Negatively biased sealed nebulizers systems and methods

NEGATIVELY BIASED SEALED NEBULIZERS SYSTEMS AND METHODS

<b>CROSS-REFERENCE TO RELATED APPLICATIONS</b>

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

Embodiments of the present invention relate to nebulizers. Specifically, the present invention relates to the use of a nebulizer with a sealed drug reservoir to establish and maintain a negative bias pressure therein.

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

Creating a negative bias pressure on the liquid side of an aperture used to aerosolize a liquid drug may allow for more efficient and consistent delivery of aerosolized liquid drugs to a patient. Such negative bias may be created by reducing the pressure in the drug reservoir of the nebulizer. This may be accomplished by sealing the drug reservoir and then draining any amount of liquid drug from the reservoir. Since neither air nor anything else can fill the space emptied by the expelled liquid drug, the pressure in the drug reservoir is reduced, thereby in the liquid drug reservoir and on the liquid side of the aperture that aerosolizes the liquid drug. Create a negative bias pressure.

In some embodiments, there may be a method for creating a negative bias pressure in a sealed reservoir. The method may include providing a liquid reservoir coupled to the aerosol generator, the aerosol generator comprising an aperture plate, the aperture plate having a liquid side and an air side. Also, the method may include receiving the liquid in the liquid reservoir. The method may include sealing the liquid reservoir to create the sealed reservoir. Ambient pressure may be maintained while the liquid reservoir is being sealed. 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 the liquid. Dispensing liquid may reduce the amount of liquid in the sealed reservoir. The method may include reducing the amount of liquid in the sealed reservoir to create a negative bias pressure between the air side and the liquid side of the aperture plate.

In some embodiments, a cap is provided, wherein the cap includes a first portion configured to couple with a liquid reservoir and a second portion configured to screw into the first portion of the cap. The method may further include screwing a second portion of the cap into the first portion of the cap, wherein the passageway is such that an ambient pressure is applied to the liquid reservoir when the second portion of the cap is screwed into the first portion of the cap. to be maintained in In some embodiments, a cap is provided, wherein the cap includes a flexible seal and pivot. The method may include pivoting the cap relative to the liquid reservoir such that the flexible seal seals the liquid reservoir. In some embodiments, a cap is provided that includes a one-way valve and a seal. The method may further include joining the cap onto the liquid reservoir such that the seal couples the cap and the liquid reservoir, wherein the ambient pressure of the one-way valve to be 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 includes a plunger and a stopper. The method may further include placing a cap on the liquid reservoir such that the cap covers the liquid reservoir, wherein an ambient pressure is maintained by the passageway between the cap and the stopper. The method may further include pulling a plunger of the cap, wherein the plunger seals the liquid reservoir by moving the stopper to block the passageway between the stopper and the cap.

In some embodiments, sealing the liquid reservoir to create a sealed reservoir uses a reservoir cap. The method may further include releasing air through the reservoir cap when the liquid reservoir is sealed to create a sealed reservoir. The method includes unsealing a liquid reservoir using a reservoir cap; placing additional liquid in the liquid reservoir; and resealing the liquid reservoir using the reservoir cap. Further, the method may include receiving a control signal by the aerosol generator from the driver unit. A 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.

In some embodiments, there is a system for generating a negative bias voltage in a liquid reservoir. 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 vibrate to dispense liquid. The liquid reservoir is configured to receive a liquid; store liquid; discharging the liquid into the aerosol generator; A negative bias pressure may be configured to seal to develop between the liquid side and the air side of the aperture plate when liquid is discharged from the liquid reservoir. The system may include a cap configured to maintain ambient pressure while the liquid reservoir is being sealed. Ambient pressure may be maintained in the sealed liquid reservoir until a portion of the liquid is dispensed.

In some embodiments, a system exists for generating a negative bias pressure in a liquid to be aerosolized. The system includes means for receiving a liquid; means for storing liquid; means for sealing the stored liquid in a sealed environment; means for maintaining ambient pressure on the stored liquid while the stored liquid is being sealed; means for maintaining ambient pressure in the sealed environment until a portion of the liquid is dispensed; means for discharging the liquid of the stored liquid to be aerosolized; means for aerosolizing the liquid of the discharged liquid; and means for causing a negative bias pressure to develop over the stored liquid and the discharged liquid.

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

1A shows a simplified embodiment of a nebulizer. 1B shows a simplified embodiment of a nebulizer with a driver unit. 1C shows a simplified embodiment of a handheld nebulizer with an integrated driver unit. 1D shows a nebulizer integrated with a ventilator. 2 shows a simplified embodiment of a cap that may seal a drug reservoir. 3 shows another simplified embodiment of a cap that may seal a drug reservoir. 4 shows another simplified embodiment of a cap that may seal a drug reservoir. 5 shows a simplified embodiment of a cap that may seal a drug reservoir . 6A and 6B show a simplified embodiment of a cap that may seal a drug reservoir. 7 shows a method for generating negative bias pressure in a drug reservoir. 8 depicts a method for creating a negative bias pressure in a drug reservoir, adding additional liquid drug, and then resealing the drug reservoir.

Devices, systems, and methods for implementation of the novel architecture of nebulizers are described. The present invention provides a variety of ways to improve the efficiency and consistency of liquid mist ejected from the vibrating aperture plate of a nebulizer. In some nebulizers, also known as aerosol generators, operating conditions, such as the presence of excess liquid on the air side (front) of the oscillating aperture plate of the nebulizer, may change over time. Such excess liquid may also result in excess of the pressure in the liquid reservoir, forcing some liquid to leak through the aperture. Also, during operation of the nebulizer, certain characteristics of the droplet ejection process may induce stray droplets that fall back onto the aperture plate. Such excess liquid may adversely affect the ejection efficiency of the nebulizer, which is directly related to the drop diameter properties and flow rate of the liquid mist ejected from the nebulizer.

Additionally, such excess liquid on the air side of the aperture plate may induce ejection of larger diameter droplets from the vibrating aperture. These larger droplet diameters may result in an inadequate amount of drug being administered to the patient, and drug depositing in the large airways of the patient's lungs as opposed to smaller passageways through which the drug may be more readily absorbed. When the pressure on the reservoir side of the aperture plate, which may be connected to the drug reservoir of the nebulizer, is less than the air pressure directly adjacent on the air side of the aperture plate, what is known as a "negative bias pressure" may be created. Such negative bias pressure may increase the efficiency of the nebulizer, thus allowing the nebulizer to achieve higher liquid flow rates with a smaller and more consistent droplet size than at comparable conditions without bias pressure. A negative bias pressure may be created by sealing the drug reservoir. When liquid drug flows out of the drug reservoir (little or no air entering to displace the volume of liquid drug dispensed), a negative bias pressure may be created.

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

Embodiments of the nebulizer 100 may use a piezoelectric ring to vibrate the perforated membrane. Additionally, other nebulizers and techniques related to such nebulizers are described in US Pat. Nos. 5,164,740; 5,938,117; 5,586,550; Nos. 5,758,637, 6,014,970, 6,085,740; 6,235,177; 6,615,824; 7,322,349, the entire disclosures of which are incorporated by reference for all purposes.

A supply of liquid generally liquid drug may be held in drug reservoir 120 (also referred to as a liquid reservoir). As shown, the drug reservoir is partially filled with liquid drug. As the weak drug is atomized, the amount remaining in the drug reservoir 120 may decrease. Depending on the amount of liquid drug in drug reservoir 120, only a portion of the reservoir may be filled with liquid drug. The remaining portion of the drug reservoir 120 may be filled with a gas such as air. This space is generally referred to as head space 130 and dead volume. Interface 140 may function to transfer amounts of liquid drug between drug reservoir 120 and nebulizer element 110 .

The nebulizer 100 - a may have a cap 150 that seals the drug reservoir. Such a cap 150 may prevent air from entering the drug reservoir 120 . The cap 150 is a drug reservoir (120) such that the ambient pressure (eg, the pressure outside the drug reservoir 120) is maintained in the drug reservoir (120) until the liquid flows out of the drug reservoir (120). 120) and may be sealed. Thus, when a liquid drug is discharged from the drug reservoir 120 , a negative bias pressure (ie, a pressure in the drug reservoir that is lower than atmospheric pressure) may appear in the drug reservoir 120 . While the 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 at which air may enter the drug reservoir 120 through the nebulizer element 110 . At a certain difference in pressure between the interior and exterior environments of the drug reservoir 120 , a plateau pressure of the nebulizer 100 will be reached. At this point, the air outside the nebulizer 100 passes the drug through the openings (referred to as "aperture plates") in the nebulizer element 100 at a rate equal to the rate at which the liquid is being atomized by the nebulizer element 110 . It is also possible to enter the storage 120 . At a stable point, air entering the reservoir 120 through the nebulizer element 110 functions to reduce the negative bias pressure, or causes the reservoir 120 to stabilize and maintain the negative bias pressure approximately at a specified pressure. You may.

A nebulizer with a sealed drug reservoir may be part of a larger system. The embodiment of FIG. 1B depicts such a system 100 - b . 1B shows a nebulizer 151 with a capped drug reservoir connected to a driver unit 152 . The capped nebulizer shown in FIG. 1B may be the capped nebulizer of FIG. 1A , or may represent some other nebulizer. The driver unit 152 may control the speed and magnitude of vibration of the atomizer element on the atomizer 151 . The driver unit 152 may be connected to the atomizer element 151 via a cable 153 . The Driver Unit is disclosed in co-pending Provisional Application Serial No. 61/226,591 (Attorney Dockett) entitled SYSTEMS AND METHODS FOR DRIVING SEALED NEBULIZERS, filed on July 17, 2009, the entire disclosure of which is incorporated by reference for all purposes. No. 015225-012600US). Such a driver unit 152 may adjust the voltage and frequency of a signal provided to the nebulizer element of the nebulizer 151 . The adjustment of the voltage and frequency of the signal may be based on the resonant frequency of the nebulizer element of the nebulizer 151 . Such a signal may vary depending on the magnitude of the negative bias pressure.

In some other embodiments of atomizers, the driver unit may be included in a handheld unit. Nebulizer 100 - c of FIG. 1C depicts one embodiment of a handheld nebulizer with an integrated driver. The atomizer 100 - c may include a case 155 , a mouthpiece 160 , and a trigger button 165 , and an electrical plug 170 . Case 155 contains some or all of the elements found in other embodiments of atomizers (such as atomizer 100 - a in FIG. 1A ) and drivers (such as driver unit 152 in FIG. 1B ). You may. Thus, included in the case 155 may be a sealed drug reservoir and/or device capable of generating an electrical signal at a specific voltage and frequency to vibrate an aperture plate that aerosolizes the liquid stored in the drug reservoir. have. A person receiving the aerosolized liquid drug may place their mouth on the mouthpiece 160 and breathe. While the person receiving the aerosolized liquid drug is breathing, he may press the trigger button 165 to trigger the aperture plate to begin aerosolizing the liquid. In some embodiments, the nebulizer 100 - c may include a sensor that detects when the person is breathing and triggers the element to vibrate without the necessary trigger button 165 .

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

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

Nebulizer 178 may be connected to drug reservoir 186 sealed by cap 180 . The drug reservoir 186 may contain any amount of the liquid drug 182 . This liquid drug may be delivered to the nebulizer 178 when the liquid drug is aerosolized by the nebulizer 178 . When the liquid drug is aerosolized, the liquid drug 182 may flow out of the drug reservoir 186 , thereby increasing the volume of the headspace 184 . The headspace 184 may include air. Headspace 184 may increase in volume, but decrease in pressure when liquid drug 182 is spilled because liquid reservoir 186 is sealed.

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

The nebulizers of FIGS. 1A-1D may create a negative bias pressure with respect to the sealed drug reservoir. The overarching principle for bias at the pressure created in the drug reservoir of the nebulizers by the expelled liquid drug may be described by the ideal gas equation.

pV = constant Equation (1)

In Equation 1, p represents pressure and V represents volume. Thus, in a sealed drug reservoir, the pressure p prior to ejection of any amount of liquid drug₁ Multiply volume V₁is the pressure p after ejection of any amount of liquid drug₂ Multiply Volume V2_Wow may be the same. Therefore, the relational expression may be expressed as follows.

<img file="KR20120052998A_D0001.tif" />

<img file="KR20120052998A_D0002.tif" /> Equation (2)

Additionally, the volume after the liquid drug is expelled may equal the volume before the drug is expelled plus the change in air volume DV due to the out-flow of the liquid drug from the drug reservoir. From this, a simplified equation may be used to express the pressure inside the reservoir 120 following the discharge of any amount of liquid drug.

<img file="KR20120052998A_D0003.tif" /> Equation (3)

Therefore, p₂To minimize , V₁This may be minimized. This may be achieved by reducing the initial amount of air space (also referred to as "headspace") in a drug reservoir, such as headspace 184 of FIG. 1D or headspace 130 of FIG. 1A .

By way of example only, the drug reservoir may be 9.5 mL. Of these 9.5 mL, 3.6 mL may be filled with a liquid drug such as amikacin. Thus, there is an initial headspace of 5.9 mL. The size of the drug reservoir may be reduced to reduce the initial headspace while still starting with the same amount of liquid drug.

Referring to FIG. 1A , when the liquid drug is discharged from the drug reservoir 120 , the negative bias pressure may increase (ie, the pressure within the drug reservoir 120 may be less than the external atmospheric pressure). The bubble point of the stationary aperture plate may be expressed by the following equation.

<img file="KR20120052998A_D0004.tif" /> Equation (4)

where P_brefers to the bias pressure, σ refers to the surface tension of the liquid drug, and r refers to the radius of the pores in the membrane on the vibrating aperture plate. By way of example only, if σ is 0.05 as for the liquid drug amikacin and the radius of the holes in the aperture plate is 2.25 microns, then the bias pressure at which air will "bubble" into the drug reservoir is 444 mbar bias pressure. By way of example only, using liquid drug amikacin with an initial headspace of 1.9 mL in the drug reservoir, this bubble point may be reached when 2.4 mL of the initial 3.6 mL of liquid drug is expelled from the drug reservoir 120 . have. The bubble point may be above a stable pressure at which air entering the aperture plate balances with the liquid ejected from the aperture plate.

Although the above example refers to the use of the liquid drug amikacin, other liquid drugs or other liquids may also be used. Additionally, if different liquids are used, the value of σ may vary based on the surface tension of the particular liquid used.

To allow negative bias pressure to exist within the drug reservoir of the nebulizer, the drug reservoir 120 is configured to prevent air from entering the periphery of the drug reservoir 120 through the perforated membrane of the nebulizer element 110 . must be sealed. Additionally, it may be desirable that the drug reservoir 120 of the nebulizer 100 is not permanently sealed. A nebulizer with a resealable drug reservoir 120 may allow the drug reservoir 120 to be reused or accessed, such as adding an additional amount of liquid drug. As such, the drug reservoir may be capped permanently or temporarily to prevent air filling the space created by the expelled liquid drug. Also, a reduction in initial dead volume may be desired to minimize V1 as described above. Thus, the cap 150 for the drug reservoir of the nebulizer serves multiple purposes; That is, it may serve to seal the drug reservoir from the external environment and fill at least a portion of the data volume.

2 shows one embodiment of a cap for sealing the drug reservoir of the nebulizer 200 . The nebulizer of FIG. 2 may be any of the nebulizers of FIGS. 1A-1D , or may be some other nebulizer. Cap 230 may be constructed of a rigid or semi-rigid material capable of holding a seal, such as plastic or metal. In one such embodiment, the cap 230 may be inserted a distance into the drug reservoir 220 . Such insertion may minimize headspace in the drug reservoir 220 of the nebulizer. The greater the distance at which the cap 230 is inserted into the drug reservoir 220, the greater the amount of headspace that may be removed (thereby, as detailed previously, V₁decreases). In the embodiment of FIG. 2 , cap 230 utilizes O-rings 235 to hold a seal against the inner edge of drug reservoir 220 . The cap 230 may include a screw-down insert 210 . The screw down insert 210 may have threads for allowing the screw down insert 210 to be screwed into the threads 260 of the outer portion of the cap 230 . The cap 230 may also use an O-ring 270 to hold the seal against the screw down insert 210 . When the screw down insert 210 is screwed into the outer portion of the cap 230 , the headspace in the drug reservoir 220 may be reduced by the amount of material 240 to be inserted into the headspace. The deeper the screw down insert 210 is screwed down, the greater the quantity of material 240 may be inserted into the drug reservoir 220 . The screw down insert 210 may be restricted from being screwed deeper into the drug reservoir 220 by the threads on the screw down insert 210 or a block at the distal end of the threads 260 .

When the drug reservoir of the nebulizer is partially filled with liquid drug and the cap is installed on the drug reservoir, the attachment of the cap may contain air in the headspace of the drug reservoir, resulting in a positive bias pressure within the drug reservoir . Such positive bias pressure may force the liquid drug out of the perforated membrane of the nebulizer. It may be desirable for this phenomenon to be minimized. In the embodiment of FIG. 2 , the screw down insert 210 and/or the mass of material 240 may include passageways 250 for maintaining ambient pressure on the insert of the cap 230 . When the cap 230 is inserted and the screw down insert 210 is screwed down, the passageway 250 may cause air to leave the cavity of the drug reservoir 220 . The passageway 250 may allow air to pass out of the o-ring 270 . Once the screw down insert 210 has been screwed down far enough, the entire passageway 250 may be under the o-ring 270 , creating a hermetic seal between the cap 230 and the drug reservoir 220 . do.

Later, the screw-down insert 210 may be unscrewed. Unscrewing the screw down insert 210 may hold a quantity of material 240 in place and maintains a hermetic seal between the nebulizer's drug reservoir 220 and the cap 230 . Alternatively, unscrewing the screw down insert 210 may remove a large amount of material 240 . This may unseal the drug reservoir 220 , allowing the liquid drug to be removed and/or added to the drug reservoir 220 . Thereafter, the screw down insert 210 may be used again to reseal the drug reservoir 220 .

It may also be desirable to invert the filled and sealed nebulizer so that the air inside the reservoir moves adjacent the aperture plate. The air may then be expelled through holes in the aperture plate. This action reduces positive pressurization in the nebulizer and may affect the performance of the nebulizer.

3 shows another embodiment 300 of a cap for a drug reservoir of a nebulizer, such as the nebulizers of FIGS. 1A-1D or some other nebulizer. The embodiment of Figure 3 uses a pivot-based design. The cap 310 may be inserted into the cavity of the drug reservoir 320 at one angle. The seal 330 attached to the cap 310 may be constructed of a flexible material capable of retaining the seal, such as plastic or rubber. The cap 310 may be plastic, or metal, or any other rigid or semi-rigid material. Using pivot portion 340 of cap 310 , cap 310 and seal 330 may be pivoted into a position to form a hermetic seal on drug reservoir 320 . Such a device for capping the drug reservoir 320 may include a deformed or partially deformed seal 330 to squeeze between the sides of the drug reservoir 320 , thereby , to create a hermetic seal. The cap 310 may be manipulated to unseal the drug reservoir 320 to remove the liquid drug and/or add the liquid drug to the drug reservoir 320 . The cap 310 may then be manipulated to reseal the drug reservoir 320 .

4 shows another embodiment 400 of a cap for sealing 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 . 4 shows one embodiment of a cap 450 having a "burp" valve 440 . Such a valve 440 prevents a positive bias pressure from being created in the nebulizer's drug reservoir 410 to equalize with the external atmospheric pressure, and allows the ambient pressure to be maintained. However, the valve 440 prevents air from moving into the drug reservoir 410 from the external environment. The cap 450 may also include an o-ring 420 to maintain a seal between the cap 450 and the drug reservoir 410 . Additionally, the flanges 430 may also form an additional hermetic seal between the cap 450 and the drug reservoir 410 . Alternatively, the flange 430 may not be sealed. It may be possible to pull out the cap 450 of the drug reservoir 410 to add and/or remove liquid drug. Thereafter, the cap 450 may be reattached to the drug reservoir 410 .

The embodiment 500 of FIG. 5 illustrates an additional manner of sealing the drug reservoir of the nebulizer that may allow for the creation of a negative bias pressure within the drug reservoir 510 . Such a manner of sealing the drug reservoir may be used with the nebulizers of FIGS. 1A-1D or some other nebulizer. Embodiment 500 may also include a one-way "buff" valve 540 to allow air to vent and maintain ambient pressure, instead of creating a positive bias pressure within drug reservoir 510 . have. The valve 540 may prevent air from the external environment from entering the drug reservoir 510 . O-ring 520 may be used to form a seal between cap 530 and drug reservoir 510 . An additional seal 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 adjust the headspace within the drug reservoir 510 . For example, as the depth of the cap 530 increases, the amount of headspace that will exist in the drug reservoir 510 decreases. Additionally, it may be possible to remove the cap 530 to add and/or remove liquid drug from the drug reservoir 510 . The cap 530 may then be reinserted to seal the drug reservoir 510 .

6A and 6B show an embodiment 600 of a cap that may be used to create a sealed drug reservoir for a nebulizer, such as the nebulizers of FIGS. 1A-1D or some other nebulizer. 6A shows the cap 630 prior to sealing the drug reservoir 610 . In such an embodiment, the cap may be placed on the drug reservoir 610 without developing a positive bias pressure due to an escape route for air as shown by dashed arrow 620 (thereby maintaining ambient pressure). ). The cap 630 may use a 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 instead of flange 640 . The cap 630 may include a plunger 605 . The plunger may be attached to the unidirectional lock 650 and the stopper 660 . The stopper may create a hermetic seal relative to the underside of the cap 630 when the plunger 605 is raised. The unidirectional lock 650 may prevent the plunger 605 from being pressed once the unidirectional lock 650 passes through the opening in the cap 650 . The unidirectional lock 650 may be constructed of a flexible or semi-flexible material. The unidirectional lock 650 may also form a hermetic seal with respect to the cap 630 . The cap 630 may be shaped to remove various amounts of headspace within the drug reservoir 610 . For example, the depth of the cap 630 may be increased to remove an increased amount of headspace from the drug reservoir 610 . Once cap 630 is inserted, plunger 605 may be pulled to seal cap 630 with drug reservoir 610 .

6B shows the cap 630 after the plunger 605 has been raised. The user may manually raise the plunger 605 . The stopper 660 may form a hermetic seal with respect to the underside of the cap 630 . In this embodiment, the unidirectional lock 650 passes through the cap 630 and the plunger 605 lowers and/or breaks the seal between the cap 630 and the drug reservoir 610 . to prevent Additionally, the unidirectional lock 650 may form a hermetic seal with respect to the top of the cap 630 . It may be possible to unseal the cap 630 by pushing the plunger 605 to cause the unidirectional lock 650 to depress the top of the 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 the unidirectional lock 650 has penetrated the cap 630 as in FIG. 6B , it may not be possible to unseal the cap 630 using the plunger 605 . However, it may still be possible to remove the cap 630 , add and/or remove additional liquid drug, and reseal the drug reservoir 610 using a new cap 630 .

As one of ordinary skill in the art will appreciate, the embodiments of FIGS. 2-6 represent examples of possible embodiments of caps for sealing the drug reservoir of a nebulizer. Other embodiments of caps may also be possible. Additionally, 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 it may include a separate cap permanently attached to the drug reservoir of the nebulizer. Such a permanently sealed drug reservoir may be discarded after being used once.

Such an embodiment of nebulizers and caps, such as the nebulizers and caps described in FIGS. You may. At stage 710 , the drug reservoir of the nebulizer may receive a liquid into the drug reservoir, such as any of the liquid drugs previously described. At stage 720 , this liquid may be stored in a drug reservoir until the liquid drug is removed or aerosolized.

At stage 730, the liquid drug may be sealed. The process of such sealing may allow air to flow out of the liquid reservoir to prevent a positive bias pressure from developing within the drug reservoir, thus maintaining ambient pressure within the drug reservoir. Once sealed, the presence of any positive pressure in the liquid reservoir may still allow air to flow, however, no air from the external environment is allowed to enter the drug reservoir. Thereafter, ambient pressure may be maintained within the drug reservoir until the liquid drug is dispensed from the drug reservoir.

At stage 740 , the liquid drug may be expelled from the drug reservoir into the aperture plate of the nebulizer. Because the drug reservoir is sealed, air may not be able to enter the drug reservoir when the liquid drug is expelled.

At stage 750 , the liquid drug may be aerosolized by the aperture plate. The aperture plate may be vibrating. When the liquid drug contacts the aperture plate and travels through openings in the aperture plate, the liquid drug may become atomized into small airborne particles. Such airborne particles may be suitable for inhalation by humans.

At stage 760, a negative bias pressure may be developed within the drug reservoir as the liquid exits the drug reservoir and is aerosolized by the aperture plate. A negative bias pressure may develop because no air or the like to displace the liquid drug is allowed to enter the drug reservoir when the liquid drug is expelled.

FIG. 8 depicts another embodiment 800 of a method for causing the drug reservoir of the nebulizer to be sealed and a negative bias pressure to build up within the drug reservoir. Additionally, embodiment 800 allows additional liquid drug to be added after the drug reservoir is sealed. Such embodiments of atomizers and caps, such as the atomizers and caps described in FIGS. 1A-1D and 2-6 , may allow embodiment 800 to be performed.

At stage 810 , the drug reservoir of the nebulizer may receive any of the previously described liquid drugs into the drug reservoir. At stage 820 , this liquid may be stored in a drug reservoir until the liquid drug is removed or aerosolized.

At stage 830, the liquid reservoir may be sealed. The process of such sealing may allow air to flow out of the liquid reservoir to prevent positive bias pressure from developing within the drug reservoir. Once sealed, any positive pressure in the liquid reservoir may still be allowed to escape, however, no air from the external environment is allowed to enter the drug reservoir.

At stage 840 , the liquid drug may be discharged from the drug reservoir into the aperture plate of the nebulizer. Because the drug reservoir is sealed, air may not be able to enter the drug reservoir when the liquid drug is expelled.

At stage 845 , the nebulizer may receive a control signal from a control unit, such as control unit 152 of FIG. 1B . The control signal may be present at one frequency and one voltage. The frequency and magnitude of the voltage may determine the speed and magnitude of vibration of the aperture plate of the nebulizer. The speed and magnitude of vibration of the aperture plate may determine the amount of aerosolized liquid and the size of liquid drug droplets produced by the aperture plate.

At stage 850 , a liquid drug may be aerosolized by the aperture plate based on the control signal received at stage 845 . When the liquid drug contacts the aperture plate and travels through openings in the aperture plate, the liquid drug may become atomized into small airborne particles. Such airborne particles may be suitable for inhalation by humans.

At stage 860 , a negative bias pressure may be developed within the drug reservoir as the liquid exits the drug reservoir and is aerosolized by the aperture plate. A negative bias pressure may develop because no air or the like to displace the liquid drug is allowed to enter the drug reservoir when the liquid drug is expelled.

At stage 865 , after some amount of liquid drug has been aerosolized and a negative bias pressure is 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 the liquid drug will be removed from the drug reservoir. Otherwise, the method may end at stage 870 . The negative bias pressure generated in stage 860 may remain until some future time.

However, if additional liquid drug is added (or removed) from the drug reservoir at stage 865 , the drug reservoir cap may be removed at stage 875 . This may include removing the entire cap. For example, referring to FIG. 3 , the cap 310 may be entirely removed so that the 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 , the screw down insert 210 may be unscrewed (or otherwise removed) while the remainder of the cap 230 remains attached to the drug reservoir 220 .

At stage 880, additional liquid may be received from the drug reservoir. It may represent the same or different liquid drug that was aerosolized in stage 850 . The drug reservoir may also be cleaned, especially if different liquid drugs are 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 aerosolized.

Although a wide variety of drugs, liquids, liquid drugs, and drugs dissolved in liquids are aerosolized, the following provides broad examples of what may be aerosolized. Additional examples are provided in US Application Serial No. 12/341,780, the entire disclosure of which is incorporated herein for all purposes. In general, any anti-gram-negative, anti-gram-positive antibiotic, or combinations thereof, may be used. Additionally, antibiotics may include antibiotics with broad spectrum effectiveness or mixed spectrum effectiveness. Polyene materials in particular antifungal agents such as amphotericin B are also suitable for use herein. Anti-gram-negative antibiotics or salts thereof include, but are not limited to, aminoglycosides or salts thereof. Examples of aminoglycosides or salts thereof include gentamicin, amikacin, kanamycin, streptomycin, neomycin, netylmycin, paramesin, tobramycin, salts thereof, and combinations thereof. For example, gentamicin sulfate is a sulfate or mixture of antibiotic substances produced by the growth of Micromonospora purprea. Gentamicin sulfate, USP, may be obtained from Fujian Fukang Pharmaceutical Co.,LTD, Fuzhou, China. Amikacin is commonly supplied as a sulfate salt and may be obtained, for example, from Bristol-Myers Squibb. Amikacin may also contain related substances such as kanamycin.

Examples of anti-gram-positive antibiotics or salts thereof include, but are not limited to, macrolides or salts thereof. Examples of macrolides or salts thereof include, but are not limited to, vancomycin, erythromycin, clarithromycin, azithromycin, salts thereof, and combinations thereof. For example, vancomycin hydrochloride is a hydrochloride salt of the vancomycin antibiotic produced by certain strains of Amycoratopsis orientalis previously designated Streptomyces orientalis. Vancomycin hydrochloride is a mixture of related substances consisting primarily of the monohydrochloride salt of vancomycin B. Like all glycopeptide antibiotics, vancomycin hydrochloride contains a central core heptapeptide. Vancomycin hydrochloride, USP, may be obtained from Alpharma, Copenhagen, Denmark.

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

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

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

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

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

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

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

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

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

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

In one or more embodiments, the compositions include an anti-infective agent and an excipient. The compositions may include a pharmaceutically acceptable excipient or carrier that may be taken with lungs that do not have significant adverse effects of toxins on the subject, particularly the lungs of the subject. In addition to the active agent, the pharmaceutical formulation may optionally include one or more pharmaceutical excipients suitable for pulmonary care. If present, these excipients are present in the composition in an amount sufficient to perform their intended function, such as stability, surface modification, and improve the effectiveness or delivery of the composition or the like. Thus, if present, excipients may range from about 0.01 wt% to about 95 wt%, such as from about 0.5 wt% to about 80 wt%, from about 1 wt% to about 60 wt%. Preferably, such excipients will function in part to further improve the properties of the active agent composition, for example, by providing more efficient and reproducible delivery of the active agent and/or facilitating manufacture. In addition, one or more excipients may be provided to function as bulking agents when it is desired to reduce the concentration of the active agent in the formulation.

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

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

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

Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose and the like; polysaccharides, such as raffinose, melechinose, maltodextrins, dextranss, starches, and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, maoinositol, and the like.

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

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

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

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

Specific details are provided in the specification to provide a thorough understanding of the embodiments. However, it will be understood by one of ordinary skill in the art that the embodiments may be practiced without these specific details. For example, well-known processes, algorithms, structures, and techniques have been described without unnecessary detail in order to avoid obscuring the embodiments. This description provides exemplary embodiments only, and is not intended to limit the scope, applicability, or configuration of the present invention. Instead, the previous description of the embodiments will provide those skilled in the art with a possible description for implementing the embodiments of the present invention. Various changes may be made in the function and arrangement of elements without departing from the spirit and scope of the invention.

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

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