Aerosol generation

Abstract

A method for aerosolizing a liquid, comprising the steps of: providing an orifice plate having at least 100 outlet orifices per mm2; delivering a liquid to the orifice plate; the aperture plate is vibrated to produce an aerosol. The viscosity of the liquid is in the range of 1-15 cP, and the surface tension of the liquid is in the range of 72-0.5 mN / m. And the output rate of the generated aerosol is greater than 0.01 mL / min.

Description

[0001] This application is a divisional application of the application No. 201680033323.8, titled "Aerosol Generation", filed on June 10, 2016. Technical Field

[0002] The present invention relates to an aerosol generator. Background Art

[0003] Vibratory orifice plates are used in a variety of aerosol devices and are typically supported around their edges by a vibratory support member vibrated by a piezoelectric element. Additionally, an aerosol device may have a passive or static orifice plate that is operated, for example, by an acoustic signal from a horn to cause a flow of medicament to filter through the orifice plate.

[0004] Aerosol generators that include a vibratable member and a plate body operably connected to the vibratable member are known. The plate body has a top surface, a bottom surface, and a plurality of holes extending from the top surface. The holes may be tapered such that when a liquid is supplied to one surface and the orifice plate is vibrated using the vibratable member, droplets are ejected from the opposite surface. Details of such known systems are described, for example, in US 6,235,177, US 2007 / 0023547 A, and US 7,066,398, the entire contents of which are incorporated herein by reference.

[0005] Currently, orifice plates are produced by a variety of different means, including electroplating and laser drilling. From a technical and economic perspective, electroplating is generally the most advantageous production method. US 6,235,177 (Aerogen) describes an electroplating-based method in which a wafer material is built up on a mandrel by an electrodeposition process in which liquefied metal (typically palladium and nickel) in a plating bath is transformed from a liquid form to a solid form on the wafer. The material is transferred to the conductive surface of the mandrel and not to the non-conductive photoresist areas. Areas where metal buildup is not desired are masked with non-conductive photoresist. After the plating process is complete, the mandrel / wafer assembly is removed from the bath and the wafer is peeled from the mandrel for subsequent processing into an orifice plate.

[0006] However, the problem with this method is that the size of the holes depends on the plating time and the thickness of the resulting wafer. The process is difficult to control and, if not fully controlled, some holes may be close to closing or closed, or be too large, and there may be out-of-tolerance variation in the size of the holes. Additionally, there is a limit to the number of holes per unit area. Moreover, with this technology, an increase in the output rate generally requires an increase in the particle size, which may often be undesirable. Summary of the Invention

[0007] The present invention provides a method for aerosolizing a liquid, which comprises the following steps:

[0008] Providing an orifice plate having at least 100 outlet holes per mm 2 ;

[0009] Delivering the liquid to the orifice plate, wherein the viscosity of the liquid is in the range of 1 - 15 cP, and the surface tension of the liquid is in the range of 72 to 0.5 mN / m; and

[0010] Vibrating the orifice plate to generate an aerosol, wherein the output rate of the generated aerosol is greater than 0.01 mL / min.

[0011] In some cases, the fraction of droplets having a size less than 3 microns is greater than 75%, greater than 80%, greater than 85%, or greater than 90%.

[0012] In some embodiments, the orifice plate has at least 500 outlet holes per mm 2 , at least 1,000 outlet holes per mm 2 , at least 1,500 outlet holes per mm 2 , at least 2,000 outlet holes per mm 2 , at least 2,500 outlet holes per mm 2 , at least 3,500 outlet holes per mm 2 or at least 5,000 outlet holes per mm 2 .

[0013] In some embodiments, the volume median diameter of the droplets is less than 5 microns, less than 4 microns, less than 3 microns, less than 2.5 microns, less than 2.0 microns, less than 1.5 microns or less than 1 micron.

[0014] In some cases, the viscosity of the liquid is less than 12 cP, less than 10 cP, less than 7 cP, less than 5 cP, or less than 2 cP.

[0015] In some embodiments, the surface tension of the liquid is less than 70 mN / m, less than 65 mN / m, less than 60 mN / m, less than 55 mN / m, less than 50 mN / m, less than 40 mN / m, less than 30 mN / m, less than 25 mN / m, less than 20 mN / m, less than 10 mN / m, less than 5 mN / m, or greater than 0.5 mN / m.

[0016] In some cases, the output rate of the resulting aerosol is greater than 0.05 mL / min, greater than 0.075 mL / min, greater than 0.1 mL / min, greater than 0.2 mL / min, greater than 0.3 mL / min, greater than 0.33 mL / min, greater than 0.5 mL / min, greater than 1.00 mL / min, or greater than 2.00 mL / min.

[0017] In some embodiments, a method for atomizing a liquid is provided, which comprises the following steps: -

[0018] Providing an orifice plate having at least 100 outlet holes per mm 2 ;

[0019] Delivering the liquid to the orifice plate; and

[0020] Vibrating the orifice plate to produce an aerosol comprising a plurality of droplets, wherein the fraction of droplets having a size less than 3 microns is greater than 75%.

[0021] In one case, the fraction of droplets having a size less than 3 microns is greater than 80%, greater than 85%, or greater than 90%.

[0022] In some embodiments, the orifice plate has at least 500 outlet holes per mm 2 , at least 1,000 outlet holes per mm 2 , at least 1,500 outlet holes per mm 2 , at least 2,000 outlet holes per mm 2 , at least 2,500 outlet holes per mm 2 , at least 3,500 outlet holes per mm 2 , or at least 5,000 outlet holes per mm 2 .

[0023] In some embodiments, the volume median diameter of the droplets is less than 3 microns, less than 2.5 microns, less than 2.0 microns, less than 1.5 microns or less than 1 micron.

[0024] In some embodiments, the viscosity of the liquid is less than 2 cP, less than 5 cP, or less than 10 cP.

[0025] In some embodiments, the surface tension of the liquid is less than 60 mN / m, less than 50 mN / m, less than 40 mN / m, less than 30 mN / m, less than 25 mN / m, less than 20 mN / m, less than 10 mN / m, less than 5 mN / m, or greater than 0.5 mN / m.

[0026] In one case, the surface tension of the liquid is in the range of 72 mN / m to 0.5 mN / m, and the viscosity is in the range of 1 to 10 cP.

[0027] In some embodiments, the output rate of the generated aerosol is greater than 0.1 mL / min, greater than 0.2 mL / min, greater than 0.3 mL / min, greater than 0.33 mL / min, greater than 0.5 mL / min, greater than 1.00 mL / min, or greater than 2.00 mL / min.

[0028] The liquid may contain a drug, a surfactant, or a medicament. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is a cross-sectional view of the wafer before bumping;

[0030] Figure 2 is a view of the orifice plate formed by bumping the Figure 1 wafer;

[0031] Figure 3 is a graph of cumulative volume and volume frequency against the particle size of the aerosol according to the present invention;

[0032] FIG. 4 is a graph showing a comparison of the droplet sizes of surfactant-based formulations produced using photo-definition technology (bottom) and plating-definition technology (top);

[0033] FIG. 5 is a graph showing a comparison of the fine particle fraction less than 5 microns of surfactant-based formulations produced using photo-definition technology (bottom) and plating-definition technology (top); and

[0034] FIG. 6 is a graph showing a comparison of the fine particle fraction less than 3 microns of surfactant-based formulations produced using photo-definition technology (bottom) and plating-definition technology (top). DETAILED DESCRIPTION

[0035] Figure 3 shows the droplet size (volume median diameter, VMD) of a surfactant-based formulation produced using photo-definition technology.

[0036] The Dv(50) [VMD] of the drug / device combination was recorded as 1.048 microns.

[0037] The geometric standard distribution (GSD) of the drug / device combination was recorded as 1.925.

[0038] The aerosol output rate of the drug / device combination was recorded as 0.33 ml / min.

[0039] Figure 4 shows a comparison of the droplet sizes (commonly referred to as volume median diameter (VMD)) determined by laser scattering of surfactant-based formulations produced using a light-limiting technique (4b) and an existing plating-limited mesh nebulizer (4a) [Reference: ISO 13320 Particle Size Analysis 2 - Laser Diffraction Method and FDA Guidance (1993): Reviewer Guidance for Nebulizers, Metered Dose Inhalers, Spacers and Actuators. Available from http: / / www.fda.gov / downloads / medicaldevices / deviceregulationandguidance / guidancedocuments / ucm081293.pdf]. It should be noted that the X-axis scale is aligned to confirm that for the light-limiting technique, the population is shifted to the right (i.e., lower droplet sizes).

[0040] Figure 5 shows a comparison of the fine particle fraction (FPF) less than 5 microns of surfactant-based formulations produced using a light-limiting technique (5b) and an existing plating-limited mesh nebulizer (5a). It should be noted that the X-axis scale is aligned to confirm that for the light-limiting technique, the population is shifted to the right (i.e., lower droplet sizes).

[0041] Figure 6 shows a comparison of the fine particle fraction (FPF) less than 3 microns of surfactant-based formulations produced using a light-limiting technique (6b) and an existing plating-limited mesh nebulizer (6a). It should be noted that the X-axis scale is aligned to confirm that for the light-limiting technique, the population is shifted to the right (i.e., lower droplet sizes).

[0042] The present invention utilizes a light-limiting technique as described in WO2012 / 092163A and the applicant's WO2013 / 186031A (both of which are incorporated by reference in their entirety) to provide an orifice plate having at least 100 outlet holes per mm 2 Liquid is delivered to the orifice plate and the plate is vibrated to generate an aerosol.

[0043] The dome orifice plate 40 is shown in Figure 2 . Figure 1 A wafer 30 formed of a plating material 31 is shown, which has a storage layer containing holes 32 and an outlet layer having outlet holes 33.

[0044] Example 1

[0045] The specific orifice plate for the gas atomized surfactant-based formulation as described above has the following reservoir layer and outlet layer characteristics: The reservoir layer has holes with a diameter of 36 μm, a layer thickness of 40 μm, and a hole pitch of 100 μm. The outlet layer has holes with a diameter of 1 μm, a layer thickness of 5.2 μm, and a hole pitch of 7.5 μm. It is driven at 20 V using a controller.

[0046] Example 2

[0047] An orifice plate with an outlet layer thickness of 6.8 - 7 μm, an inlet hole diameter of 2.0 - 2.10 μm (on the outlet layer), and an outlet hole diameter of 2.5 - 2.55 μm (also on the outlet layer) is used to atomize colistin at 0.5 - 1.5 ml / min with a volume median diameter of 4 - 5 μm. These holes are spaced apart at a pitch of 8.46 μm. The reservoir holes on the inlet layer are 50 μm and are spaced 100 μm apart. The total thickness of the orifice plate is 60 - 62 μm. The device is driven on the drive controller at 108 - 128 kHz and 12 - 15 V, which generates a maximum amplitude of 1.5 - 3 μm on the vibrating plate.

[0048] Example 3

[0049] To determine the effect of increasing viscosity and decreasing surface tension on aerosol generation, a series of standards were prepared by diluting pure glycerol with 0.9% saline and ethanol with purified water. The dilution ratios ranged from 0 - 100% w / w. The viscosity and surface tension of each solution were characterized. The results are shown below (Tables 1 and 2). Unless otherwise referenced, the instrument used to measure viscosity was a viscometer (Brookfield viscometer (DV2TLV)). Unless otherwise referenced, the instrument used to measure surface tension was an optical tensiometer (OneAttension Theta) using the pendant drop experimental method. [Reference: Lide, D.R., 1992., CRC Handbook of Chemistry and Physics, 73rd Edition, Boca Raton; Ann Arbor; London: CRC]

[0050] Example 4

[0051] The orifice plate for the gas atomized inhalable drug type formulation as described above is made of an alloy of palladium and nickel using photolithography techniques and has the following reservoir layer and outlet layer characteristics: The reservoir layer has holes with a diameter of 50 μm, a layer thickness of 58 μm, and a hole pitch of 100 μm. The outlet layer has holes with a diameter of 2.5 - 3 μm, a layer thickness of 6.5 μm, and a hole pitch of 16 μm. It is driven at 13 V using a controller.

[0052] Example 5 - Comparison

[0053] The orifice plate for the gas atomization of inhalable pharmaceutical type preparations as described above comprises a single electroplated layer structure of an alloy of palladium and nickel having the following characteristics: 210 holes per linear inch, a layer thickness of 60 μm, a hole pitch of 121 μm, an inlet hole with a diameter of 80 μm, and an outlet hole with a diameter of 3 - 5 μm. It is driven at 12V using a controller.

[0054] Viscosity

[0055]

[0056] Table 1: Viscosities of glycerol and ethanol at various concentrations (25 °C) [Reference: Lide, D.R., 1992., CRC Handbook of Chemistry and Physics, 73rd Edition, Boca Raton; Ann Arbor; London: CRC]

[0057] Surface tension

[0058]

[0059]

[0060] Table 2: Surface tensions of glycerol (18 °C) and ethanol (20 °C) at various concentrations [Reference: Lide, D.R., 1992., CRC Handbook of Chemistry and Physics, 73rd Edition, Boca Raton; Ann Arbor; London: CRC]

[0061] 2) Commercially available pharmaceutical preparations

[0062]

[0063] Table 3: Measured surface tensions and viscosities of various pharmaceutical preparations

[0064] The orifice plate (core) (photo - defined technology) described in Example 4 is used to gas - atomize various preparations as described below. All the devices of Example 4 are fabricated from the same wafer.

[0065] The results shown in Table 4 are the average flow rates (n = 3) for increasing % w / w of glycerol and % v / v of ethanol.

[0066] The flow rate is determined by measuring the time to spray a 250 μL dose using a stopwatch and inputting the data into the following formula to obtain the flow rate.

[0067]

[0068]

[0069]

[0070] Table 4: Table of flow rates achieved using the orifice plate of Example 4 (NF = no flow)

[0071] VMD

[0072] Then the effects of increasing viscosity and decreasing surface tension on the formation of aerosol droplet size were measured (n = 3), and the results are shown in Table 5 below. VMD is the volume mean diameter measured using a Malvern Instrument Spraytec laser diffraction system. Refer to the FDA guidelines (1993): Reviewer's Guide to Nebulizers, Metered Dose Inhalers, Spacers, and Actuators. Available from http: / / www.fda.gov / downloads / medicaldevices / deviceregulationandguidance / guidancedocuments / ucm081293.pdf; 1

[0073]

[0074] Table 5: Table of VMD measured when nebulizing a glycerol solution using the orifice plate of Example 4.

[0075] Comparative tests

[0076] Example 5 - Comparison

[0077] The results shown in Table 5 are for the average flow rates (n = 3) for increasing the % w / w of glycerol and % v / v of ethanol using the orifice plate of Example 5. The devices of Example 5 were fabricated from different wafers.

[0078] The measurement technique was as described above.

[0079]

[0080] Table 6: Table of flow rates using the orifice plate of Example 5 (NF = no flow)

[0081] VMD

[0082] Then the effects of increasing viscosity and decreasing surface tension on the formation of aerosol droplet size using the orifice plate of Example 5 were measured (n = 3), and the results are shown in Table 7 below. The measurement technique was as described above.

[0083]

[0084] Table 7: Table of VMD measured using glycerol solutions for the orifice plate of Example 5 (NF = no flow)

[0085] Note: In Tables 5 and 7, the maximum detectable VMD is reported. Flow was observed at higher concentrations of glycerol. However, the Malvern Instrument's Spraytec laser diffraction system could not detect the aerosolized droplets due to the low aerosol density.

[0086] In summary, depending on the device, the orifice plate of Example 5 could not operate at > 31 - 36% w / w glycerol. This indicates that using the orifice plate of Example 5 will not atomize any viscous liquid pharmaceutical formulation with a viscosity > 2.6 - 3.0 cP and a surface tension of 71 - 72 mN / m.

[0087] When compared to the orifice plate of Example 5, the orifice plate of Example 4 (manufactured using a light confinement technique) performed better. The orifice plate of Example 4 was found to be able to atomize up to 48% w / w glycerol, which is the maximum % of glycerol atomized. Additionally, the atomization of 48% w / w glycerol maintained a reasonable flow rate, which was comparable to the comparative orifice plate of Example 5 at 30% w / w glycerol. The orifice plate of Example 4 increased the maximum viscosity of the atomizable liquid to approximately 5.5 - 6.0 cP (an increase of approximately 2 - 3 cP).

[0088] In all the tested devices, it was observed that the VMD of each device decreased with an increase in viscosity and a decrease in surface tension. The greater the starting VMD of the device, the greater the decrease in VMD at the maximum % glycerol.

[0089] The prior art could not atomize formulations with a viscosity > 2 cP and a surface tension < 25 mN / m, especially some commercially available surfactants. Although there are some commercially available surfactants that can be atomized, the performance of existing atomization techniques is sub - optimal, especially in terms of flow rate and droplet size.

[0090] Another significant problem with the prior art is the tendency of surfactant formulations to foam and potentially denature when atomized.

[0091] Although the present invention is directly applicable to surfactants, using the described techniques will readily atomize all formulations or excipients having similar physicochemical properties to those described. For example, we have found that it is now possible to atomize an antibiotic, colistin, which has proven difficult to atomize using existing electroplated sieve techniques (approximately 10 times slower than aqueous solutions).

[0092] In addition, the technology allows for the generation of droplets that are consistently smaller than those that could be generated heretofore using conventional techniques. The ability to generate sub-2 micron and sub-3 micron droplets allows for sustained and maximal alveolar and forward systemic drug delivery of a variety of formulations, including proteins, gene therapeutics, biological suspensions, and surfactants.

[0093] It facilitates the delivery of surfactant to neonates and all patient types with surfactant deficiency or in need of surfactant. Pulmonary surfactant is used to increase lung compliance, prevent atelectasis (lung collapse) at the end of exhalation, and promote the re-expansion of collapsed airways. Pulmonary surfactant greatly reduces surface tension due to its physicochemical properties, increases compliance, makes lung inflation much easier, and thus reduces the work of breathing. It reduces the pressure difference required to allow the lungs to expand.

[0094] Using surfactant as a carrier for other drug types also helps enable these drugs to penetrate the lungs by taking advantage of the low surface tension properties of the surfactant.

[0095] The delivery of formulation types (such as colistin (sodium polymyxin E methanesulfonate)) with specified physiochemical characteristics (i.e., lower surface tension and / or higher viscosity compared to aqueous solutions), which is difficult for existing mesh nebulizers, is facilitated, i.e., slow delivery times.

[0096]

[0097] Table 8: Example 4 - with sodium polymyxin E methanesulfonate, saline, and VMD and flow rate with surfactant

[0098] The device of Example 4 performed well and achieved atomization with sodium polymyxin E methanesulfonate, and saline. No overflow was observed, and a strong plume was maintained throughout the process (see Table 8). The VMD results for the previously problematic formulation for atomization through a vibrating orifice plate were in the range of 3.032 - 4.154 μm, while maintaining a good flow rate range of 0.265 - 0.519. The viscosity and surface tension of the surfactant sodium polymyxin E methanesulfonate, and are listed in Table 3.

[0099] The present invention also permits the use of an excipient or diluent in a clinically and commercially beneficial amount and concentration having specified physiochemical characteristics (i.e., lower surface tension and / or higher viscosity compared to an aqueous solution), such as polysorbate, glycerin, polyethylene glycol, propylene glycol, butylene glycol, pluronics, Captisol, which heretofore have not been shown to be atomizable in terms of flow rate and / or output rate.

[0100] The present invention now facilitates the treatment of pulmonary diseases with drugs that heretofore have not been atomizable.

[0101] It is also advantageous to use the lung as a route for systemic delivery of drugs that heretofore have not been atomizable.

[0102] Enables the generation of consistently small, i.e., sub-2 micron and sub-3 micron particles, which enables a significant increase in systemic delivery of previously atomizable formulations.

[0103] Enables the treatment of surfactant-specific diseases including (A) RDS, surfactant deficiency, treatment of lower characteristics in patients with lung inhalation injury, prevention of the disease by delivering pulmonary surfactant to patients at high risk of respiratory diseases caused by inactivation of pulmonary surfactant or impaired type II alveolar cell activity, and treatment of small airway obstructive syndrome.

[0104] Surfactants can be used as a vehicle for other pharmaceutically active substances. The use of surfactants and perfluorocarbons (another low surface tension formulation) facilitates post-deposition diffusion on the lung surface.

[0105] Active substances include viral vectors and non-viral vectors for direct administration to the lung and naked gene therapeutic agents.

[0106] The technology provides at least some of the following advantages:

[0107] · Atomize formulations having a viscosity >2 cP.

[0108] · Atomize formulations having a surface tension >0.5 mN / m.

[0109] · Atomize formulations having a viscosity >2 cP and a surface tension >0.5 mN / m.

[0110] · Atomize formulations having a viscosity >2 cP and a surface tension >60 mN / m.

[0111] · Enable atomization of previously non-atomizable formulations to increase the range of drug types now aerosolizable and deliverable to the lungs of all patient types.

[0112] ·Atomization of surfactant-based formulations.

[0113] ·The technology is also applicable to all delivery modes, including mechanical ventilation, non-invasive ventilation, non-ventilation, nCPAP, high flow, and spontaneous breathing.

[0114] ·The use of surfactants and albuterol, as well as other formulations intended for systemic delivery, results in the generation and maintenance of very low droplet sizes. This is important because we do not need to filter out larger particles by using baffles, etc., and this is manifested as an ultra-fine particle (inhalable) fraction that simultaneously maintains formulation integrity. We have confirmed that surfactants retain their activity and physicochemical characteristics after atomization using light-defining technology.

[0115] ·It is possible to achieve a high aerosol output rate. In situations where it has traditionally been difficult to atomize formulations such as pulmonary surfactants, we have achieved output rates of 0.33 mL / min and higher. Individually, we have recorded output rates of over 1 and 2 mL / min in the case of using simple solutions such as saline and albuterol. Such fast flow rates provide complete control over the atomization rate. For example, the high flow rate can be adjusted to a very low output rate (which is sometimes desirable, e.g., for PDE inhibitors). The technical limitation experienced by the prior art is that a high aerosol output rate cannot be achieved in the first place.

[0116] Any suitable drug, therapeutic agent, active substance, or pharmaceutically active compound that can target the lungs can be employed.

[0117] Surfactant drugs (sometimes referred to herein as "surfactants") are protein-lipid compositions, such as phospholipids, that are naturally produced in the body and are essential for the lung's ability to absorb oxygen. They facilitate breathing by constantly changing the surface tension of the fluid normally present in air sacs or alveoli, which are connected to the interior of the lungs by tubes. In the absence of sufficient surfactant, these air sacs tend to collapse, and as a result, the lungs cannot absorb enough oxygen. Insufficient surfactant in the lungs can lead to various respiratory diseases in both animals and humans. Since most of these surfactant drugs are animal-based, the current supply is limited, and although synthetic surfactants are available, their manufacture is currently neither precise nor inexpensive. Additionally, surfactant drugs are generally highly viscous and difficult to deliver to the patient's respiratory system. It is also possible to combine surfactants with other drugs to improve distribution in the lungs and the body. Surfactants also have the ability to act as anti-adhesion agents.

[0118] The present invention facilitates the delivery, in the form of an aerosol, of, for example, the following agents: bronchodilators, including β-agonists, muscarinic antagonists, adrenaline; surfactants; pain relief medications, including anesthetics; migraine therapeutics; anti-infective agents; anti-inflammatory agents, steroids, including corticosteroids; chemotherapeutic agents; mucolytics; vasodilators; vaccines and hormones. Additionally, substances classified as the following may also be suitable: antithrombotic agents, anti-proliferative agents, monoclonal antibodies, anti-tumor agents, anti-mitotic agents, anti-sense agents, anti-microbial agents, nitric oxide donors, anticoagulants, growth factors, translation promoters, heat shock protein inhibitors, biomolecules (including proteins, polypeptides and proteins, oligonucleotides, oligoproteins, siRNA, anti-sense DNA and RNA, ribozymes, genes, viral vectors, plasmids, liposomes, angiogenic factors, hormones, nucleotides, amino acids, sugars, lipids, serine proteases), anti-adhesion agents (including but not limited to hyaluronic acid), biodegradable barrier agents.

[0119] The medicament may, for example, include long-acting β-adrenergic receptor agonists such as salmeterol and formoterol or short-acting β-adrenergic receptor agonists such as salbutamol.

[0120] The medicament may be a long-acting muscarinic antagonist such as tiotropium (Spiriva) or a short-acting muscarinic antagonist such as ipratropium (Atrovent).

[0121] Typical anti-infective agents include antibiotics such as aminoglycosides, tetracyclines, fluoroquinolones; anti-microbial agents such as cephalosporin; and anti-fungal agents. Examples of antibiotics include anti-Gram-positive agents, such as macrolides (e.g., erythromycin, clarithromycin, azithromycin) and glycopeptides (e.g., vancomycin and teicoplanin), and any other anti-Gram-positive agent capable of being dissolved or suspended and used as a suitable aerosol, such as oxazolidinone, quinupristin / dalfopristen, etc. Antibiotics that can be used as anti-Gram-negative agents may include aminoglycosides, such as gentamicin, tobramycin, amikacin, streptomycin, netilmicin), quinolones (e.g., ciprofloxacin, ofloxacin, levofloxacin), tetracyclines (e.g., oxytetracycline, doxycycline, minocycline and co-trimoxazole), and any other anti-Gram-negative agent capable of being dissolved or suspended and used as a suitable aerosol.

[0122] The anti-inflammatory agent can be a steroid such as budesonide or ciclesonide, a non-steroid such as sodium cromoglycate, or a biological type.

[0123] Typical local anesthetics are, for example, ropivacaine, bupivacaine, levobupivacaine, and lidocaine.

[0124] The chemotherapeutic agent can be an alkylating agent, an antimetabolite, an anthracycline, a plant alkaloid, a topoisomerase inhibitor, a nitrosourea, a mitotic inhibitor, a monoclonal antibody, a tyrosine kinase inhibitor, a hormonal therapeutic agent (including corticosteroids), a cancer vaccine, an antiestrogen, an aromatase inhibitor, an antiandrogen, an antiangiogenic agent, and other antitumor agents.

[0125] The present invention is not limited to the above embodiments and can vary in details.

Claims

1. A method for aerosolizing a liquid, comprising the steps of: Provided is a raised orifice plate (30) formed of a plating material (31), the orifice plate (30) having a storage layer containing orifices (32) and an outlet layer having at least 100 outlet orifices per mm 2 wherein each orifice (32) of the storage layer is connected to a plurality of the outlet orifices (33); delivering the liquid to the orifice plate, wherein the viscosity of the liquid is in the range of 1 - 15 cP and the surface tension of the liquid is in the range of 72 - 0.5 mN / m; and vibrating the orifice plate to generate an aerosol, wherein the output rate of the generated aerosol is greater than 0.01 mL / min; wherein the surface tension of the liquid is less than 30 mN / m.

2. The method according to claim 1, wherein the fraction of droplets having a size less than 3 microns is greater than 75%, greater than 80%, greater than 85%, or greater than 90%.

3. The method according to claim 1, wherein the orifice plate has at least 500 outlet holes per mm 2 at least 1,000 outlet holes per mm 2 at least 1,500 outlet holes per mm 2 at least 2,000 outlet holes per mm 2 at least 2,500 outlet holes per mm 2 at least 3,500 outlet holes per mm or at least 5,000 outlet holes per mm 2 2 ​ 4. The method according to any one of claims 1 to 3, wherein the volume median diameter of the droplets is less than 5 microns, less than 4 microns, less than 3 microns, less than 2.5 microns, less than 2.0 microns, less than 1.5 microns, or less than 1 micron.

5. The method according to any one of claims 1 to 4, wherein the viscosity of the liquid is less than 12 cP, less than 10 cP, less than 7 cP, less than 5 cP, or less than 2 cP.

6. The method according to any one of claims 1 to 5, wherein the surface tension of the liquid is less than 25 mN / m, less than 20 mN / m, less than 10 mN / m, or less than 5 mN / m; and greater than 0.5 mN / m.

7. The method according to any one of claims 1 to 6, wherein the output rate of the generated aerosol is greater than 0.05 mL / min, greater than 0.075 mL / min, greater than 0.1 mL / min, greater than 0.2 mL / min, greater than 0.3 mL / min, greater than 0.33 mL / min, greater than 0.5 mL / min, greater than 1.00 mL / min, or greater than 2.00 mL / min.

8. The method according to any one of claims 1 to 7, wherein the liquid contains a drug.

9. The method according to any one of claims 1 to 7, wherein the liquid contains a surfactant.

10. The method according to any one of claims 1 to 7, wherein the liquid contains a medicament.

11. The method according to any one of claims 1 to 10, wherein the orifice (32) covers a plurality of the outlet holes (33).

12. The method according to any one of claims 1 to 11, wherein the orifice plate has at least 2 1,000 outlet holes per mm at least.

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