Abstract:
A method is described for supplying a metered amount of a liquid medicament to an aerosolizing device. The method utilizes a dispenser comprising an elongate dispenser body having a proximal end and a tip at a distal end through which a liquid medicament is dispensed. The dispenser further comprises a dispensing mechanism that operates to dispense a metered quantity of the liquid medicament from the tip each time the dispenser body is compressed. The dispenser is grasped with one hand such that the fingers wrap around the dispenser body, with the thumb closest to the proximal end and the last finger closest to the tip. The tip is inserted into an opening of an inhaler and the elongate body is forced toward the tip to cause the dispenser body to compress, thereby operating the dispensing mechanism and causing a metered quantity of the liquid medicament to eject into the inhaler.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a nonprovisional application claiming the benefit of U.S. Provisional Application No. 61/624,531, filed Apr. 16, 2012, the complete disclosure of which is herein incorporated by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Various types of inhalers exist for aerosolizing liquids. For example, U.S. Pat. No. 5,586,550, incorporated herein by reference, describes an inhaler that comprises a dispensing apparatus in which a membrane with tapered apertures is vibrated such that liquid in contact with a rear face of the membrane is dispensed from a front face of the membrane as an aerosol. Other examples of single dose inhaler systems and medicaments that may be aerosolized are described in U.S. Patent Publication Nos. 2011/0168172 and 2001/0168170, the disclosures of which are herein incorporated by reference. 
         [0003]    One aspect of such inhalers is the need to supply a metered amount of liquid medicament to the dispensing apparatus so that the metered amount may be aerosolized and delivered to the patient&#39;s lungs. However, delivering a known quantity of a liquid medicament (that typically must be stored in a sterile environment) has proven to be challenging, particularly when the metered quantity needs to be dispensed in a controlled and repeatable fashion. Hence, this invention relates to ways for delivering such medicaments to inhalers for subsequent aerosolizing. 
       BRIEF SUMMARY OF THE INVENTION 
       [0004]    One embodiment provides a method for supplying a metered amount of a liquid medicament to an aerosolizing device in a repeatable manner. The method utilizes an aerosolization device comprising a housing having a mouthpiece, a vibratable member within the housing and disposed to eject liquid droplets through the mouthpiece, a reservoir to hold the liquid medicament until aerosolized by the vibratable member, and an opening in the housing and in communication with the chamber. While described in connection with one specific type of inhaler, it will be appreciated that other types of aerosolization devices could be used with the methods described herein. 
         [0005]    To supply a metered amount of liquid medicament, a dispenser is used that comprises an elongate dispenser body having a proximal end and a tip at a distal end through which a liquid medicament is dispensed. The dispenser further comprises a dispensing mechanism that operates to dispense a metered quantity of the liquid medicament from the tip each time the dispenser body is compressed. 
         [0006]    One critical factor of the method is the manner in which the dispenser is held and operated by a user. To facilitate dispensing, the dispenser may be grasped with one hand such that the fingers wrap around the dispenser body, with the thumb closest to the proximal end and the last or pinky finger closest to the tip. The tip of the dispenser is inserted into the opening in the housing. Then, while grasping the dispenser in the manner described, the elongate body is forced toward the tip to cause the dispenser body to compress, thereby operating the dispensing mechanism and causing a metered quantity of the liquid medicament to eject into the chamber each time the dispenser body is compressed. 
         [0007]    Because the prescription may call for more medicament than can be supplied with a single ejection from the dispenser, the process may be repeated for as many times as is needed to supply the prescribed amount into the chamber. This may be done with a “pumping action” where the user “pumps” the dispenser (causing it to compress with each pump), until the correct number of pumps have been supplied. For example, if the prescription calls for a certain volume of the liquid medicament, the dispenser may be pumped five times, with each pump dispensing a droplet having a metered volume of one-fifth the total volume. 
         [0008]    In some cases, the tip may include at least one alignment feature that assists to keep the dispenser generally perpendicular to the housing while dispensing the liquid medicament. Once the metered amount has been dispensed into the chamber, the vibratable member is actuated to eject the dispensed liquid medicament as an atomized spray. 
         [0009]    In another embodiment, the invention provides an exemplary aerosolization system. The system includes an aerosolization device comprising a housing having a mouthpiece, a vibratable member within the housing and disposed to eject liquid droplets through the mouthpiece, a reservoir to hold the liquid medicament until aerosolized by the vibratable member, and an opening in the housing that is in fluid communication with the chamber. 
         [0010]    The system further includes a dispenser comprising an elongate dispenser body having a proximal end and a tip at a distal end through which a liquid medicament is dispensed. The dispenser further comprises a dispensing mechanism that operates to dispense a metered quantity of the liquid medicament from the tip each time the dispenser body is compressed. The dispenser is separate from the housing so that it may be manually interfaced with the aerosolization device. 
         [0011]    Further, the opening defines an interface that engages with the tip such that when the tip is inserted into the opening, the interface stabilizes the dispenser in an upright orientation outside of the housing to permit the dispenser to be grasped with one hand to dispense the medicament. For example, this orientation permits a user to wrap the fingers around the dispenser body, with the thumb closest to the proximal end and the last finger closest to the tip, and while grasping the dispenser, forcing the elongate body toward the tip to cause the dispenser body to compress, thereby operating the dispensing mechanism and causing a metered quantity of the liquid medicament to eject into the chamber each time the dispenser body is compressed. 
         [0012]    In one important aspect, the tip may include at least one alignment feature that assists to keep the dispenser generally perpendicular to the top surface of the housing while dispensing the liquid medicament. This alignment feature may comprise a circular step around the tip, a plurality of tabs protruding from the tip, and the like. 
         [0013]    In yet another embodiment, the invention provides an exemplary method for supplying a metered amount of a liquid medicament to an aerosolizing device. The method utilizes an aerosolization device comprising a housing having a mouthpiece, a vibratable member within the housing and disposed to eject liquid droplets through the mouthpiece, and a reservoir to hold the liquid medicament until aerosolized by the vibratable member. The housing also includes a top surface and an opening in the top surface of the housing. The opening is in fluid communication with the chamber. 
         [0014]    The method also utilizes a dispenser that comprises an elongate dispenser body having a proximal end and a tip at a distal end through which a liquid medicament is dispensed. The dispenser further comprises a dispensing mechanism that operates to dispense a metered quantity of the liquid medicament from the tip each time the dispenser body is compressed. 
         [0015]    With this configuration, the tip is inserted into the opening in the housing such that the dispenser body is generally perpendicular to the top surface of the housing and is seated within the opening such that the dispenser body is self-standing outside of the housing. In this orientation, the dispenser body may be compressed to operate the dispensing mechanism and cause a metered quantity of the liquid medicament to eject into the chamber each time the dispenser body is compressed. 
         [0016]    The dispenser may be repeatedly compressed to dispense multiple metered quantities of the liquid medicament into the chamber. Further, the tip may include one or more alignment features that assist to keep the dispenser generally perpendicular to the housing while dispensing the liquid medicament so that it may be aerosolized. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0017]      FIG. 1  illustrates one method for grasping a dispenser in preparation for delivering a metered amount of liquid medicament to an aerosolizing apparatus. 
           [0018]      FIG. 2  illustrates the dispenser of  FIG. 1  when inserted into the aerosolizing apparatus and compressed in order to deliver the liquid medicament. 
           [0019]      FIG. 3  illustrates the dispenser of  FIG. 1  when initially inserted into the aerosolizing apparatus of  FIG. 1 . 
           [0020]      FIG. 4  illustrates the dispenser of  FIG. 3  when compressed or pumped to deliver the liquid medicament. 
           [0021]      FIG. 5  is a cross sectional side view of another embodiment of an aerosolizing apparatus according to the invention. 
           [0022]      FIG. 6  illustrates another embodiment of a dispenser having ribs to facilitate positioning of the dispenser. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0023]    Certain aspects of the invention relate to techniques for dispensing metered quantities of a liquid medicament into an aerosolizing apparatus, also referred to as an inhaler. Although useful with a wide variety of aerosolizing devices, in some cases the liquid will be dispensed into an aerosolizing apparatus comprising a housing defining a dispensing outlet or mouthpiece, a vibratable membrane or mesh having a front face exposed at the outlet and a rear face for receiving a liquid to be dispensed, and a vibrating mechanism connected to the housing and operable to vibrate the membrane to dispense aerosol of the liquid through the membrane. 
         [0024]    A variety of containers or dispensers may be used to store the liquid medicament, then to deliver a metered quantity of the liquid into a reservoir where it will contact the rear face of the membrane. In this way, a metered quantity of liquid is dispensable at the outlet or mouthpiece by operating the vibrating mechanism for an operating period sufficient to completely aerosolize the metered quantity at the rear face. The containers or dispensers will typically have a sealed region where the liquid is stored and a mechanism for dispensing a metered amount of liquid each time the mechanism is operated. For example, the container may be compressed or pumped to eject a droplet of a known volume. 
         [0025]    Exemplary aerosol generators that may be used in such inhalers are also described in U.S. Pat. Nos. 5,164,740; 6,629,646; 6,926,208; 7,108,197; 5,938,117; 6,540,153; 6,540,154; 7,040,549; 6,921,020; 7,083,112; 7,628,339; 5,586,550; 5,758,637; 6,085,740; 6,467,476; 6,640,804; 7,174,888; 6,014,970; 6,205,999; 6,755,189; 6,427,682; 6,814,071; 7,066,398; 6,978,941; 7,100,600; 7,032,590; 7,195,011, and in U.S. Patent Publication Nos. 2011/0168172 and 2001/0168170, all incorporated herein by reference. These references describe exemplary aerosol generators and ways to manufacture such aerosol generators. Each are incorporated by reference for at least these features. The aerosol generators may comprise vibratable membranes having tapered aperture with a size in the range from about 3 μm to about 8 μm, preferably from about 3 μm to about 6 μm, and in some cases around 4 μm. The membrane may be domed shaped and be vibrated by an annular piezoelectric element that circumscribes the apertures. The diameter of the membrane may be in the range from about 5 mm to about 8 mm. The membrane may also have a thickness in the range from about 50 microns to about 70 microns. Typically, the membrane will be vibrated at a frequency in the range from about 50 kHz to about 150 kHz. 
         [0026]    A variety of liquid medicaments may be dispensed from the container. For example, the liquid medicament may comprise an insulin formulation, such as a preservative free insulation, including any of those described in U.S. Patent Publication No. 2011/0168170, previously incorporated by reference. For example, a preservative free insulin formulation that may be dispensed may be free of any preservatives, including phenol, metacresol, chloro-cresol, thymol and mixtures thereof or the like. The absence of such preservatives enable the formulations to be aerosolized as a liquid spray using a vibrating mesh or aperture plate that operates at high frequencies. The absence of such preservatives permits a dosage of the formulation to come into contact with the vibrating mesh without substantial foaming of the formulation. In turn, the formulation may be aerosolized more quickly. Further, substantially all of the liquid is able to be aerosolized. Such formulations contain water in major and human insulin in minor amount. The formulations may also include various concentrations of human insulin. For example, the concentrations may be in the range from about 100 IU insulin/ml of formulation to about 1200 IU insulin/ml of formulation, and more preferably from about 200 IU insulin/ml of formulation to about 800 IU insulin/ml of formulation. In addition to water and human insulin, the formulations may also include zinc, acetate, chloride and sodium. The zinc ion and acetate ion come from the drug substance, e.g., the insulin. The chloride ion and sodium ion are added during dissolution of the insulin and adjustment of the pH. Merely by way of example, the NaCl concentration may be about 20 mM for an 800 IU insulin/ml formulation, about 10 mM for a 400 IU insulin/ml formulation, and about 5 mM for a 200 IU insulin/ml formulation. 
         [0027]    Other liquid medicaments may also be dispensed. For example, such medicaments could include other protein formulations, asthma and COPD treatments, vaccines and pain relief treatments. 
         [0028]    Referring now to the Figures, one exemplary method for dispensing a metered amount of medicament into an inhaler will be described. Shown in  FIG. 1  is an inhaler  10  that is constructed of a housing  12  having a mouthpiece  14 . Disposed within the housing is an aerosol generator comprising a vibratable mesh similar to those described herein, as well as electronics to control operation of the aerosol generator. The mesh is positioned to eject an aerosol through mouthpiece  16  when the mesh is vibrated. Housing  12  includes a top surface  13  with a slidable cover  18  is positioned over an opening  20  (see  FIG. 2 ). Cover  18  is slid back is to expose opening  20 . Further, opening  20  leads to a reservoir  22  or funnel (see  FIGS. 3 and 4 ) that tapers toward a vibratable mesh  24  that is part of an aerosol generator that may be similar to any of those described herein. More specifically, mesh  24  has a rear face that is exposed to reservoir  22  so that when liquid is supplied to reservoir  22  it comes into contact with the rear face of mesh  24 . When mesh  24  is vibrated (by actuating an “on” button  26  that energizes the aerosol generator) the liquid is ejected from the front face of mesh  24  as an atomized spray and is available for inhalation through mouthpiece  14 . 
         [0029]      FIG. 5  illustrates the internal components of an inhaler  100  that is similar to inhaler  10  as previously described. Inhaler  100  is constructed of a housing  112  that includes an opening  120  leads to a reservoir  122  that has an open bottom end  150  that funnels the dispensed liquid onto the rear face of a vibratable mesh (not shown) that is part of an aerosol generator  154  that has a vibratable element  155  (such as an annular piezoelectric transducer) that vibrates the mesh. Aerosol generator  154  has a circular opening  156  across which the mesh is disposed. When vibrated, the mesh ejects the liquid as an aerosolized spray into a capture chamber and to a mouthpiece. In this way, the aerosolized spray may be inhaled by inhaling from the mouthpiece. 
         [0030]    In one embodiment, the liquid to be aerosolized is stored in a dispenser  30  that is best illustrated in  FIGS. 3 and 4 . Dispenser  30  may conveniently be described in terms of a proximal end  32  and a distal end  34  that terminates in a tip  36 . Dispenser  30  further includes a canister  38  that stores the liquid medicament in a sterile environment. Dispenser  30  includes an internal valve such that distal end  34  may be moved relative to proximal end  32 , thus compressing dispenser  30 . In so doing, each time dispenser  30  is compressed (or “pumped”) a metered volume of liquid is ejected into reservoir  22 . For example,  FIG. 3  shows dispenser  30  in an uncompressed state. In  FIG. 4 , a force is applied to compress dispenser  30  and eject the droplet into the reservoir  22 . A similar process may be used in connection with inhaler  100  where the liquid is injected into reservoir  122 . This process may be repeated as many times as needed in order to dispense the proper volume of the liquid medicament into reservoir  22 . After dispersing the desired amount of liquid medicament, dispenser  30  may be removed and stored for future use. Exemplary unit volumes that may be dispensed with each pump may be in the range from about 5 to about 100 microliters. 
         [0031]    Tip  36  includes a shoulder  40  in the shape of an annular or circular step that serves as a stop to prevent further insertion of tip  36  into opening  20 . Shoulder  40  is inset by a distance that is sufficient so that it not only serves as a stop by also permits tip  36  to seat within opening  20  in a stable position that is generally vertical to the top surface  13  of housing  12 . As such, once dispenser  30  is placed into opening  20 , it will be self-standing in a generally vertical orientation. This position permits a user to easily grasp the disperser  30  when ready to dispense a unit volume of the liquid to the aerosol generator. Although shown with a shoulder, other seating mechanisms could be used, such as a taper that matches with the taper of opening  20 , protruding tabs or wings, detents, and the like. 
         [0032]    One exemplary technique for operating dispenser  30  is illustrated in  FIGS. 1 and 2 . It will be appreciated that a similar process may be used in connection with inhaler  100 . In  FIGS. 1 and 2 , dispenser  30  is grasped with one hand, such that the four fingers wrap around dispenser  30 , mostly about canister  38 . By using four fingers to grasp dispenser  30 , a firm grip is achieved so that dispenser  30  may easily be pumped to eject the liquid. Further, the person&#39;s thumb may rest on proximal end  32  to apply a further compressive force. With the proper grip, cover  18  may be slid back and tip  34  placed into opening  20 . As previously described, tip  34  includes a shoulder  40  that is wider than opening  20  so as to prevent tip  34  from coming into contact with mesh  24 . Further, shoulder  40  may be designed so that tip  34  is sufficiently spaced-apart from mesh  24  so that when the full metered amount of the liquid is dispensed into reservoir  22 , tip  34  does not come into contact with the dispensed liquid. In this way, when dispenser  30  is removed from the inhaler, it will not also remove some of the dispensed liquid. Typically, tip  34  will be spaced apart from mesh  24  by a distance that is in the range from about  5  mm to about  20  mm. Tip  34  may also be tapered, such as to match the taper of reservoir  22 . The taper of reservoir  22  facilitates delivery of all the dispensed liquid onto the rear face of mesh  24 , and the tapering of tip  34  prevents it from coming into contact with the walls of reservoir  22 . 
         [0033]    As best shown in  FIG. 2 , with tip  34  in place, the user presses canister  38  toward tip  34 . At the same time, inhaler  10  is held in place. This causes dispenser  30  to compress. In turn, the internal valve is opened to permit a metered amount of liquid to be dispensed from tip  34  and into reservoir  22 . Each time canister  38  is pressed downward, or pumped, another metered amount of liquid is ejected. This maneuver is performed as many times as is needed in order to supplied the prescribed dosage into reservoir  22 . 
         [0034]    By holding the dispenser  30  in the manner shown, this pumping action may easily occur. This is in contrast to a nasal spray dispenser, that is typically actuated in an upright manner by carefully and simultaneously compressing the proximal end with the middle and index finger (with the tip extending between the fingers) to the distal end of the dispenser container, that is held under equal pressure by the thumb. With this type of nasal sprayer, the spray occurs when sufficient pressure is applied equally to both ends. In contrast, dispenser  30  can be easily actuated by applying pressure solely to the distal end of the dispenser when the tip is engaged with the inhaler device. The inhaler device and mating features are constructed so that a metered amount of medicament is consistently delivered from the dispenser into the device and the user may do so with unregulated pressure, provided the force is greater than or equal to that required to compress the dispenser throughout its full range. If the inhaler device is loaded while placed on a table or any other freely supported surface, the force required to compress the dispenser into the device to the point of actuation is reduced by  50 % when compared to the amount of force required to disperse a volume of liquid when holding both the device and dispenser (without the aid of a support surface). 
         [0035]      FIG. 6  illustrates an alternative embodiment of a dispenser  80  that may be used with inhaler  10  or inhaler  100 . Dispenser  80  has a tip  82  at its distal end with multiple alignment features  84  that assist to properly align and position tip  82  within opening  20  in top surface  13 . Alignment features  84  may have a variety of shapes, sizes and configurations. Although shown with four equally spaced apart features  84 , it will be appreciated that other numbers may be used, such as only a single alignment feature. Features  84  serve as stops to limit insertion of tip  82  into opening  20 . Features  84  also provide a tactile feel to let the user know when tip  82  has been properly inserted. When all four features  84  engage the surface of inhaler  10 , dispenser  80  has been properly inserted and is ready to have a metered amount dispensed into inhaler  10 . Further, features  84  serve to hold dispenser  80  in a generally vertical or perpendicular orientation relative to top surface  13 . In this way, dispenser  80  is self-standing when inserted into opening  20  to make it easier for a user to grasp and dispense as described in connection with  FIGS. 1 and 2 . 
         [0036]    The invention has now been described in detail for purposes of clarity and understanding. However, it will be appreciated that certain changes and modifications may be practiced within the scope of the appended claims.