IDENTIFYING DRY NEBULIZER ELEMENTS
CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a PCT application of U.S. Patent Application No. 61/296,306 filed
January 19, 2010, entitled "METHODS, DEVICES AND SYSTEMS FOR IDENTIFYING
DRY NEBULIZER ELEMENTS," the entire disclosure of which is incorporated herein by
reference for all purposes.
This application is related to application number PCT/US20 10/042473, filed July 19, 2010,
and US Application Number 61/226,591 entitled SYSTEMS AND METHODS FOR
DRIVING SEALED NEBULIZERS, filed on July 17, 2009, attorney docket number 015225-
012600US, the entire disclosures of which are incorporated by reference for all purposes.
This application is also related to application PCT/US20 10/042471, filed Jul 19, 2010, and
U.S. Application Number 61/226,567 entitled NEGATIVELY BIASED SEALED
NEBULIZERS SYSTEMS AND METHODS, filed on July 17, 2009, attorney docket number
015225-012500US, the entire disclosures of which are incorporated by reference for all
purposes.
BACKGROUND
Embodiments described herein relate to nebulizers. In particular, the embodiments described
herein relate to measuring the impedance of a nebulizer element to determine whether the
nebulizer element is in contact with a liquid.
A wide variety of procedures have been proposed to deliver a drug to a patient. In some drug
delivery procedures, the drug is a liquid and is dispensed in the form of fine liquid droplets
for inhalation by a patient. A patient may inhale the drug for absorption through lung tissue.
Such a mist may be formed by a nebulizer. Operation of a nebulizer without a liquid present
may result in damage to the nebulizer.
SUMMARY
Impedance measurements may be used to determine whether a liquid is in contact with a
nebulizer element. A nebulizer element may be energized with an electrical signal at a
measurement frequency. An impedance of the nebulizer element may be measured, thereby
obtaining a measured impedance value. The impedance value may be compared to a stored
impedance value. Based on the comparison, it may be determined whether the liquid contacts
the nebulizer element.
In some embodiments, a method for determining whether a liquid is in contact with a
nebulizer element is present. The method includes energizing the nebulizer element with an
electrical signal at a measurement frequency. The method also includes measuring an
impedance of the nebulizer element, thereby obtaining a measured impedance value. The
method further includes comparing the measured impedance value to a stored impedance
value. Also, the method includes determining whether the liquid contacts the nebulizer
element using the comparison between the measured impedance value and the stored
impedance value.
In some embodiments, the measurement frequency is different from an atomization frequency
at which the nebulizer is energized to atomize the liquid. In some embodiments, the method
further includes energizing the nebulizer element with the electrical signal at one or more
atomization frequencies concurrently with the nebulizer element being energized by the
electrical signal at the measurement frequency. In some embodiments, the method further
includes atomizing the liquid while the impedance of the nebulizer element is being
measured. In some embodiments, the method further includes, if the nebulizer element is
determined to not be in contact with liquid, disabling the nebulizer element such that the
nebulizer element is not energized by the voltage at an atomization frequency. In some
embodiments, the method further includes, if the nebulizer element is determined to be in
contact with the liquid, energizing the nebulizer element with the electrical signal at an
atomization frequency. In some embodiments, the method further includes, prior to
energizing the nebulizer element with the voltage at the measurement frequency, energizing
the nebulizer element with the electrical signal at the atomization frequency; and prior to
energizing the nebulizer element with the electrical signal at the measurement frequency,
ceasing to energize the nebulizer element with the electrical signal at the atomization
frequency.
In some embodiments, a system for atomizing a liquid when the liquid is in contact with a
nebulizer element is present. The system includes a nebulizer. The nebulizer may include a
reservoir configured to store the liquid. The reservoir may be configured to dispense the
liquid to the nebulizer element. The nebulizer may also include a nebulizer element. The
nebulizer element may be configured to, when energized at an atomization frequency,
atomize the liquid in contact with the nebulizer element. The system may also include a
control module. The control module may be configured to output an electrical signal at an
atomization frequency to energize the nebulizer element. The control module may be
configured to output the electrical signal at a measurement frequency to energize the
nebulizer element. The control module may also be configured to measure an impedance of
the nebulizer element, thereby obtaining a measured impedance value. The control module
may further be configured to compare the measured impedance value to a stored impedance
value. Also, the control module may be configured to determine whether the liquid contacts
the nebulizer element using the comparison between the measured impedance value and the
stored impedance value.
In some embodiments, a computer program product residing on a non-transitory processorreadable
medium and comprising processor-readable instructions is presented. The
instructions, when executed, may cause the processor to: cause a nebulizer element to
energize with an electrical signal at a measurement frequency; cause an impedance of the
nebulizer element to be measured, thereby obtaining a measured impedance value; compare
the measured impedance value to a stored impedance value; and determine whether the liquid
contacts the nebulizer element using the comparison between the measured impedance value
and the stored impedance value.
BRIEF DESCRIPTION OF THE DRAWINGS
A further understanding of the nature and advantages of the present invention may be realized
by reference to the following drawings.
FIG. 1 illustrates an embodiment of a nebulizer.
FIG. 2 illustrates an embodiment of a nebulizer driven by a control module.
FIG. 3 illustrates a graph of the impedance of a wet nebulizer element and a dry nebulizer
element at various frequencies.
FIG. 4 illustrates an embodiment of a method for determining if liquid is in contact with a
nebulizer element.
FIG. 5 illustrates another embodiment of a method for determining if liquid is in contact with
a nebulizer element.
DETAILED DESCRIPTION
Operation of a nebulizer without a liquid present may result in damage to the nebulizer and/or
the nebulizer"s element. As such, it may be desirable to avoid energizing a nebulizer"s
element when the element is dry. Various implementations are described for determining
whether a nebulizer element is in contact with a liquid (the nebulizer element is wet) or is not
in contact with a liquid (the nebulizer element is dry).
More specifically, the invention involves measuring the impedance of a nebulizer element
and comparing the measurement to a predetermined impedance value. This comparison is
used to determine whether the nebulizer element is in contact with a liquid or not. By
measuring the impedance of a nebulizer element at one or more frequencies, it may be
determined whether a liquid is in contact with the nebulizer element.
There are various situations where a nebulizer element may potentially be operated dry. For
example, a liquid (for example, a liquid drug, such as Amikacin) may have previously been in
contact with a nebulizer element, but the supply of liquid may have become exhausted. A
particular dose of such a liquid drug may be provided to a nebulizer element to be atomized
for delivery to a patient. At the end of the dose, the nebulizer element may continue to be
energized although the entire dose of the liquid drug has been atomized, thus resulting in a
dry nebulizer element being energized. As another example, a nebulizer element may
inadvertently be energized without any liquid being in contact with to the nebulizer element.
In both of these instances, the nebulizer and/or its element may be damaged by being
energized while dry.
FIG. 1 illustrates an embodiment of a nebulizer 100. The nebulizer 100 may include
nebulizer element 110, drug reservoir 120, head space 130, interface 140, and cap 150.
Nebulizer element 110 may be comprised of a piezoelectric ring that expands and contracts
when an electric signal is applied. The piezoelectric ring may be attached to a perforated
membrane. Such a perforated membrane may have a number of holes passing through it.
When an electric signal is applied to the piezoelectric ring, this may cause the membrane to
move and/or flex. Such movement of the membrane while in contact with a liquid may cause
the atomization of the liquid, generating a mist of liquid particles. Nebulizer element 110
may also be a vibrating aperture plate.
A supply of a liquid, commonly a liquid drug (examples of which are detailed later in this
document), may be held in the drug reservoir 120. As illustrated in FIG. 1, drug reservoir
120 is only partially filled with liquid drug. As liquid drug is atomized, the amount of the
liquid drug remaining in drug reservoir 120 may decrease. Depending on the amount of the
liquid drug in the drug reservoir 120, only a portion of the reservoir may be filled with liquid
drug. The remaining portion of drug reservoir 120 may be filled with gas, such as air. This
space is referred to as head space 130. An interface 140 may serve to transfer liquid drug
between drug reservoir 120 and nebulizer element 110.
Nebulizers, and the techniques associated with nebulizers, are described generally in U.S.
Patent Nos. 5,164,740; 5,938,1 17; 5,586,550; 5,758,637; 6,014,970; 6,085,740; 6,235,177;
6,615,824; 7,322,349, the complete disclosures of which are incorporated by reference for all
purposes.
A nebulizer, such as nebulizer 100, may be connected with a control module such as
illustrated in FIG. 2. FIG. 2 illustrates a simplified block diagram of an embodiment 200 of a
nebulizer control module coupled with nebulizer 100. Nebulizer 100 of FIG. 2, which may
represent nebulizer 100 of FIG. 1 or some other nebulizer such as those described in the
referenced applications, may be connected with control module 210 via wire 230, which may
be a cable. Wire 230 may allow control module 210 to transmit an electrical signal of
varying frequency and varying voltage through wire 230 to nebulizer 100. Control module
210 may be connected to voltage supply 215 capable of supplying a DC voltage and/or an AC
voltage to control module 210.
Control module 210 may contain various components. In some embodiments of control
module 210, processor 2 11, non-transitory computer-readable storage medium 212, and
electrical signal output module 213 are present. Processor 2 11may be a general purpose
processor or a processor designed specifically for functioning in control module 210.
Processor 2 11 may serve to execute instructions stored as software or firmware. Such
instructions may be stored on non-transitory computer-readable storage medium 212. Nontransitory
computer-readable storage medium 212 may be random access memory, flash
memory, a hard drive, or some other storage medium capable of storing instructions.
Instructions stored by non-transitory computer-readable storage medium 212 may be
executed by processor 211, the execution of the instructions resulting in electrical signal
output module 213 generating an electrical signal of a varying frequency and/or varying
voltage that is output to the nebulizer element of nebulizer 100 via wire 230. The signal
output by electrical signal output module 213 may include one or more frequencies. For
example, electrical signal output module 213 may intermittently or concurrently generate an
electrical signal that at one or more frequencies is used to energize the nebulizer element to
measure the impedance of the nebulizer element and one or more frequencies used to
energize the nebulizer element to atomize liquid.
FIG. 3 illustrates an embodiment of a graph 300 of how the impedance of a nebulizer
element, such as nebulizer element 110 of FIG. 1, may vary depending on the frequency of an
applied electrical signal and whether the nebulizer element is wet or dry. Line 310 represents
the impedance of the nebulizer element when wet at various frequencies. Line 320 represents
the impedance of the nebulizer element when dry at various frequencies. Depending on the
frequency of the applied electrical signal, a wet nebulizer element may have a higher, lower,
or the same impedance as a dry nebulizer element. In order to determine whether a nebulizer
element is in contact with a liquid (e.g., whether it is wet or dry), the frequencies where the
impedances greatly diverge between wet and dry states may be analyzed. For example, a
frequency of roughly 122 kHz may be used. At roughly 122 kHz, in region 350, which has
been denoted by a dotted box as a frequency range where the impedances of the nebulizer
vary greatly between wet and dry states, the wet nebulizer has an impedance of
approximately 280 ohms. At the same frequency, the same nebulizer element not in contact
with a liquid has an impedance of over 10,000 ohms. As those with skill in the art will
recognize, differing results may be achieved for different nebulizers and/or nebulizer
elements. As such, for different nebulizers and/or nebulizer elements, different frequencies
may be preferable for determining whether the nebulizer element is wet or dry. Point 330
may represent the frequency (and associated impedance) at which this nebulizer element is
typically energized to atomize liquid. As such, the frequency used to determine whether the
nebulizer element is wet or dry may be a frequency different from the frequency used to
atomize liquid. Such a graph may be produced for each design of nebulizer and/or nebulizer
element to identify one or more frequencies to be used to determine whether an element is
wet or dry and to determine the impedance values associated with the wet and dry states.
The impedance of the nebulizer element used to produce the graph of FIG. 3 may be
measured around a frequency of 120 kHz to determine whether the nebulizer element is wet
or dry. The impedance may be monitored through a method such as method 400 of FIG. 4.
FIG. 4 illustrates an embodiment of a method for determining whether a nebulizer element is
wet or dry. Method 400 may be performed using a nebulizer such as nebulizer 100 of FIG. 1,
and a control module, such as control module 210 of FIG. 2. At block 410, the nebulizer
element may be energized by an electrical signal at a frequency generated by a control
module. The characteristics of the nebulizer element being energized may have already been
analyzed at various voltages and frequencies, such as the nebulizer element used to produce
the graph of FIG. 3. Therefore, it may already be known at what frequency or frequencies
and/or voltages the impedance of the nebulizer element while wet varies significantly from
the impedance of the nebulizer element while dry. For example, if the nebulizer element
being used while performing method 400 is the nebulizer element used to create FIG. 3, the
nebulizer element may be energized at a measurement frequency around 120 kHz. This
frequency may have been selected due to the large difference in the impedance of the
nebulizer element when wet compared to dry.
Once the nebulizer element is energized with an electrical signal at a measurement frequency
at block 410, the impedance of the nebulizer element may be measured at block 420. The
measurement frequency may be the same or a frequency different from the frequency used to
energize the nebulizer element to atomize liquid. If the frequencies are different, the control
module may temporarily suspend exciting the nebulizer element with the atomization
frequency. In some embodiments, the nebulizer element may be excited with the atomization
frequency and the measurement frequency at the same time. It some embodiments, more
than one atomization frequency and/or more than one measurement frequency may be excited
at the same time. The impedance may be measured by a control module, such as control
module 210 of FIG. 2. This measured impedance value may be stored by the control module
using non-transitory computer-readable storage medium 212 or some other storage device.
This measured impedance value may then be compared to a predetermined impedance value
at block 430. This predetermined impedance value may have been determined empirically
during a previous analysis of the characteristics of the nebulizer element while wet and dry.
For example, again assuming method 400 is using the nebulizer element used to produce the
graph of FIG. 3, the predetermined impedance value may be a threshold value, such as 1100
ohms for a frequency of 122 kHz. Therefore, if the measured impedance is determined to be
greater than 1100 ohms at this frequency, the nebulizer element is likely dry; if the measured
impedance is determined to be less than 1100 ohms at this frequency, the nebulizer element is
likely wet.
At block 440, based upon the comparison at block 430, it may be determined if a liquid is or
is not in contact with the nebulizer element. Based upon such a determination, different
courses of action may be taken. For example, if it is determined that the nebulizer element is
dry, the nebulizer element may cease to be energized, thereby preventing possible damage to
the nebulizer element. If it is determined that the nebulizer element is wet, the nebulizer
element may continue to be energized by the electrical signal at a frequency used to atomize
liquid, thereby continuing to cause the nebulizer element to atomize the liquid, such as to
produce a dose of medicine for inhalation by a patient.
Such a process may be used to determine whether a nebulizer element is wet or dry at any
point during nebulizer operation. For example, initially upon being energized, a method,
such as method 400, may be used to determine whether any liquid is in contact with the
nebulizer element. As such, the process may be used to prevent the nebulizer element from
initially being energized if a person neglected to add liquid the reservoir of the nebulizer. In
some embodiments, periodically or intermittently during operation, method 400 may be
performed to determine if the nebulizer"s supply of liquid has been exhausted.
Besides measuring impedance at one frequency, a more accurate determination of whether a
nebulizer element is wet or dry may be performed by measuring a number of different
impedance values at one or multiple frequencies for comparison to one or more
predetermined impedance values. FIG. 5 illustrates a method 500 where the impedance of a
nebulizer element is measured at multiple frequencies. An average impedance is calculated
from the measurements at these various frequencies and may be compared to a predetermined
impedance value to determine if the nebulizer element is likely wet or dry.
At block 510, normal operation of a nebulizer, such as nebulizer 100 of FIGs. 1 and 2, may
be disabled, such as by control module 210 of FIG. 2. Disabling may include the nebulizer
element ceasing to be energized by an electrical signal at one or more frequencies being used
to atomize liquid. This may be necessary if prior to block 510 the nebulizer element was
atomizing a liquid. If the nebulizer has not begun atomizing a liquid, such as immediately
upon power up, block 510 may not be necessary. In some embodiments, the nebulizer
element may be excited by a frequency used to measure impedance (e.g., a measurement
frequency) and by a frequency used to atomize liquid (e.g., an atomization frequency) at the
same time; as such, disabling atomization may not be necessary. At block 520, the nebulizer
element may be energized by an electrical signal at a predetermined voltage and/or one or
more predetermined frequencies. For example, assuming the nebulizer element used in
method 500 is the same nebulizer element as used to produce graph 300 of FIG. 3, the
voltage used may be 5 V and the first frequency used may be 118 kHz.
At block 530, the impedance of the nebulizer element may be measured. This impedance
value may be measured and stored by a control module, such as control module 210 of FIG.
2, using non-transitory computer-readable storage medium 212.
At block 540, it may be determined whether other impedance measurements are to be
collected prior to comparing the one or more measured impedance values to one or more
predetermined impedance values. If the answer is yes, returning to block 520 (via the
illustrated dotted path), the nebulizer element may immediately be energized using an
electrical signal at a frequency necessary to conduct the next impedance measurement. In
some embodiments, the nebulizer element is energized at the same frequency used at block
520 to repeat the same measurement. In some embodiments, a different frequency is used.
Alternatively, in some embodiments, the nebulizer may resume normal operation at block
550 and atomize liquid at an atomization frequency. After some period of time performing
normal operation (e.g., a tenth of a second, several seconds, a minute), normal operation may
again be disabled (e.g., ceasing to energize the nebulizer element with the electrical signal at
the atomization frequency) at block 510, with the nebulizer element being energized at the
voltage and frequency necessary for the next impedance measurement at block 520. Here,
the frequency may be the same measurement frequency or a different measurement frequency
as previously used at block 520.
The time period of normal operation may be determined by how often it is desired that a
determination of whether the nebulizer element is wet or dry be made. For example, if a total
of six frequency measurements is to be collected before comparison to a predetermined
impedance value, and it is wished that the nebulizer unit determine whether the nebulizer
element is wet or dry every 10 seconds, this would mean that the impedance of the nebulizer
element at a frequency would need to be collected at least every 1.6 seconds if a period of
normal operation is to occur between impedance measurements. This loop of either 1)
immediately energizing at the different voltage and/or frequency or 2) resuming normal
operation and energizing at a different voltage and/or frequency may continue until a
predetermined number and impedance measurements at different voltages and/or frequencies
have been collected. For example, referring again to the nebulizer element used to produce
the graph of FIG. 3, besides 118 kHz, impedance measurements may also be collected at
119.5 kHz, 121 kHz, 122.5 kHz, 124 kHz, and 125.5 kHz.
Once it is determined at block 540 that no additional measurements of impedance values at
different voltages and/or frequencies are to be collected, the process may continue to block
570. At block 570, collected impedance values at the various frequencies may be used to
calculate an average measured impedance. At block 580, this average measured impedance
may be compared to a predetermined, stored average impedance value. The comparison may
involve determining whether the average measured impedance value is greater than, equal to,
or less than the predetermined impedance value.
In some embodiments, rather than comparing an averaged measured impedance value to a
stored average impedance value, the individual measured impedance values may be
compared to individual stored impedance threshold values for each frequency. If the majority
of comparisons indicate a wet nebulizer element, the nebulizer element may be identified as
wet. If the majority of comparisons indicate a dry nebulizer element, the nebulizer element
may be identified as dry.
If, at block 585, the nebulizer element is determined to be dry, the nebulizer element may be
disabled at block 590. Disabling may include ceasing energizing the nebulizer element at one
or more frequencies. If the nebulizer was previously atomizing a liquid drug during normal
operation, the nebulizer element being determined to be dry may indicate that the entire dose
of the drug has been delivered.
If, at block 585, the nebulizer element is not dry (e.g., it is wet), at block 550 the nebulizer
may resume normal operation with the nebulizer element being energized at one or more
atomization frequencies. Normal operation may continue for predetermined amount of time,
after which method 500, with new impedance measurements being conducted at each of the
frequencies, may be repeated. Method 500 may continuously repeat until the nebulizer is
determined to be dry at block 585 or some intervening event ceases operation of the
nebulizer. In some embodiments, another process may result in the nebulizer being disabled,
such as expiration of a predetermined amount of time or receiving user input.
As it will be understood by those with skill in the art, impedance relates to a ratio of voltage
and current. If either the current or voltage is known, than the impedance can be determined
using either a measured voltage or measured current, respectively. For example, in the
preceding described nebulizer elements, if an applied voltage is constant or inferred to be a
known value, than the current measurements could be used to determine if the nebulizer
element is wet or dry. Similarly, in the preceding described nebulizer elements, if an applied
current is constant or inferred to be a known value, than voltage measurements could be used
to determine if the nebulizer element is wet or dry. Further, if the applied voltage and current
have a known relationship, then just current or voltage measurements could be used to
determine if the nebulizer element is wet or dry. Moreover, in some embodiments, the
amount of power absorbed by the nebulizer element could be used to determine if the
nebulizer element is wet or dry. Methods 400 and 500 of FIGs. 4 and 5, respectively, may be
adapted such that a constant current or constant voltage is applied to the nebulizer element,
and a resulting current, voltage, or power is measured. Information such as that presented in
graph 300 could be gathered for various applied constant voltages or constant currents to
determine at what magnitudes dry nebulizer elements and wet nebulizer elements diverge in
measured current, voltage, or power. As such, embodiments of the invention exist that rely
on voltage, current, and/or power measurements, rather than just impedance. Further, in
some embodiments, measurements of multiple different values (such as a voltage
measurement when a constant current is applied and a current measurement when a constant
voltage is applied) may be taken. Using multiple measurements may improve the accuracy of
determining whether the nebulizer element is wet or dry. For example, to determine the
nebulizer element is dry and cease energizing the nebulizer element, both measurements may
need to be in agreement that a dry nebulizer is present, otherwise the nebulizer element may
continue to be energized.
While a wide variety of drugs, liquids, liquid drugs, and drugs dissolved in liquid may be
aerosolized, the following provides extensive examples of what may be aerosolized.
Additional examples are provided in U.S. App. No. 12/341,780, the entire disclosure of
which is incorporated herein for all purposes. Nearly any anti-gram-negative, anti-grampositive
antibiotic, or combinations thereof may be used. Additionally, antibiotics may
comprise those having broad spectrum effectiveness, or mixed spectrum effectiveness.
Antifungals, such as polyene materials, in particular, amphotericin B, are also suitable for use
herein. Examples of anti-gram-negative antibiotics or salts thereof include, but are not
limited to, aminoglycosides or salts thereof. Examples of aminoglycosides or salts thereof
include gentamicin, amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin,
tobramycin, salts thereof, and combinations thereof. For instance, gentamicin sulfate is the
sulfate salt, or a mixture of such salts, of the antibiotic substances produced by the growth of
Micromonospora purpurea. Gentamicin sulfate, USP, may be obtained from Fujian Fukang
Pharmaceutical Co., LTD, Fuzhou, China. Amikacin is typically supplied as a sulfate salt,
and can be obtained, for example, from Bristol-Myers Squibb. Amikacin may include related
substances such as kanamicin.
Examples of anti-gram-positive antibiotics or salts thereof include, but are not limited to,
macrolides or salts thereof. Examples of macrolides or salts thereof include, but are not
limited to, vancomycin, erythromycin, clarithromycin, azithromycin, salts thereof, and
combinations thereof. For instance, vancomycin hydrochloride is a hydrochloride salt of
vancomycin, an antibiotic produced by certain strains of Amycolatopsis orientalis, previously
designated Streptomyces orientalis. Vancomycin hydrochloride is a mixture of related
substances consisting principally of the monohydrochloride of vancomycin B. Like all
glycopeptide antibiotics, 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. The additional active agent described herein includes an agent, drug, or
compound, which provides some pharmacologic, often beneficial, effect. This includes
foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As
used herein, the terms further include any physiologically or pharmacologically active
substance that produces a localized or systemic effect in a patient. An active agent for
incorporation in the pharmaceutical formulation described herein may be an inorganic or an
organic compound, including, without limitation, drugs which act on: the peripheral nerves,
adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system,
smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites,
endocrine and hormone systems, the immunological system, the reproductive system, the
skeletal system, autacoid systems, the alimentary 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, steroids, and combinations thereof. For instance, the steroid 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 antagnonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics),
appetite suppressants, antimigraine agents, muscle contractants, additional anti-infectives
(antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, anepileptics,
cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives,
cardiovascular drugs, antiarrhythmics, antioxicants, anti-asthma agents, hormonal agents
including contraceptives, sympathomimetics, diuretics, lipid regulating agents,
antiandrogenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics,
hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents,
vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent, when
administered by inhalation, may act locally or systemically.
The active agent may fall into one of a number of structural classes, including but not limited
to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins
capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats,
electrolytes, and the like.
Examples of active agents suitable for use in this invention include but are not limited to one
or more of calcitonin, amphotericin B, erythropoietin (EPO), Factor VIII, Factor IX,
ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF),
thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, 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
analogues (e.g., mono-acylated insulin as described in U.S. Pat. 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), insulintropin, macrophage colony stimulating factor (MCSF),
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), glucagon-like peptide thymosin alpha 1, Ilb/IIIa inhibitor,
alpha- 1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors,
bisphosphonates, respiratory syncytial virus antibody, cystic fibrosis transmembrane
regulator (CFTR) gene, deoxyreibonuclease (Dnase), bactericidal/permeability increasing
protein (BPI), anti-CMV antibody, 1 3-cis retinoic acid, oleandomycin, troleandomycin,
roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin,
josamycin, spiramycin, midecamycin, leucomycin, miocamycin, rokitamycin,
andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin,
levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin,
grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin,
amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin,
and sitafloxacin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin,
colistimethate, polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins
including penicillinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant
agents like methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram
negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and
galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin,
mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten,
ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin,
cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime,
ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid,
cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalactam,
monobactams like aztreonam; and carbapenems such as imipenem, meropenem, pentamidine
isethiouate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone
acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn
sodium, ergotamine tartrate and where applicable, analogues, agonists, antagonists,
inhibitors, and pharmaceutically acceptable salt forms of the above. In reference to peptides
and proteins, the invention is intended to encompass synthetic, native, glycosylated,
unglycosylated, pegylated forms, and biologically active fragments, derivatives, and analogs
thereof.
Active agents for use in the invention further include nucleic acids, as bare nucleic acid
molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid
constructions of a type suitable for transfection or transformation of cells, i.e., suitable for
gene therapy including antisense. Further, an active agent may comprise live attenuated or
killed viruses suitable for use as vaccines. Other useful drugs include those listed within the
Physician"s 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 deliver 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 upon the particular agent, its activity, the severity of the condition to be treated,
the patient population, dosing requirements, and the desired therapeutic effect. The
composition will generally contain anywhere from about 1wt % to about 99 wt %, such as
from about 2 wt % to about 95 wt %, or from about 5 wt % to 85 wt %, of the active agent,
and will also depend upon the relative amounts of additives contained in the composition.
The compositions of the invention are particularly useful for active agents that are delivered
in doses of from 0.001 mg/day to 100 mg/day, such as in doses from 0.01 mg/day to 75
mg/day, or in doses from 0.10 mg/day to 50 mg/day. It is to be understood that more than
one active agent may be incorporated into the formulations described herein and that the use
of the term "agent" in no way excludes the use of two or more such agents.
Generally, 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
amikacin, or gentamicin or both, and/or salts thereof and water.
Further, in one or more embodiments, the aqueous composition is preservative-free. In this
regard, the aqueous composition may be methylparaben-free and/or propylparaben-free. Still
further, the aqueous composition may be saline-free.
In one or more embodiments, the compositions comprise an anti-infective and an excipient.
The compositions may comprise a pharmaceutically acceptable excipient or carrier which
may be taken into the lungs with no significant adverse toxico logical effects to the subject,
and particularly to the lungs of the subject. In addition to the active agent, a pharmaceutical
formulation may optionally include one or more pharmaceutical excipients which 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, enhancing effectiveness or delivery of the composition or the like.
Thus, if present, excipient may range from about 0.01 wt % to about 95 wt %, such as from
about 0.5 wt % to about 80 wt %, from about 1wt % to about 60 wt %. Preferably, such
excipients will, in part, serve to further improve the features of the active agent composition,
for example by providing more efficient and reproducible delivery of the active agent and/or
facilitating manufacturing. One or more excipients may also be provided to serve as bulking
agents when it is desired to reduce the concentration of active agent in the formulation.
For instance, the compositions may include one or more osmolality adjuster, such as sodium
chloride. For instance, sodium chloride may be added to solutions of vancomycin
hydrochloride to adjust the osmolality of the solution. In one or more embodiments, an
aqueous composition consists essentially of the anti-gram-positive antibiotic, such as
vancomycin hydrochloride, the osmolality 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 sugars, derivatized sugars such as alditols,
aldonic acids, esterified sugars, and sugar polymers, which may be present singly 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 dileucyl-peptides of the invention), which may also function in a
buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid,
aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine,
aspartame, tyrosine, tryptophan, and the like. Preferred are amino acids and polypeptides that
function as dispersing agents. Amino acids falling into this category include hydrophobic
amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine,
phenylalanine, tyrosine, histidine, and proline.
Carbohydrate excipients suitable for use in the 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 raffmose, 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 an organic acid or base. Representative buffers comprise organic acid
salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid,
acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers.
The pharmaceutical formulation may also include polymeric excipients/additives, e.g.,
polyvinylpyrrolidones, celluloses and derivatized celluloses such as hydroxymethylcellulose,
hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar),
hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-beta-cyclodextrin
and sulfobutylether-beta-cyclodextrin), polyethylene glycols, and pectin.
The pharmaceutical formulation may further include flavoring agents, taste-masking agents,
inorganic salts (for example sodium chloride), antimicrobial agents (for example
benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (for example
polysorbates such as "TWEEN 20" and "TWEEN 80"), sorbitan esters, lipids (for example
phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines),
fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for
example EDTA, zinc and other such suitable cations). Other pharmaceutical excipients
and/or additives suitable for use in the compositions according to the invention are listed in
"Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995),
and in the "Physician"s Desk Reference", 52nd ed., Medical Economics, Montvale, N.J.
(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 intended
merely to be examples. It must be stressed that various embodiments may omit, substitute, or
add various procedures or components as appropriate. For instance, it should be appreciated
that, in alternative embodiments, the methods may be performed in an order different from
that described, and that various steps may be added, omitted, or combined. Also, features
described with respect to certain embodiments may be combined in various other
embodiments. Different aspects and elements of the embodiments may be combined in a
similar manner. Also, it should be emphasized that technology evolves and, thus, many of
the elements are examples and should not be interpreted to limit the scope of the invention.
Specific details are given in the description to provide a thorough understanding of the
embodiments. However, it will be understood by one of ordinary skill in the art that the
embodiments may be practiced without these specific details. For example, well-known
processes, algorithms, structures, and techniques have been shown without unnecessary detail
in order to avoid obscuring the embodiments. This description provides example
embodiments only, and is not intended to limit the scope, applicability, or configuration of
the invention. Rather, the preceding description of the embodiments will provide those
skilled in the art with an enabling description for implementing embodiments of the
invention. Various changes may be made in the function and arrangement of elements
without departing from the spirit and scope of the invention.
Further, the preceding description generally details aerosolizing liquid drugs. However, it
should be understood that liquids besides liquid drugs may be aerosolized using similar
devices and methods.
Also, it is noted that the embodiments may be described as a process which is depicted as a
flow diagram or block diagram. Although each may describe the operations as a sequential
process, many of the operations can be performed in parallel or concurrently. In addition, the
order of the operations may be rearranged. A process may have additional steps not included
in the figure.

WHAT IS CLAIMED IS:
1. A method for determining whether a liquid is in contact with a
nebulizer element, the method comprising:
energizing the nebulizer element with an electrical signal at a measurement
frequency;
measuring an impedance of the nebulizer element, thereby obtaining a
measured impedance value;
comparing the measured impedance value to a stored impedance value; and
determining whether the liquid contacts the nebulizer element using the
comparison between the measured impedance value and the stored impedance value.
2. The method of claim 1, wherein the measurement frequency is
different from an atomization frequency at which the nebulizer is energized to atomize the
liquid.
3. The method of claim 1, further comprising:
energizing the nebulizer element with the electrical signal at one or more
atomization frequencies concurrently with the nebulizer element being energized by the
electrical signal at the measurement frequency.
4. The method of claim 3, further comprising:
atomizing the liquid while the impedance of the nebulizer element is being
measured.
5. The method of claim 1, further comprising:
if the nebulizer element is determined to not be in contact with liquid, ceasing
to energize the nebulizer element with the electrical signal.
6. The method of claim 1, further comprising:
if the nebulizer element is determined to be in contact with the liquid,
energizing the nebulizer element with the electrical signal at an atomization frequency.
7. The method of claim 6, further comprising:
prior to energizing the nebulizer element with the electrical signal at the
measurement frequency, energizing the nebulizer element with the electrical signal at the
atomization frequency; and
prior to energizing the nebulizer element with the electrical signal at the
measurement frequency, ceasing to energize the nebulizer element with the electrical signal
at the atomization frequency.
8. A system for energizing a nebulizer element when a liquid is in contact
with the nebulizer element, the system comprising:
a nebulizer, wherein the nebulizer comprises:
a reservoir configured to store the liquid, wherein:
the reservoir is configured to dispense the liquid to the
nebulizer element; and
the nebulizer element, wherein:
the nebulizer element is configured to, when energized by an
electrical signal at an atomization frequency, atomize the liquid in contact with
the nebulizer element; and
a control module, wherein the control module is configured to:
output the electrical signal at the atomization frequency to
energize the nebulizer element;
output the electrical signal at a measurement frequency to
energize the nebulizer element;
measure an impedance of the nebulizer element at the
measurement frequency, thereby obtaining a measured impedance value;
compare the measured impedance value to a stored impedance
value; and
determine whether the liquid contacts the nebulizer element
using the comparison between the measured impedance value and the stored
impedance value.
9. The system of claim 8, wherein the measurement frequency is different
from the atomization frequency.
10. The system of claim 8, wherein the control module is further
configured to:
energize the nebulizer element with the electrical signal at the atomization
frequency concurrently with the nebulizer element being energized by the electrical signal at
the measurement frequency.
11. The system of claim 10, wherein the nebulizer element is further
configured to:
atomize the liquid while the impedance of the nebulizer element is being
measured.
12. The system of claim 8, wherein, if the nebulizer element is determined
by the control module to not be in contact with the liquid, the control module is configured to
disable the nebulizer element such that the nebulizer element is not energized by the electrical
signal at the atomization frequency.
13. The system of claim 8, wherein, if the nebulizer element is determined
by the control module to be in contact with liquid, the control module is configured to
energize the nebulizer element at the atomization frequency.
14. The system of claim 13, wherein:
the control module is configured to, prior to energizing the nebulizer element
with the electrical signal at the measurement frequency, energize the nebulizer element with
the electrical signal at the atomization frequency; and
the control module is configured to, prior to energizing the nebulizer element
with the electrical signal at the measurement frequency, cease energizing the nebulizer
element with the electrical signal at the atomization frequency.
15. A computer program product residing on a non-transitory processorreadable
medium and comprising processor-readable instructions configured to cause a
processor to:
cause a nebulizer element to energize with an electrical signal at a
measurement frequency;
cause an impedance of the nebulizer element to be measured, thereby
obtaining a measured impedance value;
compare the measured impedance value to a stored impedance value; and
determine whether the liquid contacts the nebulizer element using the
comparison between the measured impedance value and the stored impedance value.
16. The computer program product of claim 15, wherein the measurement
frequency is different from an atomization frequency at which the nebulizer element is
energized to atomize the liquid.
17. The computer program product of claim 15, wherein the processorreadable
instructions are further configured to cause a processor to:
cause the nebulizer element to be energized by the electrical signal at an
atomization frequency concurrently with the nebulizer element being energized by the
electrical signal at the measurement frequency.
18. The computer program product of claim 15, wherein the processorreadable
instructions are further configured to cause a processor to:
cause the liquid to be atomized by the nebulizer element while the impedance
of the nebulizer element is being measured.
19. The computer program product of claim 15, wherein the processorreadable
instructions are further configured to cause a processor to:
if the nebulizer element is determined to not be in contact with liquid, cause
the nebulizer element to cease being energized by the electrical signal at an atomization
frequency.
20. The computer program product of claim 15, wherein the processorreadable
instructions are further configured to cause a processor to:
if the nebulizer element is determined to be in contact with liquid, cause the
nebulizer element to be energized at an atomization frequency.
2 1. A method for determining whether a liquid is in contact with a
nebulizer element, the method comprising:
energizing the nebulizer element with an electrical signal at a measurement
frequency;
measuring an electrical characteristic of the nebulizer element, thereby
obtaining a measured electrical characteristic value;
comparing the measured electrical characteristic value to a stored electrical
characteristic value; and
determining whether the liquid contacts the nebulizer element using the
comparison between the measured electrical characteristic value and the stored electrical
characteristic value.