Acoustic nebulizer for delivery of active agents

Abstract

A nebulizer for spraying droplets, comprising: a housing; at least one piezoelectric substrate (2) housed within the housing and having a transducer surface (2a) on which at least one electroacoustic transducer (48) for generating acoustic wave energy in the at least one piezoelectric substrate (2) is disposed, and an opposing non-transducer surface (2b); a liquid supply system for supplying liquid to at least one of the transducer and non-transducer surfaces, the liquid supply system including a reservoir (3) for containing liquid and at least one relatively rigid supply conduit in contact with the at least one piezoelectric substrate (2) for supplying liquid from the reservoir (3) to the at least one piezoelectric substrate (2); and a sensor for detecting the volume of liquid on the at least one piezoelectric substrate (2).

Description

[Technical Field]

[0001] The described embodiments generally involve dissolving a liquid into small airborne droplets. Atomization Nebulizers for dispensing liquids, especially Atomization The present invention is directed to a nebulizer that uses acoustic wave energy to [Background technology]

[0002] liquid AtomizationThe use of surface acoustic waves (SAW) for nebulization has been proposed since the 1990s. See M. Kurosawa et al., 'Surface acoustic wave atomizer', Sensors and Actuators A:Physical, 1995, 50, 69-74. SAW nebulizers have since found applications in a variety of fields, including the administration of active drugs. Inhaled drugs are the most common form of treatment for asthma, chronic obstructive pulmonary disease (COPD), and other diseases associated with airflow limitation, such as obstructive bronchitis, emphysema, and cystic fibrosis. SAW technology has been used in a variety of applications, including fast droplet ionization for coupling with mass spectrometry (see 'SR Heron et al., 'Surface acoustic wave nebulization of peptides as a microfluidic interface for mass spectrometry', Analytical Chemistry, 2010, 82, 3985-3989), nanoparticle synthesis (see 'JR Friend et al., 'Evaporative self-assembly assisted synthesis of polymeric nanoparticles by surface acoustic wave atomization', Nanotechnology, 2008, 19, 1453010), and pulmonary delivery (see 'AERajapaksa et al., 'Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization', Respiratory Research, 2014, 15, 1). Atomization Extensive research and development is being conducted to improve the platform's performance.

[0003] Despite these ongoing efforts, the current state-of-the-art has not advanced beyond the laboratory environment to address the problems associated with converting the platform for practical and commercial use. These problems, often overlooked by researchers, include cumbersome and complex fluidic chip-to-reservoir interfaces, weak flow rates, and spurious ejection of large droplets (often occupying a large portion of the delivered volume), ultimately producing suboptimal nebulizers that can only be performed by expert users, rather than practical and commercially viable platforms that can be customized to fit specific laboratory applications and used reliably and easily by end users.

[0004] Such a SAW Atomization A particular challenge in using the platform concerns issues surrounding the liquids used and their supply to the device. A common approach has been to supply the liquid using a wick placed on the transducer surface of a piezoelectric substrate. The electroacoustic transducer, typically in the form of an interdigital transducer (IDT), is photolithographically applied to the piezoelectric substrate so that a SAW can propagate across the transducer surface. An arrangement using a supply wick is shown, for example, in US8991722 (Monash University).

[0005] However, the use of a wick on the transducer surface can result in undesired attenuation of the SAW, heating of the interface material, and sensitivity of performance to the spatial location of the liquid on the device, especially when acoustic energy is focused onto the chip. In addition, the subsequent liquid film with its complex multi-stage geometry can Atomization This often results in the generation of unintended large droplets (greater than 10 μm) and droplets up to 100 μm in size, which is particularly undesirable for pulmonary drug delivery applications where droplets on the order of 1 μm are required for deep lung deposition.

[0006] One proposed configuration to avoid at least some of the above problems is shown in WO 2014 / 132228 (RMIT University), in which the supply wick contacts the peripheral edge of the piezoelectric substrate, thereby minimizing energy losses associated with the wick and the supply liquid in contact with the transducer surface. Rather, the interaction of the SAW with the supply liquid at the peripheral edge is Atomization This leads to the formation of a thin liquid layer which may occur.

[0007] An alternative approach that has been proposed is to use conventional bulk acoustic waves (BAW) generated within the body of a piezoelectric substrate rather than SAW to penetrate the liquid. ed]] US6679436 (Omron) uses conventional bulk waves for this purpose. Atomization The SAW platform is used, but the SAW Atomization Instead, the liquid is applied to the non-transducing surface of the piezoelectric substrate, and bulk waves generated within the substrate propagate through the liquid. Atomization Used to:

[0008] The problems associated with prior art SAW and BAW platforms are due to the

Figure 1a

Figure 1b

[0009] Using SAW

Figure 1c

Figure 1d

[0010] International Publication No. WO2016 / 179664 (RMIT University) describes a method for treating a liquid

Figure 1e

Figure 2

Figure 3a

Figure 3b

[0011] An additional challenge for SAW nebulizer systems in administering active agents, including inhaled drugs, is the delivery of accurate and measurable doses to ensure the correct dose is received by the patient for therapeutic benefit. This prevents the patient from receiving, for example, an overdose. During inhalation, the flow rate of breathing gas may be variable, which may alter the dosage rate or make the inhalation therapy less effective, both of which may have adverse effects on the subject.

[0012] Considering the transient change in the load (i.e., piezoelectric chip resistance) with the increase / decrease of the fluid volume on top of the piezoelectric chip, the standard method for detecting the presence (ON / OFF state) of fluid and measuring the amount of fluid on the surface of the substrate is via a radio frequency (RF) signal supplied to the load / chip. However, this procedure requires connecting the RF signal to an oscilloscope and a current probe, which are not only expensive but also very difficult to miniaturize.

[0013] Another challenge with SAW nebulizer systems in administering active agents, including inhaled drugs, is the risk of airborne particles leaking from the surface, sides, or end of the tip.

Figure 3c

Figure 3d

Figure 3e

[0014] These and other SAW nebulizer systems also suffer from issues related to performance reliability, reproducibility, efficiency, and droplet distribution. In particular, systems utilizing single-crystal tips are prone to overheating failure, pyroelectric failure, and some configurations require the tip to be in constant contact with the liquid sample. There is room for improvement in the performance reliability and efficiency of such devices. Furthermore, for the administration of a diverse range of active pharmaceutical ingredients (APIs), various factors such as droplet size, geometric standard deviation (GSD) of droplet distribution, stabilization period (i.e., time of use), and volumetric efficiency have been identified.

Figure 4

[0015] The above discussion of the background art is included to explain the context of the described embodiments and should not be construed as an admission that the background art was known or part of the general public knowledge as of the priority date of any one of the claims herein.

[0016] Throughout this specification the word "comprise" or variations such as "comprises" or "comprising" will be understood to mean the inclusion of the stated elements, integers or steps, or groups of elements, integers or steps, and not the exclusion of any other elements, integers or steps, or groups of elements, integers or steps.

[0017] The term "acoustic wave energy" is used herein to refer to traveling and standing surface acoustic waves (SAWs), as well as bulk acoustic waves (BAWs), including surface reflected bulk waves (SRBWs), and combinations of said waves, particularly combinations of SAWs and SRBWs.

[0018] The term "liquid" is used herein to refer to a pure liquid or a liquid mixture containing a functional or therapeutic agent such as a pharmaceutical, plasmid DNA, peptide, fragrance, etc.

[0019] There is a need for an acoustic nebulizer that addresses, or at least provides an alternative to, one or more of the drawbacks associated with prior art acoustic nebulizers. Summary of the Invention

[0020] According to one aspect of the present disclosure, there is provided a nebulizer comprising: Housing and at least one piezoelectric substrate contained within the housing and having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the at least one piezoelectric substrate, and an opposing non-transducer surface; Transducer

Figure 5a

[0021] In one or more embodiments, the delivery conduit may be in the form of a nib or needle.

[0022] According to another aspect of the present disclosure, the droplets

Figure 5b

Figure 6

[0023] In one or more embodiments, the compliant material is selected from the group consisting of adhesive tape, silicone rubber, thermal paste, or combinations thereof. The compliant material may contact at least a portion of the periphery of the distal end of the at least one piezoelectric substrate.

[0024] In one or more embodiments, the at least one supply conduit may be a relatively rigid supply conduit in contact with the at least one piezoelectric substrate.

[0025] In one or more embodiments, the at least one delivery conduit is selected from the group consisting of a nib, a needle, a wick, a microchannel, or a combination thereof.

[0026] In one or more embodiments, the sensor detects the volume of liquid on the surface of the at least one piezoelectric substrate by measuring changes in current across the nebulizer, which may be direct current.

[0027] In one or more embodiments, the sensor may be configured to detect a volume of liquid on a transducer surface and / or a non-transducer surface of the at least one piezoelectric substrate.

[0028] In one or more embodiments, the nebulizer system (in which the current is measured) includes an electronic circuit and at least one piezoelectric substrate. The electronic circuit may include at least one printed circuit board. In one or more embodiments, the nebulizer may further include a control switch responsive to the sensor for controlling operation of the nebulizer.

[0029] In one or more embodiments, the nebulizer directs the liquid from the surface, side, or edge of the substrate.

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

[0030] In one or more embodiments, the liquid may be gravity fed from a reservoir or transferred from the reservoir via an active pumping system. In yet other embodiments, the liquid supply system further includes a flow regulator for providing a steady flow of liquid therefrom.

[0031] In one or more embodiments, the at least one piezoelectric substrate may be supported on a displaceable mount for controlling contact between the at least one piezoelectric substrate and the supply conduit.

[0032] In one or more embodiments, the nebulizer comprises:

Figure 15

[0033] In one or more embodiments, the housing may further include an inlet opening, and the reservoir may include a neck portion that can be received within the inlet opening.

[0034] In one or more embodiments, the nebulizer can include at least two piezoelectric substrates arranged in spaced, parallel, adjacent relationship.

[0035] In one or more embodiments, the droplet size control means controls the thickness of the meniscus of the liquid dispensed between adjacent substrate surfaces, thereby Atomization It may be configured to allow presetting of the spacing between the at least two piezoelectric substrates to control the size of the droplets.

[0036] In one or more embodiments, the droplet size control means controls the thickness of the meniscus of the liquid dispensed between the adjacent substrate surface and the interior wall, thereby Atomization The device is configured to allow presetting of the spacing of the at least two piezoelectric substrates from an inner wall of the housing to control the size of the droplets.

[0037] In one or more embodiments, the droplet size control means controls the thickness of the meniscus of the liquid supplied to the at least one piezoelectric substrate, thereby Atomization A liquid film-forming structure in fluid communication with the liquid supply conduit and the at least one piezoelectric substrate is included to control droplet size.

[0038] In one or more embodiments, the liquid film forming structure comprises a web, a mesh, one or more fibers, or slots for liquid supply conduits, or a combination thereof.

[0039] In one or more embodiments, at least a portion of the transducer surface, non-transducer surface, or a combination thereof, of the nebulizers of the described embodiments may be patterned.

[0040] In one or more embodiments, the generated acoustic wave energy may include surface acoustic waves (SAWs) propagating at the transducer surface of the at least one piezoelectric substrate. The acoustic wave energy may include surface reflected bulk waves (SRBWs) reflected between the transducer surface and a non-transducer surface of the at least one piezoelectric substrate. In one or more embodiments, the acoustic wave energy may include a combination of surface acoustic waves (SAWs) propagating at the transducer surface of the at least one piezoelectric substrate and surface reflected bulk waves (SRBWs) reflected between the transducer surface and a non-transducer surface of the at least one piezoelectric substrate. Surface acoustic waves (SAWs) may include standing waves, traveling waves, and combinations thereof. Surface reflected bulk waves (SRBWs) may include standing waves, traveling waves, and combinations thereof. As previously mentioned, an SRBW is generated when a SAW on a transducer surface of a piezoelectric substrate is internally reflected between the transducer surface and an opposing non-transducer surface of the substrate (i.e., the other side of the substrate) that is positioned in a parallel, adjacent relationship to the substrate surface. Thus, an SRBW is generated at the same frequency as a SAW. Hybrid acoustic waves that combine both SAWs and SRBWs can be generated due to their interrelationship and appear on both the transducer and opposing non-transducer surfaces.

[0041] As mentioned above, the liquid supply system Atomized In view of this and the fact that acoustic waves may appear on both the transducer surface and the opposing non-transducer surface, the liquid sample may be applied to the transducer surface, the opposing non-transducer surface, or both the transducer surface and the opposing non-transducer surface. Atomization In one embodiment, the liquid is removed from the transducer surface. Atomization In another embodiment, the liquid is removed from the non-transducer surface. Atomization In another embodiment, the liquid is drawn from both the transducer surface and the opposing non-transducer surface. Atomized will be done.

[0042] The piezoelectric substrate and electroacoustic transducer of the described embodiments may also be used to sense a liquid mass on at least one substrate. Unlike US6679436 (Omron), in which a surface acoustic wave (SAW) is used for sensing, a bulk acoustic wave (BAW) generated on the same substrate is used for sensing in the described embodiments. The electroacoustic transducer for the nebulizer according to the described embodiments may be an interdigital transducer (IDT). At least one piezoelectric substrate may be formed from lithium niobate (LiNbO).

[0043] In one embodiment, at least a portion of the non-transducer surface may further include a coating comprising at least one metal. In one embodiment, at least a portion of the transducer surface at the distal end of the substrate may further include a coating comprising at least one metal. The at least one metal may be titanium, gold, aluminum, chromium, copper, or a combination thereof.

[0044] The piezoelectric substrate may have a thickness at or near the wavelength of the SAW propagating on the transducer surface, which optimizes the generation of the SRBW within the substrate.

[0045] In one or more embodiments, the liquid is removed from the transducer surface, the non-transducer surface, or both the transducer and non-transducer surfaces. Atomization will be done.

[0046] In the nebulizer according to the described embodiment, the liquid is Atomization As a result, droplets having sizes ranging from 0.1 μm to 100 μm can be formed.

[0047] In one or more embodiments, the liquid is flowed at a rate of up to 10.0 ml / min. Atomization At the rate Atomization It can be done.

[0048] According to one embodiment of the nebulizer, the housing may be in the form of a cartridge having external electrical contacts connected to at least one electroacoustic transducer and an integrated liquid supply system.

[0049] In one or more embodiments, at least one piezoelectric substrate is bonded to a displacement mount.

[0050] In one or more embodiments, at least one piezoelectric substrate is bonded to the displacement mount with a sealing that provides a fluid-tight seal between the transducer surface and the displacement mount.

[0051] In one or more embodiments, the non-transducer surface includes one or more electroacoustic transducers.

[0052] In one or more embodiments, the droplets Atomization A nebulizer for generating acoustic wave energy is provided, the nebulizer comprising: a housing; at least one piezoelectric substrate housed within the housing and having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the at least one piezoelectric substrate; Atomization at least one opposing electroacoustic transducer for generating acoustic wave energy in opposite directions to reduce the extent to which liquid is displaced from the transducer surface prior to the piezoelectric substrate being moved; and a liquid supply system for supplying liquid to the at least one piezoelectric substrate.

[0053] In one or more embodiments, the droplets Atomization A nebulizer for generating acoustic wave energy is provided, the nebulizer comprising: a housing; at least two piezoelectric substrates contained within the housing, the at least two piezoelectric substrates being arranged in spaced-apart, parallel, adjacent relationship, each having a respective transducer surface with at least one electroacoustic transducer disposed thereon for generating acoustic wave energy within the respective piezoelectric substrate; and a liquid supply system for supplying liquid to at least one of the piezoelectric substrates. Atomizationa control means for controlling the size of the droplets, the control means controlling the thickness of a meniscus of the liquid dispensed between adjacent substrate surfaces, thereby Atomization and a control means configured to enable presetting of the spacing between the at least two piezoelectric substrates to control the size of the droplets.

[0054] In one or more embodiments, the droplets Atomization A nebulizer for generating acoustic wave energy is provided, the nebulizer including a housing, at least one piezoelectric substrate housed within the housing and having a transducer surface and an opposing non-transducer surface on which at least one electroacoustic transducer for generating acoustic wave energy within the substrate is disposed, and Atomization and a liquid supply system for supplying liquid to at least one of the non-transducer surfaces, the liquid supply system including a reservoir for containing liquid and at least one relatively rigid supply conduit in contact with the at least one piezoelectric substrate for supplying liquid from the reservoir to the at least one piezoelectric substrate.

[0055] In one or more embodiments, the droplets Atomization The nebulizer for generating acoustic wave energy includes a housing, at least one piezoelectric substrate housed within the housing and having a transducer surface and an opposing non-transducer surface on which at least one electroacoustic transducer for generating acoustic wave energy within the at least one piezoelectric substrate is disposed, a compliant material in contact with at least a portion of a peripheral surface of the at least one piezoelectric substrate, and a compliant material for generating acoustic wave energy within the at least one piezoelectric substrate. Atomization and a liquid supply system for supplying liquid to at least one of the non-transducer surfaces, the liquid supply system including a reservoir for containing liquid and at least one supply conduit for supplying liquid from the reservoir to the at least one piezoelectric substrate.

[0056] In one or more embodiments, the at least one electroacoustic transducer may be configured to provide an output indicative of a volume of liquid on the at least one piezoelectric substrate.

[0057] In one or more embodiments, the output provided by the at least one electroacoustic transducer may be an electrical current.

[0058] In one or more embodiments, the nebulizer may further include a sensor for detecting the volume of liquid on the at least one piezoelectric substrate.

[0059] In one or more embodiments, at least one electroacoustic transducer is Atomization obtain.

[0060] In one or more embodiments, the nebulizer comprises: Atomization may further include at least one opposing electroacoustic transducer for generating acoustic wave energy in an opposing direction to reduce the extent to which liquid is displaced from the at least one piezoelectric substrate prior to

[0061] In one or more embodiments, at least one opposing electroacoustic transducer may be configured to provide an output indicative of a volume of liquid on the at least one piezoelectric substrate.

[0062] In one or more embodiments, the output provided by the at least one opposing electroacoustic transducer may be an electrical current.

[0063] In one or more embodiments, at least one opposing electroacoustic transducer Atomization obtain.

[0064] In one or more embodiments, the nebulizer comprises: Atomization It may further comprise a control means for controlling the size of the droplets.

[0065] In one or more embodiments, the nebulizer can include at least two piezoelectric substrates arranged in spaced, parallel, adjacent relationship.

[0066] In one or more embodiments, the droplet size control means controls the thickness of the meniscus of the liquid dispensed between adjacent substrate surfaces, thereby Atomization It may be configured to allow presetting of the spacing between the at least two piezoelectric substrates to control the size of the droplets.

[0067] In one or more embodiments, the droplet size control means controls the thickness of the meniscus of the liquid dispensed between the adjacent substrate surface and the interior wall, thereby Atomization It may be configured to allow presetting of the spacing of the at least two piezoelectric substrates from the inner wall of the housing to control the size of the droplets.

[0068] In one or more embodiments, the droplet size control means controls the thickness of the meniscus of the liquid supplied to the at least one piezoelectric substrate, thereby Atomization A liquid film forming structure in fluid communication with the liquid supply conduit and the at least one piezoelectric substrate may be included to control droplet size.

[0069] In one or more embodiments, the liquid film forming structure may include a web, a mesh, one or more fibers, or slots of liquid supply conduits.

[0070] In one or more embodiments, a nebulizer system is provided, the nebulizer system including the nebulizers disclosed above, the nebulizers being a first nebulizer and a second nebulizer.

[0071] In one or more embodiments, the first nebulizer Atomization The second nebulizer includes a contact surface. Atomization Includes contact surface.

[0072] In one or more embodiments, the first nebulizer AtomizationThe contact surface is the second nebulizer Atomization On the contact surface Atomization do.

[0073] In one or more embodiments, the first nebulizer Atomization The contact surface may be a transducer surface or a non-transducer surface, and the second nebulizer Atomization The contact surface is a transducer surface of the second nebulizer or a non-transducer surface of the second nebulizer.

[0074] According to another aspect of the present disclosure, a method for dispensing a liquid using a nebulizer as described above or a nebulizer system as described above is provided. Atomization A method is provided.

[0075] The method comprises dissolving a liquid to form droplets having a size in the range of 0.1 to 100 μm. Atomization Smaller droplet sizes between 1 and 5 μm are ideal for inhalation applications of therapeutic agents. However, it should be understood that larger droplet sizes above 10 μm can be formed if necessary for other applications, including fragrances, cosmetics, insecticides, paints, or preservatives.

[0076] This method allows for a maximum flow rate of 10.0 ml / min. ​ Liquid at the rate ​ The method may further include:

[0077] This method involves dissolving a liquid to form droplets with a geometric standard deviation (GSD) of less than 10 μm. ​ The method may further include:

[0078] The method involves transferring a liquid containing a functional or therapeutic agent, such as a pharmaceutical, plasmid DNA, RNAi, peptide, protein, and cell, or a non-therapeutic agent, such as a fragrance, cosmetic, preservative, pesticide, or paint. ​In one or more embodiments, the functional or therapeutic agent may be delivered as a unit dose, in one or more embodiments, the unit dose is determined by a sensor for detecting the volume of liquid on the surface of the substrate.

[0079] Fluid delivery in a nebulizer according to the present disclosure and ​ The use of both transducer and non-transducer surfaces for ​ SAW rate (typical 0.1-0.2 ml / min) ​ rates (over 1 ml / min compared to previous models) but also typically have poor acoustic matching characteristics. ​ When coupled to materials typically used for fluid delivery in construction (glass, wicks, PDMS, etc.), it also avoids undesirable heating due to viscous dissipation of acoustic wave energy. Additionally, nebulizer constructions according to the present disclosure may also reduce contact of chemicals and sensitive samples with the electroacoustic transducer. This has the advantage of protecting the transducer's electrodes from harsh chemicals as well as protecting any sensitive biological samples from the strong electric fields generated by the electrodes. [Brief explanation of the drawings]

[0080] It will be convenient to further describe the embodiments with reference to the accompanying drawings, which show embodiments of a nebulizer. Other embodiments are possible, and therefore the particularity of the accompanying drawings should not be understood as superseding the generality of the foregoing description.

[0081] ​ FIG. 1 is a cross-sectional side view of a nebulizer according to one embodiment. ​ FIG. 1 is a close-up view of a liquid delivery system comprising a pen tip or needle, according to one embodiment. ​ FIG. 2 is a side detail view of a nebulizer according to one embodiment. ​ FIG. 10 is a detailed cross-sectional side view of another embodiment of a nebulizer. ​FIG. 10 is a side cross-sectional view of another embodiment of a nebulizer. ​ FIG. 1 is a perspective view of a platform that holds a piezoelectric substrate for a nebulizer. ​ FIG. 1 is an orthogonal view of the transducer surface of a nebulizer. ​ 3b is an orthogonal view of the transducer surface of another embodiment of the described nebulizer, highlighting the peripheral surface of the substrate. As described, the compliant absorbent material may be in contact with at least a portion of the peripheral surface of the substrate surfacer, which is highlighted in FIG. ​ 10A-10C are orthogonal views of the transducer surface of another embodiment of the described nebulizer-enhancing coating on the distal end of the transducer surface and areas suitable for patterning. ​ 1 is a representative example of the described nebulizer in which the non-transducer surfaces of the described nebulizer are partially coated. ​ 10A-10C are orthogonal views of the transducer surface of another embodiment of the described nebulizer-enhancing coating on the distal end of the transducer surface of the substrate. ​ 4a and 4b are side cross-sectional views of another embodiment of a nebulizer. ​ 1 is a graph of the ejected droplet size distribution of a nebulizer without a baffle. ​ 1 is a graph of the ejected droplet size distribution of a nebulizer with a baffle. ​ 1 is a graph showing mass sensing of Humalog (insulin dosing) as a function of frequency. ​ 10 is a graph showing atomization distribution data for a nebulizer according to one embodiment in which the non-transducer substrate surface is coated with titanium and gold. ​ (a) Standard method for monitoring RF loads, and (b) a representative example of a sensor for detecting the volume of liquid on a surface. ​A representative example of a sensor for detecting the volume of liquid on a surface according to the described embodiments, wherein the sensor is adapted to detect the presence (ON / OFF) of liquid and / or the volume of liquid on the surface, and the nebulizer system is adapted to administer an active agent, and the volume of liquid on the surface can be equal to a unit dose of a given active agent to be administered. ​ This is a representative embodiment in which the nebulizer includes two opposing IDTs, with the black square representing the atomization zone between the IDTs. ​ The dashed lines are representative embodiments in which the nebulizer includes structure to retain fluid on a surface, for example, indicating the location of a gasket around the atomization area. ​ Representative examples of liquid film forming structures including, for example, a. a bundle of fibers or webs at an interface and in fluid communication between a substrate and a liquid supply conduit, b. a side view of a thin meniscus formed between the fibers or webs on the substrate, c. a microslot in a liquid supply conduit, and d. a side view of a thin film generated by the microslot in the liquid supply conduit during operation. ​ 1 is an exemplary embodiment of a nebulizer including a sealing that provides a fluid-tight seal between the transducer surface and the nebulizer mount. ​ 1 is an exemplary embodiment of a nebulizer system including a first nebulizer and a second nebulizer provided at an angle relative to the first nebulizer. ​ 15 is a representative embodiment of the nebulizer system of FIG. 14 showing a first trajectory of atomization and a second trajectory of atomization. DETAILED DESCRIPTION OF THE INVENTION

[0082] 1a and 1c, a first embodiment of a nebulizer according to the present disclosure is shown. The nebulizer includes a mount 1 supporting a piezoelectric substrate 2. The piezoelectric substrate 2 includes a transducer surface 2a on which an electroacoustic transducer 48 is disposed. The electroacoustic transducer 48 includes or is in the form of an interdigital transducer (IDT) (not shown). The substrate 2 further includes a non-transducer surface 2b. The non-transducer surface 2b may be disposed or provided on a surface of the substrate 2 opposite or opposite the transducer surface 2b. As shown, the non-transducer surface 2b may be disposed in a parallel, adjacent relationship to the transducer surface 2a.

[0083] Referring to FIG. 3( a), the electroacoustic transducer 48 includes or is in the form of one or more interdigital transducers (IDTs) 35. The electroacoustic transducer 48 includes or spans at least a portion of the substrate 2 and includes a main IDT bar 30. The electroacoustic transducer 48 includes an electrical contact end 32. The electroacoustic transducer 48 includes a shield 28. The shield 28 includes a first elongated portion 60 and a second elongated portion 62. The first elongated portion 60 is substantially perpendicular to the second elongated portion 62. The first elongated portion 60 is substantially perpendicular to the main IDT bar 30. The shield 28 can help reduce the extent to which waves generated by the electroacoustic transducer 48 (e.g., surface acoustic waves or surface-reflected bulk waves, as described in more detail below) reach the substrate 2 or the periphery 64 of the electrical contact end 32. Waves that reach the perimeter 64 of the substrate 2 or the electrical contact ends 32 can cause damage and reduce the lifespan of the substrate 2 and / or the electroacoustic transducer 48. The electroacoustic transducer 48 includes bends 29. In particular, the main IDT bars 30 can each include one or more bends 29. The bends 29 can help reduce the extent to which the generated waves reach the perimeter 64 of the substrate 2 or the electrical contact ends 32. The electroacoustic transducer 48 includes reflector bars 31. The reflector bars 31 can help reduce the extent to which the generated waves reach the perimeter 64 of the substrate 2 or the electrical contact ends 32.

[0084] The nebulizer includes a liquid supply system configured to supply liquid to the substrate 2, i.e., the liquid supply system is configured to supply liquid to the transducer surface 2a and / or the non-transducer surface 2b. ​The liquid supply system further includes a liquid reservoir 3 containing a liquid 4 to be nebulized. In some embodiments, the liquid supply system includes the liquid reservoir 3. The reservoir 3 can be in the form of a bottle or vial having a threaded neck 3a that can be threaded into a threaded inlet opening 5 provided in a housing (not shown). The liquid supply system may also include a supply conduit 6, as described herein. The supply conduit 6 can be relatively rigid. The nebulizer is shown in its use position in FIGS. 1a and 1c, allowing the liquid 4 to be gravity-fed from the reservoir 3 through a relatively rigid supply conduit 6 in the form of a nib or needle 6. A liquid meniscus 7 is formed at the end of the nib or needle 6 on the transducer surface 2a (FIG. 1b). RF power is supplied to the electroacoustic transducer 48 via electrical contacts 8. This generates a surface acoustic wave (SAW) on the transducer surface 2a, which in turn generates a surface-reflected bulk wave (SRBW) that is reflected between the transducer surface 2a and a non-transducer surface 2b. The unique hybrid wave configuration of SRBW combined with SAW allows liquid 4 to be drawn from the liquid meniscus 7 across the transducer surface 2a. If accumulation of liquid 4 occurs at the edge of the transducer surface 2a, the acoustic wave energy will pull the liquid 4 around the edge of the substrate 2 onto the non-transducer surface 2b of the substrate 2, where it ​ The gravity feed configuration allows for a continuous, self-regulated flow of liquid for priming the needle or nib 6.

[0085] More specifically, the supply pump, gravity feed, or capillary action of the nib or needle 6 simply acts to prime it. The liquid 4 is then drawn onto the surface of the substrate 2 by acoustic waves, as shown in FIG. 1b. In some embodiments, the liquid delivery system, i.e., the nib or needle 6, is in contact with the substrate 2. This is in contrast to the capillary-driven liquid delivery to a feed channel etched into the substrate in International Publication No. WO 2012 / 096378 (Panasonic Corp.). By drawing the liquid from the nib or needle 6 onto the substrate 2 by acoustic waves,​ Only the liquid that is drawn onto the device is therefore avoided from spilling.

[0086] The choice of material for the nib or stylus 6 may include acoustically reflective materials. Acoustically absorbing materials tend to absorb, and therefore attenuate, acoustic energy on the substrate 2. Such materials may include metals, polymers, or ceramic materials.

[0087] Some nebulizer designs use mesh to ​ These nebulizers attempt to control and maintain droplet size uniformity. They rely on the piston action generated by ultrasound or other bulk standing waves to push and pull the liquid through a mesh to generate droplets. Without a mesh, these nebulizers would be unable to function because the standing bulk waves would generate a liquid film of uneven thickness across the associated substrate, subsequently generating large, uneven droplets. Furthermore, such meshes are prone to clogging. The nebulizer embodiments described herein provide surface acoustic waves and surface-bulk reflected waves with standing and traveling wave components, even on the non-transducer surface 2b of the substrate 2. This draws the liquid into a thin film across the substrate 2, resulting in the uniform generation of smaller droplets.

[0088] The housing may include at least one baffle 9, which may be formed, for example, by a wall of the housing. The at least one baffle 9 may be spaced apart from the transducer surface 2a and disposed in a generally parallel adjacent relationship to the transducer surface 2a. Similarly, the at least one baffle 9 may be spaced apart from the non-transducer surface 2b and disposed in a generally parallel adjacent relationship to the transducer surface 2b. The at least one baffle 9 may extend along at least a portion of the length of the substrate 2, providing a simple means of asserting control over droplet size uniformity. Due to the angle at which the acoustic wave energy couples with the liquid 4 (known as the Rayleigh angle), larger droplets 11, on the order of 10 μm to 100 μm in size, are ejected from the substrate surface 2a with greater momentum than smaller droplets. This is because droplets project at the same angle. ​ These large droplets 11 then impact the surface of the baffle 9 and are consequently redirected back to the substrate surface 2a, where they are resupplied to the existing liquid supply from the reservoir 3. Thus, the liquid that was previously part of the returned droplets 11 is again ​ On the other hand, smaller droplets 10, having a size on the order of about 1 μm, have significantly less momentum and therefore do not reach the surface of the baffle 9. Rather, the small droplets 10 are entrained in the airflow exiting the nebulizer. A similar droplet size control process also occurs between the non-transducer surface 2 b and the corresponding baffle surface 9 adjacent to the non-transducer surface 2 b.

[0089] FIG. 1d illustrates another embodiment of a nebulizer according to the present disclosure, utilizing at least two piezoelectric substrates 12, 13 supported in a stacked configuration within the nebulizer. Three or more piezoelectric substrates may also be stacked in a parallel, adjacent position within the nebulizer. Each piezoelectric substrate 12, 13 has a configuration similar to the embodiment shown in FIGS. 1a and 1c, with an electroacoustic transducer 48 disposed on a transducer surface 12a, 13a of each substrate 12, 13, generating acoustic wave energy within each substrate, which is then delivered to both the substrate surface 12a, 13a and the parallel, adjacent (or opposite) non-substrate surface 12b, 13b of each substrate 12, 13. ​ The housing also includes a lower baffle 9a positioned parallel to and adjacent to the transducer surface 13a of the lower substrate 13, which aids in droplet size control as described above. A similar effect occurs between the non-transducer surface 12b of the upper substrate 12 and the baffle 9b opposite that surface. The orientations of the transducer 12a, 13a and non-transducer 12b, 13b surfaces of the two substrates 12, 13 may be interchanged, as long as the respective transducer surfaces 12a, 13a and non-transducer surfaces 12b, 13b are opposite or parallel and adjacent to each other. However, this configuration provides an additional means for controlling droplet size uniformity. Liquid is also confined in the interstitial space 14 between the two substrates 12, 13, between the transducer surface 13a of the lower substrate 13 and the lower baffle surface 9a, and between the non-transducer surface 12b of the upper substrate 12 and the upper baffle surface 9b. The thickness of the liquid meniscus 7 is a parameter used in controlling droplet size. Therefore, by adjusting the relative spacing between each substrate 12, 13 and the baffle surfaces 9a, 9b, the meniscus thickness can be controlled, thereby ​ The droplet size can be made uniform. Therefore, this configuration makes it possible to control the droplet size by adjusting the above-mentioned spacing. It is also envisioned that by having multiple spacings, multiple droplet sizes can be obtained.

[0090] FIG. 1e illustrates another embodiment of a nebulizer according to the present disclosure, utilizing at least two piezoelectric substrates 12, 13 supported in a stacked configuration within the nebulizer. Similar to the embodiment described in FIG. 1d, the liquid is confined within the interstitial space 14 between the two substrates 12, 13. Unlike FIG. 1d, the liquid meniscus 7 need not be in contact with both substrates 12 and 13. Furthermore, in one embodiment, the nib or needle 6 may deliver the liquid 6 in direct contact with the surface of one of the substrates 12. In another embodiment, the nib or needle 6 may not contact the surface of the substrate 12, but may be positioned such that the liquid 6 is delivered in contact with the surface of the substrate 12. It is contemplated that the at least two piezoelectric substrates 12, 13 may be the same or different. For example, one or more of the substrates may be patterned, as described in detail below, to provide further control of the nebulizer output parameters.

[0091] Furthermore, considering the configurations of Figures 1d and 1e, e.g. ​ Since there are multiple substrate surfaces where ​ Adjacent substrate surfaces can be repositioned such that unintended large droplets ejected from one substrate surface are collected on the adjacent substrate surface and re-ejected until smaller droplets are generated. ​ The substrate can also function as an active baffle, providing a passive physical baffle, rather than the passive physical baffle provided by the interior walls of the housing. This approach can be thought of as an active substrate baffle, rather than the passive physical baffle provided by the interior walls of the housing. This system can be enhanced by promoting standing waves or regions of standing waves using the techniques described above.

[0092] The same piezoelectric substrates 2, 12, 13 and electroacoustic transducer 48 can also be triggered at a lower frequency (approximately 3.5 MHz for a 500 μm thick substrate) corresponding to the fundamental thickness mode (BAW) of the substrate for sensing purposes. The reason for using the thickness mode for sensing is, but is not limited to, that a single crystal, such as the 128YX lithium niobate piezoelectric crystal used, is naturally 10 4 ~10 6Such a platform has a high quality factor Q of about 10 ng. Therefore, such a platform can efficiently detect ​ The nebulizer embodiments described herein can simultaneously perform both efficient mass sensing and efficient mass sensing. Both functions can be achieved with the same electrode pattern, unlike other known devices that incorporate different electrode patterns and / or require completely different additional electrodes for different microfluidic functions. While these other devices are triggered at a specific resonant frequency, the nebulizer embodiments described herein can simultaneously perform both efficient mass sensing and efficient mass sensing. ​ and sensing functions, i.e., the same circuit can be used to operate in two modes, i.e., ​ A first mode for detecting and a second mode for sensing are enabled. In some embodiments, the sensing modes may be those described in International Publication No. WO2015054742A1, the contents of which are incorporated herein by reference.

[0093] Thus, the nebulizer according to the described embodiments uses a nebulizer to determine the actual dose administered to the user by subtracting from the total dose delivered: ​ The ability to sense residual mass within the nebulizer can be added. Additionally, the nebulizer embodiments described herein advantageously do not require multiple containment sections (e.g., fluid containment components) to enable the sensing function, which is an advantage over other devices that require multiple containment sections.

[0094] In the above embodiment of Figures 1a and 1c, liquid 4 is gravity fed to a pen tip or stylus 6. The pen tip or stylus 6 presses against the edge of the transducer surface 2a, forcing the liquid 4 into contact with the transducer surface 2a where it forms droplets 10, 11. ​Robust contact between the nib or stylus 6 is achieved by displacing the mount 1 toward the nib or stylus 6, which is preloaded with a force and applies a constant pressure under displacement (not shown). In one embodiment, the preloaded force is achieved by fastening the mount 1 to a cantilever or by configuring the mount 1 with a pivot 15 and a resilient member, for example, in the form of a spring 16 configuration fixed to a housing (not shown). The displacement of the mount 1 caused by pressing the nib or stylus 6 against the substrate 2 allows constant pressure and contact to be achieved between the end of the nib or stylus 6 and the transducer surface 2a, allowing a meniscus 7 to form and be maintained. This meniscus 7 provides a pressure equal to the pressure of the sealed reservoir 3, preventing liquid from freely flowing from the reservoir 3 onto the substrate. The ability to displace and apply pressure to the mount 1 means that a rigid nib or stylus 6 can be effectively used in direct contact with the substrate. Referring to FIG. 1b, the pen tip or stylus resonates with the acoustic wave energy, allowing the acoustic wave energy to draw the liquid 4 from the pen tip or stylus 6 across the substrate surface 2. ​During this time, the loss of liquid 4 reduces the meniscus 7. The resulting negative pressure then draws additional liquid 4 through the nib or needle 6, replenishing the meniscus 7. When the relative pressure in the reservoir 3 is low enough due to the outflow of liquid 4 through the nib or needle 6, air bubbles enter the reservoir 3 through the inlet hole 17, balancing the pressure and allowing liquid 4 to be drawn by the nib or needle 6. This process continues until the reservoir 3 is depleted. It is contemplated that multiple nibs or needles can be used to increase the flow rate and system reliability. However, it is also contemplated that a pressure relief valve can be used to provide a controlled flow of liquid over the transducer surface 2a. It is further contemplated that the edge of the substrate 2 is immersed in the meniscus, and liquid is provided through a closely spaced orifice. Alternatively, it is contemplated that an active pumping system, such as a syringe or peristaltic pump, can be used to actively deliver liquid onto the substrate surface 2a. An active pumping system may be preferred in situations where liquids with high surface tension and / or high viscosity need to be delivered to the transducer surface 2a.

[0095] The flow regulator 19 may also be used in conjunction with the gravity-feed system, adjacent orifice, or active pump system described above. It is also envisioned that the flow regulator 19 may operate similarly to a fountain pen. Such a configuration is shown in FIG. 1a, in which fluid in a reservoir 3 flows into an internal chamber 18 via the flow regulator 19. The flow regulator 19 includes a liquid outlet passage 20 through which the liquid 4 can pass and an air inlet passage 21 connected to the reservoir 3. The flow regulator 19 thus provides a steady supply of liquid 4 that would otherwise be interrupted by the release of air bubbles through the inlet passage 21, thereby balancing the air pressure outside and inside the reservoir 3. The liquid 4 is delivered to the internal chamber 18. The internal chamber 18 has a peripheral opening 22 that connects to the nib or needle 6 and through which the nib or needle 6 is housed. Therefore, the nib or needle 6 is constantly moistened with the liquid 4.

[0096] The electrical contact ends of the substrate 2 are pressed into direct contact with the mount 1 to dissipate localized heating that could damage the substrate 2. This pressing can be achieved by applying pressure via a contact cantilever 23 in which the wide electrical contact 8 is embedded, e.g. ​ The mounting surface 48 is preferably a conductive material that mitigates harmful arcing between the electrical contact 8 and the substrate 2 under the high voltages that occur during mounting. Pressure on the base of the contact cantilever 23 can be applied, for example, via a magnetic attraction effect or by using the screw 24 to depress the spring washer 25. Alternatively, pressure may be applied via a spring-loaded electrical contact. It is further envisioned that a conductive material may be bonded directly to the electroacoustic transducer 48 as an alternative to electrical contacts. A heat sink surface (not shown), which may be incorporated into the mount 1, may also be utilized by pressing the pen tip or stylus 6 against the parallel substrate 2, which then remains in contact with the heat sink. ​ The heat sink can also cool the substrate 2. ​ To further increase the robustness of the system during ​ The mount 1 may be characterized by a shape that retains a small amount of excess liquid in contact with the edge. The mount 1 may also be made from a conductive material, such as metal, that allows for easy discharge of excess pyroelectrically induced charge. This reduces the possibility of harmful arcing across the substrate 2, extending the life of the substrate 2.

[0097] It is recognized that one of the challenges of SAW nebulizer systems in administering active agents, including inhaled drugs, is the delivery of an accurate and measurable dose to ensure the correct dose is received by the patient for therapeutic benefit. Thus, in yet other embodiments, a nebulizer according to the described embodiments may include one or more sensors for detecting the volume of liquid on the surface of the substrate by measuring changes in current across the nebulizer system. In one or more embodiments, the nebulizer system includes an electronic circuit and at least one piezoelectric substrate. In some embodiments, the sensor measures changes in direct current (DC) across the nebulizer system to detect the volume of liquid on the surface of the substrate. It should be understood that the electronic circuit may include at least one printed circuit board (PCB). Thus, the same circuit (i.e., the circuit of the nebulizer including the electroacoustic transducer) may be used to ​ It can be used for both sensing and detection.

[0098] In some embodiments, the electroacoustic transducer 48 is configured to indicate the volume of liquid on the at least one piezoelectric substrate 2. That is, the electroacoustic transducer 48 is configured to provide an output indicative of the volume of liquid on the at least one piezoelectric substrate 2, as described herein. The output may be a current passing through the electroacoustic transducer 48. Thus, the electroacoustic transducer 48 may be configured to provide an output indicative of the volume of liquid on the at least one piezoelectric substrate 2, as described herein. ​ It is possible to both measure the volume of liquid on the at least one piezoelectric substrate 2 and sense the volume of liquid on the at least one piezoelectric substrate 2.

[0099] The sensors disclosed herein can function independently of the size or shape of the nebulizer's electrical circuitry (e.g., electroacoustic transducers 48, 50). The sensors can also function regardless of the size or shape of the substrate 2. These are both significant advantages offered over other nebulizers.

[0100] The approach described herein measures the DC current input across the entire circuit (shown in Figure 8b). This is not trivial, considering the many downstream variables, from the DC signal to the PCB to the load. It is envisioned that the PCB design can be carefully configured to eliminate any variations in the current input, except for changes in the load past the RF signal output. Figure 9 shows that as soon as liquid comes into contact with the chip, the overall current supplied to the entire PCB circuit increases, and then decreases as the fluid is removed (Figure 9b). ​ This is an example of a system-wide approach to fluid detection, where the PCB and board / load are considered as one entity. This approach therefore offers a very simple approach to monitoring fluid via DC current fluctuations, in contrast to existing systems that instead measure downstream RF (shown in Figure 8a). It is envisioned that DC current fluctuations can be easily monitored, for example, within an on-board current counter (i.e., a small component added to the PCB). For example, such a sensor adapted to measure DC across an entire circuit could serve as a means to measure fluid volume on the surface of the board, as well as provide a warning when the liquid volume falls below or exceeds a desired threshold. ​ It should be understood that the nebulizer may also optionally act as a switch for the process (i.e., ON / OFF). Thus, in one or more embodiments, the nebulizer of the described embodiments may further include a control switch responsive to the sensor for controlling operation of the nebulizer. In one or more other embodiments, the nebulizer may further include a control valve responsive to the sensor for controlling the flow of fluid to the substrate.

[0101] The sensor may be configured to connect a PCB circuit (e.g., a liquid sensor) to provide an indication of the amount of liquid 4 on the substrate 2. ​ The nebulizer, or an associated component (e.g., a computing device), may use the readings output by the sensor to indicate the amount of liquid on substrate 2 over a specified period of time. ​The amount of liquid dispensed can be determined. ​ The amount of liquid dispensed can be equal to or related to the amount of liquid delivered from the nebulizer (e.g., to a user of the nebulizer). ​ This can be the volume or mass of liquid dispensed. ​ This has advantages over other nebulizers because it may only be possible to determine the presence or lack of liquid, rather than the amount dispensed.

[0102] In still other embodiments, it is envisioned that this approach can be extended to other types of fluids with different conductivities or viscosities and used to monitor the properties of the fluids.

[0103] It is further understood that the sensor for detecting the volume of liquid on the surface of the substrate can be adapted for accurate and measurable dosage delivery of active agents, including inhaled drugs. In one or more embodiments, the administration of a single unit dose can be determined by the sensor for detecting the volume of liquid on the surface of the substrate. In yet other embodiments, a method for administering a functional or therapeutic agent as a single unit dose is provided.

[0104] from the surface, side, or edge of the board ​ It is understood that fluid loss remains a challenge for SAW nebulizer systems in administering active agents, including inhaled drugs. ​ This can occur if the acoustic wave drives the liquid away from the surface before the ​ Fluid loss can alter the dosage rate or make the inhalation therapy less effective, which can have adverse effects on the subject. Therefore, in one or more embodiments, ​The nebulizer further includes at least one opposing electroacoustic transducer 50 for generating acoustic wave energy in opposing directions to prevent liquid from being dislodged from the surface of the substrate prior to dislodging the liquid. The electroacoustic transducer 48 may be referred to as a first electroacoustic transducer. The at least one opposing electroacoustic transducer 50 may be referred to as a second electroacoustic transducer. The at least one opposing electroacoustic transducer 50 includes or is in the form of one or more interdigital transducers (IDTs) 35. The IDTs 35 of the at least one opposing electroacoustic transducer 50 may be similar to or the same as the IDTs 35 described with reference to the electrostatic transducer 48. The at least one opposing electroacoustic transducer 50 includes at least a portion of the substrate 2 or spans at least a portion of the substrate 2 and includes a main IDT bar 56. The electroacoustic transducer 48 includes an electrical contact end 66. The electrical contact end 66 may be similar to or the same as the electrical contact end 32 previously described. The main IDT bar 56 may be similar to or the same as the main IDT bar 30 described with reference to the electrostatic transducer 48. At least one opposing electroacoustic transducer 50 includes a shield 52. The shield 52 may help reduce the extent to which waves (e.g., surface acoustic waves or surface-reflected bulk waves) generated by the at least one opposing electroacoustic transducer 50 reach the substrate 2 or the periphery of the electrical contact edge 66. Waves reaching the periphery of the substrate 2 or the electrical contact edge 66 can cause damage and reduce the lifespan of the substrate 2 and / or the electroacoustic transducer 50. The shield 52 may be similar to or the same as the shield 28 described with reference to the electrostatic transducer 48. At least one opposing electroacoustic transducer 50 includes a bend 54. In particular, the main IDT bars 30 may each include one or more bends 54. The bends 54 may help reduce the extent to which the generated waves reach the substrate 2 or the periphery of the electrical contact edge 66. At least one opposing electroacoustic transducer 50 includes a reflector bar 58 .The reflector bar 58 may help reduce the extent to which generated waves reach the perimeter of the substrate 2 or the electrical contact edges 66. The reflector bar 58 may be similar to or the same as the reflector bar 31 described herein. Figure 10 provides a representation of such a configuration of opposing electroacoustic transducers 48, 50 (which may be in the form of IDTs), with features such as shields 28, 52, bends 29, 54, main IDT bars 30, 56, and reflector bars 31, 58 added accordingly.

[0105] Surprisingly, the distance between the opposing electroacoustic transducers 48, 50 ​ It has been found that the fluid can advantageously prevent excess fluid from being acoustically driven away from the surface, distal end, or sides of the substrate 2. Advantageously, such an arrangement of opposing electroacoustic transducers 48, 50 provides a stable acoustically coupled space between the opposing electroacoustic transducers 48, 50. ​ Provides Zone 45, ​ Area, and thus potential ​ It is assumed that this can effectively increase the rate. ​ By providing opposing electroacoustic transducers 48, 50 on either side of zone 45, the nebulizer can generate opposing acoustic waves that interact with each other. That is, at least one opposing electroacoustic transducer 50 can generate an acoustic wave that is equal in magnitude to, but in the opposite direction to, the acoustic wave generated by electroacoustic transducer 48. The opposing acoustic waves can be generated in a stable manner. ​ It may provide stability in zone 45. In some cases, if at least one opposing electroacoustic transducer 50 is not provided, a stable ​ Liquid in zone 45 may be repelled from electroacoustic transducer 48 by the acoustic waves generated by electroacoustic transducer 48. Thus, the liquid ​ The above-described embodiment is not suitable for the above-described embodiment, but may fall off the substrate 2. ​ The liquid stabilized until ​ It can be configured to ensure that it remains within zone 45, thus providing a solution to this problem.

[0106] Degradation of the substrate 2 can be reduced by providing (e.g., bonding) a relatively acoustically non-absorbing material to the substrate 2. In some embodiments, the acoustically non-absorbing material is selectively provided to the substrate. For example, the acoustically non-absorbing material may provide a stable ​ It can be bonded to the substrate above zone 45. This allows for stable ​ The deterioration of the zone 45 can be reduced. The acoustically non-absorbing material can be a metal. The metal can be applied to the substrate 2, for example, by a stable ​ Zone 45 can be electroplated.

[0107] In yet other embodiments, such as that shown in Figure 11, a nebulizer is provided in which the substrate 2 further comprises a retaining barrier structure 46. The retaining barrier structure 46 comprises: ​ Hold the liquid and / or surface before atomization ​ The purpose of the retaining barrier structure 46 is to prevent or reduce the loss of the applied liquid. By way of example, such a retaining barrier structure 46 may include a lip, a wall, a gasket, a deposited raised membrane, or a combination thereof. ​ A representation of such a retention barrier structure 46 for retaining liquid and / or preventing or reducing loss of liquid applied to a surface is provided (i.e., see the dotted area that may include a gasket on the surface of the substrate). Advantageously, the retention barrier structure 46, which may extend around the periphery of the stable atomization zone 45, may also allow for isolating the stable atomization zone 45 from the rest of the system, including the electroacoustic transducers 48, 50. This has the added benefit of protecting other elements of the system from potentially harmful fluid contact and contamination. In one embodiment, a solid hydrophobic gasket is pressed into contact around the edge of the stable atomization zone 45. It is envisioned that such a retention barrier structure 46, such as a gasket, will prevent or reduce the possibility of fluid exiting the stable atomization zone 45 and will not significantly attenuate acoustic radiation.

[0108] 2, mount 1 holds substrate 2 on narrow ledges 26 along its side edges so that if any wetting occurs between mount 1 and substrate 2, acoustic wave energy is not attenuated as it travels along substrate 2. Also, gaps 27 are provided along narrow ledges 26 of mount 1 to prevent liquid 4 from creeping up substrate 2 between the contact points of substrate 2 and mount 1.

[0109] Referring again to Figure 3(a), the transducer surface 2a has surface features such as shields 28, bends 29 in the main IDT bars 30, and reflector bars 31 at the electrical contact ends 32, which impede the propagation of acoustic wave energy and facilitate reflection and absorption of potentially harmful acoustic wave energy at the electrical contact ends 32. The reflected acoustic wave energy is reflected back to the substrate 2. ​ of liquid at end 33 ​ The naked surface 34 ​ To reduce contact between the liquid and the IDT 35, the end of the main IDT bar 30 and the device ​ It is between the end 33.

[0110] In another embodiment, the described nebulizer may further include a compliant absorbent material in contact with at least a portion of the peripheral surface of the substrate. For example, the peripheral surface of the substrate is highlighted as hashed region 40 in FIG. 3(b). It is understood that the compliant absorbent material may contact at least a portion of the highlighted peripheral surface 40 in FIG. 3(b). Surprisingly, it has been discovered that the durability of the tip can be improved by the addition of a compliant material in contact with at least a portion of the peripheral surface of the substrate. Without wishing to be bound by theory, it is believed that the addition of a compliant material may disperse or reduce excessive vibration within and / or on the tip. Furthermore, it is believed that the addition of a compliant material may prevent overheating or localized overheating within and / or on the substrate. This reduces the substrate breakage rate and improves reliability from the nebulizer, allowing it to be used without breakage or failure. For example, a suitable compliant material may include a paste, tape, or a compliant solid. In one embodiment, the compliant material is adhesive tape. In one embodiment, the compliant material is silicone rubber. In one embodiment, the compliant material is thermal paste.In one embodiment, the compliant material comprises a portion of the housing that contacts the periphery of the chip.

[0111] In one embodiment, the compliant absorbent material may be in contact with at least a portion of the periphery of the distal end of the substrate. In one embodiment, the compliant absorbent material may be in contact with at least a portion of one or more sides of the peripheral surface of the substrate. In one embodiment, the compliant absorbent material may be in contact with a portion of one or more sides and a portion of the distal end of the substrate. In particular, by being disposed around at least a portion of the peripheral surface, the compliant absorbent material may be in contact with at least a portion of the distal end of the substrate. ​ The acoustic radiation in the area is ​ It becomes possible that this is sufficient to achieve

[0112] Furthermore, it has been found that coating at least a portion of the non-transducer side of the substrate can change wave reflection and the standing wave ratio (SWR). In one embodiment, the coating can include one or more metals. In one embodiment, the coating is formed from titanium, gold, aluminum, chromium, and combinations thereof. The inventors surprisingly found that coating at least a portion of the non-transducer surface of the substrate with one or more metals can reduce overheating. Furthermore, the inventors surprisingly found that coating at least a portion of the non-transducer surface of the substrate provides a degree of control and / or ability to tailor the standing and traveling wave components in SAW, SRBW, and combinations thereof. Surprisingly, it has been found that solid or partial coatings affect the traveling and standing wave components present on and in the substrate. A representative example is shown in FIG. 3(d), i.e., the non-transducer surface 43 of the substrate is partially coated (42). The standing wave ratio can be further modified by adjusting parameters such as the hardness, thickness, and / or roughness of the coating. By adjusting the standing wave ratio between 1 and infinity, the stability and ​ It has been observed that the rate can be increased. ​ The distribution data is shown in Figure 7, where the non-transducer substrate surface was coated with titanium and gold. As a result of the coating, the overall droplet distribution was tighter, as measured by the geometric standard deviation (GSD). In comparison, when an uncoated tip was used, ​Two distinct peaks in the droplet distribution of the irradiated fluid are typically observed. This is believed to be due to the promotion or preference of traveling wave components over standing wave components in this system. Conversely, when the tip is coated, promotion or preference of standing wave components over traveling wave components is observed. By modifying the ratio of traveling wave components to standing wave components, parameters including droplet size and geometric standard deviation can be controlled or adjusted. These parameters are further described below. In one or more embodiments, the described nebulizers may utilize traveling wave components, standing wave components, and / or combinations thereof. In one or more further embodiments, the described nebulizers may utilize standing wave components in SAW, standing wave components in SRBW, traveling wave components in SAW, traveling wave components in SRBW, permutations and combinations thereof.

[0113] In addition to coatings applied to non-transducer surfaces, the inventors have surprisingly found that overheating can be reduced by coating at least a portion of the transducer surface of the substrate with one or more metals. In particular, the inventors have found that when at least a portion of the transducer surface further includes a coating at the distal end of the substrate, chip failure due to overheating or pyroelectric failure is reduced or eliminated, providing a more efficient and robust system. In one embodiment, the coating on the transducer surface can include one or more metals. In one embodiment, the coating is formed from biocompatible metals, including titanium, gold, and combinations thereof. Representative examples are shown in Figures 3(c) and 3(e), where the entire transducer surface of the substrate includes coating 41 (Figure 3c) and at least a portion of the transducer surface of the substrate includes coating 44 at the distal end of the substrate (Figure 3e).

[0114] In another embodiment, the described nebulizer may further include patterning a conductive material on a portion of the substrate surface. As used herein, the terms "patterning" and "patterned," as well as variations thereof, refer to techniques such as photolithography that transfer a geometric pattern onto a given substrate. Such techniques are typically used for patterning in the chip industry. Generally, a coating, particularly the metal coating described above, is applied, and then the surface is patterned by lithography or other means. In one embodiment, a transducer substrate surface is patterned. In another embodiment, a non-transducer substrate surface is patterned. Surprisingly, it has been found that the addition of patterning (in areas other than the functional area of ​​the transducer surface of the substrate) can help dissipate or reduce local overheating and / or pyroelectrically induced charges. Furthermore, it is understood that the non-transducer surface of the substrate may alternatively or additionally be patterned. Figure 3(c) highlights the functional areas of the substrate's transducer surface, including the main IDT bar 30, IDTs 35, shield 28, bends 29, and reflector bar 31. One area of ​​the substrate's transducer surface suitable for patterning includes coated surface 41, highlighted in grey in Figure 3(c). Those skilled in the art will understand that such patterning may be placed on any region of the surface of the chip that still allows the device to function as a nebulizer.

[0115] Additionally, it has been found that tuning of the standing wave ratio can be achieved by positioning multiple sets of IDTs so that the resulting waves interact. By way of example, it is envisioned that patterning the IDTs will disrupt destructive acoustic waves, e.g., reducing unwanted overheating and increasing the reliability of the resulting chip. Furthermore, in one embodiment, the substrate may be patterned or coated in a manner to provide distinct regions where either standing waves or traveling waves are promoted. Such a configuration may: ​It is envisioned that this provides further tunability in the range of output parameters of the selected liquid.

[0116] Although embodiments utilizing a needle or nib have been described, still other embodiments are envisioned in which at least one delivery conduit may include a wick or microchannel. The selection of a particular delivery conduit may depend, in part, on how the conduit operates in combination with other features of the nebulizer system.

[0117] Figures 4a and 4b show another embodiment of a nebulizer. This configuration integrates the substrate 2 and other key components into a single, integrated housing or cartridge 36 that can interface with an external housing featuring the appropriate electrical system and flow chamber of the nebulizer (not shown) and can be used as a single- or multi-dose cartridge 36 that can be disposed of after use. The reservoir 3 can be formed from a cavity in the cartridge 36, one surface of which can be a depressible, deformable blister or button 37 that displaces liquid in the reservoir and serves to prime the liquid 4 in the needle or nib 6, or deposit the entire dose of liquid 4 onto the substrate 2 to form a meniscus 7; other means of displacing the liquid 4, such as a syringe plunger, are also possible. Figure 4a shows the system before the blister 37 is depressed to deposit the liquid 4, and Figure 4b shows the system after the blister 37 is depressed and the liquid 4 is deposited. RF power can be supplied to the substrate 2 through an exposed spring contact 38 that is connected to a wide electrical contact 8 in contact with the substrate 2. Exposed spring contacts 38 allow cartridge 36 to be interfaced with an external body that can house a suitable nebulizer electrical system and flow chamber (not shown). Peripheral surfaces, such as the peripheral parallel surfaces around substrate 2, act as baffle surfaces 9 to control droplet size and recirculate excess liquid 4. The cartridge is configured such that liquid 4 is ​The cartridge 36 may be protected by a seal 39 that may be broken or removed before or when the cartridge 36 is connected with the outer body of the nebulizer. The cartridge may incorporate any combination of the features described and illustrated in Figures 1a, 1c, 1d, 1e, 2 and 3a, 3b, 3c or 3d.

[0118] The presented circuit is a miniaturized handheld circuit operating at a high frequency (10 MHz). The primary reason alternative radio frequency (RF) circuits overcome the bulky miniaturization bottleneck is the circuit's simplicity. Unlike typical RF circuits, whose most important components typically and intuitively rely on digital data and programming to track a target frequency and trigger various add-on components such as sensor drivers and power buttons, this circuit utilizes a fixed, single frequency that is robust and stable, regardless of the nature of the load on the circuit. Additionally, the circuit can sense the user's breathing pattern to drive a nebulizer and / or operate via a trigger button, maintaining only analog data transfer and actuation for the entire circuit.

[0119] This circuit is small and compact yet offers a dual triggering method either by 1) continuous button press or toggling, or 2) "smart" triggering by the user's inhalation, where the trigger time is predetermined and therefore accommodates for users who inhale for too long. This therefore allows for precise administration time and therefore a known dose.

[0120] The counterintuitive circuit design approach described above, utilizing analog data transfer operating in the RF domain, allowed the circuit to be powered via a small 11.1V (3-cell) lithium polymer battery.

[0121] Figure 5a shows the ejected droplet size distribution without using baffle 9. The graph shows that the majority of the droplets have a size in the range of 10 μm to 100 μm. Figure 5b shows the ejected droplet size distribution when baffle 9 is used. The graph shows that the large droplets between 10 μm and 100 μm in size are minimized.

[0122] In yet another embodiment, the droplet size control means may further comprise a liquid film forming structure 47. The liquid film forming structure 47 controls the thickness of the meniscus 7 of the liquid supplied to the substrate surface, thereby ​ In yet another embodiment, the liquid film forming structure 47 controls the thickness of the meniscus 7 of the liquid supplied to the substrate surface, thereby controlling the size of the droplets. ​ The liquid film-forming structure 47 is located at the interface between the liquid supply conduit 6 and the substrate 2 to control droplet size. In further embodiments, the liquid film-forming structure 47 is an integral part of the substrate 2 or is directly bonded to the substrate 2. This can be achieved, for example, by electroplating. Thus, the liquid film-forming structure 47 can be an electroplated structure. Figures 12a-12d show several embodiments of the liquid film-forming structure 47. The liquid film-forming structure 47 can include a web, a mesh, one or more fibers, slots in the liquid supply conduit, or a combination. The structure can contact the device surface to promote the formation of a fluid film that enables droplet size control. Figures 12a and 12b show one embodiment in which a bundle of rigid, flexible fibers 51 is pressed and spread across the surface of the substrate 2, acting as the fluid conduit 6. The fibers 51 promote the formation of a thin fluid film that promotes the formation of small droplets ideally sized for deep lung penetration. As shown in Figures 12c and 12d, fluid-conducting structures with small openings at their ends, such as micron-sized high-aspect ratio slots 53, can be brought into contact with the device surface and deliver fluid through the small openings, which in turn promotes the formation of thin films and small droplets.

[0123] In some embodiments (not shown), the non-transducer surfaces 2a, 2b, 12b, 13b include one or more electroacoustic transducers. Such non-transducer surfaces are sometimes referred to as second transducer surfaces. These embodiments may include one or more electroacoustic transducers similar to or the same as the electroacoustic transducer 48 described above. These embodiments may include at least one opposing electroacoustic transducer as described above. Thus, the non-transducer surfaces (or second transducer surfaces) of these embodiments may be stable, as described above. ​ The non-transducer surface (or second transducer surface) of these embodiments may also include zone 45, as previously described. ​ A barrier structure 46 may also be included.

[0124] Figure 13 shows another embodiment of a nebulizer. As previously mentioned, the unique hybrid waveform configuration provided by the nebulizer in the form of an SRBW combined with a SAW allows the liquid 4 to be drawn from both the transducer surface 2a and the non-transducer surface 2b. ​ In some embodiments, the nebulizer is configured so that the liquid is applied to the non-transducer surface 2b. The liquid 4 is then eluted from the non-transducer surface 2b. ​ In the embodiment of Figure 13, the liquid supply conduit 6 is configured such that the liquid 4 is provided to the non-transducer surface 2b by the liquid supply conduit 6. The liquid 4 forms a meniscus on the non-transducer surface 2b, and the liquid 4 is drawn from the non-transducer surface 2b by activation of the electroacoustic transducer 48 (not shown in Figure 13) and at least one opposing electroacoustic transducer 50 (if provided). ​ will be done.

[0125] Transducer surface 2a is bonded to mount 1. In some embodiments, one or more edges of substrate 2 are bonded to mount 1 by a sealing 70. Ceiling 70 is bonded to substrate 2 and mount 1 to seal one or more edges of substrate 2 to the mount. In some embodiments, one or more portions of transducer surface 2a are bonded to mount 1 by a sealing 70. In some embodiments, one or more edges of substrate 2 and one or more portions of transducer surface 3a are bonded to mount 1 by a sealing 70. Ceiling 70 provides a fluid-tight seal between transducer surface 2a and mount 1. By sealing transducer surface 2a and isolating it from non-transducer surfaces 2b, the nebulizer can nebulize liquid 4 without the liquid contacting transducer surface 2a. ​ This protects the transducer surface 2 a and the electroacoustic transducers 48, 50 from deterioration or fouling as a result of operation of the nebulizer. In some embodiments, the substrate 2 may be bonded to the housing in a manner similar to that described with respect to the substrate 2 being bonded to the mount 1.

[0126] 14 and 15 illustrate some embodiments of ​ 1 shows an embodiment of a system 72. ​ System 72 includes a primary nebulizer 74. Primary nebulizer 74 may take the form of any one of the nebulizers described herein. Alternatively, primary nebulizer 74 may take another form. ​ The system 74 also includes a second nebulizer 76. The second nebulizer 76 may take the form of any one of the nebulizers described herein. Alternatively, the second nebulizer 76 may take another form. The second nebulizer 76 may be considered an active baffle. The second nebulizer 76 is positioned at an angle relative to the first nebulizer 74. Specifically, the second nebulizer 76 is positioned at an angle relative to the first nebulizer 74. ​In other words, a first line tangent to the water contacting surface of the first nebulizer 74 (e.g., the transducer or non-transducer surface of the first nebulizer 74) is tangent to a second line tangent to the water contacting surface of the second nebulizer 76 (e.g., the transducer or non-transducer surface of the second nebulizer 76). ​ The water-contacting surface of the first nebulizer 74 may be a transducer surface (including an electroacoustic transducer as described above) and / or a non-transducer surface of the first nebulizer 74. Similarly, the water-contacting surface of the second nebulizer 76 may be a transducer surface (including an electroacoustic transducer as described above) and / or a non-transducer surface of the second nebulizer 76.

[0127] The liquid 4 is dispensed into a first nebulizer 74 at a liquid dispensing point 78. The first nebulizer 74 dispenses the liquid ​ A first portion 82 of the liquid ejected from the first nebulizer 74 is in the form of relatively small droplets having a diameter of less than 3 μm. These relatively small droplets have little momentum and do not travel far from the first nebulizer 74. A second portion 84 of the liquid ejected from the first nebulizer 74 is in the form of relatively large droplets having a diameter greater than 3 μm. These relatively large droplets have relatively more momentum than the small droplets having a diameter less than 3 μm and are able to contact the second nebulizer 76.

[0128] The liquid ejected from the first nebulizer 74 may have a first trajectory 80. The first trajectory 80 may be, for example, a generally upward trajectory. Upon contact with the second nebulizer 76, the droplets break up into smaller droplets (e.g., having a diameter of less than 3 μm). Thus, ​ A significant portion (e.g., most or all) of the droplets generated by system 72 are of a size below the size threshold. For example, ​The droplets produced by system 72 are of a diameter less than a diameter threshold, e.g., 3 μm. The droplets experience a minimal residence time on second nebulizer 76. Droplets that contact second nebulizer 76 are directed away from the second nebulizer along second trajectory 86. Second trajectory 86 is approximately the same as first trajectory 80. ​ Therefore, the second nebulizer 76 is ​ Additionally, the second nebulizer 76 may be configured to redirect a portion of the liquid already ​ The liquid ​ It can be thought that this is the case.

[0129] The second nebulizer 76 is angled relative to the first nebulizer 74 so that liquid contacting the second nebulizer 76 is directed away from the first nebulizer 74 (i.e., the first trajectory 80 and the second trajectory 86 are different), which helps reduce the extent to which liquid contacting the second nebulizer 76 recirculates back to the first nebulizer 74.

[0130] For sensing, an optically flat single crystal substrate is used. 4 ~10 6 This allows for bulk (e.g., Lamb) wave resonance with a quality factor Q of approximately 100 ng. Thus, very small mass loadings on the surface of the substrate can produce detectable frequency shifts, thereby enabling mass sensing of samples down to a sensitivity of 10 ng. This is illustrated in the graph in Figure 6, which shows mass sensing of Humalog (insulin dosing). The graph shows a linear frequency shift as mass increases, with a sensitivity of 100 ng.

[0131] SAW nebulizers have found applications in a variety of areas, including the administration of active agents. Inhaled medications are the most common form of treatment for asthma, chronic obstructive pulmonary disease (COPD), and other respiratory diseases such as obstructive bronchitis, emphysema, and cystic fibrosis. For example, corticosteroids, bronchodilators, and β2 agonists are typically administered by inhalation to treat asthma, COPD, and other respiratory diseases. It is envisioned that the described nebulizers can be used in combination with a range of possible active agents. Suitable active agents include, but are not limited to, corticosteroids (such as fluticasone, budesonide, mometasone, beclomethasone, and ciclesonide), bronchodilators (such as salmeterol or albuterol, formoterol, vilanterol, levalbuterol, and ipratropium). For example, albuterol, also known as salbutamol or ventolin, is a beta-2 agonist and a short-term bronchodilator that opens the medium and large airways of the lungs. Ipratropium, also known as ipratropium bromide, is a muscarinic antagonist (a type of anticholinergic) that opens the medium and large airways of the lungs. Budesonide, also known as BUD, is a type of corticosteroid used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). In one embodiment, the described nebulizer is adapted to deliver albuterol. In one embodiment, the described nebulizer is adapted to deliver ipratropium. In one embodiment, the described nebulizer is adapted to deliver budesonide.

[0132] The described nebulizers advantageously provide reliable, efficient, and precise delivery of active agents. ​ The nebulized liquid may be characterized by one or more parameters. It is understood that each active agent has different physicochemical properties. Additionally, various parameters of the described nebulizers include droplet size (microns), geometric standard deviation (GSD), volumetric efficiency, and the like. ​ It is understood that various parameters may be optimized for delivery of a given active agent, including rate, stabilization period (i.e., time of use), percentage of API administered, orbital loss, and fine particle fraction.

[0133] In one aspect, the nebulizer described comprises: ​ In particular, it provides control over the droplet size of the deposited liquid. ​ The droplet size of the nebulized liquid may be optimized for a given active agent. In one embodiment, the nebulizer described provides a droplet size in the range of 0.1-100 μm, preferably in the range of 0.1-10 μm, preferably in the range of 0.5-7.5 μm, more preferably in the range of 1-5 μm, and even more preferably in the range of 2-4 μm. ​ In one embodiment, the nebulizer described provides a droplet size of less than 10 μm, preferably less than 8 μm, preferably less than 6 μm, preferably less than 5 μm, preferably less than 3 μm. ​ Provide the liquid.

[0134] In one aspect, the nebulizer described comprises: ​ In particular, it provides control of the geometric standard deviation (GSD) of the droplets of the liquid. ​ The GSD of the nebulizer may be optimized for a given active agent. In one embodiment, the nebulizer described has a GSD of less than 10 μm, preferably less than 8 μm, preferably less than 6 μm, preferably less than 5 μm, preferably less than 3 μm, preferably less than 2.5 μm, preferably less than 2.1 μm. ​ Provide the liquid.

[0135] In one aspect, the described nebulizers provide control over the stabilization period (i.e., time of use). Advantageously, the described nebulizers shorten the stabilization period (i.e., time of use). A shorter or reduced stabilization period provides shorter lag time to use, increased efficiency, reduced sample or fluid loss, and improved accuracy of dosing and administration of the active agent. In particular, the stabilization period may be optimized for a given active agent. In one embodiment, the described nebulizers provide a stabilization period of less than 1 second, preferably less than 0.5 seconds, preferably less than 0.25 seconds, preferably less than 0.1 seconds, preferably less than 0.05 seconds, preferably less than 0.03 seconds, preferably less than 0.02 seconds, and preferably less than 0.01 seconds.

[0136] In one aspect, the nebulizer described comprises: ​ Volume of liquid removed ​ Provides rate control, in particular: ​ Volume of liquid removed ​ The rate may be optimized for a given active agent. In one embodiment, the nebulizer described ​ The flow rate is in the range of 0.1 to 10 ml / min, preferably in the range of 0.15 to 7.5 ml / min, and more preferably in the range of 0.2 to 5 ml / min. ​ In one embodiment, the nebulizer described provides: ​ Provide the liquid and volume ​ The rate is greater than 0.1 mL / min, preferably greater than 0.25 mL / min, preferably greater than 0.3 mL / min, preferably greater than 0.35 mL / min, preferably greater than 0.4 mL / min, preferably greater than 0.45 mL / min, preferably greater than 0.5 mL / min, preferably greater than 0.55 mL / min, preferably greater than 0.6 mL / min, preferably greater than 0.65 mL / min, preferably greater than 0.7 mL / min, preferably greater than 0.75 mL / min.

[0137] In one aspect, the nebulizer described comprises: ​ The nebulizer provides control over the proportion of API administered in the administered liquid. In particular, the proportion of API administered may depend on the physicochemical properties of a given active agent, but can be optimized for a given active agent with the described system. In one embodiment, the described nebulizer: ​ and the percentage of API administered is greater than 60%, preferably greater than 65%, preferably greater than 70%, preferably greater than 75%, preferably greater than 80%, preferably greater than 85%, preferably greater than 90%, preferably greater than 95%, preferably greater than 97%, preferably greater than 98%, preferably greater than 99%.

[0138] In one aspect, the nebulizer described comprises:​ In one embodiment, the nebulizer described provides control of trajectory loss in the injected liquid. In particular, trajectory loss may be optimized for a given active agent. ​ The liquid preferably has an orbital loss of less than 20%, preferably less than 15%, preferably less than 10%, preferably less than 9%, preferably less than 8%, preferably less than 7%, preferably less than 6%, preferably less than 5%.

[0139] In one aspect, the nebulizer described comprises: ​ provides control of the particulate content of the liquid. The particulate content is generally determined by the ​ It is understood as a measure of the mass deposited in the lungs during inhalation of an aerosol. The amount of aerosol inhaled with different particle definitions is compared in an approximately isotonic ​ The amount of aerosol deposited in the lungs and alveolar regions is compared to the amount of aerosol deposited in the lungs and alveolar regions for a given aerosol. Droplet stages 1-7 have been found to have 65% of the drug in a form that accumulates or targets deep lung tissue. The fine particle fraction may depend on the physicochemical properties of a given active agent, but can be optimized for a given active agent using the described system. In one embodiment, the described nebulizer provides a fine particle fraction of greater than 20%, preferably greater than 30%, preferably greater than 35%, preferably greater than 40%, preferably greater than 45%, preferably greater than 50%, preferably greater than 55%, preferably greater than 60%, preferably greater than 65%, preferably greater than 70%, and preferably greater than 75% in droplet stages 1-7.

[0140] In addition to the described active agents, the described nebulizers are capable of nebulizing fluids or samples containing delicate molecules and particles (e.g., DNA, RNAi, peptides, proteins, and cells) at high flow rates (typically greater than 1 ml / min) throughout the sample without denaturing them. ​ While maintaining ​Prior art nebulizers have to date been limited to between 0.1 and 0.4 ml / min, thereby requiring long inhalation times, typically several tens of minutes to an hour. This has therefore limited the practical uptake of conventional nebulizers. The higher inhalation rates that can be achieved by the nebulizers of the described embodiments are ​ The rate can significantly shorten administration times.

[0141] The nebulizer according to the described embodiment delivers Technetium-99m DTPA aerosol ([ 99m The nebulizer system described has been subjected to human clinical trials to determine the efficiency of delivery of active agents to the lungs by inhalation using [Tc]DTPA aerosol. Initial results have shown that the described nebulizer system: ​ These results demonstrate that the present invention provides effective delivery of the active agent to the target tissue. [Table 1]

[0142] Modifications and variations that would be obvious to one skilled in the art are included within the scope of the invention as claimed in the following claims.

[0143] In a first aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: Droplets ​ and a nebulizer for: Housing and at least one piezoelectric substrate contained within the housing and having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the substrate, and an opposing non-transducer surface; Transducer ​ and a liquid supply system for supplying liquid to at least one of the non-transducer surfaces, the liquid supply system including a reservoir for containing liquid and at least one relatively rigid supply conduit in contact with the substrate for supplying liquid from the reservoir to the substrate; Includes.

[0144] In a second aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: Droplets ​ and a nebulizer for: Housing and at least one piezoelectric substrate contained within the housing and having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the substrate, and an opposing non-transducer surface; Transducer ​ and a liquid supply system for supplying liquid to at least one of the non-transducer surfaces, the liquid supply system including a reservoir for containing liquid and at least one relatively rigid supply conduit in contact with the substrate for supplying liquid from the reservoir to the substrate; a sensor for detecting the volume of liquid on at least one piezoelectric substrate; Includes.

[0145] In a third aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: Droplets ​ and a nebulizer for: Housing and at least one piezoelectric substrate contained within the housing and having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the substrate, and an opposing non-transducer surface; a compliant material in contact with at least a portion of a peripheral surface of the at least one piezoelectric substrate; Transducer ​ and a liquid supply system for supplying liquid to at least one of the non-transducer surfaces, the liquid supply system including a reservoir for containing liquid and at least one supply conduit for supplying liquid from the reservoir to the substrate; Includes.

[0146] In a fourth aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: Droplets ​and a nebulizer for: Housing and at least one piezoelectric substrate contained within the housing and having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the substrate, and an opposing non-transducer surface; a compliant material in contact with at least a portion of a peripheral surface of the at least one piezoelectric substrate; Transducer ​ and a liquid supply system for supplying liquid to at least one of the non-transducer surfaces, the liquid supply system including a reservoir for containing liquid and at least one supply conduit for supplying liquid from the reservoir to the substrate; a sensor for detecting the volume of liquid on at least one piezoelectric substrate; Includes. The nebulizer according to the first or second aspect, wherein the delivery conduit is in the form of a nib or needle. The nebulizer of the first or second aspect, wherein the supply conduit is formed from an acoustically reflective material. The nebulizer of the first or second aspect, wherein the liquid is gravity fed from a reservoir via a supply conduit. The nebulizer of any one of the aspects, wherein the liquid is transferred from the reservoir via an active pumping system. The nebulizer of any one of the aspects, wherein the active pump system is a syringe or a peristaltic pump. The nebulizer of any one of the aspects, wherein the liquid supply system further comprises a flow regulator for providing a steady flow of liquid therefrom. The nebulizer of any one of the aspects, wherein the flow regulator includes a liquid outlet passage through which the liquid can pass and an air inlet passage connected to the reservoir. The nebulizer of any one of the aspects, wherein the sensor detects a volume of liquid on the surface of the substrate by measuring a change in current across the nebulizer system. The nebulizer of any one of the aspects, wherein the electrical current is direct current. The nebulizer of any one of the aspects, wherein the nebulizer system in which a change in current is detected includes an electronic circuit and at least one piezoelectric substrate. The nebulizer of any one of the aspects, wherein the electronic circuitry comprises at least one printed circuit board. The nebulizer of any one of the aspects, further comprising a control switch responsive to the sensor for controlling operation of the nebulizer. The nebulizer ​ 5. The nebulizer of any one of the embodiments, further comprising at least one opposing electroacoustic transducer for generating acoustic wave energy in opposite directions to prevent liquid from being dislodged from the surface of the substrate prior to The substrate is ​ Loss of liquid applied to the surface before ​

[0023] The nebulizer of any one of the embodiments, further comprising a structure for preventing and / or preventing Structure includes lip, wall, gasket, and deposit ​

[0023] The nebulizer of any one of embodiments 1 to 3, further comprising a raised membrane, a raised membrane, or a combination thereof. A nebulizer according to any one of the aspects, further comprising an internal chamber connected to the flow regulator, the internal chamber having a peripheral opening within which the peripheral tip of the supply conduit is received, and wherein liquid can pass between the peripheral opening and the peripheral tip of the supply conduit by capillary action. The nebulizer of any one of the aspects, wherein the substrate is supported on a displaceable mount for controlling contact between the substrate and the supply conduit. The nebulizer of any one of aspects, wherein the mount includes a pivot support at one end thereof and an opposite end supported on the elastic member. The nebulizer of any one of aspects, wherein the mount is supported by a cantilever. · ​ 10. The nebulizer of any one of embodiments, further comprising a control means for controlling the size of the droplets. The nebulizer of any one of the aspects, wherein the control means includes at least one baffle disposed in substantially parallel adjacent relationship to at least one of the transducer surfaces. The nebulizer of any one of aspects, wherein the baffle is provided by an inner housing wall disposed in parallel adjacent relationship from at least one of the substrate surfaces. The nebulizer of any one of the aspects, wherein the housing further includes an inlet opening, and the reservoir includes a neck portion that can be received within the inlet opening. The nebulizer of any one of the aspects, comprising at least two of the substrates arranged in spaced, parallel, adjacent relationship. The droplet size control means controls the thickness of the meniscus of the liquid dispensed between adjacent substrate surfaces, thereby ​

[00132] The nebulizer of any one of the embodiments, comprising presetting a spacing between the substrates to control droplet size. The droplet size control means controls the thickness of the meniscus of the liquid supplied between the adjacent substrate surface and the inner wall, thereby ​

[00132] The nebulizer of any one of the embodiments, comprising presetting a spacing of the substrate from an interior wall of the housing to control droplet size. The droplet size control means controls the thickness of the meniscus of the liquid dispensed between adjacent substrate surfaces, thereby ​

[00132] The nebulizer of any one of the embodiments, comprising a liquid film-forming structure at an interface between the liquid supply conduit and the substrate to control droplet size. The nebulizer of any one of the aspects, wherein the liquid film forming structure comprises a web, a mesh, one or more fibers, or a slot in the liquid supply conduit. The nebulizer of any one of the aspects, wherein the piezoelectric substrate and the electroacoustic transducer are also used to sense a liquid mass on the at least one substrate.

[0023] Aspect 10. The nebulizer of any one of aspects, wherein the compliant material is selected from the group consisting of adhesive tape, silicone rubber, thermal paste, or a combination thereof. The nebulizer of any one of the aspects, wherein the compliant material is in contact with at least a portion of a periphery of the distal end of the substrate. A nebulizer according to the third or fourth aspect, wherein at least one supply conduit is a relatively rigid supply conduit in contact with the substrate. The nebulizer of the third or fourth aspect, wherein the at least one delivery conduit is selected from the group consisting of a nib, a needle, a wick, a microchannel, or a combination thereof. The nebulizer of any one of the aspects, wherein at least a portion of the transducer surface, non-transducer surface, or a combination thereof is patterned. The nebulizer of any one of the aspects, wherein the acoustic wave energy comprises a surface acoustic wave (SAW) propagating at a transducer surface of at least one piezoelectric substrate. The nebulizer of any one of the aspects, wherein the acoustic wave energy comprises surface-reflected bulk waves (SRBW) reflected between a transducer surface and a non-transducer surface of the at least one substrate. The nebulizer of any one of the aspects, wherein the acoustic wave energy comprises a combination of surface acoustic waves (SAWs) propagating through a transducer surface of the at least one substrate and surface reflected bulk waves (SRBWs) reflected between the transducer surface and a non-transducer surface of the at least one substrate. The nebulizer of any one of the aspects, wherein the surface acoustic wave (SAW) includes a standing wave, a traveling wave, and a combination thereof. The nebulizer of any one of the aspects, wherein the surface reflected bulk wave (SRBW) includes a standing wave, a traveling wave, and a combination thereof. The nebulizer of any one of the aspects, wherein the electroacoustic transducer is an interdigital transducer (IDT). The nebulizer of any one of aspects, wherein at least one piezoelectric substrate has a thickness at or near the wavelength of a SAW propagating through the transducer surface. The nebulizer of any one of the aspects, wherein at least one piezoelectric substrate is formed from lithium niobate (LiNbO3).

[0023] The nebulizer of any one of the aspects, wherein at least a portion of the non-transducer surface further comprises a coating comprising at least one metal. The nebulizer of any one of the aspects, wherein at least a portion of the transducer surface further comprises a coating comprising at least one metal at a distal end of the substrate.

[0023] Aspect 10. The nebulizer of any one of aspects, wherein the coating comprises titanium, gold, aluminum, chromium, or a combination thereof. The liquid may come from the transducer surface, the non-transducer surface, or both the transducer and non-transducer surfaces. ​ 2. The nebulizer of any one of the embodiments, Liquid ​ to form droplets having a size range of 0.1 to 100 μm. Liquid flow rate is up to 10ml / min. ​ At the rate ​ 2. The nebulizer of any one of the embodiments, The nebulizer of any one of the aspects, wherein the mount includes a shelf to which the substrate is attached, the shelf including one or more gaps to prevent creep of the liquid along the substrate. The nebulizer of any one of the aspects, wherein the housing is in the form of a cartridge housing having external electrical contacts connected to at least one electroacoustic transducer and an integrated liquid supply system. The nebulizer according to the first or second aspect is used to nebulize a liquid. ​ How to do it. the liquid to form droplets with a size range of 0.1 to 100 μm ​

[0023] According to any one of the aspects, ​ How to do it. Maximum volume of 10ml / min ​ Liquid at the rate ​

[0023] According to any one of the aspects, ​ How to do it. The liquid is mixed to form droplets with a geometric standard deviation (GSD) of less than 10 μm. ​

[0023] According to any one of the aspects, ​ How to do it. any one of the aspects, wherein the liquid comprises a functional or therapeutic agent, such as a pharmaceutical, DNA, RNAi, peptide, protein, and cell, or a non-therapeutic agent, such as a fragrance, cosmetic, pesticide, paint, or preservative. ​ How to do it. any one of the embodiments, wherein the functional or therapeutic agent is delivered as a unit dose. ​ How to do it. any one of the aspects, wherein the unit dose is determined by a sensor for detecting a volume of liquid on the surface of the substrate. ​ How to do it.

Claims

1. 1. A nebulizer for atomizing droplets, comprising: Housing and at least one piezoelectric substrate contained within the housing, the at least one piezoelectric substrate having a transducer surface on which at least one electroacoustic transducer is disposed for generating acoustic wave energy within the piezoelectric substrate; a liquid supply system for supplying liquid to at least one of the transducer surface and the non-transducer surface, the liquid supply system including a reservoir for containing the liquid; at least one liquid supply conduit for supplying the liquid from the reservoir to the at least one piezoelectric substrate, the at least one liquid supply conduit having an end in contact with the at least one piezoelectric substrate; a droplet size control means for controlling the size of the mist droplets, the droplet size control means including a liquid film forming structure, the liquid film forming structure being in fluid communication with the liquid supply conduit and the at least one piezoelectric substrate for controlling a meniscus thickness of liquid supplied to the at least one piezoelectric substrate, thereby controlling the size of the mist droplets; Including, A nebulizer wherein the liquid film forming structure is an integral part of the piezoelectric substrate, is directly bonded to the piezoelectric substrate, or comprises one or more slots in each of the at least one supply conduit.

2. 10. The nebulizer of claim 1, wherein the liquid film-forming structure comprises a web, a mesh, or one or more fibers.

3. A nebulizer as described in claim 1, wherein the liquid film forming structure includes one or more fibers.

4. 4. The nebulizer according to claim 1, wherein the liquid film forming structure is integrally formed with the at least one piezoelectric substrate.

5. A nebulizer according to any one of claims 1 to 4, wherein the liquid film forming structure comprises one or more slots in each of the at least one liquid supply conduit.

6. 6. The nebulizer of claim 1, wherein the liquid film-forming structure includes a plurality of slots in each of the at least one liquid supply conduit, the plurality of slots being positioned adjacent to the end of the at least one liquid supply conduit, and the plurality of slots being micron-sized with a high aspect ratio.

7. A nebulizer according to any preceding claim, wherein the at least one piezoelectric substrate further comprises a non-transducer surface opposite the transducer surface.

8. A nebulizer according to any one of claims 1 to 7, further comprising a sensor for detecting the volume of liquid on the at least one piezoelectric substrate.

9. 9. The nebulizer of claim 8, wherein the at least one electroacoustic transducer comprises the sensor.

10. 10. A nebulizer as described in any one of claims 1 to 9, further comprising at least one opposing electroacoustic transducer for generating acoustic wave energy in opposite directions to reduce the extent to which liquid is dislodged from the at least one piezoelectric substrate prior to atomization.

11. 11. The nebulizer of claim 1, wherein the at least one piezoelectric substrate further comprises a retention barrier structure for retaining liquid applied to the piezoelectric substrate prior to atomization and / or preventing loss of liquid applied to the piezoelectric substrate prior to atomization.

12. 12. The nebulizer of claim 11, wherein the retaining barrier structure comprises a lip, a wall, a gasket, a deposited raised membrane, or a combination thereof.

13. 13. A nebulizer according to any preceding claim, wherein the droplet size control means comprises at least one baffle disposed in substantially parallel adjacent relationship with at least one of the transducer surface or the non-transducer surface.

14. A nebulizer according to any preceding claim, comprising at least two piezoelectric substrates arranged in spaced apart, parallel adjacent relationship.

15. 15. The nebulizer of claim 14, wherein the droplet size control means is configured to enable presetting of the spacing between the at least two piezoelectric substrates to control a thickness of a meniscus of liquid dispensed between adjacent substrate surfaces, thereby controlling the size of the mist droplets.

16. 15. The nebulizer of claim 14, wherein the droplet size control means is configured to enable presetting of the spacing of the at least two piezoelectric substrates from the inner wall to control a thickness of a meniscus of liquid supplied between adjacent substrate surfaces and the inner wall of the housing, thereby controlling the size of the mist droplets.

17. The acoustic wave energy is (i) a surface acoustic wave (SAW) propagating on the transducer surface of the at least one piezoelectric substrate; and (ii) Surface-reflected bulk waves (SRBW) reflected between the transducer surface and a non-transducer surface of the at least one piezoelectric substrate.

17. A nebulizer according to any preceding claim, comprising one or more of:

18. A nebulizer according to any preceding claim, wherein the liquid is atomised from the transducer surface, the non-transducer surface, or both the transducer surface and the non-transducer surface.

19. 19. A nebulizer according to any one of claims 1 to 18, wherein the liquid supply system is configured to supply the liquid to at least one non-transducer surface, and the at least one piezoelectric substrate is sealed to a mount so that liquid does not contact the at least one transducer surface.

20. A nebulizer according to any preceding claim, wherein the supply conduit is in the form of a nib or needle.

21. 1. A nebulizer system comprising:

21. A nebulizer according to any one of claims 1 to 20, comprising: a nebulizer which is a first nebulizer; A second nebulizer and Including, the primary nebulizer has a primary nebulizer liquid contact surface; the secondary nebulizer has a secondary nebulizer liquid contact surface; A nebulizer system wherein the liquid contacting surface of the first nebulizer intersects with the liquid contacting surface of the second nebulizer.

22. A method for atomizing a liquid using a nebulizer according to any one of claims 1 to 20 or a nebulizer system according to claim 21, comprising the steps of: The method, wherein the liquid comprises a functional or therapeutic agent, such as a pharmaceutical, DNA, RNAi, peptide, protein, and cell, or a non-therapeutic agent, such as a fragrance, cosmetic, pesticide, paint, or preservative.

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