WO2022219623A1

WO2022219623A1 - Nebulizer

Info

Publication number: WO2022219623A1
Application number: PCT/IL2022/050359
Authority: WO
Inventors: Miron Hazani
Original assignee: Omega Life Science Ltd.
Priority date: 2021-04-12
Filing date: 2022-04-06
Publication date: 2022-10-20

Abstract

The present disclosure relates substantially to the field of aerosol generation devices, and more particularly to a nebulizer.

Description

NEBULIZER

TECHNICAL FIELD

[0001] The present disclosure relates substantially to the field of aerosol generation devices, and more particularly to a nebulizing assembly and method.

BACKGROUND

[0002] Drug delivery systems for inhalable compositions are attracting interest for some time. In order to be absorbed and utilized effectively, many liquid drugs and liquid pharmaceutical compositions are required to transform into droplets with specified sizes. Nebulizers, such as ultrasonic nebulizers, are configured to convert liquid into small-diameter droplets.

[0003] Ultrasonic nebulizers use an oscillation signal to drive a piezoelectric oscillator to produce mechanical vibration. The resulting vibration is applied to an inhalable liquid to be nebulized for producing capillary waves thereon and droplets. Ultrasonic nebulizers are typically used for the administration of pharmaceutical compositions via inhalation or for other droplet/aerosol-producing applications. The typical oscillation frequency of a conventional ultrasonic nebulizer is 1.6 MHz or 2.4 MHz, resulting in a typical average/median of droplet- of 1.7-2.3 pm. [0004] Piezoelectric nebulizers are commonly constructed with a piezoelectric transducer submerged within liquid that is to be nebulized. For example, FIG. 1 illustrates a schematic diagram of a typical prior art nebulizer 10. Nebulizer 10 comprises: a liquid reservoir 20 containing liquid 30 and exhibiting an outlet 40; a piezoelectric transducer 50; and a power source 60. Piezoelectric transducer 50 is submerged within liquid 30 and is in electrical communication with power source 60. In one embodiment (not shown), liquid reservoir 20 further exhibits an inlet opening arranged to allow for injection of an inhalable composition(e.g., liquid 30 or drug to be dissolved therein) into liquid reservoir 20. In operation, power source 60 provides alternating-current (AC) power to piezoelectric transducer 50, thereby causing piezoelectric transducer 50 to vibrate at a predetermined frequency. The vibration of piezoelectric transducer 50 nebulizes liquid 30 into an aerosol which exits via outlet 40 and may be inhaled by a subject. Unfortunately, piezoelectric transducer 50 tends to suffer from overheating due to constant use (e.g., constant operation of the piezoelectric transducer 50 and power source 60). [0005] FIG. 2 illustrates a perspective view of an alternative nebulizing apparatus comprising a perforated plate 70, a circular piezoelectric transducer 80 and a power source 90. Perforated plate 70 is placed on a liquid reservoir or wicking mechanism which bring the liquid to the bottom of perforated plate 70. Power source 90 provides power to piezoelectric transducer 80 thereby vibrating perforated plate 70 at a predetermined frequency. The vibration of perforated plate 70 nebulizes the liquid into an aerosol which exits via the perforations of perforated plate. In order to avoid clogging of the perforations, perforated plate 70 is constructed such that the widths of the perforations are 10 - 20 microns, thus producing aerosol droplets of 10 - 20 microns. Unfortunately, in many cases, in particular for therapeutic purposes, smaller aerosol droplets are desired. [0006] What is desired, and not provided by the prior art, is a nebulizer capable of producing very small aerosol droplets, without overheating. In addition, it is desired, and not provided by the prior art, is a nebulizer capable of producing very small aerosol droplets of compositions comprising ingredients that are insoluble in water or that could be suspended in water or other organic solvents.

SUMMARY

[0007] Accordingly, it is a principal object of the present invention to overcome at least some of the disadvantages of prior art nebulizers. This is provided in one embodiment by a nebulizer comprising: a cartridge exhibiting a first end and a second end, the cartridge comprising: a first plate exhibiting a first face and a second face opposing the first face, the first plate positioned at the first end of the cartridge; a liquid reservoir containing liquid; a liquid drawing element arranged to draw the liquid from the liquid reservoir; a liquid deposition mechanism arranged to deposit the drawn liquid onto the first face of the first plate; and an outlet, and an actuator exhibiting a first end and a second end, the actuator comprising a first piezoelectric transducer, wherein the first end of the actuator is connectable to the first end of the cartridge, and wherein the second face of the first plate is in contact with the first piezoelectric transducer when the first end of the actuator is connected to the first end of the cartridge. According to some embodiments, there is provided a nebulizer comprising: a cartridge exhibiting a first end and a second end, the cartridge comprising: a first plate exhibiting a first face and a second face opposing the first face, the first plate positioned at the first end of the cartridge; a liquid reservoir containing liquid; a liquid drawing element arranged to draw the liquid from the liquid reservoir; and an outlet; a liquid deposition mechanism, which is at least partially disposed within the cartridge and arranged to deposit the drawn liquid onto the first face of the first plate; and an actuator exhibiting a first end and a second end, the actuator comprising a first piezoelectric transducer, wherein the first end of the actuator is connectable to the first end of the cartridge, and wherein the second face of the first plate is in contact with the first piezoelectric transducer when the first end of the actuator is connected to the first end of the cartridge.

[0008] According to some embodiments, the first piezoelectric transducer is positioned on the first end of the actuator. According to some embodiments, the first end of the cartridge exhibits an indent extending towards the first plate, the first piezoelectric transducer positioned within the indent when the first end of the actuator is connected to the first end of the cartridge. In another embodiment, the liquid drawing element is displaced from the first plate.

[0009] In one embodiment, the first piezoelectric transducer is positioned on the first end of the actuator, and wherein the first end of the cartridge exhibits an indent extending towards the first plate, the first piezoelectric transducer positioned within the indent when the first end of the actuator is connected to the first end of the cartridge. In another embodiment, the liquid drawing element is displaced from the first plate.

[0010] According to some embodiments, the actuator further comprises a control circuitry in communication with the first piezoelectric transducer, the liquid deposition mechanism or both. Each possibility represents a separate embodiment of the invention. According to some embodiments, the actuator further comprises a control circuitry in communication with the first piezoelectric transducer and the liquid deposition mechanism. According to some embodiments, the control circuitry is configured to control the liquid deposition mechanism to deposit a predetermined volume of the drawn liquid onto the first face of the first plate. According to some embodiments, the control circuitry is configured to control the first piezoelectric transducer to generate vibrations at a predetermined frequency, thereby vibrating the first plate and nebulizing the deposited liquid into an aerosol. In one further embodiment, the predetermined frequency is an ultrasonic frequency.

[0011] In one embodiment, the actuator further comprises a control circuitry in communication with the first piezoelectric transducer and the liquid deposition mechanism, the control circuitry arranged to: control the liquid deposition mechanism to deposit a predetermined volume of the drawn liquid onto the first face of the first plate; and control the first piezoelectric transducer to generate vibrations at a predetermined frequency, thereby vibrating the first plate and nebulizing the deposited liquid into an aerosol. In one further embodiment, the predetermined frequency is an ultrasonic frequency.

[0012] In another further embodiment, the control circuitry is arranged to output a first signal and a second signal, the first signal arranged to control the liquid deposition mechanism to deposit the predetermined volume of the drawn liquid and the second signal arranged to control the first piezoelectric transducer to generate the vibrations, wherein the second signal is output after the first signal has ceased. In one yet further embodiment, the control circuitry is arranged to alternately output the first signal and the second signal.

[0013] In one embodiment, the liquid drawing element comprises a wick.

[0014] In another embodiment, the liquid deposition mechanism comprises: a second plate exhibiting a plurality of perforations extending from a first face of the second plate to a second face of the second plate; and a second piezoelectric transducer in contact with the second plate, wherein the first face of the second plate is in contact with the liquid drawing element and the second face of the second plate faces the first face of the first plate. In one further embodiment, the second plate exhibits a predetermined acute angle with the first plate.

[0015] In one embodiment, the liquid drawing element comprises a stationary section and a mobile section, and wherein the liquid deposition mechanism is arranged to translate the mobile section of the liquid drawing element along the first face of the first plate. In one further embodiment, the liquid deposition mechanism is arranged to alternately translate the mobile section of the liquid drawing element along the first face of the first plate in a first direction and a second direction opposing the first direction. [0016] In another further embodiment, prior to the translation of the mobile section of the liquid drawing element in the first direction, the mobile section is in contact with the stationary section of the liquid drawing element, wherein responsive to the translation in the first direction, the mobile section is not in contact with the stationary section, and wherein subsequent to the translation in the second direction, the mobile section is in contact with the stationary section. In one yet further embodiment, prior to the translation of the mobile section of the liquid drawing element in the first direction, the mobile section is in an initial position, wherein subsequent to the translation in the second direction, the mobile section returns to the initial position.

[0017] In another further embodiment, the liquid reservoir is not positioned between the first plate and the second end of the cartridge.

[0018] In one embodiment, the liquid reservoir is compressible and exhibits a first closed end and a second open end, wherein the liquid deposition mechanism comprises: a motor and a compression element arranged, responsive to the motor, to push against the first closed end of the liquid reservoir thereby compressing the liquid reservoir, the arrangement of the liquid drawing element to draw the liquid from the liquid reservoir being responsive to the compression of the liquid reservoir. In one further embodiment, a first end of the liquid drawing element is in contact with the first open end of the liquid reservoir, wherein a second end of the liquid drawing element faces the first face of the first plate and is positioned between the first plate and the second end of the cartridge.

[0019] In another embodiment, the outlet is at the second end of the cartridge.

[0020] Additional features and advantages of the invention will become apparent from the following drawings and description.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise. As utilized herein, “and/or” means any one or more of the items in the list joined by “and/or”. As an example, “x and/or y” means any element of the three-element set {(x), (y), (x, y)}. In other words, “x and/or y” means “x, y or both of x and y”. As another example, “x, y, and/or z” means any element of the seven-element set {(x), (y), (z), (x, y), (x, z), (y, ^z (^x> y, ^z)}·

[0022] Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by anyone of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0023] In addition, use of the “a” or “an” are employed to describe elements and components of embodiments of the instant inventive concepts. This is done merely for convenience and to give a general sense of the inventive concepts, and “a” and “an” are intended to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

[0024] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, but not limiting in scope. In various embodiments, one or more of the above-described problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements.

BRIEF DESCRIPTION OF DRAWINGS

[0025] For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made, purely by way of example, to the accompanying drawings in which like numerals designate corresponding sections or elements throughout.

[0026] With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how several forms of the invention may be embodied in practice. In the accompanying drawings:

[0027] FIG. 1 illustrates a schematic diagram of a prior art nebulizer;

[0028] FIG. 2 illustrates a perspective view of a nebulizing apparatus comprising a perforated plate;

[0029] FIGs. 3A - 3B illustrate various high-level schematic diagrams of a first embodiment of a nebulizer;

[0030] FIGs. 4A - 4C illustrate various high-level schematic diagrams of a second embodiment of a nebulizer; and [0031] FIGs. 5A - 5D illustrate various high-level schematic diagrams of a third embodiment of a nebulizer.

[0032] FIGs. 6A - 6D show cumulative droplet size distributions of aerosolized compositions: Budesonide 0.5 mg/ml, 40 % EtOH (FIG. 6A); (b) Budesonide 0.5 mg/ml, 40 % EtOH, 1% Glycerol (FIG. 6B); (c) Budesonide 10 mg/ml, 100 % EtOH (FIG. 6C); and (d) commercial product of salbutamol (FIG. 6D).

[0033] FIGs. 7A - 7D show Mass Distribution on Impactor parts in aerosols produced from: Budesonide 0.5 mg/ml, 40 % EtOH (FIG. 7A); (b) Budesonide 0.5 mg/ml, 40 % EtOH, 1% Glycerol (FIG. 7B); (c) Budesonide 10 mg/ml, 100 % EtOH (FIG. 7C); and (d) commercial product of salbutamol (FIG. 7D). [0034] FIG. 8A shows cumulative droplet size distributions of aerosolized compositions:

Budesonide 10 mg/ml, 100 % EtOH (the trend line deviated to the left); and commercial product of salbutamol (the trend line deviated to the right).

[0035] FIG. 8B shows Mass Distribution on Impactor parts in aerosols produced from: Budesonide 10 mg/ml, 100 % EtOH (left bars in each set of two bars); and commercial product of salbutamol (right bars in each set of two bars). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0036] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure. In the figures, like reference numerals refer to like parts throughout. In order to avoid undue clutter from having too many reference numbers and lead lines on a particular drawing, some components will be introduced via one or more drawings and not explicitly identified in every subsequent drawing that contains that component.

[0037] FIGs. 3 A - 3B illustrate various high-level schematic diagrams of a nebulizer 100, in accordance with some embodiments. Nebulizer 100 comprises: a cartridge 110 exhibiting a first end 111 and a second end 112; and an actuator 120 exhibiting a first end 121 and a second end 122. In one embodiment, first end 111 of cartridge 110 exhibits an indent 113. FIG. 3A illustrates a high-level schematic diagram of nebulizer 100 with cartridge 110 and actuator 120 disconnected from each other. FIG. 3B illustrates a high-level schematic diagram of nebulizer 100 with cartridge 110 and actuator 120 connected.

[0038] Cartridge 110 comprises: a plate 130 exhibiting a first face 131 and a second face 132 opposing first face 131; a liquid reservoir 140 containing liquid 150; a liquid drawing element 160; a liquid deposition mechanism 170; and an outlet 180. According to some embodiments, cartridge 110 further comprises a mouthpiece (not shown). According to some embodiments, the mouthpiece is connected or connectable to outlet 180. According to some embodiments, the mouthpiece is connected to outlet 180. According to some embodiments, the mouthpiece is connectable to outlet 180 (e.g., it may be screwed to cartridge 110 at its second end 112).

[0039] Actuator 120 comprises a piezoelectric transducer 190, piezoelectric transducer 190 comprising a piezoelectric material. In one embodiment, actuator 120 further comprises: a power source 200; and a control circuitry 210. In one embodiment, power source 200 comprises a power generator, such as a battery. In another embodiment, power source 200 comprises an outlet arranged to receive power from an external source. According to some embodiments, actuator 120 further comprises a power source compartment configured to accommodate a disposable power source 200, such as a disposable battery.

[0040] According to some embodiments, liquid drawing element 160 comprises a wick or a sponge. In one embodiment, liquid drawing element 160 comprises a wick. In one embodiment, liquid drawing element 160 is a wick. According to some embodiments, liquid drawing element 160 comprises a sponge. In another embodiment, both liquid reservoir 140 and liquid drawing element 160 are cylindrically shaped with a ring-shaped cross-section. In one embodiment, liquid deposition mechanism 170 comprises: a perforated plate 70 exhibiting a first face 71, a second face 72 opposing first face 71 and a plurality of perforations 73 extending from first face 71 to second face 72; and a piezoelectric transducer 80. In one embodiment, perforated plate 70 is circular. In one further embodiment, piezoelectric transducer 80 is ring shaped. First face 71 of perforated plate 70 faces liquid drawing element 160 and is in contact therewith. Second face 72 of perforate plate 70 faces first face 131 of plate 130.

[0041] In one embodiment, perforated plate 70 exhibits a predetermined acute angle with plate 130, the angle measured between first face 131 of plate 130 and second face 72 of perforated plate 70. In one further embodiment, the predetermined acute angle is between 30 - 60 degrees. In one further embodiment, the predetermined acute angle is between 20 - 70 or 40 - 50 degrees. Each possibility represents a separate embodiment of the invention. In another embodiment, liquid reservoir 140, liquid drawing element 160 and liquid deposition mechanism 170 each exhibit a predetermined acute angle with plate 130. Advantageously, having liquid reservoir 140, liquid drawing element 160 and liquid deposition mechanism 170 at an angle with plate 130 allows to position them away from plate 130 such that a path of aerosol being produced on first face 131 of plate 130 to outlet 180 is at least partially unobstructed.

[0042] Second face 132 of plate 130 is positioned at first end 111 of cartridge 110. Plate 130 is secured to cartridge 110 in a configuration such that plate 130 can vibrate. In one embodiment, where first end 111 of cartridge 110 exhibits an indent 113, plate 130 is positioned at the edge of indent 113 such that indent 113 extends towards second face 132 of plate 130 and is defined thereby. In one embodiment, outlet 180 is located at second end 112 of cartridge 110. In another embodiment (not shown), an inlet mechanism is provided which allows for injection of inhalable pharmaceutical compositions (e.g., drug solutions) into liquid reservoir 140.

[0043] Piezoelectric transducer 190 is positioned on first end 121 of actuator 120. In one embodiment, piezoelectric transducer 190 is positioned external to the housing of actuator 120. Power source 200 is in electrical communication with piezoelectric transducer 190 and control circuitry 210 is in communication with power source 200 and/or piezoelectric transducer 190.

[0044] First end 121 of actuator 120 is connectable to first end 111 of cartridge 110. In one embodiment (not shown), cartridge 110 and actuator 120 each comprise various connection members allowing the cartridge 110 and actuator 120 to be connected. When first end 111 of cartridge 110 is connected to first end 121 of actuator 120, second face 132 of plate 130 is in contact with piezoelectric transducer 190. In one embodiment, where first end 111 of cartridge 110 exhibits an indent 113, piezoelectric transducer 190 is positioned within indent 113. In one embodiment, when first end 111 of cartridge 110 is connected to first end 121 of actuator 120, power source 200 and control circuitry 210 are in electrical communication with liquid deposition mechanism 170. In an embodiment where liquid deposition mechanism 170 comprises a piezoelectric transducer 80, power source 200 and control circuitry 210 are in electrical communication with piezoelectric transducer 80. In another embodiment (not shown), cartridge 110 comprises a separate control circuitry and/or power source.

[0045] In operation, liquid drawing element 160 draws liquid 150 from liquid reservoir 140. In one embodiment, where liquid drawing element 160 comprises a wick or a sponge, the liquid is drawn by liquid drawing element 160 through capillary action. Liquid deposition mechanism 170 is arranged to deposit at least some of the drawn liquid 150 from liquid drawing element 160 onto first face 131 of plate 130. In one embodiment, control circuitry 210 controls liquid deposition mechanism 170 to deposit a predetermined volume of the drawn liquid 150 from liquid drawing element 160 onto first face 131 of plate 130. In one further embodiment, the predetermined volume of liquid 150 is less than 1 milliliter. In another further embodiment, the predetermined volume of liquid 150 is 5 - 30 microliters. In another further embodiment, the predetermined volume of liquid 150 is about 10 microliters, optionally 9 - 11 microliters. In one embodiment, liquid deposition mechanism 170 sprays the predetermined volume of liquid 150 onto first face 131 of plate 130. [0046] In one embodiment, liquid deposition mechanism 170 is controlled such that a predetermined voltage is applied to piezoelectric transducer 80, optionally from power source 200. Responsive to the applied voltage, piezoelectric transducer 80 vibrates at a predetermined frequency. In one embodiment the predetermined frequency of the vibrations of piezoelectric transducer 80 is an ultrasonic frequency. In one further embodiment, the predetermined frequency is greater than 20 kHz. The vibrations of piezoelectric transducer 80 vibrates perforated plate 70. The vibration of perforated plate 70 nebulizes the liquid 150 in liquid drawing element 160 into droplets which are then sprayed onto first face 131 of plate 130. In one further embodiment, the diameters of the droplets are 10 - 20 microns. [0047] Control circuitry 210 further controls piezoelectric transducer 190 to generate vibration at a predetermined frequency. In one embodiment, the predetermined frequency is an ultrasonic frequency. In one further embodiment, the predetermined frequency is greater than 20 kHz. In another embodiment, piezoelectric transducer 190 generates vibrations responsive to a predetermined voltage applied thereto by power source 200. The vibrations of piezoelectric transducer 190 vibrate plate 130 and the vibrations of plate 130 nebulize the liquid 150 deposited on first face 131 into an aerosol.

[0048] According to some embodiments, piezoelectric transducer 190 vibrate plate 130 and the vibrations of plate 130 nebulize the liquid 150 deposited on first face 131 into an aerosol having a mass median aerodynamic diameter (MMAD) of at most 50 microns, at most 40 micron, at most 30 micron, at most 20 micron, at most 10 micron, at most 5 micron, or at most 3 micron. Each possibility represents a separate embodiment of the invention.

[0049] . The correlation between droplet size and deposition thereof in the respiratory tract has been established. Droplets around 10 micron in diameter are suitable for deposition in the oropharynx and the nasal area; droplets below around 4 micron in diameter are suitable for deposition in the central airways and may be especially beneficial for delivery of pharmaceutical compositions to the subjects in a need thereof. The droplets formed by aerosolization with any one of the nebulizers of the current invention (e.g., Nebulizers 100, 300, 400) are small, having droplet size in the range of 0.1 to 5 micron, according to some embodiments. [0050] In one embodiment, control circuitry 210 outputs a first signal and a second signal. The first signal output by control circuitry 210 controls liquid deposition mechanism 170 to deposit liquid 150 on first face 131 of plate 130 andthe second signal output by control circuitry 210 controls piezoelectric transducer 190 to generate vibrations. In one further embodiment, the second signal is output after the first signal has ceased, i.e., after liquid deposition mechanism 170 has deposited the predetermined volume of liquid 150 on first face 131 of plate 130. In another embodiment, control circuitry 210 alternately outputs the first signal and the second signal. Particularly, in order to nebulize a desired quantity of liquid, control circuitry 210 controls liquid deposition mechanism 170 to deposit a predetermined volume of liquid 150, then controls piezoelectric transducer 190 to nebulize the deposited liquid 150, then controls liquid deposition mechanism 170 to deposit a predetermined volume of liquid 150, and so on, until the desired quantity of liquid 150 is nebulized. In one embodiment, the desired quantity is entered at a user input device (not shown).

[0051] FIGs. 4A - 4C illustrate various high-level schematic diagrams of a nebulizer 300. Nebulizer 300 is in all respects similar to nebulizer 100, with the exception that: liquid reservoir 140 is replaced with liquid reservoir 310 exhibiting a first end 311 and a second end 312; liquid drawing element 160 is replaced with liquid drawing element 320 exhibiting a first end 321 and a second end 322; and liquid deposition mechanism 170 is replaced with liquid deposition mechanism 330. According to some embodiments, liquid deposition mechanism 330 comprising a motor 340 and a compression element 350. FIG. 4A illustrates a high-level schematic diagram of nebulizer 300 with cartridge 110 and actuator 120 disconnected from each other. FIG. 4B illustrates a high-level schematic diagram of nebulizer 300 with cartridge 110 and actuator 120 connected. FIG. 4C illustrates a high-level schematic diagram of nebulizer 300 nebulizing liquid intro aerosol.

[0052] In one embodiment, first end 311 of liquid reservoir 310 is closed and second end 352 of liquid reservoir 310 is open, i.e., liquid 150 can flow therethrough. In one embodiment, compression element 350 comprises a connection arm 351 and a contact member 352. In such an embodiment, motor 340 is coupled to contact member 352 via connection arm 351 and contact member 352 is in contact with first end 351 of compression member 350. Liquid reservoir 310 is compressible, i.e., the distance between first end 351 and second end 352 decreases responsive to a predetermined force being applied thereto. [0053] In one embodiment, motor 340 is positioned in actuator 120 and compression element 350 is positioned in cartridge 110. In another embodiment (not shown), motor 340 is positioned in cartridge 110. In another embodiment (not shown), compression element 350 is positioned actuator 120. Motor 340 is in electrical communication with power source 200 and control circuitry 210.

[0054] First end 321 of liquid drawing element 320 is connected to second end 312 of liquid reservoir 310. Second end 322 of liquid drawing element 320 faces first face 131 of plate 130. In one embodiment, second end 322 is positioned between first face 131 of plate 130 and second end 112 of cartridge 110. In one embodiment, liquid drawing element 320 is shaped as a thin tube so as to reduce the obstruction of the path between first face 131 of plate 130 and outlet 180.

[0055] In operation, as described above, control circuitry 210 controls liquid deposition mechanism 330 to deposit a predetermined volume of liquid 150 onto first face 131 of plate 130 and controls piezoelectric transducer 190 to vibrate plate 130 thereby nebulizing the deposited liquid into an aerosol. In one further embodiment, the predetermined volume of liquid 150 is less than 1 milliliter. In another further embodiment, the predetermined volume of liquid 150 is 5 - 30 microliters. In another further embodiment, the predetermined volume of liquid 150 is about 10 microliters, optionally 9 - 11 microliters.

[0056] Particularly, control circuitry 210 controls motor 340 to push compression element 350 against first end 311 of liquid reservoir 310 by a predetermined amount thereby compressing liquid reservoir 310. Responsive to the compression of liquid reservoir 310, a predetermined volume of liquid 150 enters liquid drawing element 320 and drops onto first face 131 of plate 130. The deposited liquid 150 is then nebulized, as described above. In one embodiment, as illustrated in FIG. 4C, after depositing the predetermined volume of liquid 150 on first face 131 of plate 130, control circuitry 210 controls motor 340 to pull back compression element 350 thereby preventing uncontrolled release of liquid 150 from liquid reservoir 310.

[0057] FIGs. 5 A - 5D illustrate various high-level schematic diagrams of a nebulizer 400, in accordance with some embodiments. Nebulizer 400 is in all respects similar to nebulizer 100, with the exception that: liquid reservoir 140 is replaced with liquid reservoir 410; liquid drawing element 160 is replaced with liquid drawing element 420 comprising a stationary section 421 and a mobile section 422; and liquid deposition mechanism 170 is replaced with liquid deposition mechanism 430. In one embodiment, liquid deposition mechanism 430 comprises: a translation member 440 exhibiting a plurality of teeth 445; and a gear 450 exhibiting a plurality of teeth 455. In such an embodiment, a motor (not shown) is further provided and arranged, responsive to control circuitry 210 to rotate gear 450. Gear 450 is illustrated as being positioned in actuator 120 and translation member 440 is illustrated as being positioned in cartridge 110, however this is not meant to be limiting in any way. In another embodiment (not shown), gear 450 is positioned in cartridge 110. In another embodiment (not shown), translation member 440 is positioned in actuator 120. [0058] FIG. 5 A illustrates a high-level schematic diagram of nebulizer 400 when cartridge

110 and actuator 120 are not connected. FIG. 5B illustrates a high-level schematic diagram of nebulizer 400 when cartridge 110 and actuator 120 are connected. FIG. 5C illustrates a high- level schematic diagram of nebulizer 400 when liquid deposition mechanism 430 is depositing liquid 150 on plate 130. FIG. 5D illustrates a high-level schematic diagram of nebulizer 400 when liquid deposition mechanism 430 returns to an initial position.

[0059] Teeth 455 of gear 450 mate with teeth 445 of translation member 440. Translation member 440 is secured to mobile section 422 of liquid drawing element 420. In one embodiment, stationary section 421 and mobile section 422 each comprises a wick or a sponge. Each possibility represents a separate embodiment, including a combination of wick and sponge, each for a different section. In another embodiment, mobile section 422 of liquid drawing element 420 and liquid reservoir 410 are positioned between plate 130 and a side wall of cartridge 110 and not positioned between plate 130 and second end 112 of cartridge 110.

[0060] In operation, as described above, control circuitry 210 controls liquid deposition mechanism 430 to deposit a predetermined volume of liquid 150 onto first face 131 of plate 130 and controls piezoelectric transducer 190 to vibrate plate 130 thereby nebulizing the deposited liquid into an aerosol. The predetermined volume is as defined for nebulizers 100 and 300, according to some embodiments.

[0061] Particularly, liquid deposition mechanism translates mobile section 422 of liquid drawing element 420 along first face 131 of plate 130. In one embodiment, responsive to control circuitry 210, gear 450 rotates in a first rotational direction thereby translating translation member 440 and mobile section 422 of liquid drawing element 420 along first face 131 of plate 130. Thus, mobile section 422 is translated from an initial position, in which mobile section 422 is in contact with stationary section 421, along first face 131 of plate 130 in a first direction. When translated along first face 131 of plate 130, mobile section 422 of liquid drawing element 420 is separated from stationary section 421.

[0062] As mobile section 422 of liquid drawing element 420 is translated along first face 131 of plate 130, the liquid 150 present in mobile section 422 is deposited on first face 131 of plate 130. After depositing a predetermined volume of liquid 150 onto first face 131 of plate 130, mobile section 422 is translated in a second direction, the second direction opposing the first direction. In one embodiment, responsive to control circuitry 210, gear 450 is rotated in a second rotational direction, thereby translating translation member 440 and mobile section 422 of liquid drawing element 420 away from plate 130 and back to the initial position. Thus, liquid deposition mechanism 430 alternately translates mobile section 422 of liquid drawing element 420 along first face 131 of plate 130 in the first direction and the second direction until a desired quantity of liquid 150 is nebulized.

[0063] Advantageously, it was found that the nebulizers (100, 300, 400) of the present invention is specifically beneficial for aerosolizing non-aqueous or partially aqueous composition. Thus, according to some embodiments, the liquid 150 contained in the respective cartridges 110 includes a non-aqueous solvent. According to some embodiments, the liquid 150 comprises an organic liquid, e.g., at an amount of at least 20% v/v, at least 40% v/v, at least 60% v/v or at least 80% v/v. Each range represents a separate embodiment. Such non- or partially aqueous compositions are often required when the active compound to be aerosolized and delivered to a subject in need thereof (e.g. to the lungs) has poor aqueous solubility. According to some embodiments, the non-aqueous solvent is an organic solvent. According to some embodiments, the organic solvent is an alcohol. According to some embodiments, the organic solvent is ethanol, propylene glycol or a combination thereof each possibility represents a separate embodiment.

[0064] In particular, the nebulizers (100, 300, 400) of the present invention are able to produce very fine aerosols from such non-aqueous compositions (e.g. solutions or suspensions), which is an improvement over the known nebulizers. Nebulizations of partially aqueous or non-aqueous organic formulations were found results in droplets having a mass median aerodynamic diameter (MMAD) sufficiently small (typically below 5 microns) so as to reach the lungs, rather than precipitate on their way thereto. The small droplets reaching the lungs enable efficient respiratory delivery of the water insoluble therapeutic agent. This is an overall advantage as maximizing the delivery of therapeutic agents to the lungs, while minimizing its deposition in the mouth and throat are important in treating diseases or disorders related to the respiratory system. According to some embodiments, each of the droplets comprises an organic solvent (e.g. ethanol and/or propylene glycol, as specified herein).

[0065] The terms 'droplet size' and 'mass median aerodynamic diameter', also known as MMAD, as used herein are interchangeable. MMAD is commonly considered as the median particle diameter by mass. MMAD may be evaluated by plotting droplet size vs. the cumulative mass fraction (%) in the aerosol. MMAD may then be determined according to the interpolated droplet size corresponding to the point, where the cumulative mass fraction is 50%. This points represent the estimated values of particle sizes, above which the droplets are responsible to half to masses and below which the droplets are responsible to the other halves, in each solution.

[0066] As shown in the Examples section, MMAD values lower than 2 micron can be achieved. Thus, according to some embodiments, the nebulizers (100, 300, 400) of the present invention are configured to produce an aerosol, which comprises droplets that have MMAD of at most 10 microns. According to some embodiments, the aerosol comprises droplets having an MMAD within the range of 0.3 to 7 microns. According to some embodiments, the MMAD is within the range of 2 to 10 microns. According to some embodiments, the aerosol comprises droplets having an MMAD of less than 10 microns. According to some embodiments, the aerosol comprises droplets having an MMAD within the range of 0.3 to 7 microns. According to some embodiments, the MMAD is less than 5 microns.

[0067] According to some embodiments, the aerosol comprises droplets having a Geometric Standard Diameter (GSD) within the range of about 0.4-7 microns. According to some embodiments, the aerosol comprises droplets having a GSD within the range of about 2- 5 microns.

[0068] According to some embodiments, two different liquids 150 may be separately contained in a single cartridge 110, wherein one liquid includes an aqueous composition and the other a non-aqueous composition. Alternatively, one liquid may include an aqueous composition and the other a partially aqueous composition (e.g., in aqueous ethanol) or one liquid may include a non-aqueous composition and the other a partially aqueous composition (e.g., in aqueous ethanol). The two liquids 150 may, according to some embodiments, be disposed in two separate liquid reservoirs (140, 310, 410), each liquid reservoir is individually as described herein. In one further embodiment, two separate plates 130 and two respective piezoelectric transducers 190 are provided. In such an embodiment, liquid 150 from a first reservoir (140, 310, 410) is deposited on a first plate 130 and liquid 150 from a second reservoir (140, 310, 410) is deposited on a second plate 130. Alternatively, a single plate 130 is provided, and liquid 150 from first and second reservoirs (140, 310, 410) are deposited alternately, or simultaneously, on the single plate 130.

[0069] As detailed in Example 3 it was found that upon co-aerosolization of an aqueous composition (commercial aqueous salbutamol) and organic composition (10 mg/ml budesonide in 100%EtOH), two sets of aerosols simultaneously form. Specifically, the aqueous aerosol was found to include larger droplet than the organic aerosol. Without wishing to be bound by any theory or mechanism of action, it is hypothesized that the lower surface tension and higher volatility of organic solvents, such as ethanol, compared to water results in the smaller droplets in the organic aerosol. This phenomenon may be emphasized when a small predetermined volume (e.g. 5 - 30 microliters or about 10 microliters) of the drawn liquid (150, 350, 450) is deposited onto the plate 130 to be aerosolized.

[0070] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. In particular, the invention has been described with an identification of each powered device by a class, however this is not meant to be limiting in any way. In an alternative embodiment, all powered device are treated equally, and thus the identification of class with its associated power requirements is not required.

EXAMPLES

[0071] Example 1- Measurements of aerosol droplet diameter. [0072] The cumulative droplet size distribution of aerosolized solutions produced using a nebulizer according to some embodiments, was tested. The aerosolized formulations include Budesonide 0.5 mg/ml, 40 % EtOH (Formulation A); Budesonide 0.5 mg/ml, 40 % EtOH, 1% Glycerol (Formulation B); Budesonide 10 mg/ml, 100 % EtOH (Formulation C); and Salbutamol (commercial product) (Formulation D).

[0073] The results are presented in FIGs. 6A-D. FIG 6A is directed to the aerosol formed from Formulation A of 0.5 mg/ml budesonide in 40% aqueous ethanol. This graph indicates that about 80% of the droplets have diameters of less than 5.8 microns, wherein 78% of the droplets have diameter of less than 4.7 micron. About 50% of the droplets have diameters of less than 1.5 microns, which is indicative of the very small MMAD value that can be achieved when aerosolizing this composition as described herein according to the present invention.

[0074] FIG 6B is directed to the aerosol formed from Formulation B of 0.5 mg/ml budesonide in 40% aqueous ethanol and 1% glycerol. This graph indicates that about 73% of the droplets have diameters of less than 5.8 microns, wherein 68% of the droplets have diameter of less than 4.8 micron. About 50% of the droplets have diameters of less than 3.3 microns, which is indicative of the very small MMAD value that can be achieved when aerosolizing this composition as described herein according to the present invention.

[0075] FIG 6C is directed to the aerosol formed from Formulation C of 10 mg/ml budesonide in 100% ethanol solvent. This graph indicates that about 88% of the droplets have diameters of less than 5.8 microns, wherein 84% of the droplets have diameter of less than 4.7 micron. About 50% of the droplets have diameters of less than 1.8 microns, which is again indicative of the very small MMAD value that can be achieved when aerosolizing this composition as described herein according to the present invention.

[0076] FIG 6D is directed to the aerosol formed from Formulation D which includes commercial salbutamol (commercial in water). This graph indicates that about 78% of the droplets have diameters of less than 4.8 microns. About 50% of the droplets have diameters of less than 3.7 microns, which is indicative of the small MMAD value that can be achieved, although it is higher than when using organic solvent-based compositions.

[0077] Example 2: Mass Distribution on Impactor parts: [0078] Particle size distribution testing was conducted using cascade impactor validated method with formulations A-D of Example 1. Relative mass of the nebulized solution was measured against its particle size, which was measured between 0.43 micrometers and over 10 micrometers.

[0079] Each one of FIGs 7A-D is a chart representing Mass Distribution on Impactor parts in an aerosol depicting the relative mass of the aerosol in each particle diameter size group, where the particle diameter groups are 0.43 to 0.7 microns; 0.7 to 1.1 microns; 1.1 to 2.2 microns; 2.2 to 3.3 microns; 3.3 to 4.7 microns; 4.7 to 5.8 microns; 5.8 to 9 microns; and over 10 microns. The results are presented in FIGs 7 A-D and relate to aerosolization of the formulations of Example 1: Formulation A (FIG. 7A); Formulation B (FIG.7B); Formulation C (FIG.7C); and Formulation D (FIG.7D).

[0080] FIG 7 A relates to the aerosol formed from F ormulation A of 0.5 mg/ml budesonide in 40% aqueous ethanol. As can be seen in this figure the majority of aerosol mass was provided in droplets having diameters in the range of 0.7 to 3.3 microns. More specifically, droplets in the range of 1.1 to 2.2 microns accounted for over 25% of the total aerosol mass and droplets in the range of 0.7 to 1.1 microns accounted for about 25% of the total aerosol mass. In total, droplets in the range of 0.7 to 3.3 microns amounted to over 70% of the total aerosol mass, whereas droplets having diameters of more than 5.8 microns or less than 0.7 microns contributed only very small amounts of aerosol.

[0081] FIG 7B relates to the aerosol formed from Formulation B of 0.5 mg/ml budesonide in 40% aqueous ethanol and 1% glycerol. As can be seen in this figure the majority of aerosol mass was provided in droplets having diameters in the range of 1.1 to 4.7 microns. More specifically, droplets in the range of 2.2 to 3.3 microns accounted for over 25% of the total aerosol mass, droplets in the range of 1.1 to 2.2 microns accounted for over 20% of the total aerosol mass, and droplets in the range of 3.3 to 4.7 microns accounted for over 15% of the total aerosol mass. In total, droplets in the range of 1.1 to 4.7 microns amounted to over 60% of the total aerosol mass, whereas droplets having diameters of more than 5.8 microns or less than 0.7 microns contributed only very small amounts of aerosol.

[0082] FIG 7C relates to the aerosol formed from Formulation C of 10 mg/ml budesonide in 100% ethanol solvent. As can be seen in this figure the majority of aerosol mass was provided in droplets having diameters in the range of 0.7 to 3.3 microns. More specifically, droplets in the range of 1.1 to 2.2 microns accounted for over 30% of the total aerosol mass, droplets in the range of 0.7 to 1.1 microns accounted for over 15% of the total aerosol mass, and droplets in the range of 2.2 to 3.3 microns accounted for about 15% of the total aerosol mass. In total, droplets in the range of 0.7 to 3.3 microns amounted to over 60% of the total aerosol mass, whereas droplets having diameters of more than 5.8 microns or less than 0.7 microns contributed only very small amounts of aerosol.

[0083] FIG 7D relates to the aerosol formed from Formulation D which includes commercial salbutamol (commercial in water). As can be seen in this figure the majority of aerosol mass was provided in droplets having diameters in the range of 2.2 to 4.7 microns. More specifically, droplets in the range of 3.3 to 4.7 microns accounted for over 35% of the total aerosol mass, and droplets in the range of 2.2 to 3.3 microns accounted for about 35% of the total aerosol mass. In total, droplets in the range of 2.2 to 4.7 microns amounted to over 70% of the total aerosol mass, whereas droplets having diameters of more than 5.8 microns or less than 0.7 microns contributed only very small amounts of aerosol. Again, it is shown that while the droplets presently formed from aqueous compositions, while being smaller when compared to aerosolizations with competing technologies, these droplets are somewhat larger than corresponding droplets produced from organic compositions (c.f. Examples 6A-C).

[0084] Example 3 : Co-aerosolization of two separate compositions. [0085] Two separate formulations - the ethanolic Formulation C and the aqueous

Formulation D were deposited and aerosolized from two separate vibrating plates.

Measurements of aerosol droplet diameters were performed as described in Example 1 and Mass Distribution on Impactor parts as described in Example 2.

[0086] The cumulative droplet size distribution of the aerosolized solutions is presented in FIG. 8A and the Mass Distribution on Impactor parts is presented in FIG. 8B. The aerosols were examined separately and as can be seen FIG. 8A roughly resembles a superposition of FIGs 6C-6D, while FIG. 8B roughly resembles a superposition of FIGs 7C-7D.

[0087] Thus, it is concluded that two separate compositions can be aerosolized, while substantially maintaining their inherent aerosol properties. Moreover, it is demonstrated that co-administration of an aerosol having larger droplets (aqueous aerosol) and an aerosol having smaller droplets (organic aerosol) is feasible.

[0088] Advantageously, using this approach can result in targeting Salbutamol (which is provided in an aqueous solution) to the upper airways and budesonide to the lower airways. Specifically, aerosol droplets of about 4 micrometers in diameter reach the upper airways, whereas aerosol droplets of about 2 micrometers in diameter reach the lower airways of the respiratory tract. Moreover, Salbutamol is required in the upper airways whereas the steroid budesonide is required to act at the site of infection, which is in the lower airways.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as are commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods are described herein.

[0090] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the patent specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0091] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined by the appended claims and includes both combinations and subcombinations of the various features described hereinabove as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description.

Claims

1. A nebulizer comprising: a cartridge exhibiting a first end and a second end, the cartridge comprising: a first plate exhibiting a first face and a second face opposing the first face, the first plate positioned at the first end of the cartridge; a liquid reservoir containing liquid; a liquid drawing element arranged to draw the liquid from the liquid reservoir; and an outlet; a liquid deposition mechanism, which is at least partially disposed within the cartridge and arranged to deposit the drawn liquid onto the first face of the first plate; and an actuator exhibiting a first end and a second end, the actuator comprising a first piezoelectric transducer, wherein the first end of the actuator is connectable to the first end of the cartridge, and wherein the second face of the first plate is in contact with the first piezoelectric transducer when the first end of the actuator is connected to the first end of the cartridge.

2. The nebulizer of claim 1, wherein the first piezoelectric transducer is positioned on the first end of the actuator, and wherein the first end of the cartridge exhibits an indent extending towards the first plate, the first piezoelectric transducer positioned within the indent when the first end of the actuator is connected to the first end of the cartridge.

3. The nebulizer of claim 1 or 2, wherein the liquid drawing element is displaced from the first plate.

4. The nebulizer of any one of claims 1 to 3, wherein the actuator further comprises a control circuitry in communication with the first piezoelectric transducer and the liquid deposition mechanism, the control circuitry arranged to: control the liquid deposition mechanism to deposit a predetermined volume of the drawn liquid onto the first face of the first plate; and control the first piezoelectric transducer to generate vibrations at a predetermined frequency, thereby vibrating the first plate and nebulizing the deposited liquid into an aerosol.

5. The nebulizer of claim 4, wherein the predetermined frequency is an ultrasonic frequency.

6. The nebulizer of claim 4 or 5, wherein the control circuitry is arranged to output a first signal and a second signal, the first signal arranged to control the liquid deposition mechanism to deposit the predetermined volume of the drawn liquid and the second signal arranged to control the first piezoelectric transducer to generate the vibrations, and wherein the second signal is output after the first signal has ceased.

7. The nebulizer of claim 6, wherein the control circuitry is arranged to alternately output the first signal and the second signal.

8. The nebulizer of any one of claims 1 to 7, wherein the liquid drawing element comprises a wick.

9. The nebulizer of any one of claims 1 to 8, wherein the liquid deposition mechanism comprises: a second plate exhibiting a plurality of perforations extending from a first face of the second plate to a second face of the second plate; and a second piezoelectric transducer in contact with the second plate, wherein the first face of the second plate is in contact with the liquid drawing element and the second face of the second plate faces the first face of the first plate.

10. The nebulizer of claim 9, wherein the second plate exhibits a predetermined acute angle with the first plate.

11. The nebulizer of any one of claims 1 to 8, wherein the liquid drawing element comprises a stationary section and a mobile section, and wherein the liquid deposition mechanism is arranged to translate the mobile section of the liquid drawing element along the first face of the first plate.

12. The nebulizer of claim 11, wherein the liquid deposition mechanism is arranged to alternately translate the mobile section of the liquid drawing element along the first face of the first plate in a first direction and a second direction opposing the first direction.

13. The nebulizer of claim 12, wherein prior to the translation of the mobile section of the liquid drawing element in the first direction, the mobile section is in contact with the stationary section of the liquid drawing element, wherein responsive to the translation in the first direction, the mobile section is not in contact with the stationary section, and wherein subsequent to the translation in the second direction, the mobile section is in contact with the stationary section.

14. The nebulizer of claim 13, wherein prior to the translation of the mobile section of the liquid drawing element in the first direction, the mobile section is in an initial position, and wherein subsequent to the translation in the second direction, the mobile section returns to the initial position.

15. The nebulizer of any one of claims 11 to 14, wherein the liquid reservoir is not positioned between the first plate and the second end of the cartridge.

16. The nebulizer of any one of claims 1 to 7, wherein the liquid reservoir is compressible and exhibits a first closed end and a second open end, wherein the liquid deposition mechanism comprises: a motor; and a compression element arranged, responsive to the motor, to push against the first closed end of the liquid reservoir thereby compressing the liquid reservoir, the arrangement of the liquid drawing element to draw the liquid from the liquid reservoir being responsive to the compression of the liquid reservoir.

17. The nebulizer of claim 16, wherein a first end of the liquid drawing element is in contact with the first open end of the liquid reservoir, and wherein a second end of the liquid drawing element faces the first face of the first plate and is positioned between the first plate and the second end of the cartridge.

18. The nebulizer of any one of claims 1 to 17, wherein the outlet is at the second end of the cartridge.