WO2016049532A1

WO2016049532A1 - Sequential chamber drug delivery pumps for drug mixing and delivery

Info

Publication number: WO2016049532A1
Application number: PCT/US2015/052367
Authority: WO
Inventors: Daniel Davenport; Ian Hanson; Molly WEAVER
Original assignee: Unitract Syringe Pty Ltd
Priority date: 2014-09-26
Filing date: 2015-09-25
Publication date: 2016-03-31

Abstract

The present disclosure provides drug containers that allow for the mixing of one or more substances prior to drug injection and drug delivery pumps incorporating such drug containers. Mixing of the two or more substances contained within separate, mutable chambers (64)(66) is initiated by transforming a seal assembly from a closed position to an open position in which the mutable chambers are in fluid communication with one another. Continued mixing is induced by causing the contents of one of the mutable chambers to be fully displaced. After mixing of the substances is complete one or more of the following steps may be performed by the drug delivery pump (10) : needle insertion, opening of a sterile fluid pathway, drug delivery, and needle retraction. By providing these drug containers and drug delivery pumps medicaments may be stored as two or more separate constituents and mixed at or near time of delivery.

Description

TITLE

SEQUENTIAL CHAMBER DRUG DELIVERY PUMPS FOR DRUG MIXING AND

DELIVERY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/055834, filed on September 26, 2014, which is included by reference herein in its entirety for all purposes.

FIELD

The embodiments herein relate to mixing and drug delivery pumps. More particularly, this invention relates to drug containers with two or more mutable chambers, drug delivery pumps incorporating such drug containers, the methods of operating such devices, and the methods of assembling such devices.

BACKGROUND

Parenteral delivery of various drugs, i.e., delivery by means other than through the digestive track, has become a desired method of drug delivery for a number of reasons. This form of drug delivery by injection may enhance the effect of the substance being delivered and ensure that the unaltered medicine reaches its intended site at a significant concentration. Similarly, undesired side effects associated with other routes of delivery, such as systemic toxicity, can potentially be avoided through parenteral delivery. By bypassing a digestive system, one can avoid degradation of the active ingredients caused by the catalytic enzymes in the digestive tract and liver and ensure that a necessary amount of drug, at a desired concentration, reaches the targeted site.

The number of drugs supplied in lyophilized or powdered form has been growing at an increased rate over the past several years, reflecting the increase in the introduction of biological drugs. For example, because of stability and shelf life factors, therapeutic proteins are often formulated as powders that must be reconstituted prior to injection. A growing number of drugs and biologies supplied in powder form are including reconstitution vial systems that incorporate a vial adapter or vial transfer device. Dual chamber drug cartridges and syringes go a step further and allow reconstitution to take place within the device immediately prior to injection. This allows, for example, a diluent to be added to a dehydrated, lyophilized, desiccated or powdered active substance immediately prior to injection, which is particularly useful for substances that are subject to degradation or loss of activity when stored in a liquid form.

Traditionally, manually operated syringes and injection pens have been employed for delivering parenteral drugs. More recently, parenteral delivery of liquid medicines has been accomplished by administering bolus injections using a needle and reservoir, continuously by gravity driven dispensers, or via transdermal patch technologies. Bolus injections often imperfectly match clinical needs, and usually require larger individual doses than are desired at the specific time they are given.

Continuous delivery of medicine through gravity-feed systems compromises mobility and lifestyle, and limits the therapy to simplistic flow rates and profiles. Another form of drug delivery, transdermal patches, similarly has its restrictions. Transdermal patches often require specific molecular drug structures for efficacy, and the control of the drug administration through a transdermal patch is severely limited.

Ambulatory infusion pumps have been developed for delivering liquid medicaments. These infusion devices have the ability to offer sophisticated fluid delivery profiles accomplishing bolus requirements, continuous infusion and variable flow rate delivery. These infusion capabilities usually result in better efficacy of the drug and therapy and less toxicity. Currently available ambulatory infusion devices are expensive, difficult to program and prepare for infusion, and tend to be bulky, heavy and very fragile. Filling these devices can be difficult and require a user to carry both the intended medication as well as filling accessories. The devices often require specialized care, maintenance, and cleaning to assure proper functionality and safety for their intended long-term use, and are not cost-effective.

As compared to syringes and injection pens, pump type delivery devices can be significantly more convenient, in that doses of the drug may be calculated and delivered automatically at any time during the day or night. Furthermore, when used in conjunction with metabolic sensors or monitors, pumps may be automatically controlled to provide appropriate doses of a fluidic medium at appropriate times of need, based on sensed or monitored metabolic levels. As a result, pump type delivery devices have become an important aspect of modern medical treatments of various types of medical conditions, such as diabetes, and the like.

While pump type delivery systems have been utilized to solve a number of needs, manually operated syringes and injection pens often remain a preferred choice for drug delivery as they now provide integrated safety features and can easily be read to identify the status of drug delivery and the end of dose dispensing. Additionally, syringes that allow for mixing of a powdered drug with a diluent or the mixing of two liquids provide an advantage for the delivery of medicaments that may lose efficacy over time if stored in mixed form. However, manually operated syringes and injections pens are not universally applicable and are not preferred for delivery of all drugs. There remains a need for an adjustable (and/or programmable) infusion system that is precise and reliable and can offer clinicians and users a small, low cost, light weight, simple to use alternative for mixing and parenteral delivery of medicaments.

SUMMARY

The present disclosure provides drug containers for use with mix-at-time of use medicaments, delivery pumps which incorporate such drug containers, the methods of operating such devices, and the methods of assembling such devices. The drug containers of the present disclosure provide for the storage of medicaments in two or more isolated chambers within the drug container. This presents advantages for drugs in which efficacy may be reduced by storage in a mixed condition. The present drug containers allow an operator to mix two substances just prior to injection. For example, the first mutable chamber may contain a lyophilized drug and the second mutable chamber may contain a diluent. Prior to injection the operator allows the lyophilized drug to enter the chamber containing the diluent or the operator allows the diluent to enter the chamber containing the lyophilized drug. These two substances are thereby combined and prepared for injection. Accordingly, the novel devices of the present invention alleviate one or more of the problems associated with prior art devices, such as those referred to above.

In a first embodiment, the present invention provides a drug container for a drug delivery pump which includes: a pierceable seal; a barrel; a plunger rod; a distal seal assembly axially displaceably disposed within the barrel, wherein the position of the distal seal assembly defines a mutable distal chamber and a mutable proximal chamber within the barrel; the distal seal assembly may further include a valve that regulates a fluid passage between the proximal and distal chambers; and a proximal seal axially displaceably disposed within the barrel. At least one of the proximal seal and distal seal assembly may include a connector configured to irreversibly connect the distal and proximal seals. In a further embodiment, the drug container further includes an insert housed at least partially within the distal seal assembly, wherein the insert includes an internal cavity configured to engage the distal end of the plunger rod, and wherein the insert comprises at least one fluid passage. The insert may include at least one channel or compartment that regulates movement of the plunger rod within the insert. The insert may include a connector configured to irreversibly engage the proximal seal. In some further embodiments, the plunger rod is configured to releasably engage a locking mechanism to actuate the valve. The locking mechanism may include a radial channel configured to be rotatably engaged by a plunger rod protrusion.

In at least one embodiment of the present invention, the distal chamber, proximal chamber, or both, contains a substance. The substance may be or include a diluent. The substance may be lyophilized. The substance may comprise a pharmaceutical agent. The pharmaceutical agent may be, for example, a biologic, a vaccine, a chemotherapeutic agent, a contrast agent, a small molecule, an immunogen, an antigen, an interferon, a polyclonal antibody preparation, a monoclonal antibody, an anesthetic, an interfering RNA, a gene vector, an insulin, or a combination of any of these. The pharmaceutical agent may be a lyophilized preparation.

In another embodiment, a drug delivery pump is provided that includes a drug container including: a pierceable seal; a barrel; a plunger rod; a distal seal assembly axially displaceably disposed within the barrel, wherein the position of the distal seal assembly defines a mutable distal chamber and a mutable proximal chamber within the barrel; the distal seal assembly may further include a valve that regulates a fluid passage between the proximal and distal chambers; and a proximal seal axially displaceably disposed within the barrel. The drug delivery pump further includes a drive mechanism for drug delivery and/or drug mixing. Further, the drug delivery pump may include a needle insertion assembly, a sterile fluid pathway connector, and a sterile fluid conduit. The drug delivery device may further include a handle and key for actuating the mixing of the substances within the two or more mutable chambers. The drug delivery device may further include safety mechanisms such as: a target sensor that determines if the device is placed against the target and a mixing interlock that prevents premature mixing of the substances in the two or more mutable chambers.

In an initial position, for example, the distal end of the plunger rod and the distal seal assembly may form a plug seal. Proximal displacement of the piston rod relative to the distal seal assembly may open the plug valve, allowing fluid communication between the mutable proximal chamber and mutable distal chamber. Continued proximal displacement of the piston rod may cause the distal seal assembly to move in the proximal direction relative to the barrel. This movement causes the contents of the proximal chamber to enter the distal chamber through the open plug valve. Upon full proximal displacement of the distal seal assembly the distal seal assembly comes in contact with the proximal seal and substantially all of the contents originally contained within the proximal chamber have entered the distal chamber. The distal chamber now contains mixed contents. At this time distal displacement of the seals may be activated to deliver the contents of the distal chamber from the drug container through a sterile fluid connection.

Additionally or alternatively, the fluid container and/or drug delivery pump may include a mixing biasing member. In one embodiment, the mixing biasing member is triggered to act upon the plunger rod in the proximal direction by a primary motion of the activation mechanism. Accordingly, the activation mechanism controls the activation and release of, first, the mixing biasing member and, second, the drive biasing member. For example, partial depression of the activation mechanism may trigger the mixing biasing member. Upon completion of that step, i.e., complete mixing of the substances, further depression of the activation mechanism may trigger the drive biasing member and other features of the drug delivery device of the present invention. In yet another embodiment, the mixing biasing member may be triggered by a separate mixing activation member similar to the activation mechanism. Upon actuation of the mixing activation member, the mixing biasing member is permitted to act upon and enable proximal displacement of the plunger rod. For example, the mixing activation member may be a spring-loaded button, displacement of which transforms the mixing interlock and releases a mixing biasing member to act upon and proximally displace the plunger rod.

In another embodiment, the present invention involves a method of manufacturing a drug container containing two or more isolated, mutable chambers. The method involves at least some of the steps of: inserting a pierceable seal into a barrel, filling a distal chamber with a dry or liquid medicament or a liquid diluent, inserting a distal seal assembly and plunger rod into the barrel, filling a proximal chamber with a dry or liquid medicament or a liquid diluent, and inserting a proximal seal into the barrel. In at least one embodiment, the drug container is configured such that it may be filled using standard filling processes and equipment. In another embodiment, the present invention involves a method of manufacturing of a drug delivery device including a drug container that contains two or more isolated, mutable chambers. The method includes at least some of the steps of: attaching both the drug container and the drive mechanism, either separately or as a combined sub-assembly, to an assembly platform or housing of the drug delivery device. The method of manufacturing further includes attachment of the fluid pathway connection, drug container, and insertion mechanism to the assembly platform or housing. The additional components of the drug pump, as described above, including the power and control system, the activation mechanism, and the control arm may be attached, preformed, or pre-assembled to the assembly platform or housing. An adhesive patch and patch liner may be attached to the housing surface of the drug pump that contacts the target during operation of the device. The method may further include inserting a handle through the housing and piston and attaching the handle to the plunger rod, for example by threading the distal end of the handle into the proximal end of the plunger rod. The method may additionally comprise the steps of: inserting a key through an aperture of the handle and through the housing and piston; aligning slots located on the handle and slots located on the key; and positioning a mechanical interlock in the slots of the handle and the key.

A method of operating the drug delivery device includes at least some of the steps of: removing a mechanical interlock which prevents mixing; activating drug mixing; activating, by a user, the activation mechanism; displacing a control arm to actuate an insertion mechanism; and actuation of a power and control system to activate a drive control mechanism to drive fluid drug flow through the drug pump. The method may further include the step of: engaging an optional target sensor prior to activating the activation mechanism. The method similarly may include the step of: establishing a connection between a fluid pathway connection to a drug container. Furthermore, the method of operation may include translating a plunger seal within the drug container to force fluid drug flow through the drug container, the fluid pathway connection, a sterile fluid conduit, and the insertion mechanism for delivery of the fluid drug to a target. The method of operating may further include the steps of removing the handle and key from the drug delivery device.

The disclosure describes, in one aspect, a drug pump drive mechanism for use in cooperation with a drug container having two or more mutable chambers. The drive mechanism has an axis and includes a drive housing, a piston adapted to impart movement to the plunger seal within the drug container, a plurality of biasing members disposed in parallel, and a retainer. The piston is disposed for movement from a retracted first position along the axis to an extended second position. The biasing members are adapted to move from an energized first position to a deenergized second position as a result of the release of energy. The biasing members are 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. The retainer is disposed to maintain the biasing members in the energized first position when the retainer is in a retaining first position, and to release the biasing members from the first energized position when the retainer moves to a releasing second position.

In at least one embodiment, the plurality of biasing members includes at least one of a tension spring or a compression spring. In at least one embodiment, the plurality of biasing members includes a pair of springs, in at least one embodiment of which the springs are compression springs. In at least embodiment, the compression springs are concentrically disposed, and disposed about at least a portion of the piston. In at least one embodiment, the retainer engages at least a portion of the piston to retain the piston in its retracted position when the retainer is in its retaining first position. At least one embodiment further includes a sleeve assembly disposed about at least one of the plurality of biasing members. In at least one embodiment, the sleeve assembly includes a plurality of telescoping sleeves, and the sleeve assembly is disposed to move axially with the piston. At least one embodiment further includes at least one window and at least a portion of the sleeve assembly is visible through the window with at least a portion of the sleeve assembly being visible through said window until the piston is in the extended second position. At least one embodiment further includes an end-of-dose indicator disposed substantially adjacent the window, the end-of-dose indicator being adapted to 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. In at least one embodiment, the end-of-dose indicator includes a sensor disposed to sense at least one of when the sleeve assembly is disposed subjacent the window and when the sleeve assembly is not disposed subjacent the window. In at least one embodiment, the sensor is a mechanical sensor, an electrical sensor, an ultrasonic sensor, a capacitive sensor, a magnetic sensor, or an optical sensor. In at least one embodiment, the sensor is a mechanical sensor disposed to bear against the sleeve assembly when the sleeve assembly is disposed subjacent the window.

In another aspect of the disclosure, there is provided a drug pump drive mechanism for use in cooperation with a drug container including a distal seal assembly and a proximal seal; the drive mechanism has an axis and includes a drive housing, a piston adapted to impart movement to the proximal seal within the drug container, at least one biasing member, a retainer, a sleeve assembly, and an end-of-dose indicator. The piston is disposed for movement from at least a retracted first position to an extended second position along said axis. The at least one biasing member is disposed and adapted to move from an energized first position to a deenergized second position as a result of the release of energy. The biasing member is disposed to cause movement of the piston from the retracted first position to the extended second position as the biasing member moves from the energized first position to the deenergized second position. The retainer disposed to maintain the biasing member in the energized first position when the retainer is in a retaining first position, and to release the biasing member from the first energized position when the retainer moves to a releasing second position. The sleeve assembly is adapted to move along the axis with the piston. The sleeve assembly is disposed at least partially within the drive housing, and at least a portion of the sleeve assembly being visible through a window in the housing when the piston is one of the retracted first position or the extended second position. The sleeve assembly is not visible through said window when the piston is in the other of the retracted first position or the extended second position. The end-of-dose indicator is disposed substantially adjacent the window. The end-of-dose indicator is adapted to 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.

Another aspect of the disclosure provides a drug container for a drug delivery pump, including a barrel. A pierceable seal is disposed at a distal end of the barrel. A proximal seal is disposed within the barrel. A distal seal assembly is axially displaceably disposed within the barrel, wherein the position of the distal seal assembly defines a mutable distal chamber and defines with the proximal seal a mutable proximal chamber within the barrel and a plunger rod is axially displaceably engaged with the distal seal assembly and configured to displace the distal seal assembly toward a proximal end of the barrel and thereby urge passage of a fluid in the proximal chamber to the distal chamber through a fluid passage.

Other aspects of the disclosure provide a drug container wherein the distal seal assembly may include a valve that regulates the fluid passage between the proximal and distal chambers. The proximal seal may be axially displaceably disposed within the barrel. The drug container may further include an insert housed at least partially within the distal seal assembly, wherein the insert includes an internal cavity configured to engage a distal end of the plunger rod, and wherein the insert includes at least one fluid passage. The insert may include at least one channel or compartment that regulates movement of the plunger rod within the insert. The insert may include a connector configured to irreversibly engage the proximal seal. The plunger rod may be configured to releasably engage a locking mechanism to actuate the valve. The locking mechanism may include a radial channel configured to be rotatably engaged by a plunger rod protrusion. The disclosure also provides a drug delivery pump including a drug container according to the various embodiments disclosed herein. The distal seal assembly may include a valve that regulates a fluid passage between the proximal and distal chambers and wherein the valve includes a distal end of the plunger rod selectively engageable with the distal seal assembly, wherein proximal displacement of the plunger rod opens the valve to permit fluid communication between the proximal chamber and the distal chamber, wherein distal displacement of the plunger rod closes the valve and causes the distal seal assembly to move in the distal direction. The drug delivery pump may further include a drive mechanism for one or both of drug delivery and drug mixing and a needle insertion mechanism, a sterile fluid pathway connection disposed at the distal end of the drug container, and a sterile fluid conduit fluidly connecting the sterile fluid pathway connection to the needle insertion mechanism.

The drug delivery pump may further include a target sensor that determines if the device is placed against the target and a mixing interlock that prevents premature mixing of the substances in the two or more mutable chambers.

Another aspect of the disclosure provides a method of manufacturing the drug container disclosed herein, including inserting the pierceable seal into the distal end of the barrel, filling the distal chamber with one of a dry medicament, a liquid medicament and a liquid diluent, inserting the distal seal assembly and plunger rod into the barrel, filling the proximal chamber with a different one of a dry medicament, a liquid medicament and a liquid diluent, and inserting a proximal seal into the proximal end of the barrel.

Further aspects of the disclosure provide a method of manufacturing a drug delivery device further including attaching the assembled drug container to the drug delivery device, attaching a drive mechanism to the drug delivery device, and operatively connecting the drive mechanism to the drug container. Yet another aspect of the disclosure includes attaching, performing, or pre-assembling a power and control system, an activation mechanism, and a control arm to the drug delivery device;

removing a mechanical interlock which prevents mixing; activating drug mixing;

activating, by a user, the activation mechanism; displacing the control arm to actuate the insertion mechanism; and actuating the power and control system to activate the drive mechanism to drive fluid drug flow through the drug delivery device.

Throughout this specification, unless otherwise indicated, "comprise," "comprises," and "comprising," or related terms such as "includes" or "consists of," 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. As will be described further below, the embodiments of the present invention may include one or more additional components which may be considered standard components in the industry of medical devices. The components, and the embodiments containing such components, are within the contemplation of the present invention and are to be understood as falling within the breadth and scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following non-limiting embodiments of the invention are described herein with reference to the following drawings, wherein:

FIG. 1 A is an isometric view of a drug delivery pump having safety integrated insertion mechanisms, according to one embodiment of the present invention;

FIG. IB is an isometric view of the interior components of the drug delivery pump shown in FIG. 1A;

FIG. 1C is an isometric view of the bottom of the drug delivery pump shown in FIG. 1A;

FIG. 2 is a side view of a drug container according to at least one embodiment of the present invention. FIG. 3 is an isometric view of a handle according to at least one embodiment of the present invention;

FIG. 4 is an isometric view of a key according to at least one embodiment of the present invention;

FIG. 5 is an end view of a piston according to at least one embodiment of the present invention;

FIG. 6 is an isometric view of a plunger rod according to at least one embodiment of the present invention;

FIG. 7 A is a side cross-sectional view of a plunger rod and distal seal assembly according to at least one embodiment of the present invention, in the closed position;

FIG. 7B is a side cross-sectional view of the plunger rod and distal seal assembly of FIG. 7A, in the open position;

FIG. 7C is an isometric view of the distal seal insert of the plunger rod and distal seal assembly of FIG. 7A;

FIG. 7D is an isometric view of a distal portion of the plunger rod of the plunger rod and distal seal assembly of FIG. 7A;

FIG. 8A is a side cross-sectional view of a drug container and drive mechanism prior to drug mixing, according to at least one embodiment of the present invention;

FIG. 8B is a side cross-sectional view of the drug container and drive mechanism of FIG. 8A during drug mixing;

FIG. 8C is a side cross-sectional view of the drug container and drive mechanism of FIG. 8A at completion of drug mixing;

FIG. 8D is a side cross-sectional view of the drug container and drive mechanism at completion of dose delivery of FIGS. 8A-8C;

FIG. 9A is an isometric view of a drug delivery pump prior to drug mixing, according to at least one embodiment of the present invention;

FIG. 9B is an isometric view of the drug delivery pump of FIG. 9A during drug mixing;

FIG. 9C is an isometric view of the drug delivery pump at completion of drug mixing of FIGS. 9A and 9B;

FIG. 9D is an isometric view of the drug delivery pump at completion of dose delivery of FIGS. 9A-9C; and FIG. 10A to FIG. IOC is an embodiment of a valve mechanism configured with a locking aspect, in the locked position for aspiration (FIG. 10A), an unlocked position (FIG. 10B), and opened position (FIG. IOC).

DETAILED DESCRIPTION

The novel devices of the present invention provide drug containers for use with mix-at-time of use medicaments and drug delivery pumps which incorporate such drug containers. Such devices are safe and easy to use, and are aesthetically and ergonomically appealing. The devices described herein incorporate features which make activation, operation, and lock-out of the device simple for even untrained operators. The novel devices of the present invention provide these desirable features without any of the problems associated with known prior art devices. Certain non-limiting embodiments of the novel drug delivery pumps, drug containers, and their respective components are described further herein with reference to the accompanying figures.

As used herein to describe the drug containers, drug delivery pumps, or any of the relative positions of the components of the present invention, the terms "axial" or "axially" refer generally to a longitudinal axis "A" around which the drive mechanisms are preferably positioned, although not necessarily symmetrically there-around. The term "radial" refers generally to a direction normal to axis A. The terms "proximal," "rear," "rearward," "back," or "backward" refer generally to an axial direction in the direction "P". The terms "distal," "front," "frontward," "depressed," or "forward" refer generally to an axial direction in the direction "D". As used herein, the term "glass" should be understood to include other similarly non-reactive materials suitable for use in a pharmaceutical grade application that would normally require glass, including but not limited to certain non-reactive polymers such as cyclic olefin copolymers (COC) and cyclic olefin polymers (COP). The term "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, and/or plasticizers, etc., and that can be formed or molded under heat and pressure. As used herein, the term "plastic" is not meant to include glass, non-reactive polymers, or elastomers that are approved for use in applications where they are in direct contact with therapeutic liquids that can interact with plastic or that can be degraded by substituents that could otherwise enter the liquid from plastic. The term "elastomer," "elastomeric" or "elastomeric material" refers primarily to cross-linked thermosetting rubbery polymers that are more easily deformable than plastics but that are approved for use with pharmaceutical grade fluids and are not readily susceptible to leaching or gas migration under ambient temperature and pressure. "Fluid" refers primarily to liquids, but can also include suspensions of solids dispersed in liquids, and gasses dissolved in or otherwise present together within liquids inside the fluid-containing portions of drug containers. According to various aspects and embodiments described herein, reference is made to a "biasing member," such as in the context of one or more biasing members' delivery of a medicament. It will be appreciated that the 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 of the present invention, the biasing member is a spring, preferably a compression spring.

As used herein, the term "pump" is intended to include any number of drug delivery systems which are capable of dispensing a fluid upon activation. Such drug delivery systems include, for example, injection systems, infusion pumps, bolus injectors, and the like. FIGS. 1A-1C show an exemplary drug delivery device according to at least one embodiment of the present invention. The drug delivery device may be utilized to administer delivery of a drug treatment into a target. As shown in FIGS. 1 A- 1C, the drug delivery pump 10 includes a pump housing 12. 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 pump 10 includes a pump housing 12 which includes an upper housing 12A and a lower housing 12B. The drug 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. As shown in FIG. IB, fluid pump 10 further includes a drive mechanism 100 engaged with drug container 50, sterile fluid pathway connection 300, insertion mechanism 200, and power and control system 400. The exemplary sterile fluid pathway connections, drive mechanisms, insertion mechanisms, and power and control systems shown and described herein are further described in international patent Application No. WO 2013/040032, which is incorporated herein by reference, in its entirety.

In the embodiment of FIG. 1, pump housing 12 may include one or more housing subcomponents that are fixedly engageable to facilitate ease in manufacturing, assembly, and operation of the device. Housing 12 includes upper housing 12A and lower housing 12B, which provide protection to the interior components of device 10 against environmental influences. Pump housing 12A, 12B include ergonomically and aesthetically designed size, shape, and related features, which facilitate easy packaging, storage, handling, and use by users who may be untrained or physically impaired. Lower housing 12B also provides a means of removably attaching the device 10 to the target, such as adhesive patch 26 and patch liner 28. The adhesive patch 26 provides an adhesive surface that can be used to adhere the fluid pump 10 to a target for delivery of the fluid, e.g., drug, dose. The adhesive surface of the adhesive patch 26 may initially be covered by a non-adhesive patch liner 28 that is removed from the adhesive patch 26 prior to placing fluid pump 10 in contact with the target. Removal of the patch liner 28 may further remove the sealing membrane 252 (as shown in FIG. 1C) of base 254 of insertion mechanism 200, opening the insertion mechanism to a target for fluid delivery. Additionally, the external surfaces of pump housing 12A, 12B may be used to provide product labeling, safety instructions, and the like. Housing 12A, 12B may further include certain components that provide operation feedback to the user, such as status indicator 16 and window 18. Window 18 may be any translucent or transmissive surface through which the operation of the fluid pump may be viewed. Window 18 may enable the user to view the operation of the fluid pump 10 or verify that fluid delivery has completed.

In at least one embodiment, the drug pump 10 provides an activation mechanism

14 that is displaced by the user to trigger the start command to the power and control system 400. Activation mechanism 14 may further activate the mixing of substances contained in drug container 50. In a preferred embodiment, the activation mechanism is a start button 14 that is located through the pump housing 12, such as through an aperture between upper housing 12A and lower housing 12B, and which contacts a control arm 40 of the power and control system 400. In at least one embodiment, the start button 14 may be a push button, and in other embodiments, may be an on/off switch, a toggle, or any similar activation feature known in the art. The pump housing 12 also provides a status indicator 16 and a window 18. In other embodiments, one or more of the activation mechanism 14, the status indicator 16, the window 18, and combinations thereof may be provided on the upper housing 12 A or the lower housing 12B such as, for example, on a side visible to the user when the drug pump 10 is placed on the target. Housing 12 further includes aperture 136 through which a mixing actuation member may be inserted as will be described further herein.

In the embodiment of FIG. 1 , drug pump 10 is configured such that, upon activation by a user (such as by depression of the activation mechanism 14), the drug pump is initiated to perform at least some of the following steps: initiate mixing of two or more substances contained within the drug container; insert a fluid pathway into the target; enable, connect, or open necessary connections between a drug container, a fluid pathway, and a sterile fluid conduit; and force drug fluid stored in the drug container through the fluid pathway and fluid conduit for delivery. Optionally, the step of initiating the mixing of the two or more substances may be performed prior to placing the drug pump on the target or may be performed prior to activating the other steps. The step of initiating the mixing of the two or more substances may be activated through the use of activation mechanism 14 or may be performed by the manipulation of a separate activation mechanism.

One or more optional safety mechanisms may be utilized, for example, to prevent premature mixing of the two or more substances and/or premature activation of the drug pump. For example, in at least some embodiments a mixing interlock 1 18 prevents activation of the step of initiating mixing of the two or more substances and must be removed prior to activating mixing. Interlock 1 18 may be held in place with adhesive and be removable by the user prior to activation of mixing. Interlock 1 18 may initially be at least partially disposed in aperture 1 19 of lower housing 12B. Interlock 118 may be displaced directly by the user (such as by removal from aperture 12B) or may be indirectly displaced such as by depression of activation member 14. Further, an optional sensor 24 (shown in FIG. 1C) may be provided in one embodiment as a safety feature to ensure that the power and control system 400, or the activation mechanism, cannot be engaged unless the drug pump 10 is in contact with the target. In one such embodiment, the sensor 24 is located on the bottom of lower housing 12B where it may come in contact with the target. Upon displacement of the sensor 24, depression of the activation mechanism is permitted. Accordingly, in at least one embodiment the sensor 24 is a mechanical safety mechanism, such as for example a mechanical lock out, that prevents triggering of the drug pump 10 by the activation mechanism 14. In another embodiment, sensor 24 may be an electro -mechanical sensor that sends a signal to the power and control system 400 to permit activation when sensor 24 is depressed. In still other embodiments, the sensor can be electrically based such as, for example, a capacitive- or impedance-based sensor which must detect the target 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 invention to prevent, for example, premature activation of the drug pump. In a preferred embodiment, the drug pump 10 utilizes one or more mechanical sensors. Activation of sensor 24 may further initiate one or more audible or visual signals to indicate to the user that the device is ready for activation. The one or more feedback mechanisms may include, for example, audible alarms such as piezo alarms and/or light indicators such as light emitting diodes (LEDs). Additional integrated safety mechanisms are described herein with reference to other components of the novel drug pumps.

One or more of the components of fluid drug container 50 and fluid pump 10 may be modified while remaining functionally within the breadth and scope of the present invention. For example, although the housing of fluid pump 10 is shown as two separate components (upper housing 12A and lower housing 12B) in FIG. 1, these components may be a single unified component. Adhesives or other known materials or methods may be utilized to affix one or more components of the drug container or fluid pump to each other. For example, the upper housing and lower housing may be separate components affixed together by an adhesive, a screw fit connection, an interference fit, fusion joining, welding, ultrasonic welding, laser welding, and mechanical fastening, and the like; or the upper housing and lower housing may be a single unified component. Such standard components and functional variations would be appreciated by one having ordinary skill in the art and are, accordingly, within the breadth and scope of the present embodiments. Certain optional standard components or variations of drug container 50 or fluid pump 10 are contemplated while remaining within the breadth and scope of the present embodiments.

The disclosure describes, in one aspect, a drug pump drive mechanism 100 for use in cooperation with a drug container 50 having two or more mutable chambers. The drive mechanism has an axis and includes a drive housing 130, a piston 700 adapted to impart movement to the plunger seals within the drug container 50, a plurality of biasing members 122 disposed in parallel, and a retainer 128. For the purposes of this disclosure and its claims, when used in connection with biasing members, be it a specific embodiment of biasing members, such as springs, or the general use of the term "biasing members," the terms "parallel" are to be interpreted as they would by those of skill in the art. That is, 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. Those of skill in the art will appreciate that for biasing members disposed to operate in series, the inverse of equivalent spring constant will equal the sum of the respective inverses of the spring constants of the individual biasing members. In contrast, the equivalent spring constant of biasing members 1 12 disposed to operate in a parallel relationship will be the sum of the spring constants of the individual biasing members.

Piston 700 is disposed for movement from a retracted first position along the axis to an extended second position. Biasing members 122 are adapted to move from an energized first position to a deenergized second position as a result of the release of energy. The biasing members are 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. The retainer 128 is disposed to maintain the biasing members in the energized first position when the retainer is in a retaining first position, and to release the biasing members from the first energized position when the retainer moves to a releasing second position.

In at least one embodiment, the plurality of biasing members 122 includes at least one of a tension spring or a compression spring. In at least one embodiment, the plurality of biasing members includes a pair of springs, in at least one embodiment of which the springs are compression springs. In at least one embodiment, the compression springs are concentrically disposed, and disposed about at least a portion of the piston. In at least one embodiment, the retainer engages at least a portion of the piston to retain the piston in its retracted position when the retainer is in its retaining first position. At least one embodiment further includes a sleeve assembly disposed about at least one of the plurality of biasing members. In at least one embodiment, the sleeve assembly 120 includes a plurality of telescoping sleeves, and the sleeve assembly is disposed to move axially with the piston. At least one embodiment further includes at least one window and at least a portion of the sleeve assembly is visible through the window with at least a portion of the sleeve assembly being visible through said window until the piston is in the extended second position. At least one embodiment further includes an end-of-dose indicator disposed substantially adjacent the window, the end-of-dose indicator being adapted to 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. In at least one embodiment, the end-of-dose indicator includes a sensor disposed to sense at least one of when the sleeve assembly is disposed subjacent the window and when the sleeve assembly is not disposed subjacent the window. In at least one embodiment, the sensor is a mechanical sensor, an electrical sensor, an ultrasonic sensor, a capacitive sensor, a magnetic sensor, or an optical sensor. In at least one embodiment, the sensor is a mechanical sensor disposed to bear against the sleeve assembly when the sleeve assembly is disposed subjacent the window.

In another aspect of the disclosure, there is provided a drug pump drive mechanism 100 for use in cooperation with a drug container 50 including a distal seal assembly 62 and a proximal seal 60; the drive mechanism has an axis and includes a drive housing 130, a piston 700 adapted to impart movement to the proximal seal 60 within the drug container 50, at least one biasing member 122, a retainer 128, a sleeve assembly 120, and an end-of-dose indicator. The piston is disposed for movement from at least a retracted first position to an extended second position along said axis. The at least one biasing member is disposed and adapted to move from an energized first position to a deenergized second position as a result of the release of energy. The biasing member is disposed to cause movement of the piston from the retracted first position to the extended second position as the biasing member moves from the energized first position to the deenergized second position. The retainer 128 disposed to maintain the biasing member 122 in the energized first position when the retainer is in a retaining first position, and to release the biasing member from the first energized position when the retainer moves to a releasing second position. The sleeve assembly 120 is adapted to move along the axis with the piston. The sleeve assembly is disposed at least partially within the drive housing, and at least a portion of the sleeve assembly being visible through a window in the housing when the piston is one of the retracted first position or the extended second position. The sleeve assembly is not visible through said window when the piston is in the other of the retracted first position or the extended second position. The end-of-dose indicator is disposed substantially adjacent the window. The end-of-dose indicator is adapted to 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 power and control system 400 may include a power source, which provides the energy for various electrical components within the drug pump, one or more feedback mechanisms, 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 one or more feedback mechanisms may include, for example, audible alarms such as piezo alarms and/or light indicators such as light emitting diodes (LEDs). The microcontroller may be, for example, a microprocessor. The power and control system 400 controls several device interactions with the user 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 sensor 24 and/or the activation mechanism 14 have been activated. The power and control system 400 may also interface with the status indicator 16 of the pump housing 12, which may be a transmissive or translucent material which permits light transfer, to provide visual feedback to the user. The power and control system 400 may interface 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 user. Such status indication may be presented to the user via auditory tones, such as through audible alarms, and/or via visual indicators, such as through the LEDs. In a preferred embodiment, 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 user. This is a desirable safety feature that prevents accidental operation of the drug pump and may additionally maintain the energy contained in the power source during storage, transportation, and the like. Additionally, the control interfaces may further be disabled until mixing of the substances in the drug container has completed.

Further regarding visual feedback, power and control system 400 may interface with status indicator 16 that may be a transmissive or translucent material that permits light transfer. For example, the power and control system 400 may be configured such that after the sensor or trigger mechanism have been pressed and/or mixing of substances in the proximal and distal chambers has completed, 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. During the fluid delivery process, power and control system 400 is configured to provide a dispensing status signal via status indicator 16. After fluid delivery has been completed and after the end of any additional dwell time, to ensure that substantially the entire fluid has been delivered, power and control system 400 may provide an okay-to-remove status signal via the status indicator 16. This may be verified independently by the user by viewing the drive mechanism and delivery of the fluid within the fluid container through the window 18 of pump housing 12A, 12B. Additionally, power and control system 400 may be configured to provide one or more alert signals via the status indicator 16, such as, for example, alerts indicative of fault or operation failure situations. The power and control system 400 may be configured to provide other, different status indicators to the user. Power and control system 400 may interface with drive mechanism 100 or integrated sterile fluid pathway connection 300 and fluid container 50 through one or more interconnects to relay such status indication, e.g., activation, mixing, fluid delivery, or completion of fluid delivery (e.g., substantial emptying of fluid container).

In at least one embodiment, the control interfaces between the power and control system and the other components of fluid pump 10 are not engaged or connected until activation by the user. In one embodiment, insertion mechanism 200 and drive mechanism 100 may be caused to activate directly by user operation of activation mechanism 14. This is a desirable safety feature that prevents accidental operation of the fluid pump and may also maintain the energy stored in the power source during storage, transport, and the like. In an embodiment with the optional sensor, e.g., 24 in FIG. IB, power and control system 400 powers drive mechanism 100 to deliver fluid through the integrated sterile fluid pathway connection 300 only if target sensor 24 remains in contact with the target.

Other power and control system configurations may be utilized with the novel fluid delivery devices of the present embodiments. For example, certain activation delays may be utilized during fluid delivery. One such delay optionally included within the system configuration is a dwell time that ensures that substantially the content of the fluid container 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 fluid pump 10 prior to fluid pump activation. Additionally, the system may include a feature that permits the user to respond to the end-of-delivery signals and to deactivate or power-down the fluid pump. Such a feature may similarly require a delayed depression of the activation mechanism, to prevent accidental deactivation of the device. Further, one or more mechanisms may prevent dose delivery prior to completion of the two or more substances contained within drug container 50. Such features provide desirable safety integration and ease-of-use parameters to the fluid pumps. An additional safety feature may be integrated into the activation mechanism to prevent partial depression and, therefore, partial activation of the fluid pumps. For example, the activation mechanism or power and control system may be configured such that the device is either completely off or completely on, to prevent partial activation.

A number of insertion mechanisms may be used within the fluid pumps of the present embodiments. In at least one embodiment, 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. IB and FIG. 1C). The connection of the base to the interior of the pump housing 12B may be, for example, such that the bottom of the base is permitted to pass through a hole in bottom housing 12B to permit direct contact of the base to the target. In such configurations, the bottom of the base 254 may include a sealing membrane 252 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 or a cannula, and a manifold. If an aspect of the insertion mechanism also requires or utilizes needle retraction, the insertion mechanism may further include a retraction biasing member. The manifold may connect to sterile fluid conduit 30 to permit fluid flow through the manifold, the needle or cannula, and into a target during drug delivery.

When the fluid pump is configured to deliver drug to a target, the device can use a variety of needles including conventional hollow needles, e.g., rigid hollow steel needles, and solid core needles commonly referred to as "trocars." The needle may be any size needle suitable to insert the cannula for the type of drug and drug administration intended (e.g., subcutaneous, intramuscular, intradermal, etc.). For example, the needle can be a 27 gauge solid core trocar. A sterile boot may be utilized within the needle insertion mechanism. The sterile boot is typically a collapsible sterile membrane that is in fixed engagement at a proximal end with the manifold and at a distal end with the base. In at least one embodiment, the sterile boot is maintained in fixed engagement at a distal end between the base and the insertion mechanism housing. The base includes a base opening through which the needle and cannula may pass- through during operation of the insertion mechanism, as will be described further below. Sterility of the cannula and needle are maintained by their initial positioning within the sterile portions of the insertion mechanism. Specifically, as described above, needle and cannula are maintained in the sterile environment of the manifold and sterile boot. The base opening of base 254 may be closed from non-sterile environments as well, such as by for example a sealing membrane 252 (shown in FIG. 1C).

According to at least one embodiment of the present invention, the insertion mechanism is substantially similar to that described in WO 2013033421 (Appl. No. PCT/US2012/053174), which is incorporated herein by reference, in its entirety. The insertion mechanism is initially locked into a ready-to-use stage by lockout pin(s) that are initially positioned within lockout windows of the insertion mechanism housing. In this initial configuration, the insertion biasing member and the retraction biasing member are each retained in their compressed, energized states. As shown in FIG. IB, lockout pin(s) 208 can be directly displaced by user depression of the activation mechanism 14. As the user disengages any safety mechanisms (such as optional sensor 24), activation mechanism 14 can be depressed to initiate the drug pump. Depression of activation mechanism 14 can directly cause translation or displacement of control arm 40, and directly or indirectly cause displacement of lockout pin(s) 208 from their initial position within corresponding locking windows of insertion mechanism 200. Displacement of lockout pin(s) 208 permits the insertion biasing member to decompress from its initial compressed, energized state. This decompression of the insertion biasing member drives the needle and the cannula into a target. 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 target. Accordingly, the insertion mechanism may be used to insert a needle and cannula into the target and, subsequently, retract the needle while retaining the cannula in position for drug delivery to the target. In an alternative embodiment, the needle may be retained in fluid communication within the target with or without the presence of a flexible cannula.

FIG. 2 shows an initial configuration of an embodiment of drug container 50 which includes barrel 58, proximal seal 60, distal seal assembly 62, plunger rod 68, distal seal insert 72, and pierceable seal 52. Distal seal assembly 62 and pierceable seal 52 define mutable distal chamber 64. Distal seal 62 and proximal seal 60 define mutable chamber 66. At least a portion of the distal end of plunger rod 68 may be engaged with distal seal assembly 62. The distal seal assembly may comprise a valve-type seal, wherein a portion of the seal assembly may move with reference to the remainder of the seal assembly to open and close one or more passages within the distal seal assembly, thus permitting an operator to effect fluid communication between the mutable distal chamber and the mutable proximal chamber. In at least one embodiment, the valve-type seal of the distal seal assembly has an inner plug seal oriented axially within an outer ring seal, such that a passage is closed when the plug seal and ring seal are in a first position, and the passage is opened when the plug seal is moved into a second position at least partially apart from the ring seal. The plug seal may be attached to or be an aspect of (e.g., a region of) the distal end of the plunger rod. The distal seal assembly may optionally include a locking aspect capable of locking the valve-type seal. The distal seal assembly 62 may comprise an insert 72 that provides at least part of the structure of the valve-type mechanism or locking aspect.

In at least some embodiments, mutable proximal chamber 66 and mutable distal chamber 64 may contain one or more mixing substances, i.e., first and second mixing substances (or distal and proximal substances), which substances may each be a powder, crystal, solid, fluid, liquid, suspension, gas, or other substances suitable for mixing. One or more of the substances can be pharmaceutically active. The substance in mutable proximal chamber 66 and mutable distal chamber 64 may be prefilled or filled on-demand, such as near or at the time of use.

In some embodiments, proximal chamber 66 and distal chamber 64 can be prefilled to contain one or more mixing substances, i.e., proximal and distal mixing substances, which may each be a powder, solid, liquid, suspension, gas or mixtures of these substances. For example, the distal mixing substance locatable in distal chamber 66 may be a fluid that comprises a pharmaceutically active fluid or a pharmaceutically inactive fluid, such as a diluent. The proximal mixing substance locatable in proximal chamber 66 may be a fluid that comprises a pharmaceutically active fluid or a pharmaceutically inactive fluid, such as a diluent. Alternatively, for example, the proximal substance locatable in proximal chamber 66 may comprise a pharmaceutically active solid or an inactive solid excipient, and the distal substance may comprise a pharmaceutically active fluid or a pharmaceutically inactive fluid; or the proximal substance in the proximal chamber may comprise a pharmaceutically active fluid or a pharmaceutically inactive fluid, and the distal substance may comprise a pharmaceutically active solid or an inactive solid excipient. As is well understood in the art, a pharmaceutically active component may be mixed with suitable excipients in its respective mutable chamber in the prefilled drug container. For example, a powdered drug is often lyophilized with salts, sugars, or polyols, such as mannitol or lactose; a liquid drug is often formulated in ethanol, buffers, or non-aqueous solvents.

FIGS. 3-6 show views of handle 500, key 600, piston 700, and plunger rod 68, respectively. Handle 500 includes one or more finger flanges 502, shaft 504, distal end 506, keyseat 508, aperture 510, and slots 512. Shaft 504 is configured to pass through bore 702 of piston 700. Distal end 506 of handle 500 is configured to engage proximal end 380 of piston rod 68. Handle 500 and piston rod 68 may be configured to engage in such a way that after engagement axial motion of handle 500 is transferred to piston rod 68. For example, distal end 506 of handle 500 may include a male thread feature which is configured to engage a female thread feature of proximal end 356 of piston rod 68. Alternatively, distal end 506 may include a male thread feature configured to engage a female thread feature of piston rod 68. The engagement may also be accomplished by a snap-fit, press-fit, etc.

Optionally, after engagement of handle 500 with piston rod 68 key 600 may be used to restrict rotation of handle 500 with respect to piston 700. Aperture 510 is configured to allow key 600 to be inserted from the proximal end of handle 500. Further, keyseat 508 is configured to allow elongated extension 604 to be located substantially within keyseat 508, and keyway 704 is configured to allow passage of elongated extension 604 therethrough. During insertion of key 600 through aperture 510 one or more flexible protrusions 602 of key 600 are displaced inward (i.e., toward elongated extension 604) due to interference with aperture 510. Once flexible protrusion 602 has fully passed through aperture 510 flexible protrusion 602 is able to, at least partially, flex toward its natural position. This outward movement substantially retains key 600 in position. In this position elongated extension 604 is substantially located within keyseat 508 and slots 512 of handle 500 are substantially aligned with slots 612 of key 600. Optionally, mixing interlock 118 is configured to engage slots 512 and 612 in order to prevent the premature activation of reconstitution. Mixing interlock 1 18 is restricted from proximal movement by its position within housing 12 as seen in FIG. 9A. Because of this restriction, when mixing interlock 1 18 is positioned within slots 512 and 612 proximal movement of handle 500 is restricted. This may be done to reduce the possibility of mixing being activated prematurely, for example during shipment. Handle 500 and key 600 may be removed by the user prior to activation of drug injection or during drug injection. For example, the user may remove key 600 from handle 500 by flexing flexible protrusions 602 inward and removing key 600 through aperture 510 in the proximal direction. The user may then remove handle 500 by, for example, unthreading distal end 506 of handle 500 from proximal end 380 of piston rod 68. Alternatively, shaft 504 may be configured to sever at a point proximal to distal end 506 if the user applies a force to handle 500 after it has reached its full proximal position. Distal end 506 may also be configured to disengage from proximal end 380 of piston rod 68 if the user applies sufficient force to handle 500 after distal seal assembly 62 has come into contact with proximal seal 60. In this way, the step of key removal may not be required. By removing handle 500 the user is not burdened by the handle during drug injection.

The handle and key described above is one example of a means for activating mixing of the contents of drug container 50. Alternatively, a string, rope, or other flexible component is attached to piston rod 68 and extends outside of housing 12. By pulling this component the user may displace piston rod 68 in the proximal direction and hence activate mixing of the contents in drug container 50. A mixing activation mechanism provides advantages in package size. It additionally may provide advantages in ease of use as this component may not be required to be removed by the user after mixing (i.e., it may be left on during drug delivery).

In another embodiment, proximal movement of piston rod 68 may be imparted by a biasing member acting on piston rod 68. This biasing member may initially be held in a compressed or energized state by mixing interlock 1 18 or another component. A user may transform this component from an initial, retaining position to a second, non- retaining position. Upon movement of this component into the non-retaining position the biasing member may be permitted to decompress or de-energize such that piston rod 68 is displaced in the proximal direction, allowing the contents in drug container 50 to mix. Transformation of the retaining member may be directly performed by the user or may be indirectly performed by the user, such as, by depressing activation member 14 or another activation member. In one embodiment, the mixing biasing member is triggered to act upon the plunger rod 68 in the proximal direction by a primary motion of activation mechanism 14. Accordingly, the activation mechanism controls the activation and release of, first, the mixing biasing member and, second, drive biasing member 122. For example, partial depression of activation mechanism 14 may trigger the mixing biasing member. Upon completion of that step, i.e., complete mixing of the substances, further depression of activation mechanism 14 may trigger drive biasing member 122 and other features of the drug delivery device of the present invention. In yet another embodiment, the mixing biasing member may be triggered by a separate mixing activation member similar to activation mechanism 14. Upon actuation of the mixing activation member, the mixing biasing member is permitted to act upon and enable proximal displacement of plunger rod 68. For example, the mixing activation member may be a spring-loaded button, displacement of which transforms mixing interlock 1 18 and releases a mixing biasing member to act upon and proximally displace plunger rod 68.

In the embodiment shown in FIG. 7A-D, the distal ring seal comprises exterior rings 343 configured to bear against the inner wall of barrel 58, and internal step 345 for receiving exterior protrusions 355 that extend radially from insert 72 (FIG. 7C). Plunger rod 68 extends axially through insert 72 and into inner lip formation 347 of elastomeric distal seal 70, forming a substance-proof, (e.g., fluid-tight) barrier. Plunger rod 68 may be smooth or may include circumferential ribs 335 (FIG. 7D). Lip formation 347 is held on the side opposite of plunger rod 68 by inner wall 352 of insert 72. Plunger rod 68 is configured with at least a pair of distal indentations 334 positioned axially along a distal portion of plunger rod 330 (FIG. 7D), which channels 334 are inaccessible to substances when plunger rod 68 is positioned fully distally within distal assembly 60 (FIG. 7A); but channels 334 are accessible to substances when plunger rod 68 is positioned fully proximally within distal seal assembly 340 (FIG. 7B).

In this embodiment, plunger rod 68 further comprises a pair of radially extending protrusions 134 (see details in FIG. 7D), positioned within a groove or channel 351 positioned longitudinally within insert 72 (FIG. 7C), which allow protrusions 134 limited axial displacement of plunger rod 68 between the distal stop 357 (valve in closed position, FIG. 7A) and proximal stop 356 (valve in open position, FIG. 7B) in channel 351. Plunger rod 68 may also comprise annular rings 335 (FIG. 7D), configured to bear against the interior lip 347 of distal seal 342 to enhance the substance-proof seal. Insert 72 further comprises substance passage 354, through which substances cannot flow when plunger rod 68 is in the fully distal position within distal seal assembly 60 (FIG. 7 A), but which passages 354 allow fluid passage via the indentation 334 in plunger 68 and the narrower distal end of plunger rod 68 when plunger rod 68 has been moved proximally within insert 72 as defined by channel 351 (FIG. 7B). As further shown in FIG. 7B, when plunger rod 68 has been moved axially until abutting proximal stop 356, an indentation in plunger rod 68 that forms passage 334 allow passage of substances through passage 126 in the distal end of distal ring seal of distal assembly 60.

Distal seal assembly 62 may optionally have a connector that facilitates connection between distal seal assembly 62 and proximal seal 60 once distal seal assembly 62 has been proximally translated to meet the proximal seal. Alternatively, the distal seal and the proximal seal may be connected or held in connection by a vacuum created there-between or pressure from the chamber containing the mixed substances, with or without the use of such an optional connector/connection feature. In these embodiments, when the distal seal engages the proximal seal by connection (e.g., via a connector) or physical forces within the drug container (e.g., a vacuum), the proximal seal and the distal seal may translate axially within the barrel as if a unified component. In at least one embodiment, the proximal seal is retained in a substantially fixed position within the housing until connection with the distal seal. When proximal face of distal seal assembly 62 has been brought into contact with the distal face of proximal seal 60, translation of the plunger rod in the distal direction translates both the proximal and distal seals in the distal direction to force the mixed substance from the distal end of the drug container. Because proximal seal 60 and distal seal assembly 62 remain in contact during drug delivery the contents of distal chamber 64 are prevented from flowing past the seals and hence are forced out of drug container 50 through fluid pathway connection 300.

In addition to the seal configuration described herein the seal may be any configuration of seal suitable for the application such as those described in international patent application no. PCT/US2014/046916, which is incorporated herein, by reference, in its entirety.

In at least one embodiment, the mixing of the substances is facilitated by creating a pressure differential between the mutable proximal chamber and the mutable distal chamber.

Plunger rod 68 can be glass, plastic, plastic coated with silicon oxide or plastic coated with barrier coatings such as parylene and the like, or any suitable material typically known in the art. The distal end of plunger rod 68 defines a plug seal (or similar means) configured to displaceably engage a cavity within ring seal assembly, and which serves to maintain closure of the valve mechanism until displaced, allowing mixing of the substances contained with distal chamber 64 and proximal chamber 66. Proximal seal 60 is an elastomeric element displaceably situated proximally within barrel 58 and configured to engage with distal seal assembly 60 when distal seal assembly 60 is in the most-proximal position, thereafter pressure on piston 700 in the axial, distal direction moves both proximal seal 60 and distal seal assembly 62 in the distal direction and expels contents of drug container 50 through sterile fluid pathway 300 on distal end of barrel 58.

In at least one embodiment, as plunger rod 68 moves in the proximal direction the plug seal is (optionally, temporarily) moved into the second position partially apart from the distal seal assembly, e.g., apart from the distal ring seal or an insert therein, such that the passage is opened (FIG. 7B). The passage may remain open for the transfer of substances between portions of the barrel that are proximal and distal (or vice versa) through the distal seal assembly 62. In this way, the distal seal assembly 62 defines mutable proximal chamber 66 and distal chamber 64 within the barrel 58, and facilitates the movement of substances between the mutable proximal and distal chambers.

The steps of drug mixing and delivery will be explained further with reference to FIGS. 8A-8D and FIGS. 9A-9D. Although FIGS. 8 and 9 show the handle and key described earlier as activation mechanisms for mixing the contents of drug container 50, any activation mechanism known to one of ordinary skill in the art may be used, including those described above. For example, the manual activation mechanism may be replaced or augmented by an automated and/or an automatic mechanism, initiated by pressing an electrically connected button, or through operation of a timer, or through operation of a computer-controlled algorithm, or by a sensor controlled mechanism, or any suitable means or method. The activation could be by way of the illustrated activation button 14 (for example, by a two-stage depression) or, alternatively, could be accomplished by a separate button or switch. Upon release, the spring may decompress and act to cause the plunger rod 68 to move in the proximal direction, thereby causing mixing of the substances of the drug container.

FIG. 8A and FIG. 9A show the drug container prior to initiation of mixing. The distal seal assembly 62 is in the "closed" position, in which exterior rings 343 of plunger rod 68 bear against distal seal cavity 126 formed by the interior wall of insert 72, which distal seal cavity 126 is visible once the plug seal is moved into the "open" position as shown in FIG. 8B. Insert 72 is stabilized within distal seal 70 by at least one protruding radial flange or shoulder 355 that fits into complementary ring seal step 345. A pocket or annular-shaped cavity 166 is formed in proximal seal 60.

In the view of FIGS. 8B and 9B, proximal motion of plunger rod 68 has displaced seal plug 120 from distal seal cavity 126 in insert 250. Distal seal assembly 62 maintains position in barrel 58 by pressure of radial ribs 343 against the interior wall of barrel 58. The position of seal plug 120 away from distal seal cavity 126 (i.e., retracted into the distal seal assembly) is such that the valve function of distal seal assembly 62 is "open," which allows communication between mutable distal chamber 64 and mutable proximal chamber 66. Further proximal motion of plunger rod 68 is impeded by plunger rod protrusions 134 abutting proximal stop 356 of channel 351.

As shown in FIGS. 8C and 9C, once plunger seal assembly 62 has been opened, continued proximal displacement of plunger rod 68 displaces seal assembly 62 in the proximal direction. This displaces the substance from the shrinking proximal chamber 66 through the passage in distal seal assembly 62 and into growing distal chamber 64, such that the substance from distal chamber 64 mixes with the substance from proximal chamber 66 to form a mixed substance. In the present embodiment, the user can shake, swirl or vortex the drug container or drug delivery device to achieve substantial or complete mixing, dissolving, dispersing or suspending of the mixed substance.

As further shown in FIGS. 8C and 9C, once plunger rod 68 and distal seal assembly 62 have been brought into the proximal-most position within barrel 58, the mutable proximal and distal chambers have merged and barrel 58 holds a mixed substance. Thus, the drive mechanism 100 can now be activated. As can be seen in FIG. 8 drive mechanism 100 includes one or more biasing members 122. The biasing members may be, for example, compression springs, leaf springs, an elastic component, or any other component capable of storing and releasing energy. In the configuration shown in FIGS. 8A-8C, the biasing member 122 is in its compressed or energized state. Upon activation of the drive mechanism 100, retainer 128 is transformed from a first position in which it restricts axial movement of piston 700 to a second position in which it does not restrict axial movement of piston 700. The retainer 128 may be automatically transformed upon completion of mixing of the contents of drug container 50. For example, if depression of activation member 14 causes mixing of the contents in drug container 50, the completion of mixing may be used to initiate drug delivery, thereby requiring only a single user input to complete both drug mixing and delivery. Alternatively, retainer 128 may be configured such that it cannot be transformed until drug mixing has been completed thereby reducing the risk of prematurely beginning delivery prior to completion of drug delivery. When retainer 128 is transformed to its second position the force applied to piston 700 by biasing member 122 causes piston 700 to move distally within barrel 58. The distal face of piston 700 contacts proximal seal 60 and transmits its motion to proximal seal 60 and distal seal assembly 62. This distal displacement of distal seal assembly 62 and proximal seal 60 forces the mixed substance out of barrel 58, through fluid pathway connection 300 which may be activated prior to or substantially concurrent with retainer 128 being transformed to its second configuration. A connection may be formed from the capture and retention of insert 72 within cavity 1 16 and may be configured to retain the position of the seals after mixing. Drive mechanisms suitable to be used in such drug delivery pumps are described further in International patent application nos. PCT/US2012/053241 , PCT/US2013/057367, PCT/US2013/057327, PCT/US2014/013005, PCT/US2013/057259, and PCT/US2014/032399, which are incorporated herein, by reference, in their entirety. For example, in addition to the drive mechanism shown here a drive mechanism may be used that allows for a rate controlled distribution of the contents of drug container 50. The control of the rate of the distribution may be controlled by a motor (e.g., stepper motor, AC motor) or by an escapement assembly. Additionally, the rate of decompression of the biasing members may be controlled or restricted by a tether which is engaged with the piston. The tether may provide for a direct or indirect relationship between motion of the motor or escapement and motion of the piston, thereby allowing the motor or escapement to control the rate of motion of the piston.

FIGS. 8D and 9D show the drug container and drug pump, respectively, when the mixed substance has been expelled from the drug container. As can be seen in the figures piston 700 has moved to its most distal position which has moved both the proximal and distal seal to the distal end of barrel 58. Activation of fluid pathway connection 300 causes piercing member 320 to pierce pierceable seal 52. As the proximal and distal seals are moved in the distal direction the mixed contents of the distal chamber are delivered out of drug container 50 through piercing member 320 of fluid pathway connection 300 for delivery to the target. In at least one embodiment, one or more cover sleeves 124 are located around biasing members 1 12. Cover sleeves 124 may be configured to translate and/or expand as biasing members 122 expand. For example, biasing members 122 may impart force on cover sleeves 124 as the biasing members transform from the energized state shown in FIGS. 8A-8C to their substantially deenergized state shown in FIG. 8D. The cover sleeves may be configured such that biasing members 122 are not visible at any time during drug delivery. The cover sleeve 124 may be designed to telescope as shown in the embodiment of FIG. 8 so that the cover sleeve may be compactly stored when biasing member 122 is in its energized state.

The fluid pathway connection 300 includes a sterile fluid conduit 30, a piercing member 320, a connection hub 310, and a sterile sleeve 331. The fluid pathway connection may further include one or more flow restrictors. Upon proper activation of the device 10, the fluid pathway connection 300 is enabled to connect the sterile fluid conduit 30 to the drug container 50. Such connection may be facilitated by a piercing member 320, such as a needle, penetrating a pierceable seal 52 of the drug container 50. The sterility of this connection may be maintained by performing the connection within a flexible sterile sleeve 331. Upon substantially simultaneous activation of the insertion mechanism, the fluid pathway between drug container and insertion mechanism is complete to permit drug delivery into a target.

In at least one embodiment of the present invention, the piercing member 320 of the fluid pathway connection 300 is caused to penetrate the pierceable seal 52 of the drug container 50 by direct action of the user, such as by depression of the activation mechanism by the user. 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. In a preferred embodiment, this connection is enabled by the user depressing the activation mechanism and, thereby, driving the piercing member 320 through the pierceable seal 52, because this prevents fluid flow from the drug container until desired by the user. In such an embodiment, a compressible sterile sleeve 331 may be fixedly attached between the cap 56 of the drug container and the connection hub 310 of the fluid pathway connection. The piercing member 320 may reside within the sterile sleeve 331 until a connection between the fluid connection pathway and the drug container is desired. The sterile sleeve 331 may be sterilized to ensure the sterility of the piercing member 320 and the fluid pathway prior to activation. Embodiments of the sterile fluid pathway suitable for use in drug delivery pumps of the present invention are described further in international patent application nos. PCT/US2012/054861 and PCT/US2013/030478, which are incorporated herein, by reference, in their entirety.

FIG. 10A to FIG. IOC show an embodiment of a mixing syringe having a locking mechanism incorporated within the distal seal assembly as a configuration of insert 450. In this embodiment, plunger rod 430 comprises a pair of protrusions 437 that extend radially from opposite sides of rod 430 and serve as locking pins that interface with locking groove 451(a) of insert 450 (integrated within the distal ring seal). In the locked configuration, shown in FIG. 10A, in which distal end 433 of plunger rod 430 sits in the most-distal position, distal to insert hub 452, and blocks fluid passage, the distal chamber of the device can be emptied, or filled, or filled and emptied, then refilled, etc., independent of the contents of the proximal chamber. Once locking pins 437 are moved radially (in direction R), such as by rotation of plunger rod 430 out of locking groove 451(a) and into channel 451 (as shown in FIG. 10B), the plunger rod can be moved axially (as shown by the arrow in FIG. IOC) from distal end 457 to proximal end 456 of channel 451 (as shown in FIG. IOC); which exposes plunger rod indentation 434 and opens fluid passage 454 within the distal seal assembly, for fluid transfer of the proximal substance from the syringe, or for the mixing of distal and proximal substances. The axis and rotation of the plunger rod in the unlocking motion are shown in the transition from FIG. 1 OA to FIG. 10B.

Accordingly, in the first locked position, upon proximal translation of the plunger rod, the entire distal seal assembly moves proximally within the syringe barrel in a connected closed arrangement, such as for aspiration or filling of the distal chamber through the distal end of the syringe barrel (for example, for fill-at-time-of-use). In this position, the distal chamber can be filled and emptied (e.g., a dose can be loaded and delivered) sequentially or repeatedly without mixing the distal substance with the proximal substance. Once moved into the second unlocked position the plunger rod may initially translate or move, such as axially translate, thereby opening a fluid passage within the distal seal assembly. As the fluid channel is opened, fluid may pass through the fluid passage for mixing between the first chamber and the second chamber and the plunger rod and distal seal assembly may be moved axially in the proximal direction to enable complete mixing. At the end of the mixing stage, insert connector 458 enables connection of the distal seal assembly to the proximal seal or a proximal seal insert, whereby both the proximal seal and distal seal assembly may be translated axially as a connected, unitary component. Axial translation of plunger rod in the distal direction enables the mixed substance to be pushed out of the syringe, e.g., for delivery to the target. The locking mechanism also provides a configuration for sequential injection in which the distal substance is expelled, and then the valve is opened and translated proximally to mate the distal seal assembly with the proximal seal, which moves the proximal substance into position to be expelled. In other words, sequential delivery of a distal substance followed by a preloaded proximal substance can be achieved without requiring the mixing of substances.

The drug pump is capable of delivering a range of drugs with different viscosities and volumes. The drug pump is capable of delivering a drug at a controlled flow rate (speed) and/or of a specified volume. In one embodiment, the drug delivery process is controlled by one or more flow restrictors within the fluid pathway connection and/or the sterile fluid conduit. In other embodiments, other flow rates may be provided by varying the geometry of the fluid flow path or delivery conduit, varying the speed at which a component of the drive mechanism advances into the drug container to dispense the drug therein, or combinations thereof.

In another embodiment, the present invention involves a method of manufacturing a drug container containing two or more isolated, mutable chambers. The method involves at least some of the steps of: inserting a pierceable seal into a barrel, filling a distal chamber with a dry or liquid medicament or a liquid diluent, inserting a distal seal assembly and plunger rod into the barrel, filling a proximal chamber with a dry or liquid medicament or a liquid diluent, and inserting a proximal seal into the barrel. In at least one embodiment, the drug container is configured such that it may be filled using standard filling processes and equipment.

In another embodiment, the present invention involves a method of manufacturing a drug delivery device including a drug container that contains two or more isolated, mutable chambers. The method includes at least some of the steps of: attaching both the drug container and the drive mechanism, either separately or as a combined component, to an assembly platform or housing of the drug pump. The method of manufacturing further includes attachment of the fluid pathway connection, drug container, and insertion mechanism to the assembly platform or housing. The additional components of the drug pump, as described above, including the power and control system, the activation mechanism, and the control arm may be attached, preformed, or pre-assembled to the assembly platform or housing. An adhesive patch and patch liner may be attached to the housing surface of the drug pump that contacts the target during operation of the device. The method may further include inserting a handle through the housing and piston and attaching the handle to the plunger rod, for example by threading the distal end of the handle into the proximal end of the plunger rod. The method may additionally comprise the steps of: inserting a key through an aperture of the handle and through the housing and piston; aligning slots located on the handle and slots located on the key; and positioning a mechanical interlock in the slots of the handle and the key.

A method of operating the drug delivery device includes at least some of the steps of: removing a mechanical interlock which prevents mixing; activating drug mixing; activating, by a user, the activation mechanism; displacing a control arm to actuate an insertion mechanism; and actuation of a power and control system to activate a drive control mechanism to drive fluid drug flow through the drug pump. The method may further include the step of: engaging an optional sensor prior to activating the activation mechanism. The method similarly may include the step of: establishing a connection between a fluid pathway connection to a drug container. Furthermore, the method of operation may include translating a plunger seal within the drive control mechanism and drug container to force fluid drug flow through the drug container, the fluid pathway connection, a sterile fluid conduit, and the insertion mechanism for delivery of the fluid drug to a target. The method of operating may further include the steps of removing the handle and key from the drug delivery device.

It will be appreciated that the foregoing description provides examples of the disclosed system and technique. However, it is contemplated that other implementations of the disclosure may differ in detail from the foregoing examples. All references to the disclosure or examples thereof are intended to reference the particular example being discussed at that point and are not intended to imply any limitation as to the scope of the disclosure more generally. All language of distinction and disparagement with respect to certain features is intended to indicate a lack of preference for those features, but not to exclude such from the scope of the disclosure entirely unless otherwise indicated.

The use of the terms "a" and "an" and "the" and "at least one" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" followed by a list of one or more items (for example, "at least one of A and B") is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS What is claimed is:

1. A drug delivery pump (10) comprising a housing (12), an activation mechanism (14), and a drug container (50), the drug container (50) comprising:

a barrel (58);

a pierceable seal (52) disposed at a distal end of the barrel;

a proximal seal (60) disposed within the barrel;

a distal seal assembly (62) axially displaceably disposed within the barrel distal to the proximal seal, wherein the position of the distal seal assembly defines a mutable distal chamber (64) and defines with the proximal seal a mutable proximal chamber (66) within the barrel; and

a plunger rod (68) axially displaceably engaged with the distal seal assembly and configured to displace the distal seal assembly toward a proximal end of the barrel and thereby urge passage of a fluid in the proximal chamber to the distal chamber through a fluid passage.

2. The drug delivery pump of claim 1, wherein the distal seal assembly includes a valve (68, 70, 72) that regulates the fluid passage between the proximal and distal chambers.

3. The drug delivery pump of claim 1 or 2, wherein the proximal seal (60) is axially displaceably disposed within the barrel.

4. The drug delivery pump of any one of the preceding claims, the drug delivery pump further comprising an insert (72) housed at least partially within the distal seal assembly (62), wherein the insert includes an internal cavity configured to engage a distal end (330) of the plunger rod (68), and wherein the insert includes at least one fluid passage (354).

5. The drug delivery pump of any preceding claim, wherein the distal seal assembly (62) includes a valve (68, 70, 72) that regulates a fluid passage between the proximal and distal chambers (66, 64) and wherein the valve includes a distal end (330) of the plunger rod (68) selectively engageable with the distal seal assembly, wherein proximal displacement of the plunger rod opens the valve to permit fluid

communication between the proximal chamber and the distal chamber, wherein distal displacement of the plunger rod closes the valve and causes the distal seal assembly to move in the distal direction.

6. The drug delivery pump of any preceding claim, further comprising a drive mechanism (100) for one or both of drug delivery and drug mixing and a needle insertion mechanism (200), a sterile fluid pathway connection (300) disposed at the distal end of the drug container (50), and a sterile fluid conduit (30) fluidly connecting the sterile fluid pathway connection to the needle insertion mechanism.

7. The drug delivery pump of claim 6, the sterile fluid pathway connection (300) further comprising a piercing member (320) and a sterile sleeve (331) wherein in a first configuration the piercing member (320) is disposed within the sterile sleeve (331) and in a second configuration the piercing member (320) pierces the pierceable seal (52).

8. The drug delivery pump of any preceding claim, further comprising a target sensor (24) that determines if the device is placed against the target.

9. The drug delivery pump of any preceding claim, further comprising a handle (500) removably connected with the plunger rod (68) to displace the distal seal assembly toward a proximal end of the barrel and thereby urge passage of a fluid in the proximal chamber to the distal chamber through a fluid passage.

10. The drug delivery pump of claim 9, wherein the handle (500) is connected to the plunger rod (68) by threaded engagement.

1 1. The drug delivery pump of claim 9 or claim 10, further comprising a key (600) which prevents rotation of the handle (500) with respect to the plunger rod (68).

12. The drug delivery pump of any preceding claim, further comprising a mixing interlock (1 18) that in a first configuration restricts motion of the plunger rod (68) and in a second configuration does not restrict motion of the plunger rod (68).

13. A method of manufacturing the drug container (50) of claim 1 , comprising:

inserting the pierceable seal (52) into the distal end of the barrel (58);

filling the distal chamber (64) with one of a dry medicament, a liquid medicament and a liquid diluents;

inserting the distal seal assembly (62) and plunger rod (68) into the barrel; filling the proximal chamber (66) with a different one of a dry medicament, a liquid medicament and a liquid diluents; and

inserting a proximal seal (60) into the proximal end of the barrel.

14. The method of claim 13, further comprising:

attaching the assembled drug container (50) to the drug delivery device;

attaching a drive mechanism (100) to the drug delivery device; and

operatively connecting the drive mechanism to the drug container.

15. The method of claim 14, further comprising:

attaching, performing, or pre-assembling a power and control system (400), an activation mechanism (14), and a control arm (40) to the drug delivery device;

removing a mechanical interlock (118) which prevents mixing;

activating drug mixing;

activating, by a user, the activation mechanism;

displacing the control arm to actuate the insertion mechanism; and

actuating the power and control system to activate the drive mechanism to drive fluid drug flow through the drug delivery device.