WO2023122619A1

WO2023122619A1 - Delivery device for a multi-component beneficial agent by intranasal and other routes

Info

Publication number: WO2023122619A1
Application number: PCT/US2022/082065
Authority: WO
Inventors: Amir Genosar
Original assignee: Aktivax, Inc.
Priority date: 2021-12-20
Filing date: 2022-12-20
Publication date: 2023-06-29

Abstract

A beneficial agent dispensing device configured to transition between an inactive configuration and an active configuration is provided. The beneficial agent dispensing device includes a first container including a first compartment adapted to store a first beneficial agent in the inactive configuration and a dispenser body comprising a pressure chamber and a dispensing port, the beneficial agent dispensing device configured to transition configurations by receiving a pressurized fluid in the pressure chamber, the received pressurized fluid causing penetration of the first container, the pressurized fluid to flex the first container to communicate the first beneficial agent to the dispensing port, and the pressurized fluid causing a second substance to communicate to the dispensing port. The dispensing port includes a mixing element adapted to mix the first beneficial agent and the second substance to form a beneficial agent mixture dispensable from the dispensing port.

Description

DELIVERY DEVICE FOR A MULTI-COMPONENT BENEFICIAL AGENT BY INTRANASAL AND OTHER ROUTES

CROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Application Serial No. 63/291,859 filed December 20, 2021, and entitled “Intranasal pressure drug delivery device,” which is incorporated by reference herein in its entirety. U.S. Patent Application Serial No. 16/661,824 filed on October 23, 2019, and U.S. Patents 10,716,901, 11,116,914, 11,278,682, and 11,471,618 are likewise incorporated by reference herein in their entirety. In the event that definitions or descriptive terms used in any patents or patent applications incorporated by reference conflict with definitions or descriptive terms used in the present application, the use in the present application will control.

FIELD OF THE INVENTION

[0002] The presently disclosed technology provides a beneficial agent dispensing device configured to transition between an inactive configuration and an active configuration. The beneficial agent dispensing device includes a first container including a first compartment adapted to store a first beneficial agent in the inactive configuration and a dispenser body comprising a pressure chamber and a dispensing port, the beneficial agent dispensing device configured to transition configurations by receiving a pressurized fluid in the pressure chamber, the received pressurized fluid causing penetration of the first container, the pressurized fluid to flex the first container to communicate the first beneficial agent to the dispensing port, and the pressurized fluid causing a second substance to communicate to the dispensing port. The dispensing port includes a mixing element adapted to mix the first beneficial agent and the second substance to form a beneficial agent mixture dispensable from the dispensing port.

BACKGROUND TO THE INVENTION

[0003] Intranasal dispensers such as the Narcan (Emergent Biosciences) dispenser or designs by SipNose as described in U.S. Patents 11,116,914, 11,278,682, or 11,471,618 utilize manual force to create a spray or jet of beneficial agent contained in the device. This results in potential variation in the dispensed flow characteristics depending on how strong and/or how fast the device was operated and may result in variation in the drug absorbance and effectiveness.

[0004] Previously known intranasal dispensers generally use a syringe-style form factor (i.e., a barrel and piston arrangement). The exposure of the beneficial agent to materials associated with syringes, such as silicone and rubber, may compromise drug stability and effectiveness. Glass syringes are used as an alternative but may compromise the device’s tolerance to impact.

[0005] As such, a need exists for improved intranasal dispensers which address some or all of the issues discussed above.

SUMMARY OF THE DISCLOSURE

[0006] Described herein are various embodiments of a beneficial agent dispensing device comprising a body, a pressure chamber, and at least one dispensing port. The dispensing device may have an inactive configuration and an active configuration, also referred to as a first configuration and a second configuration, respectively. A pressure chamber is located in the body. The beneficial agent is stored in a collapsible primary container responsive to the application of outside pressure by a reduction of internal volume. In one configuration, the primary container is a blister pack made from at least one of a film and a foil. Pressure in the pressure chamber depresses the primary container causing the beneficial agent to expel through the dispensing port. A pressure source causes the pressure chamber to pressurize. In one configuration, the pressure source is a small CO2 cartridge comprising a rupturable membrane, and a rupturing pin may be disposed proximally relative to the rupturable surface of the membrane. The rupturing pin ruptures the rupturable membrane when the two are moved toward each other in a relative motion. A handle mechanically connected to an activation mechanism may be used to cause said relative motion to rupture the CO2 cartridge and pressurize the pressure chamber.

[0007] The beneficial agent reservoir may comprise a pierceable membrane pierceable by a piercing element upon activation of the device, the piercing occurring upon the movement of the piston from the first configuration to the second configuration. An elastic seal may be disposed relative to the pierceable membrane to enhance sealing, and the piercing element may penetrate both the seal and the membrane to establish fluid communication with the dispensing port. [0008] The reservoir may be disposed on a piston moveable from a first position (distal position) wherein the reservoir is aseptically sealed to a second active position (proximal position) where fluid communication is being established between the reservoir and a dispensing port. These positions may correspond to the inactive and active configurations of the dispensing device, respectively, as described. The pressure in the pressure chamber may operate the movement of the piston from a first to a second position. A biasing element such as a spring may be disposed between the piston and the distal end of the device and configured to bias the piston toward the pressure chamber. The biasing element may set a pressure threshold for the movement of the piston from the first position to the second position. The biasing element may further cause the piston to retract from the second position back toward the first position when the pressure in the pressure chamber drops under a certain threshold. This piston retraction may interrupt the fluid communication between the reservoir and the dispensing port and terminate the dispensing. A venting mechanism such as a bleed hole or venting windows may be incorporated with the pressure chamber or piston to release the pressure from the pressure chamber in a controlled fashion. In an implementation, the predefined pressure drop rate through this venting mechanism determines a predefined time to reach a predefined threshold pressure for the piston retraction within specified tolerances. Such a venting mechanism may comprise a pneumatic timing element configured to control the timing of the piston retraction from the active configuration to a post-dispensing configuration wherein the piston is retracted.

[0009] A visual indicator may be incorporated into the device to inform that the device has been activated. The indicator may comprise a window in the dispenser body and an element of the piston assembly, wherein the element is not visible through said window when the piston is in the initial position, and whereupon activation and translation of the piston to the second position said element becomes visible through said window.

[0010] The primary container may comprise any of various flexible or semi-flexible packages, including a molded container, a blow molded container, a sachet, a pouch, a tube, or a combination thereof, wherein the presence of pressure in the pressure chamber causes the primary container to collapse and push the beneficial agent to the dispensing port. The primary container may further be joined to a cylinder and a piston, wherein the piston is moveable in the cylinder in response to the introduction of a pressurized fluid into the pressure chamber, which may push the drug to the dispensing port. [0011] The dispensing port may be configured for a variety of applications, including topical, oral, sub-lingual, ocular, oraticular, and for inhalation. The outlet port may be of a variety of forms, including a jet nozzle, a spray nozzle, or a topical applicator such as a brush or sponge. Other pressure sources may be used, such as pressure resulting from a chemical reaction.

[0012] In one configuration, the pressure chamber contains multiple primary containers containing the same or different beneficial agents. In one configuration, the primary container comprises multiple compartments, which may be manually or automatically merged prior to or in the course of administration. In one configuration, a first compartment stores an active ingredient in dry format and a second compartment stores a diluent, and the two compartments are merged just prior to administration to allow the two substances to reconstitute and form the beneficial agent. In one configuration, the pressure chamber contains multiple primary containers, and the content of each is dispensed through a common dispensing port. In one configuration, the pressure chamber contains multiple primary containers, and the content of each is dispensed from a different dispensing port.

[0013] In an alternative mode, any or all of the pierceable seals may comprise rupturable seals configured to burst in response to the application of pressure. As an example, a primary container may be disposed to be pierced at a pierceable membrane, and a pressurized container may be disposed against a rupturable seal configured to rupture in response to pressurization of the pressure chamber by a pressurized fluid.

[0014] An alternative mode of the invention may be configured as an oral or nasal inhaler device.

[0015] In a reusable embodiment, the apparatus comprises a reusable component and a disposable component. In an implementation, the reusable component includes at least a portion of the pressure chamber. In an implementation, the disposable component includes the beneficial agent reservoirs, a mixing element, and/or the dispensing port as described. The pressure source may be configured to a reusable form, such as a pump or valve-operated reservoir or their equivalents, or configured to a replaceable form, such as a power pack, gas-generating reactive agent, explosive agent, or propellent or their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure la illustrates an example of a dispenser. [0017] Figure lb illustrates a cross-section view of an example dispenser.

[0018] Figure 2a illustrates a side view of an example dispenser.

[0019] Figure 2b illustrates an example dispenser in an active configuration.

[0020] Figure 3a illustrates an example dispenser with a collapsed body.

[0021] Figure 3b illustrates an example dispenser in an extended configuration.

[0022] Figure 4a illustrates an example dispenser in a pre-activation, inactive configuration.

[0023] Figure 4b illustrates an example dispenser in an active configuration.

[0024] Figure 5a illustrates another example of a dispenser in a pre-activation, inactive configuration.

[0025] Figure 5b illustrates another example of the dispenser in an active configuration.

[0026] Figure 5c illustrates an example of a dispenser in a retracted, inactive configuration.

[0027] Figure 6a illustrates still another example dispenser in a pre-activation, inactive configuration.

[0028] Figure 6b illustrates still another example of the dispenser in an active configuration.

[0029] Figure 7a illustrates a further example of a dispenser in a pre-activation, inactive configuration.

[0030] Figure 7b illustrates a further example of a dispenser in an active configuration.

[0031] Figure 7c illustrates a further example of a dispenser in a retracted, inactive configuration.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Figure la & lb illustrate an example dispenser in a pre-activation configuration.

[0033] Specifically, Figure la illustrates an example dispenser 100 (e.g., an intranasal dispenser or other beneficial agent dispensing device). The dispenser 100 may include a body 111, a cap 113 attached to the body 111 at its proximal end 114, and an activation handle 112. The activation handle communicates with an activation mechanism. A section view line illustrates the section of Figure lb. [0034] Figure lb illustrates a cross-section view of the example dispenser 100 (e.g., an intranasal dispenser). The dispenser 100 comprises a pressure chamber 110 within the body 111 (also referred to herein as the dispenser body). The proximal end of the CO2 cartridge 121 confronts a rupturing pin 122. The distal end of the cartridge 121 communicates with the activation mechanism 102, which is manipulated by the handle 112. A piston 125 may define the proximal end of the pressure chamber 110 and may be moveable between a pre-activation (distal) position (shown) to an active (proximal) position in a transition of the dispenser from an inactive configuration to an active configuration. A first primary container 123a (also referred to herein as the first container) and a second primary container 123b (also referred to herein as the second container) are located in the pressure chamber 110 and are connected to the piston 125. The first primary container 123a and/or the second primary container 123b comprise a blister pack made of a formed side, a lid, a flat side, and a fitment 124. The formed side and the lid side are peripherally sealed to each other and each to the fitment 124 to form a sealed compartment. The fitment 124 is accommodated in an opening in the piston 125 in a fluid-tight fashion via seal 126. A piston seal 128 maintains a sealed connection between the piston 125 and the body 111. The piston seal 128 may be configured such that seal integrity is maintained in the active configuration. In such embodiments, the pressure chamber may remain pressurized or be vented through an alternate venting pathway. A pressure release configuration, such as a venting window 127 comprising passageways permitting fluid communication of a pressurized fluid from an interior of the pressure chamber to an external environment, may prevent pressure from building in the proximal end of the body 111. At the proximal end of the dispenser 100, a dispensing port 132 (e.g., in the form of a two-prong nasal applicator) extends from the body 111. A tube 131 runs inside the dispensing port 132 and communicates between the internal of the body 111 and the proximal end of the dispensing port 132. Cap 113 provides at least one of physical protection or an aseptic enclosure to the dispensing port 132.

[0035] Figure 2a & 2b illustrate the example dispenser 100 in an active configuration.

[0036] Specifically, Figure 2a illustrates a side view of the example dispenser 100. Figure 2a illustrates the dispenser 100 (e.g., an intranasal dispenser) in an active position. To reach this configuration, the handle 112 was rotated away from the body 111 to draw the activation mechanism 102, then depressed toward the body 111 to cause the activation mechanism to rupture the CO2 cartridge 121 and pressurize the pressure chamber 110. A section line illustrates the crosssection line of Figure 2b. The cap 113 is removed to expose the dispensing port 132.

[0037] Figure 2b illustrates the example dispenser 100 in an active configuration. Figure 2b illustrates a moment in time (e.g., a snapshot) wherein the activation mechanism 102 advances the CO2 cartridge 121 such that the rupturing pin 122 is penetrated into the cartridge 121, allowing the CO2 gas to pressurize the pressure chamber 110. The pressure advances the piston 125 toward the proximal end of the dispenser 100 to the active position (e.g., from a distal position to a proximal position in the body 111), causing the distal end of the tube 131 to penetrate the first primary container 123s and/or a second primary container 123b, allowing the pressure to depress the first primary container 123a and/or the second primary container 123b and expel the content of the first primary container 123a and/or the second primary container 123b through the dispensing port 132. The piston seal 128 may comprise a venting window 127. Implementations are contemplated in which the dispenser 100 only includes one of the first primary container 123a or the second primary container 123b.

[0038] The pressure chamber may allow gradual release of pressure after activation in a controlled manner, such as a bleeding hole, a venting hole, or a valve. In one embodiment, a bleed hole opens when the piston seal 128 reaches the activated position, allowing the gas from the pressure chamber 110 to deplete and reduce the pressure. In one configuration, a piston return spring is disposed in vented chamber 130, and the arrangement is such that after activation, when the pressure in the pressure chamber is depleted under a certain threshold pressure, the spring force overcomes the force applied by the pressure in the pressure chamber 110, causing the piston to retract and detach from the piston seal. The bleed hole serves as a timer for the piston dwelling time at the activated position such that faster bleed (e.g., via a larger bleed hole) will reduce the pressure in the pressure chamber 110 faster and the spring to retract the piston earlier. The movement of the piston from the pre-activation position to the activated position and back provides a tactile sensation to the user of the dispensing process start and end. The bleeding of the pressure from the pressure chamber 110 may provide the user with an audible sensation of the dispensing process start and end. A variety of dispensing devices can be accommodated at the proximal end of the dispensing port, such as a jet nozzle, a spray nozzle, or a mouthpiece. [0039] Figure 3a & 3b illustrate an example dispenser 300 with a telescopic body. Figures 3a&b illustrate a dispenser 300 (e.g., an intranasal dispenser) similar to the dispenser 100, comprising a telescopic body 301. In an implementation, the telescopic body 301 includes a second body 311 that extends relative to a primary dispenser body 313. A Tether 304 is attached to the cap 303 on one end and to a carabiner 305 on its other end.

[0040] Figure 3a illustrates an example dispenser 300 with a collapsed body. The dispenser 300 is illustrated with a collapsed body, which may be more convenient for storage. Figure 3b illustrates the example dispenser 300 in an extended configuration. By holding the telescopic body 301 and pulling the tether 304 in the opposite direction of the telescopic body 301, the primary dispenser body 313 extends in an axial direction relative to the second body 311 while the cap 303 is removed to expose the dispensing port 321, as shown in Figure 3b. The arrangement is such that the proximal end of the telescopic body 301 covers the distal end of the cap and prevents the cap from being removed until the body is extended. At the extended position, the handle 312 is allowed to move to the armed position for activation. The tether is printed with information to facilitate user training and operation. The distal portion of the telescopic body 301 is color coded to distinguish the dispenser from other dispensers of different medications. In the same way, the tether 304, the cap 303, and/or the carabiner 305 may be color coded. The distal end 302 of the telescopic body 301 can have a distinguished shape to help identify the treatment. The dispenser 300 facilitates the operation of the dispenser with limited dexterity or when wearing gloves as the extended configuration of the telescopic body 301 provides a better grip of the device, and the tether 304 with the carabiner 305 is easier to hold and pull than holding the cap 303 directly. For single-hand operation, the carabiner 305 can be attached to a firm object such as a garment, a carrying case, or a bag, and the extension of the body is done by merely pulling the telescopic body 301. Details of the treatment can be printed on or attached to at least one of the tether 304, the carabiner 305, or the cap. The carabiner can be attached to the garment of a subject to indicate that the subject has been treated.

[0041] As illustrated in Figures la-b, 2a-b, and 3a-b, the dispenser 100 or 300 provide separate fluid pathways for two separate elements of the dispensing port for separately dispensing the first beneficial agent and the second substance. [0042] Figures 4a-4b, 5a-5c, 6a-6b, and 7a-7b describe mixing dispensers (e.g., dispenser 400, 500, 600, or 700) in which the first beneficial agent and the second substance are mixed prior to expulsion from the relevant dispensing ports. The mixing dispensers (e.g., beneficial agent dispensing devices) may include like-named features with similar operations and configurations.

[0043] Some implementations of the mixing dispenser (e.g., a dispenser 400 described with respect to Figures 4a-4b and a dispenser 500 described with respect to Figures 5a-5c) include a second primary container. In implementations, the second primary container contains a second substance. The second substance may include an aerosolizing agent, may include an activating agent to activate at least one component of the beneficial agent mixture, may include a carrier substance adapted to yield the beneficial agent mixture in a therapeutic form, and/or may be pressurized, in the inactive configuration.

[0044] In other implementations, the mixing dispenser (e.g., a dispenser 600 described with respect to Figures 6a-6b and/or a dispenser 700 described with respect to Figures 7a-7b) includes an empty port through which fluid communication can be established between the pressure chamber and a mixing element in a transition from an inactive configuration to an active configuration. In these implementations, the second substance communicated from the pressure chamber to the mixing element may include the pressurizing fluid, which may function as a mixing or aerosolizing agent that mixes with the beneficial agent provided by the first primary container.

[0045] Implementations are further contemplated in which more than one primary container provide beneficial agents or components thereof in addition to an empty port through which the pressure chamber communicates the pressurizing fluid to the mixing element to mix or aerosolize the beneficial agents. In implementations, there is fluid communication between the pressure chamber and the mixing element in the inactive and active configurations via a pressurizing fluid passageway (e.g., the transition does not affect the fluid communication between the pressure chamber and the mixing element).

[0046] As disclosed herein, the mixing dispensers may be configured to transition between an inactive configuration and an active configuration. An implementation of a mixing dispenser may include a first primary container that is adapted to store a beneficial agent in the inactive configuration. In some implementations, the mixing dispenser includes a second primary container. The second primary container may include a second substance. The mixing dispenser may further include a body. The body may include a pressure chamber and a dispensing port. In an implementation, the dispenser is configured to transition from the inactive configuration to the active configuration by receiving a pressurized fluid in the pressure chamber. The received pressurized fluid may cause penetration of the first primary container (and, in relevant implementations, the second primary container). The received pressurized fluid may be further applied within the pressure chamber to the first primary container (and optionally the second primary container in implementations with the second primary container) to flex the first primary container to communicate the first beneficial agent (and the second primary container to communicate a second substance in implementations with the second primary container) to the dispensing port, and the received pressurized fluid causing a second substance to communicate to the dispensing port.

[0047] As disclosed herein, the mixing dispenser in its dispensing port may include a mixing element. The mixing element may be adapted to mix a beneficial agent with a second substance (e.g., an aerosolizing agent) to form a beneficial agent mixture (e.g., an aerosolized form of the beneficial agent) that is dispensable from the dispensing port. Implementations are considered in which the pressurizing fluid is the second substance. In an implementation, the mixing element includes a mixing device to actively or passively mix the beneficial agent with the second substance. The mixing device may include a mixing labyrinth, nozzle array, vortex device, flowimpinging device, deflector, rotor, mesh, sieve, or porous element.

[0048] In implementations, a piston of the mixing dispenser may be configured to advance proximally within the body from a distal position to a proximal position. The mixing dispenser may include a first piercing element with a first passageway within that is in fluid communication with a first pathway (e.g., a beneficial agent fluid or solid pathway or a beneficial agent pathway) via the first passageway. The mixing dispenser may further include a second piercing element with a second passageway within that is in fluid communication with a second pathway (e.g., an aerosolizing fluid pathway or a second substance pathway) via the second passageway. The first pathway may be adapted to provide fluid communication between the first primary compartment and the mixing element in the active configuration. The second pathway may be configured to provide fluid communication in the active configuration between the mixing element and one of the second primary compartment (in implementations with the second primary compartment) and/or the pressure chamber (in implementations in which the pressurizing fluid is the second substance). In implementations, the first pathway and the second pathway are in fluid communication exclusively via the mixing element. In implementations, the first pathway and the second pathway have different predefined geometries to maintain a predefined relative distribution of the first beneficial agent and the second substance in the beneficial agent mixture. The different geometries may include different pathway interior diameters, different pathway shapes, different pathway lengths, or different pathway outlet configurations.

[0049] In implementations, the mixing dispenser may further include a first sealing member (e.g., a first fluid-tight membrane) that is a barrier to fluid communication between the mixing element and the first primary compartment in the inactive configuration and a second sealing member (e.g., a second fluid-tight membrane) that is a barrier to fluid communication between the mixing element and a second compartment of the second primary container (in implementations with the second primary container) or the pressure chamber (in implementations in which the pressurized fluid is the second substance) in the inactive configuration. In an implementation, the first piercing element is further configured to pierce the first sealing member (e.g., the first fluid-tight membrane) to provide fluid communication between the first primary compartment and the portion passage in the first piercing element. In an implementation, the second piercing element is further configured to pierce the second sealing member (e.g., the second fluid-tight membrane) to provide fluid communication between the second primary compartment (in implementations with the second primary container) or the pressure chamber (in implementations in which the second substance is the pressurizing fluid) and the passage in the first piercing element.

[0050] In implementations, the piston of the mixing dispenser is adapted to advance from a distal position in the dispenser body by a force provided by the received pressurized fluid. The advance of the piston during the transition may cause the first piercing element to pierce the first fluid-tight membrane compartment, providing fluid communication between the first compartment and the beneficial agent pathway via a passage in the first piercing element. The advance of the piston may further cause the second piercing element to pierce the second fluid-tight membrane providing fluid communication between the second substance pathway and one of a second compartment of the second primary container or the pressure chamber via a passage in the second piercing element. In an implementation, the piston may be fixedly attached during the transition between the inactive configuration and the active configuration to the first primary container, the first fluid-tight membrane, and the second fluid-tight membrane (and, optionally, the second primary container in implementations with the second primary container).

[0051] In implementations, the mixing dispenser includes a biasing element adapted to bias the piston distally from the dispensing port and a pneumatic timer configured to control the evacuation of the pressurized fluid from the pressure chamber. The biasing element may be adapted to provide proximal translation of the piston from the proximal position to the distal position after dispensing a controlled volume of the beneficial agent mixture or after a controlled time to cease fluid communication of the first beneficial agent and the second substance to the mixing element (e.g., ceasing communication provided by the first pathway and the second pathway in the active configuration). Examples of the pneumatic timer include a bleed hole, a vent, or a venting window.

[0052] In an implementation, the dispensing port of the mixing dispenser is adapted to expel the beneficial agent mixture through a nasal applicator, an oral applicator, an otic applicator, or a jet injector applicator.

[0053] In an implementation, the mixing dispenser may include a pressurized fluid source to provide the pressurized fluid to the pressure chamber that causes the transition between the active configuration and the inactive configuration.

[0054] In an implementation, the first primary container of the mixing dispenser further includes a second compartment adapted to contain a second beneficial agent in the inactive configuration. In this implementation, the flexing of the first container may establish fluid communication between the first compartment and the second compartment to mix the first beneficial agent and the second beneficial agent to form an intra-container mixture prior to the intra-container mixture being expelled from the first primary container in the transition from the inactive configuration to the active configuration.

[0055] In an implementation, the mixing dispenser includes a reusable component and a disposable component. The reusable component may include at least a portion of the pressure chamber and may be configured to be reusable by replacing the disposable component. The disposable component may include the first primary container and/or the dispensing port. In an implementation, the dispensing port of the mixing dispenser is fixedly attached to the dispenser body to prevent the motion of the dispensing relative to the dispenser body. [0056] Figures 4a & 4b illustrate an example dispenser with separately stored substances. Figures 4a&b illustrate an example dispenser (e.g., configured for intranasal delivery) such that separately stored substances will mix in the process of activation of the delivery device. Such substances may comprise more than one component of a beneficial agent, a beneficial agent and an activator, a beneficial agent and an aerosolization substance, a beneficial agent and a carrier material, a carrier substance adapted to mix with the first beneficial agent to yield the beneficial agent mixture in a therapeutic form, or other agents complimentary to dispensing of a beneficial agent.

[0057] Specifically, Figure 4a illustrates an example dispenser 400 in a pre-activation, inactive configuration. The illustrated implementation of the dispenser 400 comprises a body 401 comprising a pressure chamber 402 and a mixing element 420 (e.g., including a mixing subcombination. In an implementation, the mixing sub-combination includes a portion of the dispensing port 421, a mixing region 422 (e.g., an aerosolization region), a nozzle 423, a portion of a first pathway 424 (e.g., a first beneficial agent fluid or solid pathway), a portion of a second pathway 425 (e.g., a second aerosolizing agent fluid pathway), a portion of a first piercing element 426, or a portion of a second piercing element 427. The mixing sub-combination of the mixing element 420 may be configured to mix, activate, or aerosolize the beneficial agent. The dispenser may further include a piston 403 disposed at the proximal end of the body 401 and fixedly joined to the elements 411-414 and a piston seal 431. Primary containers 411 and 413 of this embodiment may each comprise a reservoir comprising a flexible package such as a syringe-like container wherein pressurization by a pressurized fluid operates a plunger, a molded container, a tube, a sachet, or a blow-fill-seal container which may be configured to contain a beneficial agent, a component thereof, an activator, an aerosolization agent or some other agents adapted to mix with the first beneficial agent to yield the beneficial agent mixture in a therapeutic form. In implementations, pierceable membranes 412 and 414 may seal over the ports to the primary containers 411 and 413, respectively. The pierceable membranes 412 and 414 may each comprise a septum, and specifically, their pierceable proximal ends, which may be configured to be pierced in the course of operating the dispensing device, may comprise a pierceable resealable septum as described. The pierceable membranes may be disposed against a sealing element forming a fluid- tight seal at their distal end or may comprise such sealing elements.

[0058] The piston seal 431 comprises a seal between piston 403 and a sealing surface 432 of the body 401, thereby facilitating the displacement of the piston from the unactivated or inactive configuration 4a to the activated configuration 4b. The piston seal 431 may be configured such that seal integrity is maintained, and the pressure chamber 402 remains pressurized or allows pressure to vent through an alternative pathway. Upon activation of the device and pressurization of the pressure chamber 402, the piston 403 translates from a first inactive configuration in an initial position to a second activated configuration wherein the piston translates proximally towards the mixing element 420. As illustrated, the mixing element 420 (e.g., a sub-combination) comprises: a beneficial agent dispensing pathway comprising a first piercing element 426 comprising a first pathway 424 (e.g., a beneficial agent fluid or solid pathway) configured to communicate the stored beneficial agent and further communicating to a nozzle 423, an aerosolizing agent dispensing pathway comprising a second piercing element 427 comprising a second pathway 425 (e.g., an aerosolizing agent pathway) communicating to a dispensing port 421, said dispensing port encompassing a mixing region 422 in which the compressed gas stored in the pressurized fluid source 451 (e.g., a compressed gas storage pack) may be combined to create and dispense a beneficial agent mixture such as a beneficial agent aerosol upon device activation.

[0059] A pressurized fluid source 451 is at least partially disposed within the body 401 and is configured in this embodiment to release compressed gas such as carbon dioxide, argon, nitrogen, hexafluoroacetone propellent, or another aerosolizing or mixing substance into the pressure chamber 402 when activated. In alternative embodiments, the source of pressure may comprise a chemical reaction, explosion, controlled gas-generating reaction, an internal or external pump, liquified gas, pressurized gas source, or a reservoir communicating to the pressure chamber 402 through a port, valve, or passageway.

[0060] Figure 4b illustrates the example dispenser 400 in an active configuration. The dispenser 400 is illustrated in a configuration after the pressurized fluid source 451 has been activated and after the compressed gas has been released into the pressure chamber. The pressure advances the piston 403 toward a mixing device of a mixing element 420, causing the first piercing element 426 and the second piercing element 427 to penetrate pierceable membranes 412 and 414 and establish fluid communication between the mixing chamber of the mixing element 420 and each of the primary containers 413 and 411. The pierceable membranes 412 and 414 further provide a seal between the piston 403 and the pressure chamber 402, preventing the release of compressed gas from the pressure chamber 402. The compressed gas in the pressure chamber acts on the flexible walls of the primary containers 411 and 413 and forces the beneficial agent out of the reservoir to the mixing device. The piston seal 431 may be disposed against venting windows 428 comprising passageways permitting fluid communication of a pressurized fluid from the interior of the pressure chamber to an external environment, resulting in a gradual release of the pressure from the pressure chamber to the surrounding area.

[0061] In embodiments where at least one of the primary containers 411 or 413 is configured to store an aerosolization substance, the aerosolization substance mixes with the beneficial agent in the process of activation to form a beneficial agent aerosol, such as for intranasal, oral, otic, or other delivery. The aerosolization device may comprise various features to create a desired beneficial agent aerosol. In this genus of implementations, the mixing device or mixing element 420 (e.g., elements of a mixing sub-combination) may be referred to as the aerosolization device or aerosolization region and may have various modes and features to create a desired beneficial agent aerosol, including a mixing labyrinth, a nozzles array, a vortex device, a flow impinging device, a deflector, a rotor, a mesh, a sieve, a porous element, or an equivalent thereof to configure predefined characteristics of the aerosol.

[0062] In some embodiments comprising a plurality of primary containers 411 or 413, it is desirable to control the relative timing of activation of such primary containers, for example, to ensure a first agent has saturated the mixing region 422 before a second or a third agent and so on. In such embodiments, the relative disposition of the first piercing element 426 and the second piercing element 427 may be arranged such that said primary containers 411 and 413 expel their stored contents at different times. The relative timing of expulsion may likewise be achieved by altering the relative disposition of the primary containers 411 and 413, or the relative disposition of the first piercing element 426 and the second piercing element 427, or through control of the geometry of the first pathway 424 and/or the second pathway 425, through alternative forms of the mixing region 422 or overall mixing device of the mixing element 420 as recited, or by the selection of primary containers 411 and 413.

[0063] In particular, the elements of the first pathway 424 disposed within the first piercing element 426 may be configured differently from the elements of the second pathway 425 disposed within the second piercing element 427 in length; diameter; number or degree of curves or corners; location of the opening within the mixing region 422; or any like modifiable geometric feature. These asymmetrical modifications or differences may generally be configured to improve the mixing of the beneficial agent and the second substance to yield the beneficial agent mixture in therapeutic form.

[0064] Figures 5a - 5c illustrate an example dispenser comprising separately stored substances and a biasing element. Figures 5a-c illustrate a species of the embodiment wherein a biasing element, such as a spring, is disposed between the piston and the mixing region. Figure 5a illustrates this sub-type in the pre-activation configuration. Figure 5b illustrates the configuration upon pressurization to the activation threshold pressure. Figure 5c illustrates the piston in a retracted position after activation, dispensing, and de-pressurization of the pressure chamber.

[0065] Figure 5a illustrates another example of the dispenser 500 in a pre-activation, inactive configuration. In the pre-activation, inactive configuration, a biasing element 529 is disposed between the piston 503 and the mixing element 520. The force of the biasing element 529 sets a pressure threshold for the movement of the piston 503 from the inactive or pre-activation configuration to the activated configuration of Figure 5b. When the pressure in the pressure chamber 502 surpasses this activation threshold, the piston 503 is displaced to the proximal end. In the illustrated implementation, the biasing element 529 is biased towards forcing the spring distally from the dispensing port.

[0066] The dispenser 500 may comprise a body 501 comprising a pressure chamber 502 and a mixing element 520 for mixing, activation, and/or aerosolization. The mixing element may include one, some, or all of elements 521-528, and further comprising a piston 503 disposed at the proximal end of the body 501 and connected to elements, such as the first and second primary containers

511 and 513, pierceable membranes 512 and 514, and a piston seal 531. The pierceable membranes may seal over the port by sealing access to the first and second primary containers 511 and 513 in the inactive or pre-activation configuration. Said pierceable membranes may further provide a seal between the pressure chamber 502 and the piston 503, preventing the release of pressure from the pressure chamber 502 other than as mediated by mixing element 520. The pierceable membranes

512 and 514 may each comprise a septum, specifically their pierceable proximal ends, which may be configured to be pierced in the course of operating the dispensing device may comprise a pierceable resealable septum. The pierceable membranes may be disposed against a sealing element forming a fluid-tight seal at their distal end or may comprise such sealing elements. [0067] The pierceable membranes 512 and 514 may alternatively comprise a non-resealable rupturable membrane configured to irreversibly rupture when a pressurized fluid is introduced into the pressure chamber. Rupture may variously be accomplished by piercing by the second piercing element 527 or directly by the pressurization of the pressure chamber upon introduction of a pressurized fluid.

[0068] Each of the first and second primary containers 511 and 513 of this embodiment comprise a reservoir which may be defined by a flexible package such as a molded container, a tube, a sachet, or a blow-fill-seal container, or a syringe-like container wherein pressurization operates a plunger, the flexible package configured to contain a beneficial agent. The pierceable membranes 514 and 512 may seal over the ports to the first and second primary containers 513 and 511, respectively. Said pierceable membranes 512 and 514 further provide a seal between the piston 503 and the pressure chamber 502, preventing the uncontrolled release of compressed gas from the pressure chamber 502 through the associated ports in piston 503 in the activated configuration. Said piston seal 531 comprises a seal between piston 503 and a sealing surface 532 of the body 501, thereby facilitating the translation of the piston from the inactive configuration of Figure 5a to the activated configuration of Figure 5b.

[0069] In one embodiment, the first and second primary containers 511 and 513 are configured to store a beneficial agent and a second substance, respectively. An example of a second substance includes an aerosolization agent at a pressure above ambient pressure, as described herein. This configuration provides a metered and predictable quantity of a pressurized second substance such that the physical characteristics and delivered dose of a beneficial agent mixture may be tightly controlled.

[0070] In certain embodiments, the piston seal 531 may be configured to maintain pressurization in the activated configuration. In such embodiments, the pressure chamber may remain pressurized, or pressure may be vented through an alternate venting pathway. Upon activation of the device and pressurization of the pressure chamber 502, the piston 503 translates from a first inactive configuration in an initial position to a second activated configuration wherein the piston is translated to a position in contact with the mixing element 520. The illustrated implementation of the mixing element 520 comprises: a beneficial agent dispensing pathway comprising a first piercing element 526 comprising a first pathway 524 (e.g., a beneficial agent fluid or solid pathway) configured to communicate the stored beneficial agent and further communicating to a nozzle 523, an aerosolizing agent dispensing pathway comprising a second piercing element 527 comprising a second pathway 525 (e.g., an aerosolizing agent fluid pathway) communicating to a dispensing port 521, said dispensing port encompassing a mixing region 522 (e.g., an aerosolization region) in which the compressed gas stored in the pressurized fluid source 551 (e.g., a compressed gas storage pack) may be combined to create and dispense a beneficial agent mixture such as a beneficial agent aerosol upon device activation.

[0071] A pressurized fluid source 551 is at least partially disposed within the body 501 and is configured in this embodiment to release compressed gas such as carbon dioxide, argon, nitrogen, hexafluoroacetone propellent, or some other substance into the pressure chamber 502 when activated. The source of pressure may alternatively comprise a chemical reaction, explosion, controlled gas generating reaction, an internal or external pump, a liquified gas, a pressurized gas, or a reservoir communicating to the pressure chamber 502 through a port, valve, or passageway.

[0072] Figure 5b illustrates another example of the dispenser 500 in an active configuration. In the active configuration, the whole beneficial agent storage assembly is engaged with the mixing sub-combination and in which the first and second primary containers 511 and 513 are in fluid communication with the first pathway 524 and the second pathway 525 of the mixing element 520, which may comprise an aerosolization sub-combination. The pressure in the pressure chamber causes the first and second primary containers 511 and 513 to deplete their volume and expel their contents into the mixing device of the mixing element 520 and intranasally through the dispensing port. The piston seal 531 may be disposed against a pressure relief element 528, such as a venting window comprising passageways permitting fluid communication of a pressurized fluid from an interior of the pressure chamber to an external environment, resulting in a gradual release of the pressure from the pressure chamber to the surrounding area. Alternative embodiments may be configured for topical, oral, sub-lingual, ocular, or otic administration or for other forms of dispensing.

[0073] In some embodiments comprising the first and second primary containers 511 and 513, it is desirable to control the relative timing of flexing and the expulsion of the stored contents of such primary containers and the timing of the release of the pressurizing propellant. The relative arrangement of the first piercing element 526 and the second piercing element 527 may be such that the first and second primary containers 513 and 511 expel their stored contents at different times. The relative timing of expulsion may likewise be achieved by altering the relative disposition of the first and second primary containers 513 and the pierceable membranes 512 that affect fluid communication between the dispensing port and the pressure chamber 502, altering the relative disposition of the first piercing element 526 and the second piercing element 527, by controlling the configuration (e.g., the geometry) of the first pathway 524 and/or the second pathway 525, by controlling the configuration (e.g., the geometry) of the mixing region 522 or the mixing element 520 as recited, or by the selection of first and second primary containers 513.

[0074] In particular, the elements of the first pathway 524 disposed within the first piercing element 526 may be configured differently from the elements of the second pathway 525 disposed within the second piercing element 527 in length; diameter; number or degree of curves or corners; location of the opening within the mixing region 522; or any modifiable geometric feature thereof. These asymmetrical modifications or differences may generally be configured to improve the mixing of the beneficial agent and the second substance to yield the beneficial agent mixture in therapeutic form.

[0075] Figure 5c illustrates an example of the dispenser 500 in a retracted, inactive configuration. The piston 503 may retract after the dispensing of the beneficial agent by the action of the biasing element 529. The biasing element biases the piston 503 toward the distal end of the dispenser 500. When the pressure in the pressure chamber 502 drops below a certain threshold, this biasing action causes the piston to displace towards the distal end of the dispenser 500, causes the piercing needles to disengage, and causes dispensing of the mixed composition to discontinue. The pressure drop may be alternatively achieved by the expulsion of the contents of the primary container, release of pressure through a fluid channel, through bleeding holes in the piston 503 or pressure chamber 502, or through venting windows comprising passageways permitting fluid communication of pressurized fluid from an interior of the pressure chamber to an external environment disposed along the piston.

[0076] Control of the biasing element force and of the rate of pressure release can be used to achieve a predefined dwell time during which the dispenser 500 will remain in the activated configuration of Figure 5b and dispense the mixed combination. In this mode, the biasing element acts to regulate the timing of the dispensing process. The retracting action of the biasing element 529 acts to instantly terminate dispensing in the event of a sudden loss of pressure in the pressure chamber 502, such as by fracture of the pressure chamber 502, piston 503, or venting windows, or by the action of a safety valve. This retracting action causes the first piercing element 526 and/or the second piercing element 527 to disengage from the storage volume of the first and second primary containers 513 and 511 and/or the pressurized volume of the pressure chamber 502. In embodiments wherein the pierceable membranes 512 and 514 comprise a resealable septum, the septum may be configured to reseal to create a fluid-tight seal between the pressure chamber 502 and the dispensing port 521. The septum may comprise an elastomeric material configured to reseal when a piercing element is withdrawn. The remaining pressurized fluid in the pressure chamber 502 may be retained in the pressurized volume or may be vented through one or more bleed holes, vents, or venting windows in the piston, preventing escape through the perforated septum.

[0077] The retraction and disengagement may occur in embodiments wherein the pierceable membranes 512 or 514 may comprise a rupturable seal configured to burst in response to the application of pressure, and the one or both of the pierceable membranes 512 or 514 may remain in fluid communication with the second pathway 525 of the second piercing element 527 and/or the first pathway 524 of the first piercing element 526 when in the retracted configuration. A pressure relief element 528 may be provided by one or more bleed holes, vents, or venting windows configured to have relatively greater fluid flow than the first pathway 524 and/or the second pathway 525, which may prevent a significant volume of the pressurized fluid flow from flowing through the fluid pathways. The pressure relief elements 528 may comprise elements of the piston seal 531 and/or of the housing of the mixing element 520.

[0078] Figures 6a & 6b illustrate an example dispenser comprising an aerosolization gas cartridge. Figures 6a&b illustrate an embodiment of the invention configured for intranasal delivery such that a stored beneficial agent will aerosolize in combination with the compressed gas released from the pressure chamber upon activation of the delivery device. Figure 6a illustrates the inactive configuration, and Figure 6b illustrates the activated configuration.

[0079] Specifically, Figure 6a illustrates still another example dispenser 600 in a pre-activation, inactive configuration. The dispenser 600 comprises a body 601 comprising a pressure chamber 602 and a mixing element 620 for mixing, activation, or aerosolization. The mixing element 620 may include one, some, or all of elements 621-628. The dispenser 600 may further include a piston 603 disposed at the proximal end of the body 601 and connected to elements 612-614 and a piston seal 631. Pierceable membranes 612 and 614 may seal over the port to the pressure chamber 602 and the primary container 613, respectively, in the inactive or pre-activation configuration. Said pierceable membranes further provide a seal between the pressure chamber 602 and piston 603, preventing uncontrolled release of pressure from the pressure chamber 602 other than through the mixing element 620. The pierceable membranes 612 and 614 may each comprise a septum, specifically their pierceable proximal ends, which may be configured to be pierced in the course of operating the dispensing device. The pierceable membranes 612 and 614 may comprise a pierceable resealable septum. The pierceable membranes may be disposed against a sealing element forming a fluid-tight seal at their distal end or may comprise such sealing elements. In an implementation, one of the pierceable membranes 612 or 614 may be omitted. The omission may provide fluid communication between the pressure chamber 602 and the mixing element 620 in the inactive or pre-activation configurations.

[0080] In certain embodiments, the piston seal 631 may be configured to maintain pressurization in the activated configuration. In such embodiments, the pressure chamber may remain pressurized, or pressure may be vented through an alternate venting pathway. Upon activation of the device and pressurization of the pressure chamber 602, the piston 603 translates from a first inactive configuration in an initial position to a second activated configuration wherein the piston is translated into a connection to the mixing element 620. As illustrated, the mixing element 620 includes a beneficial agent dispensing pathway comprising a first piercing element 626 comprising a first pathway 624 (e.g., a beneficial agent fluid or solid pathway) configured to communicate the stored beneficial agent and further communicating to a nozzle 623, an aerosolizing agent dispensing pathway comprising a second piercing element 627 comprising a second pathway 625 (e.g., a beneficial agent fluid pathway) communicating to a dispensing port 621, said dispensing port encompassing a mixing region 622 (e.g., an aerosolization region) in which the compressed gas stored in the pressurized fluid source 651 (e.g., a compressed gas storage pack) may be combined to create and dispense a beneficial agent mixture such as a beneficial agent aerosol upon device activation.

[0081] A pressurized fluid source 651 is at least partially disposed within the body 601 and is configured in this embodiment to release compressed gas such as carbon dioxide, argon, nitrogen, hexafluoroacetone propellent, or another mixing or aerosolizing substance into the pressure chamber 602 when activated. The source of pressure may alternatively comprise a chemical reaction, explosion, controlled gas generating reaction, an internal or external pump, liquified gas, pressurized gas, or a reservoir communicating to the pressure chamber 602 through a port, valve, or passageway.

[0082] Figure 6b illustrates still another example of the dispenser 600 in an active configuration. The dispenser 600 is illustrated during the actual dispensing of the beneficial agent aerosol, in which the primary container 613 is in fluid communication with the fluid pathways of the mixing element 620, which may comprise an aerosolization sub-combination. In the dispensing configuration, the primary containers 613 and the pressure chamber 602 are in fluid communication with a mixing device of the mixing element 620. The pressure in the pressure chamber causes the primary container 613 to deplete its volume and expel its contents into the mixing element 620. The piston seal 631 may be disposed against venting windows 628 comprising passageways permitting fluid communication of a pressurized fluid from the interior of the pressure chamber to an external environment, resulting in a gradual release of the pressure from the pressure chamber to the surrounding area. The pressure in the pressure chamber causes the pressurizing agent to flow into the mixing element 620, wherein the same combine to form a beneficial agent aerosol. In the illustrated embodiment, said beneficial agent aerosol is dispensed intranasally through the dispensing port. Alternative embodiments may be configured for topical, oral, sub-lingual, ocular, or otic administration or for other forms of dispensing.

[0083] In some embodiments comprising a primary container 613, it is desirable to control the relative timing of activation of such primary containers and of the release of the pressurizing propellant. The relative disposition of the first piercing element 626 and the second piercing element 627 may be arranged such that the primary container 613 and pressure chamber 602 expel their stored contents at different times. The relative timing of expulsion may likewise be achieved by altering the relative disposition of the primary container 613 and the pierceable membranes 612 associated with the pressure chamber 602, the relative disposition of the first piercing element 626 and the second piercing element 627, through control of the geometry of the first pathway 624 and the second pathway 625, through alternative forms of the mixing region 622 or mixing element 620 overall as recited, or by the selection of primary container 613. [0084] In particular, the elements of the first pathway 624 disposed within the first piercing element 626 may be configured differently from the elements of the second pathway 625 disposed within the second piercing element 627 in any of length, diameter, number, or degree of curves or corners, location of the opening within the mixing region 622 of the mixing element 620, or any such feature of geometry as may be modified. These asymmetrical modifications or differences may generally be configured to improve the mixing of the beneficial agent and the second substance to yield the beneficial agent mixture in therapeutic form.

[0085] The primary container 613 this embodiment comprises a reservoir that may be defined by a flexible package such as a molded container, a tube, a sachet, or a blow-fill-seal container, or a syringe-like container wherein pressurization operates a plunger, the flexible package configured to contain a beneficial agent. In an implementation, the pierceable membranes 614 and 612 seal over the ports to the primary containers 613 and the pressure chamber 602, respectively. Said pierceable membranes 612 and 614 further provide a seal between the piston 603 and the pressure chamber 602, preventing the uncontrolled release of compressed gas from the pressure chamber 602 through the associated ports in piston 603 in the activated configuration. Said piston seal 631 comprises a seal between piston 603 and a sealing surface 632 of the body 601, thereby facilitating the translation of the piston from the inactive configuration of Figure 6a to the activated configuration of Figure 6b. Implementations are contemplated in which the pierceable membrane 612 is omitted, providing fluid communication between the pressure chamber 602 and the mixing element 620 in the inactive or pre-activation configuration.

[0086] Figures 7a - 7c illustrate an example dispenser with an aerosolization gas cartridge and a biasing element. Figures 7a-7c illustrate a species of the embodiment wherein a biasing element is disposed between the piston and the aerosolization region. Figure 7a illustrates the pre-activation configuration of this species. Figure 7b illustrates the activated or dispensing configuration. Figure 7c illustrates the piston in a retracted position after activation, dispensing, and de-pressurization of the pressure chamber.

[0087] Figure 7a illustrates a further example of a dispenser 700 in a pre-activation, inactive configuration. In the pre-activation configuration of the dispenser 700, a biasing element 729, such as a spring, is disposed between the piston 703 and the mixing element 720 (e.g., an aerosolization element). The biasing element 729 sets a pressure threshold for the activation of the dispenser. Upon exceeding this pressure threshold, the piston 703 advances proximally during the transition from the pre-activation, inactive configuration to the active configuration. When the pressure in the pressure chamber 702 surpasses this activation threshold, the piston 703 is displaced to the proximal end of the dispenser 700.

[0088] The dispenser 700 may comprise a body 701 comprising a pressure chamber 702 and a mixing element 720 for mixing, activation, or aerosolization comprising elements 721-728, and further comprising a piston 703 disposed at the proximal end of the body 701 and connected to elements 712-714 and a piston seal 731. Pierceable membranes 712 and 714 may seal over ports to the pressure chamber 702 and the primary container 713, respectively, in the inactive or preactivation configuration. Said pierceable membrane may further provide a seal between the pressure chamber 702 and the piston 703, preventing uncontrolled release of pressure from the pressure chamber 702 other than through the mixing element 720. The piston seal 731 comprises a seal between piston 703 and a sealing surface 732 of the body 701, thereby facilitating the translation of the piston from the inactive configuration of Figure 7a to the activated configuration of Figure 7b. The pierceable membranes 712 and 714 may each comprise a septum, specifically their pierceable proximal ends, which may be configured to be pierced in the course of operating the dispensing device may comprise a pierceable resealable septum. The pierceable membranes 712 and 714 may be disposed against a sealing element forming a fluid-tight seal at their distal end, or may comprise such sealing elements.

[0089] One of the pierceable membranes 712 and 714 may alternatively comprise a non-resealable rupturable membrane configured to irreversibly rupture when a pressurized fluid is introduced into the pressure chamber. Rupture may variously be accomplished by piercing by the second piercing element 727 or by the pressurization of the pressure chamber upon the introduction of a pressurized fluid.

[0090] The primary container 713 of this embodiment comprises a reservoir that may include a flexible package such as a molded container, a tube, a sachet, or a blow-fill-seal container, or a syringe-like container wherein pressurization operates a plunger, the flexible package configured to contain a beneficial agent.

[0091] In certain embodiments, the piston seal 731 may be configured to maintain pressurization in the activated configuration. In such embodiments, the pressure chamber may remain pressurized, or pressure may be vented through an alternate venting pathway. Upon activation of the device and pressurization of the pressure chamber 702, the piston 703 translates from a first inactive configuration in an initial position to a second activated configuration wherein the piston is translated to a position in contact with the mixing element 720. As illustrated, the mixing element 720 comprises: a beneficial agent dispensing pathway comprising a first piercing element 726 comprising a first pathway 724 (e.g., a beneficial agent fluid or solid pathway) configured to communicate the stored beneficial agent and further communicating to a nozzle 723, an aerosolizing agent dispensing pathway comprising a second piercing element 727 comprising a second pathway 725 (e.g., an aerosolizing agent fluid pathway) communicating to a dispensing port 721, said dispensing port encompassing a mixing region 722 (e.g., an aerosolization region) in which the compressed gas stored in a pressurized fluid source 751 (e.g., a compressed gas storage pack) may be combined to create and dispense a beneficial agent mixture such as a beneficial agent aerosol upon device activation.

[0092] A pressurized fluid source 751 is at least partially disposed within the body 701 and is configured in this embodiment to release compressed gas such as carbon dioxide, argon, nitrogen, hexafluoroacetone propellent, or some other substance into the pressure chamber 702 when activated. The source of pressure may alternatively comprise a chemical reaction, explosion, controlled gas generating reaction, an internal or external pump, liquified gas, pressurized gas, or a reservoir communicating to the pressure chamber 702 through a port, valve, or passageway.

[0093] Figure 7b illustrates a further example of the dispenser 700 in an active configuration. Figure 7b illustrates the activated configuration during the actual dispensing of the beneficial agent aerosol, in which the primary container 713 is in fluid communication with a fluid pathway of the mixing element 720, which may comprise an aerosolization sub-combination. In the dispensing configuration, the primary container 713 and the pressure chamber 702 are in fluid communication with the mixing device of the mixing element 720. The pressure in the pressure chamber causes the primary container 713 to deplete its volume and expel its contents into the mixing device of the mixing element 720. The piston seal 731 may be disposed against a pressure relief element 728 (e.g., one or more venting windows) comprising passageways permitting fluid communication of a pressurized fluid from an interior of the pressure chamber to an external environment, resulting in a gradual release of the pressure from the pressure chamber to the surrounding area. The pressure in the pressure chamber causes the pressurizing agent to flow into the mixing element 720, wherein the same combine to form a beneficial agent aerosol. In the illustrated embodiment, said beneficial agent aerosol is dispensed intranasally through the dispensing port. Alternative embodiments may be configured for topical, oral, sub-lingual, ocular, or otic administration or for other forms of dispensing.

[0094] In some embodiments comprising a primary container 713, it is desirable to control the relative timing of activation of the primary container 713 and of the release of the pressurizing propellant. The relative disposition of the first piercing element 726 and the second piercing element 727 may be arranged such that said primary container 713 and pressure chamber 702 expel their stored contents at different times. The relative timing of expulsion may likewise be achieved by altering the relative disposition of the primary container 713 and the pierceable membranes 712 associated with the pressure chamber 702, the relative disposition of the first piercing element 726 and the second piercing element 727, through control of the geometry of the first pathway 724 and the second pathway 725, through alternative forms of the mixing region 722 or mixing element 720 overall as recited, or by the selection of the primary container 713.

[0095] In particular, the elements of the first pathway 724 disposed within the first piercing element 726 may be configured differently from the elements of the second pathway 725 disposed within the second piercing element 727 in length; diameter; number or degree of curves or corners; location of the opening within the mixing region 722 of the mixing element 720; or any geometrically modifiable feature thereof. These asymmetrical modifications or differences may generally be configured to improve the mixing of the beneficial agent and the second substance to yield the beneficial agent mixture in therapeutic form.

[0096] Figure 7c illustrates a further example of the dispenser 700 in a retracted, inactive configuration. Figure 7c illustrates the retraction of the piston 703 after dispensing by the action of the biasing element 729. The biasing element biases the piston 703 toward the distal end of the dispenser 700. When the pressure in the pressure chamber 702 drops below a certain threshold, this biasing action causes the piston to displace towards the proximal end of the dispenser 700, causes the piercing needles to disengage, and/or causes dispensing of the mixed composition to discontinue. The pressure drop may be alternatively achieved by the expulsion of the contents of the primary container, release of pressure through a fluid channel, through bleeding holes in the piston 703 or pressure chamber 702, or through venting windows comprising passageways permitting fluid communication of a pressurized fluid from an interior of the pressure chamber to an external environment, these being disposed along the piston.

[0097] Control of the biasing element force and of the rate of pressure release can be used to achieve a predefined dwell time, during which the dispenser 700 will remain in the activated configuration of Figure 7b and dispense the mixed combination. In this mode, the biasing element acts to regulate the timing of the dispensing process. The retracting action of the biasing element 729 acts to instantly terminate dispensing in the event of a sudden loss of pressure in the pressure chamber 702, such as by fracture of the pressure chamber 702, piston 703, or venting windows, or by the action of a safety valve. This retracting action causes the first piercing element 726 and the second piercing element 727 to disengage from the storage volume of the primary container 713 and the pressurized volume of the pressure chamber 702. In embodiments wherein the pierceable membranes 712 and 714 comprise a resealable septum, the septum reseals. The septum may comprise an elastomeric material configured to reseal when a piercing element is withdrawn. The remaining pressurized fluid in the pressure chamber 702 may be retained in the pressurized volume or may be vented through one or more bleed holes, vents, or venting windows in the piston, preventing escape through the perforated septum.

[0098] The retraction and disengagement may occur in embodiments wherein one or both of the pierceable membranes 714 or 712 may comprise a rupturable seal configured to burst in response to the application of pressure, and the one or both of the pierceable membranes 714 or 712 may remain in fluid communication with the first pathway 724 of the first piercing element 726 and/or the second pathway 725 of the second piercing element 727 when in the retracted configuration. One or more instances of a pressure relief element 728 may be provided by one or more bleed holes, vents, or venting windows configured to have relatively greater fluid flow than the first pathway 724 or the second pathway 725, which may prevent a significant volume of the pressurized fluid flow from flowing through the fluid pathways. The pressure relief element 728 may comprise elements of the piston seal 731 and/or of the housing of the mixing element 720.

[0099] Although the technology has been described in language that is specific to certain structures and materials, it is to be understood that the invention defined in the appended claims is not necessarily limited to the specific structures and materials described. Rather, the specific aspects are described as forms of implementing the claimed invention. Because many embodiments of the 1 invention can be practiced without departing from the spirit and scope of the invention, the invention resides in the appended claims.

[0100] Unless otherwise indicated, all numbers or expressions, such as those expressing dimensions, physical characteristics, etc., used in the specification (other than the claims) are understood as modified in all instances by the term “approximately.” At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter recited in the specification or claims which is modified by the term “approximately” should at least be construed in light of the number of recited significant digits and by applying rounding techniques. Moreover, all ranges disclosed herein are to be understood to encompass and provide support for claims that recite any and all sub-ranges or any and all individual values subsumed therein. For example, a stated range of 1 to 10 should be considered to include and provide support for claims that recite any and all sub-ranges or individual values that are between and/or inclusive of the minimum value of 1 and the maximum value of 10; that is, all sub-ranges beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less (e.g., 5.5 to 10, 2.34 to 3.56, and so forth) or any values from 1 to 10 (e.g., 3, 5.8, 9.9994, and so forth).

[0101] An example beneficial agent dispensing device configured to transition between an inactive configuration and an active configuration is provided. The beneficial agent dispensing device includes a first container including a first compartment adapted to store a first beneficial agent in the inactive configuration; and a dispenser body including a pressure chamber and a dispensing port, the beneficial agent dispensing device being configured to transition from the inactive configuration to the active configuration by receiving a pressurized fluid in the pressure chamber, the received pressurized fluid causing penetration of the first container, the received pressurized fluid further applied within the pressure chamber to the first container to flex the first container to communicate the first beneficial agent to the dispensing port, and the received pressurized fluid causing a second substance to communicate to the dispensing port, wherein the dispensing port includes a mixing element adapted to mix the communicated first beneficial agent and the communicated second substance to form a beneficial agent mixture dispensable from the dispensing port. [0102] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a beneficial agent pathway adapted to provide fluid communication between the first compartment and the mixing element in the active configuration.

[0103] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a first piercing element configured during the transition from the inactive configuration to the active configuration to pierce the first compartment and provide fluid communication between the first compartment and the beneficial agent pathway via a passage in the first piercing element.

[0104] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a second substance pathway adapted to provide fluid communication in the active configuration between the mixing element and one of a second compartment of a second container or the pressure chamber.

[0105] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the beneficial agent pathway and second substance pathway are in fluid communication exclusively via the mixing element.

[0106] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the beneficial agent pathway and the second substance pathway have different predefined geometries to maintain a predefined relative distribution of the first beneficial agent and the second substance in the beneficial agent mixture.

[0107] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the different predefined geometries include different pathway interior diameters, different pathway shapes, different pathway lengths, or different pathway outlet configurations.

[0108] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a second piercing element configured during the transition from the inactive configuration to the active configuration to provide fluid communication between the second substance pathway and one of a second compartment of a second container or the pressure chamber via a passage in the second piercing element. [0109] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a first fluid-tight membrane that is a barrier to fluid communication between the mixing element and the first compartment in the inactive configuration; and a second fluid-tight membrane that is a barrier to fluid communication between the mixing element and the one of the second compartment of the second container or the pressure chamber in the inactive configuration, wherein the first piercing element is further configured to pierce the first fluid-tight membrane to provide fluid communication between the first compartment and the beneficial agent pathway via a passage in the first piercing element.

[0110] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a piston positioned in the dispenser body, the piston adapted to advance from a distal position to a proximal position in the dispenser body by a force provided by the received pressurized fluid, the advance of the piston causing the first piercing element to pierce the first fluid-tight membrane and causing the second piercing element to pierce the second fluid- tight membrane.

[OHl] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the piston being fixedly attached during the transition between the inactive configuration and the active configuration to the first container; the first fluid-tight membrane; and the second fluid-tight membrane.

[0112] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a biasing element adapted to bias the piston distally from the dispensing port; and a pneumatic timer configured to control evacuation of the pressurized fluid from the pressure chamber, the biasing element adapted to provide proximal translation of the piston from the proximal position to the distal position after dispensing a controlled volume of the beneficial agent mixture or after a controlled time, to cease fluid communication of the first beneficial agent and the second substance to the mixing element.

[0113] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the pneumatic timer includes a bleed hole, a vent, or a venting window.

[0114] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the second substance includes the received pressurized fluid. [0115] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a second container including a second compartment adapted to store the second substance in the inactive configuration, wherein the beneficial agent mixture includes the first beneficial agent aerosolized by the second substance.

[0116] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the second compartment contains the second substance under pressure in the inactive configuration.

[0117] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the dispensing port is adapted to expel the beneficial agent mixture through a nasal applicator, an oral applicator, an otic applicator, or a jet injector applicator.

[0118] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a pressurized fluid source configured to provide the received pressurized fluid to the pressure chamber.

[0119] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the second substance includes a carrier substance adapted to mix with the first beneficial agent to yield the beneficial agent mixture in a therapeutic form.

[0120] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the mixing element includes a mixing device including a mixing labyrinth, nozzle array, vortex device, flow-impinging device, deflector, rotor, mesh, sieve, or porous element.

[0121] Another example beneficial agent dispensing device of any other disclosed device is provided, further including a second beneficial agent container adapted to store a second beneficial agent in the inactive configuration, the received pressurized fluid being further applied within the pressure chamber to the second beneficial agent container to flex the second beneficial agent container to expel the second beneficial agent through the dispensing port, the beneficial agent mixture further including the second beneficial agent.

[0122] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the second beneficial agent is an activating agent configured to therapeutically activate at least one component of the beneficial agent mixture. [0123] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the first container further includes a second compartment adapted to contain a second beneficial agent in the inactive configuration, wherein the flexing of the first container establishes fluid communication between the first compartment and the second compartment to mix the first beneficial agent and the second beneficial agent to form an intra-container mixture prior to the intra-container mixture being expelled from the first container.

[0124] Another example beneficial agent dispensing device of any other disclosed device is provided, including a reusable component including a portion of the pressure chamber; and a disposable component, including the first container and the dispensing port.

[0125] Another example beneficial agent dispensing device of any other disclosed device is provided, wherein the dispensing port is fixedly attached to the dispenser body to prevent motion of the dispensing port relative to the dispenser body.

Claims

What Is Claimed Is:

1. A beneficial agent dispensing device configured to transition between an inactive configuration and an active configuration, comprising: a first container including a first compartment adapted to store a first beneficial agent in the inactive configuration; and a dispenser body comprising a pressure chamber and a dispensing port, the beneficial agent dispensing device being configured to transition from the inactive configuration to the active configuration by receiving a pressurized fluid in the pressure chamber, the received pressurized fluid causing penetration of the first container, the received pressurized fluid further applied within the pressure chamber to the first container to flex the first container to communicate the first beneficial agent to the dispensing port, and the received pressurized fluid causing a second substance to communicate to the dispensing port, wherein the dispensing port includes a mixing element adapted to mix the communicated first beneficial agent and the communicated second substance to form a beneficial agent mixture dispensable from the dispensing port.

2. The beneficial agent dispensing device as claimed in claim 1, further comprising a beneficial agent pathway adapted to provide fluid communication between the first compartment and the mixing element in the active configuration.

3. The beneficial agent dispensing device as claimed in claim 2, further comprising: a first piercing element configured during the transition from the inactive configuration to the active configuration to pierce the first compartment and provide fluid communication between the first compartment and the beneficial agent pathway via a passage in the first piercing element.

4. The beneficial agent dispensing device of claim 3, further comprising: a second substance pathway adapted to provide fluid communication in the active configuration between the mixing element and one of a second compartment of a second container or the pressure chamber.

33

5. The beneficial agent dispensing device of claim 4, wherein the beneficial agent pathway and second substance pathway are in fluid communication exclusively via the mixing element.

6. The beneficial agent dispensing device of claim 4, wherein the beneficial agent pathway and the second substance pathway have different predefined geometries to maintain a predefined relative distribution of the first beneficial agent and the second substance in the beneficial agent mixture.

7. The beneficial agent dispensing device of claim 6, wherein the different predefined geometries include different pathway interior diameters, different pathway shapes, different pathway lengths, or different pathway outlet configurations.

8. The beneficial agent dispensing device of claim 4, further comprising: a second piercing element configured during the transition from the inactive configuration to the active configuration to provide fluid communication between the second substance pathway and one of a second compartment of a second container or the pressure chamber via a passage in the second piercing element.

9. The beneficial agent dispensing device of claim 8, further comprising: a first fluid-tight membrane that is a barrier to fluid communication between the mixing element and the first compartment in the inactive configuration; and a second fluid-tight membrane that is a barrier to fluid communication between the mixing element and the one of the second compartment of the second container or the pressure chamber in the inactive configuration, wherein the first piercing element is further configured to pierce the first fluid-tight membrane to provide fluid communication between the first compartment and the beneficial agent pathway via a passage in the first piercing element.

34

10. The beneficial agent dispensing device of claim 9, further comprising: a piston positioned in the dispenser body, the piston adapted to advance from a distal position to a proximal position in the dispenser body by a force provided by the received pressurized fluid, the advance of the piston causing the first piercing element to pierce the first fluid-tight membrane and causing the second piercing element to pierce the second fluid-tight membrane.

11. The beneficial agent dispensing device of claim 10, wherein the piston being fixedly attached during the transition between the inactive configuration and the active configuration to: the first container; the first fluid-tight membrane; and the second fluid-tight membrane.

12. The beneficial agent dispensing device of claim 11, further comprising: a biasing element adapted to bias the piston distally from the dispensing port; and a pneumatic timer configured to control evacuation of the pressurized fluid from the pressure chamber, the biasing element adapted to provide proximal translation of the piston from the proximal position to the distal position after dispensing a controlled volume of the beneficial agent mixture or after a controlled time, to cease fluid communication of the first beneficial agent and the second substance to the mixing element.

13. The beneficial agent dispensing device of claim 12, wherein the pneumatic timer comprises a bleed hole, a vent, or a venting window.

14. The beneficial agent dispensing device of claim 1, wherein the second substance includes the received pressurized fluid.

15. The beneficial agent dispensing device of claim 1, further comprising: a second container including a second compartment adapted to store the second substance in the inactive configuration, wherein the beneficial agent mixture includes the first beneficial agent aerosolized by the second substance.

16. The beneficial agent dispensing device of claim 15, wherein the second compartment contains the second substance under pressure in the inactive configuration.

17. The beneficial agent dispensing device of claim 1, wherein the dispensing port is adapted to expel the beneficial agent mixture through a nasal applicator, an oral applicator, an otic applicator, or a jet injector applicator.

18. The beneficial agent dispensing device of claim 1, further comprising: a pressurized fluid source configured to provide the received pressurized fluid to the pressure chamber.

19. The beneficial agent dispensing device of claim 1, wherein the second substance includes a carrier substance adapted to mix with the first beneficial agent to yield the beneficial agent mixture in a therapeutic form.

20. The beneficial agent dispensing device of claim 1, wherein the mixing element comprises: a mixing device including a mixing labyrinth, nozzle array, vortex device, flowimpinging device, deflector, rotor, mesh, sieve, or porous element.

21. The beneficial agent dispensing device of claim 1, further comprising: a second beneficial agent container adapted to store a second beneficial agent in the inactive configuration, the received pressurized fluid being further applied within the pressure chamber to the second beneficial agent container to flex the second beneficial agent container to expel the second beneficial agent through the dispensing port, the beneficial agent mixture further including the second beneficial agent.

22. The beneficial agent dispensing device of claim 21, wherein the second beneficial agent is an activating agent configured to therapeutically activate at least one component of the beneficial agent mixture.

23. The beneficial agent dispensing device of claim 1, wherein the first container further includes a second compartment adapted to contain a second beneficial agent in the inactive configuration, wherein the flexing of the first container establishes fluid communication between the first compartment and the second compartment to mix the first beneficial agent and the second beneficial agent to form an intra-container mixture prior to the intra-container mixture being expelled from the first container.

24. The beneficial agent dispensing device of claim 1, comprising: a reusable component including a portion of the pressure chamber; and a disposable component, including the first container and the dispensing port.

25. The beneficial agent dispensing device of claim 1, wherein the dispensing port is fixedly attached to the dispenser body to prevent motion of the dispensing port relative to the dispenser body.

37