Systems and methods for driving sealed nebulizers

SYSTEMS AND METHODS FOR DRIVING SEALED NEBULIZERS

This application claims the benefit of U.S. Provisional Patent Application Serial No. 61/226,591, entitled SYSTEMS AND METHODS FOR DRIVING SEALED NEBULIZERS, filed July 17, 2009 (Attorney Docket No. 015225-012600US); FIELD OF THE INVENTION The title of the invention relates to co-pending Provisional Patent Application No. 61/226,567 (Attorney Docket No. 015225-012500US), filed July 17, 2009, entitled NEGATIVELY BIASED SEALED NEBULIZERS SYSTEMS AND METHODS, THEIR FULL DISCLOSURE Water is incorporated by reference for all purposes.

Embodiments of the present invention relate to nebulizers. Specifically, the present invention relates to the use of a variable voltage and frequency driver for a nebulizer with a sealed liquid drug reservoir capable of maintaining a negative bias pressure therein.

A wide variety of procedures have been limited to delivering drugs to patients. In some drug delivery procedures, the drug is a liquid and dispensed in the form of fine liquid droplets for inhalation by the patient. The patient may inhale the drug for absorption through the lung tissue. Additionally, the droplets that form an atomized mist may need to be very small to travel through the small airways of the lungs. Such a mist may be formed by a nebulizer.

Various systems, methods, and devices for driving a nebulizer using a driver unit are described. The nebulizer may include a sealed drug reservoir that allows a negative bias pressure to build up within the drug reservoir when liquid flows out of the drug reservoir. When 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 the nebulizer element to vibrate. The driver may output a waveform signal of variable frequency and magnitude to the nebulizer such that the nebulizer element vibrates at or near the resonant frequency and the nebulizer element atomizes the liquid at a constant rate and droplet size at or near a constant rate. .

In some embodiments, a method for determining the resonant frequency of an element of a nebulizer having a negatively biased reservoir is described. The method includes driving the nebulizer using an electrical signal, the electrical signal including a current and a voltage. The method may include measuring a phase shift between a voltage and a current of an electrical signal driving the nebulizer. The method may also include determining a resonant frequency of an element of the nebulizer based, at least in part, on a phase shift of the electrical signal driving the nebulizer.

In some embodiments, the method further comprises determining a voltage magnitude for the electrical signal based at least in part on the resonant frequency of the nebulizer determined by the driver. In some embodiments, the negatively biased liquid reservoir causes the resonant frequency of the element of the nebulizer to change when liquid exits the negatively biased liquid reservoir. In some embodiments, the method further comprises determining a negative bias pressure in a negatively biased liquid reservoir of the nebulizer based at least in part on a resonant frequency of the nebulizer determined by the driver. In some embodiments, the method further comprises adjusting the frequency of the electrical signal to the nebulizer, wherein an approximately constant phase shift is maintained between the voltage and the current of the electrical signal. In some embodiments, the voltage magnitude is determined using the stored set of values, which varies depending on the liquid in the negatively biased liquid reservoir.

In some embodiments, there is a device for driving an element of a nebulizer. The device may include an amplifier configured to generate an output waveform signal, the output waveform signal comprising an output current and an output voltage, the output waveform signal driving an element of the nebulizer at an output frequency. The device may include a phase shift detector configured to determine a phase shift between an output current and an 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 a phase shift of the output waveform signal determined by the phase shift detector module. The device may include a voltage profile configured to adjust an output voltage of an output waveform signal output by the amplifier based on a frequency of the waveform signal generated by the resonant frequency tracker.

In some embodiments, a system may be present for atomizing liquid stored in a negatively biased pressurized liquid reservoir. The system may include a nebulizer comprising an element and a negatively biased pressurized liquid reservoir. The element may be configured to vibrate to atomize the liquid exiting the negatively biased pressurized liquid reservoir. The negative bias pressure of the negatively biased reservoir may change when liquid stored in the negatively biased pressurized liquid reservoir drains. The negatively biased reservoir may be sealed such that air from the external environment does not substantially enter the negatively biased reservoir when the liquid stored in the negatively biased liquid reservoir is evacuated. The system may include a driver. The driver may include a phase shift detector configured to determine a phase shift between a current of the 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 a frequency of the output waveform signal, wherein the frequency is adjusted based on the phase shift determined by the phase shift detector module. The driver may include a voltage profile configured to adjust a voltage of the output waveform signal based on a frequency of the output waveform generated by the resonant frequency tracker.

In some embodiments, a method exists for aerosolizing a liquid. The method may include sealing the liquid within the reservoir. The method may also include generating an output waveform signal and vibrating the nebulizer element to aerosolize the liquid. A negative pressure may be created in the reservoir when 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 based at least in part on the phase shift. Additionally, the method may include adjusting a voltage of the output waveform signal based at least in part on a frequency of the output waveform signal.

A further understanding of the nature and advantages of the present invention may be realized with reference to the following drawings. In the appended drawings, similar components or properties may have the same reference label. Additionally, various components of the same type may be distinguished by a second label that distinguishes between similar components following the reference label. If only a first reference label is used in the specification, the description is applicable to any one of the similar components having the same first reference label irrespective of the second reference label.

1A shows a simplified embodiment of a nebulizer. 1B shows a simplified embodiment of a nebulizer with a driver unit. 1C shows a simplified embodiment of a handheld nebulizer with an integrated driver unit. 1D shows a nebulizer integrated with a ventilator. 2 shows a simplified embodiment of a driver coupled with a nebulizer. 3 shows a method of driving a nebulizer using a driver. 4 shows a method for initially determining the resonant frequency of a nebulizer element. 5 shows a simplified method of adjusting the frequency output by a driver using a resonant frequency tracker to keep the nebulizer element oscillating at its current resonant frequency.

Devices, systems, and methods for implementation of a novel architecture for driving nebulizers are described. The present invention allows the nebulizers to develop a negative bias pressure (meaning that the pressure in the reservoir is less than the pressure outside the reservoir), especially at the resonant frequencies of the nebulizers, when the liquid is expelled from the drug reservoir. It provides a variety of ways to drive nebulizers with sealed drug reservoirs. By creating a negative bias pressure within the nebulizer's drug reservoir, the effectiveness of the nebulizer may be increased, wherein the nebulizer achieves greater liquid flow rates with smaller, more constant droplet sizes than in comparable conditions without negative bias pressure. make it Such negative bias pressure may be created by sealing the drug reservoir. When liquid drug exits the drug reservoir (with no air entering to displace the drug volume), a negative bias pressure may be created. While the negative bias pressure helps maintain constantly sized droplets of the mist, when the negative bias pressure decreases in pressure, the flow rate of liquid from the nebulizer may increase.

The increased flow rate caused by negative bias pressure may lead to the creation of incorrect drop sizes and/or incorrect doses of drug to be delivered to the patient . Such inappropriate droplet sizes may alter how the droplets are absorbed into the human body. For example, if a patient inhales too many drops, the drops may not propagate to the patient's deep lung tissue, but rather, the drops may collect in the patient's larger airways. This may interfere with proper absorption of the drops by the patient.

Drops may be generated from a stored amount of liquid in the drug reservoir by the nebulizer element. The nebulizer element may be an aperture plate comprising a number of small holes. When an electrical signal, such as a waveform, is applied to the nebulizer element, the nebulizer element may vibrate at or near the frequency of the received waveform. While vibrating, the nebulizer element may cause any amount of liquid to penetrate the element and form airborne droplets. A nebulizer element may function more efficiently and produce consistent droplet sizes when the nebulizer element is oscillating at or near its resonant frequency.

However, when the negative bias pressure in the drug reservoir changes (eg, a larger difference is formed between the pressure in the drug reservoir and the ambient pressure outside the drug reservoir), the resonant frequency of the nebulizer element becomes It may change. In order to keep the nebulizer element oscillating at its (current) resonant frequency, it may be necessary to change the frequency of the waveform used to drive the nebulizer element.

Thus, when a negative bias pressure is maintained in the drug reservoir, the frequency and magnitude of the waveform used to drive the nebulizer element is a negative bias in the drug reservoir including maintaining a constant dose of liquid drug and constant drop sizes. It needs to change as the pressure changes to maintain efficient operation of the nebulizer element.

For the sake of clarity, a sealed reservoir refers to a reservoir that prevents air from entering the reservoir if liquid is escaping from the drug reservoir. However, it may still be possible for air to enter the sealed drug reservoir through holes in the nebulizer element. The greater the bias pressure (ie, 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.

1A shows one embodiment of a possible nebulizer 100 - a. Nebulizer 100 - a may include a nebulizer element 110 , a drug reservoir 120 , a headspace 130 , an interface 140 , and a cap 150 . The nebulizer element 100 may be constructed as a piezoelectric ring that may extend and contact when an electrical voltage is applied to the ring. The nebulizer element 110 may be a vibrating aperture plate. The piezoelectric ring may be attached to the perforated membrane. Such a perforated membrane may have a plurality of holes therethrough. When an electrical voltage is applied to the piezoelectric ring, this may cause the membrane to move and/or flex. Such movement of the membrane during contact with the liquid may cause atomization of the liquid (alternatively referred to as aerosolization).

A supply of liquid generally liquid medication may be held in medication reservoir 120 . When the weak drug is atomized, the amount of liquid drug remaining in the drug reservoir 120 may be reduced. Depending on the amount of liquid drug in drug reservoir 120, only a portion of the reservoir may be filled with liquid drug. The remaining portion of the drug reservoir 120 may be filled with a gas such as air. This space is generally referred to as headspace 130 . Interface 140 may function to transfer amounts of liquid drug between drug reservoir 120 and nebulizer element 110 .

Nebulizers and techniques related to such atomizers are described in US Pat. Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637; 6,014,970; 6,085,740; 6,235,177; 6,615,824; 7,322,349, the entire disclosures of which are incorporated by reference for all purposes.

A nebulizer with a sealed drug reservoir may be part of a larger system. The embodiment of FIG. 1B depicts such a system 100 - b . 1B shows a nebulizer 151 with a sealed drug reservoir connected to a driver 152 . The sealed nebulizer shown in FIG. 1B may be the nebulizer of FIG. 1A , or may represent some other nebulizer. The driver 152 may control the speed and magnitude of vibration of the nebulizer element on the nebulizer 151 . The driver 152 may be connected to the atomizer element 151 via a cable 153 . The driver 152 may adjust the voltage and frequency of the signal provided to the nebulizer element of the nebulizer 151 . The adjustment of the voltage and frequency of the signal may be based on the resonant frequency of the nebulizer element of the nebulizer 151 . Such a signal may vary depending on the magnitude of the negative bias pressure.

In some other embodiments of nebulizers, the driver may be included in a handheld unit with the nebulizer. Nebulizer 100 - c of FIG. 1C depicts one embodiment of a handheld nebulizer with an integrated driver. The atomizer 100 - c may include a case 155 , a mouthpiece 160 , and 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 in FIG. 1A ) and drivers (such as driver 152 in FIG. 1B ). may be Accordingly, contained within the case 155 may be a sealed drug reservoir and/or device capable of generating an electrical signal at a voltage magnitude and frequency to vibrate an element that atomizes the liquid stored in the drug reservoir. A person receiving the atomized liquid drug may place their mouth on the mouthpiece 160 and breathe. While the person receiving the atomized liquid drug is breathing, he may press the trigger button 165 to trigger the element to start aerosolizing the liquid. In some embodiments, the nebulizer 100 - c may include a sensor that detects when the person is breathing and triggers the element to vibrate without the necessary trigger button 165 .

Nebulizer 100 - c may also include an electrical plug 170 . The electrical plug 170 may be connected to an electrical outlet to power the atomizer 100 - c. The atomizer 100 - c may include a battery, thereby allowing the electrical plug 170 to be connected to an outlet and charging the battery when the atomizer 100 - c is not in use by a person. . Alternatively, in some embodiments of atomizer 100 - c , electrical plug 170 may need to be connected to an outlet when atomizer 100 - c is in use by a person. In some embodiments, nebulizer 100 - c may use replaceable batteries as its power source.

In some embodiments, the nebulizer may operate in conjunction with a ventilator. System 100 - d shows a nebulizer 178 that supplies atomized liquid drug to a person 176 via a ventilator 170 . The ventilator 170 may supply the person 176 with air suitable for breathing. The ventilator 170 may assist the person 176 to breathe by pushing air into the person's 176 lungs and then releasing the air for mimic breathing. While the person 176 is using the ventilator 170 , it may be necessary to provide the person 176 with an atomized liquid, such as a liquid drug.

Nebulizer 178 may be connected to drug reservoir 186 sealed by cap 180 . The drug reservoir 186 may contain any amount of the liquid drug 182 . This liquid drug may be delivered to the nebulizer 178 when the liquid drug is atomized by the nebulizer 178 . When the liquid drug is atomized, the liquid drug 182 may flow out of the drug reservoir 186 , thereby increasing the volume of the headspace 184 . The headspace 184 may include air. The headspace 184 may increase in volume, but decrease in pressure when the liquid drug 182 flows out because the liquid reservoir 186 allows minimal or no air into the headspace 184 . You may.

Driver 172 , which may represent the same driver as driver 152 of FIG. 1B (or may represent some other driver) may pass a signal to atomizer 178 . These signals may control vibrations of elements of the nebulizer 178 . Nebulizer 178 may be attached to a tube 179 used to deliver air and atomized liquid drug to patient 176 . The tube 179 may terminate in a mask 174 covering the mouth and/or nose of the person 176 . Thereafter, air and atomized liquid drug may enter the airways of person 176 .

A nebulizer, such as the nebulizers shown in FIGS. 1A-1D , may be connected with a driver as shown in FIG. 2 . 2 shows a simplified block diagram of a nebulizer driver unit 200 . The nebulizer 260 may be the nebulizer 100 - a of FIG. 1A , or some other nebulizer, such as the nebulizers of the referenced applications or FIGS. 1B-1D . The atomizer may be connected to the driver via a cable 270 . The driver 210 may be the driver 151 of FIG. 1B or some other driver. Cable 270 may cause driver 210 to transmit an electrical waveform signal of variable frequency and magnitude (of voltage) via cable 270 to drive atomizer 260 .

The driver 210 may include an amplifier 230 , a current phase shift detector 240 , a resonant frequency tracker 220 , and a voltage profile 250 . Based on the phase shift between the current supplied to the nebulizer 260 and the voltage generated by the amplifier 230 , the resonant frequency of the nebulizer element may be determined. From the resonant frequency, a negative bias pressure in the drug reservoir of the nebulizer may be determined, and the frequency and/or magnitude of the electrical waveform signal driving the nebulizer 260 may be adjusted.

Determination of the resonant frequency may be accomplished using a current phase shift detector 240 . The current phase shift detector 240 monitors a phase shift between the phase of the current output by the amplifier 230 to the nebulizer 260 and the phase of the voltage output by the amplifier 230 to the nebulizer 260 . Based on the phase shift between the voltage and current observed by the current phase detector 240 , the resonant frequency tracker 220 , the voltage and current of the electrical waveform signal at which the amplifier 230 drives the elements of the nebulizer 260 . The output waveform is output to the amplifier 230 to output an electrical waveform signal having a constant or nearly constant phase shift therebetween.

When the liquid is atomized and the bias pressure in the drug reservoir changes, the resonant frequency may change. Additionally, factors other than the bias pressure within the sealed drug reservoir of the nebulizer 260 may alter the resonant frequency of the nebulizer element. For example, the temperature of the nebulizer element, excess liquid on the nebulizer element, and/or damage to the nebulizer element may result in fluctuations in the resonant frequency of the nebulizer element. However, it may be generally accepted that, during operation, changes in the resonant frequency of the nebulizer element are generally due to variations in the bias pressure within the nebulizer's drug reservoir.

The resonant frequency and/or the measured change in resonant frequency may be transmitted as a voltage profile 250 by the resonant frequency tracker 220 . Voltage profile 250 may be used to determine an appropriate magnitude of voltage to apply to the nebulizer element at a particular resonant frequency to maintain a constant droplet size and dose of atomized liquid. In some embodiments, voltage profile 250 may include a table of empirically collected data. In such embodiments, the resonant frequency may be placed in a table with a corresponding analog or digital signal to be output to the amplifier 230 that specifies a voltage of the appropriate magnitude that the amplifier 230 should output. For example, the table may include predetermined voltage magnitudes that may be communicated to the amplifier 230 when a particular resonant frequency is measured by the resonant frequency tracker module 220 . Voltage profile 250 may also be represented as a graph of values, where the x-axis is the frequency of the waveform generated by the resonant frequency tracker 220 and the y-axis is where the amplifier 230 outputs an electrical signal of the correct magnitude. It represents an appropriate voltage level to be supplied to the amplifier 230 so as to do so.

A brief explanation 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 signal output to the nebulizer will decrease. At a certain threshold, if the resonant frequency continues to increase, the voltage will be held by voltage profile 250 at a minimum level. In some embodiments of voltage profile 250 , the signal output to amplifier 230 is determined based on a calculation using the resonant frequency supplied by resonant frequency tracker 220 .

The voltage profile may need to be modified or adjusted to accommodate characteristics (such as surface tension) of different liquids within the drug reservoir of the nebulizer. In some embodiments, a liquid drug such as amikacin is used. In other embodiments, a different liquid drug or liquid is used. In some embodiments, the voltage profiles needed for multiple liquids or liquid drugs may be sufficiently similar that only one voltage profile needs to be used for multiple liquids or liquid drugs. Modifying or replacing voltage profile 250 may include selecting a different liquid via a user interface on driver 210 or loading with different software, firmware, and/or hardware.

The resonant frequency tracker 220 may transmit a waveform to the amplifier 230 at or near the currently determined resonant frequency of the nebulizer element. Voltage profile 250 may send a signal to amplifier 230 indicative of a desired voltage amplitude to be output by amplifier 230 . This signal from voltage profile 250 may serve to control the gain of amplifier 230 . Based on the input from the resonant frequency tracker 220 and the desired voltage amplitude received from the voltage profile 250, the amplifier 230 generates an output electrical signal that may be used to drive the aperture 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 conjunction with a variable gain amplifier or potentiometer. Additionally, various other amplifiers or amplifier-based circuits may be used to generate the output electrical signal for driving the nebulizer 260 .

The current phase shift detector 240 may create a feedback loop for the resonant frequency tracker 220 . The current phase shift detector 240 may determine a phase shift of the current to be output from the amplifier 230 . Such a phase shift may be transmitted to the resonant frequency tracker 220, whereby the resonant frequency tracker 220 (phase shifted) in response to the changing resonant frequency of the nebulizer element when the bias pressure within the sealed drug reservoir changes. Otherwise) keep the same frequency signal, increase the frequency, or decrease the frequency of the output signal. Feedback through the current phase shift detector 240 may cause the driver 210 to periodically or continuously adjust the magnitude and frequency of the electrical signal output to the nebulizer element while the liquid is being atomized. This may allow any change in the bias pressure in the liquid reservoir to be continuously adjusted for the driver.

A driver such as driver 210 of FIG. 2 may drive the 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 use a variety of different atomizers, such as the atomizers of FIGS. 1A-1D and 2 . At block 310 , the driver may use an electrical signal to drive an element (also referred to as an aperture) of the nebulizer. This electrical signal may be a waveform of a specific frequency and magnitude.

At block 320, a phase shift between the voltage of the electrical signal output to the nebulizer and the current of the electrical signal may be measured. At block 330 , using this phase shift, the resonant frequency of the nebulizer element may be determined. As previously mentioned, this resonant frequency may shift when the negative bias pressure in the liquid reservoir of the nebulizer changes. From the resonant frequency, a bias pressure in the liquid reservoir may be determined at block 340 . In some embodiments, a 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 frequency determined at block 330 and/or the negative bias pressure determined at block 340 . The resonant frequency and/or negative bias pressure may be used to consult a table of values. This table of values may specify an appropriate magnitude of the voltage to be used for the electrical signal driving the nebulizer element. Alternatively, the resonant frequency and/or negative bias pressure may be used to calculate an appropriate voltage magnitude to drive the nebulizer element. A suitable size may correspond to a size that maintains a constant dosing rate and droplet size of the liquid to be dispensed from the dispenser. The calculations or table may vary depending on the properties of the liquid to be dispensed.

At block 360 , the electrical waveform signal driving the nebulizer element may be adjusted according to the frequency determined at block 330 and/or the magnitude determined at block 350 . If the resonant frequency of the nebulizer element does not change, the frequency and/or magnitude of the electrical signal driving the nebulizer element may not change. Method 300 may be repeated as long as the nebulizer element is being driven by a driver.

A resonant frequency tracker, such as resonant frequency tracker 220 of FIG. 2 , may follow various methods to determine and maintain an output at or near the resonant frequency of an nebulizer element, such as nebulizer element 260 of FIG. 2 . 4 shows first 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 the current of the electrical signal driving the nebulizer element detected by the current phase shift detector. A simplified flow diagram of a decay profile 400 for The method 300 of FIG. 3, when implemented in software, firmware, and/or hardware, may be implemented using the resonant frequency tracker 220 of FIG. 2, or may be implemented using some other resonant frequency tracker. have.

If the resonant frequency is not determined or "locked on" by the resonant frequency tracker, the resonant frequency tracker may perform method 400 . For example, if the driver has not yet been turned on or activated, a new nebulizer is attached to the driver unit, the nebulizer element is interfered with, or the nebulizer element is damaged, the resonant frequency tracker may not lock on to the longitudinal frequency. .

At block 411 , the resonant frequency tracker may apply an infinite impulse response filter ("IIR filter") to the phase signal received from the current phase shift detector. The IIR filter may be implemented using analog and/or digital components. From this, a filtered phase value may be obtained.

Using the filter phase value, an error between the filtered phase and a desired phase setpoint may be determined at block 412 . The desired phase set point may indicate the phase required to cause the nebulizer element to oscillate at the resonant frequency. Then at block 413, this determined error value may be used to determine if the error is less than the set point for a time greater than one second. In some embodiments, different lengths of time are used.

If the error is less than the set point for more than one second, then the current frequency of the signal output to the nebulizer is stored in block 414 . Additionally at block 415, a flag may be set to indicate that the resonant frequency is locked on by the resonant frequency tracker. Returning to block 413 , if the error is not less than the set point for more than one second, the process proceeds to block 430 .

At block 430 , if the average current is less than some threshold current value, then the output voltage may be set to a starting 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 the threshold current value, blocks 432 and 434 may not be performed. Method 400 may repeat until a flag indicating the resonant frequency of the nebulizer element is locked on.

Once the resonant frequency, which may relate to which the resonant frequency flag of block 414 is set, is determined and locked, the second method may follow. Method 500 represents a method for adjusting a frequency using a resonant frequency tracker to keep a nebulizer element oscillating at its current resonant frequency. An error between the current frequency and the resonant frequency may be determined at block 521 . From this, an error value may be obtained.

A determination may be made at block 522 if the actual frequency of the signal generated by the resonant frequency tracker is greater than the resonant frequency of the nebulizer element. If so, at block 523 the output voltage may be scaled by the decay rate multiplied by the error rate determined at block 521 , 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 thresholds. Next, the process proceeds to block 530 . If it is not determined at block 522 that the actual frequency is greater than the resonant frequency, then the output voltage is set to the starting voltage at block 525 and the method proceeds to block 530 .

At block 530, a determination is made whether the current is greater than a threshold current value. If so, the output voltage is set to the starting voltage at block 532 , and the resonant frequency is reset at block 534 .

Although a wide variety of drugs, liquids, liquid drugs, and drugs dissolved in liquids are aerosolized, the following provides broad examples of what may be aerosolized. Additional examples are provided in US Application Serial No. 12/341,780, the entire disclosure of which is incorporated herein for all purposes. In general, any anti-gram-negative, anti-gram-positive antibiotic, or combinations thereof, may be used. Additionally, antibiotics may include antibiotics with broad spectrum effectiveness or mixed spectrum effectiveness. Polyene materials in particular antifungal agents such as amphotericin B are also suitable for use herein. 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, netylmycin, paramesin, tobramycin, salts thereof, and combinations thereof. For example, gentamicin sulfate is a sulfate or mixture of antibiotic substances produced by the growth of Micromonospora purprea. Gentamicin sulfate, USP, may be obtained from Fujian Fukang Pharmaceutical Co.,LTD, Fuzhou, China. Amikacin is commonly supplied as a sulfate salt and may be obtained, for example, from Bristol-Myers Squibb. Amikacin may also contain related substances such as kanamycin.

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 example, vancomycin hydrochloride is a hydrochloride salt of the vancomycin antibiotic produced by certain strains of Amycoratopsis orientalis previously designated Streptomyces orientalis. Vancomycin hydrochloride is a mixture of related substances consisting mainly of the monohydrochloride salt of vancomycin B. Like all glycopeptide antibiotics, vancomycin hydrochloride contains a central core heptapeptide. Vancomycin hydrochloride, USP, may be obtained from Alpharma, Copenhagen, Denmark.

In some embodiments, the composition comprises an antibiotic and one or more additional active agents. Additional active agents described herein include agents, drugs, or compounds, and often provide some beneficial pharmacological effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmaceutically active substance that produces a localized or systemic effect in a patient. Active agents for incorporation into the pharmaceutical formulations described herein include peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, synoptic sites. Inorganic or organic substances including, but not limited to, drugs acting on , neuroeffector junction sites, endocrine and hormonal systems, immune system, reproductive system, skeletal system, otachoid systems, digestive and excretory systems, histamine system, and central nervous system It may be a compound.

Examples of additional active agents include, but are not limited to, anti-inflammatory agents, bronchodilators, and combinations thereof.

Examples of bronchodilators include, but are not limited to, beta-agonists, antimuscarinics, steroids, and combinations thereof. For example, the steroid may include albuterol, such as albuterol sulfate.

Active agents include, for example, hypnotics and sedatives, psychoactive agents, psychostabilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinsonians (dopamine antagnonists). ), pain relievers, anti-inflammatory drugs, anti-anxiety drugs (anxiolytics), appetite suppressants, migraine drugs, muscle contraceptives, additional anti-infectives (antivirals, antifungals, vaccines), anti-arthritic drugs Drugs, antimalarials, antiemetics, anepileptics, cytokines, growth factors, anticancer drugs, antithrombotic drugs, antihypertensives, cardiovascular drugs, antiarrhythmic drugs, antioxicants , antiasthmatics, hormones including contraceptives, sympathomimetics, diuretics, lipid regulating agents, anti-androgenic drugs, antiparasitic drugs, anticoagulants, neoplastic agents ( neoplastics), anti-tumor drugs, hypoglycemic agents, nutrients and supplements, growth supplements, anti-enteritis agents, vaccines, antibodies, diagnostic agents, and contrast agents. Active agents may act locally or globally when administered by inhalation.

Active agents include small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, etc. It may exist in one of a number of structure classes including, but not limited to.

Examples of active agents suitable for use in the present invention include calcinonin, amphotericin B, erythropoietin (EPO), factor VIII, factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF) , thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcanonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), Heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, pro-insulin, insulin derivatives (eg mono-acylated insulin as described in US Pat. No. 5,922,675, incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin derivatives including octreotide, vasopressin, Follicle Stimulating Hormone (FSH), Insulin-Like Growth Factor (IGF), Insulintrophin, Macrophage Colony Stimulating Factor (MCSF), Nerve Growth Factor (NGF), Tissue Growth Factor, Keratinocyte Growth Factor (KGF), Glia Growth factor (GGF), tumor necrosis factor (TNF), endothelial cell proliferation factor, parathyroid hormone (PTH), glucagon-derived peptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, phosphodiesterase (PDE) ) compounds, VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease, bactericidal/osmotic enhancing protein (BPI), anti- CMV antibody, 1 3-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, fluritromycin, dilithromycin, irradiation Mycin, spiromycin, madecamycin, leukomycin, myokamycin, lokitamicin, and azithromycin, and swinolide A; Ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxacin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, romefloxacin, sparfloxacin, temfloxacin Phloroquinolones such as pefloxacin, amifloxacin, pleloxacin, tosufloxacin, proliproxacin, irloxacin, pazufloxacin, clinafloxacin, and cytafloxacin polymyxins, such as teicoplanin, rampolanin, mideplanin, colistin, deptomycin, gramicidin, colistymethate, polymyxin B, capreomycin, bacitracin, penicillins; penicillinase-resistant agents such as penicillin G, penicillin V, and penicillinase-resistant agents such as methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microbial activators such as ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; anti-p. aeruginosa penicillins such as carbenicillin, chicarcillin, azlocillin, mezlocillin, and piperacillin; cefodoxime, cefprozil, ceftbutene, ceftizoxime, ceftiaxone, cepharosin, ceparillin, cephalexin, cephradrine, cefoxitin, cefamandol, cefazolin, cephaloridine, cefachloro, cefatroxil, cefalogricin, ceproxime, seforanid, cefotaxime, cefatrizine, cefacetril, cefepime, cefixime, cefoniside, sephorerazone, sephotetan, cephinetatazole cephalosporins such as , ceftazidim, lorakabev, and mosalactam, and monobactams such as aztreonam; and imipenem, meropenem, pentamidine isethionate, lidocaine, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, bunesonide acetonide, fluticasone, ipratropium bromide, flu carbapenems such as nisolide, chromoline sodium, ergotamine tartare and, where applicable, one or more of the above derivatives, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms. Not limited.

Active agents for use in the present invention are suitable for transfection or modification of bare nucleic acid molecules, vectors, related viral particles, plasmid DNA or RNA or cells, i.e. gene therapy comprising antisense. It further includes nucleic acids, such as other nucleic acid constructs of a suitable type. Additionally, the active agent may include live attenuated or attenuated viruses suitable for use as vaccines. Other useful drugs include those listed in the Physician Desk Reference (most recent edition), which is incorporated herein by reference in its entirety.

The amount of antibiotic or other active agent in a pharmaceutical formulation will be that amount necessary to deliver a therapeutically or prophylactically effective amount per single dose to achieve the desired result. In practice, this will vary widely depending on the particular agent, its activity, the severity of the condition being treated, the number of patients, the dosing requirements, and the desired therapeutic effect. In general, the composition will contain somewhere from about 2 wt% to about 95 wt% of the active agent, or from about 1 wt% to about 99 wt%, such as from about 5 wt% to 85 wt%, and will also depend on the relative amounts of additives included in the composition. will be. The compounds of the present invention provide active agents that deliver from 0.001 mg/day to 100 mg/day in a single dose, such as 0.01 mg/day to 75 mg/day in a single dose or 0.10,g/day to 50 mg/day in a single dose. especially useful for It will be understood that more than two active agents may be included in the formulations described herein, and use of the term "agent" does not in any way preclude the use of two or more such agents.

In general, the compounds are free of excess excipients. In one or more embodiments, the water-soluble compound consists essentially of an anti-gram-negative antibiotic such as amikacin, or gentamicin or both, and/or salts thereof and water.

Additionally in one or more embodiments, the water-soluble compound is preservative-free. In this regard, the water-soluble compound may be methylparaben-free and/or propylparaben-free. Still further, the water-soluble compound may be salt-free.

In one or more embodiments, the compositions include an anti-infective agent and an excipient. The compositions may include a pharmaceutically acceptable excipient or carrier that may be taken with lungs that do not have significant adverse effects of toxins on the subject, particularly on the lungs of the subject. In addition to the active agent, the pharmaceutical formulation may optionally include one or more pharmaceutical excipients suitable for pulmonary care. If present, these excipients are present in the composition in an amount sufficient to perform their intended function, such as stability, surface modification, and improve the effectiveness or delivery of the composition or the like. Thus, if present, excipients may range from about 0.01 wt% 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 function in part to further improve the properties of the active agent composition, for example, by providing more efficient and reproducible delivery of the active agent and/or facilitating manufacture. In addition, one or more excipients may be provided to function as bulking agents when it is desirable to reduce the concentration of the active agent in the formulation.

For example, the compounds may include one or more osmolality modifiers, such as sodium chloride. For example, sodium chloride may be added to solutions of vancomycin hydrochloride to adjust the osmolality of the solution. In one or more embodiments, the water-soluble compound consists essentially of an anti-gram-positive antibiotic such as vancomycin hydrochloride, an osmolality regulator, and water.

Pharmaceutical excipients and additives useful in the pharmaceutical formulations of the present invention may be present singly or in combination with amino acids, peptides, proteins, abiotic polymers, biological polymers, carbohydrates such as sugar. sugars, derivative synthetic sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers.

Exemplary protein excipients include albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids (outside the dileucyl-peptidides of the present invention) that may also function in buffering capacity are alarmin, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine , leucine, isoleucine, valine, methiodine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. Amino acids and polypeptides that function as dispersants are preferred. Amino acids within this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alarmin, methionine, phenylalinine, tyrosine, histidine, and proline.

Carbohydrate excipients suitable for use in the present invention include, for example, 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 raffinose, melechinose, maltodextrins, dextranss, starches, and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, maoinositol, and the like.

Pharmaceutical formulations may also include buffers or pH adjusting agents, typically salts prepared from organic acids or organic bases. Representative buffers include organic acid salts of citric acid, ascorbic acid, glucoic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffers.

In addition, the pharmaceutical formulation may contain polymeric excipients/additives, for example, celluloses such as polyvinylpyrrolidones, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, and Derivatives Synthesized celluloses, picoll (polymeric sugar), hydroxyethyl starch, dextrates (eg, 2-hydroxypropyl-.beta.-cyclodextrin and sulfobutylether-.beta.- cyclodextrins such as cyclodextrin), polyethylene glycols, and pectin.

Pharmaceutical formulations include fragrances, taste masking agents, inorganic salts (eg sodium chloride), antibacterial agents (eg benzalkonium chloride), sweeteners, antioxidants, antistatic agents , surfactants (eg, polysorbates such as "TWEEN 20" and "TWEEN 80"), sorbitan esters, lipids (eg, lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (eg, cholesterol), and chelating agents (eg, EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and/or excipients suitable for use in the compositions according to the present invention are described in "Remington: The Science & Practice of Pharmacy", 19.sup.th ed., Williams & Williams (1995), and "Physician's Desk Reference", 52.sup.nd ed., Medical Economics, Montvale, NJ, (1998), both of which are incorporated herein by reference in their entirety.

It should be noted that the methods, systems, and devices described above are intended to be illustrative only. It should be emphasized that various embodiments may omit, substitute, or add various procedures or components as appropriate. For example, it should be appreciated that in alternative embodiments, the methods may be performed in an order different from the described order, and various steps may be added, omitted, or combined. Also, features described with respect to particular 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 elements are illustrative, and should not be construed as limiting the scope of the invention.

Specific details are provided in the specification 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 described without unnecessary detail in order to avoid obscuring the embodiments. This description provides exemplary embodiments only, and is not intended to limit the scope, applicability, or configuration of the present invention. Instead, the previous description of the embodiments will provide those skilled in the art with a possible description for implementing the embodiments of the present invention. Various changes may be made in the function and arrangement of elements without departing from the spirit and scope of the invention.

Additionally, the previous description generally details aerosolization of liquid drugs. However, it should be understood that liquids other than liquid drugs may be aerosolized using similar devices and methods.

It is also noted that embodiments may be described as processes depicted as flowcharts or block diagrams. Although each may describe the operations as a sequential process, multiple operations may be performed in parallel or concurrently. Additionally, the order of operations may be rearranged. A process may have additional steps not included in the figures.