly, expansion of retraction biasing member 216 proximately translates hub 212 and needle 214. Clip 218, however, is locked in place by lockout surfaces 218B and the distal ends of the guide protrusions 204 (as shown in FIG. 7C), thereby preventing proximal translation of the manifold guide 220 and its assembly components distal to manifold guide ring 228 such that ferrule 232 retains cannula 234, which has been inserted within the body. Retraction of needle 214 from cannula 234 opens the fluid pathway from manifold header 242 through cannula 234. As the fluid pathway connection is made to the drug container and the drive mechanism is activated, the fluid is forced from the drug container through the fluid pathway connection and the sterile fluid conduit into manifold header 242 and through cannula 234 for drug delivery. In this way, activation of the insertion mechanism inserts needle 214 and cannula 234 into the body of the user, and sequentially retracts needle 214 while maintaining cannula 234 in fluid communication with the body. At the end of the drug delivery, cannula 234 may be removed from the body by removal of the drug pump. Accordingly, the insertion mechanism may be used to insert a needle and cannula into the subject and, subsequently, retract the needle while retaining the cannula in position for drug delivery.

[0079] FIG. 11 A and FIG. 1 IB exemplify an embodiment of a fluid pathway connection adaptable to the drug delivery device described herein. In this embodiment, the fluid pathway connection 300 includes sterile sleeve 320, sterile fluid conduit 30, piercing member 330, and connection hub 310 (see also FIG. 9A-FIG. 9C, FIG. 10D-FIG. 10E: sterile fluid conduit 30, piercing member 330, and connection hub 310; FIG. 10A-FIG. IOC: sterile fluid conduit 3030, piercing member 3330, and connection hub 3310). The fluid pathway connection may, optionally, further include one or more flow restrictors. Upon proper activation of the device by the operator (e.g., subject or patient), the fluid pathway connection 300 is connected to the drug container 50, thereby enabling fluid flow from the drug container (as may be forced by the drive mechanism 100), through the fluid pathway connection 300, the fluid conduit 30, the insertion mechanism 200 and into the body of the user. Such connection between the fluid pathway connection 300 and the drug container 50 may be facilitated by a piercing member 330, penetrating a pierceable seal 56 of the drug container 50. The sterility of this connection may be maintained by performing the connection within a flexible sterile sleeve 320. Upon substantially simultaneous activation of the insertion mechanism 200, the fluid pathway between drug container 50 and insertion mechanism 200 is complete to permit drug delivery into the body of the subject. The length, diameter, volume, or interior surface area of the fluid pathway, including the aperture(s) container tubing, needle, or cannula, may be factored into designing a drug delivery device with the desired delivery time of the drug dosage form as discussed further herein. For example, a fluid connection comprising a circuitous path within the connection hub can extend the fluid pathway or provide further flow restriction to the system.

[0080] The sterile sleeve 320 is connected at a proximal end to a connection hub 310. In one embodiment, this connection is facilitated by engagement between hub connectors 320C of sterile sleeve 320 and corresponding sleeve connectors 3 IOC of connection hub 310. This engagement can be a snap-fit, interference fit, screw fit, or a number of other connective linkages. The piercing member 330 passes through the connection hub 310 and is held in place at the piercing member connection aperture 31 OA. As described further below, in one embodiment the connection hub 310 is configured to accept a bent piercing member 330 such that the piercing member passes through and is held in place at both the piercing member connection aperture 310A and the conduit connection aperture 310B. The fluid conduit 30 is connected to the proximal end of the piercing member 330 at the conduit connection aperture 310B. As would be readily appreciated by an ordinary skilled artisan, a number of glues or adhesives, or other connection methods such as snap-fit, interference fit, screw fit, fusion joining, welding, ultrasonic welding, and the like may optionally be utilized to engage one or more of the components described herein.

[0081] FIG. 8 A and FIG. 8B show an additional embodiment of a drug container and a fluid pathway connection before and after activation; including drug container 50, plunger seal 60, pierceable seal 56, optional connection mount 54, sleeve interface surface 320A of sterile sleeve 320 contacting seal interface surface 56A of pierceable seal 56, which seal comprises seal barrier 56C. When an optional connection mount 54 is utilized, for example to ensure axial piercing of the pierceable seal 56, the piercing member 330 may pass through a piercing member recess 54A of the connection mount 54. These interface surfaces may be retained in position by cap 52, as shown in FIG. 8A and FIG. 8B. FIG. 8C and FIG. 8D show another embodiment of a drug container and a fluid pathway connection assembly before and after activation; comprising activation mechanism 14, fluid pathway connection 300 including sterile fluid conduit 30, piercing member 330, connection hub 310, and sterile sleeve 320; and drug container 50 comprising barrel 58, plunger seal 60, and pierceable seal 56; components of the connecting assembly are held in position by cap 52. Before activation, clip(s) 315 reside in opening(s) 310A to maintain position of hub 310. Activation displaces clip(s) 315 from position(s) 310A, and hub 310 translates distally causing piercing member 330 to pass through pierceable seal 56, thereby opening fluid communication between fluid pathway connection 300 and drug container 50.

[0082] As shown in FIG. 5C, embodiments of the drug delivery pump include drive mechanism 100 in communication with a drug container. The drug container, as exemplified in FIG. 8A-FIG. 8D, and FIG. 11A-FIG. 11B, contains a fluid dosage form comprising a drug within a barrel between, for example, a distal seal and a plunger seal (e.g., FIG. 8A-FIG. 8D: drug container 50, barrel 58, distal seal 56, plunger seal 60), for delivery through the insertion mechanism (e.g., FIG. 7A-FIG. 7C) of the drug pump into the body of the subject. The seals may be comprised of a number of materials but typically comprise elastomers or rubbers. The drive mechanism may further include a connection mount to guide the insertion of the piercing member of the fluid pathway connection into the barrel of the drug container. The drive mechanism contains a drive inner biasing member and a drive outer biasing member, such as one or more release mechanisms, and one or more guides, as are described further herein. The components of the drive mechanism function to force a fluid from the drug container out through the pierceable seal, or through the piercing member of the fluid pathway connection, for delivery through the fluid pathway connection, sterile fluid conduit, insertion mechanism, and needle or cannula, into the body of the subject.

[0083] Referring to an embodiment of a drive mechanism shown in FIG. 12A to FIG. 13C, drive mechanism 2100 is configured to receive drug container 2050 and fluid pathway connection 2300. Drive mechanism 2100, primary drug container 2050, and a portion of the fluid pathway connection 2300 are shown isometrically in FIG. 12A, in exploded form in FIG. 12B, and cross-sectionally in FIG. 13A. Drive mechanism 2100 includes drive housing 2130 having an axis that is coincident with the axis A of drive mechanism 2100. The axis A may be disposed coincident with axes in container 2050 and plunger seal 2060. Piston 2110 is at least partially disposed within the drive housing 2130 for longitudinal movement along the axis of the drive mechanism 2100. The term "axis" when used in connection with drive housing 2130 is not intended to require the axis to be in a central location of drive housing 2130 or that drive housing 2130 be round. Primary drug container 2050 retains the drug dosage form that is to be injected into the subject, and may be a vial or similar container from which a drug can be dosed. To provide a sterile environment for the dosage form, drug container 2050 includes cylindrical barrel 2058 with pierceable seal 2056 disposed in a distal end and plunger seal 2060 disposed within a proximal end. Pierceable seal 2056 and plunger seal 2060 may be formed of a number of materials, such as one or more elastomeric materials, and are sized and formulated to maintain a seal with barrel 2058.

[0084] A portion of fluid pathway connection 2300 includes connection mount 2054, sterile boot 2310, and piercing assembly 2320. Piercing assembly 2320 includes piercing member 2322 extending from hub 2324 which supports piercing member 2322, and provides fluid connection 2326 to which the fluid conduit 2030 or other fluid connector may be fluidly coupled to fluidly couple drug container 2050 to insertion mechanism 2200. Connection mount 2054 is disposed adjacent pierceable seal 2056 and includes an aperture adapted to guide the insertion of piercing member 2322 of fluid pathway connection into pierceable seal 2056 of drug container 2050. Sterile boot 2310 is disposed about piercing assembly 2320 and provides a sterile environment for the completion of the fluid coupling of fluid pathway connection 2300. Collar 2052 secures a flange of sterile boot 2310, connection mount 2054, pierceable seal 2056, and barrel 2058 in fixed relation to one another.

[0085] In operation, when a user activates the activation mechanism by depressing the mechanism (see FIG. 5B, activation mechanism 14), an arm coupled to the activation mechanism exerts axial force on piercing assembly 2320 moving piercing member 2322 axially so that it pierces pierceable seal 2056. Drive mechanism 2100 is adapted for use in cooperation with the proximal end of drug container 2050 such that once pierceable seal 2056 has been pierced by piercing member 2322, plunger seal 2060 is advanced within barrel 2058, thus dispensing the dosage form through fluid pathway connection 2300.

[0086] Piston 2110 is mounted to be translocated between a retracted position in which piston 2110 is at least partially disposed within the drive housing 2130 (FIG. 13A) to extended positions (FIG. 13B and FIG. 13C), wherein piston 2110 extends axially outward from drive housing 2130. Piston 2110 includes interface surface 21 IOC disposed to directly confront the plunger seal 2060 when assembled with a drug container 2050, or to otherwise transmit an actuating force to plunger seal 2060. In other words, piston 2110 of drive mechanism 2100 is configured to exert a dispensing force on plunger seal 2060 of drug container 2050 and to translate outward from a distal end of housing 2130 to advance plunger seal 2060 within drug container 2050 to dispense the dosage form. The initial position shown in FIG. 5A illustrates interface surface 21 IOC of piston 2110 as it would be disposed substantially adjacent the distal end of housing 12 of the device. In alternate embodiments, the piston may be initially disposed in a position extending outside of drive housing 2130. In such an arrangement, in initial assembly of drive mechanism 2100 with drug container 2050, piston 2110 may be initially at least partially disposed within the proximal end of drug container 2050. The dimensions of the piston are also relevant to the design of the drug delivery device as described herein.

[0087] In order to impart axial movement to piston 2010, drive mechanism 2100 further includes piston biasing members 2106, 2122 disposed to move from an energized position when piston 2110 is in the retracted position to a deenergized position when piston 2110 is in an extended position. It will be appreciated that, for the purposes of this disclosure and the accompanying claims, the term "deenergized position" is a relative term. That is, piston biasing members 2106, 2122 in the "deenergized position" have less energy than piston biasing members 2106, 2122 in the "energized position." That is not to say, however, that piston biasing members 2106, 2122 in the "deenergized position" are necessarily completely deenergized or storing no energy. In this embodiment, the biasing members are inner spring 2106 and outer spring 2122, the linear dimensions and force of which are relevant in the delivery time of the dosage form as discussed herein.

[0088] When piston 2110 is maintained in the retracted position, biasing members 2106, 2122 are maintained in their energized position (FIG. 13A). Piston 2110 can be maintained in the retracted position by a retaining element or clip 2115. Although any appropriate arrangement may be utilized to retain piston 2110 in the retracted position, clip 2115 may bear against an outside surface of the delivery device housing 12 and be received in locking groove 2110A of piston 2110. FIG. 13A illustrates clip 2115 disposed in such a retaining position. The engagement of retaining element or clip 2115 in locking groove 2110A maintains piston 2110 in its retracted position with biasing members 2106, 2122 in their energized position; allowing the drive mechanism 2100 to be handled as a self-contained unit (module) that can be assembled into the drug pump 2010, optionally in cooperation with a drug container 2050. In operation, however, once the clip 2115 is removed or moved to a releasing position (FIG. 12B), the piston biasing members 2106, 2122 exert an axial dispensing force on the piston 2110 as they move to a deenergized position, and the piston moves to its extended position. In at least one

embodiment, clip 2115 may be removed through an action caused, directly or indirectly, by movement of activation mechanism 14 (FIG. 13A, FIG. 13B; see also FIG. 8C: clip 315, FIG. 8D: retaining position 310A). An action that moves clip 2115 from the retaining position to the releasing position can be achieved in a number of ways. For example, with reference to FIG. 12B and FIG. 13 A, the action removing clip 2115 is a linear, perpendicular movement relative to the axis "A" of drug container 2050.

[0089] In accordance with an aspect of the invention as illustrated in the embodiment of FIG. 12A to FIG. 13C, drive mechanism 2100 is small in size or device footprint, yet capable of providing the dispensing force needed to push a dosage form from drug container 2050 through fluid conduit 2030 for delivery via insertion mechanism 2200 and fluid connection 2300. It will thus be appreciated by those of skill in the art that drive mechanism 2100 of FIG. 12A to FIG. 13C yields a significantly smaller footprint than prior art devices.

[0090] In this embodiment, biasing members 2106, 2122 are disposed concentrically with respect to each other and the piston 2100, in the form of a pair of concentrically disposed compression springs. Alternate arrangements are envisioned, however. For example, one or more of the biasing members could alternately, for example, be tension springs, depending upon the structure of the components of the drive mechanism. Biasing members may be alternately disposed, as, for example, in a side by side arrangement, or on opposite sides of the piston. In still further embodiments, three or more biasing members could be provided and disposed in parallel in any appropriate configuration. It will further be appreciated that an additional biasing member may be provided and disposed in series with one or more of biasing member(s) disposed in parallel. For example, in an embodiment where the piston includes an extension an additional biasing member may be provided to engage the piston extension.

[0091] Returning now to the embodiment of FIG. 12A to FIG. 13C, drive mechanism 2100 includes an end-of-dose indicator 2133. The end-of-dose indicator 2133 includes switch interconnect 2132 and contact sleeve assembly 2120 adapted for movement with piston 2110. Piston 2110 has interface surface 2112 that is capable of contacting or otherwise bearing upon plunger seal 2060 to force fluid out of barrel 2058 through the fluid pathway connection 2300 for delivery to a subject. So that an operator can see the end-of-dose indicator 2133, the interior of drive housing 2130 includes access window 2131.

[0092] Contact sleeve assembly 2120 of this embodiment includes a pair of telescoping sleeves 2124, 2126. The first sleeve 2124 is adapted for movement with the piston 2110 as the piston biasing members 2106, 2122 are deenergized. A distal, generally radially extending flange 2124A of first sleeve 2124 is disposed subjacent head 2111 of piston 2110. In this way, one or both of the biasing members 2106, 2122 bear against flange 2124A, which bears against piston head 2111 to impart axial movement to piston 2110. Second sleeve 2126 is slidably coupled to first sleeve 2124, first sleeve 2124 sliding distally outward from second sleeve 2126. In order to permit second sleeve 2126 to travel with first sleeve 2124 when first sleeve 2124 is fully extended from second sleeve 2126, a coupling structure is provided. In the illustrated embodiment, sleeves 2124, 2126 include respective flanges 2124B, 2126A that engage as the proximal end of first sleeve 2124 approaches the distal end of second sleeve 2126 (FIG. 13A), thus causing second sleeve 2126 to likewise move in an axial direction with piston 2110 (see also FIG. 8B: flexible sleeve 320).

[0093] It will be appreciated that alternate sleeve arrangements are envisioned. For example, first sleeve 2124 could alternatively be integrally formed with piston 2110. In this way, first sleeve 2124 formed with piston 2110 would telescope outward from second sleeve 2126 in a manner similar to that described above. Moreover, although a sleeve assembly has been described as including a pair of telescoping sleeves, alternate numbers of sleeves may be used, such as three or more telescoping sleeves. The number of sleeves may be dependent upon the cooperative structures, however, such as the relative dimensions of the drive housing, and the travel of the piston. For example, an embodiment utilizing a smaller drive housing, but having a similar piston travel, could comprise three or more telescoping sleeves. In embodiments where multiple sleeves are provided about the biasing members and biasing members are in the form of compression springs, the springs in a compressed, energized state may have a length equal to the un-telescoped sleeves, yet have an uncompressed, deenergized length that is equal to the length of the telescoped sleeves. Further, although the end-of-dose indicator has been described in connection with a drive mechanism that includes a plurality of biasing members disposed in parallel, the end-of-dose indicator could also be utilized in connection with a drive mechanism that comprises a single biasing device, or a plurality of biasing members disposed in series or in parallel.

[0094] As noted, the sleeve assembly 2120 moves axially outward and the proximal end 2126B of sleeve assembly 2120 passes window 2131 of drive housing 2130. In particular, as second sleeve 2126 moves axially outward, proximal end 2126B of second sleeve 2126 passes window 2131 of drive housing 2130. Switch interconnect 2132 includes sensor 2134 and electronic coupling 2136 to power and control system 400. At least a portion of sensor 2134 is disposed adjacent window 2131, and is adapted to identify a change in the presence of contact sleeve assembly 2120 proximal to window 2131 within drive housing 2130. For example, in the illustrated embodiment, sensor 2134 may read that sleeve assembly 2120 is no longer present proximal to window 2131.

[0095] In order to better illustrate the relationship of sensor 2134 and sleeve assembly 2120 during movement of sleeve assembly 2120, portions of sleeve assembly 2120 are broken away in FIG. 13A and FIG. 13B: housing 2130, sleeve 2126, biasing members 2106, 2122, and end-of-dose indicator 2133 are shown in cross-section taken along line 14 - - 14 in FIG. 12A. In the illustrated embodiment, sleeve assembly 2120 is disposed adjacent window 2131 when piston 2110 is in the retracted position (FIG. 13A), and as sleeve assembly 2120 begins to telescope outward with piston 2110 (FIG. 13B). Conversely, sleeve assembly 2120 is not disposed adjacent window 2131 when piston 2110 is in a fully extended position (FIG. 13C). As proximal end 2126B of second sleeve 2126 passes the window, switch interconnect 2132 identifies that the sleeve assembly has passed the window 2131, and that the end of dose has occurred, and provides that information to the power and control system 400. Electronic coupling 2136 may be of any appropriate design. In one embodiment, for example, sensor 2134 connects directly to a PCB board.

[0096] Switch interconnect 2132 includes a mechanical sensor 2134 in the form of pivotably mounted trigger 2135, in essence, an on/off mechanical switch. Trigger 2135 is disposed in a first position in contact with sleeve assembly 2120 when piston 2110 is in a retracted position. As piston 2110 moves outward from drive housing 2130, trigger 2135 slides along the telescoping sleeve assembly 2120 until such time as proximal end 2126B of second sleeve 2126 passes window 2131, that is, trigger 2135. As the second sleeve 2126 passes trigger 2135, trigger 2135 moves to a second position. The movement of trigger 2135 to the second position results in the electronic coupling 2135 providing a signal indicating the end-of-dose to the power and control system 400.

[0097] Switch interconnect 2132 may be of any appropriate design. For example, the switch interconnect may include a sensor of an electromechanical nature, or a sensor of an electrical nature, such as, for example, an optical reader or sensor. Additionally, or alternatively, the switch interconnect may utilize an ultrasonic sensor, a capacitive sensor, a magnetic sensor, or a number of other types of sensors. Accordingly, the sensor may not require physical contact with the corresponding reference component. In an embodiment including an optical sensor, the sensor may read when the presence or absence of the sleeve assembly, for example, reading the interior of the drive housing opposite the window. The sensor may be configured to additionally or alternatively identify at least one of when the sleeve assembly is disposed subjacent the window and when the sleeve assembly is not disposed subjacent the window, the relative motion of the sleeve assembly with reference to the window or another reference component, the stoppage of such motion, and the rate or change of rate of motion.

[0098] The drive mechanism may further include one or more contact surfaces located on corresponding components. Such contact surfaces may be electrical contact surfaces, mechanical contact surfaces, or electro-mechanical contact surfaces. Such surfaces may initially be in contact and caused to disengage, or initially be disconnected and caused to engage, to permit a signal to be sent to or from the power control system. [0099] Although illustrated as an electromechanical arrangement that reads the position of a telescoping sleeve, any appropriate arrangement may be provided to read the relative position of any appropriate component, the end-of-dose indicator providing a signal to the power and control system to indicate complete administration of the dosage form. Additionally, the switch interconnects and corresponding contacts or reference component may be utilized to provide incremental status indication in addition to an end-of-dose indication. For example, in the switch interconnect arrangement described above, the switch interconnect may be an electromechanical sensor configured to recognize a number of bumps, ridges, or grooves in the corresponding sleeve or any other reference component, such that contact permits the switch interconnect to signal an incremental status indication (e.g., delivery initiation, amount of volumes delivered, duration of plunger travel, etc.) and a final end-of-dose indication.

[0100] As described herein, an incremental status indication may be provided by utilizing a different type of sensor arrangement. For example, the switch interconnect may be an optical sensor configured to recognize a number of markings on the corresponding sleeve, or any other reference component. As the optical sensor recognizes the number of markings, it permits the switch interconnect to signal an incremental status indication (e.g., delivery initiation, amount of volumes delivered, duration of plunger travel, etc.) and a final end-of-dose indication. Any appropriate arrangement may be provided to read the relative position of a number of markings, ridges, grooves, or respective indicators on any appropriate reference component, and recognition of such indicators by the switch interconnect permits it to provide a signal to the power and control system to indicate the incremental status of drug delivery, including the final status that all of the drug has been administered. Alternatively, the indicators may not necessarily be defined aspects on a reference component, and the switch interconnects may be configured to recognize the actual travel of the reference component itself. The switch interconnects may thus be configured to recognize the rate of change, the distance of travel, or other related measurements in the actual travel of the reference components and enable a signal to the power and control system to provide the user with such information or feedback.

Additional detailed descriptions of the components that can be adapted for use in a drug delivery device are described in U.S. Patent Pubs. No. 20140296787, No. 20140200510, No. 20130066274, No. 20130060196, and No. 20130060233; as well as in International Patent Application numbers WO2016053954, WO2016145094, WO2016130679, and WO2016141082.

[0101] Analytical models for delivery time (i.e., speed), drive system forces, and primary container pressures can be useful in implementing some of the embodiments described herein. For instance, in fluid mechanics, the Reynolds number is a dimensionless quantity that is used to help predict similar flow patterns in different fluid flow situations. The Reynolds number is defined as the ratio of momentum forces (or inertial forces) to viscous forces, and quantifies the relative importance of these two types of forces for given flow conditions. Reynolds numbers are useful when performing scaling of fluid dynamics modeling, and as such can be used to determine dynamic similitude between two different cases of fluid flow. In addition, Poiseuille's equation may be used to estimate the flow characteristics through a circular fluid conduit, such as the piercing member, fluid conduit, flow restrictor, and cannula described herein. These and other equations relating to such analytical models include the

following formulae:

Formula 1 (Poiseuille Equation):

MR

[0102] in which Q is the flow rate in mL per minute; ΔΡ is the pressure drop (e.g., the difference in pressure between the target back pressure and the pressure within the drug container) in Pascal, μ is dynamic viscosity in cP (may also be calculated in Pa- s, N- s/m², or kg/(m- s)), and R is the geometric flow resistance in m^"3. Poiseuille's Law is commonly used to describe the flow of fluids and can be used to determine the flow rate of the fluid based on such parameters as described herein. The pressure drop may be, for example, dependent on the forces applied by the biasing members, which, in at least one embodiment, may vary over the duration of delivery. The target backpressure may, in the case of subcutaneous delivery, be the backpressure of human tissue. One of ordinary skill in the art will recognize that alternative units may be used for one or more of the above parameters and appropriate conversions between units applied.

Formula 2 (Geometric Flow Resistance for a circular cross section):

128 L

R

π D⁴

[0103] in which L is the length of the flow path in meters, and D is the diameter of the flow path in meters. This formula may be used to calculate the geometric flow resistance of each component of the fluid pathway assembly (e.g., the piercing member, the fluid conduit, the flow restrictor, and the cannula of the needle insertion mechanism). These component flow resistance values may then be summed to determine the geometric flow resistance of the fluid pathway assembly. This value may then be used in Formula 1 to determine the flow rate provided by the drug delivery device. The length and diameter of the components of the fluid pathway assembly may be varied to provide the desired flow rate and/or delivery time. nold's number):

in which Re is Reynolds number; Q is the flow rate in mL per minute; p is fluid density in kg/m³; μ is dynamic viscosity in cP (may also be calculated in Pa- s, N- s/m², or kg/(m- s)); and D is the hydraulic diameter in mm (the "wetted perimeter," total perimeter of all the channels in contact with the flow [the inside pipe diameter]). It may be convenient to assume the fluid has a density of l.Og/mL. Flow is laminar if the value is <2300.

[0104] In some of the embodiments described herein, the components of a delivery device have been analyzed using the designation listed in Table 1, below. Table 1 lists dimensions and values of various embodiments of the present invention.

Table 1

More More

Most

System Variable Unit Preferred Preferred Prel Ferred

Preferred

Min Max Min Max Min Max

Tubing (FR-N IM)

mm 0.41 0.35 0.45 0.29 0.49 0.17 0.57 Diameter

Tubing (FR-N IM)

mm 58.42 57 60 55.58 61.58 52.74 64.74 Length

Cannula

mm 0.45 0.4 0.5 0.35 0.55 0.25 0.65 Diameter

Cannula Length mm 6.4 6 7 5.6 7.6 4.8 8.8

[0105] These inputs may then be used to calculate various parameters of the drug delivery device. For example, the inputs may be used to calculate the forces applied by the biasing members. In addition, the geometry of the fluid pathway assembly may be used to calculate the geometric flow resistance, as shown below in Table 2, for each of the exemplary embodiment of Table 1. The value of the geometric flow resistance may then be used to calculate the flow rate and/or delivery time, as described above.

[0106] Finally, the total delivery time of the device may be calculated. Table 3 shows the delivery time for the most preferred embodiment. The parameters above may be modified to achieve desired delivery times. In addition, the impact of manufacturing tolerances and other forms of variability may be estimated as shown in Table 4 and FIG. 2. Table 3

Most

Delivery Case Unit

Preferred

Case 1: Delivery Time, Subcutaneous

Delivery Time, s 117

Delivery, with Viscosity Tolerance

Subcutaneous Delivery,

Case 2: Delivery Time, Subcutaneous

with Viscosity Tolerance s 117

Delivery, Constant Viscosity

Case 3: Delivery Time, Ambient Delivery,

s 112.6

Delivery Time, Ambient with Viscosity Tolerance

Delivery Case 4: Delivery Time, Ambient Delivery,

s 112.6 Constant Viscosity

Flow Rate - Average mL/min 1.03

Flow Rate (Case 1) Flow Rate - Initial (Highest) mL/min 1.18

Flow Rate - Final (Lowest) mL/min 0.88

[0107] Variables, components, and delivery times per example embodiments are also shown in Table 4, FIG. 1, and FIG. 2. The relationship between drive system force and the travel distance of the fluid delivered is shown in FIG. 1. Four models are further analyzed for component contribution to the time of delivery in Table 4. More specifically, Table 4 conveys the contribution (%) to delivery time variation (in seconds) related to factors such as drug delivery device components, drug viscosity, and tissue in different experimental settings. Case 1: SQ delivery and viscosity range; Case 2: SQ delivery and viscosity constant; Case 3, ambient delivery and viscosity range; Case 4: ambient delivery and viscosity range. FIG. 6 shows the contribution (%) to delivery time variation (in seconds) in Case 4, ambient delivery and viscosity range, by various groups of components:

Table 4

Relative Con( ribution to Delivery Time (seconds)

Component Case 1 Case 2 Case 3 Case 4

Glide Force 1.2% N/A 1% N/A

Diameter 2.4% 3.3% 2% 3.8%

Drug:

Viscosity 27.7% 0.0% 34% 0.0%

Dosage Volume 2.7% 3.7% N/A N/A

Tissue:

Tissue Backpressure 9.2% 12.8% 0% 0.0%

Fluid Path:

Needle Diameter 1.0% 1.3% 1% 1.8%

Needle Length 0.1% 0.1% 0% 0.2%

Tubing (SAC - FR)

1.0% 1.3% 1% 1.8% Diameter

Tubing (SAC - FR) Length 0.2% 0.2% 0% 0.3%

Flow Restrictor Diameter 9.9% 13.6% 12% 18.3%

Flow Restrictor Length 0.9% 1.2% 1% 1.7%

Tubing (SAC - NIM) Diameter 1.8% 2.5% 2% 3.4%

Tubing (SAC - NIM) Length 0.2% 0.2% 0% 0.3%

Cannula Diameter 0.1% 0.2% 0% 0.3%

Cannula Length 0.0% 0.0% 0% 0.0%

[0108] In at least one embodiment, the delivery rate of the dosage form is dictated, in part, by the geometrical flow resistance of the fluid pathway assembly 60 and by the forces exerted by the one or more biasing members on the plunger seal 60. For example, for a given flow resistance, an increase in the forces exerted by the biasing member will result in an increased flow rate. Conversely, an increased flow resistance will lead to a decreased flow rate for a given force exerted by the biasing member. Thus, by selecting appropriate geometry for the fluid pathway assembly 60 and appropriate configurations of the one or biasing members, the flow rate of the dosage form to the patient may be tailored to meet treatment goals or parameters. Additionally, the effect of changes in viscosity of the dosage form— due to, for example, changes in temperature— may be calculated. For example, the viscosity of the dosage form may be between 3 centipoise and 30 centipoise at approximately 23 °C. In another embodiment, the viscosity of the dosage form may be between 5 centipoise and 20 centipoise at approximately 23 °C.

[0109] The various embodiments of the drug delivery device described within the specification as well as in Tables 1-4. The scope of the invention is not limited to any particular invention described.

[0110] The fluid pathway assembly may be, for example, as shown in FIG. 3. The flow resistance of the fluid pathway assembly 60 is the sum of the flow resistance of each component of the assembly through which the dosage form flows during injection. The flow resistance of each of those components is defined by the geometry of the components, as illustrated by Formula 2, above. In one embodiment, the fluid pathway assembly 60 includes fluid pathway connection 300, fluid conduit 30, and needle insertion mechanism 200. The fluid pathway connection 300 may be configured to fluidly couple a drug container 50 to fluid conduit 30 as described herein and as shown in FIG. 4. The fluid conduit 30 may additionally be in fluid communication with the needle insertion mechanism 200. Thus, the fluid pathway assembly 60 provides a flow path from drug container 50, through the fluid pathway connection 300, fluid conduit 30, and needle insertion mechanism 200 for delivery to a target location. The fluid pathway assembly 60 may further include flow restrictor 34. The flow restrictor 34 may be a portion of fluid pathway connection 300. Alternatively, flow restrictor 34 may be an

intermediate portion of fluid conduit 30, as shown in FIG. 9. In other words, the flow restrictor may be connected at a first end to a first portion of the fluid conduit and at a second end to a second portion of the fluid conduit. The diameter of the flow restrictor through which the dosage form flows during injection, such as, for example, flow restrictor 34,may be between 0.02 mm and 0.32 mm. In another embodiment, the diameter of the flow restrictor is between 0.08 mm and 0.26 mm. In another embodiment, the diameter of the flow restrictor is between 0.14 mm and 0.20 mm. In another embodiment, the diameter of the flow restrictor is between 0.16 mm and 0.18 mm. The length of the flow path of the flow restrictor (i.e., the length if the flow restrictor were stretched in a straight line) may be, in one embodiment, between 5 mm and 50 mm. In another embodiment, the length of the flow path is between 10 mm and 38 mm. In another embodiment, the length of the flow path is between 16 mm and 32 mm. In another embodiment, the length of the flow path is between 20 mm and 28 mm. In another embodiment, the length of the flow path is between 22 mm and 26 mm.

[0111] In at least one embodiment, as described herein, fluid pathway connection 300 includes piercing member 330 configured to pierce pierceable seal 56 of the drug container 50. In one embodiment, the dosage form flows through a lumen of the piercing member 330 during delivery (see FIG. 10D, FIG. 10E). Hence, the geometry of the piercing member 330 contributes to the flow resistance of fluid pathway assembly 60. In one embodiment, the diameter of the lumen is between 0.1 mm and 0.5 mm. In another embodiment, the diameter of the lumen is between 0.25 mm and 0.4 mm. In one embodiment, the length of the lumen is between 10 mm and 20 mm. In another embodiment, the length of the lumen is between 13 mm and 17 mm.

[0112] In at least one embodiment, as described herein, the needle insertion mechanism 200 includes a cannula 234 through which the dosage form flows during injection. The geometry of the cannula 234, therefore, affects the flow resistance of the fluid pathway assembly. In one embodiment, the lumen of the cannula 234 has a diameter between 0.2 mm and 0.8 mm. In another embodiment, the diameter of lumen of the cannula 234 is between 0.4 mm and 0.5 mm. In one embodiment, the length of the lumen of the cannula is between 3 mm and 12 mm. In another embodiment, the length of the lumen is between 5 mm and 8 mm.

[0113] In one embodiment, the fluid conduit 30 has a tubing section with an inner diameter. The tubing diameter, in one embodiment, is between 0.2 mm and 0.6 mm. In another embodiment, the diameter of the tubing section is between 0.3 mm and 0.5 mm. In one embodiment, the length of the fluid conduit is between 48 mm and 128 mm. In another embodiment, the length of the fluid conduit 30 is between 68 mm and 108 mm. In another embodiment, the length of the fluid conduit 30 is between 78 mm and 98 mm.

[0114] The components of the fluid pathway assembly 60 contribute to the geometrical flow restriction of the device. In one embodiment, the total geometric flow resistance of the fluid pathway assembly 60 is between 0.5xl0¹⁵ m^"3 and 2xl0¹⁵ m^"3. In another embodiment, the flow resistance is between lxlO¹⁵ m^"3 and 1.5xl0¹⁵ m^"3. The individual components of the fluid pathway assembly 60 may contribute to this flow resistance. For example, in one embodiment, the flow resistance of the flow restrictor 34 is between 0.75xl0¹⁵ m^"3 and 1.5xl0¹⁵ m^"3. In another embodiment, the flow resistance of the flow restrictor 34 is between lxlO¹⁵ m^"3 and 1.25xl0¹⁵ m^"3. Additionally, the piercing member 330 of the fluid pathway connection 300 may have a flow resistance of between lxlO¹³ m^"3 and lxlO¹⁴ m^"3. In another embodiment, the flow resistance of the piercing member 330 is between 2.5xl0¹³ m^"3 and 7.5xl0¹³ m^"3. In addition, the cannula 234 of the needle insertion mechanism 200 may have a flow resistance of between 3xl0¹² m^"3 and 1.2xl0¹³ m^"3. In another embodiment, the cannula 234 may have a flow resistance of between 5xl0¹² m^"3 and 9xl0¹² m^"3.

[0115] In at least one embodiment, during operation, a biasing member provides a force which causes the plunger seal 60 to translate in the distal direction and cause the dosage form to flow through the fluid pathway assembly 60. These forces influence the delivery rate and/or delivery time as described in Formula 1 , above. In one embodiment, the biasing member is a spring such as a compression spring. In one embodiment, the biasing member has a spring constant of between 0.25 Newtons per mm and 4 Newtons per mm. In another embodiment, the biasing member has a spring constant of between 0.5 Newtons per mm and 2 Newtons per mm. In another embodiment, the biasing member has a spring constant between 0.75 Newtons per mm and 1.5 Newtons per mm. The biasing member may be a single compression spring with the spring constants noted above. Alternatively, the biasing member may be a plurality of biasing members operating in parallel with an equivalent spring constant within the ranges noted above. [0116] Additionally, the biasing member may be one or more springs with an initial length at initiation of injection and a final length at completion of drug delivery. In one embodiment, the initial length of the biasing member is between 10 mm and 30 mm. In another embodiment, the initial length of the biasing member is between 13 mm and 17 mm.

[0117] The biasing member may exert an initial force at initiation of drug delivery. In one embodiment, the initial force is between 20 Newtons and 100 Newtons. In another embodiment, the initial force is between 40 Newtons and 80 Newtons. In another embodiment, the initial force is between 50 Newtons and 70 Newtons. In another embodiment, the initial force is between 55 Newtons and 65 Newtons.

[0118] The disclosure here further includes a method of assembling a fluid pathway assembly. The method of assembly includes the steps of connecting a fluid pathway connection to a drug container; fluidly coupling a fluid conduit to the fluid pathway connection, and fluidly coupling a needle insertion mechanism to the fluid conduit, wherein the fluid pathway connection provides a geometrical flow resistance of between 0.5xl0¹⁵ m^"3 and 2xl0¹⁵ m^"3. In another embodiment, the flow resistance is between lxlO¹⁵ m^"3 and 1.5xl0¹⁵ m^"3. The method of assembly may further include the step of fluidly connecting a flow restrictor to the fluid conduit, wherein the geometric flow resistance of the flow restrictor is between 0.75xl0¹⁵ m^"3 and 1.5xl0¹⁵ m^"3. In another embodiment, the flow resistance of the flow restrictor is between lxlO¹⁵ m^"3 and 1.25xl0¹⁵ m^"3.

[0119] The disclosure here may further include assembling a fluid pathway assembly as described above, in a drug delivery device. The method of assembly may include connecting the components to a lower housing and connecting an upper housing to the lower housing. The method of assembly may further include coupling a drive system to the fluid pathway assembly. In one embodiment, the drive system may include a biasing member configured to impart a force on a plunger seal during operation.

[0120] References to "pharmaceutical agent," "pharmaceutically active,"

"pharmaceutical," "drug," "medicament," "active agent," "active drug" "active pharmaceutical ingredient," "API," and the like, refer in a general sense to substances useful in the medical and scientific arts as suitable for delivery via a syringe, including, for example, drugs, biologies, diagnostic agents (e.g., dyes or contrast agents) or other substances used for therapeutic, diagnostic, or preventative (e.g., vaccines), or research purposes. Example pharmaceutical agents include biologies, vaccines, chemotherapeutic agents, contrast agents, small molecules, immunogens, antigens, interferons, polyclonal antibody preparations, monoclonal antibodies, anesthetics, interfering RNAs, gene vectors, insulins, or combinations of any of these. As noted, a dosage form may comprise one or more active therapeutic agents, or a combination of active and diagnostic agents, etc.

[0121] "Inactive" substances refer to carriers, excipients, diluents, and the like, which are well-known in the art, although such substances may have beneficial function in the mixed injectable, such as, for example, surfactant, inorganic or organic salt, stabilizer, diluent, solubilizer, reducing agent, antioxidant, chelating agent, preservative, adjuvants, isotonic or buffering agents, or any excipient conventionally used in pharmaceutical

compositions (i.e., "pharmaceutically acceptable excipient") and the like. These active or inactive substances may also include substances having immediate, delayed, controlled, or sustained release characteristics.

[0122] A "dosage form," "pharmaceutical formulation," "formulation," or

"pharmaceutical composition" refers to a drug product that includes at least one active agent and may further include pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art. For example, a typical injectable pharmaceutical formulation includes a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity, and stability. The dosage forms delivered by the devices disclosed herein can have diagnostic, therapeutic, cosmetic, or research utility in various species, such as for example in human patients or subjects.

[0123] The term "therapeutic agent" as used herein refers to any therapeutically active substance that is administered to a subject to produce a desired, usually beneficial, effect. The term therapeutic agent includes, e.g., classical low molecular weight therapeutic agents commonly referred to as small molecule drugs; and biologies including, but not limited to, antibodies or functionally active portions thereof, peptides, lipids, protein drugs, protein conjugate drugs, fusion proteins, enzymes, nucleic acids, ribozymes, genetic material, viruses, bacteria, eukaryotic cells, and vaccines. A therapeutic agent can also be a pro-drug, which is metabolized into the desired therapeutically active substance at or after administration to a subject. In some aspects, the therapeutic agent is a prophylactic agent. In addition, the therapeutic agent can be pharmaceutically formulated. A therapeutic agent can also be a radioactive isotope. A therapeutic agent can be an agent activated by a form of energy such as light or ultrasonic energy, or activated by other circulating molecules that can be administered systemically or locally.

[0124] A pharmaceutical formulation can include a therapeutically effective amount of at least one active agent. Such effective amounts can be readily determined by one of ordinary skill in the art based, in part, on the effect of the administered dosage form, or the combinatorial effect of an agent and one or more additional active agents, if more than one agent is used. A therapeutically effective amount of an active agent can also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent (and one or more additional active agents) to elicit a desired response in the individual, e.g., amelioration of at least one condition parameter. For example, a therapeutically effective amount of a dosage form can inhibit (lessen the severity of or eliminate the occurrence of), prevent a particular disorder, or lessen any one of the symptoms of a particular disorder known in the art or described herein. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the active agent or dosage form are outweighed by the therapeutically beneficial effects.

[0125] Accordingly, an active agent can be administered to a subject as a monotherapy. Alternatively, an active agent can be administered to a subject as a combination therapy with another active agent in a combination dosage form, or as an additional treatment, e.g., another treatment for an associated or additional disorder. For example, combination therapy can include administering to the subject (e.g., a human patient) one or more agents (e.g., antibiotics, anticoagulants, anti-hypertensives, or anti-inflammatory drugs) that provide a therapeutic benefit to a subject. In some embodiments, an active agent and one or more additional active agents are administered in a single dosage form. In other embodiments, an active agent is administered first in time and an additional active agent(s) is administered second in time. In some embodiments, one or more additional active agents are administered at the same time, but using different drug delivery devices or delivery modes.

[0126] A dosage form delivered according to the devices described herein may replace or augment a previously or currently administered therapy. For example, upon treating with one pharmaceutical formulation, administration of an additional active agent(s) can cease or be diminished, e.g., be administered at lower concentrations or with longer intervals between administrations. In some embodiments, administration of a previous therapy can be maintained. In some embodiments, a previous therapy is maintained until the level of an active agent reaches a level sufficient to provide a therapeutic effect. Accordingly, two therapies can be administered in combination, sequentially, or simultaneously.

[0127] The term "antibody" includes a full antibody; a derivative, portion, or fragment thereof, such as a fragment derived from enzymatic or chemical cleavage or a portion obtained recombinantly; or a mimic of the binding region of an antibody produced either by way of protein expression techniques or through chemical synthesis, which retains functionality as a specific binding member, such as the specific binding activity of at least one antibody antigen- binding domain site. Accordingly, the term antibody includes monoclonal antibodies and all the various forms derived from antibodies, including but not limited to full-length antibodies (e.g., having an intact Fc region), bifunctional antibodies, trifunctional antibodies, antigen-binding fragments (e.g., produced via enzymatic cleavage) or portions (e.g., polypeptides produced using recombinant methods) including, for example, scFv, di-scFv, sdAb, BiTE (bi-specific T-cell engager), Fab, Fab' and F(ab' )2 fragments, diabodies, single chain antibodies, and other specific binding members comprising an antibody antigen-binding domain site. The terms "antibody" and "antibodies" as used herein also refer to human antibodies produced for example in transgenic animals or through phage display, as well as chimeric antibodies, humanized antibodies, and fully humanized antibodies or portions thereof that function as a specific binding member.

[0128] Biologies that can be advantageously delivered by the drug delivery devices as described herein include dosage forms comprising polymer solvent gels such as Eligard® (leuprolide acetate for injectable suspension); dosage forms comprising polymer solutions such as gelatin, hyaluronic acid (Hyalgan®), hylan GF 20 (Syn vise-One®), or a mixture of cyclodextrin and polymeric hyaluronate or polymeric hyaluronic acid (see U.S. Patent

No. 9,089,478) or cross-linked hyaluronic acid (U.S. Patent No. 9,050,336); dosage forms comprising oily formulations, such as fulvestrant (Faslodex®); dosage forms comprising flowable polymer formulations, see WO2002030393 for example polymer microspheres, such as Lupron Depot® (leuprolide acetate for depot suspension); dosage forms comprising biologies, such as cells, platelets, cellular extracts, hormones, lubricin (proteoglycan), cytokines (e.g., granulocyte colony-stimulating factor), biomolecules having either agonist or antagonist activity (e.g., ligands or receptors), fusion proteins (such as a macromolecule having at least first and second functional moieties). References to a biologies include variants, analogs, or derivatives thereof, such as pegylated filgastrim.

[0129] The drug delivery devices of the present embodiments can be used to deliver drugs useful in treating, ameliorating, or preventing a wide range of human and animal disease states. Non- limiting examples of disease states include atherosclerosis; arthritis; asthma;

cancers; cardiovascular diseases (such as high blood pressure, stenosis, vessel occlusion or a thrombotic event); cirrhosis; congestive heart failure; ischemia; metabolic diseases; sepsis; stroke; tumors; inflammatory disease (such as vulnerable plaque); immune or autoimmune disease (such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, pelvic inflammation, vasculitis, psoriasis, diabetes, autoimmune hepatitis, multiple sclerosis, myasthenia gravis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Hashimoto's thyroiditis, Grave's disease, ankylosing spondylitis, Sjogrens disease, limited scleroderma (CREST syndrome), systemic scleroderma, rheumatic disease, organ rejection, primary sclerosing cholangitis); pre-malignancies (such as actinic keratosis, adenoma, atrophic gastritis, leukoplakia, erythroplasia, lymphomatoid granulomatosis, preleukemia, Hurthle cell adenoma, fibrosis, cervical dysplasia, uterine cervical dysplasia, ovarian thecoma, xeroderma

pigmentosum, Barrett's esophagus, colorectal polyp); neurological disease (such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, schizophrenia, bipolar disorder, depression, autism, prion disease, Pick's disease, dementia, Huntington's disease, trisomy 21,

cerebrovascular disease, Rasmussen's encephalitis, meningitis, neuropsychiatric symptoms, amyotrophic lateral sclerosis, Creutzfeldt-Jacob disease, transmissible spongiform

encephalopathy, ischemic reperfusion damage (e.g., stroke), brain trauma, or chronic fatigue syndrome); infectious disease, such as a bacterial, viral or yeast infection. Further infectious diseases or conditions that may be treated using the delivery devices described herein include influenza, Lyme disease, respiratory syncytial virus infection, methicillin-resistant

Staphylococcus aureus, human immunodeficiency virus, hepatitis A, B or C, syphilis, Group B streptococcal infection, meningitis, malaria, tuberculosis or Whipple's disease; in which the drug delivery device can be used to deliver, e.g., viscous antibiotics or antiviral, vaccines, or passive immunizations.

[0130] Cancers that can be treated using delivery devices of the present embodiments include carcinoma, sarcoma, lymphoma or leukemia, germ cell tumor, blastoma, or other cancers. Carcinomas include epithelial and glandular neoplasms, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, adenoid cystic carcinoma, adenocarcinoma, insulinoma, pancreatic cancers (such as glucagonoma, gastrinoma, pancreatic neuroendocrine tumor (VIPoma)), hepatocellular carcinoma, cholangiocarcinoma, carcinoid tumor of appendix, linitis plastica, larynx carcinoma, hypopharynx carcinoma, mouth cancer, hypopharyngeal cancer, salivary gland carcinoma, tongue carcinoma, gastric carcinoma, prolactinoma, oncocytoma, hepatocellular carcinoma, basal cell carcinoma, kidney parenchyma carcinoma, papillary renal carcinoma, renal cell carcinoma, gall bladder carcinoma, bronchial carcinoma, Grawitz tumor, colon cancer, carcinoma of unknown primary site, multiple endocrine adenomas, endometrioid adenoma, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic, mucinous and serous neoplasms, cystadenoma, pseudomyxoma peritonei, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, Warthin's tumor, thymoma, specialized gonadal neoplasms, sex cord stromal tumor, solid tumor labial carcinoma, granulosa cell tumor, arrhenoblastoma, Sertoli Leydig cell tumor, glomus tumors, paraganglioma, pheochromocytoma, glomus tumor, nevi and melanomas, melanocytic nevus, malignant melanoma, melanoma, nodular melanoma, dysplastic nevus, lentigo maligna melanoma, superficial spreading melanoma, and malignant acral lentiginous melanoma.

Sarcomas include Askin's tumor, botryodies, chondrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, malignant hemangio endothelioma, malignant schwannoma, osteosarcoma, soft tissue sarcomas (including alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, hemangiopericytoma, hemangiosarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, pleomorphic undifferentiated sarcoma, neurofibrosarcoma, rhabdomyosarcoma, and synovial sarcoma). Lymphoma and leukemia include acute lymphoblastic leukemia, acute myeloid leukemia, hairy cell leukemia, multiple myeloma, chronic myelogenous leukemia; chronic myeloproliferative disorders; chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenstrom macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, heavy chain diseases, extranodal marginal zone B-cell lymphoma, also called malt lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non- Hodgkin lymphoma ( including diffuse large B-cell lymphoma, follicular lymphoma, Mycosis fungoides and the Sezary syndrome, mantle cell lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal NK-/T- cell lymphoma), mediastinal (thymic) large B-cell lymphoma, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia/lymphoma, enteropathy-type T-cell lymphoma, blastic NK-cell lymphoma, cutaneous T-cell lymphoma; primary cutaneous CD30-positive T-cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, unspecified, anaplastic large cell lymphoma, classical Hodgkin lymphomas (nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte depleted or not depleted, nodular lymphocyte-predominant Hodgkin lymphoma), HIV-related lymphoma (e.g., primary effusion lymphoma). Germ cell tumors include without limitation germinoma, dysgerminoma, seminoma, nongerminomatous germ cell tumor, embryonal carcinoma, endodermal sinus turmor, extracranial germ cell tumor; extragonadal germ cell tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma. Blastomas include ependymoblastoma, esthesioneuroblastoma, medulloblastoma, nephroblastoma,

and retinoblastoma.

[0131] Other cancers include lung cancers such as non-small cell lung cancer and small cell lung cancer (including small cell carcinoma (oat cell cancer), mixed small cell/large cell carcinoma, and combined small cell carcinoma), breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, head and neck squamous cell carcinoma, myeloma, adrenocortical carcinoma; adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors), basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, and plasmocytoma, anal cancer; appendix cancer; astrocytomas; atypical teratoid/rhabdoid tumor; bladder cancer; brain stem glioma; brain tumor (including brain stem glioma, central nervous system atypical teratoid/rhabdoid tumor, central nervous system embryonal tumors, astrocytomas, craniopharyngioma, ependymoma,

medulloepithelioma, pineal parenchymal tumors of intermediate differentiation, supratentorial primitive neuroectodermal tumors and pineoblastoma); breast cancer; bronchial tumors; cancer of unknown primary site; carcinoid tumor; central nervous system atypical teratoid/rhabdoid tumor; central nervous system embryonal tumors; cervical cancer; childhood cancers; chordoma; colorectal cancer; craniopharyngioma; endocrine pancreas islet cell tumors; endometrial cancer; ependymoma; esophageal cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal carcinoid tumor; gastrointestinal stromal cell tumor;

gastrointestinal stromal tumor (GIST); gestational trophoblastic tumor; glioma; head and neck cancer; heart cancer; intraocular melanoma; islet cell tumors; Langerhans cell histiocytosis; laryngeal cancer; lip cancer; liver cancer; malignant fibrous histiocytoma bone cancer;

medulloepithelioma; Merkel cell carcinoma; mesothelioma; metastatic squamous neck cancer with occult primary; multiple endocrine neoplasia syndromes; multiple myeloma; multiple myeloma/plasma cell neoplasm; myelodysplastic syndromes; myeloproliferative neoplasms; nasal cavity cancer; nasopharyngeal cancer; neuroblastoma; non-melanoma skin cancer; oral cancer; oral cavity cancer; oropharyngeal cancer; osteosarcoma; other brain and spinal cord tumors; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; ovarian low malignant potential tumor; papillomatosis; paranasal sinus cancer; parathyroid cancer; pelvic cancer; penile cancer; pineal parenchymal tumors of intermediate differentiation; pineoblastoma; pituitary tumor; plasma cell neoplasm/multiple myeloma; pleuropulmonary blastoma; primary central nervous system (CNS) lymphoma; prostate cancer; rectal cancer; renal cancer;

respiratory tract cancer; retinoblastoma; rhabdomyosarcoma; small intestine cancer; squamous neck cancer; supratentorial primitive neuroectodermal tumors; testicular cancer; thymic carcinoma; thymoma; thyroid cancer; transitional cell cancer; transitional cell cancer of the renal pelvis and ureter; trophoblastic tumor; ureter cancer; urethral cancer; uterine cancer; uterine sarcoma; vaginal cancer; vulvar cancer; or Wilm's tumor. [0132] SQ injections allow for at-home patient self-administration, which has been shown to be associated with a decreased incidence of adverse events and an increased adherence to medication. Ismael et al., Lancet Oncol. 13:869 (2012) (breast cancer patients); Wynne et al., J. Clin. Pharmacol. 53: 192(2013). Currently, most SQ injection volumes are limited to 1 mL because volumes greater than this have been associated with increased injection pain, high SQ back pressure, site leakage, or injection-site reactions. Jorgensen et al., Ann.

Pharmacother. 30:729 (1996); Zaybak & Khorshid, J. Clin. Nurs. 17:378 (2008); Patte et al., Diabetes Technol. Ther. 15:289 (2013); Heise et al., Diabetes Obes. Metab. 16:971 (2014). Self- administration of up to 1 mL SQ injections are currently clinically acceptable and in use for therapeutic monoclonal antibody products. Borras-Blasco et al., Expert Opin. Biol. Ther.

10:301(2010). To achieve volumes of this size, such therapies are often required to be formulated at concentrations of 100 mg antibody per mL, or greater, resulting in highly viscous dosage forms. Shire et al., J. Pharm. Sci. 93: 1390 (2004); Liu et al., J. Pharm. Sci. 94: 192 (2005). For example, the delivery of a target dose of 300 mg of a drug may require two SQ injections of 1 mL dosage form each comprising 150 mg of the drug. The need for multiple injections is less convenient for the patient, and may lead to non-compliance with dosing requirements. Hence, there is a need for a device and method that delivers a required dose of a drug in a single SQ injection with tolerable pain.

[0133] Importantly, a number of studies investigating SQ rehydration and SQ immunoglobulin replacement therapy have demonstrated that subcutaneous tissue can accommodate volumes larger than 1 mL with good tolerability, depending on the flow rate and method of delivery. Jorgensen et al., 1996; Gardulf et al., J. Clin. Immunol. 26: 177 (2006); Gustafson et al., Clin. Exp. Immunol. 152:274(2008); Doughty et al., J. Pharm. Sci. (2015). Additionally, reusable syringe pumps with tethered SQ insertion sets have demonstrated efficacy and favorable safety results when used for SQ delivery in immunoglobulin replacement therapy. Hagan et al., J. Clin. Immunol. 30: 734(2010). Further, delivery of a large volume of a drug, either by large volume bolus injector (LVBI) or large volume auto-injector (LVAI), would open the possibility of home administration.

EXAMPLES

[0134] The pharmacokinetic (PK) profile of 300 mg of a drug was studied to determine the effect of a 2 mL dosage form delivered via different regimens (i.e., a single injection vs multiple injections; fast vs slow delivery rates). For a single large volume (2 mL) delivery of 300 mg of a drug to be feasible, the PK profile should be similar to that delivered by two small volume (1 mL) injections; and the larger volume must be tolerable for the patient. Although a previous study showed a favorable safety profile following administration of a single large- volume SQ injection of a highly viscous placebo solution used to mimic an injection of a biotherapeutic agent (Dias et al., AAPS Pharm. Sci. Tech. (2015)), the effect on PK of larger volumes delivered at different flow rates has not been reported. Demonstration that the PK of 300 mL of a drug is not affected by administration as a 2 mL injection supports this delivery method, and allows for the administration to be classified as a bolus injection rather than a subcutaneous infusion.

[0135] Regarding tolerability of the 2 mL injection, study subjects were queried using a visual analog scale as a measure for pain. Hawker et al., Arthritis Care Res. 63:S240 (2011). The visual analog scale (VAS) of pain intensity consists of a line, most often 100 mm long, with two descriptors representing extremes of pain intensity (e.g., no pain and extreme pain) at each end. Patients rate their pain intensity by making a mark somewhere on the line that represents their pain intensity, and the VAS is scored by measuring the distance from the "no pain" end of the line. There has been discussion in the literature regarding VAS cut-offs for what is considered mild, moderate, or severe pain; and the VAS is somewhat dependent on the type of pain being measured (e.g., chronic vs acute). Jensen et al., J. Pain 4:407 (2003). Therefore, VAS descriptors were not attributed with specificity in the trial. Instead, the number of subjects who had pain >50mm were noted specifically, because this is considered moderate-severe, and hence clinically significant, pain. Additionally, it may be noted that there is considerable variability associated with pain assessments due to the subjective nature of this variable. Coghill & Eisenach, Anesthesiology 98: 1312 (2003); Nielsen et al., J. Pain 10:231(2009); Coghill, Headache 50: 1531 (2010). Nevertheless, the VAS has been used to provide valuable information on the pain associated with SQ injection. Dias et al., 2015; Heise et al., Diabetes Obes.

Metab. 16:971 (2014).

[0136] As noted, the subcutaneous tissue accommodates dose volumes up to 1 mL with acceptable pain and back pressure. Thus, prefilled syringes and auto-injectors are commonly used to inject up to 1 mL rapidly and with acceptable pain, back-pressure, and usability. For dose volumes greater than 1 mL, rapid injections could cause an increase in pain or result in unacceptable usability (i.e., hold times exceeding 15 seconds to 20 seconds). Some evidence suggests that larger injection volumes may be associated with a higher incidence of injection site reactions, particularly increased pain intensity. Jorgensen et al., 1996. This is likely due to associated increased SQ tissue pressure, which in turn may be influenced by the injection flow rate. The relationship between these variables (injection volume, injection flow rate, and local injection site tolerability) for a drug was explored as described herein. A clinical study that investigated PK, pain, and tolerability of a 2 mL dosage form, over a range of flow rates, was conducted in order to select a delivery time for at least one embodiment of a drug delivery device. Accordingly, at least one embodiment of a drug delivery device as described herein provides an on-body injection device that allows patients to receive large volumes in subcutaneous tissue over minutes to hours. The delivery time of the dosage form, controlled by the drug delivery device, allows convenient administration with effective pharmacokinetics (PK) of the drug (i.e., delivery is not too slow) as well as delivery time with acceptable pain (i.e., delivery is not too fast).

[0137] Previously, drug delivery time selection was generally based on pain alone or was selected arbitrarily. An aspect of the present embodiment provides for a clinical study that determined the dosage form delivery time based on both pain and PK, and created an operating range from which a device of the present embodiments can be designed. The data generated, and the viscosity of a drug formulation, was used to select a 2-minute nominal delivery time (i.e., 1 mL/min), deliverable using an embodiment of the present drug delivery device.

[0138] This study randomized 60 healthy adults to receive 300 mg of a drug, as either two 1 mL subcutaneous injections, or as a single injection via a flow rate selected from a range of about 0.167 mL/minute to about 12 mL/minute. No clinically meaningful difference in the PK profile of the drug was observed between cohorts. As shown in FIG. 14, mean [SD] injection- site pain intensity was lowest following 0.167 mL/minute injection (1.0 mm [27.7]) and greatest following 12 mL/minute injection (17.7 mm [15.5]). As shown in FIG. 15, mean injection-site pruritus intensity was low for all subjects. Pruritus refers to an unpleasant sensation that provokes the desire to scratch; in other words, an itch. As shown in FIG. 16, mean injection- site erythema diameter was largest following 0.167 mL/minute injection (37.5 mm [24.7]) and smallest following 12 mL/minute injection (27.8 mm [18.6]) immediately post-injection, and similar in all cohorts 10 minutes post- injection. All treatment-emergent adverse events (TEAEs) were mild. These data support a drug delivery device that delivers a drug via a single 2 mL subcutaneous injection, particularly at slower delivery rates.

[0139] This study evaluated the PK profile, safety, and tolerability of a single SQ dose of 300 mg of a drug when delivered as a 2 mL injection at different flow rates, compared with that observed with the currently used two 1 mL injections. No clinically meaningful differences were seen between the cohorts in any of the measured PK parameters, supporting the feasibility of a single 2 mL injection treatment regimen. This study provides insight into the PK profile of 300 mg of a drug when administered at different delivery rates. An aspect of the embodiment supports classifying the large volume bolus injector (LVBI) method of delivery as a bolus injector rather than an infusion pump. [0140] Importantly, 2 mL of a drug dosage form delivered at the slowest flow rate (1 mL/minute) resulted in a PK profile similar to that seen for delivery of two 1 mL injections. Also, importantly, there were no adverse consequences in terms of reducing the favorable pain tolerability profile. When 300 mg dose of a drug was delivered as a 2 mL injection at a relatively low flow rate of 0.167 mL/minute (prolonged injection time), the injection site pain intensity was lower compared with that observed following two 1 mL injections. Conversely, delivery of the 2 mL injection at a relatively high rate of 12 mL/minute (10 second injection time) resulted in higher pain scores; and a higher incidence of pain scores with an intensity of >50 mm on the VAS immediately post-injection compared with the other assessed delivery methods. These data, taken together with the PK data, support using large volume injections at intermediary volume flow rates, as provided by the embodiments described herein.

[0141] In addition to the positive PK and pain intensity findings observed, the mean intensity of injection site pruritus was low at all the queried time points post-injection, and was generally similar between all cohorts. Although not statistically significant, injection site pruritus scores immediately following drug injection were numerically higher in subjects who received a single 2 mL injection at a 12 mL/minute flow rate (Cohort 2). When taken together with the PK and injection site pain intensity data, these data further highlight the feasibility of using relatively (for drug SQ) large volume injections at intermediary volume flow rates that have been used in some LVBI devices. Furthermore, erythema and hematoma or bleeding were the only types of local injection-site reactions reported, and all were mild. Both erythema and hematoma or bleeding were reported at a higher incidence in Cohorts 3 and 4 compared with Cohorts 1 and 2. These injection- site reactions may have been related to a soft cannula insertion set, however, rather than the delivery method. The adhesive required to apply the soft cannula to the skin could have caused an increase in the reddening and itching of the skin around the injection site and the longer residence time of the cannula in the skin could have been the cause of the increase in hematoma/bleeding seen at the injection site in Cohort 3 and, particularly, in Cohort 4, rather than the volume size or flow rate of the injection. These facts are taken into account in the delivery device described herein. In sum, the overall safety profile of 300 mg drug SQ was favorable, with all TEAEs being mild in severity, and reported no serious adverse events (SAEs), discontinuations, or deaths.

[0142] This study was an open-label exploratory study with no study control. As such, the assessors, who evaluated local reactions to administration of a drug, could not be blinded to the treatment allocation of all subjects. The large variations in delivery flow rate and the difference in number of injections received also prevented blinding of the subjects to the treatment received. As different delivery apparatus was used for Cohorts 1 and 2 (rigid needle) and for Cohorts 3 and 4 (soft cannula), caution is required when directly comparing data from these groups. Finally, the small sample size prevented meaningful statistical comparisons across cohorts. Differences between the delivery apparatus were demonstrated by three subjects who had extensive leakage of a drug using a soft cannula. The observed leakage was likely due to incorrect application of the insertion set.

[0143] To summarize, there were no significant differences in the PK profile of a drug when compared across a range of injection flow rates. The overall tolerability of a single, large 2 mL injection of 300 mg of a drug was generally consistent with that of two 1 mL injections with a slow delivery rate of the larger volume the drug and may have the potential to lower the perceived pain compared with the currently approved injection regimen. Data from this study relating to PK and tolerability can be used to select a window of flow rates for the use of injectable drug.

[0144] Delivery of a dosage form comprising a drug (300 mg) via a single 2 mL SQ injection at one of a range of flow rates studied had no effect on PK, and was associated with an acceptable tolerability profile. These data support the feasibility of the single 2 mL injection treatment regimen, particularly at slower delivery rates. Thus, the present embodiments allow for a reduction of the number of injections through the administration of larger dose volumes by using alternative devices such as LVBIs that allow delivery over longer injection times. As a result, the devices of the present disclosure may be used to provide a single, large volume delivery with a similar pain profile and tolerability profile. The parameters described herein, such as geometrical flow resistance and drive system forces, may be selected to meet the desired profile.

[0145] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS We claim:

1. In a drug delivery device comprising a drive mechanism; a drug container including a plunger seal, a barrel, and a distal seal disposed within the barrel such that the barrel, the plunger seal, and the distal seal define a volume; a fluid conduit; a flow restrictor having a diameter and a length; a fluid pathway connection configured to fluidly couple the volume and the fluid conduit; and a needle insertion mechanism in fluid communication with the fluid conduit, the needle insertion mechanism configured to insert a cannula into a target location for delivery of a dosage form such that the drive mechanism causes translation of the plunger seal within the barrel to deliver the dosage form through the fluid conduit and the cannula for delivery to the target,

the improvement comprising the diameter of the flow restrictor being between about 0.02 mm and 0.32 mm and a length being between about 10 mm and 38 mm.

2. The drug delivery device of claim 1, wherein the drive mechanism comprises one or more springs configured to exhibit a total spring constant between about 0.25 Newtons per mm and about 4 Newtons per mm.

3. The drug delivery device of claim 2, wherein the one or more springs comprises two springs disposed and operating in parallel.

4. The drug delivery device of claim 1, wherein the drive mechanism further comprises one or more biasing members having an initial length prior to initiation and configured to exhibit a total force in the initial length between about 40 Newtons and about 80 Newtons.

5. The drug delivery device of claim 4, wherein the one or more biasing members are compression springs.

6. The drug delivery device of claim 4, wherein the initial length is between about 10 mm and about 30 mm.

7. The drug delivery device of claim 1, wherein the dosage form has a viscosity being between about 3 centipoise and about 30 centipoise when the temperature of the dosage form is approximately 23 °C.

8. The drug delivery device of claim 1, wherein the barrel has an internal diameter between about 10 mm and about 20 mm.

9. The drug delivery device of claim 1, wherein the fluid pathway connection comprises a piercing member configured to pierce the distal seal, the piercing member having a piercing member lumen through which the dosage form may flow, and the piercing member lumen having a diameter between about 0.1 mm and about 0.5 mm and a length between about 10 mm and about 20 mm.

10. The drug delivery device of claim 1, wherein the needle insertion mechanism comprises a cannula configured for delivery of the dosage form to the target, the cannula having a cannula lumen having a diameter between about 0.2 mm and about 0.8 mm and a length of between about 3 mm and about 12 mm.

11. The drug delivery device of claim 1, wherein the distance between the plunger seal and the distal seal is between about 10 mm and about 20 mm.

12. The drug delivery device of claim 1, wherein the fluid conduit comprises a tubing section having an inner diameter between about 0.2 mm and about 0.6 mm.

13. In a fluid pathway assembly for a drug delivery device comprising a fluid conduit; a fluid pathway connection configured to fluidly couple the fluid conduit to a drug container; and a needle insertion mechanism in fluid communication with the fluid conduit, the needle insertion mechanism configured to insert a cannula into a target location for delivery of a dosage form, the improvement comprising the fluid pathway assembly providing a total geometric flow resistance of between about 0.5xl0¹⁵ m^"3 and about 2xl0¹⁵ m^"3.

14. The fluid pathway assembly of claim 13, further comprising a flow restrictor.

15. The fluid pathway assembly of claim 14, wherein the flow restrictor has a geometric flow resistance of between about 0.75xl0¹⁵ m^"3 and about 1.5xl0¹⁵ m^"3.

16. The fluid pathway assembly of claim 13, wherein the fluid pathway connection comprises a piercing needle, the piercing needle having a geometric flow resistance between about lxlO¹³ m^"3 and about lxlO¹⁴ m^"3.

17. The fluid pathway assembly of claim 13, wherein the needle insertion mechanism comprises a cannula, the cannula having a geometric flow resistance between about 3xl0¹² m^"3 and about 1.2xl0¹³ m^"3.

18. In a drug delivery device comprising: a drive mechanism; a drug container including a plunger seal, a barrel, and a distal seal disposed within the barrel such that the barrel, the plunger seal, and the distal seal define a volume; a fluid conduit; a fluid pathway connection configured to fluidly couple the volume and the fluid conduit; and a needle insertion mechanism in fluid communication with the fluid conduit, the needle insertion mechanism configured to insert a cannula into a target location for delivery of a dosage form such that the drive mechanism causes translation of the plunger seal within the barrel to deliver the dosage form through the fluid conduit and the cannula for delivery to the target,

the improvement comprising the drug delivery device providing a total geometric flow resistance between about 0.5x10¹⁵ m^"3 and about 2x10¹⁵ m^"3.

19. The drug delivery device of claim 18, further comprising a flow restrictor.

20. The drug delivery device of claim 19, wherein the flow restrictor has a geometric flow resistance between about 0.75xl0¹⁵ m^"3 and about 1.5xl0¹⁵ m^"3.

21. The drug delivery device of claim 18, wherein the fluid pathway connection comprises a piercing needle, the piercing needle having a geometric flow resistance between about lxlO¹³ m^"3 and about lxlO¹⁴ m^"3.

22. The drug delivery device of claim 18, wherein the needle insertion mechanism comprises a cannula, the cannula having a geometric flow resistance between about 3xl0¹² m^"3 and about lxlO¹³ m^"3.

23. A method of assembling a fluid pathway assembly for a drug delivery pump comprising the steps of:

connecting a fluid pathway connection to a drug container;

fluidly coupling a fluid conduit to the fluid pathway connection; and

fluidly coupling a needle insertion mechanism to the fluid conduit;

wherein the fluid path provides a total geometric flow resistance between

about 0.5xl0¹⁵ m^"3 and about 2xl0¹⁵ m^"3.

24. The method of claim 18 further comprising the step of fluidly coupling a flow restrictor to the fluid conduit, wherein the geometric flow resistance of the flow restrictor is between about 0.75xl0¹⁵ m^"3 and about 1.5xl0¹⁵ m^"3.