WO2016049501A1

WO2016049501A1 - Concentric barrel drug containers and drug delivery pumps that allow mixing and delivery

Info

Publication number: WO2016049501A1
Application number: PCT/US2015/052311
Authority: WO
Inventors: Nicholas Collura; Molly WEAVER; Ian Hanson
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. The drug delivery pumps may be wearable by a user. Mixing of the two or more substances contained within separate, mutable chambers is initiated by transforming an outer barrel distal seal (524) from a first position in which it covers ports (518) extending through an inner barrel (510) to a second position in which the outer barrel distal seal (524) does not cover the ports. Mixing is induced by forcing the contents of the outer chamber (526) through the ports and into the inner chamber, thereby by mixing with the contents of the inner chamber. After mixing of the substances is complete the mixed contents of the inner chamber are forced out of the inner chamber by distal displacement of an injection seal (512) located within the inner barrel. The contents may be delivered through a sterile pathway connection (300) and sterile fluid conduit (320) into the body of the patient. By providing these drug containers and drug delivery pumps that incorporate them, medicaments may be stored as two or more separate constituents and mixed at or near time of delivery.

Description

CONCENTRIC BARREL DRUG CONTAINERS AND DRUG DELIVERY PUMPS THAT ALLOW MIXING AND DELIVERY

CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to U.S. Provisional Application No.

62/055,842, filed on September 26, 2014, which is incorporated 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 chambers, drug pumps integrating 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 tract, 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 the digestive system of a mammalian patient, 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 to a patient. More recently, parenteral delivery of liquid medicines into the body 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 the clinical needs of the patient, 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 the patient's 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 to a patient. 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 to the patient's system. 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 the patient 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 for patients or healthcare providers.

As compared to syringes and injection pens, pump type delivery devices can be significantly more convenient to a patient, in that doses of the drug may be calculated and delivered automatically to a patient 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 patient 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 injection 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 patients a small, low cost, light weight, simple to use alternative for mixing and parenteral delivery of medicaments.

SUMMARY

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

An aspect of the present invention provides a mixing container for a fluid delivery device, the mixing container comprising: an inner barrel having a wall comprising one or more ports extending therethrough; an outer barrel concentrically disposed about the inner barrel; one or more vents located at a distal end of the outer barrel; an outer barrel distal seal in an initial position sealingly engaging the one or more ports of the inner barrel; an outer barrel proximal seal located proximally to the outer barrel distal seal; and an inner barrel distal seal located at a distal end of the inner barrel.

In an embodiment, the present invention provides a fluid container for a drug delivery device such as a drug delivery pump, which includes: an inner barrel having a wall containing ports extending therethrough; an outer barrel concentrically disposed about the inner barrel; a vent cap located at the distal end of the outer barrel; an outer barrel distal seal initially positioned to engage the ports of the inner barrel; an outer barrel proximal seal located proximally to the outer barrel distal seal; an inner barrel distal seal located at the distal end of the inner barrel; and preferably an injection seal located within the inner barrel and proximal to the ports. The drug mixing container may further include a proximal cap located at the proximal end of the drug mixing container and disposed at least partially within the outer barrel. The drug mixing container may further include a sterility seal located within or covering the proximal end of the inner barrel. The inner barrel distal seal may be a pierceable seal configured to be used with a sterile pathway connection (e.g a piercing member) described further hereinafter. An outer chamber is defined by the annular space between the inner barrel and outer barrel and by the position of the outer barrel distal seal and outer barrel proximal seal. An inner chamber is defined by the wall of the inner barrel and by the inner barrel distal seal and by the injection seal.

In at least one embodiment of the present invention, the outer chamber, inner 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, a hormone such as insulin, or a combination of any of these. The pharmaceutical agent may be a lyophilized preparation.

In an initial configuration, the outer barrel distal seal covers the ports passing through the wall of the inner barrel. Distal displacement of the outer barrel proximal seal causes the contents of the outer chamber to impart force on the outer barrel distal seal. This force causes the outer barrel distal seal to move in a distal direction, thereby at least partially uncovering the ports through the wall of the inner barrel. Continued distal displacement of the outer barrel proximal seal therefore forces the contents of the outer chamber to pass through the ports into the inner barrel where these contents are mixed with contents of the inner chamber. The increased volume or contents in the inner chamber may cause the injection seal to move in a proximal direction. When substantially all of the contents from the outer chamber have moved to through the ports and into the inner chamber, the ports are again covered. The ports may be covered by the outer barrel proximal seal or may be partially covered by the outer barrel proximal seal and partially covered by the outer barrel distal seal.

Another aspect of the present invention provides a fluid delivery device comprising: a mixing container that comprises an inner barrel having a wall comprising one or more ports extending therethrough; an outer barrel concentrically disposed about the inner barrel; one or more vents located at a distal end of the outer barrel; an outer barrel distal seal in an initial position sealingly engaging the one or more ports of the inner barrel; an outer barrel proximal seal located proximally to the outer barrel distal seal; and an inner barrel distal seal located at a distal end of the inner barrel.

In an embodiment, a fluid delivery device is provided that includes an inner barrel having a wall containing ports extending therethrough; an outer barrel concentrically disposed about the inner barrel; a vent cap located at the distal end of the outer barrel; an outer barrel distal seal initially positioned to engage the ports of the inner barrel; an outer barrel proximal seal located proximally to the outer barrel distal seal; an inner barrel distal seal located at the distal end of the inner barrel; and preferably an injection seal located within the inner barrel and proximal to the ports. The mixing container may further include a sterility seal located within or covering the proximal end of the inner barrel. The fluid delivery device may further include a drive mechanism for drug delivery. The drive mechanism may include: an injection piston configured to move from an initial, retracted position to a final, extended position; and an injection biasing member configured to transform from an initial, compressed or energized state to a final, decompressed or de-energized state. Distal movement of the injection piston may cause or facilitate distal movement of the injection seal. The drive mechanism may further comprise a mixing piston configured to move from an initial, retracted position to a final, extended position; and, optionally, a mixing biasing member configured to transform from an initial, compressed or energized state to a final, decompressed or de-energized state. Further, the drug delivery device may include a needle insertion assembly, a sterile fluid pathway connector, and/or a sterile fluid conduit. The fluid delivery device may further comprise an intermediate fluid conduit that provides fluid communication between the sterile fluid pathway connection and the needle insertion mechanism. The drug delivery device may further include safety mechanisms such as: a patient sensor that determines if the device is placed against the patient and a mixing interlock that prevents premature mixing of the substances in the two or more chambers. Suitably, the fluid delivery device is wearable by a user. In some embodiments the fluid delivery device may comprise an adhesive patch or other device which allows the fluid delivery device to be operable while worn by the user.

The drug delivery device may further include an activation mechanism that facilitates or triggers one or more components of the drive mechanism. The activation mechanism may comprise an actuator such as a mixing activation member to activate mixing of the substances in the outer chamber and inner chamber. The mixing activation member may allow manual movement of the mixing piston as described above, or may activate the mixing biasing member to transform from an initial, compressed or energized state to a final, decompressed or de-energized state and thereby move the mixing piston as described above.

In at least one embodiment, the mixing biasing member is triggered to act upon the mixing piston by a primary motion of the mixing activation mechanism such that the mixing activation mechanism controls the activation and release of, first, the mixing biasing member and, second, the injection 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 injection biasing member and other features of the drug delivery device of the present invention. In at least one embodiment, displacement of the mixing piston is controlled instead by a mixing activation member. The mixing activation member may be attached to the mixing piston at the time of manufacturing, at the time of filling of the mixing container, or attached by the user at the time of use. Depression of the mixing activation member by the user imparts distal displacement of the mixing piston to mix the substances. After mixing is complete, the mixing activation member may be removed from the fluid delivery device or it may remain attached to drug pump. In yet another embodiment, the mixing activation member may be similar to the activation mechanism, such as a biased button, to minimize the distance that the user needs to depress the mixing activation member to enable proximal displacement of the mixing piston. For example, the mixing activation member may be a spring-loaded button, displacement of which transforms, removes or releases the mixing interlock and releases the mixing biasing member to act upon and distally displace the mixing piston.

A further aspect of the invention provides a method of manufacturing a fluid delivery device comprising a mixing container.

In an embodiment, the mixing container comprises two or more isolated, mutable chambers. The method may involve at least some of the steps of: affixing a vent cap having one or more vents to a distal end of an inner barrel, wherein the inner barrel has one or more apertures passing therethrough and the vent cap is affixed distally of the one or more apertures; placing an outer barrel in coaxial alignment over an inner barrel and connecting the distal end of the inner barrel to the vent cap, wherein the outer barrel has a diameter greater than the diameter of the inner barrel and the barrels are aligned such that the annular space between the barrels forms an outer chamber; inserting a distal seal into the outer chamber and positioning the distal seal in sealing engagement with the one or more apertures; and inserting an inner barrel distal seal into the inner chamber, such that the distal seal resides distally of the apertures, the inner barrel distal seal may be a pierceable seal.

A glue or adhesive may be utilized to affix one or more components of the mixing device to each other. Alternatively, one or more components of the mixing device may be a unified component. For example, the venting cap may be a separate component affixed by a glue to the inner and outer barrels, or the venting cap may be a preformed aspect at the distal end of the outer barrel which is glued to the inner barrel. These components may be sterilized individually or together, and may be assembled in a sterile environment or sterilized after assembly. One or more of the barrels may be siliconized prior to or after assembly.

The method of manufacturing may further include the steps of: at least partly filling a first fluid substance in the outer chamber and inserting a proximal seal into the outer chamber in contact with or proximal to the first fluid substance; and at least partly filling a second fluid substance in the inner chamber and inserting an injection seal into the inner barrel, wherein the injection seal is proximal to the apertures of the inner barrel. Alternatively, the inner chamber may be filled with a lyophilized medicament.

In another embodiment, the present invention involves a method of manufacturing a drug delivery device including a drug mixing container that contains two or more isolated chambers. The method includes at least some of the steps of: attaching both the mixing container and a 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 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 a 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 user during operation of the device. The method may further include inserting a mixing activation mechanism through the housing of the drug pump and connecting the mixing activation mechanism to the mixing piston of the drive mechanism.

A yet further aspect of the invention provides a method of operating a fluid delivery device comprising a mixing container.

An embodiment of the method 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 on-body 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 mixing container. Furthermore, the method of operation may include translating an injection seal within the drive control mechanism and mixing container to force fluid drug flow through the mixing container, the fluid pathway connection, a sterile fluid conduit, and the insertion mechanism for delivery of the fluid drug to the body of a user.

The disclosure describes, in one aspect, a drug pump drive mechanism for use in cooperation with a mixing container having two or more mutable chambers. The drive mechanism has an axis and includes a drive housing, an injection piston adapted to impart movement to the injection seal within the mixing container, at least one injection biasing member, and a retainer. The injection piston is disposed for movement from a retracted first position along the axis to an extended second position. The injection biasing member is adapted to move from an energized first position to a de-energized second position as a result of the release of energy. The injection 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 de-energized second position. The retainer is disposed to maintain the injection 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.

In some embodiments, the drive mechanism further includes a mixing piston disposed concentrically with the injection piston and injection biasing members. The drive mechanism may further include one or more mixing biasing members. The mixing piston is disposed for movement from a retracted first position along the axis to an extended second position. The mixing biasing member is adapted to move from an energized first position to a de-energized second position as a result of the release of energy. The mixing biasing member is disposed to cause movement of the piston from the retracted first position to the extended second position as the mixing biasing member moves from the energized first position to the de-energized second position.

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

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

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

FIG. 2A shows a cross-sectional side view of a mixing container, drive mechanism, and sterile pathway connection of at least one embodiment of the present invention in an initial, unmixed configuration;

FIG. 2B shows a cross-sectional side view of a mixing container, drive mechanism, and sterile pathway connection of at least one embodiment of the present invention after mixing has begun;

FIG. 2C shows a cross-sectional side view of a mixing container, drive mechanism, and sterile pathway connection of at least one embodiment of the present invention in a mixed configuration;

FIG. 2D shows a cross-sectional side view of a mixing container, drive mechanism, and sterile pathway connection of at least one embodiment of the present invention in a post-delivery configuration;

FIG. 2E shows a perspective view of a mixing container, drive mechanism, and sterile pathway connection of at least one embodiment of the present invention in a post-delivery configuration;

FIG. 3A shows an isometric view of a drug pump of at least one embodiment of the present invention in an initial, unmixed configuration;

FIG. 3B shows an isometric view of an activation mechanism of a drug pump of at least one embodiment of the present invention in an initial, unmixed configuration;

FIG. 3C shows an isometric view of an activation mechanism of a drug pump of at least one embodiment of the present invention in a mixed configuration;

FIG. 3D shows an isometric view of a drug pump of at least one embodiment of the present invention in a mixed configuration;

FIG. 4 A shows an isometric view of a drug pump of at least one embodiment of the present invention in an initial, unmixed configuration;

FIG. 4B shows a sectional view of an activation mechanism of a drug pump of at least one embodiment of the present invention in an initial, unmixed configuration; FIG. 4C shows a sectional view of an activation mechanism of a drug pump of at least one embodiment of the present invention in a mixed configuration;

FIG. 4D shows an isometric view of a drug pump of at least one embodiment of the present invention in a mixed configuration;

FIG. 5 shows an isometric view of a mixing piston according to at least one embodiment of the present invention; and

FIG. 6 shows an isometric view of a vent cap according to at least one embodiment of the present invention.

DETAILED DESCRIPTION

The novel devices of the present invention provide drug mixing containers for use with mix-at-time of use medicaments and drug delivery pumps which incorporate such drug mixing containers. Such devices are safe and easy to use, and are aesthetically and ergonomically appealing for self-administering patients. The devices described herein incorporate features which make activation, operation, and lock-out of the device simple for even untrained users. 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 fluid delivery devices (such as drug delivery pumps), mixing containers for drugs, 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". Longitudinal axis "A", axial direction "P" axial direction "D" are indicated in FIG. 2A. 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 fluid delivery systems which are capable of dispensing a fluid (e.g., a drug) to a user upon activation. Typically, the drug delivery system comprises a mixing container which may be referred to as a "drug container" for mixing substances for delivery to a user. 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 or "drug pump" according to at least one embodiment of the present invention. The drug delivery device or drug pump may be utilized to administer delivery of a drug treatment into a body of a user. As shown in FIGS. 1A-1C, the drug 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 10 may be viewed. As shown in FIG. IB, drug pump 10 further includes a drive mechanism 100 engaged with drug container 500, 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 Publication Nos. WO 2013/33421 , WO 2013/033467, WO 2013/040032, WO 2014/011879, WO 2014/036239, WO 2014/036308 and published US patent applications US 20130060233 and US 20130066274, which are incorporated herein by reference, in its entirety. As shown in FIG. 1C, lower housing 12B may comprise aperture 15 to enable a user to access and remove a mixing interlock that initially prevents activation of drive mechanism 100, as will be described in more detail hereinafter.

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 skin of the user, such as adhesive patch 26 and patch liner 28. The adhesive patch 26 provides an adhesive surface 27 that can be used to adhere the drug pump 10 to the body of a user for delivery of the fluid, e.g., drug, dose. The adhesive surface 27 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 body. Removal of the patch liner 28 may further remove the sealing membrane 252 (as shown in FIG. 1 C) of base 254 of insertion mechanism 200, opening the insertion mechanism to the body of the user for fluid delivery. Additionally, the external surfaces of pump housing 12 A, 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 drug pump 10 may be viewed. Window 18 may enable the user to view the operation of the drug 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 500. In a preferred embodiment, the activation mechanism comprises an actuator such as 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 activation mechanism 14 may comprise a push button, and in other embodiments, may comprise an on/off switch, a push-bar, a toggle, or any similar activation feature or trigger 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 12A 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 body of the user. In some embodiments, housing 12 further includes an aperture through which a mixing actuation member may be inserted as will be described further herein.

In the embodiment of FIG. 1 , drug pump 10 comprises housing 12, activation mechanism 14, drive mechanism 100, insertion mechanism 200, fluid pathway connection 300, intermediate fluid pathway 30 between the insertion mechanism 200 and the fluid pathway connection 300, control system 400 and drug mixing container 500. Drug pump 10 is configured such that, upon activation by a user (such as by depression of the activation mechanism 14), the drug pump 10 is initiated to perform at least some of the following steps: initiate mixing of two or more substances contained within the drug mixing container 500; insert a fluid pathway of insertion mechanism 200 (such as a needle or cannula, as for example described in US 20130060233) into the user; enable, connect, or open necessary connections between a drug container 500, a fluid pathway connection 300, and a sterile fluid conduit 320; and force drug fluid stored in the drug container 500 through the fluid pathway connection 300 and fluid conduit 320 for delivery into a user. Optionally, the step of initiating the mixing of the two or more substances may be performed prior to placing the drug pump 10 on the patient 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 10. For example, in at least some embodiments a mixing interlock (e.g see mixing interlock 828 in FIG. 2E) prevents activation of the step of initiating mixing of the two or more substances and must be removed prior to activating mixing. The interlock may be held in place with adhesive and be removable by the user prior to activation of mixing. Alternatively, the mixing interlock may be transformed from a first position in which mixing is prevented to a second position in which mixing may commence. The mixing interlock may, for example, be transformed by operation, by the user, of a mixing activation member located on the outside of housing 12. Further, an optional on-body 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, the mixing activation mechanism, and/or the drive system activation mechanism, cannot be engaged unless the drug pump 10 is in contact with the body of the user. In one such embodiment, the on-body sensor 24 is located on the bottom of lower housing 12B where it may come in contact with the user's body. Upon displacement of the on-body sensor 24, depression of the activation mechanism is permitted. Accordingly, in at least one embodiment the on-body sensor 24 is a mechanical safety mechanism, such as for example a mechanical lock out, that prevents triggering of the drug 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 on-body sensor can be electrically based such as, for example, a capacitive- or impedance-based sensor which must detect tissue before permitting activation of the power and control system 400. These concepts are not mutually exclusive and one or more combinations may be utilized within the breadth of the present invention to prevent, for example, premature activation of the drug pump. In a preferred embodiment, the drug pump 10 utilizes one or more mechanical on-body sensors. Activation of on-body 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 500 and drug pump 10 may be modified while remaining functionally within the breadth and scope of the present invention. For example, although the housing of drug 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 mixing container 500 or drug pump 10 are contemplated while remaining within the breadth and scope of the present embodiments.

FIG. 2A shows a cross-section of an initial configuration of a drug container 500 of at least one embodiment of the present invention, a drive mechanism 100, and a sterile pathway connection 300. Drug container 500 includes inner barrel 510, injection seal 512, outer barrel 520, outer barrel proximal seal 522, outer barrel distal seal 524, proximal cap 540, vented cap 530, and inner barrel distal seal 550. Drug container 500 may additionally include sterility seal 560 located proximal to injection seal 512. Injection seal 512 and inner barrel distal seal 550 define inner chamber 514. Outer chamber 526 is formed between wall 516 of inner barrel 510 and wall 528 of outer barrel 520. Inner barrel 510 and outer barrel 520 may be made of any of a number of materials including plastics and glass, but are preferably made of glass. Inner barrel 510 and outer barrel 520 are in a substantially concentric relationship, such that inner barrel 510 and outer barrel 520 possess a substantially common, central longitudinal axis. Inner barrel 510 and outer barrel 520 are non-rotatable with respect to each other. Inner barrel wall 516 contains one or more ports 518 therethrough. Outer barrel distal seal 524 is initially positioned such that ports 518 are covered and material is not able to flow through ports 518. Hence, inner chamber 514 and outer chamber 526 are not in fluid communication with one another. Inner barrel distal seal 550 may be a pierceable seal configured such that piercing member 320 of sterile fluid pathway connection 300 may pass through the inner barrel distal seal 550.

In at least some embodiments, inner chamber 514 and outer chamber 526 may contain one or more mixing substances, i.e., first and second mixing substances (or inner and outer 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 inner chamber 514 and outer chamber 526 may be prefilled or filled on-demand, such as near or at the time of use.

In some embodiments, inner chamber 514 and outer chamber 526 can be prefilled to contain one or more mixing substances, i.e., inner and outer mixing substances, which may each be a powder, solid, liquid, suspension, gas or mixtures of these substances. For example, the inner mixing substance locatable in inner chamber 514 may be a fluid that comprises a pharmaceutically active fluid or a pharmaceutically inactive fluid, such as a diluent. The outer mixing substance locatable in outer chamber 526 may be a fluid that comprises a pharmaceutically active fluid or a pharmaceutically inactive fluid, such as a diluent. Alternatively, for example, the outer substance locatable in outer chamber 526 may comprise a pharmaceutically active solid or an inactive solid excipient, and the inner substance may comprise a pharmaceutically active fluid or a pharmaceutically inactive fluid; or the outer substance in the outer chamber may comprise a pharmaceutically active fluid or a pharmaceutically inactive fluid, and the inner 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 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. Typically, outer chamber 526 contains a liquid substance and inner chamber 514 contains a solid substance, whereby the liquid substance is mixable with the solid substance in the inner chamber 514 to form a mixed substance suitable for injection. In at least one embodiment, however, the outer chamber 526 and inner chamber 514 both contain liquid substances.

Drug container 500 further comprises vent cap 530 comprising plurality of vents 532 (shown in FIG. 6), whereby vented space 529 is located between vent cap 530 and outer barrel distal seal 524 in an initial configuration. Because the contents do not contact vented space 529 it may be unsterile and open to the atmosphere. This feature enables displacement of distal seal 524 towards vent cap 530 during the mixing step of operation, thereby opening one or more apertures 518 for passage of fluid from the outer chamber to the inner chamber. The fluid path from outer chamber 526 to inner chamber 514 remains sterile as a result of the displaced location of outer barrel distal seal 524 (shown in FIG. 2B). Vent cap 530 may be connected to outer barrel 520 and/or inner barrel 510 in any manner known to one skilled in the art. In one embodiment, vent cap 530 is attached to inner barrel 510 and outer barrel 520 using adhesive. Although vent cap 530 is shown here as a separate component it will be appreciated that vents may be integrally formed in outer barrel 520 or inner barrel 510 thereby potentially integrating vent cap 530 into these components.

Sterility seal 560 may be included in drug container 500. Sterility seal 560 may be located proximally to injection seal 512 and be located either within inner barrel 510 or may cover the proximal end of inner barrel 510. Sterility seal 560 may be configured to allow venting of the proximal end of inner barrel 510 during mixing of the substances contained within outer chamber 529 and inner chamber 514. During mixing, injection seal 512 may be caused to move in the proximal direction due to the increased volume or pressure contained within inner chamber 514. Because of this it may be necessary to maintain sterility of the portion of the inner barrel that is initially proximal to injection seal 512 as the mixed fluid contents of chamber 514 may contact this portion of inner barrel 510. Sterility seal 560 may be constructed from a material that allows air to escape during mixing to allow injection seal 512 to move in a proximal direction, displacing the air initially contained in this portion of the barrel out, through sterility seal 560. For example, sterility seal 560 may be constructed from a non- woven material such as TYVE ® or any other material which allows for the passage of air but which acts as a filter to maintain the sterility of the portion of the inner barrel located between sterility seal 560 and injection seal 512. After mixing is complete and/or prior to delivery, the sterility seal 560 may be removed from inner barrel 510, this removal may be performed by piston 700. Alternatively, piston 700 may pierce sterility seal 560 before or during injection of the contents of inner chamber 514. Sterility seal 560 may further be displaced with and by piston 700, in the distal direction, during drug delivery.

Mixing piston 800 is slidably, axially moveable within outer chamber 526. Referring to FIG. 5, an embodiment of mixing piston 800 may further include locking prongs 802 located on shaft 804 biased outwardly from shaft 804. Locking prongs 802 are biased outwardly to engage proximal cap 540 to facilitate locking mixing piston 800 from proximal movement after mixing is complete. In some embodiments, mixing biasing member 822 may be configured to prevent proximal movement of mixing piston 800 during drug delivery.

Proximal cap 540 may be positioned at the proximal end of outer barrel 520 such that proximal cap 540 extends, at least partially, inside wall 528 or outer barrel 520. This location of proximal cap 540 provides a step within outer chamber 526. This step may be used to engage locking prongs 802 on mixing piston 800 to restrict proximal displacement of mixing piston 800 after mixing is complete. Proximal cap 540 may be attached to outer barrel 520 in any manner known to one skilled in the art. In one embodiment, proximal cap 540 is attached to outer barrel 520 using adhesive. Alternatively, outer barrel 520 may include a step integrally formed into its proximal end. Locking prongs 802 may also engage a portion of housing 130 (e.g. , the distal face of housing 130) upon completion of mixing to prevent subsequent proximal motion of mixing piston 800.

Distal seal 524 is positioned distally from proximal seal 522 within outer chamber 526. Proximal seal 522 is axially, slidably moveable within outer chamber 526 by contact with and movement of mixing piston 800. As best can be seen in FIG. 2B, apertures 518 on inner barrel wall 516 provide a fluid path that allows fluid from outer chamber 526 to flow into inner chamber 514. Initially, distal seal 524 is in sealing engagement with apertures 518 (i.e., covering apertures 518; compare FIG. 2A and FIG. 2B). Movement of proximal seal 522 distally in outer chamber 526 (i.e., axial movement towards vent cap 530 in the direction of the hatched arrow) forces liquid contained in outer chamber 526 to displace distal seal 524 (i.e., towards vent cap 530), thereby opening apertures 518 to permit fluid to transfer from outer chamber 526 to inner chamber 514. Continued distal displacement of outer barrel proximal seal 522 forces the material originally contained in outer chamber 526 through ports 518 and into inner chamber 514.

As shown in FIG. 2B and 2C, continued, axial movement of proximal seal 522 in the direction of the hatched arrow within outer chamber 526, forces fluid flow from outer chamber 526 to inner chamber 514, until proximal seal 522 is in contact with distal seal 524. Seals 522 and 524 may be caused to reach end of travel within outer chamber 526, where distal seal 524 will contact vent cap 530. In this position (shown in FIG. 2C), either proximal seal 522 is in sealing engagement (i.e., covering) with apertures 518 or both seals 522 and 524 may be in partial sealing engagement with apertures 518. The latter is possible, for example, when fluid flow form outer chamber 526 to inner chamber 514 does not require the distal seal 524 to fully uncover the apertures 514.

Injection seal 512 is axially, slidably movable in inner chamber 514 of inner barrel 510 of drug container 500 to thereby deliver the fluid contents of inner chamber 514. Injection seal 512 may also move axially, in the proximal direction in response to increased fluid volume or pressure in inner chamber 514. This increased pressure may be caused by the contents of outer chamber 526 being forced into inner chamber 514 through ports 518.

In at least one embodiment, distal movement of proximal seal 522 is caused by interaction with mixing piston 800. Distal displacement of mixing piston 800 may be caused by mixing biasing member 822. Mixing biasing member 822 is positioned between drive housing 130 and flange 806 of mixing piston 800. In the initial configuration, mixing biasing member 822 is in a compressed or energized state and is restricted from decompressing or de-energizing by contact with flange 806. Mixing piston 800 is initially restrained from distal movement. As shown in FIG. 2E, this restraint may be provided by mixing interlock 828 comprising collar 829 and tab 830 having adhesive surface 831. In one configuration, mixing interlock 828 restricts movement of mixing piston 800 by collar 829 releasably engaging protrusion 808 of mixing piston 800. In a second configuration mixing interlock 828 does not restrict the distal movement of mixing piston 800. Mixing interlock 828 may be transformed from the first configuration to the second configuration by, for example, removal of mixing interlock 828, such as by a user grasping tab 830. Alternatively, mixing interlock 828 may be transformed when the user triggers or operates activation mechanism 14. Upon transformation of mixing interlock 828 distal movement of mixing piston 800 is no longer restricted, hence mixing biasing member 822 decompresses or de-energizes and causes distal movement of mixing piston 800. Accordingly, the mixing biasing member 822 could be released by a primary motion of the activation mechanism 14 such that the activation mechanism 14 controls the activation and release of, first, the mixing biasing member 822 and, second, the drive biasing member 122. For example, partial depression of the activation mechanism 14 may trigger the mixing biasing member 822. Upon completion of that step, i.e., complete mixing of the substances, further depression of the activation mechanism may trigger the drive biasing member 122 and other features of the drug delivery device of the present invention. As would be readily appreciated by one having ordinary skill in the art, the activation mechanism 14 could be configured in a range of ways to enable this two-part functionality.

In some embodiments, proximal displacement of mixing piston 800 is initiated, driven or controlled by an actuator such as a mixing activation member, as (e.g see mixing activation member 1814 in FIG 3 and mixing activation member 2814 in FIG. 4). The mixing activation member may be attached or connected, such as releasably attached or connected, to mixing piston 800 by snap-fit, threading, adhesive, or any other method known to one skilled in the art. The mixing activation member may be attached or connected to mixing piston 800 at the time of manufacturing or at the time of filling of the drug container. Alternatively, the mixing activation member may be attached or connected by the user at the time of use. Depression of the mixing activation member by the user, imparts distal displacement (i.e., toward vent cap 530) of mixing piston 800. After mixing is complete, the mixing activation member may be removed from drug pump 10 or it may remain attached to drug pump 10. In some embodiments, axial depression of the mixing activation member by a user triggers distal movement of mixing piston 800. In some embodiments, the mixing activation member triggers decompression or de-energizing of mixing biasing member 822 to cause distal movement of mixing piston 800. In other embodiments, the mixing activation member directly causes distal movement of mixing piston 800 in the absence of mixing biasing member 822. In at least one embodiment the mixing activation member may be similar to the activation mechanism 14, such as a biased button, to minimize the distance that the user needs to depress the mixing activation member to enable distal displacement of the mixing piston 800. For example, the mixing activation member may be a spring- loaded button, displacement of which transforms a mixing interlock (not shown) and releases a mixing biasing member 822 to act upon and distally displace the mixing piston 800.

In an embodiment shown in FIG. 3A-C, mixing activation member 1814 triggers decompression or de-energizing of mixing biasing member 1822 to cause distal movement of mixing piston 1800. Displacement of mixing piston 1800 is controlled by mixing activation member 1814 mounted or otherwise located or positioned laterally to mixing piston 1800. In FIG. 3 A, mixing pump 1 10 is an in initial position prior to mixing. As shown in FIG. 3B, mixing activation member 1814 is connected to mixing piston 1800 by way of deformable arms 1817A,B that releasably engage protrusions 1808 A, B of mixing piston 1800. Protrusions 1808 A, B of mixing piston 1800 extend through arcuate slots 1 131 A, B of drive housing 1 130. Activation member 1814 may further include guide tab 1829 which engages slot 1 132 of drive housing 1 130 to restrict the motion of activation member 1814 to be parallel to the solid arrow shown in FIG. 3B. Alternatively, or additionally, activation member 1814 may include guide features which engage the upper or lower housing. Lateral, inward (i.e towards mixing piston 1800) depression of mixing activation member 1814 by a user pushing button 1818 in the direction of the solid arrow shown in FIG. 3B causes or facilitates radially outward displacement of deformable arms 1817A, B (indicated by the solid arrows in FIG. 3C) out of engagement with protrusions 1808A, 1808B of mixing activation member 1814, which causes decompression of biasing member 1822 thereby causing distal displacement (i.e., toward vent cap 1530) of mixing piston 1800. Contact between ramped surfaces 1819A, B of deformable arms 1817A, 1817B with protrusions 1808 A, 1808B assists causing the outward displacement of deformable arms 1817A, 1817B out of engagement with protrusions 1808A, 1808B. Essentially as described in FIGS 2 C and D, axial depression of mixing piston 1800 causes axial movement of proximal seal 522 within outer chamber 526 and forces fluid flow from outer chamber 526 to inner chamber 514, until proximal seal 522 is in contact with distal seal 524.

In embodiments shown in FIGS 4A-C, mixing activation member 2814 directly causes distal movement of mixing piston 2800 in the absence of a mixing biasing member 822. FIG. 4 A shows an embodiment of drug pump 210 in an initial configuration prior to mixing. Activation member 2814 comprises push bar 2816 and arms 2815 A, 2815B connected to, or integral with, mixing piston 2800. Push bar 2816 may connect to arms 2815 A, B by way of a snap-fit, mechanical fastener (such as a threaded fastener), or any other means. FIG. 4B shows drug pump 2210 in a configuration after mixing. As shown in FIG. 4C, a user may depress activation member 2814 by pushing push bar 2816 which thereby directly depresses mixing plunger 2800 (i.e in the absence of a mixing biasing member). Essentially as described in FIGS 2C and D, axial depression of mixing piston 2800 causes axial movement of proximal seal 2522 within outer chamber 2526 and forces fluid flow from outer chamber 2526 to inner chamber 2514, until proximal seal 2522 is in contact with distal seal 2524. FIG. 4D shows drug pump 210 after full depression of activation member 2814, mixing piston 2800 and completion of mixing.

Reference is now made with particularly to embodiments and numbering shown FIGS 2A-D, but which, optionally, may also be applicable to the embodiments described in FIGS 3 and/or 4 once mixing is complete.

As shown in FIG. 2D, after completion of mixing, mixing piston 800 cannot be withdrawn from outer chamber 526, as locking prongs 802 (which are outwardly biased) engage cap 540, outer barrel 520, or drive housing 130 to form a lock that prevents proximal movement of mixing plunger 800 beyond this point. Locking mixing piston 800 after mixing may be useful in directing the force of delivery piston 700 to cause fluid in inner chamber 514 to flow through sterile fluid pathway connection 300, instead of forcing the fluid substance back into outer chamber 526. This may also be achieved by the final positioning of proximal seal 524 in sealing engagement with apertures 518. Similarly, full axial movement of mixing piston 800 and/or engagement between mixing piston 800 and one or more detent aspects of outer barrel 520 may unlock delivery piston 700 or a locking aspect of inner barrel 510 to enable axial movement of delivery piston 700.

In another variation, at the end of depression mixing piston 800 may be locked to outer barrel 520 by way of complementary detent aspects (not shown) which engage at a point of axial travel in the distal direction by mixing piston 800 to prevent subsequent axial travel in the proximal direction. These complementary detents may be used together with, or as an alternative to, locking prongs 802 described previously. It will be appreciated that venting space 529 between the distal seal 570 and vent cap 530 is never in contact with any substance(s) in drug container 500, hence there is no need to maintain sterility in the area. Venting space 529 may fill with air, which is displaced out of the annular space between outer barrel 520 and inner barrel 510 and between vent cap 530 and the distal seal 524 upon axial movement of mixing piston 800 and axial movement of distal seal 524. Furthermore, because distal seal 524 initially covers apertures 518 in wall 516 of inner barrel 510, sterility of this fluid path between outer chamber 526 and inner chamber 516 is maintained during use of drug container 500. Only distal seal 524 is potentially in contact with any non-sterile portion of outer barrel 520 and inner barrel 510, as fluid is caused to flow from outer chamber 526 into inner chamber 514 without ever contacting the non-sterile portion. Accordingly, injection seal 512 may axially move in inner chamber 514 in the proximal direction in response to the distal movement of mixing piston 800. This is because distal movement of mixing piston 800 forces liquid from outer chamber 526 into the inner chamber 514 and increases the pressure and/or fluid volume within inner chamber 514. With sterile fluid pathway connection 300 still in a closed configuration, there is no space for volume expansion other than to force injection seal 512 in the proximal direction within inner barrel 510.

Upon completion of mixing of substances in inner chamber 514, drug container 500 is prepared for drug delivery. At this time fluid pathway connection 300 may be transformed to the open configuration, connecting drug container 500 to the sterile fluid pathway by, for example, piercing inner barrel distal seal 550. Distal displacement of injection seal 512 forces the mixed contents of chamber 514 through sterile fluid pathway connection 300 for delivery to the user. Drive mechanism 100 may be activated to initiate distal movement of injection seal 512. Activation of drive mechanism 100 allows injection biasing member 122 to decompress or de-energize such that injection piston 700 is displaced in the distal direction. This displacement is transferred to injection seal 512.

In addition to the drive mechanism described here, delivery of the mixed contents in chamber 514 may be performed by the drive mechanisms described in International patent Application Nos. PCT/US2013/057259 and PCT/US2013/057367. For example, the rate of delivery of the contents of inner chamber 514 may be controlled and/or varied by a motor (stepper motor, AC motor, DC motor) or an escapement assembly. The rate of decompression of injection biasing member 122 may be controlled or restricted by a tether. The tether may be connected to injection piston 700 and the motion of the tether may be controlled by the motor or escapement assembly.

In yet another variation, outer chamber 526 may be compartmentalized (i.e., comprising a plurality of compartments) such as by one more frangible or porous membranes, walls, sealing members or the like, with each compartment containing a different fluid or solid substance, whereby depression of mixing piston 800 facilitates mixing of each different fluid or solid substance. Additionally, or alternatively, inner chamber 514 may be similarly compartmentalized, each compartment comprising a different fluid or solid substance. Accordingly, drug container 500 may include two or more substances for mixing and injection.

The disclosure describes, in one aspect, a drug pump drive mechanism 100 for use in cooperation with a drug container 500 having two or more mutable chambers. The drive mechanism has an axis and includes a drive housing 130, an injection piston 700 adapted to impart movement to the inner chamber plunger seal within the drug container 500, one or more injection biasing members 122, and a retainer 128. Injection piston 700 is disposed for movement from a retracted first position along the axis to an extended second position. Injection biasing member 122 is adapted to move from an energized first position to a de-energized second position as a result of the release of energy. The injection biasing member is disposed to cause movement of the injection piston from the retracted first position to the extended second position as the biasing member moves from the energized first position to the de-energized second position. The retainer 128 is disposed to maintain the injection biasing member in the energized first position when the retainer is in a retaining first position, and to release the injection biasing member from the first energized position when the retainer moves to a releasing second position.

In at least one embodiment, the injection biasing members 122 includes at least one of a tension spring or a compression spring. In at least one embodiment, the injection biasing member 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 injection piston. In at least one embodiment, the retainer engages at least a portion of the injection piston to retain the injection piston in its retracted position when the retainer is in its retaining first position.

In some embodiments, drive mechanism 100 further includes one or more mixing biasing members 822, a mixing piston 800 adapted to impart movement to outer barrel proximal seal 522, and a mixing interlock 828. Piston 800 is disposed for movement from a retracted first position to an extended second position. Mixing biasing member 822 may be located concentrically with injection biasing member 122 and is adapted to move from an energized first position to a de-energized second position as a result of the release of energy. The biasing member 822 is disposed to cause movement of the piston 800 from the retracted first position to the extended second position as the biasing member 822 moves from the energized first position to the de-energized second position. The mixing interlock 828 is disposed to maintain the biasing member 822 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.

In some embodiments, drive mechanism 100 further includes a mixing piston 800 adapted to impart movement to outer barrel proximal seal 522, a mixing activation member 814, and a mixing interlock 828. Piston 800 is disposed for movement from a retracted first position to an extended second position. Mixing activation member 814 is engaged with mixing piston 800 such that axial movement of mixing activation member 814 is transferred to mixing piston 800. Mixing activation member 814 extends outside the body 12 of the drug pump 10 such that the user may depress mixing activation member 814 in a substantially distal direction thereby causing movement of mixing piston 800 from the retracted first position to the extended second position. The mixing interlock 828 is disposed to maintain the mixing piston 800 in the retracted first position until mixing interlock 828 is displaced by the user.

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 on-body 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.

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 on-body 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 12 A, 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 drug container 500 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 on-body 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 on-body sensor 24 remains in contact with the body of the user.

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 500. 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, e.g., the body of a user. 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 the body of the user during drug delivery.

When the fluid pump is configured to deliver drug to the body of a subject, 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 base and 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 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, insertion biasing member and 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 on-body 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 the body of the user. At the end of the insertion stage, the retraction biasing member is permitted to expand in the proximal direction from its initial energized state. This axial expansion in the proximal direction of the retraction biasing member retracts the needle while maintaining the cannula in fluid communication with the body of the user. Accordingly, the insertion mechanism may be used to insert a needle and cannula into the user and, subsequently, retract the needle while retaining the cannula in position for drug delivery to the body of the user. In an alternative embodiment, the needle may be retained in fluid communication within the body with or without the presence of a flexible cannula.

The fluid pathway connection 300 includes a sterile fluid conduit 320 comprising a piercing member 321 , a connection hub 330, a sterile sleeve 340 and a crimp cap 350. The fluid pathway connection 300 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 300 to the drug container 500. Such connection may be facilitated by a piercing member, such as a needle, penetrating inner barrel distal seal 550 of the drug container 500. The sterility of this connection may be maintained by performing the connection within a flexible sterile sleeve. Upon substantially simultaneous activation of the insertion mechanism, the fluid pathway between drug container and insertion mechanism is complete to permit drug delivery into the body of the user.

In at least one embodiment of the present invention, the piercing member of the fluid pathway connection is caused to penetrate the inner barrel distal seal 550 of the drug container 500 by direct action of the user, such as by depression of the activation mechanism 14 by the user. For example, the activation mechanism itself may bear on the fluid pathway connection such that displacement of the activation mechanism 14 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 321 of fluid conduit 320 through the inner barrel distal seal 550, because this prevents fluid flow from the drug container until desired by the user. In such an embodiment, a compressible sterile sleeve 340 may be fixedly attached between the cap 350 of the drug container and the connection hub 330 of the fluid pathway connection. The piercing member may reside within the sterile sleeve 340 until a connection between the fluid connection pathway and the drug container is desired. The sterile sleeve 340 may be sterilized to ensure the sterility of the piercing member 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.

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: affixing a vent cap having one or more vents to a distal end of an inner barrel, wherein the inner barrel has one or more apertures passing therethrough and the vent cap is affixed distally of the one or more apertures; placing an outer barrel in coaxial alignment over an inner barrel and connecting the distal end of the inner barrel to the vent cap, wherein the outer barrel has a diameter greater than the diameter of the inner barrel and the barrels are aligned such that the annular space between the barrels forms an outer chamber; inserting a distal seal into the outer chamber and positioning the distal seal in sealing engagement with the one or more apertures; and inserting a distal seal into the inner chamber, such that the distal seal resides distally of the apertures. The inner barrel distal seal may be configured to be a pierceable seal.

As discussed above, a glue or adhesive may be utilized to affix one or more components of the mixing device to each other. Alternatively, one or more components of the mixing device may be a unified component. For example, the venting cap may be a separate component affixed by a glue to the inner and outer barrels, or the venting cap may be a preformed aspect at the distal end of the outer barrel which is glued to the inner barrel. These components may be sterilized individually or together, and may be assembled in a sterile environment or sterilized after assembly. One or more of the barrels may be siliconized prior to or after assembly.

The methods of manufacturing may further include the steps of: at least partly filling a first fluid substance in the outer chamber and inserting a proximal seal into the outer chamber in contact with or proximal to the first fluid substance; and at least partly filling a second fluid substance in the inner chamber and inserting an injection plunger into the inner barrel, wherein the injection plunger is proximal to the apertures of the inner barrel. Alternatively, the inner chamber may be filled with a lyophilized medicament.

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 user during operation of the device. The method may further include inserting a mixing activation mechanism through the housing of the drug pump and connecting the mixing activation mechanism to the mixing piston of the drive mechanism.

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 on-body 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 an injection 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 the body of a user.

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

1. A fluid delivery device comprising a mixing container that comprises an inner barrel having a wall comprising one or more ports extending therethrough; an outer barrel concentrically disposed about the inner barrel; one or more vents located at a distal end of the outer barrel; an outer barrel distal seal in an initial position sealingly engaging the one or more ports of the inner barrel; an outer barrel proximal seal located proximally to the outer barrel distal seal; an inner barrel distal seal located at a distal end of the inner barrel; an activation mechanism; a sterile fluid pathway connection; and a needle insertion mechanism.

The fluid delivery device of Claim 1, further comprising a drive mechanism, the drive mechanism comprising a mixing piston configured to move from an initial, retracted position to a final, extended position.

The fluid delivery device of Claim 2, configured so that movement of the mixing piston from said initial, retracted position to said final, extended position moves or displaces the outer barrel distal seal from said initial position and out of sealing engagement with the one or more ports of the inner barrel.

The fluid delivery device of Claim 3, further comprising a mixing interlock which initially prevents or blocks operation of the mixing piston to move or displace the outer barrel distal seal from said initial position and out of sealing engagement with the one or more ports of the inner barrel and wherein removal or release of the mixing interlock allows distal movement of the mixing piston to move or displace the outer barrel distal seal from said initial position and out of sealing engagement with the one or more ports of the inner barrel.

5. The fluid delivery device of any one of Claims 2-4, wherein the activation mechanism comprises an actuator operable by a user to manually cause the mixing piston to move or displace the outer barrel distal seal from said initial position and out of sealing engagement with the one or more ports of the inner barrel.

6. The fluid delivery device of any one of Claims 2-4, the drive mechanism further comprising a mixing biasing member configured to transform from an initial, compressed or energized state to a final, decompressed or de-energized state, to thereby facilitate moving the mixing piston to the final, extended position.

The fluid delivery device of Claim 6, wherein the actuation mechanism comprises an actuator which triggers the mixing biasing member to cause the mixing piston to move or displace the outer barrel distal seal from said initial position and out of sealing engagement with the one or more ports of the inner barrel.

The fluid delivery device of any one of Claims 2-7, wherein the drive mechanism further comprises an injection piston configured to move from an initial, retracted position to a final, extended position.

The fluid delivery device of Claim 8, wherein the drive mechanism further comprises an injection biasing member configured to transform from an initial, compressed or energized state to a final, decompressed or de-energized state to thereby facilitate moving the injection piston to the final, extended position.

10. The fluid delivery device of any preceding claim, which further comprises an injection seal located within the inner barrel and proximal to the one or more ports.

1 1. The fluid delivery device of Claim 10, wherein the injection seal is capable of distal movement in the inner barrel towards the one or more ports.

12. The mixing container of any preceding claim, wherein the inner barrel and outer barrel contain respective substances for mixing wherein a first of said respective substances is transferrable from the outer barrel into the inner barrel through the one or more ports following movement of the outer barrel distal seal from said initial position and out of sealing engagement with the one or more ports of the inner barrel.

13. The fluid delivery device of any preceding claim, further comprising an intermediate fluid conduit that provides fluid communication between the sterile fluid pathway connection and the needle insertion mechanism.

14. The fluid delivery device of any preceding claim, wherein the sterile fluid pathway connection comprises a piercing member which is capable of piercing the inner barrel distal seal to enable delivery of fluid contents of the fluid delivery device to a user.

15. The fluid delivery device of any preceding claim, which is wearable by a user.

16. A method of manufacturing a fluid delivery device comprising a mixing container includes at least some of the steps of: attaching the mixing container and a drive mechanism, either separately or as a combined component, to a housing of the fluid delivery device; attaching a fluid pathway connection; and/or attaching an insertion mechanism to the housing.

17. The method of Claim 16, further including at least some of the steps of: attaching a power and control system; attaching an activation mechanism; and/or attaching an adhesive patch to the housing surface of the drug pump that contacts the user during operation of the device.

18. The method of Claim 17, further including the step of inserting a mixing activation mechanism into the housing of the fluid delivery device and connecting the mixing activation mechanism to a mixing piston of the drive mechanism.

19. A method of operating a fluid delivery device that comprises a mixing container, which method includes at least some of the steps of: removing a mechanical interlock which prevents mixing; activating drug mixing; activating, by a user, an activation mechanism; displacing a control arm to actuate an insertion mechanism; and/or actuation of a power and control system to activate a drive control mechanism to drive fluid drug flow through the drug pump.

20. The method of Claim 18 or Claim 19 which further includes the step of: establishing a connection between a fluid pathway connection to the mixing container.