WO2021203038A1

WO2021203038A1 - Delivery of ginsenosides to the respiratory system via electronic breath actuated droplet delivery device

Info

Publication number: WO2021203038A1
Application number: PCT/US2021/025634
Authority: WO
Inventors: Charles Eric Hunter; Matthew CULPEPPER
Original assignee: Pneuma Respiratory Inc
Current assignee: Pneuma Respiratory Inc
Priority date: 2020-04-03
Filing date: 2021-04-02
Publication date: 2021-10-07
Anticipated expiration: 2022-10-03

Abstract

Methods for delivering a fluid composition comprising at least one ginsenoside as an ejected stream of droplets in a respirable range to the respiratory system of a user are disclosed. The methods are able to deliver the ejected stream of droplets to the respiratory system of the user such that at least about 50% of the mass of the ejected stream of droplets is delivered in a respirable range to the respiratory system of a user during use. The ejected stream of droplets may be generated via an ejector mechanism comprising a piezoelectric actuator and an aperture plate, the aperture plate having and a plurality of openings formed through its thickness, wherein at least the fluid entrance side of one or more of said openings is configured to provide a surface contact angle of less than 90 degrees and the piezoelectric actuator is operable to oscillate the aperture plate at a frequency to thereby generate an ejected stream of droplets during use.

Description

DELIVERY OF GINSENOSIDES TO THE RESPIRATORY SYSTEM VIA ELECTRONIC BREATH ACTUATED DROPLET DELIVERY DEVICE

RELATED APPLICATIONS

[0001] The present application claims benefit under 35 U.S.C. § 119 of U.S.

Provisional Patent Application No. 63/005,081, filed April 3, 2020, and entitled “Pulmonary Delivery of Ginsenoside Compositions Using a Droplet Delivery Device”, the contents of which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] This disclosure relates to the delivery of ginsenosides to the respiratory via a droplet delivery device, and more specifically via an electronic droplet delivery device.

BACKGROUND OF THE INVENTION

[0003] Ginseng root i a popular medicinal plant used in traditional medicine and has been shown to possess pharmacological activity'. Although there are a number of ginseng species, Korean ginseng ( Panax ginseng C. A. Meyer), American ginseng ( Panax quinquefolius /..). and Chinese ginseng ( Panax notoginseng) are the most are the most commonly used. Ginsenosides, including Rbl, Rb2, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, and Rh2, are the major bioactive compounds in ginseng. When administered orally or subcutaneously, ginsenosides have been shown to have numerous pharmacological effects including immunomodulation and anti-viral activity. For instance, protopanaxatriol (PT)-type ginsenosides (Re, Rf, and Rg2) have been shown to protect HeLa cells from human rhinovirus 3 (HRV3)-induced cell death (see, e.g., Im, K.; Kim, J.; Min, H., J. Ginseng Res. 2016, 40(4), 309-314). However, to date, the targeted respiratory delivery of ginseng and particularly ginsenosides has not been investigated.

[0004] The use of droplet generating devices for the delivery of substances to the respiratory system is an area of large interest. A major challenge is providing a device that delivers an accurate, consistent, and verifiable amount of substance, with a droplet size that is suitable for successful delivery of the substance to the targeted area of the respiratory system. [0005] Currently most inhaler type systems, such as metered dose inhalers (MDI), pressurized metered dose inhalers (p-MDI), or pneumatic and ultrasonic-driven nebulizer devices, generally produce droplets are not suited for delivery of many substances. Such devices generate droplets with high velocities and a wide range of droplet sizes, including large droplets that have high momentum and kinetic energy. Droplet plumes with large size distributions and high momentum do not reach a targeted area in the respiratory system, but rather deposit throughout the pulmonary passageways, mouth and throat. Such non-targeted deposition may be undesirable for many reasons, including improper dosing and unwanted side effects.

[0006] Accordingly, there is a need for an improved method to deliver ginseng and ginsenosides to the respiratory system, wherein the droplets are delivered in a targeted manner to the respiratory system.

SUMMARY OF THE INVENTION

[0007] One aspect of the disclosure relates to a method for delivering a fluid composition comprising at least one ginsenoside as an ejected stream of droplets in a respirable range to the respiratory system of a user. In certain embodiments, the method comprises (a) generating an ejected stream of droplets from the fluid composition via a an electronically actuated droplet delivery device comprising an ejector mechanism having a piezoelectric actuator, and an aperture plate, the aperture plate having a plurality of openings formed through its thickness and the piezoelectric actuator being operable to directly or indirectly oscillate the aperture plate at a frequency to thereby generate the ejected stream of droplets, wherein at least about 50% of the ejected stream of droplets have an average ejected droplet diameter of less than about 6 pm; and (b) delivering the ejected stream of droplets to the respiratory system of the user such that at least about 50% of the mass of the ejected stream of droplets is delivered in a respirable range to the respiratory system of a user during use.

[0008] In certain embodiments, the at least one ginsenoside may be Rbl, Rb2, Rc, Rd,

Re, Rf, Rgl, Rg2, Rg3, Rhl, Rh2, and combinations thereof. In other embodiments, the at least one ginsenoside may be Rbl, Rb2, Rc, Rd, Re, Rf, Rgl, Rg2, and combinations thereof. In yet other embodiments, the at least one ginsenoside may be Re, Rg2, Rg3, Rb2, Re, and combinations thereof.

[0009] In certain embodiments, the methods of the disclosure may be used to treat various diseases, disorders and conditions, promote or regulate various physiological activities, and combinations thereof, by delivering a fluid composition comprising at least one ginsenoside to the respiratory system of a user. In this regard, the methods of the disclosure may be used to deliver at least one ginsenoside locally to the respiratory system, and/or systemically to the body. In certain embodiments, the at least one ginsenoside is delivered to a user to treat or ameliorate a disease, condition or disorder selected from cancer, diabetes, or cardiovascular disease. In other embodiments, the at least one ginsenoside is delivered to a user to promote immune functions, regulate central nervous system (CNS) function, relieve stress, or provide anti-oxidant activity.

[0010] In certain embodiments, the ejector mechanism may comprise a piezoelectric actuator and an aperture plate. In certain embodiments, the aperture plate has a plurality of openings formed through its thickness and at least the fluid entrance side of one or more of said plurality of openings configured so as to provide a surface contact angle of less than 90 degree. In certain embodiments, the piezoelectric actuator is operable to oscillate the aperture plate at a frequency to thereby generate an ejected stream of droplets such that at least about 50% of the droplets have an average ejected droplet diameter of less than about 6 microns during use. [0011] In some embodiments, at least a portion of the interior of at least one of the openings is configured so as to provide a surface contact angle of less than 90 degrees. In other embodiments, the aperture plate is configured such that at least the fluid exit side of one or more of said plurality of openings is configured to provide a surface contact angle of greater than 90 degrees.

[0012] In certain aspects, the surface contact angle of less than 90 degree at the fluid entrance side of one or more of said plurality of openings is obtained by surface coating with a hydrophilic material, surface structural modification, or a combination thereof. In other embodiments, the surface contact angle of greater than 90 degrees at the fluid exit side of one or more of said plurality of openings is obtained by surface coating with a hydrophobic polymer.

[0013] While multiple embodiments are disclosed, still other embodiments of the present disclosure will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative embodiments of the disclosure. As will be realized, the invention is capable of modifications in various aspects, all without departing from the spirit and scope of the present disclosure. Accordingly, the detailed descriptions are to be regarded as illustrative in nature and not restrictive.

DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1A-1C illustrate cross-sections of an exemplary opening configured to provide a desired surface tension, with FIG. 1A showing an embodiment with a structural well between the fluid entrance side and the fluid exit side, FIG. IB showing a linear taper between the fluid entrance side and the fluid exit side, and FIG. 1C showing a curved taper between the fluid entrance side and the fluid exit side, in accordance with embodiments of the disclosure. [0015] FIG. ID illustrates a cross-section of an exemplary aperture plate and annulus ring configuration, in accordance with an embodiment of the disclosure.

[0016] The foregoing and other objects, features, and advantages of the present disclosure set forth herein will be apparent from the following description of particular embodiments of those inventive concepts, as illustrated in the accompanying drawings. Also, in the drawings the like reference characters refer to the same parts throughout the different views. The drawings depict only typical embodiments of the present disclosure and, therefore, are not to be considered limiting in scope.

DETAILED DESCRIPTION

[0017] In certain aspects, the present disclosure generally relates to methods for delivering a fluid composition comprising at least one ginsenoside as an ejected stream of droplets in a respirable range to the respiratory system of a user. In certain aspects, the fluid composition comprising at least one ginsenoside may be delivered at a high dose concentration and efficacy, as compared to alternative dosing routes and standard inhalation technologies. [0018] Effective and efficient delivery of substances to the respiratory system of a user, and the synchronization of the administration of substances to the respiratory system of the user with the inspiration/expiration cycle of the user has always posed a problem. For instance, optimum deposition in alveolar airways generally requires droplets with aerodynamic diameters in the ranges of 1 to 6 pm, with droplets below about 4 pm shown to more effectively reach the alveolar region of the lungs and larger droplets above about 6 pm shown to typically deposited on the tongue or strike the throat and coat the bronchial passages. Smaller droplets, for example less than about 1 pm, penetrate more deeply into the lungs and have a tendency to be exhaled. As such, methods for delivering a fluid composition comprising at least one ginsenoside as an ejected stream of droplets in a respirable range in accordance with aspects of the disclosure requires the ability to precisely target droplet sizes for the particular use.

[0019] In accordance with certain aspects of the disclosure, effective deposition of an ejected stream of droplets of a fluid composition comprising at least one ginsenoside into the lungs of a user generally requires droplets less than about 5-6 pm, e.g., less than about 3.2 pm, in diameter. Without intending to be limited by theory, to deliver an ejected stream of droplets to the lungs, a droplet delivery device must impart a momentum that is sufficiently high to permit ejection out of the device, but sufficiently low to prevent deposition on the tongue or in the back of the throat. Droplets below approximately 5-6 pm in diameter are transported almost completely by motion of the airstream and entrained air that carry them and not by their own momentum.

[0020] In some aspects, the methods of the disclosure result in minimal or no mouth or throat irritation. In certain embodiments, the methods include generating an ejected stream of droplets of a fluid composition comprising at least one ginsenoside with coordinated and precise timing during a user’s inspiration cycle to as to maximize delivery into the respiratory system, while minimizing or eliminating mouth or throat irritation. Without intending to be limited by theory, as described herein, the small droplets generated via the methods of the disclosure are transported almost completely by motion of airstream and entrained air. Using this entrained motion and tuned droplet size, the ejection of droplets may be focused so as to eject during peak flow of the inspiration cycle so as to optimize inhalation into the target site in the respiratory system (e.g., deep lungs), while minimizing inadvertent delivery to non- desired sites in the respiratory system (e.g., mouth and throat).

[0021] In certain embodiments, the methods including generating an ejected stream of droplets from a fluid composition comprising at least one ginsenoside via a an electronically actuated droplet delivery device comprising an ejector mechanism having a piezoelectric actuator, and an aperture plate, the aperture plate having a plurality of openings formed through its thickness and the piezoelectric actuator being operable to directly or indirectly oscillate the aperture plate at a frequency to thereby generate the ejected stream of droplets, wherein at least about 50% of the ejected stream of droplets have an average ejected droplet diameter of less than about 6 pm; and delivering the ejected stream of droplets to the respiratory system of the user such that at least about 50% of the mass of the ejected stream of droplets is delivered in a respirable range to the respiratory system of a user during use.

[0022] As discussed above, effective delivery of droplets deep into the lung airways require droplets that are less than about 5-6 microns in diameter, specifically droplets with mass mean aerodynamic diameters (MMAD) that are less than about 5 microns. However, for certain agents and uses, droplets about 1 pm or smaller for quick adsorption in the deep lung may be desirable, e.g., it may be desired to utilize droplets less than 4 pm, less than 3.2 pm, less than 3 pm, less than 2 pm, and less than 1 pm for the delivery at least one ginsenoside to the deep lungs. The mass mean aerodynamic diameter is defined as the diameter at which 50% of the droplets by mass are larger and 50% are smaller. In certain aspects of the disclosure, in order to deposit in the alveolar airways, droplets in this size range must have momentum that is sufficiently high to permit ejection out of the device, but sufficiently low to overcome deposition onto the tongue (soft palate) or pharynx.

[0023] In certain embodiments, methods for generating an ejected stream of droplets from a fluid composition comprising at least one ginsenoside for delivery to the respiratory system of user are provided. In certain embodiments, the ejected stream of droplets is generated in a controllable and defined droplet size range. By way of example, the droplet size range includes at least about 50%, at least about 60%, at least about 70%, at least about 85%, at least about 90%, between about 50% and about 90%, between about 60% and about 90%, between about 70% and about 90%, etc., of the ejected droplets are in the respirable range of below about 5 pm, below about 4 pm, below about 3.7 pm, below about 3.5 pm, below about 3.2 pm, below about 3.0 pm, below about 2 pm, between about 0.7 pm and about 4 pm, between about 0.7 pm and about 3.2 pm, between about 0.7 pm and about 3 pm, between about 0.7 pm and about 2.5 pm, between about 0.7 pm and about 2.0 pm, between about 0.7 pm and about 1.5 pm, between about 0.7 pm and about 1.0 pm, etc.

[0024] In other embodiments, the ejected stream of droplets may have one or more diameters, such that droplets having multiple diameters are generated so as to target multiple regions in the airways (mouth, tongue, throat, upper airways, lower airways, deep lung, etc.) By way of example, droplet diameters may range from about 1 pm to about 200 pm, about 2 pm to about 100 pm, about 2 pm to about 60 pm, about 2 pm to about 40 pm, about 2 pm to about 20 pm, about 1 pm to about 5 pm, about 1 pm to about 4.7 pm, about 1 pm to about 4 pm, about 10 pm to about 40 pm, about 10 pm to about 20 pm, about 5 pm to about 10 pm, and combinations thereof. In particular embodiments, at least a fraction of the droplets has diameters in the respirable range, while other droplets may have diameters in other sizes so as to target non-respirable locations (e.g., larger than 5 pm). Illustrative ejected droplet streams in this regard might have 50% - 70% of droplets in the respirable range (less than about 5 pm), and 30% -50% outside of the respirable range (about 5 pm - about 10 pm, about 5 pm - about 20 pm, etc.)

[0025] In other embodiments, the ejected stream of droplets may have one or more diameters, such that droplets having multiple diameters are generated so as to target multiple regions in the airways (mouth, tongue, throat, upper airways, lower airways, deep lung, etc.) By way of example, droplet diameters may range from about 0.7 pm to about 200 pm, about 0.7 pm to about 100 pm, about 0.7 pm to about 60 pm, about 0.7 pm to about 40 pm, about 0.7 pm to about 20 pm, about 0.7 pm to about 5 pm, about 0.7 pm to about 4.7 pm, about 0.7 mih to about 4 mih, about 0.7 mih to about 3.0 mih, about 0.7 mih to about 2.5 mih, about 0.7 mih and about 2.0 mih, about 0.7 mih and about 1.5 mih, about 0.7 mih and about 1.0 mih, , about 5 mih to about 20 mih, about 5 mih to about 10 mhi, and combinations thereof. In particular embodiments, at least a fraction of the droplets has diameters in the respirable range, while other droplets may have diameters in other sizes so as to target non-respirable locations (e.g., larger than about 5 pm). Illustrative ejected droplet streams in this regard might have 50% - 70% of droplets in the respirable range (less than about 5 pm), and 30% -50% outside of the respirable range (about 5 pm - about 10 pm, about 5 pm - about 20 pm, etc.)

[0026] In another embodiment, methods for delivering safe, suitable, and repeatable dosages of a fluid composition comprising at least one ginsenoside to the respiratory system of a user are provided. The methods deliver an ejected stream of droplets to the desired location within the respiratory system of the user. In certain embodiments, the methods are capable of delivering a defined volume of fluid in the form of an ejected stream of droplets such that an adequate and repeatable high percentage of the droplets are delivered into the desired location within the airways, e.g., the alveolar airways of the user during use.

[0027] In certain embodiments, the at least one ginsenoside may be Rbl, Rb2, Rc, Rd,

[0028] In certain embodiments, the methods of the disclosure may be used to treat various diseases, disorders and conditions, promote or regulate various physiological activities, and combinations thereof, by delivering a fluid composition comprising at least one ginsenoside to the respiratory system of a user. In this regard, the methods of the disclosure may be used to deliver at least one ginsenoside locally to the respiratory system, and/or systemically to the body. In certain embodiments, the at least one ginsenoside is delivered to a user to treat or ameliorate a disease, condition or disorder selected from cancer, diabetes, or cardiovascular disease. In other embodiments, the at least one ginsenoside is delivered to a user to promote immune functions, regulate central nervous system (CNS) function, relieve stress, or provide anti-oxidant activity.

[0029] In other embodiments, the fluid composition comprising at least one ginsenoside may further comprise a solution of nicotine or a salt thereof, e.g., including the water-nicotine azeotrope. By way of non-limiting example, the nicotine or salt thereof may be the naturally occurring alkaloid compound having the chemical name S-3-(l-methyl-2- pyrrolidinyl)pyridine, which may be isolated and purified from nature or synthetically produced in any manner, or any of its occurring salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, pyruvate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluene sulfonate, camphorate and pamoate salts. In other embodiments, the composition may further include any pharmacologically acceptable derivative, metabolite or analog of nicotine which exhibits pharmacotherapeutic properties similar to nicotine. Such derivatives and metabolites are known in the art, and include cotinine, norcotinine, nomicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and 5- hydroxy cotinine or pharmaceutically acceptable salts thereof.

[0030] In certain embodiments, the fluid composition comprising at least one ginsenoside may further comprise an agent that may isolated or derived from cannabis. For instance, the agent may be a natural or synthetic cannabinoid, e.g., THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), CBT (cannabicitran), and various combinations thereof. In other embodiments, the agent may be a ligand that bind the cannabinoid receptor type 1 (CBi), the cannabinoid receptor type 2 (CB2), or combinations thereof. In particular embodiments, the agent may comprise THC, CBD, or combinations thereof. By way of example, the agent may comprise 95% THC, 98% THC, 99% THC, 95% CBD, 98% CBD, 99% CBD, etc.

[0031] In all embodiments, the composition or solution may be an organic solution or an aqueous solution. The compositions or solutions may further include various emulsifiers, surfactants, solubilizers, stabilizers, flavors, and other pharmaceutically acceptable carriers suitable for delivery to the respiratory system. By way of example, the compositions or solutions may include ethanol (e.g., 95% or 100% ethanol) and/or a nonionic surfactant such as polyoxyethylene (20) sorbitan monooleate (polysorbate 80) to facilitate formulation of the agent into the solution. [0032] In certain aspects, the ejected stream of droplets of a fluid composition comprising at least one ginsenoside may be generated via an ejector mechanism configured to provide coordinated and precise control of droplet size. In certain embodiments, the ejector mechanism may comprise at least one aperture plate with a plurality of openings formed through its thickness for ejecting droplets, wherein at least one surface of the aperture plate is configured to provide a desired surface contact angle. In certain embodiments, the ejector mechanism may be an electronically actuated ejector mechanism and may further comprise a piezoelectric actuator configured to directly or indirectly vibrate the aperture plate during use to thereby generate a stream of droplets. In certain embodiments, the aperture plate may be configured such that at least one surface is configured with a desired surface contact angle to facilitate generation of droplets with the desired droplet size distribution, e.g., less than 4 pm, less than about 3.2 microns, less than about 3 microns, less than about 2 microns, less than about 1.5 microns, less than about 1 micron, etc.

[0033] In certain embodiments, the aperture plate has a plurality of openings formed through its thickness and at least the fluid entrance side of one or more of said plurality of openings configured so as to provide a surface contact angle of less than 90 degrees. In certain embodiments, the piezoelectric actuator is operable to oscillate the aperture plate at a frequency to thereby generate an ejected stream of droplets such that at least about 50% of the droplets have an average ejected droplet diameter of less than about 6 microns during use. In some embodiments, at least a portion of the interior of at least one of the openings near the fluid entrance side is configured so as to provide a surface contact angle of less than 90 degree. [0034] In other embodiments, the aperture plate is configured such that at least the fluid exit side of one or more of said plurality of openings is configured to provide a surface contact angle of greater than 90 degrees. In some embodiments, at least a portion of the interior of at least one of the openings near the fluid exit side is configured so as to provide a surface contact angle of greater than 90 degrees.

[0035] In certain embodiments, at least the fluid entrance surface of one or more openings of the aperture plate and the fluid exit surface of one or more openings of the aperture plate are configured (e.g., treated, coated, surface modified, or a combination thereof) to provide a desired surface contact angle. In some embodiments, at least a portion of the interior of at least one of the openings near the fluid entrance side is configured so as to provide a desired surface contact angle. By way of example, the fluid entrance surface and/or interior surface of one or more openings of the aperture plate may be configured to have a surface contact angle of less than about 80 degrees, less than about 70 degrees, less than about 50 degrees, less than about 55 degrees, less than about 50 degrees, less than about 40 degrees, less than about 35 degrees, less than about 30 degrees, less than about 20 degrees, less than about 10 degrees, between about 10 degrees and about 80 degrees, between about 10 degrees and about 60 degrees, between about 20 degrees and about 55 degrees, between about 10 and about 35 degrees, between about 15 and about 35 degrees, etc.

[0036] In certain embodiments, the fluid exit surface of one or more openings of the aperture plate may be configured (e.g., treated, coated, surface modified, or a combination thereof) to provide a desired surface contact angle. In some embodiments, at least a portion of the interior of at least one of the openings near the fluid exit side is configured so as to provide a desired surface contact angle. By way of example, the fluid exit surface and/or interior surface of one or more openings of the aperture plate may be configured to have a surface contact angle of greater than greater than 90 degrees, between 90 degrees and 140 degrees, between 90 degrees and 135 degrees, between 100 degrees and 140 degrees, between 100 degrees and 135 degrees, between 90 degrees and 110 degrees, etc.

[0037] In certain aspects, the ejector mechanism of the disclosure is capable of delivering a defined volume of fluid (fixed dose) in the form of an ejected stream of droplets having a small average ejected diameter such that an adequate and repeatable high percentage of the droplets are delivered into the desired location within the airways, e.g., the alveolar airways of the user during use. In certain embodiments, the average droplet diameters may range from about 0.7 pm to about 5 pm, about 0.7 pm to about 4.7 pm, about 0.7 pm to about 4 pm, about 0.7 pm to about 3.2 pm, about 0.7 pm to about 2.5 pm, about 0.7 pm to about 1.3 pm, etc. In certain embodiments, the average droplet diameters may be less than about 4 microns, less than about 3.2 microns, less than about 3 microns, less than about 2 microns, less than about 1.5 microns, less than about 1 micron, etc.

[0038] In certain implementations, the aperture plate may be interfaced with or coupled to an actuator plate or ultrasonic horn that is, in turn, interfaced with or coupled to a piezoelectric actuator. The aperture plate generally includes a plurality of openings formed through its thickness and the piezoelectric actuator directly or indirectly (e.g. via an actuator plate or ultrasonic horn) oscillates the aperture plate, having fluid in contact with one surface of the aperture plate, at a frequency and voltage to generate a directed aerosol stream of droplets through the openings of the aperture plate into the lungs, as the patient inhales. In some embodiments, the aperture plate is directly or indirectly oscillated by the piezoelectric oscillator at a frequency and voltage to generate a directed aerosol stream or plume of aerosol droplets.

[0039] In certain embodiments, one or more surfaces of the aperture plate may be modified, treated, coated, or a combination thereof to achieve the desired surface contact angle. In certain aspects, the one or more surfaces of the aperture plate may be modified, treated, coated, or a combination thereof so as to affect surface hydrophobicity. By way of examples, one or more surfaces of the aperture plate may be modified, treated, coated, or a combination thereof so as to result in at least one more hydrophilic surface on the aperture plate, optionally at least one more hydrophobic surface on the aperture plate, or a combination thereof. In certain embodiments, at least the fluid entrance side, and optionally the fluid exit surface side are configured so as to have a desired surface contact angle. In certain embodiments, at least a portion of the interior surface of one or more openings may be configured so as to have a desired surface contact angle.

[0040] Without intending to be limited by theory, the surface contact angles described herein are believed to more effectively attract a fluid composition into the openings of the ejector aperture plate during the vibration of the aperture plate by the piezo element, thereby increasing the mass flow of aerosol droplets out of the aperture plate.

[0041] In addition to aperture plate surface contact angle, several features of the ej ector mechanism allow for precise dosing of specific droplet sizes. For instance, droplet size is set, in part, by the diameter of the openings in the aperture plate, which are formed with high accuracy. By way of example, the openings in the aperture plate at the fluid exit side of the aperture plate may range in size from 1 pm to 6 pm, from 2 pm to 5 pm, from 3 pm to 5 pm, from 3 pm to 4 pm, about 1.7 pm, about 2.0 pm, about 3.5 pm, about 3.9 pm, etc. In certain embodiments, the aperture plate may include openings having different cross-sectional shapes or diameters to thereby provide ejected droplets having different average ejected droplet diameters. Ejector rate also influences droplet size. Ejection rate, in droplets per second, is fixed by the frequency of the aperture plate vibration, e.g., 108-kHz, etc.

[0042] In certain aspects of the disclosure, desired surface contact angles may be formed by creating hydrophilic surfaces, e.g., through treating, coating, surface modifying, or a combination thereof. A surface is considered to be hydrophilic when that angle is less than about 80 degrees, about 70 degrees, about 60 degrees, about 55 degrees, about 50 degrees, etc., and may be considered to be super hydrophilic when that angle is less than about 10 to 20 degrees (droplet tends to spread out across the surface). The strength of the hydrophilic effect may be measured by the angle between the edge of a droplet of water and the surface of the aperture plate.

[0043] By way of example, the aperture plate can formed of a metal, e.g., stainless steel, nickel, cobalt, titanium, iridium, platinum, or palladium or alloys thereof, and configured to achieve the desired contact angles as described herein. Alternatively, the aperture plate can be formed of suitable polymeric material, and be configured to achieve the desired surface contact angles, as described herein. By way of example, the aperture plate may be composed of a material selected from the group consisting of poly ether ketone (PEEK), polyimide, polyetherimide, polyvinylidine fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), nickel, nickel-cobalt, nickel-palladium, palladium, platinum, metal alloys thereof, and combinations thereof. Further, in certain aspects, the aperture plate may comprise a domed shape.

[0044] By way of example, the desired surface contact angle may be created on a surface of an aperture plate by increasing the surface energy through creation of a polar surface. Exemplary methods to increase surface energy comprise forming an oxide surface on a metallic ejector aperture plate which is polar. In accordance with aspects of the disclosure, exemplary methods for creating a hydrophilic surface contact angle on an aperture plate including dip coating methods, etching methods, and chemical deposition methods. Dip coating methods comprise dipping the aperture plate into a solution comprising a desired coating and a solvent, which solution will form a hydrophilic coating on the surface when the solvent evaporates. Chemical deposition methods include known deposition methods, e.g., plasma etch, plasma coating, plasma deposition, CVD, electroless plating, electroplating, etc., wherein the chemical deposition uses a plasma or vapor to open the bonds on the surface of the aperture plate so that oxygen or hydroxyl molecules attach to the surface rendering it polar. Etching methods include non-chemical etching methods using surface roughening.

[0045] In certain embodiments, any deposited hydrophilic layer is significantly thinner than the opening size such that it does not impact the size of the generated droplets. In certain embodiments, the surface treatment may extend into at least a portion of one or more openings of the aperture plate so as to form a hydrophilic surface within at least a portion of one or more openings. [0046] In certain embodiments, the desired surface contact angle may be obtained through surface roughening achieved, e.g., via non-chemical etching. Without intending to be limited by theory, as an approximation, the Wenzel Contact Angle equation, “Apparent Contact Angles on Rough Surfaces: the Wenzel Contact Angle Revisited”, Wolansky and Marmur, Colloids and Surfaces A, 156 (1999) pp. 381-388, may be used to estimate surface contact angle. The Wenzel equation yields contact angles for liquid drops on rough surfaces. It assumes no hysteresis in the contact angle, and this is an approximation.

[0047] In certain embodiments, the aperture plate may optionally be surface sputtered with a thin layer (e.g., about 30 to about 150 nm, about 60 nm to about 100 nm, about 30 nm, about 60 nm, about 80 nm, about 100 nm, etc. thick sputtering) of a precious metal, such as gold (Au), palladium (Pd), platinum (Pt), silver (Ag) and precious metal alloys. In certain embodiments, the surface may be sputtered with a thin layer of palladium. The precious metal layer may then be etched at varying etch powers, e.g., low, medium or high etching power to provide a desired surface contact angle. To provide the desired contact angle, the etch may be performed once, twice, three times, four times, etc.

[0048] In other embodiments, the aperture plate may be coated on at least the fluid entrance side of the aperture plate with a hydrophilic polymer to achieve the desired surface contact angle. In yet other embodiments, the aperture plate may be coated on at least a portion of the interior surface of one or more openings, within the entire interior surface of one or more openings, on both the fluid entrance side and the fluid ejection surface of the aperture plate, and combinations thereof. Any known hydrophilic polymer suitable for use in medical applications may be used.

[0049] Any suitable hydrophilic coating to achieve the desired surface contact angle on the fluid entrance side of the ejector aperture plate may be used. Exemplary hydrophilic coating materials include, but are not limited to siloxane based coatings, isocyante based coatings, ethylene oxide based coatings, polyisocyanate based coatings, hydrocyclosiloxane based coatings, hydroxyalkylmethacrylate based coatings, hydroxyalkylacrylate based coatings, glycidylmethacrylate based coatings, propylene oxide based coatings, N-vinyl-2-pyrrolidone based coatings, latex based coatings, polyvinylchloride based coatings, polyurethane based coatings, etc.

[0050] By way of non-limiting example, a suitable hydrophilic coating may comprise a single layer hydrophilic surface formed by a process of cleaning the intended surface with a low pressure plasma and then dipping the surface into a solution of organophosphorous acids which self-assemble into a polar monolayer (e.g., see Aculon US Patent 8658258A, which is incorporated herein by reference). These layers are typically less than 10 nm thick, which is significantly less than a micron-sized hole. Contact angles as low as 10 degrees can be achieved using such coatings.

[0051] In other embodiments, the aperture plate may optionally be coated on the fluid exit side with a hydrophobic coating. Any known hydrophobic polymer suitable for use in medical applications may be used, e.g., polytetrafluoroethylene (Teflon), siloxane based coatings, paraffin, polyisobutylene, etc. The surface of the hydrophobic coating may be chemically or structurally modified or treated to further enhance or control the surface contact angle, as desired.

[0052] In certain embodiments, the aperture plate may be coated with a siloxane based coating to provide an initial hydrophobic coating, which siloxane based coating is thereafter masked or shielded in a suitable manner on the fluid exit side. Following masking, the masked aperture plate may thereafter be exposed to an oxidizing treatment to render the siloxane coating hydrophilic on the exposed (unmasked) portions thereof, i.e., the fluid entrance sides. In this manner, in certain embodiments of the disclosure, the same siloxane based coating may provide both hydrophilic and hydrophobic coatings to surfaces of the aperture plate. By way of example, such siloxane coatings may be selected from siloxanes known for use in medical applications, such as 2,4,6,8-Tetramethylcyclotetrasiloxane, or 1,1,3,3-Tetramethyldisiloxane.

[0053] The aperture plate may be metallic or polymer with openings about the diameter of the desired droplets (as discussed further herein). By way of non-limiting example, the aperture plate may be formed from silicon, silicon carbide, nickel palladium, or a high stiffness polymer such as polyether ether ketone (PEEK), poly-amide, Kapton or Ultra High Molecular Weight Polyethylene (UHMWPE). When using a polymer aperture plate, the openings may be produced by rolling, stamping, laser ablation, bulk etching or other known micro-machining processes. When using silicon and SiC for the aperture plate, the openings may be formed using typical semiconductor processes. Without being limited, these silicon materials can be formed by bulk micro-machining processes, such as wet etching. In addition, the aperture plate opening area may be formed to have a dome-like shape to increase the stiffness of the aperture plate and to creating uniform ejection accelerations.

[0054] The aperture plate may have an array of opening ranging from, e.g., 100 to

10,000 openings, 500 to 10,000 openings, etc. The openings may generally have a fluid exit side diameter similar to that of the desired droplets, e.g., of 0.5 pm to 100 pm diameter, 1 pm to 20 mih, 1 mih to 10 mih, 1 mih to 5 mih, 1 mih to 4 mih, etc., as described further herein. The fluid entrance side diameter may range from between about 30 mih to 300 mih, about 75 mih to about 200 mih, about 100 mih to about 200 mih, etc. Aperture plates may be formed to have a thickness of between about 100 pm to about 925 pm, between about 100 pm and about 300 pm.

[0055] As described above, the aperture plate may include various treatments, coatings surface modifications, or combinations thereof, on one or more surfaces thereof. For example, in certain embodiments, the aperture plate may include various combinations of: a hydrophilic coating on one or more surfaces, an optional hydrophobic coating on one or more surfaces, native surfaces, surface etchings, etc. In one embodiment, the aperture plate may be non- chemically etched on the fluid entrance side of the aperture plate (fluid reservoir facing side), with etching, a hydrophobic coating, or no treatment on the fluid exit side. In another embodiment, the aperture plate may include a hydrophilic coating on at least the fluid entrance side of the aperture plate (fluid reservoir facing side), a hydrophilic coating within at least a portion of the interior of one or more openings, or combinations thereof. In other embodiments, the aperture plate may include a hydrophobic coating on the droplet exit side of the aperture plate - alone or in combination with one or more hydrophilic coatings. A gas or liquid process may be used to form the hydrophobic and hydrophilic surfaces. For example, hydrophilic and hydrophobic surfaces can be formed using liquid coating, sputtering, CVD, plasma deposition, ion implantation, etc.

[0056] FIG. 1A shows a cross-section of an exemplary surface treated opening 1200 of an aperture plate in accordance with an embodiment of the disclosure. As shown, the opening 1200 is configured to have a structural well 1202 extending through the aperture plate thickness from the fluid entrance side 1204 to the fluid exit side 1206. As shown, the opening 1200 may be surface treated on the fluid entrance side 1204 to be hydrophilic 1208 (contact angle between about 2 and about 80 degrees, between about 2 and about 60 degrees, between about 2 and about 40 degrees, between about 5 and about 40 degrees, between about 5 and about 20 degrees, between about 5 and about 10 degrees, etc.). In certain embodiments, the fluid exit side 1206 may optionally be treated to be hydrophobic 1210 (contact angle between about 80 and about 160 degrees, between about 80 and about 130 degrees, etc.). In the illustrated embodiment, the hydrophilic 1208 surfaces and hydrophobic 1210 are also formed on at least some of the interior surfaces within the structural well 1202. Without intending to be limited, such hydrophobic treatments may act to minimize “weeping” of fluid from the aperture plate openings during use. [0057] FIG. IB and FIG. 1C illustrate similar surface treated openings 1200, except the opening 1200 is configured to taper 1214 from the fluid entrance side 1204 to the fluid exit side 1206 (rather than having a structural well). FIG. IB illustrates a linear taper, while FIG. 1C illustrates a curved taper. Without intending to be limited by theory, because the fluid entrance region tapers to a smaller diameter near the fluid exit side 1206, the fluid entrance side 1204 is treated to be hydrophilic 1208 (e.g., contact angle of 2 to 80 degrees) to facilitate fluid reaching the ejection openings by capillary action. In certain aspects, the liner versus curved taper is generally a result of fabrication technique and, to some degree, on the need for specific properties such as dispensing a fluid of higher or lower viscosity or the need to preserve material to maximize the stiffness of the aperture plate against flexure or a resonant point that is too low.

[0058] FIG. ID illustrates an aperture plate 1216 (e.g., palladium-nickel) supported by a stainless steel annulus 1218. The aperture plate is welded or bonded 1220 to the stainless steel annulus, thereby allowing a thicker support material which is much less expensive than aperture plate material, e.g., palladium-nickel. Again hydrophilic and hydrophobic surface treatments may be used on both the fluid entrance side and the droplet exit side of the aperture plate and support structure.

[0059] The aperture plates, structural wells, and tapers may be produced, e.g., by semiconductor techniques, stamping, rolling or laser ablation. Rolling may be preferred because more precise forming pressures are possible and continuous production for material from rolls allows lower-cost manufacturing. Because the material stiffness of polymers (especially the UHMWPE) is lower than metals such as stainless steel or palladium-nickel, ribs on the fluid or air side of the aperture plate may also be formed at the time of rolling or prior to laser ablation. Similarly, a metallic annulus may be used to stiffen the edge of the aperture plate against flexure. In addition, the aperture plate area can be formed to have a dome-like shape to increase the stiffness of the aperture plate and creating uniform ejection accelerations. [0060] In certain aspects, the aperture plate may be bonded to a reservoir or fluid cartridge. Further, if desired, the aperture plate may be bonded to an intermediary structural material, e.g., a stainless steel annulus to reduce costs by minimizing the ejector plate, to increase the aperture plate stiffness or to facilitate attachment to the cartridge. With polymer materials, the aperture plate may have raised ribs at intervals to stiffen the aperture plate against flexure. Ribs can be produced by rolling or stamping in a polymer heated above its transition temperature. [0061] In specific embodiments, the ejector mechanism is electronically breath activated by at least one differential pressure sensor located within the housing of a droplet delivery device upon sensing a pre-determined pressure change within the housing. In certain embodiments, such a pre-determined pressure change may be sensed during an inspiration cycle by a user of the device.

[0062] In certain embodiments, the ejected stream of droplets of a fluid composition comprising at least one ginsenoside may be generated via a droplet delivery device, the device comprising a housing, a reservoir for receiving a volume of fluid, and an ejector mechanism including a piezoelectric actuator and an aperture plate having a desired surface contact angle on at least the fluid entrance side thereof and optionally a desired surface contact angle on a fluid exit surface thereof.

[0063] In accordance with the disclosure, any suitable droplet deliver device may be used in connection with the ejector mechanisms of the disclosure. By way of example, the ejector mechanism of the disclosure may be used with the droplet delivery devices disclosed in co-owned PCT applications WO 2017/192767, WO 2019/071008; and WO 2020/227717, the contents of which are herein incorporated by reference in their entireties.

[0064] In one embodiment, the device may be configured to provide for ejection of droplets after a breath initiation period, e.g., 0.1-0.5 seconds. The device may be configured to sense the initiation of the inspiration cycles, allowing a short period of time, e.g., 0.1-0.5 seconds as to form a steady inspiration flow. Once the device senses a steady inspiration flow, the device may activate the ejector mechanism to initiate ejection of the small droplets for inhalation into the target site of the respiratory system. Optionally, the device may control the ejector mechanism to discontinue generation of droplets at a specified end portion of the inspiration cycle, so as to allow for complete inhalation of the droplets to the target site of the respiratory system. Such a device provides for an improved method of delivering droplets to the respiratory system of a user with minimal or no mouth or throat irritation.

[0065] In certain aspects of the disclosure, a droplet delivery device for delivering an ejected stream of droplets from a fluid composition comprising at least one ginsenoside to the respiratory system of a user is provided. The droplet delivery device generally includes a housing and a reservoir disposed in or in fluid communication with the housing, an ejector mechanism in fluid communication with the reservoir, and at least one differential pressure sensor positioned within the device. The differential pressure sensor is configured to electronically breath activate the ejector mechanism upon sensing a pre-determined pressure change within the device, and the ejector mechanism is configured to generate a controllable plume of an ejected stream of small droplets. The ejector mechanism may include a piezoelectric actuator, which is directly or indirectly coupled to an aperture plate having a plurality of openings formed through its thickness and exhibiting a desired surface contact angle at least at the fluid entrance side thereof, and an optional a desired surface contact angle at the fluid exit surface thereof (e.g., at the fluid entrance side, at the fluid exit side, within at least a portion of one or more openings, or combinations thereof). The piezoelectric actuator is operable to directly or indirectly oscillate the aperture plate at a frequency to thereby generate an ejected stream of droplets.

[0066] By way of non-limiting example, in certain embodiments, the droplet delivery device may generally include a housing and a reservoir disposed in or in fluid communication with the housing, an ejector mechanism in fluid communication with the reservoir, and at least one differential pressure sensor positioned within the housing. The differential pressure sensor is configured to electronically breath activate the ejector mechanism upon sensing a pre determined pressure change within the housing, and the ejector mechanism is configured to generate a controllable plume of an ejected stream of droplets. The ejected stream of droplets is formed from low surface tension compositions, particularly compositions comprising agents that are insoluble or sparingly soluble in water. The ejector mechanism comprises a piezoelectric actuator which is directly or indirectly coupled to an aperture plate of the disclosure. The piezoelectric actuator is operable to directly or indirectly oscillate the aperture plate at a frequency to thereby generate an ejected stream of droplets.

[0067] In certain embodiments, the droplet delivery device may be configured in an in line orientation in that the housing, ejector mechanism and related electronic components are orientated in a generally in-line or parallel configuration so as to form a small, hand-held device.

[0068] In certain embodiments, the droplet delivery device may include a combination reservoir/ejector mechanism module that may be replaceable or disposable either on a periodic basis, e.g., a daily, weekly, monthly, as-needed, etc. basis, as may be suitable for a prescription or over-the-counter medication.

[0069] As explained in further detail herein, the ejector mechanism may be orientated at various angles within the device, with respect to the direction of droplet generation, airflow through the device, and internal surfaces within the device. Without intending to be limited by theory, it is believed that orientation of the ejector mechanism with respect to the direction of droplet generation, airflow through the device, and internal surface within the device serves to optimize droplet size distribution via inertial filtering, which filters and excludes larger droplets from the droplet plume.

[0070] In certain embodiments of the droplet device, the housing and ejector mechanism are oriented such that the exit side of the aperture plate is perpendicular to the direction of airflow and the stream of droplets is ejected in parallel to the direction of airflow. In other embodiments, the housing and ejector mechanism are oriented such that the exit side of the aperture plate is parallel to the direction of airflow and the stream of droplets is ejected substantially perpendicularly to the direction of airflow such that the ejected stream of droplets is directed through the housing at an approximate 90 degree change of trajectory prior to expulsion from the housing.

[0071] In some embodiments, the ejector mechanism may be oriented perpendicularly

(e.g., vertical) to the direction of airflow through the device, such that droplets are initially ejected into the direction of airflow. Such a configuration minimizes inertial filtering of generated droplets, allowing most droplets to flow in the entrained airflow within the mouthpiece (other than impacts of droplets at the sidewalls of the mouthpiece and inertial settling along the air flow path). In other embodiments, the ejector mechanism may be orientated at an angle with respect to the direction of airflow through the device. By way of example, the ejector mechanism may be oriented at about 5° from perpendicular, about 10° from perpendicular, about 15° from perpendicular, about 20° from perpendicular, about 25° from perpendicular, about 30° from perpendicular, about 35° from perpendicular, about 40° from perpendicular, about 45° from perpendicular, etc. In such embodiments, the droplets may be ejected into the airflow at an angle, such that smaller droplets are able to flow in the entrained airflow within the mouthpiece, and larger droplets are more likely to impact the sidewalls of the mouthpiece along the air flow path (or settle out along the air flow path).

[0072] In other embodiments, the droplet delivery device may comprise a body housing, a mouthpiece having an ejector mechanism, and a fluid cartridge having at least one fluid reservoir. In certain embodiments, the ejector mechanism may comprise at least one ultrasonic actuator and at least one aperture plate of the disclosure (i.e., having the desired surface contact angle(s) at one or more surfaces). The device may further comprise at least one differential pressure sensor configured to activate the ejector mechanism upon sensing a pre determined pressure change within the device to thereby generate the ejected stream of droplets. [0073] More specifically, in certain embodiments, an exemplary droplet delivery device may generally comprise a mouthpiece, a fluid cartridge, a body housing, and at least one differential pressure sensor. In certain embodiments, the mouthpiece is positioned at an airflow exit of the device, the mouthpiece comprising one or more air flow entrance ports, an airflow exit opening, an electronically actuated ejector mechanism of the disclosure, an ejection chamber, and a fluid transport mating extension. The fluid cartridge generally comprises at least one reservoir for receiving a volume of fluid, and at least one sealing mechanism, the fluid cartridge disposed within or in fluid communication with the mouthpiece. The body housing comprises a power source and control board. The at least one differential pressure sensor is positioned within the mouthpiece or positioned within the body housing and in fluid communication with the mouthpiece, the at least one differential pressure sensor configured to activate the ejector mechanism upon sensing a pre-determined pressure change within the mouthpiece to thereby generate the ejected stream of droplets.

[0074] In certain embodiments, the electronically actuated ejector mechanism is in fluid communication with the reservoir at a fluid cartridge side of the ejector mechanism, and configured to generate the ejected stream of droplets, the ejector mechanism comprising a piezoelectric actuator and an aperture plate of the disclosure, the piezoelectric actuator operable to oscillate the aperture plate at a frequency to thereby generate the ejected stream of droplets; and the ejection chamber is located adjacent the ejector mechanism on the fluid cartridge side of the ejector mechanism.

[0075] In specific embodiments, the ejector mechanism is electronically breath activated by at least one differential pressure sensor located within the ultrasonic droplet delivery device upon sensing a pre-determined pressure change within the mouthpiece. In certain embodiments, such a pre-determined pressure change may be sensed during an inspiration cycle by a user of the device. In certain embodiments, the pressure sensor may be located in the mouthpiece, on the airflow exit side of the ejector mechanism. In other embodiments, the pressure sensor may be located in the body housing, and may be in fluid communication with the airflow exit side of the ejector mechanism.

[0076] In some aspects, the droplet delivery device further includes one or more air inlet flow elements positioned in the airflow at the airflow entrance of the device and configured to facilitate non-turbulent (i.e., laminar and/or transitional) airflow across the exit side of at least one aperture plate and to provide sufficient airflow to ensure that the ejected stream of droplets flows through the droplet delivery device during use. In some embodiments, the air inlet flow element may be positioned within the mouthpiece. In certain embodiments, the air inlet flow element(s) may be positioned behind the exit side of the aperture plate along the direction of airflow, or in-line or in front of the exit side of the aperture plate along the direction of airflow. In certain embodiments, the air inlet flow element(s) comprises one or more openings configured to increase or decrease internal pressure resistance within the droplet delivery device during use. For instance, in certain embodiments, the air inlet flow element(s) comprise an array of one or openings. In other embodiments, the air inlet flow element(s) comprise one or more baffles, e.g., wherein the one or more baffles comprise one or more airflow openings.

[0077] The airflow exit of the mouthpiece of the droplet delivery device through which the ejected aerosol of droplets exit as they are inhaled into a user’s airways, may be configured and have, without limitation, a cross sectional shape of a circle, oval, rectangular, hexagonal or other shape, while the shape of the length of the tube, again without limitation, may be straight, curved or have a Venturi -type shape.

[0078] The droplet delivery devices of the disclosure may include one or more sealing mechanisms. In certain embodiments, devices of the disclosure are configured to minimize evaporation from multi-use cartridges or single-use cartridges that are placed in the device after removing sealing tape from the fluid cartridge. By way of example, in one embodiment, the mouthpiece may include one or more sealing mechanisms to cover any fluid exit paths when not in use and/or to cover the aperture plate when not in use. For example, in one embodiment, a face seal may be provided which covers the aperture plate when not in use. Any suitable face seal may be used, for instance, a seal may be part of a mouthpiece cap that is closed by the user after an inhalation. The cap may include a spring loaded face seal that presses against a smooth stainless steel surface within the mouthpiece but outside the aperture plate. In another embodiment, a seal may be provided at the interface of an ultrasonic hom and the fluid cartridge.

[0079] In other embodiments, the fluid cartridge and/or mouthpiece may include one or more sealing mechanisms at the interface of the fluid cartridge and the ejector mechanism to minimize evaporation of the fluid within the reservoir. In some embodiments, the fluid cartridge may have a removable sealing tape which prevents evaporation prior to attachment to the body. In other embodiments, the device may include one or more sealing mechanisms to minimize evaporation at the connection point between the fluid cartridge and body.

[0080] In certain aspects, the droplet delivery device further includes a surface tension plate between the aperture plate and the reservoir, wherein the surface tension plate is configured to increase contact between the volume of fluid and the aperture plate. In other aspects, the ejector mechanism and the surface tension plate are configured in parallel orientation. In yet other aspects, the surface tension plate is located within 2 mm of the aperture plate so as to create sufficient hydrostatic force to provide capillary flow between the surface tension plate and the aperture plate.

[0081] In certain embodiments, the droplet delivery device may include a combination reservoir/ejector mechanism module that may be replaceable or disposable either on a periodic basis, e.g., a daily, weekly, monthly, as-needed, etc. basis, as may be suitable for the solution to be delivered. The reservoir may be prefilled and stored in a pharmacy or other suitable location for dispensing to users or filled at the pharmacy or elsewhere by using a suitable inj ection or fill means such as a hollow inj ection syringe driven manually or driven by a micro pump. The syringe or fill means may fill the reservoir by pumping or filling fluid into or out of a rigid container or other collapsible or non-collapsible reservoir. In certain aspects, such disposable/replaceable, combination reservoir/ejector mechanism module may minimize and prevent buildup of surface deposits or surface microbial contamination on the aperture plate, owing to its short in-use time.

[0082] The droplet delivery device may be altitude insensitive. In certain implementations, the droplet delivery device is configured so as to be insensitive to pressure differentials that may occur when the user travels from sea level to sub-sea levels and/or high altitudes, e.g., while traveling in an airplane where pressure differentials may be as great as 4 psi. As will be discussed in further detail herein, in certain implementations of the disclosure, the droplet delivery device may include a superhydrophobic filter, optionally in combination with a spiral vapor barrier, which provides for free exchange of air into and out of the reservoir, while blocking moisture or fluids from passing into the reservoir, thereby reducing or preventing fluid leakage or deposition on aperture plate surfaces.

[0083] In certain embodiments, the droplet delivery device is comprised of a separate fluid delivery ampoule with an ejector mechanism embedded on a surface of the fluid reservoir, and a handheld unit containing a differential pressure sensor, a microprocessor and three AAA batteries. The microprocessor controls fluid delivery, delivery counting and software designed monitoring parameters that can be transmitted through wireless communication technology (e.g., Bluetooth, wifi, cellular, etc.). The piezoelectric ejector mechanism optimizes droplet delivery to the user by creating droplets in a predefined range with a high degree of accuracy and repeatability. [0084] In certain aspects, the methods of the disclosure eliminate the need for patient / device coordination by using a differential pressure sensor to initiate the piezoelectric ejector mechanism in response to the onset of inhalation. The methods do not require manual triggering of droplet delivery.

[0085] In certain embodiments, as the user inhales through a droplet delivery device as described herein, the differential pressure sensor detects flow by measuring the pressure drop across a Venturi plate at the back of the mouthpiece. When a desired pressure decline (e.g., 8 liters/minute) is attained, the microprocessor activates the piezoelectric ejector to initiate droplet generation. The microprocessor then stops the ejector mechanism at the desired dosing time, e.g., 1.45 seconds after initiation (or at a designated time so as to achieve a desired administration dosage). In this way, the microprocessor ensures exact timing and actuation of the piezoelectric element.

[0086] Along with the aperture plate coatings described herein, several additional features of the device allow precise dosing of specific droplet sizes. Droplet size is set by the diameter of the holes in the aperture plate which are formed with high accuracy. By way of example, the holes in the aperture plate may range in size from 0.7 pm to 6 pm, from 0.7 pm to 5 pm, from 0.7 pm to 4.7 pm, from 0.7 pm to 4 pm, from 0.7 pm to 3.5 pm, from 0.7 pm to 3 pm, from 0.7 pm to 2.5 pm, about 1.7 pm, about 2.0 pm, about 3.5 pm, about 3.9 pm, etc. Ejection rate, in droplets per second, is generally fixed by the frequency of the aperture plate vibration, e.g., 108-kHz, which is actuated by the microprocessor. In certain embodiments, there is less than a 50-millisecond lag between the detection of the start of inhalation and full droplet generation.

[0087] Droplet production within the respirable range occurs early in the inhalation cycle, thereby minimizing the amount of droplets being deposited in the mouth or upper airways at the end of an inhalation. The design of the droplet delivery device maintains constant fluid contact with the ejection mechanism, thus obviating the need for shaking and priming. The ejector door and vent configuration limit active agent or carrier evaporation to less than 150 pL to 350 pL per month. This avoids changes in active agent concentration due to evaporation that would change the amount of agent contained in the droplets.

[0088] The device may be constructed with materials currently used in FDA cleared devices. Manufacturing methods may be employed to minimize extractables. [0089] By way of example, the aperture plate can formed of a metal, e.g., stainless steel, nickel, cobalt, titanium, iridium, platinum, or palladium or alloys thereof, and configured to achieve the desired contact angles as described herein. Alternatively, the aperture plate can be formed of suitable polymeric material, and be configured to achieve the desired surface contact angles, as described herein. By way of example, the aperture plate may be composed of a material selected from the group consisting of poly ether ketone (PEEK), polyimide, polyetherimide, polyvinylidine fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), nickel, nickel-cobalt, nickel-palladium, palladium, platinum, metal alloys thereof, and combinations thereof. Further, in certain aspects, the aperture plate may comprise a domed shape.

[0090] Any suitable material may be used to form the housing of the droplet delivery device. In particular embodiment, the material should be selected such that it does not interact with the components of the device or the fluid to be ejected (e.g., drug or medicament components). For example, polymeric materials suitable for use in pharmaceutical applications may be used including, e.g., gamma radiation compatible polymer materials such as polystyrene, polysulfone, polyurethane, phenolics, polycarbonate, polyimides, aromatic polyesters (PET, PETG), etc.

[0091] The fluid cartridge and reservoir may be constructed of any suitable materials for the intended use. In particular, the fluid contacting portions are made from material compatible with the desired agent(s). By way of example, in certain embodiments, the agent only contacts the inner side of the fluid reservoir and the inner face of the aperture plate and piezo drive. Wires connecting the piezoelectric ejector to the batteries contained in the base unit are embedded in the fluid ampoule shell to avoid contact with the fluid. The piezoelectric ejector is attached to the fluid reservoir by a flexible bushing. The bushing contacts the fluid and may be, e.g., any suitable material known in the art for such purposes such as those used in piezoelectric nebulizers. The piezoelectric actuator may be constructed from any suitable piezoelectric material suitable for medical application, including but not limited to lead zirconium titanate (PZT) and its modified ceramic materials. In certain embodiments, the piezo ceramic material may be sputter coated with a thin film coating of a precious metal or polymer on one or more surfaces. In certain embodiments, the piezo ceramic may be sputter coated on at least a surface fluid contact surface thereof, so as to minimize any interactions with the fluid to be delivered via the droplet deliver device. [0092] The device mouthpiece, may be removable, replaceable and may be cleaned.

Similarly, the device housing and fluid ampoule can be cleaned by wiping with a moist cloth. The aperture plate may be recessed into the ampoule and cannot be damaged without removing the ampoule from the base and directly striking the sprayer with a sharp object.

[0093] In certain aspects of the disclosure, an electrostatic coating may be applied to the one or more portions of the housing, e.g., inner surfaces of the housing along the airflow pathway such as the mouthpiece, to aid in reducing deposition of ejected droplets during use due to electrostatic charge build-up. Alternatively, one or more portions of the housing may be formed from a charge-dissipative polymer. For instance, conductive fillers are commercially available and may be compounded into the more common polymers used in medical applications, for example, PEEK, polycarbonate, polyolefins (polypropylene or polyethylene), or styrenes such as polystyrene or acrylic-butadiene-styrene (ABS) copolymers. Alternatively, in certain embodiments, one or more portions of the housing, e.g., inner surfaces of the housing along the airflow pathway such as the mouthpiece, may be coated with anti-microbial coatings, or may be coated with hydrophobic coatings to aid in reducing deposition of ejected droplets during use. Any suitable coatings known for such purposes may be used, e.g., polytetrafluoroethylene (Teflon).

[0094] Any suitable differential pressure sensor with adequate sensitivity to measure pressure changes obtained during standard inhalation cycles may be used, e.g., ± 5 SLM, 10 SLM, 20 SLM, etc. For instance, pressure sensors from Sensirion, Inc., SDP31 or SDP32 (US 7,490,511 B2) are particularly well suited for these applications.

[0095] In certain aspects, the microprocessor in the device may be programmed to ensure exact timing and actuation of the ejector mechanism in accordance with desired parameters, e.g., based duration of piezoelectric activation to achieve desired dosages, etc. In certain embodiments, the device includes or interfaces with a memory (on the device, smartphone, App, computer, etc.) to record the date-time of each ejection event, as well as the user’s inhalation flow rate during the dose inhalation to facilitate user monitoring, as well as drug ampoule usage monitoring. For instance, the microprocessor and memory can monitor doses administered and doses remaining in a particular drug ampoule. In certain embodiments, the drug ampoule may comprise components that include identifiable information, and the base unit may comprise components that may “read” the identifiable information to sense when a drug ampoule has been inserted into the base unit, e.g., based on a unique electrical resistance of each individual ampoule, an RFID chip, or other readable microchip (e.g., cryptoauthentication microchip). Dose counting and lockouts may also be preprogramed into the microprocessor.

[0096] In certain embodiments of the present disclosure, the signal generated by the pressure sensors provides a trigger for activation and actuation of the ejector mechanism to thereby generate droplets and delivery droplets at or during a peak period of a patient’s inhalation (inspiratory) cycle and assures optimum deposition of the plume of droplets and delivery of the composition into the respiratory system of the user.

[0097] In accordance with certain aspects of the disclosure, the droplet delivery device provides a reliable monitoring system that can date and time stamp actual delivery of substance, and record/store inspiratory airflow in a memory (on the device, smartphone, App, computer, etc.). Bluetooth or other wireless communication capabilities may then permit the wireless transmission of the data.

[0098] Wireless communication (e.g., Bluetooth, wifi, cellular, etc.) in the device may communicate date, time and number of actuations per session to the user’s smartphone. Software programing can provide charts, graphics, medication reminders and warnings to patients and whoever is granted permission to the data. The software application will be able to incorporate multiple uses and users of the device (e.g. multiple substances, different users, etc.).

[0099] In certain embodiments, the reservoir/cartridge module may include components that may carry information read by the housing electronics including key parameters such as ejector mechanism functionality, drug identification, and information pertaining to patient dosing intervals. Some information may be added to the module at the factory, and some may be added at the pharmacy. In certain embodiments, information placed by the factory may be protected from modification by the pharmacy. The module information may be carried as a printed barcode or physical barcode encoded into the module geometry (such as light transmitting holes on a flange which are read by sensors on the housing). Information may also be carried by a programmable or non-programmable microchip on the module which communicates to the electronics in the housing.

[00100] By way of example, module programming at the factory or pharmacy may include a drug code which may be read by the device, communicated via Bluetooth to an associated user smartphone and then verified as correct for the user. In the event a user inserts an incorrect, generic, damaged, etc., module into the device, the smartphone might be prompted to lock out operation of the device, thus providing a measure of user safety and security not possible with passive inhaler devices. In other embodiments, the device electronics can restrict use to a limited time period (perhaps a day, or weeks or months) to avoid issues related to drug aging or build-up of contamination or particulates within the device housing.

[00101] The droplet delivery device may further include various sensors and detectors to facilitate device activation, spray verification, patient compliance, diagnostic mechanisms, or as part of a larger network for data storage, big data analytics and for interacting and interconnected devices used for user care and treatment, as described further herein. Further, the housing may include an LED assembly on a surface thereof to indicate various status notifications, e.g., ON/READY, ERROR, etc.

[00102] In accordance with certain aspects of the disclosure, effective deposition into the lungs generally requires droplets less than about 5-6 pm in diameter. Without intending to be limited by theory, to deliver fluid to the lungs a droplet delivery device must impart a momentum that is sufficiently high to permit ejection out of the device, but sufficiently low to prevent deposition on the tongue or in the back of the throat. Droplets below approximately 5- 6 pm in diameter are transported almost completely by motion of the airstream and entrained air that carry them and not by their own momentum.

[00103] In certain aspects, the present disclosure includes and provides an ejector mechanism configured to eject a stream of droplets within the respirable range of less than about 5-6 pm, preferably less than about 5 pm. The ejector mechanism is comprised of an aperture plate configured to provide a desired surface contact angle. The aperture plate is directly or indirectly coupled to a piezoelectric actuator. In certain implementations, the aperture plate may be coupled to an actuator plate that is coupled to the piezoelectric actuator. The aperture plate generally includes a plurality of openings formed through its thickness and the piezoelectric actuator directly or indirectly (e.g. via an actuator plate) oscillates the aperture plate, having fluid in contact with one surface of the aperture plate, at a frequency and voltage to generate a directed aerosol stream of droplets through the openings of the aperture plate into the lungs, as the patient inhales. In other implementations where the aperture plate is coupled to the actuator plate, the actuator plate is oscillated by the piezoelectric oscillator at a frequency and voltage to generate a directed aerosol stream or plume of aerosol droplets.

EXAMPLES

Introduction

[00104] This study evaluated the aerosolization of a fluid composition comprising at least one ginsenoside using a test fixture to emulate the behavior of a droplet delivery device described herein. The study utilized ginsenosides that have shown antiviral, anti-carcinogenic, immunomodulatory activity, and other pharmacological activities, including protopanaxatriol (PT)-type ginsenosides (Re, Rf, and Rg2) as well as others.

[00105] Ejector mechanisms with nickel -palladium alloy aperture plates were used to investigate the ability of aperture plates with controlled contact angles to eject small droplets. In general, native nickel-palladium alloy exhibit contact angles of about 90 degrees. Aperture plates formed from such nickel-palladium alloys generate efficient droplets in the respirable range, but not droplets in the small respirable range. Test aperture plates treated to form hydrophilic surfaces on the fluid entrance surface were tested per the examples below. Results are summarized below.

Formulations

[00106] Formulations tested: All were dissolved in 100% ethanol

• Formulation 1: Ginsenoside mix (Rbl, Rb2, Rc, Rd, Re, Rf, Rg2) - 0.75 mg/mL

• Formulation 2: Ginsenoside Re - 5 mg/mL; Ginsenoside Re has been found to provide anti-viral activity.

• Formulation 3: Ginsenoside Rg2 - 1 mg/mL; Ginsenoside Rg2 has been found to provide anti-viral activity.

• Formulation 4: Ginsenoside Re & Rg2 combo - 2 mg/ml & 0.75 mg/mL respectively

• Formulation 5: Ginsenoside Rb2 - 2.5 mg/mL; Ginsenoside Rb2 improves glucose metabolism in hepatocytes by activating AMPK and reduces cholesterol and triacylglycerol levels.

• Formulation 6: Ginsenoside Rg3 - 1 mg/mL; Ginsenoside Rg3 has been found to be an effective contributor to the anti-carcinogenic activity of ginseng. Rg3 has also been shown to possess significant anticancer activity. This ginsenoside has been shown to inhibit the growth of cancer in various cancer models and exert cancer-preventive effects in both in vitro and in vivo studies.

Droplet Delivery Device/E iector Mechanism Description

[00107] The droplet delivery device of the disclosure is comprised of a fluid cartridge (referred to as “cartridge”) and an electronics unit (referred to as “base unit”). The cartridge contains a microfluidic ejector mechanism system designed to deliver a composition to the lungs by generating droplets with an average initial ejection diameter within a predefined range of optimal sizes. The base unit is comprised of a differential pressure sensor, microprocessor, wireless communication technology, and battery/power supply. The microprocessor in the droplet delivery device ensures the timing and actuation of the ejector mechanism system. [00108] The microfluidic ejector mechanism includes an aperture plate in combination with a piezoelectric actuator. In this example, a nickel-palladium aperture plate was used. The NiPd aperture plates were sputter coated with 80 nm of palladium, and etched (3X at high power etch) to obtain the below indicated surface contact angles.

• DO 1-1.7 (1.7 micron exit hole diameter, entrance openings between 20-30 microns with taper from entrance to exit) o Entrance - 80 degrees o Exit - 100 degrees

• D01-2.0 (2.0 exit hole diameter, entrance openings between 20-30 microns with taper from entrance to exit) o Entrance - 53 degrees o Exit - 88 degrees

• D01-3.5T-003 (3.5 exit hole diameter, entrance openings between 20-30 microns with taper from entrance to exit) o Entrance - 51 degrees o Exit - 88 degrees

• D01-3.9 (3.9 exit hole diameter, entrance openings between 20-30 microns with taper from entrance to exit) o Entrance - 78 degrees o Exit - 102 degrees

Particle Size Testing

[00109] To determine the particle size distribution and mass median aerodynamic diameter (MMAD), the solutions were tested with an Aerodynamic Particle Sizer (APS) spectrometer. The target MMAD range was 1.0 ± 0.3 pm.

[00110] More specifically, an Aerodynamic Particle Sizer (APS) spectrometer model 3321 produced by TSI Incorporated was used for evaluating the aerosol particle size by sampling the aerosol delivered by the test fixture. The APS measures true aerodynamic particle size similar to a cascade impactor, with a range of 0.35 pm to 20.0 pm. Testing was performed at a flow rate of 5 1pm. [00111] TSI Incorporated Aerodynamic Particle Sizer (APS) Spectrometer 3321; TSI Incorporated Aerosol Diluter 3302A with dilution ratio of 100:1; TSI Incorporated Aerosol Diluter 3302A with dilution ratio of 20:1; Mettler Toledo XS204 Analytical balance.

Tensiometer measurements [00112] A calibrated Theta Lite Optical Tensiometer may be used to measure the contact angles of the devices. A 3 - 4 pL drop of ultrapure water may be placed on each side of the device. On the entrance side of the device, the drop may be placed on the mesh, between the ceramic ring and the center depression. On the exit side of the piezo, the drop may be placed on the ceramic ring. Images of the water droplet on the piezo may be captured by the Theta Lite camera and accompanying software. The software, using the Young-Laplace model, can then fit a curve to the drop and calculate the contact angle between the water droplet and the surface of the piezo.

Testing Conditions:

• Approximately 2 mis of test compositions were filled into test device reservoir · 3 second ejections

• 5 individual shots were taken for each ejector and surfactant percentage/formulation

• The data was averaged together, and the standard deviation was determined o If one data point fell far outside the standard it was ignored

• Samples were collected at ambient temperature and > 50% humidity APS and Mass Ejection Results:

[00113] During testing, little to no foaming was observed at the ejector surfaces or in the fluid reservoir. As can be seen in the tables above, delivery of up to 34 mg of solution with droplet diameters between about 0.7 microns to 3.2 microns, and respirable fractions above about 50% were obtained for the ginseng compositions for most ejector mechanisms under the test conditions. Not only can the methods of the disclosure achieve high respirable fraction, the results demonstrate delivery of 168 pg of ginsenosides per actuation.

[00114] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically, and individually, indicated to be incorporated by reference.

[00115] While the invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

WHAT IS CLAIMED:

1. A method for delivering a fluid composition comprising at least one ginsenoside as an ejected stream of droplets in a respirable range to the respiratory system of a user, the method comprising:

(a) generating an ejected stream of droplets from the fluid composition via a an electronically actuated droplet delivery device comprising an ejector mechanism having a piezoelectric actuator, and an aperture plate, the aperture plate having a plurality of openings formed through its thickness and the piezoelectric actuator being operable to directly or indirectly oscillate the aperture plate at a frequency to thereby generate the ejected stream of droplets, wherein at least about 50% of the ejected stream of droplets have an average ejected droplet diameter of less than about 6 pm; and

(b) delivering the ejected stream of droplets to the respiratory system of the user such that at least about 50% of the mass of the ejected stream of droplets is delivered in a respirable range to the respiratory system of a user during use.

2. The method of claim 1, wherein the fluid composition comprising at least one ginsenoside is an organic solution or an aqueous solution.

3. The method of claims 1, wherein the at least one ginsenoside is selected from the group consisting of Rbl, Rb2, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, Rh2, and combinations thereof.

4. The method of claim 1, wherein the at least one ginsenoside is selected from the group consisting of Rbl, Rb2, Rc, Rd, Re, Rf, Rgl, Rg2, and combinations thereof.

5. The method of claim 1, wherein the at least one ginsenoside is selected from the group consisting of Re, Rg2, Rg3, Rb2, Re, and combinations thereof.

6. The method of claim 1, wherein the fluid composition comprising at least one ginsenoside is delivered to a user to treat or ameliorate a disease, condition or disorder selected from the group consisting of cancer, diabetes, and cardiovascular disease.

7. The method of claim 1, wherein the fluid composition comprising at least one ginsenoside is delivered to a user to promote immune functions, regulate central nervous system (CNS) function, relieve stress, or provide anti-oxidant activity.

8. The method of claim 1, wherein the aperture plate of the ejector mechanism has at least the fluid entrance side of one or more of said plurality of openings configured so as to provide a surface contact angle of less than 90 degrees.

9. The ejector mechanism of claim 1, wherein the aperture plate of the ejector mechanism is configured such that at least the fluid entrance side of one or more of said plurality of openings is configured to provide a surface contact angle of between 2 and 80 degrees.

10. The droplet delivery device of claim 1, wherein at least a portion of the interior of at least one of the openings is configured so as to provide a surface contact angle of less than 90 degrees.

11. The method of claim 8, wherein the surface contact angle of less than 90 degrees at the fluid entrance side of one or more of said plurality of openings is obtained by surface coating with a hydrophilic material, surface structural modification, or a combination thereof.

12. The ejector mechanism of claim 11, wherein the hydrophilic material is selected from siloxane based coatings, isocyante based coatings, ethylene oxide based coatings, polyisocyanate based coatings, hydrocyclosiloxane based coatings, hydroxyalkylmethacrylate based coatings, hydroxyalkylacrylate based coatings, glycidylmethacrylate based coatings, propylene oxide based coatings, N-vinyl-2-pyrrolidone based coatings, latex based coatings, polyvinylchloride based coatings, or polyurethane based coatings.

13. The method of claim 1, wherein at least about 50% of the ejected stream of droplets have an average ejected droplet diameter of less than about 3.2 pm.

14. The method of claim 1, wherein at least about 50% of the ejected stream of droplets have an average ejected droplet diameter between about 0.7 pm and about 3.2 pm.

15. The method of claim 1, wherein the ejected stream of droplets is delivered over a period of time less than about 2 seconds.