HK1242633B - Self-puncturing liquid drug cartridges and associated dispenser - Google Patents

Description

Self-piercing liquid drug cartridges and related dispensers

CROSS-REFERENCE TO RELATED APPLICATIONS

This Patent Cooperation Treaty application claims priority to U.S. Patent Application No. 14/732,247, filed June 5, 2015; which claims priority to U.S. Provisional Patent Application No. 62/009,704, filed June 9, 2014, and which also claims priority to U.S. Provisional Patent Application No. 62/099,806, filed January 5, 2015, the entire contents of which are incorporated herein by reference for all purposes.

Background Art

There are various types of inhalers for atomizing liquids. For example, U.S. Pat. No. 5,586,550 (the contents of which are incorporated herein by reference) describes an inhaler comprising a dispensing device in which a membrane having a tapered hole is vibrated so that liquid in contact with the back of the membrane is dispensed from the front of the membrane in the form of an aerosol.

Although liquid can be atomized effectively, this inhaler may not be particularly suitable for certain purposes, such as atomizing unit doses of insulin for pulmonary administration. In addition, with regard to liquid delivery to the dispensing device, dosage control, and microbial control, this inhaler can adopt a less than ideal method.

Therefore, improved methods for aerosolizing doses of insulin for pulmonary administration, liquid drug delivery to dispensing devices, dose control between doses, and/or microbiological control are desirable.

Summary of the Invention

The present invention provides a liquid medicine box and a related inhaler. In many embodiments, the box comprises a liquid medicine container and a filter core. The filter core is used to filter the liquid medicine in the container before spraying from the ejection port of the container. The box comprises a piston, which moves relative to the container so that a certain volume of liquid is ejected from the container via the ejection port. In many embodiments, the liquid medicine box and the related inhaler are particularly suitable for atomizing a dose of insulin so that pulmonary administration. The liquid medicine box provides a convenient method for providing the liquid medicine to an aerosol generator. In many embodiments, the combination of the box and the related inhaler provides improved dosing control and improved microbial growth inhibition between administrations.

Therefore, in one aspect, a liquid medicine cartridge is provided. The cartridge includes a container for storing the liquid medicine, an end cap coupled to a first end of the container, a filter element, and a piston. The end cap has an injection port through which a volume of the liquid medicine can be selectively ejected from the container. The filter element is configured to filter the liquid medicine before being ejected from the injection port. The piston seals the second end of the container. The piston can be repositioned relative to the container to selectively eject a volume of the liquid medicine from the container through the injection port.

The liquid medicine box may include additional elements and/or structures. For example, the end cap may have a protrusion in which the injection port is disposed. The box may include a removable cover configured to dock with the end cap to prevent the flow of the liquid medicine through the injection port. The end cap may include a conduit in fluid communication with the injection port to deliver the liquid medicine to the injection port. The conduit may be coated to prevent microorganisms from entering the container. For example, the conduit may be coated with silver or made of silver to prevent microorganisms from entering the container.

The liquid drug cartridge can be configured to prevent any amount of liquid drug from leaking out of the container without repositioning the piston relative to the container. For example, the catheter can be configured to prevent any amount of liquid drug from leaking out of the container without repositioning the piston relative to the container. For example, to prevent gravity-induced outflow of the liquid drug from the cartridge without movement of the piston, the catheter can have an inner diameter that is sufficiently small relative to the surface tension and/or viscosity of the liquid drug to prevent flow of the liquid drug through the catheter. The filter can also be configured to prevent any amount of liquid drug from leaking out of the container without repositioning the piston relative to the container.

The liquid drug cartridge can be configured to prevent microorganisms from entering the container. For example, the catheter can be coated (e.g., with silver) to prevent microorganisms from entering the container. The filter element can also be configured to prevent microorganisms from entering the container. For example, the filter element can contain one or more antimicrobial substances and/or compounds (e.g., silver).

In another aspect, an atomization system is provided. The system may include any of the liquid drug cartridge embodiments described herein, an aerosol generator including a vibratable membrane having a front and a back surface, a housing defining a mouthpiece, and an actuator for repositioning a piston relative to a container so as to dispense a dose of drug via an ejection port to the back surface of the vibratable membrane. The aerosol generator includes a vibratable element for vibrating the vibratable membrane. The housing includes a receptacle configured to at least partially receive the cartridge and engage with the cartridge to position the ejection port so as to dispense the liquid drug directly onto the back surface of the vibratable membrane for atomization by controlled vibration of the vibratable element.

The system can be configured so that the liquid medicine box can be removed at any time to enable a more thorough cleaning of the dispenser. When the liquid medicine box is equipped with a detachable cover, the cover and the liquid medicine box receiving slot can be configured so that the liquid medicine box cannot be inserted into the slot until the cover is removed from the box.

In many embodiments, the housing is configured to provide a mixture of air and atomized liquid medicine for inhalation by the user. For example, the housing may include a mixing chamber in fluid communication with the front of the vibrating membrane and the mouthpiece, and one or more air inlets in fluid communication with the mixing chamber and configured to introduce air into the mixing chamber in response to the user's inhalation via the mouthpiece. The system may also include an air flow restrictor array, which has a greater resistance to air flow than the one or more air inlets and places the mixing chamber in fluid communication with the one or more air inlets. In many embodiments, the restrictor array includes a plurality of orifices arranged in an annular arrangement. In many embodiments, the air flow through the mixing chamber in response to the user's inhalation via the mouthpiece is laminar flow and surrounds a dose of medicine atomized using the vibrating membrane, thereby preventing contact between the atomized medicine and the surrounding surface of the mixing chamber. The system may include a pressure port connected to a pressure sensing system for detecting the patient's inhalation.

The vibratable mesh may be coupled to the housing to improve the efficiency of the aerosol generator.For example, the vibratable mesh may be coupled to the housing via a suitable isolator member (eg, an elastomeric isolator).

Described system can comprise ultraviolet light source so that microbial control between administration is provided.For example, can use one or more ultraviolet light sources to radiate the chamber of the housing that is arranged on the back side of vibratory member and the box that medicine is ejected into from liquid medicine box via injection port.

In many embodiments, the housing is configured to keep the liquid medicine box inside the accommodating tank. Any suitable method can be adopted to keep the liquid medicine box inside the accommodating tank. For example, the housing can be configured to form a pressurized container that holds the liquid medicine box. The actuator can be configured to apply pressure to the container so that the piston is repositioned relative to the container so that a dose of medicine is distributed to the back side of the film via the jet port. The injection of air into the container can be controlled so that the liquid medicine of a predetermined desired amount is distributed via the jet port so that it is atomized by the aerosol generator. For example, the piston can be arranged to be slightly lower than the end of the container so as to form a space that can be pressurized by sealing against the container end or the inner wall of the container. As another example, the side opposite to the liquid medicine can be hollowed out so as to form a space that can be pressurized. When distributing liquid, this pressurized space will increase. The removal of air pressure (pressure relief) can be used to immediately stop the piston from moving further until air pressure is reapplied.

In many embodiments, the actuator mechanically displaces the piston relative to the container to dispense a predetermined desired amount of liquid medicine through the ejection port for aerosolization by the aerosol generator. The actuator may include an adjustable metering mechanism operable to only allow the piston to be repositioned a selectable amount relative to the container to dispense a selectable dose of the liquid medicine.

In many embodiments, the atomization system includes a control system for controlling various aspects of the atomization system. For example, the control system may include one or more processors and a tangible memory storing non-transitory instructions that, when executed by the one or more processors, cause the one or more processors to control an actuator to complete a priming cycle, wherein the actuator repositions a piston relative to a container until a droplet of liquid medication is ejected from an ejection orifice. The instructions may be configured to cause the one or more processors to determine that a droplet of liquid medication has been ejected from the ejection orifice by detecting when a vibratable member has been wetted by a droplet of the ejected liquid medication.

A self-puncture liquid medicine box and a related inhaler are also provided. In many embodiments, the liquid medicine box comprises a liquid medicine container and a needle assembly that is connected to this container. When the liquid medicine box is inserted into the related inhaler, the hollow needle of the needle assembly pierces the liquid medicine box, forming a fluid path thus, utilizing this fluid path the liquid medicine in the container interior can be sprayed so that it is atomized by the inhaler. In many embodiments, the liquid medicine box and the related inhaler are particularly suitable for atomizing the insulin of dosage so that pulmonary administration. This self-puncture liquid medicine box generally provides a convenient method for liquid medicine to be provided to an aerosol generator. In many embodiments, the combination of the liquid medicine box and the related inhaler provides improved dosage control and improved microbial growth inhibition between administrations.

Therefore, in one aspect, a self-puncturing liquid medication cartridge is provided. The liquid medication cartridge includes a container for storing a liquid medication, a septum configured to seal a first end of the container, a needle assembly coupled to the first end of the container, and a piston configured to seal a second end of the container. The needle assembly includes a hollow needle and is repositionable between a first configuration in which the hollow needle does not extend through the septum and a second configuration in which the hollow needle extends through the septum. The piston is repositionable relative to the container to selectively eject a volume of liquid medication from the container through the hollow needle.

In many embodiments, the needle assembly includes a cover configured to couple the needle assembly to the container. For example, the cover can include a receiving groove shaped to receive and hold the end of the container (e.g., utilizing a surface with a complementary shape that provides a snap connection between the cover and the container end). In many embodiments, the cover includes a hole configured to accommodate the movement of a portion of the hollow needle and the hollow needle during the resetting of the needle assembly from a first configuration to a second configuration. In many embodiments, there is an elastomeric seal disposed between the cover and the container end. The elastomeric seal prevents liquid from leaking out of the container and prevents the entry of microorganisms and other contaminants.

In many embodiments, the needle assembly includes a guide element. The guide element can be configured to support the hollow needle in a fixed position and orientation relative to the guide element. The guide element can be configured to guide movement of the hollow needle relative to the container during resetting of the needle assembly from a first configuration to a second configuration. The guide element can include a receiving groove configured to receive a lid and a portion of the container and engage with at least one of the lid and a portion of the container to limit relative movement between the container and the guide element to translational movement parallel to that of the hollow needle. In many embodiments, an end of the hollow needle, from which the liquid medication is ejected, protrudes a predetermined, controlled distance from an end face of the guide element.

In many embodiments, the needle assembly includes a spring element for biasing the needle assembly into a first configuration without causing displacement of the container relative to the guide element. For example, the needle assembly can include a coil spring disposed within the guide element receiving slot and between an end wall of the guide element receiving slot and the needle assembly cover. Without causing displacement of the container and cover relative to the guide element receiving slot, the spring is in an undeformed configuration and the needle assembly is in a first configuration in which the hollow needle does not extend through the septum. By further displacing the container and cover into the guide element receiving slot, the spring can be sufficiently compressed to reset the needle assembly into a second configuration in which the hollow needle extends through the septum, thereby providing a fluid pathway for ejecting liquid drug from the container through the hollow needle from the liquid drug cartridge.

In many embodiments, the guide element includes a structure to prevent the spring from pushing the guide element away from the cover. For example, the guide element may include a protruding structure on the inner surface of the guide element that slides in a groove located on the outer surface of the cover. The groove can be further configured to have the shape of a capital letter "L" so that it is locked in the first configuration for shipping. The patient will be asked to twist the guide element before use to unlock it and allow the protruding structure to slide in the axial direction of the cover. Alternatively, the two ends of the spring can be mechanically fixed to the guide element and the cover to provide a holding force between these components. In many embodiments, the spring maintains a constant and specific distance between the outlet of the needle and the back side of the aerosol generating net, thereby preventing contact between the needle and the net but still being tight enough to transfer droplets to the net.

In many embodiments, the hollow needle is coated to prevent microorganisms from entering the hollow needle and the container. For example, the needle can be coated with silver to inhibit microbial growth and/or entry. As another example, the self-piercing liquid drug cartridge can include a filter configured to inhibit microorganisms from entering the container.

In another aspect, an aerosolization system is provided. The aerosolization system may include any of the self-puncturing liquid medication cartridge embodiments described herein, a housing defining a mouthpiece, an aerosol generator disposed within the housing, and an actuator configured to reposition a piston of the liquid medication cartridge relative to a container so as to dispense a dose of liquid medication to the aerosol generator via a hollow needle. The housing includes a receptacle configured to at least partially receive the cartridge and engage with a needle assembly to reposition the needle assembly from a first configuration to a second configuration during insertion of the cartridge into the receptacle. The aerosol generator includes a vibrating membrane having a front and back surface and a vibrating element for vibrating the membrane. The actuator is configured to reposition the piston relative to the container so as to dispense a dose of medication via the hollow needle to the back surface of the vibrating membrane. The system may be configured so that the liquid medication cartridge can be removed at any time, thereby enabling more thorough cleaning of the dispenser. When the liquid medication cartridge is equipped with a removable lid, the lid and the receptacle for receiving the liquid medication cartridge may be configured so that the liquid medication cartridge cannot be inserted into the receptacle until the lid is removed from the liquid medication cartridge.

In many embodiments, the housing is configured to provide a mixture of air and aerosolized liquid medicine for inhalation by the user. For example, the housing may include: a mixing chamber in fluid communication with the front of the vibrating membrane and the mouthpiece, and one or more air inlets in fluid communication with the mixing chamber and configured to introduce air into the mixing chamber in response to the user's inhalation via the mouthpiece. The system may also include an air flow restrictor array having a greater resistance to air flow than the one or more air inlets and placing the mixing chamber in fluid communication with the one or more air inlets. In many embodiments, the restrictor array includes a plurality of orifices arranged in an annular arrangement. In many embodiments, the air flowing through the mixing chamber in response to the user's inhalation via the mouthpiece is laminar and surrounds a dose of medicine aerosolized using the vibrating membrane, thereby preventing contact between the aerosolized medicine and the surrounding surfaces of the mixing chamber. The system may include a pressure port connected to a pressure sensing sensor system for detecting patient inhalation.

The vibratable mesh may be coupled to the housing to improve the efficiency of the aerosol generator.For example, the vibratable mesh may be coupled to the housing via a suitable isolator member (eg, an elastomeric isolator).

The system can include an ultraviolet light source to provide microbial control between dosings. For example, one or more ultraviolet light sources can be used to irradiate a chamber in the housing that is disposed between the back of the vibratory member and the box and into which the drug is ejected from the liquid drug box via a hollow needle.

In many embodiments, the housing is configured to keep the liquid medicine box inside the accommodating tank. Any suitable method can be utilized to keep the liquid medicine box inside the accommodating tank. For example, the housing can be configured to form a pressurized container that holds the liquid medicine box. The actuator can be configured to apply pressure to the container so that the piston is repositioned relative to the container so that a dose of medicine is distributed to the back side of the film via a hollow needle. The injection of air into the container can be controlled so that the liquid medicine of a predetermined desired amount is distributed via a hollow needle so that it is atomized by an aerosol generator. For example, the piston can be arranged to be slightly lower than the end of the container, so as to form a space that can be pressurized by sealing and abutting the end of the container or the inner wall of the container. As another example, the piston can be hollowed out on a side opposite to the liquid medicine, so as to form a space that can be pressurized. When distributing liquid, this pressurized space will increase. The removal (emptying) of air pressure can be used to immediately stop the further movement of the piston until air pressure is reapplied.

In many embodiments, the actuator mechanically displaces the piston relative to the container to dispense a predetermined desired amount of liquid medicament via the hollow needle for aerosolization by the aerosol generator. The actuator may include an adjustable metering mechanism operable to allow only a selectable amount of repositioning of the piston relative to the container to dispense a selectable dose of the liquid medicament.

In many embodiments, the atomization system includes a control system configured to control various aspects of the system. For example, the control system may include one or more processors and a tangible memory storing non-transitory instructions that, when executed by the one or more processors, cause the one or more processors to control an actuator to complete a priming cycle, wherein the actuator repositions a piston relative to a container until a droplet of liquid medication is ejected from the hollow needle. The instructions can be configured to cause the one or more processors to determine that a droplet of liquid medication has been ejected from the hollow needle by detecting when a vibratory member has been wetted by the ejected droplet of liquid medication.

BRIEF DESCRIPTION OF THE DRAWINGS

1 is a cross-sectional view of a liquid medicine cartridge, in accordance with many embodiments.

2 is a cross-sectional view illustrating an inhaler into which a drug cartridge may be inserted, in accordance with many embodiments.

3 is a cross-sectional view illustrating the drug cartridge of FIG. 1 inserted into the inhaler of FIG. 2 and held by an end member, and liquid drug ejected from the liquid drug cartridge being aerosolized for inhalation by a user, in accordance with many embodiments.

4 is an end view illustrating the flow restriction orifice array of the inhaler of FIG. 2 , in accordance with many embodiments.

5 is a simplified schematic diagram illustrating components of an inhaler for receiving liquid medication from a medication cartridge, in accordance with many embodiments.

6 is a cross-sectional view of another liquid medicine cartridge, in accordance with many embodiments.

7 is a cross-sectional view of a liquid medication cartridge including a one-way valve, in accordance with many embodiments.

8 is a cross-sectional view illustrating the drug cartridge of FIG. 7 inserted into the inhaler of FIG. 2 , and liquid drug ejected from the cartridge being aerosolized for inhalation by a user, in accordance with many embodiments.

9 is a side view, partially in cross-section, of a self-piercing liquid medication cartridge, in accordance with many embodiments.

10 is a partial cross-sectional side view of a removable cover coupled to an end of the medication cartridge of FIG. 9 , in accordance with many embodiments.

11 is a side view illustrating the medication cartridge of FIG. 9 partially inserted into the inhaler of FIG. 2 , in accordance with many embodiments.

12 is a side view illustrating the medication cartridge of FIG. 9 inserted into the inhaler of FIG. 2 to a depth sufficient to cause the hollow needle to penetrate through the septum, thereby forming a fluid passage for ejecting liquid medication from the cartridge, in accordance with many embodiments.

13 is a side view illustrating the drug cartridge of FIG. 9 fully inserted into the inhaler of FIG. 2 and retained by the end member, with liquid drug ejected from the cartridge being aerosolized for inhalation by a user, in accordance with many embodiments.

14 is a side view of another self-piercing liquid medication cartridge partially inserted into the inhaler of FIG. 2 , in accordance with many embodiments.

15 is a side view illustrating the self-piercing liquid medication cartridge of FIG. 14 inserted into the inhaler of FIG. 2 to a depth sufficient to cause the hollow needle to penetrate through the septum and into the filter, thereby forming a fluid pathway for ejecting the liquid medication from the cartridge, in accordance with many embodiments.

DETAILED DESCRIPTION

Liquid medicine cartridges and related inhalers are described herein. In many embodiments, a liquid medicine cartridge containing a pharmaceutical formulation is inserted into a dispenser until the cartridge contacts a protruding stop of the dispenser. In many embodiments, continuous dispensing of the pharmaceutical formulation and dispensing of very small and very large doses from the same cartridge are possible.

The liquid medicine cartridge can be biased into contact with the mating surface of the inhaler to ensure accurate and tight positioning of the jet port relative to the vibratory membrane of the inhaler so that when liquid medicine droplets are dispensed via the jet port, surface tension will cause the droplets to adhere to the vibratory membrane, even when the inhaler is in a horizontal orientation. This adherence is controlled by the distance between the jet port and the vibratory membrane, the internal diameter of the jet port, and the geometry of the jet port in which the droplets are present.

The membrane vibrates to produce an aerosol and causes a pumping action, which pulls the droplets away from the jet orifice and through the membrane. At the end of the administration, there are no residual droplets to be atomized due to the pumping action of the membrane. In many embodiments, the vibrating membrane is coupled to the housing of the inhaler using elastic vibration isolators to maximize the efficiency of aerosol generation.

In many embodiments, when a patient inhales, air flows through the air inlet into the shunt tube and then through the restrictor array. This air flow delivers the aerosol to the patient. In many embodiments, the air inlet has a significantly smaller resistance than the restrictor array. A pressure port and an associated pressure sensor may be included to detect the patient's inhalation intensity.

The liquid drug cartridge can be configured to prevent microorganisms from entering the liquid drug container. For example, the end cap can include a conduit that is coated (e.g., with silver) to prevent microorganisms from entering the conduit and the liquid drug container. In many embodiments, after dispensing a dose, there is no reverse flow back into the container (i.e., any drug in the conduit comes into contact with the antimicrobial coating to inhibit the proliferation of pathogens). The liquid drug cartridge can include a filter configured to prevent microorganisms from entering the container.

The liquid medicine box is configured to prevent an unexpected needle stick from occurring to the user. For example, the ejection port can be integrally formed into the end cap to avoid the use of a needle. A removable protective cover can be used to prevent the ejection port from being damaged and contaminated. The shape of the protective cover can be designed so that the liquid medicine box cannot be inserted into the inhaler until the protective cover is removed.

The liquid medication cartridge includes a piston slidably disposed within the container for dispensing the liquid medication without introducing air. This feature improves the physical stability of the medication product, supports horizontal use of the liquid medication cartridge, and maintains the container in a sealed configuration for consistent dosing.

Can adopt any suitable method for actuating piston.For example, can be by seal being added between end member and the housing of inhaler and air driven piston, perhaps can utilize the actuating mechanism that is connected with end member or make it through end member and mechanically drive piston.

The pre-fill cycle can be used to eject air from the container and/or the ejection port. For example, after a liquid medicine cartridge is loaded into a relevant inhaler, a mechanical plunger can be brought into contact with a piston and pushed until droplets of the formulation are dispensed. This can be sensed by the aerosol generator software, which can be used to detect the difference between a damp vibrating membrane and a dry vibrating membrane.

The inhaler may include additional microbial control features. For example, a violet lamp may be added to the chamber where the droplets are ejected from the ejection port, thereby providing additional microbial control between doses.

Liquid medicine box and inhaler can be configured to make and can at any time liquid medicine box be taken out and inserted.For example, can at any time liquid medicine box be taken out thereby improve accessibility so that cleaning inhaler.In many embodiments, the reinsertion of liquid medicine box has caused starting cycle.

In many embodiments, inhaler comprises: limit and distribute outlet housing, have the front that exposes at the outlet and be used to receive the back side that is distributed liquid but vibrating film and be connected to housing and operationally make film vibrate thereby distribute the aerosol of liquid through film.Utilize liquid delivery system that metered amount of liquid is delivered to the back side of film.Like this, reach the operating period that enough makes the metered amount of liquid that is delivered to the back side of vibrating member be atomized fully by operating vibrating mechanism, can distribute the liquid of metered amount at the outlet.

An advantage of this device is that it is convenient to distribute the liquid that contacts with the back side of film substantially whole in the form of single dose, particularly when the volume of the dosage of metering is relatively small.By distributing whole dosage, from one-time administration to next administration, there is basically no liquid on the film.Like this, can avoid contact between liquid and the surrounding air during the non-use period between using successively thus.This is especially important for pharmaceutical preparation, because this can get rid of the needs of using preservative in liquid and avoid evaporation loss.For example, spendable various preservative-free insulin preparations comprise U.S. patent application the 13/004th, No. 662nd, called " preservative-free insulin preparation and for the system and method of atomizing " and U.S. provisional patent application the 62/120th, No. 573, called " liquid insulin preparation ", and the full content of each patent application is incorporated herein by reference.

Such a device is particularly useful for administering inhaled pharmaceutical liquid products which require a fine aerosol of the liquid to be entrained in the inhaled air stream passing through the mouthpiece. An example of such a liquid is an insulin composition.

In many embodiments, the liquid drug box is a multi-dose box. For example, the liquid drug box can hold enough medicine for 1 day, 1 week or 1 month of treatment. The volume of the dose dispensed from the liquid drug box can be controlled by any suitable method (for example, by the positioning of the piston). The motion position of the piston can be set by an external controller. For example, the piston can be moved in sufficiently small increments to eject a very small volume of liquid (for example, 10 μL of liquid) or a large volume of liquid (for example, 1000 μL of liquid), thereby delivering a small or large amount of medicine. After administration, the position of the piston can be maintained in a fixed position until future administration is needed. In order to distribute subsequent doses, the piston can be moved through the rear position to deliver another dose until the drug box is empty.

Turning now to the drawings, wherein like reference numerals refer to like components, FIG1 illustrates a liquid medicine cartridge 10 according to many embodiments. The liquid medicine cartridge 10 includes a container assembly 12, an end cap assembly 14, and a filter 16.

The container assembly 12 is configured to store liquid medication for subsequent dispensing into an inhaler. The container assembly 12 includes a container 18 having openings at two opposing ends of the container 18. An end cap assembly 14 seals a first end of the container 18. A piston 20 seals a second end of the container 18. The piston 20 selectively slides within the container 18 to eject a selected amount of liquid medication from the container 18.

The end cap assembly 14 has an ejection port 22 from which liquid medicine is ejected. In many embodiments, the end cap assembly 14 is configured so that the ejection port 22 is located at the end of the protrusion of the end cap assembly 14 and is located in a precise position relative to the docking surface 24 of the end cap assembly 14.

The end cap assembly 14 comprises an end cap body 26, a conduit 28, and a removable lid 30. The lid 30 can be used to provide a microbial barrier before the first use of the box. The microbial barrier can be achieved by sealing and abutting the end cap assembly 14, or by merging the lid 30 with the lid assembly 14 into a whole that separates when the lid is disassembled. The end cap body 26 can be made of a suitable material (e.g., a suitable elastic material), and its shape is designed to dock with the end of the container 18 with a complementary shape. In the illustrated embodiment, the conduit 28 is a cylindrical metal member with a suitable inner diameter. For example, the inner diameter of the conduit 28 can be selected to be large enough to allow the controlled flow of the liquid drug when the piston is controllably displaced relative to the container 18, but small enough to stop the flow of the liquid drug when there is no piston 20 relative to the movement of the container 18.

The filter 16 is used to filter the liquid medicine ejected from the container 18 before passing through the conduit 28. In the illustrated embodiment, the filter 16 has a cylindrical body made of a suitable filter material. For example, a sintered polyethylene filter with a pore size of 0.2 to 100 μm, or a film made of nylon, PTFE, polypropylene or other materials compatible with the liquid medicine 10. This filter can be designed to be similar to a syringe filter. The controlled movement of the piston 20 relative to the container 18 causes the liquid medicine in the container to flow through the filter 16. After passing through the filter 16, the liquid medicine is discharged through the conduit 28 and then through the injection port 22. The filter 16 can be configured to prevent the liquid medicine from flowing into the conduit 28 without the movement of the piston relative to the container 18.

Fig. 2 shows a cross-sectional view of an inhaler 40 according to many embodiments, that is configured to use medicine box 10. Inhaler 40 comprises housing 42 and an aerosol generator 44 that is assembled to housing 42 via vibration isolator 46. Housing 42 forms an accommodating groove 48 that is configured to slidably accommodate medicine box 10. The inner surface 50 of accommodating groove 48 is configured to dock with the outer surface of box 10 so that medicine box 10 is limited to sliding translation relative to accommodating groove 48. The docking surface 24 of end cap assembly 14 contacts with the protruding stop 52 of inhaler 40, thereby ejection port 22 is positioned in a fixed position relative to aerosol generator 44.

The aerosol generator 44 comprises a vibratable membrane having a front face 54 exposed to a mixing chamber 72 and a back face 58 which, in use, contacts liquid ejected from the cartridge 10. The aerosol generator 44 is mounted to the housing 42 via a vibration isolator 46 and is operable to dispense an active agent in the form of an aerosol through a mouthpiece 60. Exemplary aerosol generators that can be used are also described in U.S. Patents 5,164,740, the contents of which are incorporated herein by reference. These references have described exemplary aerosol generator, the method for making this aerosol generator and the method that liquid is provided to aerosol generator, and are incorporated herein by reference for at least these features.This aerosol generator can comprise the vibrating film with tapered hole, the size of this tapered hole is in the scope of about 3 meters to about 8 meters, preferably about 3 meters to about 6 meters, is about 4 meters in some cases.Film can have dome shape and utilize the annular piezoelectric element 45 circumscribed with hole to make it vibrate.The diameter of film can be in the scope of about 5mm to about 8mm.Film also can have the thickness in the scope of about 50 microns to about 70 microns.Usually, film will vibrate with the frequency in the scope of about 50kHz to about 150kHz.

3 shows the drug cartridge 10 installed in the inhaler 40. The end member 66 holds the drug cartridge 10 to maintain contact between the docking surface 24 of the end cap assembly 14 and the protruding stop 52 of the inhaler 40, thereby precisely controlling the position of the ejection port 22 relative to the back surface 58 of the vibratable membrane.

The inhaler 40 can include a suitable actuator for displacing the piston 20 relative to the container 18 to thereby eject a desired preselected dose of liquid medicament from the container 18 through the injection port 22. For example, the end member 66 and the housing 42 can form a pressurizable container into which air can be injected to displace the piston 20 toward the injection port 22. As another example, the piston 20 can be controllably displaced toward the injection port 22 using an actuation mechanism coupled to or acting through the end member 66.

In use, a user inhales through the mouthpiece 60 and the aerosol generator 44 simultaneously aerosolizes a dose of liquid medicament which is ejected from the ejection port 22 in response to actuation of the piston 20. The housing 42 includes one or more air inlets 68 and a restrictor array 70 by which air is directed into a mixing chamber 72 for mixing with the aerosolized dose of liquid medicament before being inhaled by the user.

FIG4 shows an end view of a restrictor array 70 comprising an annular array of orifices 74. The size of the orifices 74 is designed so that the user inhales in a sufficient period of time so that the liquid drug dose is properly atomized. In many embodiments, one or more air inlets 68 have a significantly smaller resistance to air flow than the restrictor array 70. In many embodiments, the restrictor array 70 is configured to generate a laminar air flow surrounding the formed atomized liquid drug flow, thereby preventing or even substantially preventing contact between the atomized drug and the mixing chamber 72 surface.

In many embodiments, the inhaler 40 includes an ultraviolet light source for irradiating at least a portion of the chamber into which the liquid medication is ejected by the ejection end of the hollow needle 316. The ultraviolet light source can be used to provide enhanced microbial control, for example, during the period between dosing.

In many embodiments, the inhaler 40 includes a pressure port 78 that is coupled to a pressure sensing system to detect the patient's inhalation. For example, the pressure sensor can be used to determine when the patient begins to breathe, thereby activating the aerosol generator, and when the patient stops breathing, thereby suspending aerosol generation, to prevent waste, maximize dosage efficiency, and maintain constant delivery.

Fig. 5 shows the simplified schematic diagram of each component of inhaler 40.Inhaler 40 comprises control electronics 80, input/output device 82, aerosol generator 44, inhalation intensity monitoring system 84, ultraviolet light source 86, piston actuation system 88, one or more batteries 90 and/or external port 92.Control electronics 80 operationally couples with input/output device 82, aerosol generator 44, inhalation intensity monitoring system 84, ultraviolet light source 86, piston actuation system 88, one or more batteries 90 and/or external port 92.

Any suitable configuration of the control electronics 80 may be employed. For example, in the illustrated embodiment, the control electronics 80 includes one or more processors 94 and tangible memory 96. The memory 96 may include read-only memory (ROM) 98 and/or random access memory (RAM) 100. The memory 96 stores instructions that, when executed by the one or more processors 94, cause the processors to control the operation of the various subsystems of the inhaler 40.

For example, these instructions can be used to cause the control electronics 80 to receive input from the user via the input/output device 82 regarding the desired dose of liquid medicine dispensed by the inhaler 40. The control electronics 80 can receive a signal from the inhalation intensity monitoring system 84 that is an indication that the user has inhaled via the inhaler 40. In response to the signal indicating that the user has inhaled, the control electronics can cause the actuation system 88 to eject a dose of liquid medicine to the aerosol generator 44 and cause the aerosol generator 44 to atomize the ejected dose while the patient is inhaling, in response to the signal indicating when the patient has stopped inhaling. The control electronics can be configured to stop aerosol generation.

Any suitable configuration of input/output device 82 may be used. For example, input/output device 82 may include input keys and a display device (eg, an LCD screen and/or one or more indicator lights).

The inhalation monitoring system 84 may include a pressure sensor operably coupled to the pressure port 78. The pressure sensor outputs a signal indicative of the pressure at the pressure port 78 to the control electronics 80. The control electronics 80 may be configured to monitor the pressure signal from the pressure sensor to detect a decrease in pressure associated with air flow through the inhaler due to an inhalation by the user.

The UV light source 86 can be energized periodically for any suitable length of time to provide microbial control between doses. The UV light source can be selected to provide a spectrum with an appropriate wavelength to kill microorganisms. For example, the control electronics 80 can be configured to energize the UV light source 86 according to a predetermined schedule after the administration of any particular dose.

One or more batteries 90 can be connected to the various subsystems of the inhaler in any suitable manner. For example, one or more batteries 90 can be directly wired to any specific subsystem with control electronics 80 to control the associated switches for controlling the power provided from one or more batteries 90 to that specific subsystem. One or more batteries 90 can be replaceable and/or rechargeable.

In embodiments where one or more of the batteries 90 are rechargeable, recharging may be accomplished via the external port 92. The external port 92 may also be used to transmit data to and/or from the control electronics 80, such as program instructions and/or operating parameters for operational control of the inhaler 40, and/or inhaler usage data that is output to an external system for review and/or analysis.

The inhaler 40 can be operated to deliver a metered amount of liquid medicine from the cartridge 10 to the back 58 of the vibratable membrane 64. Thus, for each use, a metered amount of aerosolized medicine can be dispensed at the mouthpiece 60 outlet by operation of the aerosol generator 44.

Box 10 holds the reservoir of active agent, and can dispense the medicament of predetermined dose from this reservoir.For example, about 80 to about 120 microlitre dosage of insulin.The lower limit is generally at least about 15 microlitres, and the upper limit is generally about 1,000 microlitres to about 2,000 microlitres.A particularly useful scope is about 80 microlitres to about 120 microlitres and concentration is about 100 insulin units/ml or larger, more preferably between about 200-800 units/ml, and up to 2,500 units/ml in some cases.

The conduit 28 provides a fluid passage for the liquid drug to the vibratable membrane 64. The injection port 22 is located very close to the back surface 58 of the vibrating membrane 64. Typically, the injection port 22 will be located less than 5 mm, more preferably less than 2 mm, from the back surface 58. The conduit 28 can be made of, for example, a 316 type stainless steel alloy having a gage size ranging from 22 gage to 26 gage.

When box 10 was installed in inhaler 40, thereby indicator light can start to flash and tell the patient that inhaler 10 is ready to use. At any time immediately thereafter, the patient can inhale through mouthpiece 60. Patient inhalation is detected by flow sensor. Detecting that the patient inhales causes the startup of aerosol generator 44 to produce the aerosol particles that enter mixing chamber 72. Aerosol is entrained in the inhaled air flow and flows to the patient's lung via the respiratory system. When full dose was atomized (one or more breaths can be adopted), thereby " end of administration " indicator light can light up for the second time and tell the patient that full dose has been delivered. When at least about 95% dosage, more preferably 98%, most preferably greater than 99% dosage was delivered, realize the delivery of full dose. In order to receive this dosage, the patient can adopt several inhalations or single inhalation based on the volume of the liquid medicine that is delivered to vibrating membrane 64 and the patient's vital capacity. Each inhalation should be a deep breath to guarantee that aerosol reaches the deep part of the lung.

Inhaler can be configured to adapt to the cleaning and/or sterilization of the chamber into which the vibrating membrane and/or box 10 will eject liquid medicine. Inhaler can include vent and/or discharge structure, so that cleaning fluid (for example, water or any suitable fluid) can be introduced into or discharged from the chamber into which the medicine box 10 will eject liquid medicine. Control electronics can be sealed in one or more separate chambers to avoid contact with cleaning fluid. Cleaning boxes containing cleaning fluid (for example, water or any suitable fluid) can be installed occasionally to clean the net. If someone attempts to inhale water vapor, pressure sensing can be reversed thereby inhaler is closed. There can be a "soaking" mode in which water droplets are allowed to be located on the net and have occasional vibrations, for example thereby providing alternate soaking, cleaning, soaking, cleaning cycles. A simpler construction will adopt a plastic funnel with a small opening at the top so that the patient will insert this plastic funnel into the box groove and drip water into the inhaler. This small opening can be used to limit the amount of water to slowly dripping.

Fig. 6 shows another kind of liquid medicine box 110 that can be used in inhaler (for example, inhaler 40) according to many embodiments.This medicine box 110 comprises container 112, filter 16, end cap 114 and detachable cover 116.End cap 114 has the projection 118 that fluid conduit 120 and jet port 22 are provided, and liquid medicine is sprayed into the back side 58 of vibratory membrane 64 by this fluid conduit and jet port.As fluid conduit 28, the inside diameter of conduit 120 can be selected to: be big enough to allow the controlled flow of liquid medicine when controllably making piston 20 relative to container 112 displacements, but still be small enough to stop the flow of liquid medicine when piston 20 does not move relative to container 112.Can be coated (for example, with silver) to suppress microorganism to enter box 110 to the inside of conduit 120.

FIG7 illustrates another liquid medication cartridge 210 according to many embodiments. This medication cartridge 210 is similar in construction to medication cartridge 10, but in addition to the container assembly 12 and end cap assembly 14 described herein with respect to medication cartridge 10, it also includes a one-way valve 212. Although not included in the illustrated embodiment, the liquid medication cartridge 210 may also include a filter cartridge, such as the filter cartridge of medication cartridge 10. For example, one or more filters identical to or similar to filter 16 may be positioned upstream of the one-way valve 212 and/or downstream of the one-way valve 212.

In many embodiments, the one-way valve 212 is used to provide a physical barrier to prevent microorganisms from entering the liquid drug stored inside the container 18. Any suitable structure can be used for the one-way valve 212 to ensure that only the liquid drug flows from the container 18 to the conduit 28 in one direction. For example, the one-way valve 212 can be a duckbill valve or a mechanical valve, such as a spring-loaded ball valve. The opening and closing of the one-way valve 212 can be controlled by the pressure inside the container 18 generated by the actuation of the piston 20, as described herein. The one-way valve 212 can be mechanically actuated and/or electrically actuated. Exemplary suitable one-way valve structures that can be used are described in U.S. Patents 5,759,101 and 6,089,260, and U.S. Patent Applications 2015/0048119 and 2012/0041381; the entire disclosures of these patent documents are incorporated herein by reference.

8 shows the cartridge 210 installed in the inhaler 40. The end member 66 holds the cartridge 210 to maintain contact between the docking surface 24 of the end cap assembly 14 and the protruding stop 52 of the inhaler 40, thereby precisely controlling the position of the ejection port 22 relative to the face 58 of the vibratable membrane.

As described herein, in many embodiments, the inhaler 40 is configured to controllably displace the piston 20 relative to the container 18. The displacement of the piston 20 relative to the container 18 can be used to increase the internal pressure of the container 18 to open the one-way valve 212, thereby ejecting a desired preselected dose of liquid medicine from the container 18 through the ejection port 22 for inhalation by the user, as described herein.

Self-piercing liquid medication cartridge

Also described herein are embodiments of self-puncture liquid medicine boxes. In many embodiments, the self-puncture liquid medicine box that will hold pharmaceutical preparation is inserted in the distributor, until the guide element of box contacts with the protruding stopper of distributor. When box is further inserted in the distributor, the lid of liquid medicine box and container assembly slide in the guide element inside and abut the sharp end of the hollow needle of medicine box. Thereby the hollow needle pierces the septum and forms fluid path, thereby this fluid path is used for liquid medicine to be ejected from the container of medicine box and is atomized by inhaler so that is sucked by the user. In many embodiments, the continuous distribution of preparation and from same box, distributing very little and very large dosage are feasible.

The medicine box comprises a spring, and this spring guarantees that the guide element keeps contacting with the protruding stop portion and is kept by the end member of the inhaler after the medicine box is fully inserted into the inhaler. The protruding stop portion provides the accurate and tight positioning of the hollow needle with respect to the vibratory membrane of the inhaler, so when dispensing the drop of liquid medicine via the hollow needle, surface tension makes the medicine drop adhere to the vibratory membrane, even when the inhaler is in the horizontal direction. This attachment is controlled by the distance between the hollow needle and the vibratory membrane, the internal diameter of the hollow needle and the geometry of the hollow needle that wherein has the drop.

The membrane vibrates to generate the aerosol and causes a pumping action, thereby pulling the droplets away from the hollow needle and through the membrane. At the end of the dose, due to the pumping action of the membrane, no droplets remain to be atomized. In many embodiments, elastomeric vibration isolators are used to connect the vibrating membrane to the housing of the inhaler to maximize the efficiency of aerosol generation.

The hollow needle can be coated (e.g., with silver) to prevent microorganisms from entering the hollow needle and the liquid drug container. In many embodiments, after dispensing a dose, there is no reverse flow back into the container (i.e., any drug in the needle remains therein and contacts the antimicrobial coating to inhibit the proliferation of pathogens). The self-puncturing liquid drug cartridge can include a filter configured to prevent microorganisms from entering the container.

The liquid medication cartridge is designed to protect the user from accidental needle sticks. Only one end of the hollow needle is sharpened, and a guide element supports and surrounds the needle, preventing the sharp end from being exposed and oriented toward the septum. The exposed end of the needle is not sharp. A removable protective cap protects the exposed end of the needle from damage and contamination. The cap is shaped so that the cartridge cannot be inserted into the inhaler until the cap is removed.

The drug cartridge includes a piston slidably disposed within the container for dispensing the liquid drug without introducing air. This feature keeps the hollow needle submerged during dispensing, improves the physical stability of the drug product, supports horizontal use of the liquid drug cartridge, and maintains the container in a sealed configuration for consistent dosing.

Medicine box and inhaler can be configured to make and can take out and reinsert the liquid medicine box at any time.For example, can take out the liquid medicine box at any time to strengthen the path of cleaning inhaler.In many embodiments, the reinsertion of liquid medicine box causes the precharge cycle.In this embodiment, septum can be configured to be pierced repeatedly under the situation that does not affect the container sterility.

9 illustrates a self-puncturing liquid medication cartridge 310 , in accordance with many embodiments. The liquid medication cartridge 310 includes a container assembly 312 and a needle assembly 314 coupled to the container assembly 312 and including a hollow needle 316 .

Container assembly 312 is for storing liquid medicine so that be distributed to inhaler subsequently.Container assembly 312 comprises: the container 318 with the opening at two opposite ends of container 318, the septum 320 that the first end of container 318 is sealed and the piston 322 that the second end of container 318 is sealed.Thereby septum 320 is configured to be pierced by hollow needle 316 and forms the fluid path that can distribute the liquid medicine in container 318 inside to inhaler.Piston 322 can selectively slide in container 318 insides, thereby the liquid medicine of selected amount is ejected from container 318 via hollow needle 316.

Needle assembly 314 is repositionable between a first configuration (shown in FIG. 9 ) in which hollow needle 316 does not extend through septum 320 and a second configuration (see, e.g., FIG. 13 ) in which hollow needle 316 extends through septum 320. Needle assembly 314 includes hollow needle 316, cap 324, guide element 326, and spring 328. In the illustrated embodiment, cap 324 is configured to couple needle assembly 314 to container assembly 312. Needle assembly 314 and container assembly 312 may be coupled using any suitable means. For example, in the illustrated embodiment, cap 324 is configured to receive a first end portion of container assembly 312 and retain the received portion using complementary snap-fit structures between cap 324 and container assembly 312. Guide element 326 includes a receiving slot 330 configured to slidably receive and engage cap 324 and a portion of container assembly 312. The opposite ends of the spring 328 are respectively coupled to the end wall 332 of the receiving slot 330 and the cover 324. In a first configuration, the spring 328 is in an unbiased configuration and maintains the illustrated separation between the cover 324 and the end wall 332 of the receiving slot 330, thereby positioning the hollow needle 316 in the illustrated position relative to the septum 320. The guide element 326 has an outer surface 334 and an outer end wall surface 336.

Figure 10 shows a removable protective cap 362 coupled to the box 310. The protective cap 362 prevents damage and contamination to the hollow needle 316. The shape of the cap 362 is designed to prevent the box 310 from being inserted into the inhaler 40 unless the cap 362 is disassembled.

11 shows the cartridge 310 partially inserted into the inhaler 40. When the cartridge 310 is inserted into the receiving slot 48, the cartridge 310 remains in the first configuration in which the hollow needle 316 does not extend through the septum 320 until the end wall outer surface 336 contacts the protruding stop 52.

12 shows the cartridge 310 almost fully inserted into the inhaler 40. In the illustrated configuration, the guide element 326 is in contact with the protruding stop 52 and the container assembly 312 has been urged toward the guide element 326, thereby partially compressing the spring 328 and inserting the sharp end of the hollow needle 316 through the septum 320. The force of the spring 328 maintains the guide element 326 in contact with the protruding stop 52, thereby fixing the position of the ejection end of the hollow needle 316 relative to the vibratable membrane 64 of the aerosol generator 44.

Figure 13 shows the box 310 that is fully inserted in the inhaler 40.End member 66 is keeping box 310 and resisting the force that is applied to container assembly 312 by compressed spring 328.Compressed spring 328 keeps guide element 326 in contact with protruding stop 52, thus keeps the ejection end of hollow needle 316 in the preferred predetermined position relative to vibratory membrane 64.Although the sharp end of hollow needle 316 is illustrated as being positioned at the position of the significant distance that exceeds diaphragm 320 inner walls in Figure 13, the sharp end of hollow needle 316 is positioned at the position closer to diaphragm 320 thereby increase the amount of insulin that can be dispensed from liquid medicine box in many embodiments.

The inhaler 40 can include a suitable actuator for displacing the piston 322 relative to the container 318 to thereby eject a desired preselected dose of liquid medicament from the container 318 through the ejection end of the hollow needle 316. For example, the end member 66 and the housing 42 can form a pressurizable container into which air can be injected to displace the piston 322 toward the guide element 326. As another example, the piston 322 can be controllably displaced toward the guide element 326 by an actuating mechanism coupled to or acting through the end member 66.

In use, a user inhales through the mouthpiece 60 and the aerosol generator 44 simultaneously aerosolizes a dose of liquid medicament which is ejected from the discharge end of the hollow needle 316 by corresponding actuation of the piston 322. The housing 42 includes one or more air inlets 68 and a restrictor array 70 through which air is directed into a mixing chamber 72 for mixing with the aerosolized dose of liquid medicament before being inhaled by the user.

As an example, from puncture liquid medicine box can have the structure that is similar to box 310 shown in Figure 9, but without spring 328.In this structure, this box can be reset between the first configuration (first configuration that is similar to box 310 shown in Figure 9) that hollow needle 316 does not extend through septum 320 and the second configuration (second configuration that is similar to box 310 shown in Figure 13) that wherein hollow needle 316 extends through septum 320.For example, this box can comprise one or more locking structures (for example, one or more docking structures of guide element 326 and lid 324), and this structure maintained the liquid medicine box in the first configuration before being installed into inhaler.When medicine box is installed into inhaler, one or more locking structures can allow relative motion between guide element 326 and the lid 326 in response to the compressive force produced by the installation, thus liquid medicine box is reset to second configuration.In many embodiments without spring 328, after being reset to second configuration, liquid medicine box is in second configuration. In addition, when the drug box is in the second configuration, one or more additional locking structures of the docking (for example, one or more docking structures of the guide element 326 and the cover 324) can be used to maintain the guide element 326 in contact with the protruding stop portion 52, thereby maintaining the preferred predetermined position of the injection end of the hollow needle 316 relative to the vibratable membrane 64.

14 and 15 illustrate a self-piercing liquid medication cartridge 430 for use with inhaler 40, in accordance with many embodiments. Medication cartridge 430 includes container assembly 412, filter 416, septum 432, and needle assembly 434 coupled to container assembly 412 and including a hollow needle 436.

Container assembly 412 is configured to store liquid medicine so that is assigned to inhaler subsequently.Container assembly 412 comprises: the container 418 with the opening at two opposite ends of container 418, filter 416, the septum 432 that the first end of container 418 is sealed and the piston 420 that the second end of container 418 is sealed.Septum 432 is configured to be pierced by hollow needle 436 and forms fluid path, utilizes this fluid path the liquid medicine in container 418 insides to be assigned to inhaler.Hollow needle 436 can partly pierce filter 416, makes liquid medicine pass through filter 416 of at least a portion before entering hollow needle 436.Piston 420 can selectively slide in container 418 insides, thereby the liquid medicine of selected amount is ejected from container 418 via hollow needle 436.

Needle assembly 434 is repositionable between a first configuration (shown in FIG. 14 ) in which hollow needle 436 does not extend through septum 432 and a second configuration (see, e.g., FIG. 15 ) in which hollow needle 436 extends through septum 432. Needle assembly 434 includes hollow needle 436, cap 438, guide element 440, and spring 442. In the illustrated embodiment, cap 438 is configured to couple needle assembly 434 to container assembly 412. Needle assembly 434 and container assembly 412 may be coupled using any suitable method. For example, in the illustrated embodiment, cap 438 is configured to receive a first end portion of container assembly 412 and retain the received portion using complementary snap-fit structures between cap 438 and container assembly 412. Guide element 440 includes a receiving slot 444 configured to slidably receive and engage cap 438 and a portion of container assembly 412. The opposite ends of the spring 442 are respectively coupled to the end wall 446 of the receiving groove 444 and the cover 438. In a first configuration, the spring 442 is in an unbiased configuration and maintains the illustrated separation between the cover 438 and the end wall 446 of the receiving groove 444, thereby positioning the hollow needle 436 in the illustrated position relative to the septum 432. The guide element 440 has an outer surface 448 and an outer end wall surface 450.

14 shows the cartridge 430 partially inserted into the inhaler 440. When the cartridge 430 is inserted into the receiving slot 448, the cartridge 430 remains in the first configuration in which the hollow needle 436 does not extend through the septum 432 until the end wall outer surface 450 contacts the protruding stop 52.

Figure 15 shows the box 430 that is inserted into the inhaler 40 fully.In the illustrated configuration, guide element 440 contacts with the protruding stop 52, and container assembly 412 has been promoted towards guide element 440, and partially compressed spring 442 is inserted through diaphragm 432 of the pointed end of hollow needle 436 thus.The power of spring 442 keeps guide element 440 to contact with the protruding stop 52, and the ejection end of hollow needle 436 is fixed with respect to the position of vibrating membrane 64 of aerosol generator 44 thus.End member can be used for box 430 being remained on inhaler inside and antagonism is applied to the power of container assembly 412 by compressed spring 442.Compressed spring 442 keeps guide element 440 and the contact of protruding stop 52, keeps the ejection end of hollow needle 436 with respect to the preferred predetermined position of vibrating membrane 64 thus.

The inhaler 40 can include a suitable actuator for displacing the piston 420 relative to the container 418 to thereby eject a desired preselected dose of liquid medicament from the container 418 through the ejection end of the hollow needle 436. For example, the end member and the housing 42 can form a pressurizable container into which air can be injected to displace the piston 420 toward the guide element 440. As another example, the piston 420 can be controllably displaced toward the guide element 440 using an actuation mechanism coupled to or acting through the end member.

In use, a user inhales through the mouthpiece 60 and simultaneously the aerosol generator 44, by corresponding actuation of the piston 420, aerosolizes a dose of liquid medicament which is ejected from the ejection end of the hollow needle 436. The housing 42 includes one or more air inlets 68 and a restrictor array 70 which directs air into a mixing chamber 72 for mixing with the aerosolized dose of liquid medicament before being inhaled by the user.

Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the disclosure as set forth in the claims.

Other variations are within the spirit of the present disclosure. Thus, while the disclosed technology is susceptible to various modifications and alternative constructions, certain illustrative embodiments thereof are shown in the drawings and have been described in detail above. However, it should be understood that there is no intention to limit the present disclosure to the specific forms disclosed, but rather, the intention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the present disclosure as defined in the appended claims.

In the context of describing the disclosed embodiments (particularly in the context of the appended claims), the use of the terms "a" and "an" and "the" and similar referents in the context should be understood to include both the singular and the plural, unless otherwise specified herein or the context clearly indicates the contrary. The terms "comprise", "have", "include" and "contain" should be understood as open terms (i.e., meaning "including but not limited to"), unless otherwise specified. The term "connected" should be understood to mean partially or completely contained within, attached to, or connected together, even if there is something in between. The recitation of value ranges herein is intended to be used as a shorthand method of referring individually to each individual value falling within the range, unless otherwise specified herein, and each individual value is incorporated into this specification as if it were individually stated herein. All methods described herein can be performed in any suitable order, unless otherwise specified herein or the context clearly indicates the contrary. The use of any and all examples or exemplary terms (e.g., "for example") provided herein is intended to better illustrate the embodiments of the present disclosure rather than to limit the scope of the present disclosure, unless otherwise required. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

Disjunctive language, such as the phrase "at least one of X, Y, or Z," unless specifically stated otherwise, is intended to be understood in context as generally used to indicate that an object, term, etc. can be X, Y, or Z, or any combination thereof (e.g., X, Y, and/or Z). Thus, such disjunctive language is generally not intended and should not mean that certain embodiments require that at least one of X, at least one of Y, or at least one of Z each be present.

Preferred embodiments of the present disclosure are described herein, including the best mode for implementing the present disclosure known to the inventor. Variations of these preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that those skilled in the art will adopt such variations as appropriate, and it is the inventor's intention that the present disclosure may be implemented in a manner other than that specifically described herein. Therefore, the present disclosure includes all modifications and equivalents of the subject matter recited in the appended claims, as permitted by applicable law. In addition, any combination of the above-mentioned elements in all possible variations thereof is included in the present disclosure, unless otherwise noted herein or the context clearly indicates otherwise.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Claims (27)

1. A self-puncturing liquid medicine box comprising: Containers for storing liquid medications; a septum configured to seal the first end of the container; a needle assembly comprising a cap and a hollow needle, the cap coupled to a first end of the container, the needle assembly being repositionable between a first configuration in which the hollow needle does not extend through the septum and a second configuration in which the hollow needle extends through the septum, wherein the hollow needle moves relative to the cap during repositioning of the needle assembly between the first and second configurations, and wherein the cap has an aperture configured to accommodate a portion of the hollow needle and movement of the hollow needle relative to the cap during repositioning of the needle assembly from the first configuration to the second configuration; a piston sealing the second end of the container, the piston being repositionable relative to the container to selectively eject a volume of liquid drug from the container through the hollow needle; and A guide element, the guide element being configured to: supporting the hollow needle in a fixed position and orientation relative to the guide element; guiding movement of the hollow needle relative to the container during resetting of the needle assembly from the first configuration to the second configuration; and A receiving slot is defined, the receiving slot being configured to receive the cover and a portion of the container and to interface with at least one of the cover and the portion of the container to limit relative movement between the container and the guide element to translation parallel to the hollow needle. 2. The cartridge of claim 1 , wherein the needle assembly further comprises a spring element for biasing the needle assembly to the first configuration in the absence of displacement of the container relative to the guide element. 3. The cartridge according to claim 1, wherein one end of the hollow needle from which the liquid medicine is ejected protrudes from an end surface of the guide member by a predetermined controlled distance. 4. The cartridge of claim 3, further comprising a removable cover adapted to interface with the needle assembly and enclose the protruding end of the hollow needle. 5. The cartridge of any one of claims 1 to 4, wherein the hollow needle is coated to prevent microorganisms from entering the hollow needle and the container. The cartridge of claim 5 , wherein the hollow needles are coated with silver. 7. The cartridge of any one of claims 1 to 4, further comprising a filter configured to prevent microorganisms from entering the container. 8. The cartridge of any one of claims 1 to 4, wherein fluid is ejected from the cartridge in controlled doses by controlled movement of the piston. 9. The cartridge of claim 8, wherein the size of each of the controlled doses is set by an external controller. 10. The cartridge of claim 8, wherein the cartridge contains multiple doses of a drug, and the drug is deliverable from the cartridge in multiple individual doses. 11. A box as described in claim 2, wherein the cover has a proximal portion, the first end of the container is retained and received in the proximal portion using a complementary snap structure of the cover and the container, and the spring has a first end connected to the cover and a second end connected to the end wall of the guide element. 12. The cartridge of claim 11, wherein The hollow needle has a sharp end and a non-sharp end; In the first configuration, the spring is in an unbiased configuration and maintains separation between the cap and an end wall of the guide element such that the sharp end of the hollow needle does not extend through the septum; In the first configuration, the sharp end of the hollow needle is disposed in the hole of the cap; and In the second configuration, the spring is partially compressed such that the sharp end of the hollow needle extends through the septum. 13. An atomization system comprising: A box as claimed in any one of claims 1 to 12; a housing defining a mouthpiece, the housing including a receptacle configured to at least partially receive the cartridge and interface with the needle assembly to reset the needle assembly from the first configuration to the second configuration during insertion of the cartridge into the receptacle; an aerosol generator disposed in the housing and comprising a vibratable membrane having a front face and a back face, and a piezoelectric element for vibrating the vibratable membrane; An actuator is provided for repositioning the piston relative to the container to dispense a dose of the drug through the hollow needle to the back side of the vibratable membrane. 14. The system of claim 13, wherein the housing further comprises: a mixing chamber in fluid communication with the front face of the vibratable membrane and the mouthpiece; and One or more air inlets are in fluid communication with the mixing chamber and are configured to introduce air into the mixing chamber in response to inhalation by a user through the mouthpiece. 15. The system of claim 14, further comprising an array of air flow restrictors having a greater resistance to air flow than the one or more air inlets and placing the mixing chamber in fluid communication with the one or more air inlets. 16. The system of claim 15, wherein air flowing through the mixing chamber in response to user inhalation through the mouthpiece is laminar and surrounds a dose of medicament aerosolized through the vibratable membrane, thereby preventing contact between the aerosolized medicament and surrounding surfaces of the mixing chamber. 17. The system of claim 15, further comprising a pressure port connected to a pressure sensing system for detecting inhalation by a user. 18. The system of claim 15, wherein the air flow restrictor array comprises a plurality of orifices disposed in an annular arrangement. 19. The system of any one of claims 13 to 18, further comprising: one or more processors; a tangible memory storing non-transitory instructions that, when executed by the one or more processors, cause the one or more processors to control the actuator to reposition the piston relative to the container until a droplet of the liquid drug is ejected from the hollow needle. 20. The system of claim 19, wherein the instructions, when executed by the one or more processors, cause the one or more processors to determine that a drop of the liquid drug has been ejected from the hollow needle by detecting when the vibratable membrane has been wetted by the ejected drop of liquid drug. 21. The system of any one of claims 13 to 18, wherein the cartridge is configured to be removed to provide access for cleaning the system. 22. The system of any one of claims 13 to 18, wherein the receptacle is configured such that the cartridge cannot be inserted into the receptacle until a removable cover is removed from the cartridge. 23. The system of any one of claims 13 to 18, wherein the vibratable membrane is coupled to the housing via elastomeric isolators. 24. The system of any one of claims 13 to 18, further comprising an ultraviolet lamp for providing microbial control between administrations. 25. The system of any one of claims 13 to 18, wherein: The housing forms a pressurizable container; and The actuator applies pressure to the pressurizable container to reposition the piston relative to the container, thereby dispensing a dose of medication through the hollow needle to the back side of the vibratable membrane. 26. The system of any one of claims 13 to 18, wherein the actuator mechanically displaces the piston relative to the container to dispense a predetermined desired amount of the liquid drug through the hollow needle. 27. The system of claim 26, wherein the actuator further comprises an adjustable metering mechanism operable to allow only a measured amount of repositioning of the piston relative to the container to dispense a measured amount of the liquid drug.