Patent Abstract:
Dry powder inhaler systems for pulmonary delivery of pharmaceuticals are disclosed. The dry powder inhalation systems comprise a dry powder inhalation device or inhaler and a cartridge containing a pharmaceutical formulation comprising an active ingredient for delivery to the pulmonary circulation. The present devices provide rugged devices which are reusable, use pre-metered unit dose cartridges which deliver a medicament in a liner manner, and can be disassembled for cleaning. The devices also provide a high resistance inhalation system which enables deagglomeration of dry powder particles, have a consistent airflow, are easy to manufacture and are simple and relatively easy to use.

Full Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Nos. 61/040,112 filed Mar. 27, 2008 and 61/143,370 filed Jan. 8, 2009; the contents of each of these applications are incorporated by reference herein in their entirety. 
     
    
     TECHNICAL FIELD 
       [0002]    A pulmonary drug delivery system is disclosed. The system includes a dry powder inhaler; and a unit dose cartridge for using with the inhaler. The cartridge can contain a drug delivery formulation for pulmonary delivery, for example, a formulation comprising a diketopiperazine and an active ingredient including peptides and proteins such as insulin and glucagon-like peptide 1. The dry powder inhaler is compact and comprises a housing, and a mouthpiece having a chamber to install the unit dose cartridge containing medicament and can be separated from its housing for ease of cleaning. 
         [0003]    All references cited in this specification, and their references, are incorporated by reference herein in their entirety where appropriate for teachings of additional or alternative details, features, and/or technical background. 
       BACKGROUND 
       [0004]    Drug delivery systems for the treatment of disease which introduce active ingredients into the circulation are numerous and include oral, transdermal, inhalation, subcutaneous and intravenous administration. Drugs delivered by inhalation are typically delivered using positive pressure relative to atmospheric pressure in air with propellants. Such drug delivery systems deliver drugs as aerosols, nebulized or vaporized. More recently, drug delivery to lung tissue has been achieved with dry powder inhalers. Dry powder inhalers can be breath-activated to deliver drugs by converting drug particles in a carrier into a fine dry powder which is entrained into an airflow and inhaled by the patient. Drugs delivered with the use of a dry powder inhaler can no longer be intended to treat pulmonary disease only, but also specific drugs can be used to treat many conditions, including diabetes and obesity. 
         [0005]    Dry powder inhalers, used to deliver medicaments to the lungs, contain a dose system of a powder formulation usually either in bulk supply or quantified into individual doses stored in unit dose compartments, like hard gelatin capsules or blister packs. Bulk containers are equipped with a measuring system operated by the patient in order to isolate a single dose from the powder immediately before inhalation. Dosing reproducibility requires that the drug formulation is uniform and that the dose can be delivered to the patient with consistent and reproducible results. Therefore, the dosing system must operate to completely discharge all of the formulation effectively during an inspiratory maneuver when the patient is taking his/her dose. Flow properties of the powder formulation, and long term physical and mechanical stability in this respect, are more critical for bulk containers than they are for single unit dose compartments. Good moisture protection can be achieved more easily for unit dose compartments such as blisters, however. foils used to seal the blisters and subsequent drug formulation lose viability with long storage. 
         [0006]    Dry powder inhalers such as those describe in U.S. Pat. No. 7,305,986 and U.S. patent application Ser. No. 10/655,153 (US 20040182387), the disclosures of which are incorporated herein by reference in their entirety for all they disclose regarding dry powder inhalers, can generate primary drug particles or suitable inhalation plumes during an inspiratory maneuver by deagglomerating the powder formulation within a capsule. The amount of fine drug discharged from the inhaler&#39;s mouthpiece during inhalation is largely dependent on the interparticulate forces in the powder formulation (between drug and drug particles or between drug and excipient particles) and the efficiency of the airflow as measured by pressure drop and flow rate entering and exiting the dry powder dispenser. The benefits of delivering drugs via the pulmonary circulation are numerous and include, rapid absorption into the arterial circulation, avoidance of drug degradation by liver metabolism, ease of use, i.e., lack of discomfort of administration by other routes of administration. 
         [0007]    Dry powder inhaler products developed for pulmonary inhalation have met with limited success to date, due to lack of practicality. Some of the persistent problems observed with prior art inhalers, include ruggedness of device, inconsistency in dosing, inconvenience of the equipment, and/or lack of patient compliance. Therefore, the inventors have designed and manufactured a dry powder inhaler with consistent drug delivery properties, ease of use without discomfort, improved ruggedness, and discrete geometries which would allow for better patient compliance. 
       SUMMARY 
       [0008]    Dry powder inhaler systems for pulmonary delivery of pharmaceuticals are disclosed. The dry powder inhalation systems comprise a dry powder inhalation device or inhaler and at least one cartridge containing a pharmaceutical formulation comprising at least one active ingredient for delivery to the pulmonary circulation. The present inhalation systems provide rugged devices which are reusable, use pre-metered unit dose cartridges and can be separated into their principal component parts for ease of cleaning. The devices also provide high resistance inhalation systems which enable deagglomeration of dry powder particles, have consistent airflow and are simple and easy to use. 
         [0009]    In one embodiment, a dry powder inhaler comprises a housing, and a mouthpiece, wherein the housing comprises a mouthpiece engaging section structurally configured to engage with the mouthpiece, and the mouthpiece being removable at predetermined positions relative to the housing, and having a conduit permitting airflow between an air inlet and an air exit port, and comprising a chamber and an oral placement section; the mouthpiece further being structurally configured to be moveable within the housing in an engaged position and releasable from the housing at a predetermined position. The dry powder inhaler mouthpiece is structurally configured to receive, hold and/or release a medicament containing cartridge in the chamber. 
         [0010]    In another embodiment, the housing comprises a container structurally configured to adapt to the mouthpiece and has one or more openings for allowing air intake into the mouthpiece chamber. In such an embodiment, the housing has securing mechanisms to hold the mouthpiece chamber and permit the mouthpiece assembly to be moveable within the housing to a storage position, to a cartridge loading/unloading position, mouthpiece separable position, to an inhalation position and in reversed order. 
         [0011]    In still another embodiment, the mouthpiece assembly engages the mouthpiece at the mouthpiece engaging section of the housing. The housing can comprise an air intake section having an air conduit with one or more first openings to allow ambient air intake and a second opening in communication with the mouthpiece engaging section which allows airflow through the air conduit and out into the housing engaging section, the engagement of the mouthpiece substantially prevents ambient air from entering the conduit except at the one or more first openings in the housing for air intake. In one embodiment, the housing also comprises a mouthpiece storage section. 
         [0012]    In yet another embodiment, the dry powder inhaler mouthpiece assembly can move relative to the housing and the movement of the mouthpiece within the housing can reconfigure a cartridge seated in the inhaler from a closed configuration to an open configuration, or from an open to a closed configuration. Movement of the mouthpiece within the housing can be of various types, such as translational or rotational. In one such embodiment, movement about the housing is rotational, and can be restricted at predetermined locations relative to the housing to provide registration of positions of the mouthpiece in use. In one embodiment, for example, movement of the mouthpiece assembly is rotational and the mouthpiece can rotate from the storage position to a cartridge loading/unloading position to an inhalation position. In another embodiment, the mouthpiece further comprises a mouthpiece oral placement section and a medicament containing cartridge receiving section; the cartridge receiving section configured to permit and direct air flow through and around the cartridge. 
         [0013]    In a further embodiment, the air conduit of the air intake section of the housing is in communication with the air exit port of the mouthpiece when the cartridge is in an open configuration. The airflow conduit is established between one or more first openings in the housing; then air passes through the airflow conduit within the housing and exits a second opening of the mouthpiece engaging section and enters into the mouthpiece chamber wherein a percentage of intake air volume goes through the cartridge and a percentage of intake air volume goes around the cartridge during an inhalation maneuver. In this embodiment, the airflow path then enters the mouthpiece chamber and enters and exits the conduit of the mouthpiece oral placement section. In a further embodiment, with a cartridge containing medicament placed in the chamber, airflow entering the chamber from the housing outlet port is diverted so that a percentage of the airflow volume goes through the cartridge and a percentage of the airflow volume goes around the cartridge. Both air flow volumes, exiting the cartridge with a medicament and airflow around the cartridge, converge prior to entering and exiting the air exit port of the mouthpiece of the oral placement section. 
         [0014]    In another embodiment, a dry powder inhaler is provided comprising a housing, and a mouthpiece assembly, the housing having a top wall, a bottom wall, side walls; a mouthpiece engaging section, a mouthpiece storage section, and an air intake section having a conduit with a first opening to allow ambient air intake and a second opening in communication with the mouthpiece engaging section which allows air flow therethrough; the mouthpiece subassembly being removable and comprising a chamber structurally configured to house a cartridge and to engage with the mouthpiece engaging section of the housing; an oral placement section extending from the chamber and having an air inlet which communicates with the chamber and an air outlet in communication with ambient air. 
         [0015]    In embodiments described herewith, a breath-powered inhaler is provided comprising, an inhaler with resistance values that can be tunable or changed as required by the patient being an adult or a child. In one embodiment, the resistance values of the inhaler can be altered by changing the geometries or configuration of the air conduits so that airflow distribution through the cartridge and around the cartridge can vary. In one embodiment, inhaler resistance values can range between 0.08 and 0.15 √kPa/liters per minute. In certain embodiments, flow balance distribution can range from about 10% to about 30% through the cartridge and from about 70% to 90% going around the cartridge. 
         [0016]    In still a further embodiment, the dry powder inhalation system comprises a breath-activated dry powder inhaler, a cartridge containing medicament, wherein the medicament can comprise a diketopiperazine and an active agent. In some embodiments, the active agent comprises peptides and proteins. In another embodiment, the inhalation system comprises a cartridge containing medicament wherein the peptide or protein can be an endocrine hormone: including, insulin, glucose-like peptide (GLP-1), parathyroid hormone, parathyroid hormone related protein (PTHrP), and the like. 
         [0017]    In one embodiment, the dry powder inhalation system can comprise a cartridge including a formulation for pulmonary delivery which can be provided for use with different dosage strengths, wherein the system can deliver the dosage with consistency and in a linear manner. In this embodiment, for example, multiple cartridges of a single dose to be administered to a subject can be interchangeably replaced or substituted by providing the system with a single cartridge of the sum of the dosage strength of the multiple cartridges, wherein the system can deliver a bioequivalent dose with a single cartridge. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0018]      FIG. 1  illustrates a three dimensional side view of an embodiment of a dry powder inhaler in a storage position. 
           [0019]      FIG. 2  illustrates the back side view of the dry powder inhaler of  FIG. 1  showing the mouthpiece subassembly moved from the storage position to a cartridge loading position wherein the cap is opened. In this embodiment, this is also the position at which the mouthpiece can be separated. 
           [0020]      FIG. 3  illustrates the back side view of the dry powder inhaler of  FIG. 1  showing the mouthpiece subassembly has been moved to the inhalation position for use. 
           [0021]      FIG. 4  illustrates the back side view of the dry powder inhaler of  FIG. 1  showing the mouthpiece subassembly has been moved to an unloading position after inhalation. 
           [0022]      FIG. 5  illustrates the dry powder inhaler of  FIG. 1 , showing the housing subassembly and the mouthpiece subassembly disengaged from one another. 
           [0023]      FIG. 6  illustrates a top view section of a housing subassembly of a dry powder inhaler. 
           [0024]      FIG. 7  illustrates the dry powder inhaler shown in  FIG. 3  in cross-section. 
           [0025]      FIG. 8  illustrates the dry powder inhaler of  FIG. 1 , showing an exploded view of the housing subassembly. 
           [0026]      FIG. 9  illustrates the dry powder inhaler of  FIG. 1 , showing the mouthpiece subassembly removed from the housing component. 
           [0027]      FIG. 10  illustrates the dry powder inhaler of  FIG. 1 , showing an exploded view of the mouthpiece subassembly. 
           [0028]      FIG. 11  illustrates an alternate embodiment of the dry powder inhaler system showing the inhaler in a cartridge loading position.  FIG. 1  also depicts a cartridge embodiment for use with a dry powder inhaler according to the present description. 
           [0029]      FIG. 12  illustrates the embodiment of  FIG. 11  with a cartridge loaded into the dry powder inhaler with the cap open. 
           [0030]      FIG. 13  illustrates the embodiment of  FIG. 11  showing the dry powder inhaler in an inhalation position. 
           [0031]      FIG. 14  illustrates the embodiment of  FIG. 13  showing the dry powder inhaler in inhalation position as a cross-section through the mid-longitudinal axis. 
           [0032]      FIG. 15  illustrates a cross-section of an embodiment wherein the dry powder inhaler is shown in the dosing position and containing a cartridge. 
           [0033]      FIG. 16  illustrates an embodiment of a three dimensional side view of a cartridge for use with the dry powder inhalation system. 
           [0034]      FIG. 17  illustrates an embodiment of a three dimensional back side view cartridge for use with the dry powder inhalation system. 
           [0035]      FIG. 18  illustrates an embodiment of an exploded three dimensional view of the cartridge for use with the dry powder inhalation system. 
           [0036]      FIG. 19  illustrates a mean baseline-corrected GIR (glucose infusion rate) for two 15 U cartridges and one 30 U cartridge of an inhalation powder comprising insulin and fumaryl diketopiperazine, and for 10 IU of RAA. 
           [0037]      FIG. 20A  depicts a schematic representation of a cartridge loaded into a cartridge rig in cross-section for measuring pressure across the cartridge.  FIG. 20B  illustrates a diagram of a resistance circuit illustrating the various resistors associated with the cartridge rig illustrated in  FIG. 20A . 
           [0038]      FIG. 21A  illustrates a schematic representation of a portion of the inhaler in cross-section showing components parts.  FIG. 21B  illustrates a diagram of a resistance circuit of an inhaler embodiment of  FIG. 21A  used for measuring the resistance and pressure of the device. 
           [0039]      FIG. 22  depicts a linear regression plot illustrating the resistance measured through an exemplary cartridge rig tested or R 3 , at flow rates between 2 and 9 liters/min. 
       
    
    
     DETAILED DESCRIPTION 
       [0040]    In embodiments disclosed herein, there are disclosed dry powder inhalation systems for delivering pharmaceutical medicaments to the pulmonary circulation. The inhalation systems comprise a breath-powered or breath activated, dry powder inhaler, one or more cartridges containing a pharmaceutical formulation comprising one or more pharmaceutically active substances or active ingredients, and a pharmaceutically acceptable carrier. 
         [0041]    One embodiment of a dry powder inhaler is shown in  FIG. 1 . Therein, dry powder inhaler  100  comprises housing  102 , and removable mouthpiece assembly or subassembly  104 .  FIG. 1  illustrates dry powder inhaler  100  in a closed or storage position, wherein mouthpiece oral placement section  106  (illustrated in  FIG. 2 ) is stowed away under cover  108 .  FIG. 1  also illustrates cover or lid  110  over mouthpiece chamber  112  (illustrated in  FIG. 2 ). In one embodiment of  FIG. 1 , housing  102  is structurally configured to be relatively rectangular in shape and has top wall  114 , bottom wall  116 , back wall  118 , first side wall  120 , second side wall (not illustrated), mouthpiece engaging section  122 , mouthpiece storage section  124 , and an air intake section as part of housing  102 . 
         [0042]      FIG. 2  illustrates dry powder inhaler  100  from  FIG. 1 , showing the inhaler in a cartridge loading/unloading position with lid  110  open to allow a mating cartridge to be inserted into the central cavity of mouthpiece chamber  112 .  FIG. 2  also illustrates removable mouthpiece subassembly  104  is movable from the storage position in the housing to about 90° relative to longitudinal x-axis  202  of housing  102  rotated about y-axis  204 . In certain embodiments, the cartridge loading/unloading position of mouthpiece assembly  104  can be any predetermined angle as desired. As illustrated in  FIG. 2 , mouthpiece engaging section  122  of housing  102  is relatively circular in shape on the side wall and is shorter in height compared to the rest of housing  102  to accommodate mouthpiece chamber  112  and can form one end of inhaler  100 . Housing  102  can also comprise an air conduit with one or more first openings to allow ambient air intake and a second opening in communication with mouthpiece engaging section  122  which allows air flow from the intake section through the conduit into mouthpiece chamber  112  in the inhalation position. 
         [0043]      FIG. 3  depicts dry powder inhaler  100  illustrated in  FIG. 1 , showing removable mouthpiece assembly  104  in an extended or inhalation position. In this embodiment, removable mouthpiece assembly  104  is at about 180° angle relative to the longitudinal x-axis  202  of housing  102  rotated about y-axis  204 . In some embodiments, the inhalation position of mouthpiece assembly  104  can be varied depending on the structural configuration of the cartridge design to be adapted with the inhaler, and the rotational degrees a cartridge may be rotated to properly align apertures that allow air to enter and exit the cartridge carrying a plume of medicament into mouthpiece exit port  302 . 
         [0044]      FIG. 4  illustrates dry powder inhaler  100  of  FIG. 1  showing removable mouthpiece assembly  104  being moveable about the loading/unloading position after use. It should be noted that lid  110  remains closed during movement of removable mouthpiece assembly  104  about housing  102 .  FIG. 4  also illustrates mouthpiece oral placement section  106  can be configured with tongue depressor  402  which acts to properly depress the tongue of a user. 
         [0045]      FIG. 5  illustrates dry powder inhaler  100  of  FIG. 1  comprising the component parts, removable mouthpiece assembly  104  and housing  102 . Removable mouthpiece assembly  104  comprising mouthpiece chamber  112  structurally configured with cartridge holder area  502 , one or more belts  504  and one or more flanges  506 , lid  110  and air inlet port  508  which communicates with the housing second opening to engage with mouthpiece engaging section  122  of housing  102 ; mouthpiece oral placement section  106  extending from mouthpiece chamber  112  and having air inlet port  508  which communicates with mouthpiece chamber  112  and mouthpiece exit port  302  which is in communication with ambient air. Drive key  510  structurally configured to have indicator  512 , for example, in the shape of a tear drop for proper placement of a cartridge in dry powder inhaler  100  is also shown in  FIG. 2  and  FIG. 5 . Proper alignment of a cartridge in the inhaler indicates the correct relative rotational orientation and determines successful cartridge seating, insertion and emptying in use. In such an embodiment, a cartridge cannot be properly seated unless tear drop  1602  of cartridge  1600  ( FIG. 11 ) and drive key  510  align with one another. 
         [0046]    Lid  110  is positioned over mouthpiece chamber  112  and is mechanically connected to removable mouthpiece assembly  104  by hinge  514 . Lid  110  has an outer surface and an inner surface and it is structurally configured with an anvil in its inner top surface and relatively centered within the top. Lid  110  can only be opened when removable mouthpiece assembly  104  is in the loading/unloading position. When removable mouthpiece assembly  104  is engaged into housing  102  an interlocking mechanism prevents movement to a dosing/inhalation position or to a storage position when lid  110  is opened or raised. The interlocking mechanism can comprise, for example, one or more belts or flexible radial arms, which are incorporated into the walls of mouthpiece chamber  112  and act as a self-synching mechanism  602  in  FIG. 6 . The interlocking mechanism allows removable mouthpiece assembly  104  to obtain proper registration of the various positions when dry powder inhaler  100  is in use. Lid  110  can be maintained in a closed position by a locking mechanism, for example, a spring loaded boss such as a lock-out button which can engage a receiving detent within housing  102 . In an alternate embodiment, the locking mechanism comprises an upward extension of the housing wall. The locking mechanism  602  can also serve to secure the mouthpiece subassembly against further rotation. Position registration of removable mouthpiece assembly  104  allows the inhaler to be properly used and prevents movement of removable mouthpiece assembly  104  to the dosing position without lid  110  being depressed. 
         [0047]      FIG. 5  also illustrates housing  102  separated from removable mouthpiece assembly  104  showing mouthpiece engaging section  122  having an opening or cavity  516  with top wall  114  partially discontinuous to adapt, receive and hold removable mouthpiece assembly  104  and structurally configured to accommodate the mouthpiece. Housing  102  is configured to have an upward projection of the wall or second flange  518  around the top outer portion of mouthpiece engaging section  122  and a protrusion configured as a drive key in its bottom wall configured to mate with a keying structure of a cartridge. The proper alignment of a cartridge within dry powder inhaler  100  is dependent on drive key  510  having an indicator  512  and one or more indentation  126  ( FIG. 2 ) in removable mouthpiece assembly  104  and drive key  510  and of housing  102 . 
         [0048]    Housing  102  comprises mouthpiece engaging section  122  having an outer wall, an inner wall and a bottom wall contiguous with the side and bottom walls respective of housing  102 , and configured to adapt to the mixing section of removable mouthpiece assembly  104 .  FIG. 6  illustrates a parallel cross-section through the mid-longitudinal plane of housing  102  containing a portion of mouthpiece chamber  112 .  FIG. 6  also illustrates interlocking mechanism  604  (belts  504  in  FIG. 5 ); chamber inner wall  606  defining a space for housing a cartridge. Circular structure or plug  608  is the wall of the air conduit of housing  102  which is continuous with back wall  118  of housing  102 . 
         [0049]      FIG. 7  illustrates a cross sectional view of dry powder inhaler  100  in a dosing or inhalation position. As seen in  FIG. 7 , housing  102  has a substantially rectangular shape, however other shapes are also suitable. Housing  102  comprises one or more inlet ports or first openings  702 , air conduit  704  housing piston  706  and spring  708 , and outlet port  710  opening into mouthpiece engaging section  122  and aligns with the inlet port of mouthpiece chamber  112 . Air conduit  704  has one or more openings  712  that allow airflow to enter. 
         [0050]    Mouthpiece engaging section  122  is partially configured in the shape of a cup further comprising second drive key  802  as seen in  FIG. 8  from bottom wall  116  configured to receive and hold a medicament containing cartridge.  FIG. 7  also shows the engagement between flange  506  of mouthpiece chamber  112  in housing  102 ; hinge  514 , lid  110  and mouthpiece oral placement section  106  with tongue depressor  402  and airflow conduit  714  of removable mouthpiece assembly  104 . 
         [0051]      FIG. 8  depicts an exploded view of housing  102  illustrating integral components of dry powder inhaler  100 , including plug  608 , piston  706  and spring  708  which assemble into air conduit  704 ; housing  102  outer structure comprising back wall  118 , side wall  120 , top wall  114 , and bottom wall  116 ; mouthpiece engaging section  122  with second drive key  802 , and slide door  804  which covers the storage compartment for mouthpiece oral placement section  106 . Air conduit  704  is configured to have an aperture or opening  712  which allows and directs airflow entering housing  102  into mouthpiece engaging section  122  during an inspiratory maneuver. Mouthpiece engaging section  122  can also comprise a securing mechanism which can comprise protrusions or projections from the inner wall of the chamber which mates with flange  506  and mating structure  902  as seen in  FIG. 9  of mouthpiece chamber  112 . In this embodiment, piston  706  and compression spring  708  act as an indicator mechanism positioned in air conduit  704  of housing  102  structurally configured to indicate inspiratory effort. Piston  706  and spring  708  can be placed at other positions in the airflow pathway of dry powder inhaler  100 . During an inspiratory maneuver, airflow entering the air conduit  704  within housing  102  goes around piston  706 , and moves piston  706  to compress spring  708 . This airflow control mechanism during inhalation indicates inspiratory effort through a tactile sensation. In one embodiment, the mechanism indicates inspiratory effort through an audible click. In another embodiment, the mechanism indicates inspiratory effort through a tactile sensation and/or an audible click. Mouthpiece engaging section  122  of housing  102  has one or more protrusions such as mating structures  902  that mates with mouthpiece chamber  112  to secure mouthpiece when dry powder inhaler  100  is in use. 
         [0052]    In operation, removable mouthpiece assembly  104  is rotated from a storage position to a cartridge loading/unloading position wherein lid  110  is opened and a cartridge containing medicament is placed into mouthpiece chamber  112  and securely seated. Lid  110  contains an anvil  1102  ( FIG. 11 ) inside which, if a cartridge is inserted in the correct position, the anvil will further insure the cartridge achieves a proper vertical alignment. A downward push of lid  110  closes the cover and removable mouthpiece assembly  104  can rotate to the dosing position, wherein a registration securement holds removable mouthpiece assembly  104  in place. If the proper vertical alignment is not achieved lid  110  cannot be fully closed and subsequent removable mouthpiece assembly  104  rotation cannot occur. This provides an interlock mechanism. 
         [0053]      FIG. 9  illustrates removable mouthpiece assembly  104  which has been separated from housing  102 . Removable mouthpiece assembly  104  comprises mouthpiece chamber  112 , lid  110  articulated to removable mouthpiece assembly  104  so that in a closed position lid  110  covers mouthpiece chamber  112 , and mouthpiece oral placement section  106  having airflow conduit  714  with mouthpiece exit port  302 . Mouthpiece chamber  112  comprises air inlet port  508 , one or more flanges  506  having gaps and mating structure  902  for mating with and securing removable mouthpiece assembly  104  with housing  102 . Flange  506  positioned at the bottom end of mouthpiece chamber  112  is provided which is structurally configured to engage with housing  102 , and comprises multiple segments having gaps in between the segments; the gaps section contains mating structure  902  for mating with housing  102 . The multiple segments of flange  506  and gaps between the segments can be position at predetermined positions of mouthpiece chamber  112  to effectuate proper securement of removable mouthpiece assembly  104  in housing  102 . 
         [0054]      FIG. 10  is an exploded view of removable mouthpiece assembly  104 . Mouthpiece chamber  112  comprises drive key  510  with indicator  512 , lid  110 , mouthpiece oral placement section  106 , cartridge securing mechanism  1002 , a radial spring  1004 , one or more belts  504  and interlock detents  1006 . 
         [0055]    In embodiments described herein, dry powder inhaler  100  is structurally configured to effectuate a tunable airflow resistance, which is modular. The resistance of dry powder inhaler  100  can be modified, by varying the cross-sectional area at any section of air conduit  704  of the inhaler. In one embodiment, dry powder inhaler  100  can have a airflow resistance value of from about 0.08 to about 0.13 square root of kPa/liters per minute. 
         [0056]    In an alternate embodiment illustrated in  FIGS. 11-14 , dry powder inhaler  100  comprises alternate housing  1104  configured to be compact and comprises a square-shape configuration which snuggly fits with removable mouthpiece assembly  104 . Removable mouthpiece assembly  104  is similar in structure, if not identical in some embodiments, to the embodiment described with respect to  FIGS. 1-10 .  FIG. 11  depicts alternate dry powder inhaler  1100  in the cartridge load/unload position with lid  110  open, mouthpiece oral placement section  106 , mouthpiece exit port  302 , anvil  1102 , mouthpiece chamber  112  and interlocking mechanism  604  ( FIG. 6 ). Cartridge  1600  has tear drop  1602  indicator for aligning to the indicator  512  of mouthpiece chamber  112  for proper insertion. Alternate housing  1104  in this embodiment, has an air inlet located in one of the side walls; however, in alternate embodiments the air inlet can be one or more holes placed in other positions, for example, in alternate housing bottom wall  1106 . Alternate dry powder inhaler  1100  can have one or more openings in the housing of variable size or shape and locations. 
         [0057]    Cartridges such as cartridge  1600  can be adapted to the dry powder inhaler containing a dry powder medicament for inhalation, and are configured to deliver a single unit dose of a medicament. In one embodiment, cartridge  1600  can be structurally configured to contain a dose of, for example, 0.5 mg to about 30 mg of dry powder for inhalation. 
         [0058]      FIG. 12  illustrates an alternate dry powder inhaler  1100  with cartridge  1600  loaded and ready for closure of lid  110 . As can be seen, lid  110  is in the open position, mouthpiece chamber  112  and alternate housing  1104  with alternate air inlet  1202 .  FIG. 13  depicts the dry powder inhaler system of  FIG. 12  in the dosing position and ready for inhalation. 
         [0059]      FIG. 14  depicts a cross-section of alternate dry powder inhaler  1100  of  FIG. 13 , showing the internal features of the inhaler and cartridge system. Lid  110  securely holds cartridge  1600  by way of anvil  1102 , which is then securely installed in mouthpiece chamber  112 . The airflow conduit  714  of mouthpiece oral placement section  106  with mouthpiece inlet port  1402  and mouthpiece exit port  302 . 
         [0060]    In some embodiments, as shown in  FIG. 15 , dry powder inhaler  100  comprises a removable mouthpiece assembly  104  comprising lid  110  over cartridge holder area  502  movable from a closed to an open position, having anvil  1102  which engages with cartridge  1600  in a closed position, wherein the housing further comprises an air flow control mechanism comprising check valve  1502 . 
         [0061]    In embodiments described herein, the dry powder inhaler system in use has a predetermined airflow distribution around and through a cartridge operably configured to mix a medicament with air forming a powder plume for delivery to a patient&#39;s pulmonary system. Predetermined airflow distribution through the cartridge can range from about 10 to about 30% of total airflow volume entering the dry powder inhaler during inhalation. Predetermined airflow distribution around the cartridge can range from about 70 to about 90% of total airflow volume. Predetermined cartridge bypass airflow and exiting airflow through the cartridge converge to further shear and deagglomerate the powder medicament prior to exiting the mouthpiece outlet port. 
         [0062]    In one embodiment, the medicament containing cartridge  1600  as shown in  FIGS. 16-18  can comprise a structure with a defined shape having a wall with one or more first apertures  1604 , second aperture  1702  and third aperture  1802 , tear drop  1602 , grasping feature  1606 , and first inhaler keying mechanism  1608  and second inhaler keying mechanism  1610 . Cartridge  1600  has a closed configuration moveable to an open configuration for dosing a powder medicament or from an open to a closed position after use. Cartridge  1600  further comprises an outer surface and an inner surface defining an internal volume; wherein the closed configuration restricts communication, such as air transit to or through the internal volume, and the open configuration forms an air passage through the internal volume to allow a powder medicament contained therein to be aerosolized and delivered to a patient in an airflow stream created by the user. The open configuration is established by providing one or more apertures (e.g. first aperture  1604 , second aperture  1702  and third aperture  1802 ), holes, slits or windows in the cartridge walls that can have beveled edges to direct airflow. In one embodiment, cartridge  1600  can be configured of two elemental parts, for example, two segments (e.g. first segment  1804  and second segment  1806 ) that can have apertures in their walls that can align with one another in the open configuration and in opposing positions where the apertures at not in alignment. In one embodiment, for example, cartridge  1600  can be structurally configured as two separate elements which can fit into one another and be moveable about one another; each having openings which can align with one another, similarly as the capsules described in U.S. Pat. No. 7,305,986, which is fully incorporated herein by reference as if part of this specification. In this embodiment, however, cartridge  1600  is designed to integrally function with the dry powder inhaler and can be moved within the inhaler to predetermined positions 
         [0063]    In one embodiment, a method of delivering an active ingredient comprising: a) providing a dry powder inhaler comprising, a housing and a mouthpiece, the mouthpiece comprising a chamber containing a cartridge with a dry powder formulation comprising a diketopiperazine and the active agent; the inhaler having a flow distribution of about 10% to 30% of the airflow going through the cartridge, and b) delivering the active ingredient to an individual in need of treatment by inhaling deep and rapidly for about 4 to 6 seconds and optionally repeating step b). 
         [0064]    In embodiments described herein, the dry powder inhaler can deliver a dose of a dry powder formulation to a patient at pressure differentials between 2 and 20 kPa. 
         [0065]    In still yet a further embodiment, the method of treating hyperglycemia and/or diabetes comprises the administration of an inhalable dry powder composition comprising a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder composition can comprise a diketopiperazine salt. In still yet another embodiment of the present invention, there is provided a dry powder composition, wherein the diketopiperazine is 2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine (FDKP), having the structure: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    with or without a pharmaceutically acceptable carrier, or excipient. 
         [0066]    In one embodiment, the inhalation system comprises a breath-activated dry powder inhaler, a cartridge containing medicament, wherein the medicament can comprise a diketopiperazine and an active agent. In some embodiments, the active agent comprises peptides and proteins. In another embodiment, the inhalation system comprises a cartridge containing medicament wherein the peptide or protein can be an endocrine hormone, including, insulin, GLP-1, calcitonin, parathyroid hormone, parathyroid hormone related protein (PTHrP), and analogs thereof and the like. 
         [0067]    In another embodiment, the dry powder medicament may comprise a diketopiperazine and a pharmaceutically active ingredient. In this embodiment, the pharmaceutically active ingredient can be any type. In certain embodiments, the active ingredient comprises a peptide, a protein, a hormone, analogs thereof or combinations thereof, wherein the active ingredient is insulin, parathyroid hormone 1-34, glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide YY, interleukin 2-inducible tyrosine kinase, Bruton&#39;s tyrosine kinase (BTK), inositol-requiring kinase 1 (IRE1), heparin, or analogs thereof. In a particular embodiment, the pharmaceutical composition comprises fumaryl diketoperazine and insulin. 
         [0068]    In a particular embodiment, the dry powder inhalation system can comprise a cartridge including a formulation for pulmonary delivery comprising FDKP and a peptide including, for example, insulin or GLP-1, which can be provided for use in different dosage strength in a single or multiple cartridges. In one embodiment, the system can deliver the dosage efficiently, with consistency and in a linear manner. In this embodiment, for example, multiple cartridges of a single dose to be administered to a subject can be interchangeably replaced or substituted by a providing the system with a single cartridge having the sum of the dosage strength of the multiple cartridges. In further embodiment, the system can deliver a proportional, bioequivalent dose with a single cartridge. In an exemplary embodiment using the system for treating diabetes with inhalable insulin powders, the system can use two 15 U cartridges of an inhalation powder comprising insulin and FDKP or the system can use one 30 U single cartridge containing an inhalation powder comprising FDKP and deliver bioequivalent doses of insulin to a patient. Similarly, the system can be used to deliver higher doses, for example, three 15 U cartridges of an inhalation powder comprising insulin and FDKP can be used, or one 15 U cartridge plus one 30 U cartridge, or a single 45 U cartridge containing the inhalable insulin and FDKP formulation; or four 15 U cartridges of an insulin and FDKP formulation can be interchangeable with one 60 U cartridge of insulin and FDKP formulation. Alternatively, two 30 U cartridges containing an inhalable insulin and FDKP formulation can be interchanged for one 60 U cartridge of the insulin and FDKP formulation. 
         [0069]    In the embodiments described herein, the dry powder inhalation system accomplishes insulin exposure proportional to a dosage so that the dosages are interchangeable. In an embodiment, the dosage can be provided as filled dose. 
       EXAMPLES 
       [0070]    The following examples are included to demonstrate certain embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples elucidate representative techniques that function well in the practice of the present invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. 
       Example 1 
     Dosage Strength Interchangeability 
       [0071]    The study was conducted in subjects with type 1 diabetes mellitus. This study was conducted to determine if a formulation for pulmonary delivery comprising insulin and a diketopiperazine in the formulation, 1) could be delivered consistently using different dosage strengths and 2) if linearity of dosing could be achieved with proportional doses, given that interchangeability of dosage strengths can be important for patient safety. A prior art marketed inhaled insulin did not achieve this and dose combinations were nonequivalent leading to a potential risk of incorrect dosing. Therefore, an important goal in the development of the pulmonary delivery system with a formulation comprising insulin and FDKP (insulin-FDKP) was to achieve dose linearity across the therapeutic dose range. 
         [0072]    In the study, comparisons of insulin exposure following inhalation of two 15 U cartridges of an insulin inhalation powder to one 30 U cartridge of insulin inhalation powder were made. In addition, insulin bioavailability from a 30 U cartridge of insulin-FDKP inhalation powder was calculated, compared to a 10-IU subcutaneous (sc) injection of insulin lispro (rapid acting analogue [RAA]). 
         [0073]    A phase I, open-label, single-dose, repeat administration study in subjects with type 1 diabetes (T1DM) was conducted to assess the pharmacokinetic profile or PK of 30 U of insulin-FDKP dosed as a single 30 U cartridge and compared to two 15 U cartridges administered with the present inhalation system. A 10 U subcutaneous injection of the rapid acting insulin analogue (RAA, HUMALOG® (Eli Lilly and Company, Indianapolis, Ind.)) was also tested. Subjects (age: 19-61 yrs) were randomized to 1 of 6 sequences. Fasted subjects received insulin-FDKP or RAA 4 to 6 hrs after initiating a hyperinsulinemic-euglycemic clamp. Randomization determined the order of insulin-FDKP dosing (first 2 treatment (tx) visits), and the location of the RAA injection (abdomen, arm or leg; 3 rd  tx visit). After dosing blood samples were taken and analyzed for insulin, insulin lispro and fumaryl diketopiperazine (FDKP (insulin-FDKP tx only)). When studying insulin-FDKP, the basal insulin infusion was performed with HUMALOG®, and when studying HUMALOG®, regular human insulin was used. The analytical methodologies enabled the independent measurement of each insulin tested. 
         [0074]    Table 1 shows the results from the study. The mean insulin exposures (AUC 0-360 ) of a single 30 U cartridge or two 15 U cartridges were comparable. FDKP mean exposure (AUC inf ) was also similar. Insulin and FDKP exposure, t max  and t 1/2  (FDKP) were the same regardless of the number of cartridges. Due to the significantly different PK profiles of insulin-FDKP and RAA, the mean relative exposure (AUC) ratio is dependent upon the time interval studied. The mean relative insulin exposure (insulin-FDKP: HUMALOG® AUC, dose normalized geometric means) when assessed at time intervals of 0-180 min and 0-360 min was 24% to 18%. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
             
               
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 2 × 15 U TI 
                 1 × 30 U TI 
                   
               
               
                   
                 cartridges 
                 cartridge 
                 10 IU Humalog 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Insulin PK parameters 
                   
                   
                   
               
               
                 AUC 0-360  (μU * min/mL) 
                 3337 
                 3397 
                 5915 
               
               
                 AUC 0-180  (μU * min/mL) 
                 3121 
                 3199 
                 4432 
               
               
                 C max  (μU/mL) 
                 65.72 
                 69.08 
                 42.60 
               
               
                 t max  (min) 
                 10 
                 10 
                 60 
               
             
          
           
               
                 90% CI (Geometric Mean 
                 0.846, 1.141 
                 ND 
               
               
                 Ratio: AUC 0-360 ) 
               
               
                 FDKP PK parameters 
               
             
          
           
               
                 AUC 0-480  (ng * min/mL) 
                 19552 
                 20159 
                 — 
               
               
                 AUC 0-inf  (ng * min/mL) 
                 23146 
                 24355 
                 — 
               
               
                 C max  (ng/mL) 
                 118 
                 131 
                 — 
               
               
                 t max  (min) 
                 6 
                 5 
                 — 
               
             
          
           
               
                 90% CI (Geometric Mean 
                 0.867, 1.084 
                 — 
               
               
                 Ratio: AUC 0-480 ) 
               
               
                   
               
             
          
         
       
     
         [0075]    This study also evaluated the effects of the dosages administered and the glucose infusion rate (GIR) requirements of the patients in the study.  FIG. 19  illustrates the results of the GIR evaluation. The data show the mean baseline-corrected glucose infusion rate (GIR) for two 15 U cartridges and one 30 U cartridge of insulin-FDKP inhalation powder and for the 10 IU of RAA. GIRs after both treatments of insulin-FDKP inhalation powders reached a maximum level by approximately 30 minutes after administration, whereas GIR peaked approximately 150 minutes after administration of sc RAA. The GIRs for insulin-FDKP inhalation powder returned toward baseline by approximately 180 minutes versus 300 minutes for RAA. In conclusion, the glucose-lowering effect of insulin-FDKP inhalation powder of both dosage forms tested was comparable based on GIR AUC, GIR max , and GIRt max . 
       Example 2 
     Dry Powder Inhaler Resistance Value Measurements 
       [0076]    The total inhaler and cartridge resistance can be measured due to inlet and outlet ports of a cartridge acting as resistors in series. First, the resistance due to the inlet port is measured in the cartridge rig. The representation of a circuit diagram form for the cartridge rig is illustrated in  FIGS. 20A and 20B , wherein the cartridge sits in the holder in an open configuration and the circuitry is defined such that R 3  represents the resistance to airflow into the cartridge; R 4  represents the resistance to airflow leaving the cartridge; Pa is the pressure differential across the cartridge and P represents the pressure measured across the inlet and outlet ports. Secondly, the resistance due to the inhaler system comprising the inhaler and cartridge is determined as illustrated in  FIGS. 21A and 21B , wherein R 1  represents the resistance due to the float or valve; R 2  represents the resistance to air flow around the cartridge; R 3  represents the resistance to airflow through the cartridge; R 4  represents the resistance to airflow leaving the cartridge; P represents the measured pressure; Pa represents the pressure across the system and F represents the total flow measurement. Once values are determined for the resistors and having pressure drop measurements, the flow balance distribution through and around the cartridge can be determined. 
         [0077]    Measurements were made of the cartridge and cartridge/inhaler system dosing configuration and the resistance to airflow through the cartridge, R 3  was determined from the formula: 
         [0000]    
       
         
           
             
               R 
                
               
                   
               
                
               3 
             
             = 
             
               
                 P 
               
               F 
             
           
         
       
     
         [0078]    Based on the measurements made as illustrated in  FIGS. 20A-21B , the resistance due to the inlet and outlet ports were determined and the values used to calculate the flow balance of the system in particular the flow balance through the cartridge using the formula above, which is determined as the √P divided by R 3 . The flow balance distribution through the cartridge for the present inhaler and cartridge system was calculated to be in the range from about 10% to about 30% with an average of approximately 15.92%. 
         [0079]    The resistance for the inhaler cartridge system tested herewith can be determined experimentally from the values obtained in the same manner. The resistance for the present inhalers when calculated from the measurements resulted in airflow resistance values of between 0.08 and 0.15 √kPa/liters per minute.  FIG. 22  depicts a linear regression plot illustrating the resistance measured through an exemplary cartridge rig tested or R 3 , at flow rates between 2 and 9 liters/min. As shown in  FIG. 22 , the resistance through the cartridge (R 2 ) tested was determined as equaling to 0.999 √kPa/liters per minute. 
         [0080]    Therefore, the inhalers can be structurally configured to have tunable airflow resistance by varying the cross-sectional area at any section of the airflow pathway of the inhaler and cartridge system. 
         [0081]    The preceding disclosures are illustrative embodiments. It should be appreciated by those of skill in the art that the techniques disclosed herein elucidate representative techniques that function well in the practice of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. 
         [0082]    Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. 
         [0083]    The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. 
         [0084]    Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims. 
         [0085]    Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. 
         [0086]    Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety. 
         [0087]    Specific embodiments disclosed herein may be further limited in the claims using consisting of or and consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein. 
         [0088]    In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Technology Classification (CPC): 0