Spraying method and device

Abstract

A method for producing atomized droplets is disclosed. A spray device (10) having an acoustic wave interactive surface (18) is provided, the spray device including an acoustic transducer (12) configured to generate and propagate acoustic waves to the acoustic wave interactive surface. The device further includes a dispenser (20) positioned relative to the acoustic wave interactive surface and configured to dispense a suspension formulation including a suspension of insoluble particles in a carrier liquid. The suspension formulation is deposited onto the acoustic wave interactive surface using the dispenser in a time series of isolated volumes (26), each isolated volume of suspension formulation having a volume of 50 μL or less. The acoustic waves propagate to the acoustic wave interactive surface and interact with the suspension formulation to produce atomized droplets (28) of the suspension formulation. During the step of depositing the suspension formulation onto the acoustic wave interactive surface, the dispenser is isolated from acoustic waves propagating within the suspension formulation, preventing or reducing acoustic clustering of the insoluble particles within the dispenser.

Description

[Technical Field]

[0001] The present invention relates to methods and devices for nebulizing suspension formulations, which are of particular interest in, but not necessarily limited to, application to the preparation of therapeutic agents suitable for delivery to a subject. [Background technology]

[0002] According to the World Health Organization (WHO), 262 million people suffer from asthma and 392 million from chronic obstructive pulmonary disease (COPD), resulting in 3.7 million deaths annually worldwide. Millions of people also suffer from lung infections, cystic fibrosis, pulmonary hypertension, allergic rhinitis, and other underdiagnosed chronic respiratory diseases. The cost of treating patients with lung diseases caused by tuberculosis (TB), COPD, cystic fibrosis, pneumonia, asthma, and smoking is estimated at 380 billion euros annually (European Respiratory Society European Lung White Paper http: / / www.erswhitebook.org / [accessed October 7, 2022]). Summary of the Invention [Problem to be solved by the invention]

[0003] Drug delivery by inhalation is known as the best route for treating respiratory diseases. One of the major advantages of the inhaled pulmonary route is the ability to deliver drugs directly to the lungs. In fact, effective drug delivery has been shown to be highly dependent on the droplet size distribution within the drug aerosol [1]. Generally, if the droplet size is too small (<0.5 μm), the droplets are expelled during exhalation, whereas if the droplet size is too large (>9.0 μm), the droplets are trapped in the upper airway or throat. It is believed that for drug delivery to the lungs, the droplet size distribution of the aerosol should be approximately 1–5 μm. To treat the nasal passages, droplets up to 100 μm in size may be required.

[0004] Liquid formulations used to treat these diseases are dispersed in the form of an aerosol for inhalation by patients. Water-insoluble active ingredients (APIs) can be formulated as suspended particles, called suspension formulations. Suspension formulations have proven difficult to nebulize, especially when used with ultrasonic nebulizers. [2][3] Ultrasonic nebulizers irradiate the liquid formulation with a focused ultrasound beam, forming a cone of liquid from which droplets separate to generate the aerosol. Particles are trapped at the base of the cone and do not disperse.

[0005] Atomization of suspensions using mesh nebulizers is limited by the mesh size. Studies have shown that passive and active mesh nebulizers perform significantly better than ultrasonic nebulizers in nebulizing commercially available budesonide (Pulmicort™) suspensions; however, the nebulized drug volume remains low (<22%) relative to the drug volume loaded into the device. [4][5] For example, the average particle size of commercially available budesonide suspensions is 3–4 μm. [6][7] However, the mesh openings in mesh nebulizers are typically 2–3 μm in diameter. Therefore, budesonide particles can clog the mesh openings, resulting in the majority of the drug suspension not being delivered.

[0006] In general, aerosolization of suspension formulations has proven challenging for various types of nebulizers, and studies have shown considerable variability in their performance, as measured by particle size.[8][9] Thus, drug delivery could be significantly improved by preparing aerosol droplets with a high concentration of suspended particles that are particularly well-suited for penetration of the appropriate tissues, for example, in the lungs. Such technology would enable the development of new therapies and the improvement of existing ones, leading to reduced healthcare costs and improved clinical outcomes. [Means for solving the problem]

[0007] The present invention has been devised with the above considerations in mind.

[0008] In a first aspect, the present invention provides a method for preparing atomized droplets, comprising providing an apparatus comprising an acoustic wave interactive surface and an acoustic wave transducer adapted to generate and propagate acoustic waves across said acoustic wave interactive surface; the device further comprising a dispenser positioned relative to the sound wave interactive surface and configured to dispense a suspension formulation comprising a suspension of insoluble particles in a carrier liquid; The method comprises the following steps: depositing the suspension formulation onto the acoustic wave interactive surface in a time series of discrete volumes using the dispenser, wherein each discrete volume of the suspension formulation has a volume of 50 μL or less; and propagating acoustic waves to the acoustic wave interactive surface to interact with the suspension formulation and generate atomized droplets of the suspension formulation; Including, During the step of placing the suspension formulation on the acoustic wave interactive surface, the dispenser is isolated from acoustic waves propagating within the suspension formulation, thereby preventing or reducing acoustic clustering of insoluble particles within the dispenser.

[0009] In a second aspect, the present invention provides a system for preparing spray droplets, said system comprising a spray device and a suspension formulation of insoluble particles suspended in a carrier liquid, said spray device comprising: with sound wave interaction surfaces; an acoustic wave transducer adapted to generate and propagate acoustic waves to the acoustic wave interactive surface; a dispenser configured to deposit the suspension formulation onto an acoustic wave interactive surface in time-sequential, isolated volumes, wherein each isolated volume of the suspension formulation has a volume of 50 μL or less; Including, during operation, acoustic waves propagating to the acoustic wave interactive surface interact with the suspension formulation to generate atomized droplets of the suspension formulation; The atomizing device is configured to isolate the dispenser from acoustic waves propagating to the acoustic wave interactive surface.

[0010] Ensuring that the suspension formulation is delivered to the acoustic wave interactive surface as a series of isolated volumes is believed to have the advantage of reducing or avoiding the impact of insoluble particles of the suspension formulation on the liquid within the dispenser, which tend to cluster due to acoustic coupling with the transducer.

[0011] The volume of each isolated volume will vary somewhat depending on the scale of the system, but relevant effects may be observed with volumes up to 50 μL. However, more pronounced effects may be observed with smaller isolated volumes, e.g., up to 40 μL, up to 30 μL, up to 20 μL, up to 10 μL, up to 5 μL, up to 4 μL, up to 3 μL, up to 2 μL, or up to 1 μL. For example, in some embodiments, the isolated volumes of the suspension formulation in the time series of isolated volumes have initial volumes ranging from 0.5 μL to 5.0 μL.

[0012] The device may include a cavity array opening onto the acoustic wave interaction surface for containing the suspension formulation. It is intended that acoustic waves interact with the suspension formulation in the cavities to generate a mist of droplets. The cavity array may be formed within a substrate that also serves as a substrate for the acoustic wave transducer. Alternatively, the cavity array may be formed within a separate superstrate substrate configured to acoustically couple with the acoustic wave transducer.

[0013] The acoustic wave transducer may be operable, for example, to generate and / or propagate a common surface acoustic wave (SAW) although the invention is not necessarily so limited and other acoustic waves may be used. Thus, the acoustic wave transducer may be operable to generate and / or propagate an acoustic mode selected from one or more of Rayleigh waves (i.e., SAW), Lamb waves, bulk acoustic waves, and thickness modes.

[0014] During the step of disposing the suspension formulation on the acoustic wave interactive surface, each isolated volume of the suspension formulation may, for example, be in direct contact with only one of the dispenser and the acoustic wave interactive surface at a time, or may be in contact with neither the dispenser nor the acoustic wave interactive surface. Thus, the isolated volume itself should not allow acoustic coupling between the dispenser and the acoustic wave interactive surface. Therefore, it is preferred that an air (or other gas) gap exists between each isolated volume during the dispensing operation.

[0015] The outlet of the dispenser may be separated from the acoustic wave interactive surface by a minimum distance of 0.1 mm or more. Depending on the volume isolated, this distance may be 0.2 mm or more, 0.3 mm or more, 0.4 mm or more, 0.5 mm or more, 0.6 mm or more, 0.8 mm or more, 1 mm or more, 1.5 mm or more, 2 mm or more, 3 mm or more, 4 mm or more, 5 mm or more, 6 mm or more, 7 mm or more, 8 mm or more, 9 mm or more, or 10 mm or more.

[0016] The time interval between dispensing successive isolated volumes in the time series of isolated volumes may be variable. For example, this variability can be set according to the rate of suspension loss from the system due to atomization. The method can include determining the atomization rate and / or evaporation rate of the suspension formulation located on the interaction surface and setting the time interval and / or the volume of the isolated volume based on the determination. Such steps of determining the atomization rate and / or evaporation rate and setting the time interval can be repeated.

[0017] Each isolated volume of suspension formulation can be placed at the same location on the acoustic interactive surface, ensuring temporal repeatability of nebulization and therefore temporal consistency of the plume nebulized from the system.

[0018] The insoluble particles may include an active pharmaceutical ingredient.

[0019] The insoluble particles have a particle size distribution with a D90 of up to 50 μm. Depending in part on the intended use and function of the insoluble particles, the insoluble particles may have a particle size distribution with a D90 of up to 40 μm, up to 30 μm, up to 20 μm, up to 10 μm, up to 8 μm, up to 6 μm, up to 5 μm, up to 4 μm, or up to 3 μm.

[0020] The acoustic wave interactive surface may be a surface acoustic wave (SAW) transmitting surface. Thus, the acoustic wave transducer may be a SAW transducer and the acoustic wave may be a SAW. Other acoustic energy sources may also be used.

[0021] The present invention includes combinations of the described aspects and preferred features except where such combinations are expressly not permitted or explicitly avoided.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present invention will now be described with reference to the accompanying drawings. [Brief explanation of the drawings]

[0023] [Figure 1] Figure 1 shows a schematic diagram of a system for the preparation and analysis of nebulized droplets. [Figure 2] FIG. 2 shows a modified version of FIG. [Figure 3] Figure 3 shows the API recovery results from different parts of the system when solutions (containing 1% saline and 1.1 mg / ml Allura Red AC) with (right bar) and without (left bar) 4.8 μm polystyrene beads were sprayed in contact mode with the microcavity configuration. [Figure 4] Figure 4 shows the results of nebulization in contact mode of a suspension investigating the fluorescent signal of 4.8 µm green fluorescent polystyrene beads collected from the ACI stage. [Figure 5] FIG. 5 illustrates the effect of modifying the approach used in FIG. 4 to avoid contact of the dispensing needle with the substrate surface and to provide a dropwise delivery of the suspension onto the substrate surface to achieve atomization. [Figure 6] FIG. 6 shows APSD of 1.1 mg / ml ARAC in 1% NaCl solution, sprayed by continuously supplying the solution (200 μl / min) with a dispenser needle in contact with the microcavity array spraying the solution. [Figure 7] Figures 7-11 show the fluorescence measured at various stages of ACI when polystyrene beads (4.8 μm beads in Figure 8, 1.0 μm beads in Figure 9, 0.5 μm beads in Figure 10, 0.2 μm beads in Figure 11, and 0.1 μm beads in Figure 12) were added to a 1% NaCl solution to create a monodisperse suspension. These results were obtained by spraying the suspension by contacting a dispenser needle with the microcavity array into which the suspension was being sprayed and delivering the suspension continuously (200 μl / min). [Figure 8] Figures 7-11 show the fluorescence measured at various stages of ACI when polystyrene beads (4.8 μm beads in Figure 8, 1.0 μm beads in Figure 9, 0.5 μm beads in Figure 10, 0.2 μm beads in Figure 11, and 0.1 μm beads in Figure 12) were added to a 1% NaCl solution to create a monodisperse suspension. These results were obtained by spraying the suspension by contacting a dispenser needle with the microcavity array into which the suspension was being sprayed and delivering the suspension continuously (200 μl / min). [Figure 9] Figures 7-11 show the fluorescence measured at various stages of ACI when polystyrene beads (4.8 μm beads in Figure 8, 1.0 μm beads in Figure 9, 0.5 μm beads in Figure 10, 0.2 μm beads in Figure 11, and 0.1 μm beads in Figure 12) were added to a 1% NaCl solution to create a monodisperse suspension. These results were obtained by spraying the suspension by contacting a dispenser needle with the microcavity array into which the suspension was being sprayed and delivering the suspension continuously (200 μl / min). [Figure 10]Figures 7-11 show the fluorescence measured at various stages of ACI when polystyrene beads (4.8 μm beads in Figure 8, 1.0 μm beads in Figure 9, 0.5 μm beads in Figure 10, 0.2 μm beads in Figure 11, and 0.1 μm beads in Figure 12) were added to a 1% NaCl solution to create a monodisperse suspension. These results were obtained by spraying the suspension by contacting a dispenser needle with the microcavity array into which the suspension was being sprayed and delivering the suspension continuously (200 μl / min). [Figure 11] Figures 7-11 show the fluorescence measured at various stages of ACI when polystyrene beads (4.8 μm beads in Figure 8, 1.0 μm beads in Figure 9, 0.5 μm beads in Figure 10, 0.2 μm beads in Figure 11, and 0.1 μm beads in Figure 12) were added to a 1% NaCl solution to create a monodisperse suspension. These results were obtained by spraying the suspension by contacting a dispenser needle with the microcavity array into which the suspension was being sprayed and delivering the suspension continuously (200 μl / min). [Figure 12] Figure 12 shows the mass distribution of 4.8 μm beads on the ACI stage when sprayed at low flow rates (50 μl / min each) in contact and non-contact modes. DETAILED DESCRIPTION OF THE INVENTION

[0024] Aspects and embodiments of the present invention will now be described with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned herein are incorporated by reference.

[0025] First, a summary of the present disclosure is provided. Suspension formulations for inhalation therapy are often necessary because drugs (e.g., corticosteroids) cannot be fully dissolved in physiologically acceptable solvent systems to deliver effective doses. However, delivery of suspensions is often complicated by incompatibility between the inhaler system and the suspension particle size (e.g., mesh nebulizers) and undesirable particle interactions as a result of the aerosolization mechanism (e.g., ultrasonic nebulizers). While this disclosure explores the nebulization of suspension formulations using surface acoustic waves (SAW), the use of different acoustic energies is also contemplated to realize the benefits of the present invention. This work also explores the use of microstructures to confine liquids.

[0026] Nebulization of monodisperse suspensions with particle sizes ranging from 4.8 μm to 0.1 μm has been demonstrated, and specific factors that can be adjusted to improve aerosolization have been disclosed. For example, particle dispersibility has been found to be affected by the transmission of acoustic energy to the liquid dispensing system and the microstructure that confines the liquid. Acoustic cavity effects promote particle aggregation at larger particle sizes above 0.5 μm. This resulted in insufficient suspension delivery to the particle size analyzer (in this case, an Andersen cascade impactor).

[0027] It was found that by decoupling the dispensing system and suspension formulation reservoir from the SAW propagation path and adjusting the dispensing mode to a non-continuous transducer, delivery of particles 4.8 μm and larger was improved by 250%.

[0028] Further background is now provided to better understand this disclosure.

[0029] Inhalation drug delivery is known to be a particularly useful route for treating respiratory disorders. Liquid medications used to treat these disorders are dispensed in the form of an aerosol, which the patient can inhale. In some cases, aqueous formulations containing water-insoluble active pharmaceutical ingredients (APIs) in the form of suspended particles are used. These are called suspension formulations.

[0030] The particle size in suspension formulations is usually 10 -2 The particle size ranges from 10 to 10 μm. Ideally, suspensions are monodisperse, but particle-particle interactions and physical instability of the formulation can lead to heterogeneous dispersions. -2 Particle sizes and clusters of ~10 μm can cause problems during drug filling and administration. Because suspensions of larger particles are prone to settling and agglomeration, users must ensure that the particles are fully suspended and dispersed in the solution before filling. This will help prevent dose errors. Once loaded into the inhaler, treatment times must be kept short to avoid settling and coagulation within the device itself. Failure to do so could result in inaccurate doses.

[0031] As mentioned above, atomization of suspensions is considered difficult, especially in ultrasonic nebulizers. When a formulation is irradiated with a focused beam of ultrasound, a cone of liquid is formed from which droplets separate and form an aerosol. Suspended particles are trapped at the base of the cone, preventing diffusion and reducing the amount of particles attached to the aerosol droplets.

[0032] Nebulization of the suspension using a mesh nebulizer was also described above.

[0033] Thus, in general, aerosolization of suspension formulations has proven very difficult with various types of nebulizers, and studies have shown considerable variability in performance depending on particle size.

[0034] Embodiments of the present invention will now be described in terms of experimental work that has been carried out.

[0035] Figures 1 and 2 each show a system for preparing spray droplets. Figure 1 will be described first, followed by a description of the key differences in the system of Figure 2.

[0036] The system of Figure 1 includes a nebulizer device 10 that includes a transducer 12 having a piezoelectric material substrate 14 and an electrode arrangement 16, typically in the form of an interdigitated electrode arrangement. The electrode arrangement 16 is disposed on the upper surface of the substrate 14, which is planar in this embodiment. There is also an area on the upper surface of the substrate 14 where no electrode arrangement is disposed. This area includes an acoustic wave interactive surface 18 through which a suspension formulation is dispensed, as described below.

[0037] The system includes a dispenser 20 that includes a suspension reservoir 22 and a discharge conduit 24, which in this example is a needle. The dispenser may also include a pump (not shown) for dispensing and metering the suspension from the dispenser.

[0038] Suspension formulations comprise a suspension of insoluble particles in a carrier liquid.

[0039] In operation, an appropriate electrical signal is applied to the electrode arrangement 16. In combination with the piezoelectric substrate 14, this forms a transducer that generates a surface acoustic wave (SAW) that propagates along the acoustic wave interactive surface 18. The SAW interacts with a suspension formulation disposed on the acoustic wave interactive surface 18, generating atomized droplets of the suspension formulation. The atomized plume 28 is shown schematically in FIG. 1.

[0040] The effect of spatially separating the end of the dispensing needle 24 from the acoustic wave interactive surface 18 and not contacting the transducer 12 is to isolate the dispenser 22 from the SAW propagating along the acoustic wave interactive surface 18. The inventors have discovered that this prevents or reduces acoustic clustering of non-soluble particles in the formulation within the dispenser.

[0041] In this embodiment, droplet 26 falls by gravity from the tip of the dispensing needle onto acoustic wave interactive surface 18. The action of the SAW propagating along the surface causes acoustic streaming of the liquid along the surface, with stationary droplet 27 positioned slightly offset from where droplet 26 impacts acoustic wave interactive surface 18, as shown schematically in Figure 1. It will be appreciated that various modes of delivering the suspension formulation to acoustic wave interactive surface 18 are possible, for example, metering a segregated volume of suspension formulation by spraying, slug flow, or other equivalent approaches.

[0042] Each droplet is an isolated volume of the suspension formulation, typically with a constant particle concentration. It is contemplated that the rate of generation of the atomized droplets (by volume) will be the same as or comparable to the delivery rate of the suspension formulation at the acoustic wave interactive surface 18. To achieve this, the transducer may be operated continuously or intermittently, without substantial accumulation of excess liquid at the acoustic wave interactive surface 18.

[0043] To conduct the experiments reported here, the mist plume 28 is drawn into a particle size analyzer 30. In this example, this is an Andersen cascade impactor with an inlet 32, a cascade of eight stages 34, as described below, and a flow pump 36 that draws the mist plume 28 toward the inlet 32 ​​and generates an air flow within the inlet 32, as shown in FIG.

[0044] FIG. 2 shows a similar arrangement to FIG. 1, and the same features as FIG. 1 will not be described again in FIG. 2. The difference is that a microcavity arrangement 40 is disposed on the surface of the substrate 14. This microcavity arrangement is an arrangement of wells (microcavities) 44 formed in the surface of a material plate 42 disposed on top of the substrate. During operation, a SAW is coupled from the substrate surface to the material plate. Based on previous research, this has been found to further improve the particle size distribution of the mist plume. Droplets are directed into the microcavity arrangement and sprayed from the microcavity arrangement.

[0045] Surface acoustic wave devices with an interdigital transducer design were fabricated on 128° Y-cut lithium niobate piezoelectric substrates using standard photolithography and metal lift-off processes.

[0046] The microcavity array (also referred to herein as microstructure chip) consists of an array of wells and was fabricated by a dry etching process.

[0047] Atomization was performed using a microstructured tip placed above the SAW device.

[0048] A pump was used to inject the suspension into the nebulizer device through a syringe needle, the tip of which was initially in contact with the surface of the nebulizer device (contact mode), and then adjusted to a non-contact mode.

[0049] A monodisperse suspension formulation model was prepared using a 1% (wt%) sodium chloride solution. Fluorescently labeled polystyrene particles were added to the solution (Table 1).

[0050] [Table 1]

[0051] The aerosol (mist plume) was characterized using an Anderson Cascade Impactor (ACI). Size-separated aerosol particles were collected from the ACI stage by washing with 5 ml of deionized water. The fluorescence signal of the washing solution was analyzed using a plate reader, and the signal value was calculated as the fold change relative to the blank signal of deionized water and used to qualitatively evaluate the spray behavior of the suspension.

[0052] A 1% (wt%) sodium chloride solution containing 1.1 mg / ml Allura Red AC (ARAC) dye and 2 mg / ml 4.8 μm fluorescent beads was used to investigate the aerosol particle size distribution (APSD) during suspension nebulization and the effect of nebulization method. The dye concentration at each ACI stage was quantified using UV / VIS spectroscopy (504 nm). The concentration of 4.8 μm particles was measured using a plate reader. Standard curves for dye and particle quantification were generated prior to nebulization.

[0053] The inventors believe that particle agglomeration can occur when a substantial volume of suspension is in direct contact with the piezoelectric substrate for an extended period of time. Furthermore, particle agglomeration can also occur when the suspension is wicked into a porous matrix that is in continuous contact with the SAW substrate. Furthermore, particle agglomeration can occur in large volumes of liquid (such as large, stationary droplets) that are in direct contact with the SAW substrate, where the action of traveling or standing waves within the liquid can cause particle agglomeration at nodal pressure points.

[0054] The Andersen cascade impactor used in this study was operated to investigate the range of particle sizes at the various stages of the cascade, shown in Table 2 as Stage 0 to Stage 7.

[0055] [Table 2]

[0056] This disclosure demonstrates that it is possible to reduce the aggregation process of suspended particles, which provides technological advantages for ultrasound-based aerosol generation. These effects are believed to be enabled by a combination of controlled liquid ejection rate, liquid ejection method, and liquid driving for aerosolization within microstructures with cavities.

[0057] Figure 3 shows the results of API recovery from various parts of the system when spraying solutions with and without suspended particles using the arrangement in Figure 2. Figure 3 shows the amount of API recovered from various locations. IDT is the transducer surface containing the microcavity arrangement, IP is the induction port of the cascade impactor, and stages 0 through 7 are the stages of the cascade impactor as shown in Table 2. Figure 3 shows the aerodynamic particle size distribution (APSD) when spraying 1% sodium chloride with and without suspended particles. The graph shows the amount of analyte (Allura Red AC) recovered from each stage of the setup and the ACI. IDT: SAW device, IP: induction port of the ACI. The numbers represent the cutoff stages within the ACI and are according to Table 2. Spraying was performed at 13.4 MHz, -5 dBm, and 200 μl / min. The results in Figure 3 are for the dispensing needle in contact with the SAW substrate and the microcavity arrangement. Nebulization was performed at 13.4 MHz, −5 dBm, and 200 μl / min.

[0058] Figure 4 shows the nebulization results of a suspension, examining the fluorescent signal of 4.8 μm green fluorescent polystyrene beads collected from the ACI stage. The results in Figure 4 are from a dispensing needle in contact with a SAW substrate. Nebulization was performed at 13.4 MHz, -5 dBm, and 200 μl / min.

[0059] Figure 5 shows the results of a modification of the method used in Figure 4, where the dispensing needle is prevented from contacting the substrate surface and the suspension is atomized dropwise onto the substrate surface. Figure 5 again uses a suspension of 4.8 μm green fluorescent polystyrene beads dispensed at a rate of 50 μl / min. Comparing Figure 5 with Figure 4, it can be seen that the mist plume contains smaller particle-sized droplets carrying the fluorescent marker.

[0060] The results will be explained in more detail with reference to FIGS.

[0061] APSD of 1.1 mg / ml ARAC in 1% NaCl solution showed a typical bimodal particle size distribution with peaks at 9 μm and 1.1 μm (Figure 6). This result was obtained by continuously supplying the solution (200 μl / min) to a dispenser needle in contact with a microcavity array that sprayed the solution.

[0062] Figures 7–11 show the fluorescence measured at each stage of ACI when polystyrene beads (4.8 μm beads in Figure 7, 1.0 μm beads in Figure 8, 0.5 μm beads in Figure 9, 0.2 μm beads in Figure 10, and 0.1 μm beads in Figure 11) were added to a 1% NaCl solution to form a monodisperse suspension. These results were obtained by contacting a dispenser needle with a microcavity array that sprayed the suspension and delivering the suspension continuously (200 μl / min).

[0063] The bead distribution within the ACI differed from that of the APSD shown in Figure 6 in that the bimodal distribution of the suspensions containing 4.8 μm, 1 μm, and 0.5 μm beads was not observed (Figures 7-11). Only the suspensions containing 0.2 μm and 0.1 μm beads (Figures 10 and 11, respectively) exhibited a bimodal distribution. Furthermore, a large amount of beads accumulated on the nebulizer platform, and the microcavity array observed after the experiment showed a significant amount of bead aggregation within the microcavity array.

[0064] The acoustic cavity effect is thought to generate acoustic forces that promote bead aggregation within the microcavity array and the tip of the dispensing needle. Continuously dispensing the suspension into the microcavity array to generate a stable liquid film volume can form a standing wave with a pressure node optimal for bead aggregation. Furthermore, coupling acoustic energy to a continuous flow of the suspension mixture can concentrate the beads, reducing their dispersibility prior to the spraying process and potentially resulting in the formation of large aggregates on the platform (i.e., spraying failure).

[0065] To increase the efficiency of delivery of 4.8 μm beads into the ACI, a reduction in the flow rate (from 200 μl / min to 50 μl / min) and avoiding direct exposure of the suspension mixture to acoustic pressure were considered.

[0066] Figure 12 compares contact and non-contact approaches to delivering a suspension formulation to a microcavity array for nebulization. In the contact mode, the needle is in continuous contact with the microcavity array, and the liquid flows continuously into the microcavity array. In the non-contact mode, the needle is spaced from the microcavity array, and the liquid falls as free, independent droplets from the needle onto the microcavity array, as shown in Figure 2.

[0067] Non-contact mode nebulization of the liquid reduces contact of the acoustic waves with most of the remaining liquid in the reservoir and needle.

[0068] Figure 12 shows the mass distribution of 4.8 μm beads on the ACI stage when sprayed at low flow rates (50 μl / min each) in contact and non-contact modes. In non-contact mode, 300 μg of beads were recovered across the cutoff stages from >9 μm to 3.3 μm, compared with 117 μg of beads recovered in contact mode. APSD data (not shown) for non-contact and contact modes indicate a 28% increase in ARAC mass across the aforementioned stages, indicating a shift to larger droplet sizes, which can only partially explain the 250% increase in bead mass shown in Figure 12. The primary contribution is likely due to the change in dispensing method.

[0069] The microcavity array approach, combined with controlled ejection speed and mode, appears to suppress particle aggregation and generate smaller droplet sizes, as can be seen, for example, in Figure 5.

[0070] Traditional ultrasonic nebulizers require direct contact between an acoustic energy source and the suspension formulation, or indirect contact via a transmission medium. Typical devices drive the entire liquid drug to generate an aerosol. While this works well for single-phase solutions, two-phase solutions containing insoluble (e.g., solid) particles in suspension are subject to the acoustic forces generated by ultrasound. Here, acoustic radiation forces cause particles to accumulate at nodal pressure points within the liquid suspension or at the solid-liquid interface of the drug reservoir, depending on the transmission medium. Accumulation of drug particles into larger clusters can prevent the formation of drug-laden aerosol particles, resulting in insufficient dosage.

[0071] This phenomenon has also been observed in SAW-based actuation techniques, where the suspension reservoir is in direct contact with a piezoelectric substrate

[10] . In this study, a dispensing needle contacts the actuation surface, inducing acoustic energy coupling. The needle's inner diameter (160 μm diameter) is suitable for acting as an acoustic cavity supporting standing waves that cause particles to aggregate in a size-dependent manner. Furthermore, this microstructure can act as a cavity to confine the liquid before atomization and support standing waves that promote further particle clustering. Initial ACI experiments (Figures 7–11) showed a correlation between APSD and bead distribution for bead sizes below 0.5 μm. While 4.8 μm beads are expected to be absent at the lower cutoff stage, the absence of 1 μm and 0.5 μm beads indicates a change in droplet size formation and supports the effect of acoustic radiation forces, which are dependent on bead size.

[0072] The effect of acoustic forces becomes even more pronounced when using contact and non-contact spray modes (i.e., adjusting the dispensing technique). The non-contact liquid dispensing mode significantly improves the dispensing performance of 4.8 μm beads. Compared to the contact mode (see Figure 12), the non-contact mode reduces the effect of constant exposure of the liquid to acoustic energy. Droplet delivery with continuous droplet dispensing is believed to further reduce the resonance phenomenon caused by unstable volume distribution within the cavities in the microcavity array.

[0073] Therefore, nebulization of suspension formulations using ultrasound-based transducers, such as SAW devices, requires careful consideration of the transfer of acoustic energy to the liquid in the drug reservoir and dispensing system. Particle clustering due to traveling and standing wave acoustic forces inhibits efficient aerosolization of suspensions. Separating the reservoir and dispensing system from the actuation surfaces reduces acoustic energy transfer and particle clustering prior to nebulization. Therefore, using a non-contact mode for dispensing formulations for nebulization can prevent the strong resonance effects associated with particle clustering.

[0074] The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, are appropriately expressed in their specific form, or in terms of means for performing a disclosed function, or methods or processes for obtaining a disclosed result, and such features can be used individually or in any combination to realize the invention in its various forms.

[0075] While the present invention has been described in conjunction with the exemplary embodiments set forth above, many equivalent modifications and variations will be apparent to those skilled in the art upon reading this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are to be considered illustrative and not limiting. Various changes can be made to the described embodiments without departing from the spirit and scope of the invention.

[0076] For the avoidance of doubt, the theoretical explanations provided herein are provided for the purpose of enhancing the reader's understanding, and the inventors do not intend to be bound by these theoretical explanations.

[0077] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0078] Throughout this specification, including in the claims which follow, unless the context otherwise requires, the words "comprises" and "comprises," and variations such as "comprises," "including," "comprising," etc., will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of other integers or steps or groups of integers or steps.

[0079] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. As used herein, expressions may be expressed as "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will understand that the particular value constitutes another embodiment. The term "about" in reference to numerical values ​​is arbitrary and may mean, for example, ±10%.

[0080] References Numerous publications have been cited above in order to more fully describe and disclose the present invention and the state of the art to which it pertains. The full text of these references is set forth below. All of these references are incorporated herein by reference. [1] PPHL Brun, AH de Boer, HW Frijlink, and HGM Heijerman, Pharm. World Sci., 2000, 22, 75-81. [2] Nikander K, Turpeinen M, Wollmer P. “The Conventional Ultrasonic Nebulizer Proved Inefficient in Nebulizing a Suspension” J. Aero. Med. 1999 12:2, 47-53 [3] Pulmicort Respules Patient information, accessible here https: / / www.rxlist.com / pulmicort-respules-drug.htm#description [4] R.H.M. Hatley, J. Parker, L.E.A. Hardaker & S. Byrne. “Ultrasonic and Mesh Nebulizers Are Not the Same - Delivery of a Budesonide Suspension” Drug Delivery to the Lungs, DDL 2015 [5] L Slator, Y Degtyareva, R Potter & RHM Hatley. “Passive Mesh, Active Mesh and Ultrasonic Nebulizers - Ability to Deliver a Budesonide Suspension” Drug Delivery to the Lungs, DDL 2017 [6] H.S.M. Ali, P. York, A. Amani, N. Blagden, Evaluation of a Nanodispersion Formulation Prepared through Microfluidic Reactors for Pulmonary Delivery of Budesonide Using Nebulizers, Iran J Pharm Res, 13 (2014) 785-795. [7] W.K. Kraft, B. Steiger, D. Beussink, J.N. Quiring, N. Fitzgerald, H.E. Greenberg, S.A. Waldman, The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers, J Clin Pharmacol, 44 (2004) 67-72. [8] Najlah M, Parveen I, Alhnan MA, Ahmed W, Faheem A, Phoenix DA, Taylor KMG, Elhissi A. “The effects of suspension particle size on the performance of air-jet, ultrasonic and vibrating-mesh nebulisers”. Int. J. Pharm. 2014, Vol 461, pp 234-241, https: / / doi.org / 10.1016 / j.ijpharm.2013.11.022. [9] Angela Mary Fonceca, William Graham Fox Ditcham, Mark L. Everard, Sunalene Devadason, Drug Administration by Inhalation in Children, Editor(s): Robert William Wilmott, Robin Deterding, Albert Li, Felix Ratjen, Peter Sly, Heather J. Zar, Andrew Bush, Kendig's Disorders of the Respiratory Tract in Children (Ninth Edition), Elsevier, 2019, Pages 257-271.

[10] Witte C , Reboud J, Wilson R , Cooper J M, Neale S: Microfluidic resonant cavities enable acoustophoresis on a disposable superstrate, Lab Chip, 2014; 14: 4277 - 4283.

Claims

1. 1. A method for preparing atomized droplets, comprising providing an apparatus comprising an acoustic wave interactive surface and an acoustic wave transducer adapted to generate and propagate acoustic waves to the acoustic wave interactive surface; the device further comprising a dispenser positioned relative to the sound wave interactive surface and configured to dispense a suspension formulation comprising a suspension of insoluble particles in a carrier liquid; The method comprises the following steps: depositing the suspension formulation in a time series of discrete volumes onto the acoustic wave interactive surface using the dispenser, wherein each discrete volume of the suspension formulation has a volume of 50 μL or less; and propagating acoustic waves to the acoustic wave interactive surface to interact with the suspension formulation and generate atomized droplets of the suspension formulation; Including, During the step of placing the suspension formulation on the acoustic wave interactive surface, the dispenser is isolated from acoustic waves propagating within the suspension formulation, thereby preventing or reducing acoustic clustering of insoluble particles within the dispenser.

2. 10. The method of claim 1, wherein the device comprises an array of cavities opening to the acoustic wave interactive surface for containing the suspension formulation, and wherein the acoustic waves interact with the suspension formulation in the cavities to generate the atomized droplets.

3. 3. The method of claim 1 or 2, wherein during the step of placing the suspension formulation on the acoustic wave interactive surface, each isolated volume of the suspension formulation is always in direct contact with only one of the dispenser and the acoustic wave interactive surface, or is not in contact with either the dispenser or the acoustic wave interactive surface.

4. The method of claim 3 , wherein the outlet of the dispenser is separated from the sound wave interactive surface by a minimum distance of 0.1 mm or more.

5. The method according to any one of claims 1 to 4, wherein the time interval between the dispensing of successive isolated volumes in the time series of isolated volumes is variable.

6. 6. The method of claim 5, comprising determining a spray rate and / or evaporation rate of the suspension formulation located on the interaction surface and setting the time interval and / or the isolated volume based on said determination.

7. 7. The method of claim 6, wherein the steps of determining the atomization rate and / or evaporation rate and setting the time interval are repeated.

8. 8. The method of any one of claims 1 to 7, wherein each isolated volume of the suspension formulation in the time series of isolated volumes has an initial volume in the range of 0.5 to 5.0 μL.

9. The method of any one of claims 1 to 8, wherein each isolated volume of the suspension formulation is disposed at the same location on the acoustic wave interactive surface.

10. The method of any one of claims 1 to 9, wherein the insoluble particles comprise an active pharmaceutical ingredient.

11. The method of any one of claims 1 to 10, wherein the acoustic wave interactive surface is a surface acoustic wave (SAW) transmission surface, the acoustic wave transducer is a SAW transducer, and the acoustic wave is a SAW.

12. 12. The method according to any one of claims 1 to 11, wherein the particle size distribution of the insoluble particles is such that D90 is at most 50 μm.

13. 1. A system for preparing spray droplets, the system comprising: a spray device; and a suspension formulation of insoluble particles suspended in a carrier liquid, the spray device comprising: a sound wave interaction surface; an acoustic wave transducer adapted to generate and propagate acoustic waves to the acoustic wave interactive surface; a dispenser configured to deposit the suspension formulation onto an acoustic wave interactive surface in time-sequential, isolated volumes, wherein each isolated volume of the suspension formulation has a volume of 50 μL or less; Including, during operation, acoustic waves propagating to the acoustic wave interactive surface interact with the suspension formulation to generate atomized droplets of the suspension formulation; The system, wherein the atomizing device is configured to isolate the dispenser from acoustic waves propagating to the acoustic wave interactive surface.

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