Systems and methods for driving sealed nebulizers.

(54) Title: SYSTEMS AND METHODS FOR OPERATING SEALED NEBULIZERS.

(54) Title: SYSTEMS AND METHODS FOR DRIVING SEALED NEBULIZERS.

(57) Summary

Various methods, devices, and systems for spraying a liquid are described. Modalities may include sealing the liquid within a reservoir. An output waveform signal can be generated. A nebulizer element can be vibrated to spray the liquid. Negative pressure can build up inside the reservoir as the liquid is sprayed on. The output waveform signal can cause the nebulizer element to vibrate. Modalities may comprise determining a phase shift between an output waveform signal current and an output waveform signal voltage. Also, the modalities may comprise adjusting a frequency of the output waveform signal based at least partially on the phase change. In addition, the modalities may comprise adjusting the output waveform signal voltage based at least partially on the output waveform signal frequency.

(57) Abstract

Various methods, devices, and systems are described for aerosolizing a liquid. Embodiments may inelude sealing the liquid within a reservoir. An output waveform signal may be generated. A nebulizer element may be vibrated 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. Embodiments may involve determining a phase shift between a current of the output waveform signal and a voltage of the output waveform signal. Also, performances may involve adjusting a frequeney of the output waveform signal at least partially based on the phase shift. Further, performances may involve adjusting the voltage of the output waveform signal at least partially based on the frequeney of the output waveform signal.

SYSTEMS AND METHODS FOR OPERATING SEALED NEBULIZERS

FIELD OF THE INVENTION

The embodiments of the present invention relate to nebulizers. In particular, the present invention relates to the use of an actuator of variable frequency and voltage for a nebulizer having a sealed liquid drug reservoir capable of maintaining a negative internal bias pressure.

BACKGROUND OF THE INVENTION

A wide variety of procedures have been proposed for administering a drug to a patient. In some drug administration procedures, the drug is a liquid and is dispensed in the form of fine liquid drops for inhalation by a patient. A patient can inhale the drug by absorption through lung tissue. Additionally, the droplets that make up the mist spray need to be very small to travel through the small airways of the lungs. This mist can be formed by a nebulizer.

BRIEF DESCRIPTION OF THE INVENTION

Various systems, methods and devices for driving a nebulizer using a drive unit are described. The nebulizer may include a sealed drug reservoir such that a negative bias pressure can form within the drug reservoir as liquid is drained therefrom. As the negative bias pressure changes, the resonant frequency of the nebulizer element can change. An actuator can be used to drive the nebulizer element and make it vibrate. The actuator can transfer a waveform signal of varying frequency and magnitude to the nebulizer such that the nebulizer element vibrates at a resonant or near-resonant frequency and the nebulizer element atomizes liquid at a constant or near-constant rate and size of droplet.

In some embodiments, a method of determining a resonant frequency of a nebulizer element with a negatively polarized liquid reservoir is described. The method may include operating a nebulizer using an electrical signal, the electrical signal comprising a current and a voltage. The method may include measuring a phase shift between the voltage and current of the electrical signal that drives the nebulizer. The method may also include, based at least in part on the phase change of the electrical signal driving the nebulizer, determining a resonant frequency of the nebulizer element.

In some embodiments, the method further comprises, based at least in part on the resonant frequency of the nebulizer determined by the actuator, determining a voltage magnitude for the electrical signal. In some embodiments, the negatively polarized liquid reservoir causes the resonant frequency of the nebulizer element to vary as liquid is drained from the negatively polarized liquid reservoir. In some embodiments, the electrical signal driving the nebulizer causes the nebulizer element to vibrate and atomize the liquid stored in the negatively polarized liquid reservoir. In some embodiments, the method further comprises based, at least in part on the resonant frequency of the nebulizer determined by the actuator, determining, by the actuator, a negative bias pressure within the liquid reservoir, negatively biased of the nebulizer. In some embodiments, the method further comprises adjusting the frequency of the electrical signal to the nebulizer, where an approximately constant phase change is maintained between the voltage and current of the electrical signal. In some embodiments, the magnitude of voltage is determined using a stored set of values, and the stored set of values ​​varies depending on the liquid in the liquid reservoir, negatively polarized.

In some embodiments, a device is present to drive 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, wherein the output waveform signal₅ Output drives the nebulizer element at the output frequency. The device may include a phase shift detector, configured to determine the phase shift between the output current and the output voltage of the output waveform signal. The device may include a₁₀ Resonant frequency tracker, configured to generate a variable frequency waveform signal input to the amplifier, where the variable frequency is adjusted based on the phase change of the output waveform signal determined by the phase change. fifteen The device may include a voltage profile, configured to adjust the output voltage of the output waveform signal produced by the amplifier based on the frequency of the waveform signal generated by the resonant frequency follower.

In some embodiments, a system for atomizing liquid stored in a pressurized, negatively polarized liquid reservoir may be present. The system may include a nebulizer, comprising a negatively polarized, pressurized element and liquid reservoir.

The element can be configured to vibrate to atomize the liquid drained from the pressurized, negatively polarized liquid reservoir. A negative pressure of pressurized, negatively polarized can change 5 as the liquid stored in the liquid tank is drained, pressurized, negatively polarized. The negatively polarized pressurized reservoir may be sealed such that no ambient air enters substantially the pressurized, negatively polarized reservoir as ₁₀ Drains the liquid stored in the liquid tank, pressurized, negatively 'polarized. The system may include an actuator. The actuator 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 actuator may include a resonant frequency tracker configured to generate an output waveform that adjusts the frequency of the output waveform signal, where the frequency is adjusted based on the phase change determined by the phase change. The actuator 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 follower.

In some embodiments, a method of spraying a liquid is presented. The method may include sealing the liquid inside a reservoir. The method may also include generating an output waveform signal and vibrating a nebulizer element to spray-apply the liquid. Negative pressure can build up inside the reservoir as the liquid is sprayed on. The output waveform signal can cause the nebulizer element to vibrate. The method may include ₁₀ determining a phase shift between an output waveform signal current and an output waveform signal voltage. The method may include adjusting a frequency of the output waveform signal, at least partially based on the phase change. Additionally, the method may include adjusting the output waveform signal voltage, at least partially based on the frequency of the output waveform signal.

BRIEF DESCRIPTION OF THE FIGURES

A further understanding of the nature and advantages of the present invention can be achieved by reference to the following figures. In the attached figures, components or similar features may have the same reference label. Additionally, several components of the same type can be distinguished by following the reference label for a second label that distinguishes between similar components. If only the first reference tag is used in the specification, the description applies to any of the similar components that have the same or first reference tag despite the second reference tag.

Figure 1A illustrates a simplified embodiment of a nebulizer.

Figure IB illustrates a simplified embodiment of a nebulizer with an actuator unit.

Figure 1C illustrates a simplified embodiment of a portable nebulizer with an integrated actuator unit.

Figure ID illustrates an integrated nebulizer with a fan.

Figure 2 illustrates a simplified embodiment of an actuator coupled with a nebulizer.

Figure 3 illustrates a method of driving a nebulizer with an actuator.

Figure 4 illustrates a method for initially determining a resonant frequency of a nebulizer element.

Figure 5 illustrates a simplified method for adjusting the frequency produced by an actuator using a resonant frequency follower to keep the nebulizer element vibrating at its current resonant frequency.

DETAILED DESCRIPTION OF THE INVENTION

Devices, systems and methods for the implementation of a new architecture to drive a nebulizer are described. The invention provides several ways to drive nebulizers at the resonant frequencies of the nebulizer, particularly nebulizers with sealed drug reservoirs capable of developing a negative bias pressure (meaning that the pressure within - £ Q of the reservoir is less than the pressure outside the reservoir ) as liquid is evacuated from the drug reservoir.

By creating a negative bias pressure within the drug reservoir of a nebulizer, the efficiency of a nebulizer can be increased, thereby allowing it to achieve higher liquid flow rates, with smaller and more consistent droplet sizes, than in comparable conditions without negative bias pressure.

This negative bias pressure can be created by sealing the drug reservoir. As the liquid drug is drained from the drug reservoir (with little or no air entering to replace the drug volume), a negative bias pressure can be created. While the negative bias pressure can help keep mist droplets consistent in size, as the negative bias pressure decreases in pressure, the liquid flow rate of the nebulizer can increase.

An increased flow rate caused by negative bias pressure can lead to the wrong dose of a medicine being administered to a patient and / or the generation of inappropriate droplet sizes. These inappropriate gout can alter with the drops are absorbed into the human body. For example, if a patient inhales drops that are too large, the drops cannot spread in₁₀ the patient's deep lung tissue, but rather, the droplets can congregate in the patient's larger airways. This can prevent proper absorption of the drops by the patient.

Droplets can be created from a stored amount of liquid in the drug reservoir by a nebulizer element. The nebulizer element may be an aperture plate that contains several 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 can allow a quantity of liquid to pass through the element and form airborne droplets. The nebulizer element can operate more efficiently and produce consistent droplet sizes when the nebulizer element is vibrating at or near its resonant frequency.

However, as the polarized negative pressure within the drug reservoir changes (for example, a greater difference between the pressure within the drug reservoir and the ambient pressure outside the drug reservoir forms) the resonant frequency of the nebulizer element You can change. In order to keep vibrating the element of₁₀ nebulizer at its resonant (current) frequency, it may be necessary to change the frequency of the waveform used to drive the nebulizer element.

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 the drug reservoir changes. in order to maintain efficient operation of the nebulizer element, including maintaining a consistent dose of the liquid drug and consistent droplet sizes.

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. However, it may 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 ambient pressure ₅ external pressure and pressure inside the drug reservoir), the faster air can enter through the nebulizer element.

Figure 1A illustrates one embodiment of a possible nebulizer 100-a. The nebulizer 100-a can include a₁₀ nebulizer element 110, a drug reservoir 120, an upper clearance 130, an interconnect 140, and a cap

150. Nebulizer element 110 may be comprised of a piezoelectric ring that can expand and contract when an electrical voltage is applied to the ring. The nebulizer element 110 may be a vibrating aperture plate. The piezoelectric ring can be attached to a perforated membrane. This perforated membrane can have several holes that pass through it. When an electrical voltage is applied to the piezoelectric ring, this 2 0 can cause the membrane to move and / or flex. This movement of the membrane, as long as it is in contact with a liquid, can cause the atomization (alternatively referred to as aerosol application) of the liquid.

A supply of a liquid, commonly a liquid drug, can be retained in the drug reservoir 120. As illustrated, a drug reservoir is partially filled with a liquid drug. As the liquid drug is atomized, the amount of liquid drug remaining in the drug reservoir 120 may decrease. Depending on the amount of the liquid drug in the drug reservoir 120, only a portion of the reservoir can be filled with liquid drug. The remaining portion of the drug reservoir 120 can be refilled with gas, such as air. This space is commonly referred to as a free upper space 130. An interconnect 140 can serve to transfer amounts of liquid drug between drug reservoir 120 and nebulizer element 110.

Nebulizers, - and the techniques associated with these nebulizers, are generally described in US Patent 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 full descriptions 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 Figure IB illustrates this system 100-b. Figure IB illustrates a nebulizer 151 with a sealed drug reservoir connected to an actuator 152. The sealed nebulizer illustrated in Figure IB may be the nebulizer of Figure 1A, or may represent some other nebulizer. Actuator 152 can control the speed and magnitude of vibration of the nebulizer element in nebulizer 151. Actuator 152 can be connected to nebulizer element 151 via cable 153. Actuator 152 can regulate the voltage and frequency of the signal provided to the Nebulizer element of the nebulizer 151. Regulation of the signal voltage and frequency can be based on the resonant frequency of the nebulizer element of the nebulizer 151.

This signal can vary depending on the magnitude of the negative bias pressure.

In some other nebulizer embodiments, an actuator can be incorporated into a portable unit with the nebulizer. The nebulizer 100-c of Figure 1C illustrates one embodiment of a portable nebulizer with an integrated actuator. The nebulizer 100-c may include a sleeve 155, a nozzle 160, a trigger button 165, and an electrical plug 170. Sleeve 155 may contain some or all of the items found in the nebulizer (such as nebulizer 100-a of Figure 1A) and actuators (such as actuator 152 of Figure IB) modalities. Therefore, contained within the sleeve 155 may be a sealed drug reservoir and / or a device capable of generating an electrical signal at a magnitude and frequency of voltage to vibrate an element that atomizes the liquid stored therein. drug depot. A person receiving the liquid spray drug can place his mouth on mouthpiece 160 and 5 breathe. While the person receiving the atomized liquid drug is breathing, she can press the activator button 165 to activate the element to begin aerosolizing the liquid. In some embodiments, the 100-c nebulizer may contain a sensor that detects when₁₀ the person is breathing and activates the element to vibrate without the need for activator button 165.

The nebulizer 100-c may also include an electrical outlet 170. The electrical outlet 170 can be connected to an electrical outlet to energize the nebulizer 100-c. The 100-c nebulizer can contain a battery, thereby allowing the electrical outlet

170 connect to an electrical outlet when the 100-c nebulizer is not in use by a person, allowing the battery to charge. Alternatively, in some embodiments of nebulizer 100-c, it may be necessary to connect electrical plug 170 to an electrical outlet while the nebulizer 100-c is in use by one person. In some embodiments, the 100-c nebulizer may use replaceable batteries as its power source.

In some embodiments, a nebulizer can operate in conjunction with a fan. System 100-d illustrates a nebulizer 178 that supplies atomized liquid drug to a person 176 via a ventilator 170. Ventilator 170 can supply adequate breathing air to the person

176. Ventilator 170 can assist person 176 to breathe by forcing air into person 176's lungs 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.

Nebulizer 178 can be connected to drug reservoir 186 which is sealed by a cap 180. Drug reservoir 186 can contain a quantity of liquid drug

182. This liquid drug can be distributed to the nebulizer

178 as the liquid drug is atomized by the nebulizer

178. As the liquid drug is atomized, the liquid drug 182 can be drained from the drug reservoir 186, thereby increasing the volume of the upper free space 184. The upper free space 184 can contain air. Upper clearance 184 may increase in volume, but may decrease in pressure as liquid drug 182 is drained because fluid reservoir 186 does not allow or allow little air in the upper clearance

184 .

The actuator 172, which may represent the same actuator as the actuator 152 of FIG. IB (or may represent some other actuator) can distribute a signal 5 to the nebulizer 178. This signal can control the vibration of a nebulizer element 178. The nebulizer

178 can be attached to tube 179 used to deliver air and atomized liquid drug to patient 176. Tube 179 may end in a mask 174 covering the mouth and / or nose of the person 176. Air and atomized liquid drug they can then enter the airway of person 176.

A nebulizer such as those illustrated in Figures 1A-1D can be connected to an actuator, such as that illustrated in Figure 2. Figure 2 illustrates a simplified block diagram of a nebulizer drive unit 200. Nebulizer 260 can be the nebulizer

100-a of Figure 1A or it may be some other nebulizer such as those in the referred applications or Figures 1B1D. The nebulizer may be connected to the actuator by a cable 270. The actuator 270 may be the actuator 151 of Figure IB, or it may be some other actuator. The wire

270 it may allow actuator 210 to transmit an electrical waveform signal of variable frequency and magnitude (voltage) through wire 270 to drive nebulizer 2 60.

Actuator 210 may include an amplifier

230, a current phase change detector 240, a resonant frequency follower 220, and a voltage profile ₅ 250. Based on the phase change between the current supplied to the nebulizer 260 and the voltage generated by the amplifier 230, the resonant frequency of the nebulizer element can be determined. From the resonant frequency, you can determine the negative bias pressure within the

1Q drug reservoir from the nebulizer, and you can adjust the frequency and / or magnitude of the electrical waveform signal that drives the 260.

Determination of the resonant frequency can be accomplished using the current phase change detector 240. The current phase change detector 240 monitors the phase change between the phase of the current transferred by the amplifier 230 to the nebulizer 260 and the phase of the voltage transferred by the amplifier 230 to the nebulizer 260. Based on the phase change between the voltage

0 and current observed by current phase change detector 240, resonant frequency follower 220 produces an output waveform to amplifier 230 such that amplifier 230 produces an electric waveform signal with constant or near phase change constant between voltage and current of the electrical waveform signal driving the nebulizer element 260.

As the liquid is atomized and changed by the bias pressure in the drug reservoir, you can change the resonant frequency. Furthermore, factors in addition to the bias pressure within the sealed drug reservoir of the nebulizer 260 can change the resonant frequency of the nebulizer element. For example, the temperature of the nebulizer element, excess liquid₁₀ in the nebulizer element, and / or damage to the nebulizer element can cause a variation in the resonant frequency of the nebulizer element. However, it is generally accepted that during operation, changes in the resonant frequency of the nebulizer element in general are due to variations in the bias pressure within the drug reservoir of the nebulizer.

The resonant frequency and / or the measured change in resonant frequency can be transmitted to voltage profile 250 by resonant frequency follower 220. Voltage profile 250 can be used to determine the appropriate magnitude of voltage to apply to the nebulizer element at a particular resonant frequency to maintain a consistent droplet size and the dosage of the atomized liquid. In some embodiments, the voltage profile 250 may include a table of empirically obtained data. In these modes, the resonant frequency can be located in the table, with a corresponding analog or digital signal being transmitted to amplifier 230 5 that specifies what appropriate magnitude of voltage amplifier 230 should be produced. For example, a table may include a predetermined voltage magnitude that can be communicated to amplifier 230 when a particular resonant frequency is measured by the frequency follower module] _ ₀ resonant 220. Voltage profile 250 can also be expressed as a graph of values, with the x axis being the frequency of the waveform generated by the resonant frequency follower 220, and the y axis representing the magnitude of voltage appropriate to be supplied to amplifier 230 such that amplifier 230 produces an electrical signal of correct magnitude.

A rough description of a 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 transmitted to the nebulizer will decrease. At a certain threshold, as the resonant frequency continues to increase, the voltage will be maintained by the 250 voltage profile at a minimum level. In some embodiments of voltage profile 250, the signal transmitted to amplifier 230 is determined based on a calculation using the resonant frequency supplied by resonant frequency follower 220.

The voltage profile may need to be modified or adjusted to accommodate the characteristics (such as surface tension) of different liquids within the nebulizer drug reservoir. In some embodiments, a liquid drug is used, such as

Amikasin.

In other embodiments, a different liquid drug or liquid is used. In some embodiments, the voltage profiles required for multiple liquids or liquid drugs may be similar enough that only one voltage profile for multiple liquids or liquid drugs need be used. Modifying or replacing the voltage profile

250 it may comprise selecting a different liquid through a user interface on the actuator 210 or by loading different software, circuit program and / or hardware on the actuator 210.

Resonant frequency tracker 220 can transmit a waveform at or near the current, determined, resonant frequency of the nebulizer element to amplifier 230. Voltage profile 250 can transmit a signal indicating the desired amplitude of voltage to be left to be transferred by amplifier 230 to amplifier 230.

This voltage profile signal 250 can serve to control the gain of amplifier 230. Based on the input waveform of the resonant frequency follower

220 and to the desired voltage amplitude received from the ₅ At voltage 250, amplifier 230 generates an electrical output signal that can be used to drive an opening in the nebulizer. An amplifier 230 may be a variable gain linear power amplifier. In some embodiments, a power amplifier of₁₀ Fixed gain in conjunction with a variable gain amplifier or potentiometer. Additionally, various other amplifiers or amplifier-based circuits can be used to generate the electrical output signal to drive the 2S0 nebulizer.

The current phase change detector 240 can create a feedback loop to the resonant frequency follower 220. The current phase change detector 240 can determine the phase change of current that occurs from amplifier 230. This change in phase of can transmit to resonant frequency follower

220, thereby allowing the resonant frequency follower 220 to either maintain the same frequency signal (if the phase has not changed), increase the frequency, or decrease the frequency of the output signal in response to the resonant frequency of the nebulizer element that changes as the bias pressure changes within the sealed drug reservoir. Feedback through current phase change detector 240 may allow actuator 210 to periodically adjust continuously the magnitude and frequency of the electrical signal transmitted to the nebulizer element while the liquid is being atomized. This may allow any change in bias pressure in the liquid reservoir to be continuously adjusted by the actuator.

An actuator, such as actuator 210 of FIG. 2, can drive a nebulizer element according to a method, such as method 300 of FIG. 3.

Alternatively, method 300 can be performed using some other actuator. Method 3 00 may employ several different nebulizers, such as the nebulizers in the figures. 1A-1D and FIG. 2. At block 310, the actuator may actuate an element (also referred to as an opening) of a nebulizer with an electrical signal. This electrical signal can be a waveform at a particular frequency and magnitude.

At block 320, the phase shift between the voltage of the electrical signal transmitted to the nebulizer and the current of the electrical signal can be measured. Using this phase change, at block 330, the resonant frequency of the nebulizer element can be determined. As noted above, this resonant frequency may change as the negative bias pressure within the nebulizer fluid reservoir changes. From the resonant frequency, in block 340, the bias pressure within the liquid reservoir can be determined. In some embodiments, the negative bias pressure is not determined.

2Q In block 3 50, the magnitude of the voltage of the electrical signal used to drive the nebulizer element can be determined. The magnitude can be determined using the resonant frequency determined in block 330 and / or the negative bias pressure determined in block 340. The resonant frequency and / or negative bias pressure can be used to consult a table of values. This table of values ​​can specify the appropriate magnitude of voltage to be used for the electrical signal that will drive the nebulizer element. Alternatively, the resonant frequency and / or negative bias pressure can be used to calculate the appropriate magnitude of voltage to drive the nebulizer element. The appropriate magnitude may correspond to a magnitude that maintains a constant dose rate and a constant droplet size of the liquid dispensed from the nebulizer. The calculations or table can vary depending on the properties of the liquid that is dispensed.

At block 360, the electrical waveform signal driving the nebulizer element can be adjusted according to the frequency determined in block 330 and / or the magnitude determined in block 350. If the resonant frequency of the nebulizer element, the frequency and / or the magnitude of the electrical signal that ₁₀ operates the nebulizer element cannot change. Method 300 can be repeated as long as the nebulizer element is being actuated by the actuator.

A resonant frequency tracker, such as resonant frequency tracker 220 of FIG. 2, can follow various methods for determining and maintaining an output at or near the resonant frequency of a nebulizer element, such as nebulizer element 260 of figure 2. FIG. 4 illustrates a simplified flow chart of a decomposition profile 400 to initially determine the resonant frequency of the nebulizer element and adjust the electrical output signal that drives the nebulizer element based on the phase change between voltage and current. of the electrical signal that activates the nebulizer element detected by the current phase change detector. Method 300 of Figure 3 can be implemented using a resonant frequency tracker 220 of Figure 2, or can be implemented using some other resonant frequency tracker, which is ₅ Implement in software, circuit program and / or hardware.

If the resonant frequency has not been determined by a resonant frequency tracker, a resonant frequency tracker can carry out method 400. The resonant frequency tracker cannot have followed the 3_0 resonant frequency if, for example, the actuator only has been turned on or activated, a new nebulizer is attached to the drive unit, the nebulizer element has been interfered with, or the nebulizer element has been damaged.

At block 411, the resonant frequency follower 25 can apply an infinite impulse response filter (IIR filter), to the phase signal received from the current phase change detector. The IIR filter can be implemented using analog and / or digital components. From this, a filtered phase value can be obtained.

Using the filtered phase value, at block 412 the error between the filtered phase and desired phase set point can be determined. The desired phase set point can indicate the phase required for the nebulizer element to vibrate at a resonant frequency. This determined error value can then be used to determine if the error has been a value smaller than the set point for more than one second in block 413. In some 5 modes, a different length of time is used.

If the error has been less than the set point for more than one second, the current frequency of the signal transmitted to the nebulizer is stored in block 414.

Additionally, an indicator can be set to indicate 2_q that the resonant frequency has been followed by the resonant frequency tracker in 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.

In block 430, if the average current is less than some threshold current value, the output voltage can be adjusted to a start voltage in block 432. In block 434, the resonant frequency determined by the follower of resonant frequency can be reset to an initial value. If the voltage current is not less than a threshold current value, blocks 432 and 434 cannot be performed. Method 400 can be repeated until the indicator indicates that the resonant frequency of the nebulizer element has been followed.

Once the

Res resonant frequency, which may comprise adjusting the resonant frequency indicator of block 414, a second method can be followed. Method 500 represents a method of adjusting the frequency using a resonant frequency tracker to keep the nebulizer element vibrating at its resonant current frequency. The error between the current frequency and the resonant frequency can be determined in block 521. From this, an error value can be obtained.

3_q A determination if the current frequency of the signal that is generated by the resonant frequency follower is greater than the resonant frequency of the nebulizer element can be made in block 522. If yes, in block 523, the output voltage it can be scaled by a decomposition rate multiplied by the error ratio determined in block 521, and the output voltage can be limited to the terminal voltage in block 524. This can prevent the output voltage from exceeding some maximum and / or minimum threshold value. The process then proceeds to block 530. If the actual frequency is not determined to be greater than the resonant frequency in block 522, the output voltage is adjusted to a start voltage in block 525, and the method proceeds to block

530.

At block 530, a determination is made whether the current is less than a threshold current value. If so, the output voltage is adjusted to the start voltage in block 532 and the resonant frequency is reset in block 534.

While a wide variety of drugs, liquids, liquid drugs, and drugs dissolved in liquid can be aerosolized, the following provides extensive examples of what can be applied by aerosol.

Additional examples are provided in United States Patent Application No. 12 / 341,780, the full disclosure of which is incorporated herein for all purposes. Almost any anti-gram-negative, anti-gram-positive antibiotic or combinations thereof can be used. Additionally, antibiotics may comprise those that have broad spectrum effectiveness, or mixed spectrum effectiveness. Antifungal agents, 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, amycin, kanamycin, streptomycin, neomycin, netilmycin, paramecin, tobramycin, salts thereof, and combinations thereof. For example, gentamicin sulfate is the sulfate salt, or a mixture of these salts, of the antibiotic substances produced by the growth of Micromonospora purpurea. Gentamicin sulfate, USP, can be obtained from

Fujian Fukang Pharmaceutical Co., LTD, Fuzhou, China.

Amicacin is typically supplied as a sulfate salt, and can be obtained, for example, from Bristol-Myers Squibb. Amicacin can include 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 vancomycin hydrochloride salt, an antibiotic produced by certain strains of Amycolatopsis orientalis, formerly designated Streptomyces orientalis. Vancomycin hydrochloride is a mixture of related substances consisting mainly of vancomycin B monohydrochloride, like all glycopeptide antibiotics, vancomycin hydrochloride contains a core, central heptapeptide. Vancomycin hydrochloride, USP, can be obtained from

Alpharma, Copenhagen, Denmark.

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 compound, which provides some pharmacological, 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 active agent for incorporation into the pharmaceutical formulation described herein can be an inorganic or organic compound, including, without limitation, drugs that act on: peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuro-effector binding sites, endocrine and hormonal systems, the immune system, the reproductive system, the skeletal system , autacoid systems, the food and excretory systems, the histamine system, and the central nervous system.

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, anti-muscarinic agents, spheroids, and combinations thereof. For example, the spheroid may comprise albuterol, such as albuterol sulfate.

Active agents may comprise, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagonists), pain relievers, anti-inflammatories, anti-anxiety drugs (anxiolytics), appetite suppressants, agents antimigraine, muscle contractors, additional anti-infectives (antiviral, antifungal, vaccines) antiarthritic, antimalarial, antiemetic, anepileptic, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, anti-arrhythmics, antioxidants, anti-asthma agents, hormonal agents, including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasites , anticoagulants, neoplastic, antineoplastic, hypoglycemic, nutritional agents and nutritional supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents and contrast agents. The active agent, when administered by inhalation, can act locally or systemically.

The active agent can fall into one of several structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, spheroids, proteins capable of producing physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and Similar.

Examples of suitable active agents for use in this invention include but are not limited to one or more Calcitonin, Amphotericin B, Erythropoietin (EPO), Factor

VIII, Factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-l-proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), hormone growth, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, beta interferon, gamma interferon, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin6, luteinizing hormone-releasing hormone (LHRH), factor

IX, insulin, proinsulin, insulin analogues (eg, mono-acylated insulin as described in US Patent Nos.

United States No. 5,922,675, which is incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle-stimulating hormone (FSH), insulin-like growth factor ( IGF), ₁₀ insulintropine, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factors, parathyroid hormone (PTH), thymosin alpha I inhibitor, glucagon peptide Ilb / lIIa, alpha-1antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibodies, cystic fibrosis transmembrane regulatory gene (CFTR), deoxyribonuclease (DNase), protein that increases permeability / bactericide (BPI), anti-CMV antibody, 1-3-cis-retinoic acid, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin,

<td>spiramycin,</td><td>midecamycin,</td><td>leukomycin,</td><td>myocamycin,</td>

<td>roquitamiciña,</td><td>azithromycin, and</td><td colspan="2">swinolide A, fluoroquinolones</td>

<td>such as</td><td>ciprofloxacin,</td><td>ofloxacin,</td><td>levofloxacin,</td>

<td>trovafloxacin</td><td>alatrofloxacin</td><td>moxifloxicin,</td><td>norfloxacin,</td>

<td colspan="3">enoxacin, grepafloxacin, gatifloxacin,</td><td>lomefloxacin,</td>

<td>sparfloxacin</td><td>temafloxacin</td><td>pefloxacin,</td><td>amifloxacin,</td>

<td>fleroxacin,</td><td>tosufloxacin,</td><td>prulifloxacin,</td><td>irloxacin,</td>

<td>pazufloxacin,</td><td>clinafloxacin and</td><td>sitafloxacin,</td><td>teicoplanin,</td>

<td>rampolanin,</td><td>mideplanin,</td><td>colistin,</td><td>daptomycin,</td>

gramicidin, colistimethate, polymyxins such as polymyxin B, capreomycin, bacitracin, penems; penicillins including penicillinase-sensitive agents such as penicillin G, penicillin V, penicillinase-resistant agents such as methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin, active agents to large-negative microorganisms, such as ampicillin, amoxicillin, and hetacillin, cylillin , and galampicillin; antipseudomonal penicillins such as carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin, cephalosporins, such as cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cefalotin, cephapyrin, cephalexin, cephrinaphine, cephrinaphine, cephrinaphine, cephrinaphine, cephrinaphine, cepharillin, cephrinaphine, cephrinaphine, cepharillin, cepharillin, cepharillin, cephrinaphine, cepharin cefuroxime, ceforanide, cefotaxime, cefatrizine, cefacetril, cefepime, cefixime, cefonicide, cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef and moxalactam, monobactams such as aztreonam, and carbapenems such as imipenem, meropenem, pentamidine isethionate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolonaacetamide, budesonide-acetonide, fluticasone, bromide

<td>ipratropio,</td><td>beclomethasone, cromolyn sodium, tartrate</td>

<td>ergotamine</td><td>and where applicable, analogs, antagonists,</td>

<td>agonists,</td><td>inhibitors, and forms of salts pharmaceutically</td>

<td>acceptable</td><td>of the above. In reference to peptides and</td>

<td>proteins,</td><td>the invention is proposed to encompass forms</td>

<td>synthetic,</td><td>native, glycosylated, non-glycosylated, pegylated</td>

and biologically active fragments, derivatives and analogs thereof.

Active agents for use in the invention further include nucleic acids, such as naked nucleic acid molecules, vectors, associated viral particles, DNA or

Plasmid RNA or other nucleic acid constructs of a type suitable for transfection or transformation of cells, ie, suitable for gene therapy including antisense. Additionally, an active agent can comprise live attenuated or killed viruses for use as vaccines. Other useful drugs include listings within the Physician's Desk Reference (most recent edition), which is incorporated herein by reference in its entirety.

The amount of antibiotic or other active agent in the pharmaceutical formulation will be that amount necessary to administer a therapeutically or prophylactically effective amount of the active agent per unit 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 patient population, the 1Q dosage requirements, and the desired therapeutic effect. The composition will generally contain any from about 1% by weight to about 99% by weight, such as from about 2% by weight to about 95% by weight, or from about 5% by weight to 85% by weight, of the agent active, and will also depend on the relative amounts of additives contained in the composition. The compositions of the invention are particularly useful for active agents that are administered in doses of 0.001 mg / day at

100 mg / day, such as in doses from 0.01 mg / day to 75 mg / day, or 20 in doses from 0.10 mg / day to 50 mg / day. It is to be understood that more than one active agent is to be incorporated into the formulations described above and that the use of the term agent in no way excludes the use of two or more of these agents.

In general, the compositions are free of excessive excipients. In one or more embodiments, the aqueous composition consists essentially of the anti-gram-negative antibiotic, such as amicacin, or gentamicin or both, and / or salts thereof and water.

<td colspan="3">Additionally, in a</td><td>or more modalities,</td><td>the</td>

<td colspan="2">aqueous composition is free</td><td>of</td><td colspan="2">conservatives. To this</td>

<td>respect, the</td><td colspan="2">aqueous composition</td><td>can be free</td><td>of</td>

<td>methylparaben</td><td>I free</td><td>of</td><td>propylparaben.</td><td>Yet</td>

<td>further,</td><td>the composition</td><td colspan="2">watery can be free</td><td>of</td>

<td>Saline solution</td><td></td><td></td><td></td><td></td>

In one or more embodiments, the compositions comprise an anti-infective and an excipient. The compositions may comprise a pharmaceutically acceptable carrier or excipient that can be carried into the lungs without significant adverse toxicological effects to the subject, and particularly to the subject's lungs.

In addition to the active agent, a pharmaceutical formulation may optionally include one or more pharmaceutical excipients that are suitable for 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, improvement in effectiveness, or administration of the composition or the like. Thus, if present, the excipient can range from about 0.01% by weight to about 95% by weight, such as from about 0.5% by weight to about 80% by weight, from about 1% by weight to about 60% in weigh. 5 Preferably, these excipients will serve, in part, to further enhance the characteristics of the active agent composition, for example, by providing more efficient and reproducible administration of the active agent and / or to facilitate manufacture. One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of the active agent in the formulation.

For example, the compositions can include one or more osmolarity adjusters, such as sodium chloride. For example, sodium chloride can be added to vancomycin hydrochloride solutions to adjust the osmolarity of the solution. In one or more embodiments, an aqueous composition consists essentially of the anti-gram-positive antibiotic, such as. vancomycin, osmolarity adjuster, and water.

Pharmaceutical excipients and additives useful in the present pharmaceutical formulation include but are not limited to amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates, such as

9 sugars, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present individually or in combination.

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 of the dileucylpeptides of the invention), which can also function with a buffering capacity, include alanine, glycine, arginine, betaine histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. Acidic amines and polypeptides that function as dispersing agents are preferred. Amino acids that fall into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline.

Carbohydrate excipients useful for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannossa, sorbose, and the like; and saccharides, such. as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The pharmaceutical formulation may also comprise a buffer or a pH adjusting agent, typically a salt prepared from a base or organic acid.

Representative buffers comprise organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or italic acid, Tris, tromethamine hydrochloride, or phosphate buffers.

The pharmaceutical formulation may also include polymeric excipients / additives, eg, polyvinylpyrrolidones, celluloses, and derivatized celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose, Ficoll (such as a polymeric sugar), hydroxyethyl starch, dextrans (eg, cyclodextrins -hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin), polyethylene glycols and protein.

The pharmaceutical formulation may further include flavoring agents, flavor masking agents, inorganic salts (eg sodium chloride), antimicrobial agents (eg benzalkonium chloride), sweeteners, antioxidants, anti-static agents, surfactants (eg polysorbates such such as TWEEN 20 and TWEEN 80), sorbitan esters, lipids (eg phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, spheroids (for example cholesterol), and chelating agents (for example, EDTA, zinc and other suitable cations). Other pharmaceutical excipients and / or additives suitable for use in the compositions according to the invention are listed in

Remington: The Science &amp; Practice of Pharmacy, 19.sup.th of., Williams &amp; Williams, (1995), and in the Physician's Desk

Reference, 52.sub.nd er., Medical Economics, Montvale, NJ

(1998), both of which are incorporated herein by reference in their entireties.

It should be noted that the methods, systems, and devices discussed above are proposed only as examples. It should be emphasized that various modalities may omit, substitute, or add various procedures or components as appropriate. For example, it should be appreciated that, in alternative modalities, the methods can be performed in a different order from that described, and that several steps can be added, omitted or combined. Also, the features described with respect to certain modalities can be combined into several different modalities. In a similar way, different aspects and elements of the modalities can be combined. Also, it must be emphasized that technology evolves and from this!

Many of the elements are examples and should not be construed as limiting the scope of the invention.

Specific details are given in the description to provide a full understanding of the modalities.

However, it will be understood by one skilled in the art that the modalities can be practiced without these specific details. For example, processes have been shown,₁₀ well-known algorithms, structures, and techniques without unnecessary detail in order to avoid hindering the modalities. This description provides exemplary embodiments only, and is not intended to limit the scope, applicability, or configuration of the invention. Rather, the foregoing description of embodiments will provide those skilled in the art with an enabling description for implementing embodiments of the invention. Various changes can be made in the function and arrangement of the elements without departing from the spirit and scope of the invention.

Additionally, the foregoing description generally details the aerosol application of liquid drugs.

However, it should be understood that liquids in addition to liquid drugs can be applied by aerosol using similar devices and methods.

Also, it is pointed out that the modalities can be described as a process that is presented as a flowchart or block diagram. Although each can describe operations as a sequential process, many of the operations can be performed in parallel or concurrently. In addition, the order of operations can be re-arranged. A process may have additional steps not included in the figure.