WO2009111612A1

WO2009111612A1 - Aerosolization device

Info

Publication number: WO2009111612A1
Application number: PCT/US2009/036135
Authority: WO
Inventors: James Fink
Original assignee: Novartis Ag
Priority date: 2008-03-07
Filing date: 2009-03-05
Publication date: 2009-09-11

Abstract

An aerosolization device (10) comprising a nebulizer body(12), housing an aerosol generator (14), and comprising a fluid pathway for liquid to impinge upon the aerosol generator, and for aerosolized liquid generated thereby to be conducted to a patient. The body includes a liquid supply cartridge (24) and actuator means (70) for delivering liquid to the aerosol generator. The device further includes an aerosolized liquid flow path (28,29) comprising at least one air inlet means (86) and at least one exhalation exhaust means (90). A patient interface means (27) conducts the aerosolized liquid to the patient, and a power supply and control means is provided to power and control operation of the aerosol generator.

Description

53353

AEROSOLiZATION DEVICE

BACKGROUND OF THE INVENTION

[0001] The present invention generally relates to systems and methods for the delivery of aerosolized medicaments. More specifically, one or more embodiments of the invention relate to a device or system for the aerosolization and delivery of liquids, of liquid medicaments, and vaccines, and for safe, rapid and efficient delivery of the aerosolized liquids, liquid medicament and vaccines to the pulmonary system of a patient.

[0002] Aerosolized medicaments are used to treat patients suffering from a variety of ailments. Medicaments can be delivered directly to the lungs by having the patient inhale the aerosol through a tube and/or mouthpiece coupled to an aerosol generator. By inhaling the aerosolized medicament, the patient can quickly, safely and efficiently receive a dose of medicament.

[0003] Aerosolized medicaments can be administered directly to the lungs to treat diseases and/or conditions of the lung, and to treat diseases or conditions having a systemic effect or component thereof. Many medicaments cannot be administered orally, due to their sensitivity to metabolism and/or degradation and resulting inactivation in the gastrointestinal tract, thus pulmonary delivery avoids the need for intramuscular, subcutaneous or transdermal delivery and associated needles. Additionally or alternatively, it may be safer and/or more efficacious to deliver the medicament directly to the lungs and/or pulmonary system instead of other administration routes.

[0004] Where the medicament is a vaccine, safety and efficacy are enhanced due to the indications for which they are used. Some vaccines are or therapeutic, for example, vaccines against certain forms of cancer. Many vaccines are administered prophylatϊcally (e.g. to prevent or ameliorate the effects of a future infection by any natural or "wild" pathogen) even if there are no manifest symptoms or even signs of exposure to the disease for which the vaccine is designed to treat. Children are, for 53353

example, routinely given vaccines for one or more of polio, measles, mumps, smallpox, rubella, chickenpox, typhoid, and related diseases, to name a few. Other diseases for which vaccination is important include Flu (Seasonal, SARS, Avian) Hantivirus, Pneumococcol, Bacterial/eukaryotic, Malaria, Meningococal, Tuberculosis, Francisella tularenis, and Smallpox.

[0005] While some vaccines are degraded if administered orally, others may be administered orally, but for reasons of scale, and/or stability and/or patient compliance are not sufficiently efficacious if so administered.

[0006] Currently vaccines given on a large scale (i.e. 10-1000 or more patients per day) are administered by several routes. Most commonly, vaccines are injected, or otherwise administered intramuscularly, intradermally, transdermal^, subcutaneously, or intravenously. Vaccines capable of oral administration may be given directly as a liquid formulation, or may be incorporated in a palatable food item, and swallowed by the patient. Some vaccines are given nasally, as by spraying. Aerosolization of vaccines is also used for large scale vaccination, however, this is typically performed using a jet nebulizer. This method suffers from the disadvantages of requiring a compressor and sufficient electrical power to drive it, thus is relatively expensive, less portable and potentially more subject to contamination, and /or safety concerns. Administration in this manner is disadvantageous also due to the relatively long time (greater than 30 seconds) to inhale an effective dose.

[0007] in addition to being useful defenses against naturally occurring viruses, vaccines are also important agents in defending against biological attacks and/or bioterrorism, and/or threats thereof. Under these conditions, rapid response, that is, quickly and efficiently delivering effective doses to those affected by the attack, or threat thereof, is critical.

[0008] Administration of vaccines is further problematic in view of the patient demographics and logistics. As noted, children are the primary recipient of vaccines, and they are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to the vaccines, typically at age nine months to six years. Additional 'booster' shots often required to achieve full immunity. This has led to the development of complex vaccination schedules.

[0009] In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Center for Disease Control, recommends routine vaccination of children against: hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chicken pox, rotavirus, influenza, meningococcal disease and pneumonia. The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance.

[0010] Adults and children both are recommended for immunization with influenza vaccines. Elderly people are particularly susceptible to various influenzas, thus it is important they be vaccinated.

[0011] Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended at other ages or for repeated injections throughout life - most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is currently recommended in the U.S. and UK for ages 9-25. Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chicken pox virus, which usually affects the elderly.

[0012] Vaccines may be conveniently divided into four types of traditional classes. First, vaccines containing killed microorganisms - these are previously virulent microorganisms that have been killed with chemicals or heat. Examples are vaccines against flu, cholera, bubonic plague, and hepatitis A. Second are vaccines containing live, attenuated virus microorganisms - these are live micro-organisms that have been cultivated under conditions that disable their virulent properties or which use closely- related but less dangerous organisms to produce a broad immune response. They typically provoke more durable immunological responses and are the preferred type for healthy adults. Examples include yellow fever, measles, rubella, and mumps. Third are the toxoids - these are inactivated toxic compounds in cases where these (rather than

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the micro-organism itself) cause illness. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for micro-organisms; for example, Crotalis atrox toxoid is used to vaccinate dogs against rattlesnake bites. Fourth are the subunit type - rather than introducing an inactivated or attenuated micro-organism to an immune system, a fragment of it can create an immune response. Characteristic examples include the subunit vaccine against HBV that is composed of only the surface proteins of the virus (produced in yeast) and the virus-like particle (VLP) vaccine against human papillomavirus (HPV) that is composed of the viral major capsid protein.

[0013] Vaccines may be formulated with adjuvants such as squalene or phosphate to boost immune response, and with preservatives to preserve stability, potency, and safety. Vaccine performance is dependant upon a number of factors such as the type and nature disease itself, the strain of vaccine, the timing and schedule of the vaccination, and ethnicity or genetic predisposition. It can thus be appreciated that dosing and dosing schedule is an important factor in successful vaccination.

[0014] Vaccines (and thus vaccinations) may also be administered to animals, both pets and stock, for the same reasons as humans are vaccinated, i.e. to prevent or treat diseases or conditions.

[0015] Generally, existing modes of administration are unsatisfactory for large-scale purposes. Injections are time-consuming, relatively costly and have significant compliance problems, particularly in developing countries. Oral administration is not suitable for many vaccines, and existing pulmonary administration methods suffer form one or more of requiring expensive and/or bulky equipment, long administration times, or contamination concerns.

[0016] For these reasons, it's desirable to increase the aerosol delivery efficiencies of nebulizer systems. Embodiments of the present invention address these and other problems with conventional systems and methods of treating patients with aerosolized medicaments. [0017] The present invention relates to the technical field of liquid aerosolization systems, and particularly to medical aerosol generator and delivery systems,

10018J The present invention provides devices and methods for improving a level of safety to the patient and for providing an increased efficiency of delivery of an aerosol to the patient,

[0019] References herein to 'embodiment" or embodiments" means one or more such embodiments, unless the context clearly indicates otherwise.

[0020] Embodiments of the invention also include a method of treating a patient by administering to the patient a nebulized aerosol comprising from about 100 μg to about 5 mg; additionally or alternatively about 10μ!_ to about 5 mL of a medicament, such as a vaccine.

[0021] Embodiments of the invention still further include methods of vaccination by administering to a patient an aerosolized vaccine formulation comprising a vaccine dissolved in an aqueous solution that is adjusted to a pH between about 5.5 and 8.5.

[0022] Embodiments of the invention include one or more methods of administering a medicament by nebulization using a vibratable member with apertures, the member configured to produce about 70% or more of aerosol particles with mass mean aerodynamic diameters from about 1 μm to about 6 μm.

[0023] Embodiments of the invention include one or more methods of administering by nebulization using a vibratable member with apertures, the member configured to produce about 60% or more of aerosol particles with mass mean aerodynamic diameters from about 1 μm to about 5 μm.

[0024] Embodiments of the invention include one or more methods of administering by nebulization wherein the medicament is administered continuously.

[0025] Embodiments of the invention include one or more methods of administering by nebulization wherein the medicament is administered intermittently,

[0026] Embodiments of the systems are configurable to administer aerosolized medicament, such as vaccine, to a freely-breathing patient.

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[0027] Embodiments of the invention include one or more devices and methods of administering medicaments, such as vaccines, by nebulization wherein substantially all of the device is reused for multiple patients before disposing thereof,

[0028] Embodiments of the invention include one or more devices and methods of administering medicaments, such as vaccines, by nebulization wherein the device is used for only a single patient, then disposed,

[0029] Embodiments of the invention include one or more devices for administering medicaments, such as vaccines, by nebulization wherein some components of the device are reusable, and other components are disposable after a single use.

[0030] Embodiments of the invention include one or more methods of administering medicaments by nebulization wherein some components of the device are used for multiple patients before disposal of the component, and other components used for only a single patient.

[0031] Embodments of the invention comprise a device which is small and portable, easy to transport, with low power requirements.

[0032] In one or more embodiments, the device of the present invention can nebulize and deliver 500 - 1000 doses (each dose comprising 100-300 uL) of medicament, such as a vaccine, from single charge of 3 AAA batteries.

[0033] In one or more embodiments, the device of the present invention can nebulize and deliver individual doses of medicament, such as a vaccine, totaling at least about 0.05 liters, from a single charge of 3 AAA batteries.

[0034] In one or more embodiments, the device of the present invention affords efficient aerosolization and delivery of vaccine, with less than about 0.2 mL, or less than about 0.1 mL, or less than about 0.05 mL, of vaccine wasted per vial of vaccine.

[0035] In one or more embodiments, one device of the present invention can aerosolize and deliver to a plurality of patients equivalent to at least about 220 or 230 or 240 doses of vaccine per day. 53353

[§036] In one or more embodiments, the device of the present invention can aerosolize and deliver to a patient an inhaled mass of at least about 20% or 21% or 22% (infant breathing pattern) and at least about 30% or 33% or 35% (pediatric breathing pattern).

[0037] In one or more embodiments, the device of the present invention can aerosolize and deliver to a patient a medicament, such as a vaccine, in less than about 30 seconds.

[0038] In one or more embodiments, the device of the present invention can aerosolize and deliver a medicament, such as a vaccine, in less than about 20 seconds.

[0039] One or more embodiments of the present invention include one or more methods for administration of aerosolized vaccine to a patient wherein the vaccine is aerosolized and delivered with an efficiency of at least about 20%.

[0040] In one or more embodiments, the device of the present invention can aerosolize and deliver to a patient a medicament, such as a vaccine, in a volumetric manner, such as a constant aliquot of +/-10 uL.

[0041] In one or more embodiments, the device of the present invention can aerosolize and deliver a medicament, such as a vaccine, in a volumetric manner, such as a constant aliquot of +/- 5 uL.

[0042] In one or more embodiments, the device of the present invention can aerosolize and deliver a medicament, such as a vaccine, in a volumetric manner, such as a constant aliquot of +/-10% of the total liquid volume.

[0043] In one or more embodiments, the device of the present invention can aerosolize and deliver a medicament, such as a vaccine, in a volumetric manner, such as a constant aliquot of +/-5% of the total liquid volume.

[0044] Further embodiments comprise any two or more of any of the foregoing features, aspects, versions or embodiments.

[0045] Additional embodiments and features are set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the invention. The features and 53353

advantages of the invention may be realized and attained by means of the instrumentalities, combinations, and methods described in the specification.

[0046] It is to be understood that unless otherwise indicated the present invention is not limited to specific formulation components, drug delivery systems, manufacturing techniques, administration steps, or the like, as such may vary. In this regard, unless otherwise stated, a reference to a compound or component includes the compound or component by itself, as well as the compound in combination with other compounds or components, such as mixtures of compounds.

[0047] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[0048] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a process" includes a plurality of such processes and reference to "the electrode" includes reference to one or more electrodes and equivalents thereof known to those skilled in the art, and so forth.

[0049] Also, the words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, acts, or groups. 53353

[0050] "Fluid" means a liquid, or a gas, or a combination thereof, specifically including an aerosol.

[0051] "Medicament" comprises any drug, agent, vaccine, compound, biological material which beneficially treats, prevents, helps to prevent, mitigates or alleviates any disease or condition, unless the context clearly indicates otherwise.

[§052] "Vaccine" comprises any agent which elicits, triggers, enhances or boosts an immune response, or capability for immune response.

[0053] μL means microliters, or 0.00001 Liters. [0054] μm means microns.

[0055] Reference herein to "one embodiment", "one version" or "one aspect" shall include one or more such embodiments, versions or aspects, unless otherwise clear from the context.

[0056] As used herein, the terms "treating" and "treatment" refer to reduction in severity, duration, and/or frequency of symptoms, elimination of symptoms and/or underlying cause, reduction in likelihood of the occurrence of symptoms and/or underlying cause, and improvement or remediation of damage. Thus, "treating" a patient with a medicament as provided herein includes prevention or delay in onset or severity of a particular condition, disease or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual.

[0057] As used herein, "effective amount" refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts.

[0058] As used herein, "therapeutically effective amount" refers to an amount that is effective to achieve the desired therapeutic result. A therapeutically effective amount of a given medicament will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient. 53353

[0059] The entire contents and disclosure of each reference referred to herein, including US Patents and US Patent Application publications, is hereby incorporated herein by reference for all purposes.

53353

SUMMARY OF THE INVENTION

[0060J The device according to one or more embodiments of the invention comprises an aerosolization device for aerosolizing liquid medicament, and for rapidly, efficiently and safely delivering a therapeutic dose of the liquid aerosolized thereby to multiple patients. In one or more embodiments of the invention comprises aerosolization device for aerosolizing liquid medicament which possesses one or more of the following attributes: portable, free-standing, small, low powered, light weight, inexpensive and combinations thereof.

[0061] The present invention thus comprises a device and system for efficient, safe and rapid administration of aerosolized medicaments, especially vaccines. The device comprises a nebulizer body, housing an aerosol generator, and comprising a fluid pathway for liquid to impinge upon the aerosol generator, and for aerosolized liquid generated thereby to be conducted to a patient. The body further comprises a liquid supply cartridge and actuator means for delivering liquid to the aerosol generator. The device further comprises an aerosolized liquid flow path comprising at least one air inlet means and at least one exhalation exhaust means. A patient interface means conducts the aerosolized liquid to the patient, and a power supply and control means is provided to power and control operation of the aerosol generator. In one or more embodiments, the device is configured to deliver vaccines to a large number of patients rapidly, efficiently and safely, with minimal danger of cross or back contamination.

53353

DESCRIPTION OF THE DRAWINGS

[0062] These aspects and others will become apparent from the following description.

[0063] FIG, 1 is a perspective view of an aerosolization and delivery device/system in accordance with one or more embodiments of the present invention;

[0064] FlG 2 shows a portion of the device of the present invention with one embodiment of a patient interface device;

[0065] FiGs. 3A-3B are top and bottom perspective views, respectively, of one the embodiment of the device, illustrating the aerosol generator component;

[0066] FIG 4 is a perspective view of one embodiment of a subassembly of the aerosol generator of the system of present invention;

[0067] FIG 5 is a magnified, schematic side sectional view of an aerosol generator of the device of the present invention;

[0068] FIG 6 is a magnified, schematic side sectional view of an aperture plate of the aerosol generator of FIG 5;

[0069] FIG 7 is a side view of one embodiment of a liquid supply cartridge of the present invention;

[0070] FIG 8 is a side view of one embodiment of a cartridge support structure and actuator of the present invention, showing the relationship of the liquid supply cartridge with the system;

[0071] FIG 9 is a perspective view of one embodiment of a portion of the aerosolization system of the present invention;

[0072] FIG 10 is a perspective view of one embodiment of a portion of the aerosolization system of the present invention;

[0073] FIGS 11 A-11C are side views, partially in section, of one embodiment of the device of Fig 1 ; showing a mode of operation thereof; and

[0074] FIG 12 is a perspective view of one embodiment of patient interface device of the present invention, comprising a disposable mask. 53353

DETAILED DESCRIPTION

[0075] Referring now to the figures, an exemplary embodiment of an aerosol transfer and nebulizing apparatus or system 10 will be described. As best illustrated in FIGs. 1 and 2, the nebulizing apparatus 10 includes a generally tubular nebulizer body 12 and an aerosol generator 14 disposed therewithin. For illustrative purposes, the nebulizer body 12 may be conveniently subdivided into three components: an upper body 12A, and intermediate body 12B and a lower body 12C. In one or more embodiments of the upper body 12A there is fluidically coupled thereto a medicament source 22, which in one or more embodiments comprises a liquid supply cartridge 24, such as a vaccine- type vial. In one or more embodiments, the intermediate body 12B comprises the aerosol generator 14. In one or more embodiments, the lower body 12C comprises an aerosolized medicament outlet 26, to which a patient interface, e.g. a mouthpiece 27 (shown in FIG 2) may be attached. It is to be noted that reference herein to the bodies 12A-12C is not to be construed as limiting to three discrete components, nor to exactly three components, nor to a particular order or arrangement of components. Rather, the references are illustrative only, and to aid in an understanding in one or more embodiments of the present invention, which includes other possible versions, alterations, permutations and equivalents of the embodiments shown, as will become apparent to those skilled in the art upon a reading of the specification. Furthermore, certain terminology has been used for the purposes of descriptive clarity, and not to limit the present invention.

[0076] Aerosol generated by the aerosol generator 14 is delivered into a vented aerosol passage 28 defined by the nebuliser body 12. Air is admitted into the vented aerosol passage 28 and thereby entrains the aerosolised medicament, which is then delivered to the patient through the aerosolized medicament outlet 26 via an aerosolized outlet passage 29.

[0077] Referring to FIGS 3-6, there is illustrated the aerosol generator 14 which comprises a vibratable member 40 also known as an aperture plate, and a piezoelectric element 41. The vibratable member 40 has a plurality of tapered apertures 42 extending between a first surface 43 and a second surface 44 thereof, as described further in US 53353

Patents Numbers: 5,164,740; 5,586,550; 5,758,637; 6,085,740; 6,467,476; 6,640,804; 6,629,646; 6,926,208; and 6,968,840.

[0078] The first surface 43 of the vibratable member 40, which in use faces upwardly, receives a liquid, such as medicament, from the liquid supply cartridge 24, and the aerosoϋsed liquid is generated at the second surface 44 of the vibratable member 40 by ejecting an aerosol comprising droplets 45 of liquid upon vibration of the member 40. In use the second surface faces downwardly. In one or more embodiments, the apertures in the vibratable member 40 may be sized to produce an aerosol in which about 65% or 70% or 75% or 80% or 85% or more of the droplets by weight have a size in the range from about 1 to about 5 micrometers. In one or more embodiments, about 65% or 70% or 75% or 80% or 85% or more (by weight) of the droplets have sizes ranging from about 1 to about 6 micrometers, or about 1 to about 5 micrometers, or 1 to about 4 micrometers. In one or more embodiments, the vibratable member 40 is substantially non-planer, and in one or more embodiments, comprises a dome-shaped geometry 46.

[0079] In one or more embodiments, the vibratable member 40 may be mounted on a substantially planar, disk-shaped aerosol actuator 47, which helps to define the dome portion 46 of the vibratable member 40. In one or more embodiments, the piezoelectric element 41 may also comprise a substantially planer disk-shaped, annular or semicircular, element. In one or more embodiments, substantially all of liquid expelling surface of the member 40, that is, the aperture 42 containing portion of the member 40, comprises a dome or non-planer shape. The vibratable member 40 may be vibrated in such a manner as to draw liquid through the apertures 42, and expel the liquid as a nebulized mist of droplets 45. The vibratable member 40 may be mounted to the aerosol actuator 47, such that vibration of the piezoelectric element 41 may be mechanically transferred through the aerosol actuator 47 to the vibratable member 40.

(0080] In one or more embodiments, the piezoelectric element 41 has an electrical connection to which a connector plug element 48 is mounted as illustrated in FIG 4. The piezoelectric element 41 and the plug 48 may then be overmolded to form a sub- assembly 49 for ease of integration into the nebulizer body 12. 53353

l§081] The apparatus 10 also includes a controller (not shown), to control operation of and to supply power to the aerosol generator 14. The plug element 48 defines a signal interface port 50 (FIGS 3) fixed to the nebulizer body 12 to receive a control signal from the controller. The controller may be connected to the signal interface port 50 by means of a control lead or connector for mating with the plug 48 at the interface port 50. A control signal and power may be passed from the controller through the lead to the aerosol generator 14 to control the operation of and supply power to the aerosol generator 14.

[00821 In one or more embodiments the controller may comprise a battery operated unit. Additionally or alternatively, the controller may connect directly to a mains power source. In this case the controller would have has an integral AC-DC circuit (not shown) as well as control circuitry (not shown) mounted in a single housing. In one or more embodiments electrical connections to supply power to, and to control vibration of the vibratable member 40 are achieved by any means known in the art such as by direct electrical connection, wireless coupling, or any other means by which current and voltage can be supplied to the piezoelectric element 41. Power may be supplied from an electrochemical cell or cells, line current, or any other source. The low power requirements (about 2 - 3 watts, or less) of the device make it well suited for uses in remote area wherein power is not readily available. The device can thus advantageously be powered also by internal sources, such as small batteries, or local external sources such as solar, wind, small hydroelectric, or manually-generated (e.g. hand cranked) power.

[0083] The aerosol generator 14 is contained within the nebulizer body 12, and in one or more embodiments, is positioned to manner that is generally coaxial with a central axis AA of the nebulizer body 12. However, it is noted that the aerosol generator 14 may be offset from, and/or angled with respect to the central axis AA, as long as there is an unimpeded fluid path from the liquid supply cartridge 24 to the aerosol generator 14. In one or more embodiments, the aerosol generator 14 may be supported within the body 12, such as within the body 12B, by an internal generally coaxial annular support 52 (shown in Fig 3B). In some embodiments, the aerosol generator 14 may be supported 53353

within the nebulizer body 12 by any means known to the art such as adhesives, mechanical, securing means such as tabs flanges etc. In some embodiments, an elastomeric O-ring may be placed adjacent to the aerosol generator 14 to dynamically isolate the aerosol generator 14.

I0084] Referring to FIG 7, in one or more embodiments the liquid supply cartridge 24 comprises a vaccine-type vial, comprising a bottle or vial 54 and an elastomeric dropper 56. The dropper 56 is made of a semi-rigid, flexible material, such as a polymeric material, which is squeezable or compressable. An orifice 58 allows the liquid contents to flow out by gravity, thus impinge upon the aerosol generator 14, when the cartridge 24 is inverted. The orifice 58 may be sized such that, in relation to the viscosity of the liquid, droplets of liquid must be urged out by compressing the dropper 56. In one or more embodiments, the dropper 56 is volumetric, capable of delivering a defined volume drop upon compression. In other embodiments, the aerosolization device of the present invention may be configured such that the drops of liquid are conducted to the aerosol generator by means other that by gravity, such as by pressure. In one or more embodiments, the droplets each comprise a volume of about 10 - 60 μl_.

[0085] FIGS 1 and 8 show the liquid supply cartridge 24 held in an inverted position generally over a central aperture 59 coaxial with axis AA of the nebulizer body 12, by a cartridge support structure 60. In one or more embodiments, the cartridge support structure 60 comprises a relatively rigid or semi rigid material, such as a polymeric material (polyacrylate) In one or more embodiments, the cartridge support structure 60 is integrally formed with the nebulizer body 12A, and comprises a generally semicircular retaining band 62, a pair of opposed partial side walls 66A and 66B, and a retainer tab 68 disposed about the semi-circular upper band 62. The vial 54 can be inserted into the retaining band 62, which is slightly smaller in curvature that the vial 54, such that the vial 54 snaps therein, thus and is releasably held in the structure 60. In one or more embodiments, the retaining band 62 may be formed as two opposing semicircles and disposed on opposite sides of the support structure and vertically displaced such that the vial 54 may be inserted therebetween. 53353

[§086] The cartridge support structure 60 may also be formed as an independent component, and permanently or releasably attached to the nebulizer body 12A, Moreover, it can be appreciated that there are a variety of suitable elements, dimensions and features which can be utilized to form the cartridge support structure 60, thus its exact nature and configuration is not important, as long as the structure 60 securely holds the liquid supply cartridge 24 during use, and permits release thereafter.

[0087] In some embodiments, the cartridge support structure 60 and liquid supply cartridge 24 may be formed such that the latter is releasable from the former, such that the structure 60 may be re-used with multiple liquid supply cartridges 24.

[0088] In some embodiments, the cartridge support structure 60 and liquid supply cartridge 24 may be formed to be a unitary component, or are formed separately, but joined so as to be not readily separable. The components comprising the cartridge support structure 60 are preferably formed as a unitary piece, as by molding, blow molding, thermoforming, vacuum forming, or the like.

[0089] In some embodiments, the cartridge support structure 60 and liquid supply cartridge 24 may be formed to be a unitary component, and the aerosol generator 14 is further formed into the nebulizer body 12A, such that a fluid path from the liquid supply cartridge 24 to aerosol generator 14 exists in a unitary component. In such an embodiment, for instance, the nebulizer body 12A may be fitted to the nebulizer body 12B or to 12C, or to another component, or to a set of components which may be used to entrain air with the nebulized aerosol, and to deliver the aerosol to the patient. For example, this embodiment of the nebulizer body 12A may be adapted to fluidically couple to an air entrainment and delivery structure which itself may be disposable, such as being made from paper, plastic or a readily available, naturally-occurring material.

[0090] The cartridge support structure 60 further includes an actuator 70 which is configured and positioned to apply a compressive force to the semi-rigid, flexible dropper 56.

[0091] In one or more embodiments, the actuator 70 comprises two diametrically opposed levers 72A and 72B, affixed to the cartridge support structure 60, for example, 53353

to the nebulizer body 12A, The levers 72A and 72B extend upwardly, and each include a cam 74 positioned and dimensioned to impinge upon, and apply an axial force to, the dropper 56. When the levers 72A and 72B are urged together, for example, by manually squeezing, liquid is urged out of the container 54 where it flows to the aerosol generator 14 and is thereby aerosolized.

[0092] In one or more embodiments the actuator 70 may comprise any means for applying a compressive force to the elastomeric dropper 56 thereby squeezing out the drops of the fluid medicament such as vaccine contained therein. For example, a force application means may comprise a threaded ring and tapered collar (not shown), into which the dropper 56 is inserted. The ring is rotated onto the collar, which is thereby compressed and thus supplies a radial inward force about a circumference of the elastomeric dropper 56. Additionally or alternatively, an axial force exerted downwardly upon the vial 54 may be converted into a radial inward force by appropriate structure, such as a conical or tapered housing. Compressive force upon the dropper 56 may also be supplied by a pair of appropriately-shaped, such as eccentric, rotating cams (not shown), which exert force as the vial 54 and dropper 56 are urged downwardly therebetween. The cams 74 may also be mounted to travel linearly inward upon squeezing.

[0093] Moreover, if desired, the compressive force may be automated, such as by a solenoid which could apply compressive force at discrete points such as diametrically opposed points, or at a plurality of points around the circumference of the dropper 56. Further, structural elements for supplying compressive force to the dropper 56 may comprise any known to the art for applying compressor force on the dropper 56.

[0094] Referring to FIG 9, the aerosol generator 14 discharges the aerosol generated thereby into the lower, portion of the nebulizer body 12, that is, into nebulizer body 12C where it is aerosolized and conducted to the aerosolized medicament outlet 26 via the passages 28 and 29. Attached thereto is the patient interface device which, in one or more embodiments, comprises the mouthpiece 27. Other patient interface devices, such as a mask, cannula, hood, tent or chamber are equally suitable. At a lower end of the nebulizer body 12C, there is an inlet valve 86, which allows ambient air into the 53353

nebulizer body 12 to mix with the medicament aerosol generated, thereby providing the appropriate mixture of air and medication for the patient. The valve 86 may comprise a silicone flap-type valve, a coaxial valve or a fluidic valve. Additionally or alternatively, in some embodiments the valve 86 may be omitted entirely, and replaced by a fixed orifice (not shown) or by a porous membrane or filter-type material.

[0095] In one or more embodiments, an aerosolized dose of medication may require about 10 to 60 seconds to administer. In one or more embodiments, an aerosolized vaccine may require about 20 to 50 seconds to administer, and typically requires about 20-30 seconds. During administration, the patient typically breathes multiple times, such as about 10 - 40 times per minute, thus multiple inspiration and expiration cycles take place while the medication is being aerosolized and administered. For this reason, in one or more embodiments it is preferable to incorporate one or more exhaust port(s) 90 into the nebulizer body 12 to permit the exhaustion of exhaled air from the patient. Referring to FIGS 9 and 10, in one or more embodiments, the exhaust port 90 may comprise a simple orifice around a circumference of a conduit 92 intermediate to the body 12C and the outlet 26. In one or more embodiments, the port or ports 90 are fitted with an exhalation filter element 94 to filter any remaining vaccine or medicament that may remain in the exhaled gases. In one or more embodiments, the exhalation filter element 94 comprises a band of filter material encircling the portion of the conduit 92 containing the port or ports 90. In one or more embodiments, the filter element 94 is sized and positioned to cover only an individual port or ports 90. The filter element 94 comprises a membrane or depth type filter, and may be made of any suitable filter material such as polymeric membranes, porous plastic, sintered porous plastic, filter paper, woven or nonwoven fabric, textile or paper material. Additionally, the exhaust port 90 may comprise a valve (not shown), substantially as described in respect of inlet valve 86.

[0096] In one or more embodiments of the present invention, rather than forming the conduit 92 of a durable solid material, with a port or ports 90, the conduit 92 may be formed of a porous material, for example, as a disposable filter material, such as those described above for the filter element 94. The conduit thus formed is sufficiently strong 53353

and durable to be free standing, and thus acts as structural conduit, fluid passage and filter, In one or more embodiments, the disposable filter material may be strengthened by adding structural elements, such as ribs or stringers. Similarly, the entire nebulizer body 12C could be formed wholly or partially of a sufficiently porous filter material, and function in a like manner, with the further advantage that the inlet valve 86 could also be omitted. In such an embodiment, the nebulizer body 12C would be disposable, and thus disposed after a predetermined number of uses, or after a predetermined physical or microbiological threshold has been reached, or after a measured parameter (such as time or bacterial count) has been reached. An indicator, such as a use-up indicator (not shown) characteristic of one or more such parameters may be incorporated into the nebulizer body 12C as thus constituted to assure timely disposal. For example, the indicator may measure time, a component of exhaled breath or a component of a delivered medicament. Additionally or alternatively, in one or more embodiments, the aerosol generator controller may be configured to shut off the aerosol generator after one or more parameters, qualities or thresholds (as described above) are reached, such as shutting of the aerosol generator after a predetermined amount of nebulization time.

[0097] Operated of the system is as follows, with reference to FIGS 11A-11C. The liquid supply cartridge 24 is inserted into the cartridge support structure 60, and is retained therein as described. In one or more embodiments, the liquid container 24 comprises a standard vaccine vial comprising a glass container 54 having an elastomeric, such as plastic, dropper 56. Once the liquid supply cartridge 24 is inserted in the device, a patient interface device is affixed to the aerosolized medicament outlet 26. The patient interface device, as previously described in one or more embodiments, comprises a mouthpiece 27 or a mask. However it may comprise a cannula, tent, hood or other patient interface depending on the type of medication to be administered and the age and condition of the patient. The patient interface device is secured to the patient's mouth, nose or both, to provide a fluidic coupling with the patient's respiratory system. The system 10 is connected to an appropriate power and control source, and the caregiver or patient then squeezes the actuator 70 (indicated by the straight arrows in FIG 11A) to release liquid dropwise. In one or more embodiments, the upper body 12A, and/or the cartridge support 60, or a portion thereof, is clear so that the operator/patient 53353

can observe the number of drops impinging upon the aerosol generator 14. The drop(s) of liquid impinges upon the appropriate face of the aerosol generator 14, where, it is converted to an aerosol plume. Initially, the inlet valve 86 is closed during the generation of aerosol. The sizing of the port 90, or the sizing of the port 90 coupled with the covering filter element 94 provides sufficient impedance to prevent escape of aerosol. As the patient inhales, inlet valve 86 opens, allowing air to mix with the aerosol plume, which travels through the conduits 28 and 29 and exits the outlet 26, where it is inhaled by the patient. The port 90 and/or filter element 94 continue to prevent escape of aerosol during this step. As the patient exhales, the pressure is sufficient close inlet valve 86, and to overcome the impedance of port 90 and/or filter element 94, and exhalation gases are expelled through the exhaust port 90, where excess medication or vaccine is trapped by the filter element 94. It is to be noted that the system 10 operates substantially as described, even if no filter element 94 is present covering the port or ports 90.

(0098] In this manner, a dose of a medicament, such as a vaccine, for example 100 to 300 microliters, may be given to the patient in a simplified, efficient, safe and rapid manner. In one or more embodiments wherein the medicament comprises a vaccine, where hundreds of doses are administered to a like number of patients, it is preferable that the patient interface device, such as mouthpiece 27 or a mask, be comprised of a disposable material. Thus, when each patient has been administered his or her appropriate dose, the mouthpiece 27 or mask is discarded and a new one fitted to the outlet port 26.

[0099] In one or more embodiments, the liquid supply cartridge 24 contains approximately 1 to 10 milliliters of liquid and multiple patients may be serviced by a single cartridge 24. In embodiments where the liquid comprises a vaccine, an appropriate dose of vaccine may be administered to up to about fifty patients (depending upon vaccine type and patient characteristics and condition) from the same vial 54. The system 10 is thus transferred by the caregiver and/or patient from patient to patient. In one or more embodiment, the reusable nebulizer body 12, and/or individual components 12A, and/or 12B and/or 12C, containing the nebulized fluid path, 53353

coupled with the disposable patient interface, such as mouthpiece 27, and filter element 94 afford a safe, efficacious, sanitary means of medicament, such as vaccine, delivery, essentially free of any source of cross-contamination or retrograde between patients or back contamination by an individual patient.

[OQ100J In one or more embodiments, the aerosol generator is controlled by an electronic controller as described, for example in US patents 6,540,154, 6,546,927 and 6,968,840 and in US Patent Application Publication 2005/0217666, published October 6, 2005. In one or more embodiments, it is sufficient that the controller supply power to the piezoelectric generator and to switch generation of the aerosol on and off between patients. In other embodiments, the controller may supply power and switch the aerosol generator 14 on and off according to a predefined protocol, or according to measured or calculated breathing characteristics, or both. For example a pressure sensor (not shown) may be fitted to a port (not shown) in the nebulizer body 12, and used to measure breathing characteristics.

[00101] In some embodiments of the invention, the filter element 94 may be used in any device wherein a port or ports are dimensioned and configured to exhaust an aerosolized liquid, and safety, efficacy or efficiency is improved by filtering the expelled gas comprising the aerosolized liquid, or trace thereof.

[00102] Referring to FIG. 12 one or more embodiments of a disposable patient interface device comprising a mask 100 will be described. The mask 100 is formed of a disposable filter material, such as described in connection with the filter element 94. The mask has a patient opening 102 for fitting to the patient's face and for conducting the aerosolized medicament, such as vaccine thereto. A nebulizer port 104 allows fluidic coupling of an aersolization device of the present invention, For example, referring to FIG 8, the upper body 12A could be fabricated with the nebulizer 14 positioned therein (as described above) affording a durable, re-usable aerosolization component, which could then be fitted to the disposable mask 100 at the port 104, that is, by coupling the aperture 59 of the body 12A to the port 104. The nebulizer body 12A is then operated as described, and the mask 100 disposed of after each patient. The use of a disposable filter material for the mask 100 provides both the aerosol transfer 53353

function, and allows exhalation gases to be exhausted through the body of the mask 100. The mask is dimensioned and configured to be easily manufactured, stored and transported, thus facilitating mass dosing, especially of vaccines. In one or more embodiments, the mask 100 may further comprise two thin overlapping leaves (not shown) of a material, such as plastic or paper, fitted to removably seal the opening 102, thus acting as valve to create an aerosol containment chamber within the mask 100. In one or more embodiments, additionally or alternatively, a similar plastic or paper valve could be fitted to the nebulizer port 104, permitting the mask 100 to function as an aerosol transfer device.

[00103] The system 10 may also be fitted with additional port and/or fluid couplings to permit addition of other gasses, such as oxygen, and/or to measure or sample patient breathing characteristics and/or gases.

[00104] The device 10 generally is comprised of any material which is sufficiently durable to withstand handling, non-reactive to the medicaments, and which can be readily cleaned and sterilized, where the device is intended for re-use. Preferred are polymeric materials such as acrylics, or biodegradable plastics, or naturally-occurring materials such as paper, the latter materials intended for disposable and/or recyclable components.

Exemplary Nebulizers

[00105] In regard to the nebulizers (i.e., aerosol generators), they may be of the type, for example, where a vibratable member is vibrated at ultrasonic frequencies to produce liquid droplets. In one or more embodiments, the ultrasonic frequency of vibration comprises at least about 45 kHz. Some specific, non-limiting examples of technologies for producing fine liquid droplets is by supplying liquid to an aperture plate having a plurality of tapered apertures and vibrating the aperture plate to eject liquid droplets through the apertures. Such techniques are described generally in U.S. Patent Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637, 6,014,970, and 6,085,740, the complete disclosures of which are incorporated by reference. In one or more embodiments of the present invention, the aerosol generator comprises a vibrating mesh type, wherein vibrational energy is supplied via a piezoelectric element in communication (directly or 53353

indirectly) with the mesh element. In particular, a suitable nebulizer body 12 is dimensioned and configured to accept a vibrating mesh aerosol generator 14 as manufactured and/or distributed by Aerogen, Inc., Galway, Ireland, having a vibrating mesh aerosolization engine, comprising a dome-shaped aperture plate and a piezoelectric ring, which vibrates the aperture plate at a very high (ultrasonic) rate, forcing liquid through apertures in the plate to yield a fine and consistent particle size. However, it should be appreciated that the present invention is not limited for use only with such devices.

[00106] The aerosolization element may be constructed of a variety of materials, comprising metals, which may be electroformed to create apertures as the element is formed, as described, for example, in U.S. patent No. 6,235,177 assigned to the present assignee and incorporated by reference herein in its entirety. Palladium is believed to be of particular usefulness in producing an electroformed, multi-apertured aerosolization element, as well as in operation thereof to aerosolize liquids. Other metals that can be used are palladium alloys, such as PdNi, with, for example, 80 percent palladium and 20% nickel. Other metals and materials may be used without departing from the present invention.

[00107] In one or more embodiments, the aerosol generator comprises a tube core design, as described in WO 2006/127181 , assigned to the same assignee as the invention herein.

Exemplary Vaccines

[00108] Embodiments of the invention contemplate a variety of vaccines, such as those directed to Mumps, Rubella and combined MMR; Flu (Seasonal, SARS, Avian); Hantivirus; Pneumococcol; Bacterial/eukaryotic; Malaria; Smallpox; Anthrax; Meningococal; Tuberculosis; and Francisella tularenis.

[00109] Vaccines generally reconstituted dry powders, and as such storage instable, heat labile and are thus short-lived, requiring reconstitution immediately before use, and disposal of any remaining portion immediately thereafter.

Other Exemplary Medicaments 53353

100110] Embodiments of the invention contemplate a variety of medicaments that can be aerosolized and delivered to a patient's lungs. These medicaments may comprise antibiotics such as aminoglycosides, β-lactams, and quinolines, among others. The aminoglycosides may comprise amikacin, gentamycin, kanamycin, streptomycin, neomycin, netilmicin, and tobramycin, among other aminoglycosides. Other medicaments may also be used, including anti-oxidants, bronchodilators, corticosteroids, leukotrienes, prostacyclins, protease inhibitors, and surfactants, among other medicaments. Liquid insulin, both basal and prandial, may also be delivered by the device and methods of the present invention. Table 1 lists exemplary classes of medicaments and some of the aliments they may be used to treat in their aerosolized state, however, the disclosure of Table 1 is exemplary only, and not to be construed as limiting.

Table 1 : Classes of Aerosolizable Medicaments

fβθlllj AECOPD: acute exacerbation of COPD 53353

[00112] ALl: Acute lung injury

[00113] ARDS: Acute respiratory distress syndrome

[00114] BPD: Bronchopulmonary dysplasia

[00115] COPD: chronic obstructive pulmonary disease

[00116] PPHN: persistent pulmonary hypertension

[00117] RDS: Respiratory distress syndrome (also known as infant respiratory distress syndrome)

[00118] RSV: Respiratory syncytial virus

[00119] In other embodiments of the present invention, the nebulizer may comprise a pneumatically controlled, ultrasonic and vibrating-membrane devices in particular, as well as pressurised canisters with a metering valve.

EXPERIMENTAL

Example 1

[00120] Infant and pediatric respirator patterns were measured, as follow.

[00121] Two drops of an albuterol solution (comprising a patient dose) was applied to Aerosol generator using the device as described in FIG 1. The nebulizer was set to a volume median diameter (VMD) of 5.07; a flow rate of about 0.38 ml/min; a geometric standard deviation (GSD) of 2.3; and an fine particle fraction (FPF) 1-7 micron of 59.5. The aerosolized dose was administered through a mouthpiece. Results showed an 53353

average pediatric respirable dose of 38.1% (Max 41.6% Min 37,5%); and an average Infant respirable dose of 22.7%,

Claims

53353CLAIMS We Claim:

1. An aerosolization device comprising a nebulizer body, an aerosol generator, disposed within the nebulizer body; a liquid supplier for supplying liquid to the aerosol generator, the liquid supply means comprising a liquid source having a compressable elastomeric dropper element and an actuator dimensioned and positioned to compress the dropper element thereby urging liquid therefrom; a fluid pathway formed by the nebulizer body wherein liquid from the liquid supplier may impinge upon the aerosol generator to generate an aerosolized liquid, and an aerosolized liquid flow path for aerosolized liquid generated thereby to be conducted to a patient.

2. The device of claim 1 wherein the liquid comprises a medicament.

3. The device of claim 2 wherein the medicament comprises a vaccine.

4. The device of claim 1 further comprising at least one air inlet means and at least one exhalation exhaust means formed within the nebulizer body.

5. The device of claim 1 wherein the liquid supply means comprises a vaccine vial.

6. The device of claim 1 further comprising a patient interface, fluidically coupled to the aerosolized liquid flow path, the patient interface selected from a mouthpiece, a mask, a cannula, a hood and a chamber.

7. The device of claim 6 wherein the patient interface comprises a disposable material. 53353

8. The device of claim 7 wherein the patient interface comprises a fabric or paper mask.

9. The device of claim 1 wheren the actuator means comprises a pair of opposed levers and cams dimensioned and positioned to compress the elastomeric dropper.

10. The device of claim 1, wherein the aerosolized liquid comprises droplets having a size in the range from about 1 micron to about 6 micron.

11. The device of claim 10, wherein at least about 80% of the droplets are in the range from about 1 micron to about 6 micron.

12. The device of claim 11 , wherein the liquid supplier is configured to deliver the liquid in droplets of about 10 to about 60 microliters.

13. A method for aerosolizing and delivering a liquid, the method comprising providing a nebulizer body, an aerosol generator disposed within the nebulizer body, the aerosol generator comprising an aperture plate comprising a front surface, a rear surface, and a plurality of apertures extending therebetween, said apertures being tapered to narrow from the rear surface to the front surface; supplying a liquid to the rear surface, the aperture plate having a vibrating element capable of vibrating at a frequency of at least about 45 kHz to produce an aerosol having a particle size of about 1 to 6 microns, a liquid supplier for supplying liquid to the aerosol generator, the liquid supply means comprising a liquid source having a compressable elastomeric dropper element and an actuator dimensioned and positioned to compress the dropper element thereby urging liquid therefrom, a fluid pathway formed by the nebulizer body wherein liquid from the liquid supplier may impinge upon the rear surface of the aperture plate, an aerosolized liquid flow path for aerosolized liquid generated thereby to be conducted to a patient; compressing the elastomeric dropper element to supply drops of liquid to the aperture plate of the aerosol generator; and 53353

vibrating the aperture plate wherein vibrations of the aperture plate cause the fluid to be ejected through the apertures wherein it may be inhaled by the patient.

14. The method of claim 13 wherein the liquid is delivered in droplets of about 10 to about 60 microliters.

15. The method of claim 13, wherein the aperture plate is non-planar in geometry.

16 The method of claim 13 and further including the step of providing a disposable patient interface whereby the aerosolized liquid may be delivered to a patient therethrough.

17. A method for aerosolizing and delivering a liquid, the method comprising

providing an aerosolization device comprising a nebulizer body, an aerosol generator, disposed within the nebulizer body a liquid medicament supplier for supplying liquid medicament to the aerosol generator, the liquid supplier comprising a liquid source having a compressable elastomeric dropper element and an actuator dimensioned and positioned to compress the dropper element thereby urging liquid therefrom, the nebulizer body forming a fluid pathway wherein liquid medicament from the liquid supplier may impinge upon the aerosol generator to generate an aerosolized liquid medicament, the nebulizer body further defining an aerosolized liquid flow path to conduct an aerosolized liquid medicament generated thereby to a patient via a patient interface; providing a disposable patient interface; aerosolizing the liquid medicament for a duration sufficient to provide a therapeutic dose thereof; ceasing aerosolization of the liquid medicament; and disposing of the of patient interface.

18. The method of claim 17 wherein the patient interface comprises a mask.