Methods and apparatus for storing chemical compounds in a portable inhaler

Information

  • Patent Grant
  • 6755189
  • Patent Number
    6,755,189
  • Date Filed
    Tuesday, May 18, 1999
    25 years ago
  • Date Issued
    Tuesday, June 29, 2004
    20 years ago
Abstract
The invention provides exemplary aerosolization apparatus and methods for aerosolizing a substance. According to one exemplary method, a liquid is transferred from a first chamber into a second chamber having a substance that is in a dry state to form a solution. The solution is then transferred from the second chamber and onto an atomization member. The atomization member is operated to aerosolize the solution.
Description




BACKGROUND OF THE INVENTION




The invention relates generally to the field of inhalation drug therapy, and in particular to the inhalation of aerosolized chemical substances. In one aspect, the invention provides a portable inhaler having a cartridge for storing a chemical substance in a dry state and a liquid dispenser to introduce a liquid to the substance to form a solution. Immediately after formation of the solution, the inhaler aerosolizes the solution so that it may be administered to a patient.




The atomization of liquid medicaments is becoming a promising way to effectively deliver many medicaments to a patient. In particular there is a potential for pulmonary delivery of protein peptides and other biological entities. Many of these are easily degraded and become inactive if kept in a liquid form. Proteins and peptides often exhibit greater stability in the solid state. This results primarily from two factors. First, the concentration of water, a reactant in several protein degradation pathways, is reduced. See Stability of Protein Pharmaceuticals, M. C. Manning, K. Patel, and R. T. Borchardt, Phann. Res. 6, 903-918 (1989), the complete disclosure of which is herein incorporated by reference. Second, the proteins and other excipients are immobilized in the solid state. Water is a reactant in hydrolysis reactions, including peptide change and cleavage, and deamidation. Reducing the water concentration by freeze-drying or spray drying, reduces this reactant concentration and therefore the rates of these degradation pathways.




The mobility of the peptides or proteins, as well as other molecules in the formulation, are reduced in the solid or dry state. See Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures, B. C. Hancock, S. L. Shamblin, and G. Zografi, Pharm. Res. 12, 799-806 (1995), the complete disclosure of which is herein incorporated by reference. For the peptides or proteins, this reduces the rate of intermolecular interactions as well as intramolecular conformational changes or fluctuations in conformation. Minimization of intermolecular interactions will reduce protein and peptide aggregation/precipitation, and will also reduce the rate of diffusion of chemical reactants to the protein or peptide which will slow the rate of chemical degradation pathways. Reduction in intramolecular conformational changes reduces the rate at which potentially reactive groups become available for chemical or intermolecular interaction. The rate of this reaction may decrease as the water concentration, and mobility of the protein, is reduced.




One way to produce protein in solid or dry state is to transform the liquid into a fine powder. When used for inhalation delivery, such powders should be composed of small particles with a mean mass diameter of 1 to 5 microns, with a tight particle size distribution. However, this requirement increases the processing and packaging cost of the dry powder. See also U.S. Pat. No. 5,654,007 entitled “Methods and System for Processing Dispersible Fine Powders” and U.S. Pat. No. 5,458,135 entitled “Methods and Devices for Delivering Aerosolized Medicaments”, the disclosures of which are incorporated herein by reference.




An easier way to transform a liquid solution to solid or dry form is to use a freeze drying process where a liquid solution is converted to a solid substance that can be readily reconstituted to a liquid solution by dissolving it with a liquid, such as water. Hence, one object of the present invention is to provide a way to store a solid substance and combine the solid substance the with a liquid to form a solution. Once the solution is formed, it is another object of the invention to rapidly transport the solution to an atomization device to allow the solution to be aerosolized for administration. In this way, the solution is aerosolized immediately after its reconstitution so that the degradation rate of the substance is reduced.




A variety of nebulization devices are available for atomizing liquid solutions. For example, one exemplary atomization apparatus is described in U.S. Pat. No. 5,164,740, issued to Ivri (“the '740 patent”), the complete disclosure of which is herein incorporated by reference. The '740 patent describes an apparatus which comprises an ultrasonic transducer and an aperture plate attached to the transducer. The aperture plate includes tapered apertures which are employed to produce small liquid droplets. The transducer vibrates the plate at relatively high frequencies so that when the liquid is placed in contact with the rear surface of the aperture plate and the plate is vibrated, liquid droplets will be ejected through the apertures. The apparatus described in the '740 patent has been instrumental in producing small liquid droplets without the need for placing a fluidic chamber in contact with the aperture plate, as in previously proposed designs. Instead, small volumes of liquid can be placed on the rear surface of the aperture plate and held to the rear surface by surface tension forces.




A modification of the '740 apparatus is described in U.S. Pat. No. 5,586,550 (“the '550 patent”) and U.S. Pat. No. 5,758,637 (“the '637 patent”), the complete disclosures of which are herein incorporated by reference. These two references describe a liquid droplet generator which is particularly useful in producing a high flow of droplets in a narrow size distribution. As described in the '550 patent, the use of a non-planar aperture plate is advantageous in allowing more of the apertures to eject liquid droplets. Furthermore, the liquid droplets may be formed within the range from about 1 μm to about 5 μm so that the apparatus will be useful for delivering drugs to the lungs.




Hence, it is a further objective of the invention to provide devices and methods to facilitate the transfer of liquid solutions (preferably those which have just been reconstituted) to such aerosolizing apparatus so that the solution may be atomized for inhalation. In so doing, one important consideration that should be addressed is the delivery of the proper dosage. Hence, it is still another object of the invention to ensure that the proper amount of liquid medicament is transferred to an aerosol generator so that a proper dosage may be delivered to the lungs.




SUMMARY OF THE INVENTION




The invention provides exemplary systems, apparatus and methods for reconstituting a solid phase substance, e.g., a substance that is in a dry state, with liquid to form a solution and for transporting the solution to an aerosol generator for subsequent atomization. In one exemplary embodiment, the system comprises a liquid dispenser, a cartridge containing a substance in a dry state, and an aerosol generator. In use, the cartridge is coupled to an outlet of the dispenser and the dispenser is operated to dispense liquid from the outlet and into the cartridge. The liquid then flows through the substance and exits the cartridge as a solution.




In an exemplary aspect, the cartridge is replaced and disposed after each use. After removal of the cartridge the user may optionally operate the liquid dispenser to deliver liquid to the aerosol generator for a subsequent cleaning cycle. In another exemplary aspect, a liquid outlet of the cartridge is positioned near the aerosol generator such that the solution is dispensed onto the aerosol generator and is readily available for atomization.




The Liquid Dispenser




In an exemplary embodiment, the liquid dispenser comprises a mechanical pump that is attached to a canister. The liquid dispenser is disposed within a housing of the inhaler and is configured to deliver a predetermined volume of liquid each time the mechanical pump is operated. The dispensed liquid then flows directly from the pump to the cartridge to form a solution which in turn is deposited on the aerosol generator.




In one particular aspect, the liquid is a saline solution or sterile water and may optionally contain an anti-microbial additive. As previously mentioned, the solid substance in the cartridge preferably comprises a chemical that is in the dry state which is reconstituted into a solution upon introduction of the liquid from the liquid dispenser.




In one particularly preferable aspect, the mechanical pump comprises a piston pump that is connected to the canister. The piston pump comprises a spring-loaded piston member that is slidable within a cylindrical member which defines a metering chamber. When the piston member is moved to a filling position, the metering chamber is filled with liquid from the canister. When released, the piston member moves to a dispensing position to dispense a known volume of liquid from the metering chamber. In this way, each time the pump is operated, a unit volume of liquid is dispensed from the piston pump.




In one particularly preferable aspect, movement of the piston member toward the filling position creates a vacuum inside the cylindrical member that gradually increases until the piston member reaches a point where a passage is provided between the piston member and the cylindrical member. At this point, the piston member has reached the filling position to allow liquid from the canister to be drawn by the vacuum into the metering chamber of the cylinder. At this point, the piston member is released and returns by the force of the spring back to the dispensing position. During the return travel of the piston member to the dispensing position, the liquid in the metering chamber is displaced through an outlet of the pump.




In another particular aspect, the piston pump is configured to deliver volumes of liquid in the range of about 10 μL to about 50 μL each time the pump is operated. In another aspect, the piston pump is configured such that it will dispense a full unit volume only if the user fully depresses the piston to the filling position. If the piston member is only partially depressed, no liquid will be dispensed. In this manner, partial dosing is prevented.




In still yet another aspect, the liquid dispenser further includes a valve which serves to eliminate the dead volume in the piston pump, thereby inhibiting microbial inflow into the liquid dispenser. The valve preferably comprises a tubular valve seat that is slidably disposed about a distal end of the piston member. In this way, the liquid within the metering chamber moves the tubular valve seat distally over the piston member to allow the liquid in the metering chamber to be dispensed by flowing between the piston member and the tubular valve seat when the piston member is moved toward the dispensing position. The tubular valve seat is also slidable within the cylindrical member, and the cylindrical member defines a stop to stop distal movement of the tubular valve seat relative to the piston member after the unit volume of liquid has been dispensed from the metering chamber. Further, when the spring forces the distal end of the piston member into a distal end of the tubular valve seat, a seal is provided between the piston member and the tubular valve seat to prevent microbial inflow into the piston pump. Hence, use of the tubular valve seat in combination with the piston member and the cylindrical member allows for a unit volume of the liquid within the piston pump to be dispensed and further provides a seal to prevent microbial inflow into the piston pump.




The Drug Cartridge




The cartridge of the invention allows for the storage of a chemical in a dry state. When a liquid is introduced into the cartridge, the chemical substance dissolves within the liquid to form a solution just prior to aerosolization of the solution.




In one exemplary embodiment, the cartridge comprises a housing having an inlet opening and an outlet opening. Disposed in the housing is a chemical substance which is in a dry state. As liquid flows through the housing, the substance dissolves and flows through the outlet opening as a solution. The chemical substance may be any one of a variety of chemical substances, such as proteins, peptides, small molecule chemical entities, genetic materials, and other macromolecules and small molecules used as pharmaceuticals. One particular substance is a lyophilized protein, such as interferon alpha or alpha 1 prolastin. The lyophilized substance is preferably held in a support structure to increase the surface area that is in contact with the liquid, thereby increasing the rate by which the substance is dissolved. The support structure is preferably configured to hold the lyophilized substance in a three-dimensional matrix so that the surface area of the substance that is contact with the liquid is increased. Exemplary types of support structures include open cell porous materials having many tortuous flow paths which enhance mixing so that the solution exiting from the outlet end is homogenized. Alternatively, the support structure may be constructed of a woven synthetic material, a metal screen, a stack of solid glass or plastic beads, and the like.




When used in connection with the aerosolizing apparatus of the invention, actuation of the liquid dispenser introduces liquid into the inlet opening, through the support structure to dissolve the substance, and out the outlet opening where it is disposed on the aerosol generator as a solution. The aerosol generator is then operated to aerosolize the solution. In this way, the substance is stored in a solid state until ready for use. As previously described, the flow of liquid from the liquid dispenser is produced during the return stroke of the piston member, i.e. as the piston member travels to the dispensing position. Since the return stroke is controlled by the spring, it is not dependent on the user. In this way, the flow rate is the same each time the liquid dispenser is operated, thereby providing a way to consistently and repeatedly reconstitute the solution.




In one particular aspect, the cartridge includes a coupling mechanism at the inlet opening to couple the cartridge to the liquid dispenser. In this way, the cartridge is configured to be removable from the liquid dispenser so that it may be removed following each use and discarded. In still another aspect, the cartridge is filled with the chemical substance while in a liquid state. The substance is then freeze dried and converted to a solid state while in the cartridge.




The Aerosol Generator




In an exemplary embodiment, the aerosol generator that is employed to aerosolize the solution from the cartridge is constructed in a manner similar to that described in U.S. Pat. Nos. 5,586,550 and 5,758,637, previously incorporated herein by reference. In brief, the aerosol generator comprises a vibratable member having a front surface, a rear surface, and a plurality of apertures which extend between the two surfaces. The apertures are preferably tapered as described in U.S. Pat. No. 5,164,740, previously incorporated herein by reference. In one particular aspect, the vibratable member is preferably hemispherical in shape, with the tapered apertures extending from the concave surface to the convex surface. In use, the solution from the cartridge is supplied to the rear surface of the vibratable member having the large opening. As the vibratable member is vibrated, the apertures emit the solution from the small openings on the front surface as an aerosolized spray. The user then simply inhales the aerosolized spray to supply the chemical to the patient's lungs.




Alternative Embodiments




The invention further provides exemplary methods and apparatus for aerosolizing a solution. In one exemplary embodiment, an apparatus comprises a cartridge having a first chamber, a second chamber, and a moveable divider between the first and the second chambers. An exit opening is included in the cartridge and is in communication with the second chamber. A liquid is disposed in the first chamber, and a substance that is in a dry state is in the second chamber. The apparatus further includes a piston that is translatable within the cartridge to transfer the liquid from the first chamber and into the second chamber to form a solution. An aerosol generator is further provided and is disposed near the exit opening to receive the solution from the cartridge and produce an aerosolized solution. In this way, the substance may be maintained in a dry state as with other embodiments until ready for aerosolization. To form the solution, the piston is moved within the cartridge to force the liquid from the first chamber and into the second chamber. Further translation of the piston forces the recently formed solution from the second chamber and onto the aerosol generator where the solution is aerosolized.




In one particular aspect, the divider has a home position where a seal is formed between the divider and the cartridge. In this way, the liquid may be held in the first chamber until the piston is translated. Preferably, the cartridge includes at least one groove that is disposed at least part way between the first and second chambers. In this way, as the piston is moved within the first chamber, the liquid (which is generally incompressible) moves the divider toward the second chamber to allow the liquid to pass around the divider and into the second chamber. The groove preferably terminates at the second chamber so that when the piston moves the divider into the second chamber, a seal is formed between the cartridge and the divider to force the solution from the second chamber and out the exit opening.




In some cases, it may be desirable to draw the solution back into the first chamber to facilitate mixing. This can be accomplished by withdrawing the piston back through the first chamber to create a vacuum in the first chamber. To dispense the solution, the piston is translated back through the first and second chambers as previously described.




In one particular aspect, a filter is disposed across the exit opening to prevent larger particles from exiting the chamber and clogging the aerosol generator. In another aspect, the apparatus includes a motor to translate the piston. In this way, an aerosolized solution may be supplied to the patient simply by actuating the motor.











BRIEF DESCRIPTION OF THE DRAWINGS





FIG. 1

illustrates a partial cutaway view of an exemplary apparatus having an aerosol generator for aerosolizing liquids according to the invention.





FIG. 2

is a schematic diagram of an inhalation flow sensor for detecting when a patient begins to inhale from an aerosolizing apparatus according to the invention.





FIG. 3

is a cross-sectional side view of an aerosol generator of the aerosolizing apparatus of FIG.


1


.





FIGS. 4-9

illustrate cross-sectional side views of a container and a piston pump used in the apparatus of

FIG. 1

to deliver a predetermined volume of liquid to the aerosol generator. The views illustrated in

FIGS. 4-9

show various states of the piston pump when metering and transferring liquids from the container to the aerosol generator.





FIG. 10

is a schematic view of an aerosolizing system having a removable cartridge holding a substance that is in a solid state according to the invention.





FIG. 11

illustrates the aerosolizing system of

FIG. 10

having the cartridge removed for cleaning of the aerosol generator according to the invention.





FIG. 12

is a cross sectional side view of an alternative apparatus for aerosolizing a solution according to the invention.





FIG. 13

illustrates a dual chamber drug cartridge and an aerosol generator of the apparatus of FIG.


12


.





FIGS. 14-17

illustrate the drug cartridge of

FIG. 13

in various states of operation to dispense a solution onto the aerosol generator according to the invention.





FIG. 18

illustrates the apparatus of

FIG. 1

with an alternative cartridge to deliver liquids to the aerosol generator according to the invention.





FIG. 19

illustrates the cartridge and aerosol generator of FIG.


18


.





FIG. 20

is a cross-sectional view of the cartridge of FIG.


19


.





FIG. 21

is a more detailed view of the cartridge of FIG.


19


.





FIG. 22

is a cross-sectional side view of a dispensing system having a drug cartridge and a piston pump according to the invention.











DESCRIPTION OF THE SPECIFIC EMBODIMENTS




The invention provides exemplary systems, apparatus and methods for reconstituting a solid substance that is in a dry state with liquid, such as water, to form a solution and for transporting the solution to an aerosol generator for subsequent atomization. In one exemplary embodiment, the system comprises a liquid dispenser, a cartridge containing the substance that is in the dry state, and an aerosol generator. In use, the cartridge is coupled to an outlet of the dispenser. The user then actuates the liquid dispenser so that liquid is dispensed from the dispenser and enters into the cartridge. As the liquid flows through the cartridge, the dry substance is dissolved into the liquid and exits the cartridge as a solution. Preferably, the cartridge is replaced and disposed after each use. In a preferred embodiment, an outlet end of the cartridge is positioned near the aerosol generator so that the solution disposed on the aerosol generator is readily available for atomization.




In one alternative, a two step process is employed to reconstitute the solution and deliver the solution to the aerosol generator. First, a portion of a unit volume of liquid, such as one-half a unit volume, is supplied to the cartridge when the liquid dispenser is operated. The user then waits a predetermined amount of time, such as about 10 seconds, and again operates the liquid dispenser to deliver sufficient liquid into the cartridge to force a unit volume of solution from the cartridge an onto the aerosol generator. In this way, a period of time is provided to allow more of the substance to dissolve in the liquid.




In another aspect of the invention, exemplary systems and methods are provided for metering relatively small volumes of liquid directly from a container and for delivering the metered volume to an atomizer. The systems and methods are configured to precisely meter and deliver relatively small volumes of liquid, typically in the range from about 10 μL to about 100 μL. When delivering volumes in the range from about 10 μL to 50 μL, the invention preferably employs the use of a piston pump that is connected to a canister as described in greater detail hereinafter. For volumes in the range from about 50 μL to about 100 μL, a pharmaceutical pump is preferably employed, such as metered dose S4 pump, commercially available from Somova S. p.A. Milano, Italy. Optionally, such pharmaceutical pumps may also contain a pharmaceutical medicament which may be delivered directly to the aerosol generator. As one example, the pharmaceutical medicament may comprise a suspension of colica steroid for treatment of asthma.




Another feature of the liquid dispensers of the invention is that they are configured to prevent or substantially reduce the possibility of contamination. In this way, each subsequent dosage delivered by the liquid dispenser is not contaminated when delivered to the atomizer. Referring now to

FIG. 1

, an exemplary apparatus


10


for atomizing a liquid will be described. Apparatus


10


comprises a housing


12


which is configured to hold the various components of apparatus


10


. Housing


12


is preferably constructed to be lightweight and pocket-sized, typically being molded of a plastic material. Housing


12


is divided into two separable portions. A first portion


14


includes an electronics compartment and a second portion


16


includes a liquid holding compartment for holding a canister


18


, an aerosol generator


22


, and a mouthpiece


20


through which the atomized liquids are dispensed to the patient. Conveniently, second portion can be separated from first portion


14


by sliding a knob


23


. Optionally, second portion


16


having the liquid holding component may be disposed following separation from first portion


14


. Second portion


16


may be disposed along with canister


18


, or canister


18


may be disposed separately.




Apparatus


10


further includes an inhalation flow sensor


24


which detects the inhalation flow produced by the patient when inhaling from mouthpiece


22


. Upon detection of the inhalation, sensor


24


sends an electrical signal to an electronic circuit (not shown) which in turn sends an alternating voltage to vibrate a piezoelectric member


26


of aerosol generator


22


to aerosolize a liquid. Sensor


24


preferably comprises a flexure foil and an electro-optical sensor. The flexible foil deflects in response to the inhalation airflow produced when a patient inhales from mouthpiece


20


. The optical sensor is configured to detect deflection of the flexible foil so that a signal may be produced to vibrate piezoelectric member


26


.




Referring now to

FIG. 2

, a schematic diagram of an inhalation flow sensor


24


will be described. Flow sensor


24


comprises a flexible foil


28


having an extension


30


. Inhalation flow sensor


24


further includes an optical sensor


32


which includes a light emitting diode (LED)


34


and a light sensitive transistor


36


placed in apposition to LED


34


so that LED


34


continuously transmits a light beam


38


to transistor


36


. When the patient inhales, the inhalation airflow causes flexible foil


28


to deflect and move extension


30


downward until it crosses light beam


38


and causes an optical interruption that is detected by transistor


36


. Transistor


36


then sends a signal to trigger activation of an aerosol generator to produce an aerosol.




By configuring inhalation flow sensor


24


in this manner, aerosol generator


22


is actuated only in response to the detection of an inhalation airflow produced by a patient. In this way, the patient may be administered a single dose using either a single inhalation or multiple inhalations. Preferably, inhalation flow sensor


24


is triggered at an inhalation flow rate of at least 15 liters per minute. However, it will be appreciated that sensor


24


may be constructed to trigger at either lower or higher flow rates. Adjustment of the actuation point may be accomplished by altering the flexible stiffness of foil


28


, by selecting different materials for constructing foil


28


or by changing the thickness of foil


28


.




Alternatively, the inhalation flow sensor may be constructed from a piezoelectric film component. The piezoelectric film component produces an electrical signal when it deflects. The magnitude of the electrical signal is proportional to the magnitude of deflection. In this way, the electrical signal that is produced by the piezoelectric film component can be used to detect the magnitude of the inhalation flow. In this manner, the output of the aerosol generator may be adjusted in proportion to the inhalation airflow. Such a proportional output from the aerosol generator is particularly advantageous in that it prevents the coalescence of particles and controls the aerosol production according to the inhalation flow. Control of the aerosol output may be adjusted by turning the aerosol generator on and off sequentially. The ratio between the on time and the off time, generally defined as the duty cycle, affects the net flow. An exemplary piezoelectric film component with such characteristics is commercially available from ATO Autochem Sensors, Inc., Valley Forge, Pa.




Referring back to

FIG. 1

, the electronic circuit (not shown) within first portion


14


includes electrical components to detect the presence of liquid on aerosol generator


22


and to send a signal to the user indicating that all of the liquid has been aerosolized. In this way, the user will know if additional inhalations will be required in order to receive the prescribed amount of medicament. The sensing circuit preferably comprises a voltage sensing circuit (not shown) which detects the voltage across piezoelectric element member


26


. Since the voltage across piezoelectric member


26


is proportionally related to the amount of liquid in surface tension contact with an aperture plate


40


(see

FIG. 3

) of aerosol generator


22


, it can be determined, based on the voltage, whether any liquid is left remaining. For example, when aerosolization is initiated, the voltage is high. At the end of aerosolization, the voltage is low, thereby indicating that the aerosolization process is near completion. Preferably, the sensing circuit is configured to be triggered when about 95% of the liquid has been aerosolized. When triggered, the sensing circuit turns on a light emitting diode (LED)


42


indicating that the prescribed dosage has been delivered.




Referring now to

FIG. 3

, construction of aerosol generator


22


will be described in greater detail. As previously described, aerosol generator


22


includes a vibratable aperture plate


40


and annular piezoelectric member


26


. Aerosol generator


22


further comprises a cup-shaped member


44


to which piezoelectric member


26


and aperture plate


40


are attached as shown. Cup-shaped member


44


includes a circular hole


46


over which aperture plate


40


is disposed. Wires (not shown) connect piezoelectric member


26


to the electrical circuitry within portion


14


(see

FIG. 1

) which in turn is employed to vibrate piezoelectric member


26


.




Cup-shaped member


44


is preferably constructed of a low damping metal, such as aluminum. Aperture plate


40


is disposed over hole


46


such that a rear surface


48


of aperture plate


40


is disposed to receive liquid from canister


18


(see FIG.


1


). Although not shown, aperture plate


40


includes a plurality of tapered apertures which taper from rear surface


48


to a front surface


50


. Exemplary aperture plates which may be used with the invention include those described the '740 patent, the '550 patent, and the '637 patent, previously incorporated by reference.




Aperture plate


40


is preferably constructed of a material that may be produced by a metal electroforming process. As an example, aperture plate


40


may be electroformed from palladium or a palladium alloy, such as palladium cobalt or palladium nickel. Aperture plate


40


may further be gold electroplated to enhance its corrosion resistance or may be constructed of solid gold or gold alloys. Alternatively, aperture plate


40


may be constructed of nickel, a nickel-gold alloy, or a combination of nickel and nickel-gold alloy arranged such that the nickel-gold alloy covers the external surfaces of the aperture plate. The nickel-gold alloy may be formed using a gold electroplating process followed by diffusion at an elevated temperature as described generally in Van Den Belt, TGM, “The diffusion of platinum and gold in nickel measured by Rutherford Fact Scattering Spectrometry”, Thin Solid Film, 109 (1983), pp. 1-10. The complete disclosure of this reference is incorporated herein by reference. One particular material that may be used to construct the aperture plate comprises about 80% palladium and about 20% nickel, as well as other palladium-nickel alloys as described generally in J. A. Abys, et al., “Annealing Behavior of Palladium-Nickel Alloy Electro Deposits”,


Plating and Surface Finishing


, August 1996, the complete disclosure of which is herein incorporated by reference. A small amount of manganese may also be introduced to the nickel during the electroforming process so that the nickel can be heat treated at an elevated temperature as described generally in U.S. Pat. No. 4,108,740, incorporated herein by reference. The gold-nickel alloy is particularly useful in protecting the nickel components, and particularly the electroformed nickel components, from corrosion caused by plating porosity. The diffusion process may be useful for other applications which require corrosion protection for nickel components, and particularly nickel electroformed components, such as, for example, inkjet aperture plates, other spray nozzle plates, and the like.




As another alternative, corrosion resistance of the aperture plate may be enhanced by constructing the aperture plate of a composite electroformed structure having two layers, with the first electroformed layer comprising nickel and the second electroformed layer comprising gold. The thickness of the gold in the composite in preferably at least two microns, and more preferably, at least five microns. Alternatively, the second layer may be electroformed from palladium or another corrosive-resistant metal. The external surfaces of the aperture plate may also be coated with a material that prevents bacteria growth, such as polymyxin or silver. Optionally, other coatings that enhance wetability may be applied to the aperture plate.




In one embodiment, the aperture plate is protected from corrosive liquids by coating the aperture plate with agents that form a covalent bond with the solid surface via a chemical linking moiety. Such agents are preferred because the are typically biocompatable with acidic pharmaceutical liquids. The agent may be photoreactive, i.e. activated when subjected to light or may be activated when subjected to moisture or to any other means of energy. Further, the agent may have various surface properties, e.g. hydrophobic, hydrophilic, electrically conductive or non-conductive. Still further, more than one agent may be formed on top of each other. Types of coatings that may be included on the aperture plate are described in U.S. Pat. Nos. 4,979,959; 4,722,906; 4,826,759; 4,973,493; 5,002,582; 5,073,484; 5,217,492; 5,258,041; 5,263,992; 5,414,075; 5,512,329; 5,714,360; 5,512,474; 5,563,056; 5,637,460; 5,654,460; 5,654,162; 5,707,818; 5,714,551; and 5,744,515. The complete disclosures of all these patents are herein incorporated by reference.




Cup-shaped member


44


is disposed within a housing


52


which prevents liquids from coming into contact with piezoelectric member


26


and with cup-shaped member


44


. Cup-shaped member


44


is suspended within housing


52


by two elastic rings


54


and


56


. Ring


54


is positioned between housing


52


and the circumference of cup-shaped member


44


. Ring


56


is positioned between the inner diameter of piezoelectric member


26


and a shield member


58


. Such an arrangement provides a hermetic seal that prevents the contact of liquids with the piezoelectric member


26


without suppressing the vibratory motion of cup-shaped member


44


.




Referring back now to

FIG. 1

, aerosol generator


22


is axially aligned with mouthpiece


20


so that when piezoelectric member


26


is vibrated, liquid droplets are ejected through mouthpiece


20


and are available for inhalation by the patient. As previously described, disposed within second portion


16


is a canister


18


which holds the liquid medicament to be atomized by aerosol generator


22


. Canister


18


is integrally attached to a mechanical pump


60


which is configured to dispense a unit volume of liquid through a nozzle


62


to aerosol generator


22


. Pump


60


is actuated by pressing a knob


64


which pushes canister


18


downward to generate the pumping action as described in greater detail hereinafter. Pressing on knob


64


also puts pressure on an electrical microswitch


66


within second portion


16


. When actuated, microswitch


66


sends a signal to the electrical circuit within first portion


14


causing a light emitting diode (LED) (not shown) to blink indicating that apparatus


10


is ready for use. When the patient begins to inhale, the inhalation is sensed causing actuation of the aerosol generator.




As illustrated in

FIG. 3

, pump


60


delivers a unit volume of liquid


68


(shown in phantom line) to rear surface


48


of aperture plate


40


. The delivered volume


68


adheres to aperture plate


40


by solid/liquid surface interaction and by surface tension forces until patient inhalation is sensed. At that point, piezoelectric member


26


is actuated to eject liquid droplets from front surface


50


where they are inhaled by the patient. By providing the delivered volume


60


in a unit volume amount, a precise dose of liquid medicament may be atomized and delivered to the lungs of the patient. Although canister


18


of

FIG. 1

is shown as being configured to directly deliver the dispensed liquid to the aperture plate, pump


60


may alternatively be configured to receive a cartridge containing a chemical in a dry state as described in greater detail hereinafter.




Referring now to

FIGS. 4-10

, a schematic representation of a canister


138


and a piston pump


140


will be described to illustrate an exemplary method for dispensing a unit volume of a liquid medicament to an aperture plate, such as aperture plate


40


of apparatus


10


(see FIGS.


1


and


3


). Canister


138


comprises a housing


142


having an open end


144


about which a cap


146


is placed. Disposed against open end


144


is a washer


148


which provides a seal to prevent liquids from escaping from housing


142


. On top of washer


148


is a cylindrical member


150


. Cap


146


securely holds cylindrical member


150


and washer


148


to housing


142


. Cylindrical member


150


includes a cylindrical opening


151


which allows liquids to enter from canister


138


. Cylindrical member


150


in combination with washer


148


also serve to securely position a holding member


152


about which a compression spring


154


is disposed.




Piston pump


140


comprises a piston member


156


, cylindrical member


150


, a valve seat


158


and compression spring


154


. Piston member


156


has a frontal end


156


A and a distal end


156


B, with frontal end


156


A providing the piston action and distal end


156


B providing the valve action.




Piston pump


140


is configured such that every time valve seat


158


is depressed toward canister


138


and then released, a unit volume of liquid is dispensed through a tapered opening


161


in valve seat


158


. Valve seat


158


includes a valve seat shoulder


158


A which is pressed to move valve seat inwardly, causing valve seat


158


to engage with distal end


156


B to close tapered opening


161


.




As shown in

FIG. 5

, as piston member


156


is further depressed into cylindrical member


150


, spring


154


is compressed and a metering chamber


168


begins to form between frontal end


156


A and cylindrical member


150


. Frontal end


156


A and distal end


156


B are preferably constructed from a soft elastic material which provides a hermetic seal with cylindrical member


150


and valve seat


158


, respectively. Due to the seal between frontal end


156


A and cylindrical member


150


, a vacuum is created within metering chamber


168


upon depression of piston member


156


.




As piston member


156


is further moved into cylindrical member


150


(see FIG.


6


), spring


154


is further compressed and frontal end


156


A moves past cylindrical opening


151


so that a gap is provided between frontal end


156


A and cylindrical member


150


. As frontal end


156


A passes the edge of cylindrical member


150


, liquid from canister


138


is drawn into cylindrical member


150


by the vacuum that was created within metering chamber


168


. In

FIG. 6

, piston member


156


is in the filling position.




At the end of inward travel, the user releases the pressure on valve seat


158


, allowing spring


154


to push piston member


156


back toward its starting position. As illustrated in

FIG. 7

, upon the return travel of piston member


156


to the starting position, frontal end


156


A again engages cylindrical member


150


and forms a seal between the two surfaces to prevent any liquid within metering chamber


168


from flowing back into canister


138


.




Since the liquid within metering chamber


168


is generally incompressible, as spring


154


pushes on piston member


156


, the liquid within metering chamber


168


forces valve seat


158


to slide distally over piston member


156


. In so doing, the liquid within metering chamber


168


is allowed to escape from the metering chamber through tapered opening


161


of valve seat


158


as illustrated in FIG.


8


.




As illustrated in

FIGS. 7-9

, liquid from metering chamber


168


is dispensed from tapered opening


161


as frontal end


156


A travels length L. As frontal end


156


A passes through length L, it is in contact with cylindrical member


150


. In this way, the liquid within metering chamber


168


is forced out of tapered opening


161


during this length of travel. After passing through Length L, frontal end


156


A passes out of sealing relationship with cylindrical member


150


so that no further liquid is dispensed from tapered opening


161


. Hence, the amount of liquid dispensed is proportional to the diameter of cylindrical member


150


over length L. As such, piston pump


140


may be designed to dispense a known volume of liquid each time piston member


156


travels from the starting position to the filling position and then back to the starting position. Since piston member


156


must be fully depressed to the filling position in order to create a gap between frontal end


156


A and cylindrical member


150


, a way is provided to ensure that partial volumes can not be dispensed.




As shown in

FIG. 9

, valve seat


158


includes a shoulder


170


which engages a stop


172


on cylindrical member


150


to stop distal movement of valve seat


158


relative to cylindrical member


150


. At this point, piston pump


140


is at an ending dispensing position which corresponds to the starting position as initially illustrated in FIG.


4


. In this position, spring


154


forces distal end


156


B of piston member


156


into tapered opening


161


to provide a seal and prevent contaminants from entering into piston


140


.




Valve seat


158


is preferably coated with a material that inhibits proliferation of bacteria. Such coatings can include, for example, coatings having a positive electric charge, such as polymyxin, polyethylinimin, silver, or the like.




The invention further provides a convenient way to store chemical substances in the solid or dry state and then to dissolve the chemical substance with liquid from the canister to form a solution. In this way, chemical substances that are otherwise susceptible to degradation can be stored in the dry state so that the shelf life of the product is extended. An exemplary embodiment of a cartridge


180


for storing such chemical substances that are in the dry state is illustrated in FIG.


10


. For convenience of illustration, cartridge


180


will be described in connection with piston pump


140


and canister


138


, which in turn may be coupled to an aerosolization apparatus, such as apparatus


10


, to aerosolize a medicament as previously described. Cartridge


180


comprises a cylindrical container


182


having an inlet opening


184


and outlet opening


186


. Inlet opening


182


is sized to be coupled to piston pump


140


as shown. Disposed within container


182


is a first filter


188


and a second filter


190


. Filter


188


is disposed near inlet opening


184


and second filter


190


is disposed near outlet opening


186


. A chemical substance


192


which is in a dry state is disposed between filters


188


and


190


. Chemical substance


192


is preferably held within a support structure to increase the rate in which the chemical substance is dissolved.




The support structure may be constructed of a variety of materials which are provided to increase the rate in which the chemical substance is dissolved. For example, the support structure may comprise an open cell material such as a polytetrafluoroethylene (PTFE) matrix material commercially available from Porex Technologies, Farburn, Ga. Preferably, such an open cell material has a pore size in the range from about 7 μm to about 500 μm, and more preferably about 250 μm. Alternatively, various other plastic materials may be used to construct the open cell matrix, including olyethylene (HDPE), ultra-high molecular weight polyethylene (UHMW), polypropylene (PP), polyvinylidene fluoride (PVDF), nylon 6 (N6), polyethersulfone (PES), ethyl vinyl acetate (EVA), and the like. Alternatively, the support structure may be constructed of a woven synthetic material, a metal screen, a stack of solid glass or plastic beads, and the like.




An exemplary method for placing chemical substance


192


into container


182


is by filling container


182


with the chemical substance while the chemical substance is in a liquid state and then lyophilizing the substance to a dry state while the substance is within the cartridge. In this way, filling of cartridge


180


with a chemical substance may be precisely and repeatedly controlled. However, it will be appreciated that the chemical substance may be placed into cartridge


180


when in the solid state.




Lyophilization is one exemplary process because it will tend to reduce the rate of various physical and chemical degradation pathways. If the substance comprises a protein or peptide, both the lyophilization cycle (and resulting moisture content) and product formulation can be optimized during product development to stabilize the protein before freezing, drying and for long term storage. See Freeze Drying of Proteins, M. J. Pikal, BioPharm. 3, 18-26 (1990); Moisture Induced Aggregation of Lyophilized Proteins in the Solid State, W. R. Liu, R. Langer, A. M. Klibanov, Biotech. Bioeng. 37, 177-184 (1991); Freeze Drying of Proteins. II, M. J. Pikal, BioPharm. 3, 26-30 (1990); Dehydration Induced Conformational Transitions in Proteins and Their Inhibition by Stabilizers, S. J. Prestrelski, N. Tedeschi, S. Arakawa, and J. F. Carpenter, Biophys. J. 65, 661-671 (1993); and Separation of Freezing and Drying Induced Denaturation of Lyophilized Proteins Using Stress-Specific Stabilization, J. F. Carpenter, S. J. Prestrelski, and T. Arakawa, Arch. Biochem. Biphys. 303, 456-464 (1993), the complete disclosures of which are herein incorporated by reference. Adjustment of the formulation pH and/or addition of a wide variety of additives including sugars, polysaccharides, polyoles, amino-acids, methylamines, certain salts, as well as other additives, have been shown to stabilize protein towards lyophilization.




As an example, which is not meant to be limiting, a cartridge was packed with small glass beads having a diameter of approximately 0.5 mm. The cartridge was filed with a solution of lysozyme at a concentration of 10 mg/ml. To enhance its stability, the solution was combined with a form of sugar and with a buffer solution. The buffer solution was sodium citrate, and the sugar was mannitol. A twin


20


surfactant was also added to the solution. The solution was then lyophilized in the cartridge.




The lyophilized substance may optionally contain a solubility enhancer, such as a surfactant as described in Journal of Pharmaceutical Science Technology which is J. Pharmsei. Technology, 48; 30-37 (1994) the disclosure of which is herein incorporated by reference. To assist in protecting the chemical substance from destructive reactions while in the dry state, various sugars may be added as described in Crowe, et al., “Stabilization of Dry Phospholipid Bilayer and Proteins by Sugars”, Bichem. J. 242: 1-10 (1987), and Carpenter, et al. “Stabilization of Phosphofructokinase with Sugars Drying Freeze-Drying”, Biochemica. et Biophysica Acta 923: 109-115 (1987), the disclosures of which are herein incorporated by reference.




In use, cartridge


180


is coupled to piston pump


140


and piston pump


140


is operated as previously described to dispense a known volume of liquid into cartridge


180


. The supplied liquid flows through chemical substance


192


and chemical substance


192


dissolves into the liquid and flows out of outlet opening


186


as a liquid solution


194


. Outlet opening


186


is spaced apart from an aperture plate


196


of an aerosol generator


198


so that liquid solution


198


will be deposited on aperture plate


196


as shown. Aerosol generator


198


further includes a cup shaped number


200


and a piezoelectric member


202


and operates in a manner similar to the aerosol generator


22


as previously described. Hence, when aerosol generator


198


is operated, liquid solution


194


is ejected from aperture plate


196


in droplet form as shown.




One important feature of the invention is that cartridge


180


is removable from piston pump


140


so that cartridge


180


may be discarded following each use. As illustrated in

FIG. 11

, after cartridge


180


has been removed, the user may optionally actuate piston pump


140


to again deliver a volume of liquid


204


directly to aperture plate


96


. Aerosol generator


198


is then operated so that, similar to an ultrasonic cleaner, the vibratory action removes any residual solution from aperture plate


196


. Liquids that may be held within canister


138


to form the solution and to clean aperture plate


196


include sterile water, a mixture of water with ethanol or other disinfectant, and the like.




In summary, the invention provides a portable aerosolizing apparatus that is able to store a chemical substance in the dry state, and to reconstitute the chemical substance with liquid to form a solution just prior to administration. The invention further provides techniques for aerosolizing the solution and for cleaning the aerosol generator. Also, it will be appreciated that the aerosolization apparatus as described herein may be used to aerosolize a liquid medicament that is not stored within a cartridge so that the liquid medicament is passed directly from the piston pump and on to the aperture plate for aerosolization.




Apparatus


10


may optionally be configured to warn the user when cleaning is needed. Such a feature is best accomplished by providing a processor within second portion


14


which is programmed to include an expected amount of time required to aerosolize a dose received from canister


18


. If the expected amount of time exceeded before the entire dose is aerosolized, it may be assumed that the apertures in the aperture plate are clogged, thereby requiring cleaning to clear the apertures. In such an event, the processor sends a signal to an LED on apparatus


10


indicating that cleaning is needed.




To determine whether all of the liquid has been aerosolized in the expected time period, the processor records the amount of time that the aerosol generator is actuated. When the aerosol generator has been actuated for the expected time, the voltage sensing circuit is actuated to detect whether any liquid remains on the aperture plate as previously described.




Referring now to

FIG. 12

, an alternative embodiment of an apparatus


300


for atomizing a liquid solution will be described. Apparatus


300


includes a housing


302


that is divided into two separable portions similar to the embodiment of

FIG. 1. A

first portion


304


includes various electronics and a second portion


306


includes a liquid holding compartment. An aerosol generator


308


which is similar to aerosol generator


22


of

FIG. 1

is disposed in second portion


306


to aerosolize a solution where it will be available for inhalation through a mouthpiece


310


. Conveniently, aerosol generator


308


includes a lip


312


to catch the solution and maintain it in contact with the aerosol generator


308


until aerosolized. Disposed above aerosol generator


308


is a drug cartridge


314


. As will be described in greater detail hereinafter, cartridge


314


is employed to produce a solution which is delivered to aerosol generator


308


for aerosolization.




Coupled to cartridge


314


is a lead screw


316


. In turn, lead screw


316


is coupled to a micro-coreless DC motor


318


. When motor


318


is actuated, it causes a shaft


320


to rotate. This rotational motion is converted to linear motion by lead screw


316


to translate a piston


322


within cartridge


314


as described in greater detail hereinafter. Motor


318


is actuated by appropriate electronics held in first portion


304


. Further, a power source, such as a battery, is also held within first portion


304


to supply power to motor


318


. Aerosol generator


38


is operated in a manner essentially identical to that previously described in connection with the apparatus of FIG.


1


.




Referring now to

FIG. 13

, construction of cartridge


314


will be described in greater detail. Piston


322


includes a docking knob


324


which mates with a connector


326


of lead screw


316


. Docking knob


324


and connector


326


are configured to facilitate easy coupling and uncoupling. Typically, motor


318


and lead screw


316


are securely coupled to housing


308


(see FIG.


12


), while cartridge


314


is configured to be removable from housing


302


. In this way, each time a new drug cartridge is required, it may be easily inserted into apparatus


300


and coupled with lead screw


316


.




Lead screw


316


is configured such that when motor


318


causes shaft


320


to rotate in a clockwise direction, lead screw


316


is moved downward. Alternatively, when motor


318


is reversed, lead screw


316


is moved upward. In this way, piston


322


may be translated back and forth within cartridge


314


. Motor


318


is preferably calibrated such that piston


322


can be moved to selected positions within cartridge


314


as described in greater detail hereinafter.




Cartridge


314


includes a first chamber


328


and a second chamber


330


. Although not shown for convenience of illustration, first chamber


328


is filled with a liquid and second chamber


330


includes a substance that is in a dry state. Such a substance preferably comprises a lyophilized drug, although other substances may be employed similar to the embodiment of FIG.


1


. Separating first chamber


328


and second chamber


330


is a divider


332


. As shown in

FIG. 13

, divider


332


is in a home position which forms a seal between divider


332


and cartridge


314


so that the liquid is maintained within first chamber


328


until divider


332


is moved from its home position as described hereinafter.




Cartridge


314


includes an exit opening


333


which is disposed in close proximity to aerosol generator


308


. Once the solution is formed within cartridge


314


, it is dispensed through exit opening


333


and on to aerosol generator


308


where it will be aerosolized for delivery to the patient. Disposed across exit opening


333


is a filter


334


which serves to prevent larger drug particles from being flushed out onto aerosol generator


308


, thus causing potential clogging of the apertures within aerosol generator


308


.




Referring now to

FIGS. 14-17

, operation of cartridge


314


to produce a solution which is delivered to aerosol generator


308


will be described. Cartridge


314


is constructed in a manner similar to the drug cartridge described in U.S. Pat. No. 4,226,236, the complete disclosure of which is herein incorporated by reference. As shown in

FIG. 14

, cartridge


314


is in the home position where divider


332


maintains the liquid within first chamber


328


. When in the home position, cartridge


314


may be inserted into apparatus


300


and coupled to lead screw


316


(see FIG.


13


). When ready to deliver an aerosolized solution to a patient, motor


318


(see

FIG. 13

) is actuated to cause lead screw


316


to translate piston


322


within cartridge


314


as illustrated in FIG.


15


. As piston


322


is translated within cartridge


314


, it begins to move through first chamber


328


. Since the liquid is generally incompressible, the liquid will force divider


332


to move in the direction of second chamber


330


. Formed in the walls of cartridge


314


are one or more grooves


336


which are placed in communication with first chamber


328


as divider


332


moves away from its home position. As such, the liquid within first chamber


328


is forced into chamber


330


as illustrated by the arrows. Once the liquid is able to flow around divider


332


, the pressure acting against it is relieved so that it remains in the position generally shown in FIG.


15


. As the liquid enters into second chamber


330


, the lyophilized drug is dissolved into the liquid to form a solution.




As illustrated in

FIG. 16

, piston


322


is translated until it engages divider


332


. At this point, all of the liquid has been transferred from first chamber


328


into second chamber


330


. At this point, it may optionally be desired to mix the solution that has just been formed within second chamber


330


. This may be accomplished by translating piston


322


backward toward the position illustrated in FIG.


15


. In so doing, a vacuum is created within first chamber


328


to draw the solution from second chamber


330


into first chamber


328


. As the solution flows through grooves


336


, the solution is agitated, causing mixing. Piston


322


may then be translated back to the position shown in

FIG. 16

to move the liquid back into second chamber


330


. This process may be repeated as many times as needed until sufficient mixing has occurred.




After proper mixing, the solution is ready to be dispensed onto the aerosol generator. To do so, piston


332


is moved through second chamber


330


as illustrated in FIG.


17


. In turn, divider


332


is pushed against filter


334


to completely close second chamber


330


and force all of the liquid out exit opening


333


.




One particular advantage of cartridge


314


is that a precise volume of drug is dispensed onto aerosol generator


308


to ensure that the patient will receive the proper dosage. Further, by maintaining the drug in the dry state, the shelf life may be increased as previously described.




Following dispensing of the solution, cartridge


314


may be removed and replaced with another replacement drug cartridge. Optionally, a cleaning cartridge may be inserted into apparatus


300


which includes a cleaning solution. This cleaning solution is dispensed onto aerosol generator


308


upon operation of motor


318


. Aerosol generator


308


may then be operated to clean its apertures using the cleaning solution.




Referring now to

FIG. 18

, an alternative apparatus


400


for atomizing a liquid will be described. Apparatus


400


is essentially identical to apparatus


10


except that canister


18


has been replaced with a continuous feed cartridge


402


. Cartridge


402


is configured to continuously feed liquid to aerosol generator


22


on demand so that enough liquid will always be available each time aerosol generator


22


is actuated. Cartridge


402


also ensures that excessive liquid will not be supplied, i.e. it will supply only as much liquid as is atomized. Cartridge


402


is constructed similar to the cartridges described in co-pending U.S. patent application Ser. No. 08/471,311, filed Apr. 15, 1995, the complete disclosure of which is herein incorporated by reference.




As illustrated in

FIGS. 19-21

, cartridge


402


comprises a liquid reservoir


404


and a face


406


which is adjacent the aperture plate of aerosol generator


22


to supply liquid from liquid reservoir


404


to the aperture plate. A capillary pathway


408


extends between reservoir


404


and face


406


to supply liquid to face


406


by capillary action. In order to overcome the vacuum that is produced in reservoir


404


, a venting channel


410


is in communication with pathway


408


. In this way, air is able to enter into reservoir


404


to reduce the vacuum and allow additional liquid to be transferred from reservoir


404


.




In another embodiment, a drug cartridge may be coupled to a piston pump to form a dispensing system that is used to supply a formulation to an aerosol generator. For example, as shown in

FIG. 22

a dispensing system


430


comprises a cartridge


432


and a piston pump


434


. Cartridge


432


is patterned after cartridge


314


of FIG.


14


and includes a first chamber


436


and a second chamber


438


. Disposed in chamber


436


is a liquid (not shown) and disposed in second chamber


438


is a dried substance


440


. A divider


442


separates the chambers. In use, a plunger


444


is moved through chamber


436


to force divider


442


forward and to allow the liquid to enter chamber


438


and form a solution.




Piston pump


434


may be constructed similar to pump


138


of FIG.


4


. Pump


434


is operated to dispense a volume of the solution from chamber


438


. Pump


434


may be disposed near an aerosol generator so that a volume of the solution will be available for atomization. In this way, known volumes of a solution that was formed from a direct substance may be provided in an easy and convenient manner.




The invention has now been described in detail, however, it will appreciated that certain changes and modifications may be made. For example, although illustrated in the context of delivering liquid to an aperture plate, the apparatus and methods may be employed to deliver known quantities of liquid to other types of atomization devices. Therefore, the scope and content of this invention are not limited by the foregoing description. Rather the scope and content are to be defined by the following claims.



Claims
  • 1. An aerosolizing system, comprising:a liquid dispenser which is adapted to deliver a volume of liquid upon operation of the liquid dispenser; a cartridge to receive liquid from the liquid dispenser, the cartridge comprising a housing having a substance which is in a dry state, wherein the housing includes a support structure that comprises an open cell porous material, wherein the substance is disposed in the support structure, and wherein receipt of the volume of liquid from the liquid dispenser dissolves the substance to form a solution; and an aerosol generator disposed near the cartridge and which is adapted to receive the solution from the cartridge.
  • 2. An aerosolizing system, comprising:a liquid dispenser which is adapted to deliver a volume of liquid upon operation of the liquid dispenser; a cartridge to receive liquid from the liquid dispenser, the cartridge comprising an inlet opening, an outlet opening, and a housing having a substance which is in a dry state, wherein the housing includes a support structure, wherein the substance is disposed in the support structure, and wherein receipt of the volume of liquid from the liquid dispenser dissolves the substance to form a solution; a coupling mechanism at the inlet opening to couple the cartridge to the liquid dispenser; and an aerosol generator disposed near the cartridge and which is adapted to receive the solution from the cartridge.
  • 3. A system as in claim 2, wherein the cartridge further includes a filter near the inlet opening and a filter near the outlet opening, and wherein the support structure is disposed between the filters.
  • 4. A method for aerosolizing a substance, the method comprising:transferring a liquid from a first chamber into a second chamber having a substance in a dry state to form a solution, wherein the first and second chambers are disposed in a cartridge, the cartridge including at least one groove disposed at least part way between the first and second chambers; positioning a divider between the first and the second chamber at a home position to hold the liquid in the first chamber; moving a piston through the first chamber to transfer the liquid to the second chamber by moving the piston towards the divider to move the divider away from the home position and to allow the liquid in the first chamber to pass around the divider, through the groove, and into the second chamber; transferring the solution from the second chamber onto an atomization member; operating the atomization member to aerosolize the solution; and withdrawing the piston from the first chamber to draw the solution from the second chamber and into the first chamber, and then moving the piston through the first chamber and into the second chamber to force the solution out the exit opening.
  • 5. A method for aerosolizing a substance, the method comprising:transferring a liquid from a first chamber into a second chamber having a substance in a dry state to form a solution, wherein the first and second chambers are disposed in a cartridge, and wherein the cartridge is held in a housing of an inhaler; moving a piston through the first chamber to transfer liquid to the second chamber; transferring the solution from the second chamber onto an atomization member; operating the atomization member to aerosolize the solution; removing the cartridge from the housing following dispensing; discarding the cartridge; introducing a cleaning cartridge into the housing; dispensing a cleaning solution from the cleaning cartridge onto the atomization member; and operating the atomization member to clean the atomization member.
  • 6. A method of nebulizing a fluid, comprising the steps of:providing a nebulizer having a vibrating assembly, a sealing element and a first elastomeric element disposed between the vibrating assembly and the sealing element, the vibrating assembly including a piezoelectric element, a substrate and a nebulizing element, the piezoelectric element being mounted to the substrate to cause the nebulizing element to vibrate upon excitement of the piezoelectric element, the nebulizing element having a plurality of holes therein, the sealing element and the first elastomeric element forming a seal on a side of the vibrating assembly; providing a fluid to a rear surface of the nebulizing element; vibrating the nebulizing element of the vibrating assembly by exciting the piezoelectric element, the fluid being ejected through the holes in the nebulizing element as the nebulizing element vibrates.
  • 7. The method of claim 6, wherein:the providing step is carried out with the sealing element having a recess which receives the first elastomeric element.
  • 8. The method of claim 6, wherein:the providing step is carried out with the first elastomeric element being an o-ring.
  • 9. The method of claim 6, wherein:the providing step is carried out with the first elastomeric element contacting the substrate.
  • 10. The method of claim 6, wherein:the providing step is carried out with the piezoelectric element surrounding the first elastomeric element.
  • 11. The method of claim 6, wherein:the providing step is carried out with the nebulizing element being non-planar.
  • 12. The method of claim 11, wherein:the providing step is carried out with the nebulizing element being dome-shaped.
  • 13. The method of claim 6, wherein:the providing step is carried out with a second elastomeric element contacting the vibrating assembly.
  • 14. The method of claim 13, wherein:the providing step is carried out with the second elastomeric element engaging a surface which extends perpendicular to a surface on the vibrating assembly which the first elastomeric element engages.
  • 15. The method of claim 6, wherein:the providing step is carried out with the sealing element positioned to isolate the piezoelectric element from the fluid.
  • 16. The method of claim 6, wherein:the providing step is carried out with the fluid being provided to a rear surface of the vibrating assembly and the sealing element sealing a front surface of the vibrating assembly.
  • 17. A method of nebulizing a fluid, comprising the steps of:providing a nebulizer having a body, a vibrating assembly, and a first elastomeric element, the vibrating assembly including a piezoelectric element, a substrate and a nebulizing element, the piezoelectric element being mounted to the substrate to cause the nebulizing element to vibrate upon excitement of the piezoelectric element, the nebulizing element having a plurality of holes therein, the first elastomeric element being disposed between the vibrating assembly and the body; providing a fluid at the rear surface of the nebulizing element; vibrating the nebulizing element of the vibrating assembly by actuating the piezoelectric element, the fluid being ejected through the holes in the nebulizing element, wherein the first elastomeric element provides an interface between the body and the vibrating assembly while the vibrating assembly is vibrating.
  • 18. The method of claim 17, wherein:the providing step is carried out with the nebulizer having a second elastomeric element disposed between a sealing element and the vibrating assembly.
  • 19. The method of claim 18, wherein:the providing step is carried out with the sealing element having a recess which receives the second elastomeric element.
  • 20. The method of claim 18, wherein:the providing step is carried out with the second elastomeric element contacting the substrate.
  • 21. The method of claim 18, wherein:the providing step is carried out with the piezoelectric element surrounding the second elastomeric element.
  • 22. The method of claim 18, wherein:the providing step is carried out with the first elastomeric element engages a surface which extends generally perpendicular to a surface on the vibrating assembly which the second elastomeric element engages.
  • 23. The method of claim 17, wherein:the providing step is carried out with the first elastomeric element being an o-ring.
  • 24. The method of claim 17, wherein:the providing step is carried out with the nebulizing element being non-planar.
  • 25. The method of claim 24, wherein:the providing step is carried out with the nebulizing element being dome-shaped.
  • 26. The method of claim 17, wherein:the providing step is carried out with the fluid being provided to a rear surface of the vibrating assembly and the sealing element sealing a front surface of the vibrating assembly.
  • 27. The method of claim 17, wherein:the providing step is carried out with the sealing element positioned to isolate the piezoelectric element from the fluid.
  • 28. A method of nebulizing a fluid, comprising the steps of:providing a nebulizer having a body, a vibrating assembly, and a first elastomeric element, the vibrating assembly including a piezoelectric element, a substrate and a nebulizing element, the piezoelectric element being mounted to the substrate to cause the nebulizing element to vibrate upon excitement of the piezoelectric element, the nebulizing element having a plurality of holes therein, the first elastomeric element being an o-ring disposed between the vibrating assembly and the body; providing a fluid at a rear surface of the nebulizing element; vibrating the nebulizing element of the vibrating assembly by actuating the piezoelectric element, the fluid being ejected through the holes in the nebulizing element, wherein the first elastomeric element provides an interface between the body and the vibrating assembly while the vibrating assembly is vibrating.
  • 29. The method of claim 28, wherein:the providing step is carried out with the nebulizer having a second elastomeric element disposed between a sealing element and the vibrating assembly.
  • 30. The method of claim 29, wherein:the providing step is carried out with the sealing element having a recess which receives the second elastomeric element.
  • 31. The method of claim 29, wherein:the providing step is carried out with the second elastomeric element contacting the substrate.
  • 32. The method of claim 29, wherein:the providing step is carried out with the piezoelectric element surrounding the second elastomeric element.
  • 33. The method of claim 29, wherein:the providing step is carried out with the first elastomeric element engaging a surface which extends generally perpendicular to a surface on the vibrating assembly which the second elastomeric element engages.
  • 34. The method of claim 28, wherein:the providing step is carried out with the nebulizing element being non-planar.
  • 35. The method of claim 34, wherein:the providing step is carried out with the nebulizing element being dome-shaped.
  • 36. The method of claim 29, wherein:the providing step is carried out with the sealing element positioned to isolate the piezoelectric element from the fluid.
  • 37. The method of claim 29, wherein:the providing step is carried out with the fluid being provided to a rear surface of the vibrating assembly and the sealing element sealing a front surface of the vibrating assembly.
CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation in part application of U.S. patent application Ser. No. 09/095,737, filed Jun. 11, 1998, now U.S. Pat. No. 6,014,975, which is a continuation in part application of U.S. patent application Ser. No. 09/149,426, filed Sep. 8, 1998, now U.S. Pat. No. 6,205,999, and of U.S. patent application Ser. No. 08/417,311 CiP, filed Apr. 5, 1995, now U.S. Pat. No. 5,938,117, the complete disclosures of which are herein incorporated by reference.

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Continuation in Parts (3)
Number Date Country
Parent 09/095737 Jun 1998 US
Child 09/313914 US
Parent 09/149426 Sep 1998 US
Child 09/095737 US
Parent 08/417311 Apr 1995 US
Child 09/149426 US