Abstract:
A canister of pressurized medicament is removed from a metered dose inhaler actuation assembly and thereafter subjected to a cleaning firing to dislodge any material that can be built up on the interior of the canister&#39;s valve stem. During the cleaning firing, backpressure in the valve stem is reduced and/or eliminated by routing the resulting flow to atmosphere along an improved flow path. The improved flow path can be such that there are no constrictions less than about 75% of the size of the valve stem&#39;s outlet port. Thus, the backpressure experienced by the valve stem is greatly reduced versus that experienced during a normal dosing firing. As a result, the flow rate of medicament through the valve stem during the cleaning firing can be higher than during a normal dosing firing, allowing the built-up material to be dislodged during the cleaning firing.

Description:
CROSS-REFERENCE SECTION TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of U.S. Provisional Patent Application No. 60/887,422, filed Jan. 31, 2007, which is hereby incorporated by reference in its entirety. 
     
    
     BACKGROUND 
       [0002]    The present invention relates to metered dose inhalers for delivery of medicament to patients via aerosolization of the medicament, and related cleaning methods and devices. 
         [0003]    Delivery of drugs via metered dose inhalers is well known for treating various conditions such as asthma. Typically, a metered dose inhaler includes a canister containing a pressurized supply of medicament that is mated to an inhaler actuator assembly. Typically, the supply of medicament is triggered by displacing a hollow valve stem of the canister toward the main body of the canister. This releases a metered portion of the medicament (e.g., a predetermined metered amount) into the inhaler actuator assembly. The significant pressure differential between the canister pressure and the atmosphere results in the released material being propelled through the inhaler actuator assembly. More particularly, the released material is typically directed through a very small nozzle orifice (or “nozzle”) that aerosolizes the spray. This aerosolized spray is then inhaled by the patient so as to be preferentially deposited in the lungs. 
         [0004]    The nozzle orifice is an important determinant of the resultant aerosol droplet size and size distribution. A smaller orifice tends to produce a finer spray, which is typically more therapeutically effective. However, a small nozzle orifice also creates a constriction in the flow path, which creates some backpressure that is communicated along the valve stem. The presence of this backpressure causes the flow of material through the valve stem to be slower than it otherwise would be. Because of the slower flow rate, there is an increased possibility of having some medicament deposit on the interior of the valve stem. Build up of the medicament inside the valve stem can undesirably lead to sporadic break off of the material, which can result in clogging of the downstream nozzle orifice, or lead to undesirable biological contamination of the device, or affect dose uniformity. 
         [0005]    The extent of deposition inside the valve stem depends on the medicament formulation, valve stem material properties, and on the design of the inhaler actuator assembly. Conventional metered dose inhalers for asthma may not experience significant build up of material in the valve stem due to the formulations used. Thus, while patients arc typically instructed to clean the inhaler using various techniques, no known cleaning approach addresses cleaning of the inside of the canister valve stem. However, as metered dose inhalers are adapted for use with other formulations, such as formulations with larger molecule sizes (e.g., macromolecules) and/or different chemistries, internal valve stem build up is believed to become more of a consideration for proper operation. 
         [0006]    Thus, there remains a need for alternative approaches to using and/or cleaning metered dose inhalers, advantageously approaches that allow the interior of the valve stein to be easily cleaned. 
       SUMMARY OF THE INVENTION 
       [0007]    Various embodiments of the present invention are intended to allow a canister of pressurized medicament to be removed, fully or partially, from a metered dose inhaler actuation assembly and thereafter subjected to a cleaning actuation to dislodge undesirable material that can be present on the interior of the canister&#39;s valve stem. During the cleaning actuation, backpressure in the valve stem is substantially reduced and/or eliminated by routing the resulting flow to atmosphere along an improved flow path. The improved flow path in some embodiments, has no constrictions less than about 75% of the size of the valve stem&#39;s outlet port, and advantageously no constrictions less than the size of the valve stem&#39;s outlet port. Thus, the backpressure experienced by the valve stem is greatly reduced versus that experienced during a normal dosing actuation. As a result, the flow rate of medicament through the valve stem during the cleaning actuation can be higher than during a normal dosing actuation, allowing the built-up material to be dislodged during the cleaning actuation. 
         [0008]    In one embodiment, a method of cleaning at least a portion of a metered dose inhaler comprises: joining a canister to a body; the canister having a pressurized supply of medicament therein and a hollow outlet stem terminating at an outlet port; the canister operative to output a metered amount of the medicament via the outlet port in response to being triggered: the outlet port having a first size; the body having a passage therethrough; triggering the canister to fire by displacing the canister toward the body passage so as to thereby spray medicament from the canister into the passage to generate a pressurized exhaust from the passage; routing the exhaust from the passage to atmosphere such that the exhaust encounters no constrictions smaller than about 75% of the first size. The exhaust can be routed directly to atmosphere or can be routed through a collection chamber associated with the body. 
         [0009]    Other aspects of various embodiments of a related inventive device and other related methods are also disclosed in the following description. The various aspects can be used alone or in any combination, as is desired. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0010]      FIG. 1  shows a metered dose inhaler of the prior art. 
           [0011]      FIG. 1A  shows an enlarged partial cut-away view of the canister of  FIG. 1 . 
           [0012]      FIG. 2  shows a canister and a cleaning body according to one embodiment of the present invention. 
           [0013]      FIG. 3A  shows a cross-section taken along line III-III with the canister in the ready position. 
           [0014]      FIG. 3B  shows a cross-section taken along line III-III with the canister in the firing position. 
           [0015]      FIG. 3C  shows an enlarged view of a portion of  FIG. 3A . 
           [0016]      FIG. 4  shows a canister and a cleaning body according to another embodiment of the present invention. 
           [0017]      FIG. 5A  shows a cross-section of the cleaning body along line V-V. 
           [0018]      FIG. 5B  shows the assembly of  FIG. 4  with the cleaning body cross-sectioned at line V-V. 
           [0019]      FIG. 6  shows a canister and a cleaning body according to another embodiment of the present invention with an extended flange to actuate a dose counter associated with the canister. 
           [0020]      FIG. 7  shows the canister and cleaning body of  FIG. 4  being inserted into an inhaler assembly in preparation for a cleaning actuation. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0021]    The present invention relates to metered dose inhalers. Referring to  FIG. 1  and  FIG. 1A , a metered dose inhaler  10  typically includes a canister  30  and an inhaler assembly  20 . The canister  30  typically includes a main canister body  32  and a valve stem  40  moveably coupled thereto. The main canister body  32  advantageously takes the generally cylindrical form shown in  FIG. 1 . The operative end of the canister body  32 , sometimes referred to as the canister ferrule, typically includes a generally cylindrical central boss  36  peripherally surrounded by an annular collar  34  of larger diameter. The canister body  32  houses a medicament  5  stored under pressure, typically due to the presence of a low vapor pressure propellant, and therefore acts as a pressure vessel. The valve stem  40  extends forward from the main canister body  32 , and typically takes the form of a hollow cylindrical tube with an internal bore  44  of relatively constant internal diameter. The valve stem  40  typically includes a small radially oriented hole (not shown) towards its proximate end that acts as an input to the internal bore  44  in a fashion well known in the art. The distal end of the valve stem  40  forms the valve stem outlet port  46 , and typically takes the form of a simple circular opening of a known size X. The valve stem  40  is moveably mated to the main canister body  32  so as to be displaceable between a ready position relatively away from the main body  32  and a firing position relatively closer to the main body  32 , and is biased toward the ready position. Movement of the valve stem  40  toward the main canister body  32 , from the ready position to the firing position, allows the pressurized medicament to enter the central bore  44  of the valve stem. The pressurized medicament rapidly expands to fill the central bore  44  and flows out outlet port  46  as a pressurized spray. 
         [0022]    The inhaler assembly  20  can take a wide variety of forms known in the art. One exemplary inhaler assembly  20  is a generally L-shaped body as shown in  FIG. 1 . The lower portion  24  of the “L” includes a mouthpiece  26  from which the medicament is drawn and/or propelled into the patient&#39;s mouth. The upper portion  22  of the “L” includes a recess for receiving the canister  30 . The inhaler assembly  20  includes suitable internal structures to allow the canister  30  to be triggered for the delivery of one “charge” of medicament in any fashion known in the art, so that the medicament can be administered to a patient by an inhalation technique. Further, the inhaler assembly  20  can include a variety of features, including a dose counter  12 , a vortex nozzle, breath actuation mechanisms, and the like, as is known in the art. Attention is directed to U.S. Pat. No. 6,418,925: and to U.S. patent applications Ser. No. 10/625,359 (U.S. Patent Application Publication No. 2005/0028815) and Ser. No. 10/908,133 (U.S. Patent Application Publication No. 2006/0243275), which are all incorporated herein by reference. 
         [0023]    In exemplary embodiments of the present invention, the canister  30  is removed from inhaler assembly  20  after several firings, joined to a separate cleaning body  50  for cleaning of the interior of valve stem  40 , and then rejoined to the inhaler assembly  20 . One embodiment of a cleaning body  50  is shown in  FIG. 2-3C . The cleaning body  50  of  FIG. 2  is generally disc-shaped and advantageously significantly larger in diameter than the canister main body  32 . A central bore or passage  60  leads from the upper surface  52  to the lower surface  54  of cleaning body  50 . The central passage  60  has a proximal upper portion  62  of a relatively larger diameter and a distal lower portion  64  of a relatively smaller diameter that are advantageously collinear. The proximal portion  62  can advantageously be of a constant diameter, but can include a tapered entry if desired. The proximal portion  62  is sized and shaped to receive the valve stem  40 , and therefore can advantageously have a diameter just slightly larger than the exterior of the valve stern  40 . In contrast, the distal portion of the passage is advantageously sized to be smaller than the exterior of the valve stem  40 , but larger than the bore  44  of valve stem  40 . The distal portion  64  can likewise be of a constant diameter. The two sections  62 , 64  interface in abutting fashion to form an internal shoulder  66 . Thus, the outlet port  46  of valve stem  40 , when the valve stem  40  abuts shoulder  66 , opens directly into passage distal portion  64 . 
         [0024]    The medicament can be administered to the patient by initially mating the canister  30  to the inhaler assembly  20  in any conventional fashion. The canister  30  is then triggered to supply the medicament  5  to the aerosolizing portions of the assembly  20 , and the aerosolized medicament is inhaled by the patient. A single “charge” of medicament  5  can correspond to a dose, or a dose can comprise multiple charges taken in short succession. This dosing regimen is advantageously repeated multiple times over a period of time. For example, the dosing regimen can be repeated three times a day for several days. When the dosing regimen exceeds a threshold, the valve stem  40  is cleaned. This threshold can be set as a given number of actuations of the canister  30 , or a given amount of time, or a combination thereof. Or, a cleaning cycle can be initiated if the patient suspects some problem with the inhaler  10 . 
         [0025]    To clean the valve stem  40 , the canister  30  is removed from the inhaler assembly  20  and joined to the cleaning body  50 . To do this, the valve stem  40  is inserted into the upper portion  62  of cleaning body central passage  60  until the valve stem  40  abuts against shoulder  66 . The canister  30  is pressed toward the cleaning body  50 , so that the valve stem  40  presses against shoulder  66 . During this action, the combination of the cleaning body  50  and the canister  30  can be supported in a variety of ways. For example, the lower surface  54  of cleaning body  50  can be supported by two spread fingers of one hand and the thumb of the hand placed over the flat base  38  of canister  30  (which is facing away from cleaning body  50 ). As the canister  30  is pressed, the valve stem  40  is forced to move relative to the canister main body  32 , until the valve stem  40  relatively retracts to the firing position. 
         [0026]    Movement of the valve stem  40  to the firing position causes a charge of pressurized medicament to be released into the valve stem  40 , where it rapidly expands and flows out stem outlet port  46  due to the relative pressure differential. The medicament  5  flows directly from the stem outlet port  46  into lower portion  64  of passage  60 , though the lower portion  64 , and out the passage  60  as an exhaust  68 . As can be appreciated, this exhaust  68  is vented directly to atmosphere in this embodiment because passage  60  opens directly to atmosphere. As Such, exhaust  68  does not encounter any constrictions less than the size of valve stem outlet port  46  before being reaching ambient atmosphere. Because of this, it is believed that that significant backpressure is not generated in the valve stem  40 , and the resulting flow rate through the valve stem  40  is maximized. It should be noted that this flow rate is higher than that experienced during normal inhalation activation. The higher flow rate tends to strip away any undesired deposits that could have formed inside bore  44  of valve stem  40 . Further, any stripped material is simply carried away to atmosphere in exhaust  68 , and therefore cannot result in blockage of the nozzle orifice of the inhaler assembly  20 . In most situations, only one firing of the canister  30  will be appropriate for complete cleaning, although multiple firings can be appropriate in some situations. After the cleaning firing(s), the canister  30  is removed from the cleaning body  50  and re-mated to the inhaler assembly  20 . If desired, the exterior  42  of valve stem  40  can be striped or otherwise cleaned prior to re-mating with the inhaler assembly  20 . Also, the inhaler assembly  20  can be cleaned using any appropriate technique while the canister  30  is unmated therefrom. The inhaler  10  is then ready for additional use. 
         [0027]    In other embodiments, the cleaning body  50  can be more complex. For example, a more complex cleaning body  50  is shown in  FIGS. 4-5B . This cleaning body  50  includes an outer housing  70  and a stop plate  80 . The housing  70  is a generally cylindrical hollow body, with an open proximal end and a closed distal end. The proximal end of the housing includes a peripheral rim  72 , but is otherwise open. The distal end of the housing is bounded by an impingement surface  74  disposed generally normal to the axis of housing  70 . An interior shelf  76  runs around the interior periphery in spaced relation to impingement surface  74 . The stop plate  80  in this example is a relatively thin, generally circular, body with a central passage  60  and a plurality of exhaust outlets  86 . As with the cleaning body  50  of  FIG. 2 , the central passage  60  in  FIGS. 5A-5B  includes a proximal portion  62  of a relatively larger diameter and a distal portion  64  of a relatively smaller diameter. The proximal portion  62  and distal portion  64  are advantageously collinear and of respective constant diameters, and the two sections  62 , 64  interface in abutting fashion to form an internal shoulder  66 . The proximal portion  62  is advantageously sized and shaped to just receive valve stem  40 , and therefore has a diameter just slightly larger than the exterior  42  of valve stem  40 . The distal portion  64  of passage  60  is advantageously sized to be smaller than the exterior  42  of valve stem  40 , but larger than bore  44  of valve stem  40 . Thus, the interior of the valve stem  40  opens directly into the distal portion  64  of passage  60  at outlet port  46 . The shoulder  66  is advantageously spaced from the impingement surface  74  by a distance Y that is approximately the same as the length of valve stem  40  or more. The exhaust outlets  86  can be defined by a plurality of spokes  82  that extend generally radially from proximate central passage  60  laterally toward peripheral rim  84  of stop plate  80 . The combined cross-sectional area of the exhaust outlets  86  is advantageously larger than the cross-sectional area of valve stem outlet port  46 ; indeed, the cross-sectional area of each individual exhaust outlet  86  is advantageously larger than the cross-sectional area of valve stem outlet port  46 . The peripheral rim  84  rests against shelf  76  so that the main portion of stop plate  80  is held in spaced relation from impingement surface  74 . If desired, stop plate  80  can also include one or more distally extending support posts  88  for aiding in support of stop plate  80  in this position. As can be seen, a collection chamber  90  is formed between the distal surface of stop plate  80  and impingement surface  74 . The central passage  60  acts as an inlet to this chamber  90 , and the exhaust outlets  86  act as the outlet for this chamber  90 . Upon firing of the canister  30 , the exhaust  68  from the central passage  60  flows along a flow path  100  from the central passage  60  into chamber  90 , through the chamber  90 , and out to ambient atmosphere via exhaust outlets  86 . Note that for optimal performance, the canister annular collar  34  should be spaced from the proximal peripheral rim  72  of the cleaning body  50 , when the valve stem  40  is in the firing position, by an amount such that the cross-sectional area between the two is larger than the cross-sectional area of valve stem outlet port  46 . As such, the exhaust  68  again does not encounter any constrictions less than the size of the valve stem interior cross-section along flow path  100  before being reaching ambient atmosphere. 
         [0028]    The cleaning body  50  embodiment of  FIG. 5  can be used similarly to the embodiment of  FIG. 2 . However, the cleaning body  50  of  FIG. 5  can be more easily held between a single finger and a thumb, and the ultimate gaseous output of the cleaning process is directed more radially than longitudinally. Further, it should be noted that exhaust  68  from passage  60  is directed at impingement surface  74  rather than at the surroundings. Further still, some embodiments can include an optional absorbent material (e.g., foam)  92  disposed just upstream of the exhaust outlets  68 . This absorbent material  92  can help absorb medicament  5  that is sprayed into chamber  90 . 
         [0029]    It has been assumed above that cleaning body  50  does not substantially longitudinally overlap canister main body  32 . However, in some embodiments, a portion of the cleaning body  50  can longitudinally overlap a significant length of the canister main body  32 . For example, the cleaning body  50  of  FIG. 6  includes a proximal flange portion  78  of substantial longitudinal length. This flange  78  can advantageously be curved so as to follow the cylindrical side of the canister main body  32 , but with a larger radius of curvature so that a gap is formed therebetween. The purpose of the flange  78  is to actuate an optional dose counter  12  that can be associated with the canister  30 . Thus, the flange  78  should be of sufficient length so as to be able to reach the relevant portions of dose counter  12 . In other embodiments, the flange  78  can be extended so as to substantially or fully peripherally enclose canister  30 , as can be appropriate. The flow path  100  of the exhaust  68  for such a cleaning body  50  can be similar to any of those discussed above, and care should be taken with such embodiments to have adequate clearances and/or dedicated openings to avoid creating undesirable constrictions in the flow path  100 . 
         [0030]    The discussion above has assumed that the flow path  100  from the valve stem outlet port  46  reaches ambient atmosphere without encountering any constrictions smaller than the cross-sectional size of the valve stem interior. However, slightly smaller constrictions can be present in some embodiments of the present invention. For example, the lower portion  64  of passage  60  call have a cross-section that is 75% of the cross-sectional size of the valve stem interior. Advantageously, this size is larger, such as 80%, 85%. 90%, or 95%, with larger size ratios being preferred. It is believed that a size ratio of ≧100% is more advantageous, but constrictions sized between 100% and about 75% (inclusive) cannot generate significant backpressure, and the flow rates of the medicament through the valve stem  40  can be maintained at desired levels. These sizes are in stark contrast to the typical 1%-5% sizes of the nozzle orifices typically employed. 
         [0031]    The discussion above has assumed that the cleaning body  50  is directly supported by the user&#39;s hand; however, such is not required in all embodiments. In some embodiments, the cleaning body  50  can be supported by a suitable fixture, which in turn can be handheld or placed on a suitable surface during the cleaning actuation. Indeed, as shown in  FIG. 7 , the cleaning body  50  can be inserted into the inhaler assembly  20  for the cleaning operation, and subsequently removed. Further still, the cleaning body  50  can be formed as a suitable exterior feature (not shown) on the inhaler assembly  20 . 
         [0032]    Several tests have been run to examine the effect of using a cleaning body  50 , and the results indicate that following a cleaning regimen that encourages periodic cleaning of the valve stem interior will lead to better performance. Each of the tests used a pressurized insulin medicament in the canister  30 , with the formulation being a relatively high strength suspension formulation. The weight of the medicament sprayed from the canister (“shot weight”) was measured for each actuation, with a ten second wait between each actuation. A substantially similar inhaler assembly  20  was used for each test, and three canisters were tested at each test condition. 
         [0033]    Test A used a five minute wait between sets of three actuations, without a cleaning regimen. The inhaler was found to be clogged after approximately twenty-seven actuations of the first canister. The second canister caused clogging after approximately forty-five actuations. The third canister did not cause clogging after one hundred twenty actuations, but showed a marked variation in shot weight around sixty actuations and again around eighty actuations. 
         [0034]    Test B used a sixty minute wait between sets of three actuations, without a cleaning regimen. The inhaler was found to be clogged after approximately thirty-six actuations of the first canister. The other two canisters caused clogging after approximately eighty-seven actuations each. 
         [0035]    Test C used a five minute wait between sets of three actuations (similar to Test A), with a cleaning actuation using a cleaning button  50  after every thirty actuations. The inhaler was found to be clogged after approximately ninety-two actuations for the first canister. The second canister caused clogging after approximately one hundred eighteen actuations. The other canister did not clog or show a significant drop off in shot weight until the canister was emptied after approximately one hundred forty actuations. 
         [0036]    Test D was similar to Test C, but the cleaning cycle was changed to be a cleaning actuation using a cleaning button  50  after every twenty actuations. None of the three canisters caused clogging or showed a significant drop off in shot weight through approximately one hundred forty actuations (at which point the canisters were emptied). 
         [0037]    The instances of clogging during the testing outlined above appear to be the result of build up of material on the inside of the valve stem, and subsequent break off of the agglomerated material. It is believed that the broken off material moves downstream, probably during that “shot” but possibly during a subsequent shot, to block a downstream constriction, such as the nozzle orifice. 
         [0038]    Based on the above, it is clear that subjecting the canisters  30  to a cleaning regimen using a cleaning button can improve performance of an inhaler  10 . It is believed that the appropriate frequency of the cleaning regimen will vary based on a number of factors, including medicament composition, valve stem material, valve stem size, nozzle orifice size, and the like. Nevertheless, a cleaning frequency of approximately every ten to twenty actuations is believed appropriate for most situations. 
         [0039]    The present invention can be carried out in other specific ways than those herein set forth without departing from the scope and essential characteristics of the invention. Further, the various aspects of the disclosed device and method can be used alone or in any combination, as is desired. The disclosed embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, and all changes coming within the meaning and equivalency range of the appended claims are intended to be embraced therein.