BACKGROUND

[0001] Embodiments of the present invention relate to nebulizers. In particular, the present invention relates to use of a nebulizer with a sealed drug reservoir to build up and maintain an internal negative bias pressure.

[0002] A wide variety of procedures has been proposed to deliver a drug to a patient. In some drug delivery procedures, the drug is a liquid and is dispensed in the form of fine liquid droplets for inhalation by a patient. A patient may inhale the drug for absorption through lung tissue. Further, the droplets forming the mist may need to be very small to travel through small airways of the patient's lungs, and consistent in size to assure proper absorption. Such a mist may be formed by a nebulizer.

SUMMARY

[0003] Creating a negative bias pressure on the liquid side of an aperture used for an aerosolizing liquid drug may allow for more efficient and consistent delivery of aerosolized liquid drugs to a patient. Such a negative bias may be created by reducing the pressure within the drug reservoir of a nebulizer. This may be accomplished by sealing the drug reservoir, then discharging an amount of liquid drug from the reservoir. Because neither air, nor anything else, is able to fill the space vacated by the discharged liquid drug, the pressure within the drug reservoir decreases, thereby creating a negative bias pressure within the liquid drug reservoir and on the liquid side of the aperture aerosolizing the liquid drug.

[0004] In some embodiments, a method for creating a negative bias pressure within a sealed reservoir may be present. The method may include providing a liquid reservoir coupled with an aerosol generator, the aerosol generator comprising an aperture plate, the aperture plate having a liquid side and an air side. The method may also include receiving a liquid in the liquid reservoir. The method may include sealing the liquid reservoir to create the sealed reservoir. An ambient pressure may be maintained while the liquid reservoir is being sealed. The ambient pressure may be maintained in the sealed liquid reservoir until a portion of the liquid is dispensed. The method may include vibrating the aperture plate to dispense liquid. Dispensing liquid may decrease the amount of liquid in the sealed reservoir. The method may include decreasing the amount of liquid in the sealed reservoir to create a negative bias pressure between an air side and a liquid side of the aperture plate. [0005] In some embodiments, a cap is provided, wherein the cap comprises a first portion configured to couple with the liquid reservoir and a second portion configured to screw into the first portion of the cap. The method may further comprise screwing the second portion of the cap into the first portion of the cap, wherein a passageway allows the ambient pressure to be maintained in the liquid reservoir as the second portion of the cap is screwed into the first portion of the cap. In some embodiments, a cap is provided, wherein the cap comprises a flexible seal and a pivot. The method may include pivoting the cap against the liquid reservoir, such that the flexible seal seals the liquid reservoir. In some embodiments, a cap is provided that comprises a one-way valve and a seal. The method may further include pressing the cap onto the liquid reservoir such that the seal couples the cap with the liquid reservoir, wherein the one-way valve ensures the ambient pressure is maintained as the liquid reservoir is sealed. In some embodiments, the cap is shaped to reduce headspace within the liquid reservoir. In some embodiments, a cap is provided that comprises a plunger and a stopper. The method may further include placing the cap on the liquid reservoir such that the cap covers the liquid reservoir, wherein the ambient pressure is maintained by a passageway between the cap and the stopper. The method may further comprise pulling the plunger of the cap, wherein the plunger seals the liquid reservoir by moving the stopper to obstruct the passageway between the stopper and the cap.

[0006] In some embodiments, sealing the liquid reservoir to create the sealed reservoir uses a reservoir cap. The method may further comprise releasing, via the reservoir cap, air as the liquid reservoir is sealed to create the sealed reservoir. The method may further comprise unsealing the liquid reservoir using a reservoir cap; placing additional liquid in the liquid reservoir; and resealing the liquid reservoir using the reservoir cap. Also, the method may comprise receiving, by the aerosol generator, a control signal from a driver unit. The control signal from the driver unit may be used to vibrate the aperture plate to dispense liquid. The liquid may be a drug and the liquid reservoir may be a liquid drug reservoir.

[0007] In some embodiments, a system for creating a negative bias pressure within a liquid reservoir is present. The system may include an aerosol generator comprising an aperture plate having a liquid side and an air side, wherein the aerosol plate is configured to be vibrated to dispense liquid. The liquid reservoir may be configured to: receive liquid; store liquid; discharge liquid to the aerosol generator; and seal, such that a negative bias pressure develops between the liquid side and the air side of the aperture plate as liquid is discharged from the liquid reservoir. The system may include a cap configured to maintain an ambient pressure while the liquid reservoir is being sealed. The ambient pressure may be maintained in the sealed liquid reservoir until a portion of the liquid is dispensed.

[0008] In some embodiments, a system for creating a negative bias pressure on liquid to be aerosolized is present. The system may include means for receiving liquid; means for storing liquid; means for sealing the stored liquid in a sealed environment; means for maintaining an ambient pressure on the stored liquid while the stored liquid is being sealed; means for maintaining the ambient pressure in the sealed environment until a portion of the liquid is dispensed; means for discharging liquid of the stored liquid to be aerosolized; means for aerosolizing liquid of the discharged liquid; and means for allowing a negative bias pressure to develop on the stored liquid and discharged liquid.

[0009] In some embodiments, a nebulizer system is present. In such a system, an aerosol generator comprising an aperture plate may be present. The aperture plate may be configured to be vibrated to aerosolize a liquid. The system may include a liquid reservoir that is configured to: store the liquid such that a headspace is present within the liquid reservoir, and discharge the liquid to the aerosol generator. The system may include a cap configured to seal the liquid reservoir and decrease a volume of the headspace of the liquid reservoir when the cap is coupled with the liquid reservoir. The cap may include a passageway that permits air to pass from the potential headspace of the liquid reservoir into an external environment. The cap may be configured to maintain an ambient pressure while the liquid reservoir is being sealed by allowing air to exit the potential headspace through the passageway. The cap may be configured to permit a negative pressure within the liquid reservoir to develop as the liquid is discharged from the liquid reservoir after the liquid reservoir has been sealed using the cap.

[0010] Embodiments of such a cap may include one or more of the following features: The cap may include a first port connected with the passageway and a second port connected with the passageway, the first port and the first port positioned perpendicularly on the cap to the second port on the cap. The liquid reservoir may include a port block configured to block a first port connected with the passageway when the cap has been placed in a fully closed position on the liquid reservoir. The port block may include a protruding portion of an inside surface of the liquid reservoir. The first port of the cap may include a compressible ring of material configured to be compressed by the port block when the cap is placed in the fully closed position on the liquid reservoir. The liquid reservoir may be molded using a single type of material. The cap may include a seal located on an exterior surface of the cap and is positioned between the first port of the passageway and a second port of the passageway. The seal may be configured to prevent air from passing between an outer surface of the cap and an inner surface of the liquid reservoir when the cap is coupled with the liquid reservoir. The liquid reservoir may include a plurality of bayonet guides, each bayonet guide of the plurality of bayonet guides configured to guide a corresponding bracket of the cap such that the cap simultaneously descends into the liquid reservoir and twists towards a closed position. The cap and the liquid reservoir may be configured to lock together when the cap is twisted to the fully closed position on the liquid reservoir such that the cap is locked into position and inhibited from being removed from the liquid reservoir. The cap may include exactly two finger protrusions configured to receive rotational force from fingers of a user to twist the cap onto the liquid reservoir. [0011] In some embodiments, a liquid storage system is presented. The liquid storage system may include a liquid reservoir that is configured to store a liquid such that a headspace is present within the liquid reservoir and discharges the liquid to an aerosol generator. The liquid storage system may include a cap for use in sealing the liquid reservoir and decreasing a volume of the headspace of the liquid reservoir. The cap may include a passageway that permits air to escape from the potential headspace of the liquid reservoir. The cap may help maintain an ambient pressure in the liquid reservoir while the liquid reservoir is being sealed by allowing air to exit the potential headspace through the passageway. The cap may permit a negative pressure within the liquid reservoir to develop as the liquid is discharged from the liquid reservoir after the liquid reservoir has been sealed using the cap. [0012] Embodiments of such a liquid storage system may include one or more of the following features: The cap may include a first port connected with the passageway on the cap and a second port connected with the passageway on the cap, the first port positioned perpendicularly on the cap to the second port on the cap. The liquid reservoir may include a port block configured to block a first port of the passageway when the cap has been coupled with the liquid reservoir placed into a fully closed position. The port block may include a protruding portion of an inside surface of the liquid reservoir. The first port of the cap may include a compressible ring configured to be compressed when the cap is coupled with the liquid reservoir and the compressible ring is in contact with the port block. The liquid reservoir may be molded using a single type of material of polycarbonate. The cap may include a seal positioned between the first port of the passageway and a second port of the passageway and the seal may be configured to prevent air from passing between an outer surface of the cap and an inner surface of the liquid reservoir when the cap is coupled with the liquid reservoir. The liquid reservoir may include a plurality of bayonet guides, each bayonet guide of the plurality of bayonet guides configured to guide a corresponding bracket of the cap such that the cap simultaneously descends into the liquid reservoir and twists toward a locked position on the liquid reservoir. The cap and the liquid reservoir may be configured to lock together when the cap is twisted to the fully closed position on the liquid reservoir such that the cap is inhibited from being removed from the liquid reservoir.

[0013] In some embodiments, a method for using a liquid storage system for a nebulizer is presented. The method may include receiving a bracket of a cap by a bayonet guide of a liquid reservoir such that a portion of the cap occupies a portion of a headspace within the liquid reservoir. The method may include venting air from the potential headspace of the liquid reservoir through a passageway of the cap into an external environment. The method may include rotating the cap such that the cap descends into the liquid reservoir and air continues to vent from the potential headspace through the passageway of the cap into the external environment. The method may include, after the cap has been rotated, obstructing the passageway of the cap by a port block of the liquid reservoir positioned on an inner surface of the liquid reservoir, wherein obstructing the passageway prevents air from entering or exiting the headspace through the passageway. The method may include decreasing pressure within the liquid reservoir by the cap and the obstructed passageway preventing air from entering the liquid reservoir as a liquid is drained from the liquid reservoir.

[0014] In some embodiments, a nebulizer system is presented. The system may include an aperture plate that is configured to be vibrated to aerosolize a liquid. The system may include a liquid reservoir. The system may include a cap that is configured to seal the liquid reservoir when the cap is moved to a sealed position on the liquid reservoir. The cap may include a passageway that extends from a first port in the cap to a second port in the cap. The first port of the cap may be sealed when the cap is moved into the sealed position. When the cap is in the sealed position, the cap may permit a negative pressure to develop within the liquid reservoir. [0015] In some embodiments, a method for using a liquid storage system for a nebulizer may be presented. The method may include receiving a cap on a liquid reservoir such that a portion of the cap occupies a portion of a potential headspace of the liquid reservoir. The method may include venting air from the potential headspace of the liquid reservoir through a passageway of the cap into an external environment. The method may include moving the cap such that the cap descends into the liquid reservoir and air continues to vent from the potential headspace through the passageway of the cap into the external environment until the cap is moved to a sealed position on the liquid reservoir. The method may include obstructing the passageway of the cap, wherein obstructing the passageway prevents air from entering or exiting a headspace of the liquid reservoir through the passageway. The method may include preventing air from entering the liquid reservoir as a liquid is drained from the liquid reservoir.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] A further understanding of the nature and advantages of the present invention may be realized by reference to the following drawings. In the appended figures, similar components or features may have the same reference label. Further, various components of the same type may be distinguished by following the reference label by a second label that distinguishes among the similar components. If only the first reference label is used in the specification, the description is applicable to any one of the similar components having the same first reference label irrespective of the second reference label.

[0017] FIG. 1 A illustrates a simplified embodiment of a nebulizer.

[0018] FIG. IB illustrates a simplified embodiment of a nebulizer with a driver unit.

[0019] FIG. 1C illustrates a simplified embodiment of a handheld nebulizer with an integrated driver unit.

[0020] FIG. ID illustrates a nebulizer integrated with a ventilator.

[0021] FIG. 2 illustrates a simplified embodiment of a cap that may seal a drug reservoir.

[0022] FIG. 3 illustrates another simplified embodiment of a cap that may seal a drug reservoir.

[0023] FIG. 4 illustrates yet another simplified embodiment of a cap that may seal a drug reservoir.

[0024] FIG. 5 illustrates a simplified embodiment of a cap that may seal a drug reservoir.

[0025] FIGs. 6A and 6B illustrate a simplified embodiment of a cap that may seal a drug reservoir.

[0026] FIG. 7 illustrates a method for creating a negative bias pressure in a drug reservoir.

[0027] FIG. 8 illustrates a method for creating a negative bias pressure in a drug reservoir, adding additional liquid drug, and then resealing the drug reservoir.

[0028] FIGs. 9A and 9B illustrate two views of an embodiment of a cap that can be used to seal a liquid reservoir.

[0029] FIG. 10 illustrates an embodiment of an exploded view of a cap that can be used to seal a liquid reservoir.

[0030] FIGs. 11 A and 1 IB illustrate side and bottom views of an embodiment of a cap that can be used to seal a liquid reservoir. [0031] FIG. 12 illustrates a top view of an embodiment of a cap that can be used to seal a liquid reservoir.

[0032] FIGs. 13 A and 13B illustrate a side view and cross-section view of a cap that can be used to seal a liquid reservoir. [0033] FIGs. 14A and 14B illustrate a cross-section view of a cap and a detailed view of a portion of the cap, respectively.

[0034] FIGs. 15A and 15B illustrate side views of a liquid reservoir with which embodiments of the caps of FIGs. 9A-14B can couple.

[0035] FIG. 16 illustrates a top angled view of a liquid reservoir. [0036] FIG. 17 illustrates a cross-section of a cap while in the process of being sealed with the liquid reservoir.

[0037] FIG. 18 illustrates the cross-section of the cap of FIG. 17 after sealing the liquid reservoir.

[0038] FIG. 19 illustrates an embodiment of a method for using a cap with a liquid reservoir. DETAILED DESCRIPTION

[0039] Devices, systems, and methods are described for the implementation of a novel architecture of nebulizers. The invention provides various ways of improving the efficiency and consistency of a liquid mist ejected from the vibrating aperture plate of a nebulizer. In some nebulizers, also known as aerosol generators, operating conditions, such as the existence of excess liquid on the air-side (front face) of the vibrating aperture plate of the nebulizer, may change over time. Such excess liquid may arise from overpressure of the liquid reservoir, forcing some liquid to leak through the aperture. Also, during operation of the nebulizer, certain features of the droplet ejection process may lead to stray droplets falling back onto the aperture plate. This excess liquid may adversely affect the ejection efficiency of the nebulizer, which is directly related to the flow rate and droplet diameter properties of the liquid mist ejected from the nebulizer.

[0040] In addition, such excess liquid on the air-side of the aperture plate may lead to the ejection of larger diameter droplets from the vibrating aperture. These larger droplet diameters may result in an improper amount of the drug being administered to the patient and the drug being deposited in the large airways of the patient's lungs as opposed to the smaller passageways where the drug may be absorbed more readily. When the pressure on the reservoir side of the aperture plate, which may be connected to the drug reservoir of the nebulizer, is lower than the air-pressure immediately on the air-side of the aperture plate, what is known as a "negative bias pressure" may be created. Such a negative bias pressure may cause the efficiency of the nebulizer to be increased, thus allowing it to achieve higher liquid flow rates, with smaller and more consistent droplet size, than in comparable conditions without a bias pressure. The negative bias pressure may 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 dispensed liquid drug's volume), a negative bias pressure may be created. Therefore, in the context of a drug reservoir, a negative bias pressure refers to a pressure that is lower than a pressure of an external environment outside of the drug reservoir.

[0041] FIG. 1A illustrates an embodiment of a possible nebulizer 100-a. The nebulizer 100-a may include a nebulizer element 110 (which is alternatively referred to as an aperture plate), a drug reservoir 120, a headspace 130, an interface 140, and a cap 150. The nebulizer element 110 may be comprised of a piezoelectric ring that may expand and contract when an electric voltage is applied to the ring. The piezoelectric ring may be attached to a perforated membrane. Such a perforated membrane may have a number of holes passing through it. When an electric voltage is applied to the piezoelectric ring, this may cause the membrane to move and/or flex. Such movement of the membrane while in contact with a liquid may cause the nebulization of the liquid, generating a mist of liquid droplets.

[0042] Embodiments of nebulizer 100-a may utilize a piezoelectric ring to vibrate a perforated membrane. Further, other nebulizers, and the techniques associated with such nebulizers, are described generally in U.S. 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; and 7,322,349, the complete disclosure of which are

incorporated by reference for all purposes.

[0043] A supply of a liquid, commonly a liquid drug, may be held in the drug reservoir 120 (also referred to as a liquid reservoir). As illustrated, a drug reservoir is partially filled with the liquid drug. As the liquid drug is nebulized, the amount remaining in the drug reservoir 120 may decrease. Depending on the amount of liquid drug in the drug reservoir 120, only a portion of the reservoir may be filled with liquid drug. The remaining portion of the drug reservoir 120 may be filled with gas, such as air. This space, when the liquid reservoir is sealed, is commonly referred to as headspace 130 and dead volume. Prior to the liquid reservoir being sealed, this space can be referred to as a potential headspace. An interface 140 may serve to transfer amounts of liquid drug between the drug reservoir 120 and the nebulizer element 110. [0044] The nebulizer 100-a may have a cap 150 sealing the drug reservoir. Such a cap 150 may prevent air from entering the drug reservoir 120. Cap 150 may be attached and sealed to the drug reservoir 120 such that the ambient pressure (e.g., the pressure outside of the drug reservoir 120) is maintained in the drug reservoir 120 until liquid is drained from the drug reservoir 120. Therefore, as the liquid drug is evacuated from the drug reservoir 120, a negative bias pressure may appear in the drug reservoir 120 (i.e. a lower pressure in the drug reservoir than the atmospheric pressure). While the drug reservoir 120 is sealed, air may still enter the drug reservoir 120 through the nebulizer element 110. The greater the difference in pressure between the external environment and the drug reservoir 120, the greater the rate air may enter the drug reservoir 120 through the nebulizer element 110. At a certain difference in pressure between the inside of the drug reservoir 120 and the external environment, the plateau pressure of the nebulizer 100-a will be reached. At this point, air external to the nebulizer 100 may enter the drug reservoir 120 through openings in the nebulizer element 110 (also referred to as the "aperture plate") at the same rate that liquid is being nebulized by the nebulizer element 110. At the plateau point, air entering the reservoir 120 via nebulizer element 110 may serve to reduce the negative bias pressure or cause it to stabilize and stay roughly at a certain pressure negative bias pressure.

[0045] A nebulizer with a sealed drug reservoir may be part of a larger system. The embodiment of FIG. IB illustrates such a nebulizer system 100-b. FIG. IB illustrates a nebulizer 151 with a capped drug reservoir connected to a driver unit 152. The nebulizer with a cap illustrated in FIG. IB may be the nebulizer with a cap of FIG. 1 A, or may represent some other nebulizer. The driver unit 152 may control the rate and size of vibration of the nebulizer element on the nebulizer 151. The driver unit 152 may be connected to the nebulizer 151 and nebulizer element via cable 153. The driver unit may be the driver unit described in co-pending provisional 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 disclosure of which is incorporated by reference for all purposes. Such a driver unit 152 may regulate the voltage and frequency of the signal provided to the nebulizer element of nebulizer 151. The regulation of the voltage and frequency of the signal may be based on the resonance frequency of the nebulizer element of nebulizer 151. Such a signal may vary depending on the magnitude of the negative bias pressure.

[0046] In some other embodiments of nebulizers, the driver unit may be incorporated into a handheld unit. Nebulizer 100-c of FIG. 1C illustrates an embodiment of a handheld nebulizer with an integrated driver. Nebulizer 100-c may include a case 155, a mouthpiece 160, and trigger button 165, and an electrical plug 170. Case 155 may contain some or all of the elements found in other embodiments of nebulizers (such as nebulizer 100-a of FIG. 1 A) and drivers (such as driver unit 152 of FIG. IB). Therefore, contained with case 155 may be a sealed drug reservoir and/or a device capable of generating an electrical signal at a particular voltage and frequency to vibrate an aperture plate that aerosolizes liquid stored in the drug reservoir. A person receiving the aerosolized liquid drug may place her mouth on mouthpiece 160 and breathe in. While the person receiving the aerosolized liquid drug is breathing in, she may press trigger button 165 to trigger the aperture plate to begin aerosolizing liquid. In some embodiments, nebulizer 100-c may contain a sensor that detects when the person is breathing in and triggers the aperture plate to vibrate without trigger button 165 being necessary.

[0047] Nebulizer 100-c may also include an electrical plug 170. Electrical plug 170 may be connected to an electrical outlet to power nebulizer 100-c. Nebulizer 100-c may contain a battery, thereby allowing electrical plug 170 to be connected to an electrical outlet when nebulizer 100-c is not in use by a person to charge the battery. Alternatively, in some embodiments of nebulizer 100- c, electrical plug 170 may need to be connected to an electrical outlet while nebulizer 100-c is in use by a person. In some embodiments, nebulizer 100-c may use replaceable batteries as its power source.

[0048] In some embodiments, a nebulizer may operate in conjunction with a ventilator. Nebulizer system 100-d illustrates a nebulizer 178 that supplies aerosolized liquid to a person 176 via a ventilator 171. Ventilator 171 may supply air suitable for breathing to person 176. Ventilator 171 may assist person 176 in breathing by forcing air into the lungs of person 176 and then releasing air to mimic breathing. While person 176 is using ventilator 171, it may be necessary to provide person 176 with aerosolized liquid, such as a liquid drug.

[0049] Nebulizer 178 may be connected to a drug reservoir 186 that is sealed by a cap 180. Drug reservoir 186 may contain an amount of liquid drug 182. This liquid drug may be delivered to nebulizer 178 as liquid drug is aerosolized by nebulizer 178. As liquid drug is aerosolized, liquid drug 182 may drain from drug reservoir 186, thereby increasing the volume of headspace 184. Headspace 184 may contain air. Headspace 184 may increase in volume, but also decrease in pressure as liquid drug 182 drains because liquid reservoir 186 is airtight. [0050] Driver 172, which may represent the same driver as driver unit 152 of FIG. IB (or may represent some other driver unit), may deliver a signal to nebulizer 178. This signal may control an aperture plate of nebulizer 178. Nebulizer 178 may be attached to a tube 179 used to deliver the air and liquid drug to person 176. Tube 179 may terminate in a mask 174 covering the mouth and/or nose of person 176. The air and aerosolized liquid drug may then enter the airways of person 176.

[0051] Nebulizers of FIGs. 1A-1D may create a negative bias pressure with a sealed drug reservoir. The overarching principle behind the bias in pressure formed in the drug reservoir of the nebulizers by the evacuated liquid drug may be described by the ideal gas equation: pV= constant Eq. 1

In equation l, p represents pressure and J ⁷ represents volume. Accordingly, in a sealed drug reservoir, the pressure pi multiplied by the volume Vi prior to the evacuation of an amount of the liquid drug may equal the pressure p ₂ multiplied by the volume V ₂ after the evacuation of the amount of the liquid drug. Therefore, the relationship may be expressed as:

:. p ₂ = P^ Eq. 2

² V ₂

[0052] Further, the volume after the liquid drug has been evacuated may be the same as the volume prior to the drug being evacuated plus the change in air volume DV due to the outflow of the liquid drug from the drug reservoir. From this, a simplified equation may be used to represent the pressure inside the reservoir 120 following evacuation of an amount of the liquid drug:

Therefore, to minimize P ₂ , Vi may be minimized. This may be accomplished by minimizing the initial amount of air space (also referred to as "headspace") in the drug reservoir, such as headspace 184 of FIG. ID or headspace 130 of FIG. 1 A.

[0053] By way of example only, a drug reservoir may be 9.5 mL. Of this 9.5 mL, 3.6 mL may be filled with a liquid drug, such as Amikacin. Therefore, an initial headspace of 5.9 mL is present. To decrease the initial headspace while still beginning with the same amount of liquid drug, the size of the drug reservoir may be reduced.

[0054] Referring to FIG. 1 A, as liquid drug is evacuated from the drug reservoir 120, the negative bias pressure may increase (in other words, the pressure inside the drug reservoir 120 may become lower than the external atmospheric pressure). The bubble point of a stationary aperture plate may be expressed by the following equation:

Here, Pb refers to the bias pressure, σ refers to surface tension of the liquid drug, and r refers to the radius of the holes in the membrane on the vibrating aperture plate. By way of example only, if σ is 0.05, such as for the liquid drug Amikacin, and the radius of the holes in the aperture plate is 2.25 microns, the bias pressure at which air will begin to "bubble" into the drug reservoir is 444 mbar bias pressure. By way of example only, using the liquid drug Amikacin, where the initial headspace in the drug reservoir is 1.9 mL, this bubble point may be reached when 2.4 mL of the initial 3.6 mL of the liquid drug has been evacuated from the drug reservoir 120. The bubble point may be greater than or equal to the plateau pressure where the air entering the aperture plate balances the liquid being ejected from the aperture plate.

[0055] While the above example refers to the use of the liquid drug Amikacin, other liquid drugs or other liquids may also be used. Further, if a different liquid is used, the value of σ may change based on the surface tension of the particular liquid used.

[0056] To allow the negative bias pressure to exist within the drug reservoir of the nebulizer, the drug reservoir 120 must be sealed to prevent air from entering the drug reservoir 120 through the perforated membrane of the nebulizer element 110. Further, it may be desirable that the drug reservoir 120 of the nebulizer 100 not be permanently sealed. A nebulizer with a resealable drug reservoir 120 may allow for the drug reservoir 120 to be reused or accessed, such as to add an additional amount of liquid drug. As such, the drug reservoir may be either permanently or temporarily capped to prevent air from filling the space created by the evacuated liquid drug. Also, a decrease in the initial dead volume may be desired to minimize VI as previously described. Therefore, a cap 150 for a drug reservoir of a nebulizer may serve multiple purposes: to seal the drug reservoir from the external environment and to fill at least a portion of the dead volume.

[0057] FIG. 2 illustrates an embodiment of a cap to seal a drug reservoir of a nebulizer 200. The nebulizer of FIG. 2 may be any of the nebulizers of FIGs. 1 A-1D, or it may be some other nebulizer. A cap 230 may be made of a rigid or semi-rigid material capable of maintaining a seal, such as plastic or metal. In such an embodiment, the cap 230 may be inserted a distance into the drug reservoir 220. Such an insertion may minimize the headspace in the drug reservoir 220 of the nebulizer when drug reservoir 220 is sealed. The greater the distance the cap 230 is inserted into the drug reservoir 220, the greater the amount of potential headspace that may be removed

(thereby reducing Vi, as previously detailed). In the embodiment of FIG. 2, the cap 230 utilizes O- rings 235 to maintain a seal against the inner edge of the drug reservoir 220. The cap 230 may contain a screw down insert 210. The screw down insert 210 may have threads to allow screw down insert 210 to be screwed into threads 260 of an outer portion of the cap 230. The cap 230 may also use O-rings 270 to maintain a seal against the screw down insert 210. As the screw down insert 210 is screwed into the outer portion of the cap 230, the potential headspace within the drug reservoir 220 may be reduced by a mass of material 240 being inserted into the potential headspace. The farther the screw down insert 210 is screwed down, the farther the mass of material 240 may be inserted into the drug reservoir 220. The screw down insert 210 may be limited from being screwed too far into the drug reservoir 220 by a block at the end of the threads 260 or the threads on screw down insert 210.

[0058] When a drug reservoir of a nebulizer is partially filled with liquid drug and a cap is installed on the drug reservoir, the attachment of the cap may compress air within the headspace of the drug reservoir if the drug reservoir is sealed, resulting in a positive bias pressure within the drug reservoir. Such a positive bias pressure may cause liquid drug to be forced out of the perforated membrane of the nebulizer. It may be desired that this phenomenon be minimized. In the embodiment of FIG. 2, the screw down insert 210 and/or the mass of material 240 may contain a passageway 250 to maintain the ambient pressure upon insertion of the cap 230. The passageway 250 may allow air to exit the cavity of the drug reservoir 220 as the cap 230 is inserted and the screw down insert 210 is screwed down. The passageway 250 may allow air to pass to outside of O-ring 270. Once the screw down insert 210 is screwed down far enough, the entire passageway 250 may be below the O-ring 270, creating an airtight seal between the cap 230 and the drug reservoir 220. [0059] The screw down insert 210 may later be unscrewed. Unscrewing the screw down insert 210 may leave the mass of material 240 in place, maintaining the air tight seal between the cap 230 and drug reservoir 220 of the nebulizer. Alternatively, unscrewing screw down insert 210 may remove mass of material 240. This may unseal drug reservoir 220, allowing liquid drug to be removed and/or added to drug reservoir 220. The screw down insert 210 may then be used again to reseal drug reservoir 220.

[0060] It may also be desired to invert the filled and sealed nebulizer so the air inside the reservoir moves to be adjacent to the aperture plate. The air may then exit through the holes in the aperture plate. This action may reduce the positive pressurization in the nebulizer, and affect the performance of the nebulizer.

[0061] FIG. 3 illustrates another embodiment 300 of a cap for a drug reservoir of a nebulizer, such as the nebulizers of FIGs. 1 A-ID, or some other nebulizer. The embodiment of FIG. 3 utilizes a pivot-based design. The cap 310 may be inserted at an angle into the cavity of the drug reservoir 320. A seal 330 attached to the cap 310 may be made of a flexible material capable of maintaining a seal, such as plastic or rubber. The cap 310 may be plastic, or metal, or any other rigid or semirigid material. Using a pivot portion 340 of the cap 310, the cap 310 and seal 330 may be pivoted into position to form an air-tight seal on the drug reservoir 320. Such a device to cap the drug reservoir 320 may involve the seal 330 deforming or partially deforming to squeeze between the sides of the drug reservoir 320, thereby creating an airtight seal. Cap 310 may be manipulated to unseal drug reservoir 320 to remove and/or add liquid drug to drug reservoir 320. Cap 310 may then be maneuvered to reseal drug reservoir 320.

[0062] FIG. 4 illustrates another embodiment 400 of cap to seal a nebulizer, such as the nebulizers of FIGs. 1A-1D, or some other nebulizer. The embodiment of FIG. 4 may include a one-way valve such as valve 440. FIG. 4 illustrates an embodiment of a cap 450 with a "burp" valve 440. Such a valve 440 prevents a positive bias pressure from being generated in the drug reservoir 410 of the nebulizer to equalize with the external atmospheric pressure and allows the ambient pressure to be maintained. However, valve 440 does not allow air to move from the external environment to inside drug reservoir 410. Cap 450 may also include O-rings 420 to maintain a seal between the cap 450 and the drug reservoir 410. Further, flanges 430 may also form an additional airtight seal between cap 450 and the drug reservoir 410. Alternatively, flange 430 may not be airtight. It may be possible to pull cap 450 off of drug reservoir 410 to add and/or remove liquid drug. Cap 450 may then be reattached to drug reservoir 410. [0063] Embodiment 500 of FIG. 5 illustrates an additional way of sealing a drug reservoir of a nebulizer that may allow for the creation of a negative bias pressure within drug reservoir 510. Such a way of sealing a drug reservoir may be used in conjunction with the nebulizers of FIGs. 1 A-ID, or some other nebulizer. Embodiment 500 may also include a one-way "burp" valve 540 to allow air to exit and the ambient pressure to be maintained, instead of creating a positive bias pressure within the drug reservoir 510. Valve 540 may prevent air from the external environment from entering drug reservoir 510. O-rings 520 may be used to form the seal between the cap 530 and the drug reservoir 510. Additional seals 550 may be present to create a seal between the drug reservoir 510 and the cap 530. In such an embodiment, the depth of the cap 530 may be varied to regulate the headspace within the drug reservoir 510. For example, the greater the depth of cap 530, the smaller the amount of headspace that will be present in the sealed drug reservoir 510. Additionally, it may be possible to remove cap 530 to add and/or remove liquid drug from drug reservoir 510. Cap 530 may then be reinserted to seal drug reservoir 510. [0064] FIGs. 6A and 6B illustrate embodiment 600A and embodiment 600B, respectively, of a cap that may be used to create a sealed drug reservoir for a nebulizer, such as the nebulizers of FIGs. 1 A-1D, or some other nebulizer. FIG. 6A illustrates the cap 630 prior to sealing with the drug reservoir 610. In such an embodiment, the cap may be placed on the drug reservoir 610 without a positive bias pressure developing because of an escape route for the air (thereby the ambient pressure being maintained), illustrated by dotted arrow 620. The cap 630 may use flange 640 to create a seal between the drug reservoir 610 and the edge of the cap 630. In some embodiments, an O-ring is used in place of flange 640. Cap 630 may contain plunger 605. The plunger may be attached to a unidirectional lock 650 and a stopper 660. The stopper may be capable of creating an airtight seal with the bottom of the cap 630 when the plunger 605 has been elevated. The unidirectional lock 650 may prevent the plunger 605 from being depressed once the unidirectional lock 650 has passed through an opening in the cap 630. The unidirectional lock 650 may be made of a flexible or semi-flexible material. The unidirectional lock 650 may also form an airtight seal with the cap 630. The cap 630 may be shaped to eliminate various amounts of headspace within the drug reservoir 610. For example, the depth of cap 630 may be increased to eliminate an increased amount of headspace from drug reservoir 610. Once cap 630 has been inserted, plunger 605 may be pulled to seal the cap 630 to the drug reservoir 610.

[0065] FIG. 6B illustrates cap 630 after the plunger 605 has been raised. A user may raise plunger 605 manually. The stopper 660 may have formed an airtight seal with the bottom of the cap 630. In this embodiment, the unidirectional lock 650 has passed through the cap 630, preventing the plunger 605 from descending and/or breaking the seal between the cap 630 and the drug reservoir 610. Additionally, unidirectional lock 650 may form an airtight seal with the top of cap 630. It may be possible to unseal cap 630 by pushing plunger 605 such that unidirectional lock 650 is forced back through the top of cap 630. Cap 630 may be removed to allow liquid drug to be added and/or removed from drug reservoir 610. In some embodiments, once unidirectional lock 650 has passed through cap 630, such as in FIG. 6B, it may not be possible to unseal cap 630 using plunger 605. However, it may still be possible to remove cap 630, add and/or remove additional liquid drug and reseal drug reservoir 610 using a new cap 630. [0066] As those with skill in the art will realize, the embodiments of FIGs. 2-6 represent examples of possible embodiments of caps to seal a drug reservoir of a nebulizer. Other embodiments of caps may also be possible. Further, it may be possible to create a permanently capped reservoir. Such a permanently sealed reservoir may be formed from a single piece of material or may include a distinct cap permanently attached to the drug reservoir of the nebulizer. Such a permanently sealed drug reservoir may be used once and then disposed.

[0067] Such embodiments of nebulizers and caps, such as those described in FIGs. 1 A-1D, and FIGs. 2-6 may allow for a drug reservoir of a nebulizer to be sealed using a method, such as method 700 of FIG. 7. At block 710, a drug reservoir of a nebulizer may receive liquid, such as any of the previously described liquid drugs into a drug reservoir. At block 720, this liquid may be stored in the drug reservoir until the liquid drug is either removed or aerosolized.

[0068] At block 730, the liquid reservoir may be sealed. The process of such sealing may allow for air to escape from the liquid reservoir to prevent a positive bias pressure within the drug reservoir from developing, and thus maintain the ambient pressure within the drug reservoir. Once sealed, if any positive pressure within the liquid reservoir is present, it may still be allowed to escape;

however air from the external environment is not permitted to enter the drug reservoir. The ambient pressure may then be maintained within the drug reservoir until liquid drug is dispensed from the drug reservoir.

[0069] At block 740, liquid drug may be discharged from the drug reservoir to the aperture plate of the nebulizer. Because the drug reservoir is sealed, air may not enter the drug reservoir as the liquid drug is discharged.

[0070] At block 750, the liquid drug may be aerosolized by the aperture plate. The aperture plate may be vibrating. As liquid drug contacts the aperture plate and moves through openings in the aperture plate, the liquid drug may become nebulized into small airborne particles. Such airborne particles may be suitable for inhalation by a person.

[0071] At block 760, as liquid is discharged from the drug reservoir and is aerosolized by the aperture plate, a negative bias pressure may develop within the drug reservoir. The negative bias pressure may develop because neither air nor anything else is permitted to enter the drug reservoir to take the place of the liquid drug as it is being discharged. [0072] FIG. 8 illustrates another embodiment 800 of a method that allows for a drug reservoir of a nebulizer to be sealed and a negative bias pressure to form within the drug reservoir. Further, embodiment 800 allows for additional liquid drug to be added after the drug reservoir has been sealed. Such embodiments of nebulizers and caps, such as those described in FIGs. 1A-1D, and FIGs. 2-6 may allow for embodiment 800 to be performed.

[0073] At block 810, a drug reservoir of a nebulizer may receive liquid, such as any of the previously described liquid drugs into a drug reservoir. At block 820, this liquid may be stored in the drug reservoir until the liquid drug is either removed or aerosolized.

[0074] At block 830, the liquid reservoir may be sealed. The process of such sealing may allow for air to escape from the liquid reservoir to prevent a positive bias pressure within the drug reservoir from developing. Once sealed, any positive pressure within the liquid reservoir may still be allowed to escape; however, air from the external environment is not permitted to enter the drug reservoir.

[0075] At block 840, liquid drug may be discharged from the drug reservoir to the aperture plate of the nebulizer. Because the drug reservoir is sealed, air may not enter the drug reservoir as the liquid drug is discharged.

[0076] At block 845, the nebulizer may receive a control signal from a control unit, such as driver unit 152 of FIG. IB. The control signal may be at a frequency and a voltage. The frequency and magnitude of the voltage may determine the rate and amplitude of the vibration of the aperture plate of the nebulizer. The rate and amplitude of the aperture plate's vibration may determine the amount of liquid drug aerosolized and the size of the liquid drug droplets that are created by the aperture plate.

[0077] At block 850, the liquid drug may be aerosolized by the aperture plate based on the control signal received at block 845. As liquid drug contacts the aperture plate and moves through openings in the aperture plate, the liquid drug may become nebulized into small airborne particles. Such airborne particles may be suitable for inhalation by a person. [0078] At block 860, as liquid is discharged from the drug reservoir and is aerosolized by the aperture plate, a negative bias pressure may develop within the drug reservoir. The negative bias pressure may develop because neither air nor anything else is permitted to enter the drug reservoir to take the place of the liquid drug as it is being discharged.

[0079] At block 865, after some amount of liquid drug has been aerosolized and a negative bias pressure has been created within the drug reservoir, it may be determined whether additional liquid drug is to be added to the drug reservoir. Additionally, it may be determined whether liquid drug will be removed from the drug reservoir. If no, the method may end at block 870. The negative bias pressure created at block 860 may remain until some future time.

[0080] However, if at block 865 additional liquid drug is to be added (or removed) from the drug reservoir, the drug reservoir cap may be removed at block 875. This may involve removing the entire cap. For example, referring to FIG. 3, cap 310 may be entirely removed such that drug reservoir 320 may be accessed. This may involve manipulating only a portion of the cap. In some embodiments, only a portion of the cap may be removed. For example, referring to FIG. 2, screw down insert 210 may be unscrewed (or otherwise removed) while the remainder of cap 230 remains attached to drug reservoir 220. [0081] At block 880, additional liquid may be received in the drug reservoir. This may represent the same or different liquid drug than what was aerosolized at block 850. Drug reservoir may also be cleaned, especially if a different liquid drug is to be aerosolized. This additional liquid drug may be stored by the drug reservoir at block 890. The method may then return to block 830, where the drug reservoir may be resealed using the same cap or a different cap. The method may then continue until no additional liquid drug is to be aerosolized.

[0082] In addition to the cap embodiments of FIGs. 2-6, FIGs. 9A-14B illustrate embodiments of a cap that may be used to seal a liquid reservoir. The cap of FIGs. 9A-14B may be used in conjunction with embodiments of a liquid reservoir as described in relation to FIGs. 15A-16. In some embodiments, the cap of FIGs. 9A-14B may require a liquid reservoir as described in relation to FIGs. 15A-16 to function properly. The embodiments of caps and liquid reservoirs (e.g., liquid drug reservoirs) of FIGs. 9A-14B and FIGs. 15A-16, respectively, can perform similar functions to that of the other cap embodiments detailed in this document; that is, the cap may permit the sealing of the liquid reservoir while, at the same time, decreasing a volume of the potential headspace of the liquid reservoir and preventing an increase of pressure during the sealing process by allowing air to escape as the volume of the potential headspace is decreased. Further, following sealing of the liquid reservoir with the cap, pressure roughly equivalent to that of the external environment may be maintained within the liquid reservoir and its headspace until liquid is drained from the liquid reservoir for nebulization. When liquid is drained, a negative bias pressure forms within the liquid reservoir by virtue of the cap having sealed the liquid reservoir and air being prevented from entering the headspace. While the cap may seal the liquid reservoir and allow a negative bias pressure to develop within the liquid reservoir, it may be possible for air to enter the liquid reservoir through the nebulizer's aperture plate. That is, once the negative bias pressure within the liquid reservoir becomes great enough, air may enter through holes present in the nebulizer's aperture plate.

[0083] FIGs. 9A and 9B illustrate two views of an embodiment of a cap 1000 that can be used to seal a liquid reservoir. FIG. 9 A represents a top angled view of cap 1000, FIG. 9B represents a bottom angled view of cap 1000. Cap 1000 may include components: chassis 910, headspace filler 920, first passageway port 930, passageway seal structure 935, sealing structure 940, cover 950, passageway port 960, and bayonet 970 (970-1 and 970-2).

[0084] Chassis 910 may form the main body of cap 1000. Chassis 910 may be molded as a single piece of material. Typically, chassis 910 may be a form of plastic or, more specifically, polycarbonate such as Makrolon ^® 2458. Chassis 910 may be shaped to include finger grips, such as finger grip 911. Finger grip 911 may provide a surface, such as a traction-enhancing surface (e.g., by virtue of the presence of one or more raised ribs), that allows a user to easily grip the cap and rotate it. In some embodiments, a cover 950 can be coupled with chassis 910. Cover 950 may serve to obscure from view empty space or internal components of chassis 910. Cover 950 may serve as a convenient location to display a graphical symbol and/or word mark on the cap. Cover 950 may be removable from chassis 910, or, alternatively, may be permanently coupled with chassis 910 such that it cannot be removed or at least is not easily removed from chassis 910.

[0085] Headspace filler 920 represents a portion of chassis 910, along with other components of cap 1000, that is inserted a distance within a liquid reservoir when cap 1000 is used to seal the liquid reservoir. As such, headspace filler 920 represents the portion of cap 1000 that, when coupled with a liquid reservoir, decreases the volume of the liquid reservoir's potential headspace.

[0086] Present on chassis 910 may be passageway port 930 and passageway port 960.

Connecting passageway port 930 and passageway port 960 may be a passageway that allows air to move between passageway port 930 and passageway port 960. When both passageway port 930 and passageway port 960 are unobstructed, air can move in and/or out of the two ports and through the connecting passageway. Therefore, if cap 1000 is inserted on top of a liquid reservoir such that headspace filler 920 displaces a volume of air within the liquid reservoir, air may enter

unobstructed passageway port 960 and may exit passageway port 930. This movement of air can help prevent a positive pressure from developing within the liquid reservoir when cap 1000 is being used to seal the liquid reservoir.

[0087] Encircling passageway port 930 may be passageway seal structure 935. Passageway seal structure 935 may be made of a compressible material such that, when pushed up against a surface, passageway port 930 becomes sealed or otherwise obstructed and prevents air from entering or escaping. The compressible material of passageway seal structure 935 may be injection molded such that a portion is contained within chassis 910.

[0088] Sealing structure 940 may prevent air from entering or escaping the liquid reservoir when cap 1000 is fully coupled with a liquid reservoir. In some embodiments, such as illustrated in FIGs. 9A and 9B, sealing structure 940 may be an O-ring or other form of gasket formed of a compressible material, such as rubber or silicone. Chassis 910 may have an indented circular portion on headspace filler 920 to permit installation of sealing structure 940 after manufacture of chassis 910. For example, an O-ring may be stretched and installed on headspace filler 920 sometime after manufacture of chassis 910; once the O-ring is in position on the indented circular portion of headspace filler 920, the O-ring may at least partially contract.

[0089] Bayonet 970 may serve to allow cap 1000 to be screwed onto a liquid reservoir. Bayonet 970 may cause cap 1000 to descend a distance within the liquid reservoir, may rotate as cap 1000 descends, and may serve to hold cap 1000 in a fixed location once fully coupled with the liquid reservoir. In some embodiments, bayonet 970 may be shaped such that once cap 1000 has been fully screwed onto the liquid reservoir, cap 1000 cannot (at least not without excessive force or risk of damage to cap 1000 and/or liquid reservoir) be uncoupled from a liquid reservoir. Bayonet 970 may be part of chassis 910; that is, bayonet 970 may be formed as part of the injection molding process used to create chassis 910. Locking screw blocks 971 (971-1 and 971-2) may serve to help prevent cap 1000 from being unscrewed once cap 1000 has been fully screwed into a liquid reservoir by interfacing with an unscrew block of the liquid reservoir. While being coupled with the liquid reservoir, bayonet 970 may be configured to flex outward around a portion of the liquid reservoir (e.g., bracket expander 1521) and then snap back inwards once beyond the protruding portion of the liquid reservoir such that screw blocks 971 prevent unscrewing of cap 1000 (e.g., by interfacing with bracket screw block 1522). In the illustrated embodiment of FIG. 9B, two bayonet 970 and two locking screw blocks 971 are present. It should be understood that in other embodiments, it may be possible for more than two bayonet and/or screw blocks to be present. Further, it may even be possible for a single screw bracket and/or a single screw block to be present.

[0090] FIG. 10 illustrates an embodiment of an exploded view of cap 1000 that can be used to seal a liquid reservoir. In the exploded view of FIG. 10, cap 1000 is broken into its three constituent parts: chassis 910, cover 950, and sealing structure 940. Sealing structure 940, which is illustrated in the form of an O-ring, can be stretched and attached to chassis 910 by allowing sealing structure 940 to contract over indented portion 1010 of chassis 910. Cover 950 may be inserted onto a top of chassis 910. It should be understood that while cap 1000 is in the form of three constituent parts, other embodiments may involve fewer or greater numbers of constituent parts. As a variation, cap 1000 may function without cover 950. As another example, sealing structure 940 may be injection molded as part of chassis 910 similarly to passageway seal structure 935.

[0091] FIGs. 11A and 11B illustrate side and bottom views of an embodiment of cap 1000 that can be used to seal a liquid reservoir. In FIG. 11 A, headspace filler 920 is more specifically denoted by a bracket. Further it should be understood that in various embodiments headspace filler 920 may be smaller or greater, defined by the amount of cap 1000 that descends within the liquid reservoir and thus displaces air from the potential headspace of the liquid reservoir. FIG. 12 illustrates a top view of an embodiment of cap 1000 that can be used to seal a liquid reservoir. In FIG. 12, cover 950 is circular and serves to provide a roughly flat surface for the top of chassis 910. A partially hollow space may be present between chassis 910 and cover 950.

[0092] FIGs. 13 A and 13B illustrate a side view and cross-section view of cap 1000 that can be used to seal a liquid reservoir. FIG. 13 A represents, via dotted line, the location of cross section 1300. Cross section 1300 illustrates that cover 950 may be depressed into chassis 910 such that a top surface of cover 950 is roughly level with a top lip 1305 of chassis 910. Top lip 1305 of chassis 910 may encircle cover 950. Cover 950 and chassis 910 may be made from the same material, such as polycarbonate plastic (e.g., MAKROLON ^® 2458). Further, cross section 1300B illustrates how air spaces (e.g., air spaces 1320, 1321) may be present between chassis 910 and cover 950 within cap 1000.

[0093] The cross section of FIG. 13B illustrates passageway 1310 which connects passageway port 930 with passageway port 960. Passageway 1310, when neither of passageway ports 930 and 960 are obstructed, allows air to pass. Thus, as cap 1000 is coupled with a liquid reservoir, headspace filler 920 of cap 1000 displaces air within the liquid reservoir, air passes through passageway 1310 to escape into the ambient environment. While passageway 1310 forms roughly a right angle, it should be understood that other angles and shapes (e.g., a curved path) are also possible.

[0094] Passageway seal structure 935 protrudes from a side of chassis 910 a distance around passageway port 930. At least the protruding portion of passageway seal structure 935 can be compressed by a protrusion of the liquid reservoir to obstruct passageway port 930, and thus prevent air from passing through passageway 1310. The illustrated embodiment of cross section 1300B illustrates that passageway seal structure 935 is formed by a compressible material being injected (e.g., injected from an opening in a top surface of chassis 910 during manufacturing) into a cavity of chassis 910. Such an arrangement permanently attaches passageway seal structure 935 to chassis 910 such that passageway seal structure 935 is prevented from accidentally becoming detached from chassis 910. [0095] FIG. 14 illustrates a detailed view 1350 of a portion of the cross section of FIG. 13B. Detailed view 1350 illustrates an embodiment of how cover 950 may be attached to chassis 910. Chassis 910 may have a hollow circular protrusion 1420. Cover 950 may also have a hollow circular protrusion 1410 on its bottom with a greater radius than circular protrusion 1420. The two circular protrusions 1410 and 1420 may couple by virtue of friction, circular protrusion 1410 being deformed outward, and/or circular protrusion 1420 being deformed inward. It should be understood that various other ways of connecting cover 950, either permanently or removably, to chassis 910 may be possible.

[0096] FIGs. 15A and 15B illustrate side views of a liquid reservoir assembly 1500 with which embodiments of cap 1000 of FIGs. 9A-14B can couple. Liquid reservoir 1510 may form a cavity that can store a liquid, such as a liquid drug. When liquid reservoir 1510 is partially filled with liquid, above the liquid is air that forms the potential headspace of the liquid reservoir. This potential headspace can be reduced in volume by placing an object in its place (e.g., a portion of a cap) such that less air is present within the liquid reservoir when sealed. A potential headspace becomes a headspace, which defines a volume of air within a sealed liquid reservoir, once the liquid reservoir is sealed. Prior to sealing of the liquid reservoir, a potential headspace is present. Liquid reservoir 1510 may include: bayonet guide 1520, bracket screw block 1522, bracket expander 1521, and alignment indicator 1560. Liquid reservoir 1510 may be molded, such as injection molded, from a single material, such as a clear polycarbonate plastic. Additionally, liquid reservoir 1510 may be attached to nebulizer element 1540, which may function similarly to the previously detailed nebulizer elements, and electrical connector 1550, which may permit wiring to be connected to deliver an electrical signal to nebulizer element 1540. Together, liquid reservoir 1510, nebulizer element 1540, and electrical connector 1550 may form liquid reservoir assembly 1500.

[0097] The screw bracket may serve to guide a headspace filler 920 of cap 1000 a distance down into liquid reservoir 1510 and may lock cap 1000 into place once cap 1000 has been fully screwed onto liquid reservoir 1510. Bayonet guide 1520 may also cause cap 1000 to be rotated to a position such that a passageway port of cap 1000 is obstructed such that air cannot pass through the passageway coupled to the passageway port. Arrows 1530, 1531, and 1532 roughly illustrate the movement of a cap when a screw bracket of cap 1000 is inserted into bayonet guide 1520 and rotated. First, cap 1000 may descend roughly vertically in the direction of arrow 1530. During this descent, air being displaced from within the potential headspace of the liquid reservoir may escape through passageway 1310 and, possibly, around a gap between an inner edge of liquid reservoir 1510 and sealing structure 940. The shape of bayonet guide 1520 may then cause cap 1000 and its associated headspace filler portion to descend further into the liquid reservoir 1510 while, at the same time, cap 1000 is being rotated. During this descent and rotation, air being displaced from within the potential headspace of liquid reservoir 1510 may escape through passageway 1310. Finally, horizontal rotation of cap 1000 illustrated by arrow 1532 results in cap 1000 being rotated to a position in which a passageway port, such as passageway port 930, becomes obstructed (e.g., by a portion of liquid reservoir 1510). In some embodiments, this portion of the liquid reservoir may be port block 1610, which is a protruding portion of the liquid reservoir located on an inner surface of the liquid reservoir. When port block 1610 forms a seal with passageway seal structure 935, air cannot enter or leave the liquid reservoir through cap 1000 because sealing structure 940 has become seated within liquid reservoir 1510 and passageway 1310 is obstructed.

[0098] The upper region of liquid reservoir 1510 may have a greater internal diameter in the vicinity of port block 1610. This greater internal diameter may allow for sufficient room for passageway seal structure 935 to rotate and allow air to escape through the passageway 1310 into the external environment. Once passageway seal structure 935 engages with port block 1610, air ceases to be able to pass between the now-sealed environment of liquid reservoir 1510 and the external environment.

[0099] When a screw bracket of cap 1000 passes against bracket expander 1521, the screw bracket may be temporarily deformed by bending outwards. Bracket expander 1521 may represent a roughly wedge-shaped protrusion from the outer surface of liquid reservoir 1510 that causes a screw bracket of a cap to be bent a greater distance outwards as cap 1000 is rotated onto liquid reservoir 1510. Once the screw bracket has fully passed over bracket expander 1521, the screw bracket may cease being deformed, may cease being bent outwards, and may become seated in bracket pocket 1523. When a screw bracket is seated within bracket pocket 1523, bracket screw block 1522, which can represent an edge of bracket expander 1521, may prevent the cap from being unscrewed. Bracket end 1524 may prevent cap 1000 from being rotated onto liquid reservoir 1510 beyond a point where bracket end 1524 impacts an edge of screw bracket. When a screw bracket impacts bracket end 1524 and/or the screw bracket seats within bracket pocket 1523, the cap can be understood as having reached a fully closed position on the liquid reservoir. [0100] In some embodiments, bracket screw block 1522 and bracket expander 1521 may not be present, thus allowing the cap to be easily unscrewed from the liquid reservoir. In embodiments where bracket screw block 1522 and bracket expander 1521 are present, cap 1000 and liquid reservoir assembly 1500 may be understood to be "single use" because they are designed to have liquid put in the liquid reservoir, use a cap to seal the liquid reservoir, and never be unsealed again.

[0101] Alignment indicator 1560 may be aligned with alignment indicator 1020 when a cap is to be coupled with liquid reservoir 1510. By alignment indicator 1560 being vertically aligned with alignment indicator 1020, bayonet (e.g., bayonet 970-1) may be aligned with a bayonet guide (e.g., bayonet guide 1520). Once aligned, a user may move the cap vertically such that bayonet enter corresponding bayonet guides of liquid reservoir 1510 as illustrated by arrow 1530.

[0102] In FIG. 15 A, a single bayonet guide 1520 is visible. It should be understood that liquid reservoir 1510 has an equal number of bayonet guides 1520 to match the bayonet on a cap. Thus, in some embodiments, such as for the cap of FIG. 9B, two bayonet are present on liquid reservoir 1510. Similar to the number of bayonet of the caps, the number of bayonet guides can be varied by embodiment. In some embodiments, the number of bayonet guides 1520 may be greater or less than the number of bayonets.

[0103] FIG. 16 illustrates a top angled view of a liquid reservoir assembly 1500. Visible in FIG. 16 is port block 1610. Port block 1610 may be a portion of liquid reservoir 1510 that protrudes inward from an inner surface of liquid reservoir 1510. When a cap is rotated into a fully closed or locked position on liquid reservoir 1510, passageway port 930 may become aligned with port block 1610. The horizontal movement represented by arrow 1532 results in passageway port 930 passing over indented region 1613 then angled side 1611 of port block 1610 and coming to rest on a flat center portion 1612 of port block 1610. Flat center portion 1612 may mate with passageway seal structure 935 such that pressure is applied to passageway seal structure 935 that partially deforms passageway seal structure 935. Port block 1610 may obstruct passageway 1310 by compressing passageway seal structure 935 and thus forming an airtight seal preventing air from entering or leaving passageway 1310. Indented region 1613, which represents a recessed region on an inner surface of liquid reservoir 1510, may serve to prevent liquid from being forced out of the aperture plate when the cap is closed by creating an additional pathway for air to escape as cap 1000 is being twisted shut. Air may exit through passageway port 930 into indented region 1613 and then into the exterior environment. As such, indented region 1613 may facilitate air escaping from the potential headspace through passageway port 930 into the exterior environment. [0104] FIG. 17 illustrates an embodiment 1700 of cross-section 1300 of cap 1000 in the process of being attached and sealed to liquid reservoir 1510. In embodiment 1700, cap 1000 is in the process of being attached with liquid reservoir 1510 by movement indicated by arrows 1530 and/or 1531 as noted in FIG. 15A. Bayonets 970 of cap 1000 may be slid within bayonet guide 1520. A seal 1705 may be formed between sealing structure 940 and an inside surface 1710 of liquid reservoir 1510.

[0105] While seal 1705 is present, air may pass from the headspace above a liquid within liquid reservoir 1510, through passageway 1310 and into an external environment, thus allowing air to vent from the headspace of liquid reservoir 1510 and preventing a positive pressure (as compared with the external environment) from developing within the liquid reservoir as a headspace filler 920 portion of cap 1000 descends into the liquid reservoir 1510. A gap 1715 may be present between passageway seal structure 935 and inside surface 1710, thus allowing air to escape into the external environment via passageway 1310. In other embodiments, rather than gap 1715 being present, passageway seal structure 935 may press against inside surface 1710, but with insufficient pressure to substantially prevent air from escaping passageway 1310.

[0106] FIG. 18 illustrates an embodiment 1800 of cross-section 1300 of cap 1000 after being attached and sealed to liquid reservoir 1510 (thus, liquid reservoir 1510 is rotated in relation to cross section 1300 as compared to in FIG. 17). As such, embodiment 1800 represents embodiment 1700 after the sealing process has been completed. In embodiment 1800, cap 1000 is fully attached with liquid reservoir 1510. Seal 1705 remains formed between sealing structure 940 and an inside surface 1710 of liquid reservoir 1510.

[0107] Flat center portion 1612 of port block 1610 forms a seal with passageway seal structure 935, thus preventing air from escaping from the headspace of liquid reservoir 1510. Port block 1610 protrudes from an inner surface of liquid reservoir 1510, thus preventing gap 1715 from being present. Therefore, the headspace of liquid reservoir 1510 is sealed from the external environment by cap 1000, including seal 1705 and the seal formed between port block 1610 and passageway seal structure 935, which blocks passageway 1310 from venting air. As such, when liquid is drained from liquid reservoir 1510, a negative pressure (as compared to the external environment) can develop within liquid reservoir 1510. [0108] FIG. 19 illustrates an embodiment of a method 1900 for using a cap with a liquid reservoir. Method 1900 may be performed using cap 1000 and liquid reservoir 1510 or liquid reservoir assembly 1500 for storing a liquid drug for nebulization. The liquid drug may be desired to be stored in the liquid reservoir such that headspace within the liquid reservoir is decreased in volume, the decreasing of volume of the headspace does not result in an increased pressure within the liquid reservoir, and as liquid is drained from the liquid reservoir (for nebulization), pressure within the liquid reservoir decreases with reference to an external pressure.

[0109] At block 1910, the liquid reservoir is partially filled with liquid. Above the liquid within the partially filled liquid reservoir, a headspace filled with air is present. At block 1920, bayonet of the cap may be inserted into the bayonet guides of the liquid reservoir. A user may visually align alignment indicators 1560 and 1020, which causes the bayonet of the cap and the bracket guides of the liquid reservoir to become aligned. While embodiments detailed in this document focus on bracket guides being present on the liquid reservoir, and bayonet being present on the cap, it should be understood that in other embodiments the bayonet may be located on the liquid reservoir and the bracket guides may be present on an embodiment of the cap. By the bayonet of the cap being inserted into the bracket guides of the liquid reservoir, a headspace filler portion of the cap may begin descending into the liquid reservoir, thereby decreasing the volume of the potential headspace present above the liquid within the liquid reservoir. [0110] At block 1930, as the headspace filler portion of the cap is being inserted into the liquid reservoir, air may be vented from the potential headspace of the liquid reservoir. Such venting may occur, at least partially, via in unobstructed passageway present on the cap. This venting may occur via passageway port 960 passageway 1310, and passageway port 930. That is, air from the potential headspace of the liquid reservoir may enter passageway port 960, pass through passageway 1310, and exit passageway port 930. As such, an escape route for air from the liquid reservoir is present even if the seal has already been formed between an inner surface of the liquid reservoir and sealing structure 940. This venting of air prevents a positive pressure, as compared to the external environment of the liquid reservoir, from developing within the liquid reservoir.

[0111] At block 1940, the cap may be rotated such that bayonet of the cap follow a path defined by bracket guides of the liquid reservoir resulting in a headspace filler portion of the cap descending further into the liquid reservoir and the cap twisting or rotating. The movement of the bayonet guides of the liquid reservoir, as the cap is rotated or twisted, may eventually result in the cap no longer descending into the liquid reservoir but rather, only rotating. Therefore, at this point, since the headspace filler portion of the cap is not descending farther into the liquid reservoir, there is no opportunity for a positive pressure to develop and the passageway to vent air from the liquid reservoir is no longer needed to be unobstructed.

[0112] At block 1950, the passageway through which the air was vented is obstructed such that air can no longer enter or exit the liquid reservoir through the passageway. The obstruction of block seven 1850 may occur by virtue of a passageway port of the cap becoming obstructed by a port block of the liquid reservoir as detailed in relation to FIGs. 13B and FIG. 16. The passageway is sealed, obstructed at block 1950 after the headspace filler portion of the cap has descended to its maximum distance within the liquid reservoir; therefore the pressure within the liquid reservoir remains the same as the external environment until liquid begins being drained from the liquid reservoir for nebulization. Further, at this point, sealing structure 940 has formed an airtight seal between an outer edge of the cap and an inner surface of the liquid reservoir.

[0113] At block 1960, the cap may be locked into place such that the cap is hindered from being unscrewed or otherwise removed from the liquid reservoir by a user. Locking the cap in place may involve the cap becoming "permanently" coupled with the liquid reservoir. It may be possible to uncouple a permanent coupling of a cap to a liquid reservoir by applying excessive force, deforming the cap and/or liquid reservoir, or damaging either the cap or liquid reservoir. For example, cap 1000 may be locked to liquid reservoir 1510 by a screw bracket being deformed outwards and passing over bracket expander 1521 until bayonet 970-1 is seated within bracket pocket 1523. Bracket screw block 1522 impacts locking screw blocks 971-1 to prevent unscrewing if unscrewing of cap 1000 is attempted by a user.

[0114] At block 1970, liquid may be discharged from the liquid reservoir to an aerosol generator, such as a nebulizer element, for nebulization of the liquid at block 1980. Therefore, as liquid is nebulized at block 1980, additional liquid will be discharged from the liquid reservoir. As this liquid is discharged or drained from the liquid reservoir, a negative bias pressure as compared with the external environment, develops within the liquid reservoir at block 1990 due to the volume of liquid within the liquid reservoir being decreased and the liquid reservoir having been sealed by the cap (which had its passageway blocked or obstructed at block 1950).

[0115] 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-gram-positive antibiotic, or combinations thereof may be used. Additionally, antibiotics may comprise those having broad spectrum effectiveness, or mixed spectrum effectiveness. Antifungals, such as polyene materials, in particular, amphotericin B, are also suitable for use herein. Examples of anti-gram-negative antibiotics or salts thereof include, but are not limited to, aminoglycosides or salts thereof.

Examples of aminoglycosides or salts thereof include gentamicin, amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin, tobramycin, salts thereof, and combinations thereof. For instance, gentamicin sulfate is the sulfate salt, or a mixture of such salts, of the antibiotic substances produced by the growth of Micromonospora purpurea. Gentamicin sulfate, USP, may be obtained from Fujian Fukang Pharmaceutical Co., LTD, Fuzhou, China. Amikacin is typically supplied as a sulfate salt, and can be obtained, for example, from Bristol-Myers Squibb. Amikacin may include related substances such as kanamicin.

[0116] 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 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 monohydrochlonde of vancomycin B. Like all glycopeptide antibiotics, vancomycin hydrochloride contains a central core heptapeptide. Vancomycin hydrochloride, USP, may be obtained from Alpharma, Copenhagen, Denmark. [0117] 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.

[0118] Examples of additional active agents include, but are not limited to, anti-inflammatory agents, bronchodilators, and combinations thereof.

[0119] Examples of bronchodilators include, but are not limited to, β-agonists, anti -muscarinic agents, steroids, and combinations thereof. For instance, the bronchodilator may comprise albuterol, such as albuterol sulfate. [0120] 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, antiepileptics, 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, anti androgenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, anti enteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent, when administered by inhalation, may act locally or systemically.

[0121] 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.

[0122] 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 (GURH), 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 (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), 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, alatr ofloxacin, 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 penicllinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant agents like methicillin, oxacillin, cl oxacillin, dicl oxacillin, fl oxacillin, 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, fluni solide, 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.

[0123] 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. [0124] 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 1 wt % 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. [0125] 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.

[0126] Further, in one or more embodiments, the aqueous composition is preservative-free. In this regard, the aqueous composition may be methylparab en-free and/or propylparaben-free. Still further, the aqueous composition may be saline-free.

[0127] In one or more embodiments, the compositions comprise an anti-infective and an excipient. The compositions may comprise a pharmaceutically acceptable excipient or carrier which may be taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject. In addition to the active agent, a pharmaceutical 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 1 wt % 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. [0128] 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.

[0129] 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.

[0130] 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. [0131] Carbohydrate excipients suitable for use in the invention include, for example,

monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; di 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.

[0132] 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. [0133] 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),

hydroxy ethyl starch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-P-cyclodextrin and sulfobutylether-P-cyclodextrin), polyethylene glycols, and pectin. [0134] 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", 19.sup.th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52.sup.nd ed., Medical Economics, Montvale, N.J. (1998), both of which are incorporated herein by reference in their entireties. [0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.