Patent Publication Number: US-8539944-B2

Title: Devices and methods for nebulizing fluids for inhalation

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     This application is a divisional application of U.S. patent application Ser. No. 10/338,194, filed on Jan. 7, 2003, now U.S. Pat. No. 7,360,536, which claims the benefit of U.S. Provisional Application No. 60/403,454, filed on Aug. 13, 2002, and U.S. Provisional Application No. 60/346,789, filed on Jan. 7, 2002, the complete disclosure of which is hereby incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention is directed to the field of methods and devices for nebulizing fluids. In particular, the present invention is directed to methods and devices by which a user may select a dose of medication from a multi-dose vial and nebulize the selected dose for inhalation. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention provides a nebulizing device that is preferably a hand-held nebulizing device for inhalation of the nebulized fluid. The device has a nebulizing element and a mouthpiece through which the user inhales the nebulized fluid. The nebulizing element, which may interchangeably be referred to as an aerosolization element, may be a vibrating element with holes through which the fluid is ejected as a mist, although other suitable nebulizing elements may be used without departing from the present invention. 
     The fluid is held in a container that holds a number of doses of the fluid. The container delivers the fluid to a reservoir. A plunger acts on the container to cause fluid to flow from the container into the reservoir. A screw mechanism controls the distance of travel of the plunger. A dosing mechanism allows a user to select a particular dose to be administered by inhalation, and the dosing mechanism cooperates with the screw mechanism to set a distance of travel of the plunger that corresponds to the dose selected by the user. The dosing mechanism may rotate within a plane. An actuation mechanism is operated by the user to carry out the actual movement of the plunger according to the distance of travel set by the dosing mechanism. In this manner, a user can verify the amount of fluid selected for aerosolization before that amount of fluid is moved into the reservoir for aerosolization. If a user sees that the dose amount needs to be modified, the user can do so by further operation of the dosing mechanism before any fluid is actually released from the container. In this manner, an inadvertent selection of a dose will not result in loss of that amount of fluid, because the user has the opportunity to verify and if called for readjust the selection before fluid is moved from the container into the reservoir. 
     The actuator will typically travel in a direction perpendicular to the plane of rotation of the dosing mechanism. In this manner, dosing can be done easily and accurately by the user with a simple rotation action prior to attempting to deliver the dosed amount into a reservoir for aerosolization. The actuation can be done simply, in a discrete manner, prior to or while the user has oriented the device for inhalation through the mouthpiece of the device. In addition, the actuation mechanism is configured so that a single, predetermined movement of the actuation mechanism causes the plunger to travel the entire distance that a user selects, regardless of the particular distance of travel chosen by the user. Thus, delivery of the fluid from the container to the reservoir for aerosolization may be carried out by a single motion by the user operating the actuation mechanism, thus reducing encumbering maneuvering that could be required in delivering a particular amount of fluid from the container to the reservoir. This contributes to ease of operation of the nebulizer, and thus improves the level of care that a user may administer in using the nebulizer. In some cases, a patient may not comply with a particular drug regimen because it is perceived as inconvenient or embarrassing, as might be the case with injunctions or cumbersome inhalation devices. Accordingly, the present invention minimizes such potential non-compliance factors because the user may dial a dose out of the line of sight of others, the user may operate the actuator with a simple button press, and the user needs only a single hand to bring the nebulizer to the mouth. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Embodiments of the invention will be described in greater detail below with reference to the drawings. 
         FIG. 1  is schematic representation of a partial exploded side view of a nebulizer embodiment according to the present invention. 
         FIG. 2  is a perspective view of the nebulizer of  FIG. 1 . 
         FIG. 3  is a flow chart showing a method and steps in accordance with the present invention. 
         FIG. 4  is a cutaway cross-sectional view along axis A of the device as depicted in  FIG. 2  and in accordance with the present invention. 
         FIG. 5A  is a detail cross-section view of the nebulizer of  FIG. 1  taken along line A-A. 
         FIG. 5B  is a detail cross-section view of the nebulizer of  FIG. 1  taken along line A-A. 
         FIG. 6  is a detail cross-sectional cutaway view of the nebulizer of  FIG. 2  taken along line B-B. 
         FIGS. 7A and 7B  are detail cross-sectional cutaway views of the nebulizer depicted in  FIG. 2  taken along line C-C. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Referring to  FIG. 1 , a nebulizing inhaler according to the present invention is represented schematically. The device  10  comprises a titration mechanism  20 , a vial mechanism  22 , a reservoir  90  and an aerosol generator  100 . The titration mechanism comprises a titration control mechanism, which may be referred to a dosing mechanism  30 , a screw mechanism  50 , a plunger  60 , an actuator  40 , a retainer  41 , a release mechanism  43 , and a reset mechanism  44 . The plunger is configured to travel to and fro, as explained in further detail below, in the direction of arrow  62  (this being the “to” motion, the “fro” motion being the reverse thereof). Accordingly, and as depicted in  FIG. 1 , arrow  62  defines the axis of travel of the plunger  60 . The actuator is configured to travel to and fro, as explained in further detail below, in the direction of the arrow  42  (this being the “to” motion, the “fro” motion being the reverse thereof). Accordingly, and as depicted in  FIG. 1 , the arrow  42  defines the longitudinal axis of travel of the actuator  40 . The axis of travel of the actuator  40  is also represented as the broken line A in  FIG. 2 . The retainer  41  is employed to releasably capture the actuator  40  when the actuator  40  is fully moved a distance from an initial position to a predetermined actuation position. The release mechanism  43  releases the retainer  41  to allow the actuator  40  to return to the initial position from the predetermined actuation position. The release mechanism  43  and the reset mechanism  44  are linked together such that the release mechanism  43  causes the reset mechanism  44  to reset a visual indictor. 
     The vial mechanism  22  comprises a container, such as a vial  23  that defines a central longitudinal axis  24  and movable seal  70  movably captured in the vial  23 . The moveable seal  70  is movable along the central axis  24  of the vial  23  by action of plunger  60  upon the moveable seal  70  in the direction of arrow  62 . A liquid  80  is provided in the vial mechanism  22 . The liquid  80  is moved into a reservoir  90  by action of the movable seal  70  against the liquid  80 , as the moveable seal is moved, in the direction of arrow  62 , by action of the plunger in the direction of arrow  62 , upon the moveable seal  70 . Once the liquid is in the reservoir  90 , the liquid  80  can be nebulized for inhalation by a user. 
     Upon exhaustion of liquid from the vial, the vial may be removed and replaced as necessary with a new vial containing liquid, thus putting the nebulizer in a state ready for operation. The vial  23  may be of a transparent material, such as glass, and thus the level of fluid  80  within it can readily be seen. The level of fluid in the vial  23  can be seen through window  25  in the device  10  (see  FIG. 2 ). 
     Liquid in the reservoir may be nebulized by an aerosolization element  100  ( FIG. 1 ). The aerosolization element may comprise a first face  102  that faces into the reservoir and a second face  104  that is directed to a mouthpiece. The aerosolization element may have a plurality of apertures  106  extending through from the first face  102  to the second face  104  (see  FIGS. 5A and 5B ). Liquid on the reservoir side of the aerosolization element may be drawn through the apertures and emitted, as an aerosolized mist  110 , from the other. For example, the liquid may be drawn through the apertures by vibratory motion of the element. The apertures of the element may be tapered. The taper may have a wider portion  107  toward the reservoir and narrower portion  108  away from the reservoir and toward the mouthpiece ( FIG. 5B ). The aerosolization element may be non-planar, and may be concave. The concave side may be positioned toward the reservoir  90 . The side emitting the aerosolized mist  100  may be convex. Other configurations of moving fluid from the reservoir through the aerosolization element and emitting the fluid as a mist therefrom may be employed without departing from the present invention. 
     When a new vial assembly is needed, the device  10  may be opened by operation of latch assembly  27 , thus allowing removal of a spent vial assembly or vial and replacement thereof. The reservoir  90  may also be removed and replaced by opening the device  10  by operation of latch assembly  27 . The vial assembly  22  may be linked to the reservoir  90  in such a manner that one cannot be removed from the other without breakage to one or both of these components. The vial assembly  22  may have a collar  25  with one or more tabs  26 , and the reservoir  90  may have one or more detents  93  that can interlock with the tabs  26 . In this manner, the tabs  26  and detents  93  may hold the vial assembly  22  and the reservoir  90  together and prevent their disassembly from each other. With the vial assembly  22  and the reservoir  90  being assembled in such a manner, inadvertent use of the vial for purposes other than use with the nebulizer, such as injection, can be avoided, as the concentration of drug within the liquid may be far greater for inhalation than the concentration of the same drug in a liquid for injection. In this manner, both the vial assembly  22  and the reservoir  90  may need to be removed and replaced as a tandem assembly. The present invention is embodied in the nebulizer described herein without one or both of the vial assembly  22  and the reservoir  90 , as these subassembly components are likely to be removed and reassembled to each other and back into the nebulizer. Removable vial assemblies and removable reservoirs are described in co-assigned and co-pending application Ser. No. 10/043,075 which is hereby incorporated herein in its entirety. The present invention is also embodied in the nebulizer described herein comprising the vial assembly and the reservoir, as well as in methods of nebulizing liquid comprising providing a vial assembly and a reservoir. The present invention is also embodied in methods of nebulizing liquid comprising inserting the vial assembly in to a nebulizer and comprising inserting a reservoir into a nebulizer. 
     The vial mechanism  22  may be received within the device  10  to align with the titration mechanism such that the direction of travel of the actuator  40 , the direction of travel of the plunger  60  and the direction of travel of the movable seal  70  in the vial  23  are all substantially parallel. The vial mechanism  22  may be received within the device  10  to align with the titration mechanism in a substantially coaxial manner, such that the action of the actuator  40 , the plunger  60  and the movable seal  70  in the vial  23  are all substantially coaxial. Thus, when the vial mechanism  22  is placed within the device  10  the central axis  24  of the vial  23 , and thus the axis of movement of the movable seal  70 , which is captured within the vial  23 , the axis of travel of the plunger  60 , and the axis of travel of the actuator  40  may be substantially parallel and may be coaxial (see  FIGS. 1 ,  2  and  4 ). The dosing mechanism  30  defines an axis of rotation, and this axis may be and preferably is coaxial with the longitudinal axis of the vial  23  when the vial mechanism is placed in the nebulizer. Accordingly, the axis of rotation of the dosing mechanism, the longitudinal axis of the vial and the axis of travel of the plunger are all coaxial. An object of the present invention is a nebulizer of an overall longitudinal dimension (substantially parallel to the longitudinal axis of the vial) that will essentially fit in the hand of a user and be used substantially inconspicuously to increase user compliance with a chosen administration regimen ( FIG. 2 ). Similarly, an object of the present invention is a nebulizer that can fit easily in a garment pocket or a small bag. In order to fit a sufficient quantity of fluid in the vial, for example, a week&#39;s supply of insulin, while maintaining these size dimension considerations and accommodating the reservoir, mouthpiece and other components of the nebulizer, the present invention, in one embodiment, resides in a nebulizer having a vial of unconventional dimension with respect to vials typically used in injection devices. Accordingly, in one embodiment, the nebulizer of the present invention has a vial assembly with a vial having a ratio of the internal diameter D, in the portion where the movable seal can travel, to the overall length L 1  of the vial ( FIG. 7A ), for example, in the range of about 1:3.5 to about 1:4.5, or between about 1:3.7 to about 1:4.2. Similarly, the ratio may be between about 1:3.8 to about 1:4.0. The ratio may be about 1:3.9 For example, the vial may have a diameter of about 12 mm and a length of about 47 mm. Likewise, the vial may have a diameter of about 12.0 mm and a length of about 46.8 mm. Alternatively, the measurement of vial length can be taken as the length of the effective volume of the vial L 2  ( FIG. 7A ), the effective volume including only the portion of the vial in which moveable seal can occupy (as opposed to the narrowing neck), and thus the ratio of vial diameter to length of the effective volume may be between about 1:3.0 and abut 1:3.8, or between about 1:3.2 to about 1:3.6, or between 1:3.3 to about 1:3.5, or about 1:3.4. For example, this length may be about 38 mm, or this length may be about 37.7 mm. 
     In operation, a user operates the dosing mechanism  30  to select a particular dose amount that the user desires to have nebulized for inhalation. The dosing mechanism acts upon the screw mechanism  50 . The screw mechanism  50  is linked to the plunger  60 . The actuator  40  is linked to the screw mechanism  50  so that linear movement of the actuator  40  in the direction of arrow  42  causes linear movement of the plunger  60  in the direction of arrow  62 . 
     There is, however, no actual movement of the plunger  60  against the moveable seal by operation of the dose mechanism  30 ; rather, operation of the dose control  30  only sets the distance that the plunger will be able to travel in the subsequent stroke of the actuator  40 . Thus, if a user in advertently selects an incorrect dose, the user may readjust the dosing mechanism  30  for the desired amount of drug without wasting the previous incorrectly selected dose amount. In this manner, the user may select a dose to be nebulized, and after verification correct this dose if that is necessary, before nebulization begins. Once the user has determined and selected the correct dose amount by operation of dosing mechanism  30 , the user presses the actuator  40  in the direction of arrow  42 . The pressing action of the actuator  40  acts upon the screw mechanism  50 , which then moves the plunger  60  in the direction of arrow  62 . The distance that the plunger  60  travels, in the direction of arrow  62 , is controlled by the screw mechanism  50  according to the selected dose amount based on the user&#39;s operation of the dosing mechanism  30 . In this manner, when the user is ready to commence inhalation, after discreetly selecting a dose, the user may bring the device to the user&#39;s mouth and at this point press the actuator  40  with a single button press motion to deliver medication to the reservoir for nebulization. Alternatively, the user may select the dose and operate the actuator to deliver the dose into the reservoir prior to raising the nebulizer to the user&#39;s mouth. Discreet dosing and delivery is an important feature of the present invention, because it increases user compliance with a prescribed regimen. Certain drugs, such as insulin, require administration during the course of a day, perhaps in conjunction with meals; thus a user may be forced to take a dose in a public setting. In some cases, a user will not comply with a drug regimen because it is perceived as inconvenient or embarrassing. Accordingly, the present invention minimizes such potential non-compliance factors—the user may dial a dose out of the line of sight of others, the user may operate the actuator with a simple button press, and the user needs only a single hand to bring the nebulizer to the mouth. 
     Accordingly, the actuator  40  is configured to travel a fixed distance X (see  FIGS. 1 and 2 ) and the screw mechanism  50  permits the plunger  60  to travel a variable distance Y (see  FIG. 1 ), based on the dose amount selected by operation of the dosing mechanism  30 . The specific distances of travel for the plunger  60  according to dose amounts selected by operation of the dosing mechanism  30  may be determined based upon interior diameter of the vial  23 . 
     Screw mechanisms such as screw mechanism  50 , that selectively control the linear distance a plunger may travel, based on a selected setting of a dosing mechanism, with such travel being carried out by a user moving an actuator a fixed distance, are known, for example, in injection pens used by diabetics to selectively inject a chosen amount of insulin. Such injection pens are widely available, for example, from Disetronic Medical Systems, AG, Burgdorf, Switzerland. Such pens and are described in the art, as for example, U.S. Pat. Nos. 4,883,472; 5,730,629; 6,090,080; 6,106,501; 6,280,421 and 5,954,699, the entire contents of which are hereby incorporated herein by reference. 
     When the plunger travels a variable distance Y according the dose amount selected by a user in first operating the dosing mechanism  30  and then operating the actuator  40 , it acts upon the movable seal  70 . The movable seal  70  moves within the vial  23  to displace an amount of liquid  80  from the vial  23  into the reservoir  90 . The reservoir  90  is in fluid communication with an aerosol generator  100 , so that liquid displaced from the vial  23  into the reservoir  90 , upon operation of the aerosol generator  100 , is emitted from the device as fine droplets that form a mist  110 . 
     With reference to  FIG. 2  the device  10  comprises a housing  12 . The dosing mechanism  30  is rotatably attached to the housing  12 . The dosing mechanism rotates circularly in a plane as shown by arrow  35  ( FIGS. 1 and 2 ). Rotation of the dosing mechanism  30  causes operation of the screw assembly (see  FIG. 1 ). An indicator  32  displays selectable dose amounts based on rotation of the dosing mechanism  30  by a user, so that a user may select a displayed dose amount by rotating the dosing mechanism  30 . Once a user has determined that the selected dose amount is correct, the user presses actuator  40  in the direction of arrow  42 . The to and fro (i.e. forward and reverse) directions of travel of the actuator  40  may be substantially perpendicular to the plane of rotation of the dosing mechanism  30  (see  FIGS. 1 and 2 ). The motion of the actuator  40  in the direction of the arrow  42  moves the selected dose amount of medication into the reservoir (see  FIG. 1 ), so that operation of the aerosol generator  100  causes the fluid to be ejected from the device as a mist  110  (see  FIG. 1 ). 
     Referring now to  FIG. 3 , a flow chart of steps according to the present invention is shown. Step  200  is the selection of a dose by operation of a dose mechanism. Step  210  is the operation of a screw mechanism, based on the selection of the dose mechanism, to set a distance of travel of a plunger. Step  220  is the operation of an actuator to move the plunger according to the distance set by the screw mechanism. Step  230  is the displacement of fluid, by action of the plunger moving the set distance, from a vial into a reservoir. Step  240  is the operation of an aerosol generator that is in fluid communication with the reservoir. Step  250  is the aerosolization of the fluid. 
     Referring again to  FIG. 2 , the window  25  may be covered with a transparent pane  26 . The window  25 , and thus the transparent pane  26 , may have a curvature for better viewing of the vial  23  which may be substantially cylindrical. The indicator  32  comprising a displayed dose  34  so that a user may see the dose selected prior to pushing the actuator  40 . The dosing mechanism  30  has a circular motion as shown by arrow  35 . The circular motion of the dosing mechanism, as shown by arrow  35 , is substantially perpendicular to the axis of travel of the actuator  40 . 
     Referring to  FIG. 4 , a reservoir  90  receives the liquid that is displaced from the vial  23  upon actuation of the plunger  60 . The liquid may travel from the vial  23  to the reservoir  90  through a cannula  91 . The reservoir may have a channel such as a delivery tube  92  and a lumen  94 , which lumen may be defined by a wall  95 . The liquid may flow from the vial  23  through the cannula  91  and then through the delivery tube  92  into the lumen  94 . The reservoir is in fluid communication with an aerosolizing element  100  as described above. The first face  102  of the aerosolizing element  100  may be contiguous with the reservoir, so that fluid in the reservoir will abut the first face of the aerosolizing element. In this manner, a wide range of dosages of liquid may be placed within the reservoir by the user carrying out the single actuation motion; for example, the dose moved into the reservoir may be 30 microliters or, alternatively, for example, the dose moved into the reservoir may be 250 microliters. By placing the entirety of the liquid to be aerosolized in the reservoir at once, uninterrupted aerosolization may be carried out smoothly, without inconsistencies that might occur if liquid were to be provided to the aerosolization element other than as a single bolus, such as, for example, by a drop-by-drop delivery, or if other modes of aerosolization are used, such as ultrasonic or jet nebulizers, both of which apply energy or force directly to the liquid. By creating aerosol from the liquid by vibration of an apertured aerosolization element, less potential degradation of the drug and far greater aerosol particle size control can be achieved, and likewise better dose accuracy can be achieved. The second face of the aerosolization element is positioned such that aerosol emanating from it may be drawn through a mouthpiece  120  of the nebulizer  10 . The fluid is delivered into the reservoir in such a manner that the liquid may also be in contact with the first face  102  of the aerosolization element  100  while in the reservoir. 
     The aerosolization element may be constructed of a variety of materials, comprising metals, which may be electroformed to create apertures as the element is formed, as described, for example, in U.S. Pat. No. 6,235,177 assigned to the present assignee and incorporated by reference herein in its entirety. Palladium is believed to be of particular usefulness in producing an electroformed, multi-apertured aerosolization element, as well as in operation thereof to aerosolize liquids. Other metals that can be used are palladium alloys, such as PdNi, with, for example, 80 percent palladium and 20% nickel. Other metals and materials may be used without departing from the present invention. The aerosolization element may be configured to have a curvature, as in a dome shape, which may be spherical, parabolic or any other curvature. The aerosolization element may have a curvature over its majority, and this may be concentric with the center of the aerosolization element, thus leaving a portion of the aerosolization element as a substantially planar peripheral ring. The aerosolization element may be mounted on an aerosol actuator  112  having an aperture therethrough, and this may be done in such a manner that the curved or domed portion of the aerosolization element extends through the aperture of the aerosol actuator and the substantially planar peripheral ring of the aerosolization element abuts a face of the aerosol actuator. The face of the aerosol actuator  112  closest to the first face of the aerosolization element may similarly be referred to, by convention, as the first face  114  of the aerosol actuator. The face of the aerosol actuator  112  closest to the second face of the aerosolization element may likewise by convention be referred to as the second face  115  of the aerosol actuator. The aerosolization element may be affixed to the aerosol actuator  112  with by its substantially peripheral ring portion being mounted to the first face  114  of the aerosol actuator  112 , with the dome of the aerosolization element extending through the aperture of the aerosol actuator toward the second face of the aerosol actuator and may extend beyond the second face of the aerosol actuator  112 . 
     The aerosolization element may be vibrated in such a manner as to draw liquid through the apertures  106  of the aerosolization element  100  from the first face to the second face, where the liquid is expelled from the apertures as a nebulized mist. The aerosolization element may be vibrated by a vibratory element  130 , which may be a piezoelectric element. The vibratory element may be mounted to the aerosol actuator, such that vibration of the vibratory element may be mechanically transferred through the aerosol actuator to the aerosolization element. The vibratory element may be annular, and may surround the aperture of the aerosol actuator, for example, in a coaxial arrangement. A circuitry may provide power from a power source, such as an internal battery, which may be rechargeable. A switch may be operable to vibrate the vibratory element and thus the aerosolization element, and aerosolization performed in this manner may be achieved within milliseconds of operation of the switch. Further, this manner of aerosolization provides full aerosolization with a substantially uniform particle size of mist being produced effectively instantaneously with operation of the switch. The switch may be operable by a pressure transducer, which may be positioned in the mouthpiece of the nebulizer. The pressure transducer may be in electrical communication with the circuitry, and a microprocessor may also be in electrical communication with the circuitry, and the microprocessor may interpret electrical signals from the pressure transducer, and may also operate the switch to begin aerosolization. In this manner, nebulization can begin substantially instantaneously with the inhalation of a user upon the mouthpiece. An example of such a sensor switch can be found in co-assigned and co-pending U.S. application Ser. No. 09/705,063 assigned to the present assignee, the entire content of which is hereby incorporated herein by reference. 
     Another transducer may be used to sense the absence or presence of liquid in the reservoir, by sensing, for example, a difference between vibration characteristics of the aerosolization element, such as, for example, differences in frequency or amplitude, between wet vibration and substantially dry vibration. In this manner, the circuitry, may, for example by way of the microprocessor, turn the vibration off when there is essentially no more liquid to aerosolize, i.e., when the end of the dose has been achieved, thus minimizing operation of the aerosolization element in a dry state. Likewise, the switch may prevent vibration prior to delivery of a subsequent dose into the reservoir. An example of such a switch is shown in co-assigned and co-pending U.S. application Ser. No. 09/805,498, the entire content of which is hereby incorporated herein by reference. 
     The microprocessor may also have a timing capability, such that once aerosolization begins, it proceeds for a predetermined time, after which aerosolization stops. In this manner, a particular regimen of breathing and aerosolization may be carried out. For example, a user may be instructed to inhale for five seconds while the timing is set to aerosolize for only the first four seconds of such a breath maneuver. This timing may be predetermined based on a particular drug and a particular target of the drug, such as, for example, the deep lung, which may be the target of administration for a systemic drug, such as insulin. 
     The circuitry may also operate visual signals to a user, such as the illumination of a light, a blinking of a light, or the illumination or blinking of one or more of a plurality of lights. Further, a plurality of lights in a plurality of colors may be used. For example, a light may be illuminated to inform the user that the main power to the device is on, such that once a breath is taken, the breath switch will operate the aerosolization element. Another light signal may inform the user that the selected dose has been received in the reservoir, thus informing the user that the nebulizer is ready for the user to take a breath through the mouthpiece. A light signal may also inform the user that aerosol delivery has stopped based on a predetermined time for aerosolization, and, likewise, a light signal may inform the user when a predetermined regimen time for inhalation has elapsed, whereupon the user may stop inhalation of a breath. Similarly, a light signal may inform the user that the end of dose has been reached, as, for example, described above, and that the aerosolization is no longer taking place. Such a signal light may conveniently be a different color than other signal lights. Accordingly, a user may be informed from this information that the user has completed inhaling the chosen dose, and additional inhalation is not needed. 
     The screw mechanism  50  may comprise an internally threaded nut, which can be moved rotationally but not longitudinally. The threaded nut may mate with an externally threaded rod, which may be the rod portion  61  of the plunger  60 , which can be moved longitudinally but not rotationally. Thus, rotation of the nut may move the rod longitudinally. Rotation of the actuator may be linked to cause rotation of the nut, thus advancing the rod and plunger. The rotation of the actuator may be calibrated to correspond to a predetermined longitudinal distance that corresponds to a volume of liquid displaced by movement of the plunger against the vial by that longitudinal distance. The plunger, however, may be maintained at a fixed distance from the stopper  63 , so that advancing the plunger by rotation of the actuator does not immediately result in the displacement of liquid from the vial. After the user determines that the correct dosage has been chosen, for example by observing the visual display showing the dose that will be displaced into the reservoir for aerosolization if actuation is carried out, the actuator is moved longitudinally the fixed distance X. Movement of actuator causes longitudinal movement of the nut, which in turn carries the rod longitudinal a distance of X. The plunger is moved the distance Y which corresponds to X+D. Because D will vary from dose to dose, the distance Y of the longitudinal travel of the plunger will also vary. 
     One example of such a scheme is illustrated in  FIG. 6 . As shown, the dosing mechanism  30  extends into the housing and has a central opening into which the plunger  60  is housed. The dosing mechanism  30  is rotatable about the actuator  40 , and when the actuator  40  is depressed, the dosing mechanism  30  moves axially into the device housing. Coupled to the dosing mechanism  30  is a threaded nut  31  that is threadably connected to plunger  60  (that also has mating threads about its shaft). The plunger  60  also includes an elongate detent (not shown) that is axially slidable within a groove formed in a stop  32  that is fixed to the device housing. In this way, the plunger  60  may move axially through stop  32 , but not rotationally. Further, a spring  33  is positioned between the nut  31  and the stop  32  to bias actuator in the home position. 
     In operation, the user rotates the dosing mechanism  30  to set the desired dose. In so doing, the nut  31  also rotates. However, since plunger the  60  is prevented from rotating due to the stop  32 , it moves axially downward toward the vial, thus reducing the distance between plunger  60  and the vial. When the desired dose is set, the user pushes down on the actuator  40 . In turn, the dosing mechanism  30  and the nut  31  are also axially moved downward. In so doing, the plunger  60  is moved down the same distance. The plunger  60  will therefore engage the vial and dispense the appropriate dose. The travel of the plunger  60  is stopped when the nut  31  hits the stop  32 . The actuator  40  may then be released to return to the initial position. 
     Such screw mechanisms are known to those skilled in the art, and are described, for example, in U.S. Pat. Nos. 4,883,472; 5,370,629; and 5,954,699 previously incorporated herein by reference. 
     Over the course of a user dispensing the contents of a vial, which may contain, for example, a one week supply of a drug, such as insulin, the plunger may have incrementally moved from its initial position near the actuator to a final position abutting the plunger which has been moved essentially to the forward-most portion of the vial (see  FIGS. 7A and 7B ). The plunger must return to its initial position to act upon a new vial. The screw mechanism  50  may have a release that permits the plunger to travel back to its original position. The release may have a lock to prevent inadvertent return of the plunger prior to exhaustion of a vial. An example of such a release and lock is described, for example, in U.S. Pat. No. 5,954,699 previously incorporated herein. 
     U.S. Pat. No. 5,954,699 discloses an unlocking slide attached to a rear section that is connected to an internal spreader bushing in the rear section, with shifting of the unlocking slide in distal direction causing the spreader bushing to be shifted in distal direction. 
     The spreader bushing surrounds a driving member and comprises four vertical tracks, which extend towards the proximal end of the spreader bushing outwardly at an angle. The tracks serve to accommodate cams of the threaded flanges. When the spreader bushing is in the proximal position, the threaded flanges surround a threaded rod. When the spreader bushing is moved to its distal position with the unlocking slide, the threaded flanges open as soon as their cams move over the angled section of the tracks and the threaded rod can be freely shifted in axial direction. A notched surface of the unlocking slide arranged on the main body fits into a counter notched surface on the proximal part of the spreader bushing. 
     In principle, the spreader bushing is retained in its proximal position by a spring. In order to release the threaded flange the user must actively shift the unlocking slide into its distal position by simultaneously pushing it down. During this process, the notched surface of the unlocking slide engages in the counter notched surface of the spreader bushing, moving it backwards. Because of this movement, the cams must run over corresponding outwardly extending tracks of the spreader bushing. This forced movement causes the threaded flanges to open and releases the threaded rod. When at the same time the injection device is held with a dosing button down, gravity causes the threaded rod to automatically fall back into its distal position. Upon releasing the unlocking slide, the spreader bushing slides forward again. At the same time the cams slide back in the tracks to their stop position in which the threaded flange is closed. The unlocking slide is moved into the proximal position. 
     Various alternative configurations to control the linear distance of travel of the plunger by rotation of a dosing mechanism may be employed without departing from the scope of the present invention. For example, rotation of the dosing mechanism may not cause longitudinal movement of the plunger, but instead such rotation of the dosing mechanism may cause a threaded member to move longitudinally to control the longitudinal distance the plunger may travel on actuation. Alternatively, rotation of the dosing mechanism may cause threaded members to cooperate with each other to lengthen or shorten the distance of longitudinal travel of the plunger or the screw mechanism, which may carry the plunger in longitudinal travel with a stroke of the actuator. 
     It should be appreciated that, the present invention may be practiced with alternative embodiments and with a variety of devices and methods. Accordingly, it should be appreciated that the foregoing is descriptive of the present invention and that certain changes or modifications may be made without departing from the scope of the present invention.