Systems and methods for driving sealed nebulizers

1 217512/3

SYSTEMS AND METHODS FOR DRIVING SEALED NEBULIZERS

BACKGROUND OF THE INVENTION

[0001 - 0002] Embodiments of the present invention relate to nebulizers. In particular, the present invention relates to use of a variable voltage and frequency driver for a nebulizer having a sealed liquid drug reservoir capable of maintaining a negative internal bias pressure.

[0003] A wide variety of procedures have been proposed to deliver a drug to a patient. In some drug delivery procedures the drug is a liquid and is dispensed in the form of fine liquid droplets for inhalation by a patient. A patient may inhale the drug for absorption through lung tissue. Further, the droplets forming the atomized mist may need to be very small to travel through small airways of the lungs. Such a mist may be formed by a nebulizer.

[0003a] US 6,569,109 describes an ultrasonic driving apparatus that consists mainly of a digital oscillatory circuit, an amplifier, a detection circuit, a phase difference detection circuit, a register, a data transfer circuit, and a switching circuit. The digital oscillatory circuit is used to drive an ultrasonic transducer at the resonance frequency of the ultrasonic transducer. The amplifier amplifies a driving signal output from the digital oscillatory circuit. The detection circuit detects the phase θv of an applied voltage and the phase θΐ of an induced current from the driving signal applied to the ultrasonic transducer via the amplifier. The phase difference detection circuit detects a difference between the phases θv and θί. The register holds digital frequency data with which a frequency at which the digital oscillatory circuit is oscillated is determined, and changes the digital frequency data. The data transfer circuit transfers the digital frequency data to the register. The switching circuit is interposed between the phase difference detection circuit and register.

[0003b] US 2007/0152081 describes a micro-spray system resonance frequency modulation method and device designed to minimize resonance frequency drift during atomization involving using a resonance frequency modulation unit for modulating resonance frequency and nodes, controlling and calibrating resonance frequency, and performing real-time measurement and correction to prevent operating frequency from drifting beyond a preferred operating frequency range, with a view to increasing spray flow and spray area, minimizing effects of ambient factors, and overcoming drawbacks of prior art.

[0003c] US 5,349,852 describes a system for controlling the flow of fluid through a line. The system may include first and second valves in the line. Between the first and second valves is located a chamber, part of which may be filled with fluid having a variable volume, and another part of which is filled with a measurement gas, such as air. The chamber may be isolated from the pressure effects in the rest of the line by closing both valves. The valves may also permit fluid to flow into or out of the chamber. The second portion of the chamber has a common boundary with the first part in such a way that the combined volume of the first and second parts is constant. A loudspeaker creates sound waves in the gas in the second part of the chamber, in order to measure the volume of the fluid in the first part. A controller directs the operation of the valves and controls positive and negative pressure sources, which may be used to create subsonic pressure variations to produce the desired flow. The volume measurement is achieved by acoustic volume measurement techniques.

[0003d] US 6,978,779 describes a nebulizer that determines the pressure and flow direction of the receiving gas for atomized liquid. A member of the apparatus is subjected to pressure exerted by the gas. The member is coupled to a bi-directional mechanical-electrical conversion element, such as a piezoelectric element, to form a pressure transducer. The member exerts a mechanical loading on the element responsive to the gas pressure to which it is subjected. In one embodiment, the element mechanically vibrates responsive to alternating electrical energization to discharge the liquid into the gas. The electrical admittance of the element is alterable by the mechanical loading applied to the element by the member. The difference between admittances measured in the loaded condition of the element and in an unloaded condition at the selected energization frequency is an indication of the pressure of the gas. By observing whether the magnitude of the admittance in the loaded state is greater or less than that in the unloaded state, the flow direction of the gas may also be determined. Or the flow direction may be determined by observing the changes in admittance as the frequency of the electrical energization is varied. In another embodiment, the piezoelectric element is not energized.

The electrical output of the element, when subjected to a mechanical loading from the gas pressure, is used to detect gas pressures and/or as an indication of the gas pressure. [0003e] US 5,853,665 describes an apparatus for automatically drawing a blood sample from a sealed container having an internal pressure below that of atmospheric pressure comprising an aspirating needle which serves to pierce the sealed container to aspirate liquid from the container, and to vent the interior of the container to the surrounding atmosphere through a suitable vent line connected to the needle. Such apparatus further comprises a vacuum pump connected to the needle through an aspiration line for aspirating blood from the sealed container. To warn the user of the possibility that fluid (e.g. cleansing diluent) in the aspirating needle has been drawn into the sealed container in the event of a vent line failure, apparatus is provided for detecting the pressure in the container immediately after the aspirating needle has pierced the container seal, and for comparing this pressure with a predetermined nominal value (typically, the negative pressure rating of the vacuum pump).

[0003f] US 7,155,980 discloses a resonating pressure transducer operable to measure an applied pressure by measuring changes in a resonant frequency. The pressure transducer comprises a plurality of diaphragms formed in a wafer of semi-conducting material between two layers, wherein each of the diaphragms is divided into a plurality of electrically isolated sections; a cavity in one of the covering layers opposite a corresponding one of the diaphragms, a first via formed through a selected one of the layers enables application of a potential to selected ones of the diaphragm sections; and a second via formed through a selected one of the layers enables transmission of a measure from selected ones of the diaphragm sections.

[0003g] US 7,197,948 describes a method for dosing liquid volumes, wherein a sample pickup portion with a pickup volume, the boundary of which is perforated with a liquid passage guiding to the outside and a gas passage, is dipped into a liquid with the liquid passage, a negative pressure is suddenly applied to the gas passage, which is generated by a gas displacement system, a drive of the gas displacement system is readjusted such that a constant negative working pressure exists in the sample pickup portion, the taken sample volume is detected with the aid of the readjusted driving path of the drive, the detected taken volume is compared with a predetermined value of the volume that is to be taken, when the predetermined value is reached by the taken volume, the negative pressure applied on the sample pickup portion is suddenly abated, the sample pickup portion with the liquid passage is pulled out of the liquid the sample pickup portion with the liquid passage is directed towards a releasing location, one or more flow parameters is/are determined from the values of the taken volume, the negative working pressure and the time period required to take up the volume, an overpressure is applied to the gas passage of the sample pickup portion, the moment at which a volume that is to be released is released is determined with the aid of the flow parameter(s) and the overpressure, and when the moment is reached, the overpressure applied to the sample pickup portion is suddenly abated.

SUMMARY

[0004] Various systems, methods, and devices are described for driving a nebulizer using a driver unit. The nebulizer may include a sealed drug reservoir such that a negative bias pressure may form within the drug reservoir as liquid is drained from it. As the negative bias pressure changes, the resonant frequency of the nebulizer element may change. A driver may be used to drive the nebulizer element and cause it to vibrate. The driver may output a waveform signal of varying frequency and magnitude to the nebulizer such that the nebulizer element vibrates at or near a resonant. frequency and. the nebulizer element atomizes liquid at a constant or near constant rate and droplet size. (0005] In some embodiments, a. method for determining a resonant frequency of an element of a nebulizer -with a negatively biased liquid reservoir is described. The method may include driving 5 a nebulizer using an electrical signal, foe electrical signal comprising a current and a voltage.

The method may include measuring a phase shift between foe voltage and foe current of the electrical signal driving the nebulizer. The method may also include, based at least in part .on the phase shift of the electrical signal driving the nebulizer, determmmg. a resonant frequency of the element of the nebulizer . 10 [0006] fa some embodiments, the method further comprises based at least in part on the resonant frequency of the nebulizer determined by the driver, determining, a voltage magnitude for the electrical signal. In some embodiments, foe negatively biased liquid reservoir causes, the resonant frequency of the element of foe nebulizer to vary as liquid Is drained from the negatively biased liquid reservoir. In some embodiments, the electrical signal driving the 15 nebulizer causes the element of the nebulizer to vibrate and atomize liquid stored in foe negatively biased liquid reservoir. In some embodiments, the method further comprises based at least in part on the resonant frequency of the nebulizer determined by the driver, determining, by the driver, a negative bias pressure within foe negatively biased liquid reservoir of the nebulizer. In some embodiments, the method farther comprises adjusting the frequency of the electrical 20 signal to foe nebulizer, wherein a roughly constant phase shift is maintained between the voltage and current of the electrical signal. In some embodiments, the voltage magnitude is determined using a stored set of values, and the stored set of values vary depending on a liquid in foe negatively biased liquid reservoir.

[©007J In some embodiments, a device for dri ving an element Of a nebulizer is present. Hie 25 device may include an amplifier, configured to generate an output waveform signal, foe output waveform signal comprising an -unpin current and an output voltage, wherein the output waveform signal drives foe element of the nebulizer at foe output frequency. The device may include a phase shift detector, configured to determine foe phase shift between the output current and the output voltage of the output waveform signal. The device may .include a resonant •frequency tracker, configured to generate a waveform signal of a variable frequency input to the amplifier, wherein the variable frequency is adjusted based on fee phase shift of the output waveform signal determined by the phase shift detector module. The device may include a voltage profile, configured to adjust the output voltage of the output waveform signal output by 5 the amplifier based on the frequency of the waveform signal generated by the resonant frequency tracker.

[0008] in some, embodiments, a system for atomizing liquid stored in a negatively bias pressured liquid reservoir may be present. The system may include a nebulizer, comprising as element and the negatively bias pressured liquid reservoir. 'The element may be configured to vibrate to 10 atomize liquid drained from the negatively bias pressured liquid reservoir. A negative bias pressure of the negatively bias pressured reservoir may change as liquid stored in. the negati vely bias pressured liquid reservoir is drained. The negatively bias pressured reservoir may be sealed such that air from the external environment substantially does not enter the negatively bias pressured reservoir as liquid stored in the negatively bias pressured liquid rfesetvoir is drained. 15 The system may include a driver. The driver may include a phase shift detector, configured to determine the phase shift between a current of an output Waveform signal and a voltage of the output waveform signal. The driver may include, a resonant frequency tracker, configured to generate an output waveform that adjusts the frequency of the: output waveform signal, wherein die frequency is adjusted based on die phase shift dctcimmed by the phase shift detector tnoikde 20 The driver may include a voltage profile, configured to adjust a voltage of the output waveform signal based on the frequency of the output waveform generated by the resonant frequency tracker.

[0099] In some embodiments, a method for aerosolizing a liquid is present. The method may include sealing the liquid within a reservoir. The method may also include generating an output 25 -waveform signal and vibrating a nebulizer element, to aerosolize the liquid. A negative pressure may be produced within, the reservoir as the liquid is aerosolized. The output waveform signal may cause the nebulizer element to vibrate. The method may include determining a phase shift between a current of the output waveform signal and a voltage of the output waveform signal. The method may include adjusting a frequency of the output waveform signal at least parti ally based, on the phase shift. Further, the method may include adjusting, the voltage of the output waveform signal at least partially based on the frequency of foe output waveform signal.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010) A further understanding of the nature, and advantages of the present invention may be realized by reference to the following drawings. In the appended figures, similar components or features may have the same reference label. Further, various components of the same type may be distinguished by following the reference label by a second label that distinguishes among the similar components. If only the first reference label is used in the specification, the description is applicable to any one o f the similar components having the same first reference label irrespective of the second reference label. (Wll| FIG. 1A illustrates a simplified embodiment of a nebulizer.

[0812] FIG, 1B Illustrates a simplified embodiment of a nebulizer with a driver unit.

[0013] FIG. 1C illustrates a simplified embodiment of a handheld nebulizer with an Integrated driver unit.

[OOM] FIG. I D Illustrates a nebulizer integrated with a ventilator.

[0815 ] FIG. 2 illustrates a simplified embodiment of a driver coupled with a nebulizer,.

[0816] FIG., 3 Illustrates a method of driving a nebulizer with a driver.

[0817] FIG . 4 Illustrates a method of initially determining a resonant, frequency of a nebulizer element.

[0018] FIG. 5 illustrates a simplified method of adjusting the frequency output by a driver using a resonant frequency tracker to maintain the nebulizer element vibrating at its current resonant frequency

DETAILED DESCRIPTION OF THE INVENTION

[0019] Devices, systems, and methods are described for the implementation of a no vel architecture for driving a nebulizer. The invention provides various ways for driving nebulizers at the nebulizers’ resonance frequencies, particularly nebulizers with sealed drug reservoirs capable of developing a negative bias pressure (meaning the pressure within the reservoir is less than the pressure outside of the reservoir) as liquid is evacuated from the drug reservoir.

[302Θ] By creating a negative bias pressure-within the drug reservoir of a nebulizer, the efficiency of a nebulizer may be increased, thus allowing it to achieve higher liquid flow rates, 5 with smaller and more consistent droplet sizes, than in comparable conditions without a negative bias pressure. Such a negative bias pressure may he created by sealing tbe drug reservoir. As the liquid drag is drained from the drag reservoir (with .little to no air entering to replace the drug’s volume), a negative: bias pressure may he created. While the negative bias pressure may assist in maintaining consistently sized droplets of mist, as the negative bias pressure decreases 10 in pressure, the flow rate of liquid, from the nebulizer/may increase.

[0021] An increased Bow rate caused by a negative bias pressure may lead to the wrong dose of a medicine being delivered to a patient and/or the generation of improper droplet sizes. Such improper droplet sizes may alter how the droplets are absorbed into the human body. For example, if a patient inhales droplets that are too large, the droplets, may not propagate into tbe 15 deep lung tissue of the patient, but rather, the droplets may gather in the patient’s larger airways. This may prevent proper absorption of the droplets by the patient.

[0622] The droplets may be created from a stored amount of li quid in the drug reservoir by a nebulizer element , The nebulizer element may be an aperture plate containing a number of small holes. When an electrical signal, such as a waveform, is applied to the nebulizer element, the 20 nebulizer element may vibrate at or near the frequency of the waveform received , While. vibrating, the nebulizer clement may allow an amount of the liquid to pass through the element and form airborne droplets. The nebulizer element may function more efficiently and produce consistent droplet sizes when the nebulizer element is vibrating at or near its .resonant frequency.

[0023] However, as the negative bias pressure within the drug reservoir changes (e.g., a greater 25 difference between the pressure inside tbe drug reservoir and the ambient pressure outside of the drug reservoir is formed) the resonant frequency of the nebulizer element may change, in order to -maintain the nebulizer element vibrating at its (current) resonant frequency, it may be necessary to change the frequency of waveform used to drive the nebulizer element. (00241 Therefore, if a negative bias pressure is maintained in the drug reservoir, the frequency and magnitude of the waveform used to drive the nebulizer element needs to vary as the negative bias pressure within die drug reservoir changes in order to maintain efficient operation of the nebulizer element, including maintaining consistent dosing of the liquid drag and consistent droplet sizes. (0025| To be clear, a sealed reservoir refers to a reservoir that prevents air from entering the reservoir as liquid is drained from the drug reservoir. It may, however, still be possible for air to enter the sealed drug reservoir through holes in the nebulizer element. The greater the negative bias pressure (that is, the greater the difference between the pressure of the external environment and the pressure within the drug reservoir) the faster air may enter through the nebulizer element.

[6026] FIG. 1A il lustrates an embodiment of a possible nebulizer 100-a. The nebulizer 100-a may include a nebulizer element 1.10, a drug, reservoir 120,.a'head space 130,: an interface 140, and a cap 150. The nebulizer element 110 may be comprised of a piezoelectric ring that may expand and contract, when an electric voltage Is applied: to the ring. The nebulizer element 110 may be a vibrating aperture plate. The piezoelectric ring may be attached to a perforated membrane. Such a perforated membrane may have a number of holes passing through it When an electric voltage Is applied to the-piezoelectric ring, this may .cause the membrane to move and/or flex. Such movement of the membrane, while in contact with a liquid may cause the atomization (alternatively referred to as aerosclization) of the liquid. (0027J A supply of a liquid, commonly a liquid drag, may be held, in the drag reservoir 120. As illustrated, a drug reservoir is partially filled with a liquid, drag. As the liquid drag is atomized, the amount of liquid drug remaining in the drug reservoir 120 may decrease. Depending on the amount of liquid drug in the drag reservoir 120, only a portion of the reservoir may be filled with liquid drag. The remaining portion of the drug reservoir 120 may be filled with gas, such as air. This space is commonly referred to as head space 130. An interface-140 may serve to transfer amounts of liquid drug between the drug reservoir 120 and the nebulizer element 110. (0028] Nebulizers, and the techniques associated with such nebulizers,-are described generally in U.S. PatentNos. 5,164,740; 5.,93.8,117; 5,586,550; 5,758,63.7; 6,014,970; 6,085,740; 6,235,177- 6,615,824; and 7,322,349.

[0029] A nebulizer with a sealed drug reservoir may be part of a larger system. The embodiment of FIG. 1B illustrates such a system 100-b. FIG. 1B illustrates a nebulizer 151 with a sealed drug reservoir connected to a driver 152. The sealed nebulizer illustrated in FIG. 1B may be the nebulizer of FIG. 1A, or may represent some other nebulizer. Driver 152 may control the rate and magnitude of vibration of the nebulizer element on nebulizer 151. Driver 152 may be connected to nebulizer element 151 via cable 153. Driver 152 may regulate the voltage and frequency of the signal provided to the nebulizer element of nebulizer 151. The regulation of the voltage and frequency of the signal may be based on the resonant frequency of the nebulizer element of nebulizer 151. Such a signal may vary depending on the magnitude of the negative bias pressure.

[0030] In some other embodiments of nebulizers, a driver may be incorporated into a handheld unit with the nebulizer. Nebulizer 100-c of FIG. 1C illustrates an embodiment of a handheld nebulizer with an integrated driver. Nebulizer 100-c may include a case 155, a mouthpiece 160, a trigger button 165, and an electrical plug 170. Case 155 may contain some or all of the elements found in other embodiments of nebulizers (such as nebulizer 100-a of FIG. 1A) and drivers (such as driver 152 of FIG. 1B). Therefore, contained within case 155 may be a sealed drug reservoir and/or a device capable of generating an electrical signal at a voltage magnitude and frequency to vibrate an element that atomizes liquid stored in the drug reservoir. A person receiving the atomized liquid drug may place her mouth on mouthpiece 160 and breath in. While the person receiving the atomized liquid drug is breathing in, she may press trigger button 165 to trigger the element to begin aerosolizing liquid. In some embodiments, nebulizer 100-c may contain a sensor that detects when the person is breathing in and triggers the element to vibrate without trigger button 165 being necessary.

[0031] Nebulizer 100-c may also include an electrical plug 170. Electrical plug 170 may be connected to an electrical outlet to power nebulizer 100-c. Nebulizer 100-c may contain a battery, thereby allowing electrical plug 170 to be connected to an electrical outlet when nebulizer 100-c is not in use by a person, allowing a battery to be charged. Alternatively, in some embodiments of nebulizer tG0~c, electrical plug 170 may need to be connected to an. electrical outlet while nebulizer 100-c is in use by a person, in some embodiments, nebulizer 100-c may use replaceable batteries as its power source. |MS2j In some embodiments, a nebulizer may operate in conjunction with a ventilator. System 5 100-d illustrates a nebulizer 178 that supplies atomized, liquid drug to a person 176 via a. ventilator 170. Ventilator 170 may supply air suitable .for breathing to person 176. Ventilator 170 may assist person 176 in breathing by forcing air into the lungs of person 176 and then releasing air to mimic breathing. While person 176 is using ventilator 170, it may be. necessary to provide person 176 with atomized liquid, such-as a liquid drug. 10 pi®33) Nebulizer 178 may be connected to a drug reservoir 186 that is sealed by a cap 180., Οι

Drag reservoir 186 may .contain an amount of liquid -drug 1.82. This liquid drug may be delivered- to nebulizer 178 as liquid drug is atomized by nebulizer 178, As liquid drug is atomized, liquid drug 182 may drainfrom, drug reservoir 186, thereby increasing the volume of headspace 184, Headspace 184 may contain air. Headspace 184 may increase in volume, but may decrease in pressure as liquid drug 182 drains because liquid reservoir 186 allows no or minimal air into headspace 184.

[0034) Driver 172, which may represent the same driver as driver 15:2 of .FIG, IB (or may represent some other driver) may deliver a signal to nebulizer 178. This signal tnay-control the vibration of an element of nebulizer 17 8 . Nebulizer 178' may be attached to a tube 179 used to 20 deliver air and atomized liquid drug to patient 176. Tube 179 may terminate in a mask 174 covering, the mouth and/or nose of person 176. The air and atomized liquid drug may then enter the airways of person 176.

[(MBS) A nebulizer such as those illustrated in FIGs. 1A-1D may be connected with a driver such as illustrated in FIG. 2. FIG. 2 illustrates a simplified block diagram of-a nebulizer driver unit 200, Ihe nebulizer 260 may be the nebulizer 100-a of FIG. 1A or it may be some other nebulizer such as those- in the referenced applications or FIGs. 1B4D. Ihe nebulizer may be connected to the driver via a cable-270. Driver 210 may be driver 151 of FIG. IB, or may be some other driver. Cable 270 may allow driver 210 to transmit an electrical waveform signal of varying frequency and magnitude (of voltage) through cable 270 to- drive nebulizer 260. ί» [8036] Driver 210 may include an amplifier 230, a current phase shift detector 240, a resonant frequency tracker 220, and a voltage profile 250. Based upon fee phase shift between the current supplied to nebulizer 260 and the voltage generated by amplifier 230, the nebulizer element’s resonant frequency may be determined. From the resonant frequency, the negative bias pressure within the drug reservoir of the nebulizer may be determined, and fee -frequency and/or magnitude of the electrical waveform signal driving nebulizer 260 -may be adjusted. (01)37] The determination of the resonant frequency may be accomplished using current phase shift detector 240. Current phase shift detector 240 monitors the phase shift between fee phase of the current output by amplifier 230 to .-nebulizer 260 and the phase of the voltage output by 10 amplifier 230 to nebulizer 260, Based upon the phase shift between the voltage and current observed by current, phase shift, detector 240, resonant frequency tracker 220 outputs an output waveform to amplifier 230 such that amplifier 230 outputs an electrical waveform signal with constant or'near constant phase shift between the voltage, and current, of the. electrical waveform signal driving fee element of nebulizer 260, 15 (0038] As liquid is atomized and the bias pressure in the drug reservoir changes, the resonant frequency may change. Further, factors besides the bias pressure within the sealed drug reservoir of the nebulizer 260 may change fee nebulizer element’s resonant frequency. For example, the temperature of the nebulizer element, excess liquid, on the nebulizer element, and/or damage to the nebulizer element may cause a variation in fee nebulizer -element’s· resonant frequency. 20 However, it may be generally accepted that during operation, changes in the nebulizer element’s resonant frequency is generally due to -variations in the bias: pressure within fee drug reservoir of the nebulizer. (0039] The resonant frequency and/or fee measured change in resonant frequency may be transmitted to voltage profile 250 by resonant frequency tracker 220. Voltage profile 250 may 25 be .used to determine the proper magnitude of voltage to apply to the nebulizer dement at a particular resonant frequency to maintain consistent droplet size and dosing of fee atomized liquid. In some embodiments, voltage profile 250 may include a table of empirically gathered data. In such embodiments, the resonant frequency may be located in fee fable, wife a corresponding -.analog or digital signal being output.to amplifier 230 that specifies the appropriate 10 magnitude of voltage amplifier 230 should output. For example , a table may include a predetermined voltage magnitude that may be communicated to amplifier 230 when a particular resonant frequency is measured by resonant frequency tracker module 220. Voltage profile 250 may also be expressed as a graph of values, with the χ-axis being frequency of the waveform 5 generated· by resonant frequency tracker 220, and the y-axis representing the appropriate voltage magnitude to be supplied to amplifier 230 such that amplifier 230 outputs an electrical signal of correct magnitude.

[0940) A rough description of one set of possible values: for voltage profile 250 is that as the resonant frequency of the nebulizer element increases, the desired amplitude of the electrical 10 signal output to the nebulizer will decrease. At a certain threshold. as the resonant frequency continues to increase, the voltage will be held by voltage profile 250 at a minimum level, hi some embodiments of voltage profile 250, the signal output to amplifier 230 are determined based on a calculation using the resonant frequency supplied by resonant.frequency-tracker 220. (0041-1 Th?· voltage profile may need to be modified or adjusted to accommodate the 15 characteristics (such as surface tension) of different liquids within the drag reservoir of the nebulizer , In some-embodiments,-a liquid drag, such as Amikasin, is used. In other embodiments, a different liquid drug .or liquid is used. In some embodiments, the voltage profiles necessary for a number of liquids or liquid drags may be simi lar enough that only one voltage profile needs to be used for multiple liquids or liquid drags. Modifying or replacing 20 voltage profile 250 may involve selecting a different liquid via a user interface on driver 210 or loading different software, firmware, and/or hardware info driver: 210.

[9042) Resonant frequency tracker 220 may transmit a waveform at or near the nebulizer element’s current determined resonant frequency to amplifier 230. Voltage profile 250 may transmit a signal indicating the desired voltage amplitude to be output by amplifier 230 to 25 amplifier 230. This signal from voltage profile 250 may serve to control the gain of the amplifier 230. Based upon the input waveform from resonant frequency tracker 220 and the desired voltage amplitude received from voltage profile 250.. amplifier 230 generates an output electrical signal that may be used to drive an apertur e of the nebulizer. Amplifier 230 may be a variable gain linear power amplifier. In some embodiments, a fixed gain power amplifier may be used in 11 conjunction with a variable gain amplifier or a -potentiometer. Further, various other amplifiers or amplifier based circuits may be used to generate the output electrical signal to drive nebulizer 260. (0043] Current phase shift detector 240 may create a feedback loop to resonant frequency tracker 5 220, Current phase shift detector 240 may determine the phase shift of the current'being output from the amplifier 230. Such a phase shift may be transmitted to resonant frequency tracker 2,20, thereby allowing resonant frequency tracker 220 to either maintain the same frequency signal (if the phase has not shifted), increase the frequency, or decrease the frequency of the output signal in response, to the-resonant'frequency of the nebulizer element changing as the bias pressure 10 -wifinn the seal drug reservoir changes. Feedback through current phase shift detector 240 may allow driver 210 to periodically of continually adjust the magnitude and -frequency of the electrical signal output to the nebulizer element while liquid is being atomized. This may allo w for any change in the bias pressure in the: liquid reservoir to be continually adjusted for by the driver. 15 (0044] A driver, such as driver 21β of FIG. 2,. may drive a, nebulizer element according to a method, such as method 300 of FIG. 3,. Alternatively* method 300: may be performed: using some other driver. Method 300 may employ various different nebulizers, such as the nebulizers of FI'Gs. lA-’ lD, and FIG. 2. At block 310, the driver may drive an element (also referred to as an aperture) of a-nebulizer with an electrical signal. This electrical signal may be a waveform at a 20 particular frequency and magnitude, (0045] At block 320, the phase shift between the voltage of the electrical sign-al output to the nebulizer and the current of the electrical signal may be measured. Using this phase shift, at block 330, the resonant frequency of the nebulizer element may be determined. As previously noted, this resonant frequency may shift as the negative bias pressure within the liquid, reservoir 25 of the nebulizer changes. From the resonant frequency, the bias pressure within die liquid reservoir may be determined at block 340. In some embodiments, the negative bias pressure is not determined.

At. block 350, the magnitude of the voltage of the electrical signal used to drive the nebulizer element may be determined. The magnitude may be determined using the resonant 12 frequency determined at block 330 and/or the negative bias pressure determined at block 340.

The resonant frequency and/or the negative bias pressure may be used fo consult a table of values . This table of values may specify the appropriate magnitude of voltage to be used for the electrical signal driving the nebulizer element. Alternatively, the resonant -frequency and/or the 5 negative bias pressure may be used to calculate the appropriate voltage magnitude to drive the nebulizer element The appropriate magnitude may correspond to a magnitude that maintains a constant dosage rate and droplet size: of the liquid being dispensed from the nebulizer. The calculations or table may vary depending on the properties of the liquid being dispensed.

[00.47| At block 360, the electrical waveform signal driving the nebulizer element may be 10 adjusted according to the frequency determined at block 330 and/or tire magnitude determined,at block 350. If the resonant frequency of the nebulizer element has not changed, the frequency and/or the /magnitude of the electrical signal driving the nebulizer element, may not change. Method 300 may repeat as long.as the-nebulizer, .element is being driven by the driver. romsi a resonant frequency tracker, such as resonant frequency tracker 220 of FIG, 2, may 15 follow various methods fo: determine and maintain an output alor near the resonant frequency of a nebulizer element, such as nebulizer element. 260' of FIG. :2. FIG. 4 illustrates a simplified flowchart of a decay profile 400 for initially determining the resonant frequency of the nebulizer element and adjusting the output electrical signal driving the nebulizer element based on the phase shift between the voltage and current of the electrical signal driving the nebulizer element 20 detected by the current phase shift detector. Method 300 of FIG. 3 may be implemented using resonant frequency tracker 220 of FIG, 2, or may be implemented using some other .resonant frequency tracker, be it implemented in software, firmware, and/or hardware, [00491 If the resonant frequency has not been determined or "locked on” to by a resonant frequency tracker, a resonant frequency tracker may conduct method 40(). The resonant 25 frequency tracker may not have locked on to the resonant frequency if, for example, the driver has just been turned on or activated, a new nebulizer is attached to die driver unit, the nebulizer element has been interfered with, or the nebulizer element has been damaged. (O050j At-block 411, the resonant frequency tracker may apply an infinite impulse response filter (“HR. filter”), to the phase signal received from the current phase shift detector. The HR filter 13 may be implemented using analog and/or digital components. From this, a filtered phase value may be obtained. '(005.1] Using the filter phase value,· the error between the filtered phase and desired phase setpoint may be determined at block 412. The desired phase set point may indicate the phase necessary to cause the nebulizer element to vibrate at a resonant frequency. This determined error value may then be used to determine if the error has been a smaller value 'than the set point for greater than a second at block 413. In some embodiments, a different length of time is used. (0052] If the error has been less than the set point for more than one second, the .current frequency of the signal output to the nebulizer is stored at block 4.14. Further, a flag may be set to indicate that the resonant frequency has been locked on to by the resonant frequency tracker at block 415. Returning to block 413, if the error has not been less than the set. point for more than one second, the process proceeds to block 430. (0053] At block 430,if the average current Is less than some threshold current value, the outpu t voltage may be set to a start, voltage at. block 432.. At block 434, the resonant frequency determined by the resonant-frequency tracker may be reset: to an initial value, if the average current is not less than a threshold current 'value, blocks 432 and 434 may not be performed. Method 400 may repeat until the flag indicating the resonant frequency of the nebulizer element has been locked on to. (0(154] Once the resonant, frequency has been determined and locked, which may involve the resonant frequency flag of block 414 being set, a second method may be followed. Method 500 represents a method for adjusting die frequency using a resonant frequency tracker to maintain the nebulizer element vibrating at its current resonant frequency. The error between the current frequency and resonant frequency may be determined at block 521, From. this, an error value may be obtained· (9055] A determination of whether the actual frequency of the signal being generated by the resonant frequency tracker is greater than the resonant frequency of the nebulizer element may be made at block 522. If yes, at. block 523, the output voltage may be scaled by a decay rate multiplied by the error rate determined st block 52.1, and the output voltage may be limited to the end voltage at block 524. This may prevent the output voltage from exceeding some maximum and/or minimum threshold value. Next, the process proceeds to block 530. If the actual frequency is not determined to be greater than the resonant frequency at block 522, the output voltage is set to a start voltage at block 525, and the method proceeds to block 530.

[0056] At block 530, a determination is made if the current is less than a threshold current value. If so, the output voltage is set to the start voltage at block 532 and the resonant frequency is reset at block 534.

[0057] While a wide variety of drugs, liquids, liquid drugs, and drugs dissolved in liquid may be aerosolized, the following provides extensive examples of what may be aerosolized. Additional examples are provided in U.S. App. No. 12/341,780, which corresponds to patent publication US 2009/0288658 A1. Nearly any anti-gram-negative, anti-gram-positive antibiotic, or combinations thereof may be used. Additionally, antibiotics may comprise those having broad spectrum effectiveness, or mixed spectrum effectiveness. Antifungals, such as polyene materials, in particular, amphotericin B are also suitable for use herein. Examples of anti-gram-negative antibiotics or salts thereof include, but are not limited to, aminoglycosides or salts thereof. Examples of aminoglycosides or salts thereof include gentamicin, amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin, tobramycin, salts thereof, and combinations thereof. For instance, gentamicin sulfate is the sulfate salt, or a mixture of such salts, of the antibiotic substances produced by the growth of Micromonospora purpurea. Gentamicin sulfate, USP, may be obtained from Fujian Fukang Pharmaceutical Co., LTD, Fuzhou, China. Amikacin is typically supplied as a sulfate salt, and can be obtained, for example, from Bristol-Myers Squibb. Amikacin may include related substances such as kanamicin.

[0058] Examples of anti-gram-positive antibiotics or salts thereof include, but are not limited to, macrolides or salts thereof. Examples of macrolides or salts thereof include, but are not limited to, vancomycin, erythromycin, clarithromycin, azithromycin, salts thereof, and combinations thereof. For instance, vancomycin hydrochloride is a hydrochloride salt of vancomycin, an antibiotic produced by certain strains of Amycolatopsis orientalis, previously designated Streptomyces orientalis. Vancomycin hydrochloride is a mixture of related substances consisting principally of the monohydrochloride of vancomycin B. Like all glycopeptide antibiotics, 15 vancomycin hydrochloride eontaius a central core heptapeptide. Vancomycin hydrochloride, USE, maybe obtained from Alpharma, Copenhagen, Denmark, [0059] In some embodiments, the composition comprises an antibiotic and one or more additional active agents. The additional active agent described herein includes an agent, drug, or 5 compound, which provides some pharmacologic, often beneficial, effect This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As.used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. An acti ve agent for incorporation in the pharmaceutical formulation described herein may be-an inorganic or an organic compound, 10 including, without limitation, drugs· which act on: the peripheral nerves^ adrenergic receptors, cholinergic-.receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system,: the reproductive system, the skeletal system, antacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous 15 system.

[0060] Examples of additional active agents include, but are not limi ted to, anti -Inflammatory ageflts, bronchodllators, and combinations thereof. (00611 Examples of bronchodllators include, but are not limited to, ,beta,-agonists, anti-muscarinic agents, steroids, and combinations thereof. For instance, the steroid may comprise 20 albuterol, such as albuterol sulfate.

[0062] Active agents may comprise, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antipsrkinson agents (dopamine antagonists), analgesics, anti-inflammatories, antianxiety drugs »Anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, additional antidnfeetives 25 (antivirals, antifungals, vaccines) anriarfhrifics, antimalarials, antiemetics, anepiiepti.es, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives. cardiovascular drugs, antianrhythmics, anfioxicants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents,, anti-androgenic agents, antiparasitics, anticoagulants, neoplasties, antineoplastics, -hypoglycemics, nutritional 16 agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent when administered by inhalation, may act locally or systemically. |'0063J The active agent may fall into one of a number of structural classes, including but not 5 limited to small molecules, -peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

[8864] Examples Of active agents suitable for use in this -invention include but are not limited® one or more of calcitonin, amphotericin B, erythropoietin (EPO),'Factor Vlfl, Factor IX, 10 eeredase', eerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (H6H), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, Interferon gamma, interleukin-1 receptor, intsrlehkm-2,. interleukin-l receptor antagonist, 15' interleukin-3, interleukin-4, interleukin-^, luteinizing hormone releasing hormone (LHRH), factor IX, Insulip, pro-insulin, insulin analogues (e.g.,. mono-acylated insulin as described in U.S. Pat. No. 5,922,675), amylin, G-peptide, •somatostatin somatostatin .analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insuUn-like growth·, factor (IGF), insulihtrepi® macrophage colony stimulating 20 factor (M-CSF), nerve growth lactor (NGF), tissue growth factors, keratinocyte growth factor: (KGF), glial growth factor (GGF), tumor necrosis; factor (TNF), endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide thymosin, alpha 1, flb/lfla inhibitor, alpha-1 antitrypsin, phosphodiesterase (PDF) compounds, VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, 25 deoxyreibonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, I 3-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycih, dirithromycin, josamyein,-spiromyem, midecamycin, leucomycin, miocamycin, rokitamycin, andazifhromycjn, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, aiatiofloxacm, moxifloxicin, 30 norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, 17 pefioxacin, amiiloxacin, fleroxacin. tosufioxacin, pmlifloxacin, irloxacin, pazufloxaoin, clmafloxacm, and sitafloxacin, teieopianln, rarapolanin, mideplanin, colistin, daptomydn, gramicidin, colistlmethate, polymixihs such as polymixin B, capreomyein, bacitracin,- penems; penicillins including penicliinase-sensitive agents like penicillin G. penicillin V, penicillinase- 5 resistant agents like methicillin, oxacillin, cloxaeillin, dieloxacitiin. floxaciilin, nafcillin: gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, .cillin, and galampicillin; -aniipseudomonai penicillins like carbenicillin, ticareillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, c-efprozil ceftbuten, ceftizoxime, ceftriaxone, cepfealothin,. cephapirin, cephalexin,.cephradrine, cefoxitin, cefamahdole, cefazolin, '10 eephaloridine, cefaclor, cefedroxil, cephalpglyds, ceferoxime, ©eforanide, cefotaxime, cefatrizme, cephacetrile, cefepime, cefixime, cefonieid, cefopemotie, cefoietan, oefinetazole,. ceftazidime, loracarhef, and moxalactam, monobactams like aztreqnam;- and carbapenems such as imipenem, meropenem,- pentamidine isethionate, lidocaine, .metaproterenol sulfate, beclomeihasoue diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, 15 ipratropium bromide, ilunisolide, cromolyn sodium., ergotamme tartrate and where applicable, analogues, .agonists, antagonists. Inhibitors, and pharmaceutically acceptable salt forms- of the above. In reference to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, ungjyeosylated, pegylated forms, and biologically active fragments, derivatives, and analogs thereof. 20 [0065] Active agents for use in. the invention further include nucleic acids, as bare nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA-or other nucleic acid constructions of a type suitable for transfection or transformation of cells, i.e,, suitable for gene therapy including antisense. Further, an active agent may comprise live attenuated or killed viruses suitable for use as vaccines. Other useful drugs include those listed within the Physician's 25 Desk Reference (most recent edition).

The amount of antibiotic or other active agent In the pharmaceutical formulation will be that amount necessary to deliver a therapeutically or prophyiaetieally effective 'amount of the active agent per unit dose to achieve the desired result. In practice, this will vary widely depending upon the particular agent, its activity, the severity of the condition to be treated, the patient population, dosing requirements, and the desired therapeutic effect. The composition will WO 2011/009133 18 generally contain anywhere from about 1 wt % 'to -about 99 wt. %, such as front about 2 wt % to about 95 wt %, or from about 5 wt % to 85 wt %, of the active agent, and will also depend upon the relative amounts of additives contained in the composition. The compositions of the invention are particularly useful for active agents that are delivered in doses-of from 0.001 5 mg/day to 100 mg/day, such as in doses from 0,01 mg/day to. 75 mg/day, or in doses from 0.10 mg/day to 50 mg/day. It is to fee understood that more than one active agent may be incorporated into the formulations described herein and that the use of the term "agent" in no way excludes the use of two or more such agents. (0067} Generally, the compositions are free of excessive excipients. In one or more 10 embodiments, the aqueous composition, consists essentially of-the anti -gram-negative antibiotic, such as amikacin, or gentamicin or both, and/or salts thereof and water.

[0068J Further, in one or more embodiments, the aqueous composition is preservative-free, in this regard, the aqueous composition may be metoylparabeu-free and/or propylparaben-free, Still further, the aqueous composition may be saline-free. 15 [0069j In. one or- more embodiments, the compositions comprise an anti'-infective and an excipient. The compositions-may comprise a pharmaceutically -acceptable: excipient or-carrier which may be taken into the lungs, with no significant adverse toxicological effects to the subject, and particularly to-the lungs, of the subject. In addition to the active agent, a pharmaceutical foimulatidn may optionally include one or more pharmaceutical excipients which are suitable .for 20 pulmonary administration. These excipients, If present, are generally present in the composition in amounts sufficient to perform their, intended function, such as stability, surface modification, enhancing effectiveness or delivery of the composition or the like. Thus if present, excipient may range from about 0,01 wl %' to about. 95 wt %, such as from about 0.5 wt % to about 80 wt %, from about 1 wt % to about 60 wt %, Preferably, such excipients will, in part, serve to further. 25 Improve the features of the active agent composition, for example by providing more efficient and reproducible delivery of the active agent and/or facilitating manufacturing. One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of active agent In the formulation. WO 2011/009133 19 (0070] For instance, the compositions may include one or more osmolality adjuster, such as sodium chloride. For instance, sodium chloride may be added to solutions of vancomycin hydrochloride io adjust the osmolality of the solution, in one or more embodiments, an aqueous composition consists essentially of the anti -gram-positive -antibiotic, such as vancomycin 5 hydrochloride, the osmolality adjuster, and water.

[007 Ij Pharmaceutical excipients and additives useful in the present pharmaceutical formulation include but are not limited to amino .acids, peptides, proteins, nan-biological polymers, biological polymers, carbohydrates, such as sugars, derivatized sugars such as alditols, aidonie acids, esterified sugars, and sugar polymers, which may be present singly or in combination. 10 [0072] Exemplary protein excipients include albumins such as human serum, albumin (HSA), .recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable ammo acids (outside of the. dileubyl-peptides of the invention), which .may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine,.glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, 15 tryptophan,· and- the like. Preferred are amino acids and polypeptides that function as dispersing agents . Amino acids falling into this category include'hydrophobic amino acids such: as: leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline.

[0073;] Carbohydrate excipients suitable for use in the invention include, for example, 20 monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffmose, melezitose, maltodextrins, dextrans, starches, and the like: and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyi sorbitol, myoinositol and the like. 25 [0074] The pharmaceutical formulation may also comprise a buffer or a pH adjusting agent, typically a. salt prepared .from an organic acid or base. Representative buffers comprise organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic- acid, Tris, tromethamine, hydrochloride, or phosphate buffers. 217512/3 20 [0075] The pharmaceutical formulation may also include polymeric excipients/additives, e.g.. polyvinylpyrrolidones, celluloses and derivatized celluloses such, as hydrpxymethylcellulose, hydroxyethyleellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g,, e.yclodextrins, such as 2-hydroxypropyi~.beta.-cyclodextrin 5 and sulfobutylether-.beta,<yclodextrin), polyethylene glycols, and pectin.

[0076] The pharmaceutical formulation may further include flavoring agents, taste-masking agents, inorganic salts (for example sodium chloride), antimicrobial agents (for example benzalkonium chloride), sweeteners, antioxidants,'antistatic agents, surfactants (for'example polysorbates such..as "TWEEN 20” and "TWEEN 80”), sorbitan esters, lipids (for example 0 phospholipids such, as lecithin and other phosphaddyleholines, phosphaiidylethanolamin.es), fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for example EDTA, zinc and-other-such suitable cations). Other pharmaceutical excipients and/or additives suitable for use in the compositions according to the-.invention are. listed in "Remington: The Science & Practice of Pharmacy”, i0.sup.th ed., Williams-& Williams, (1995),-and in the 5 "Physician's Desk Reference”, 52.sup.nd.ed., Medical Economies, Montvale, NJ. (1998). (0077] It should be noted that the methods, systems, and devices discussed above are intended merely to be examples. It must be .'stressed· that various embodiments may omit, substitute, or add various procedures or components as appropriate. For Instance, It should be appreciated 0 that, in alternative embodiments, the methods- may-be· performed in an order different from that described, and that various steps may he added, omitted, or combined. Also, features described with respect to certain embodiments may be combined in various other embodiments. Different aspects and elements of the embodiments may be combined in a similar manner. Also, it should be emphasized that .technology evolves and, thus, many of the elements -are examples and should 5 not be interpreted to limit the scope of the invention.

[0078] Specific details are given In the description to provide a thorough understanding of the embodiments. However, it will be understood by one of ordinary skill in the art that the embodiments may be practiced without these specific details. For example, well-known processes, algorithms, structures, and techniques' have been shown without unnecessary detail in WO 2011/009133 21 order to-avoid obscuring-the embodiments. This description provides example embodiments only, and is not intended .to limit the scope, applicability, or- configuration of the invention. Rather, the preceding description of the embodiments will provide those skilled in the art with an enabling description for implementing embodiments' of the invention. Various changes may he made in the function and arrangement of elements without departing from the spirit and scope of the invention.

[0070| Further, the preceding' description generally details aerosolizing liquid drugs. However, it- should be understood .that liquids besides liquid drugs may be aerosolized using similar devices and methods.

[0080] Also, it is noted that the. embodiments may be described as a process which is depicted as a Oow diagram or block diagram. Although each may describe the operations as a-sequential process, many of the operations can be performed in parallel or concurrently. In addition, the order of the operations may be rearranged. A process may have additional steps not included in the figure.