Dry powder aerosol generator

Dry powder aerosol generators and related methods are provided. The dry powder aerosol generator includes a dispersion chamber having an internal cavity therein capable of receiving a dry powdered drug. The dispersion chamber includes a dosing port defined therein that is in fluid communication with the internal cavity. A dosing chamber for receiving a test subject is attachable to the dosing port, such that, when an airflow is created within the internal cavity, any dry powdered drug contained therein may fluidize and travel into the dosing chamber to provide opportunity for inhalation of the dry powdered drug by a test subject contained within the dosing chamber.

TECHNICAL FIELD

The subject matter described herein relates to dry dose drug delivery systems and methods. More specifically, the present subject matter relates to a self-contained dry powder aerosol generator and methods of delivering drugs to the respiratory tracts of intended test subjects.

BACKGROUND

The delivery of drugs through dry powder aerosols to the respiratory tract of the intended patient or test subject is a common way to ensure the transfer of the drug into the system of the patient or test subject.

A variety of inhaler systems and methods exist for delivering dry powder to the respiratory tract of patients and/or test subjects. Metered dose inhalers deliver a metered dose of powdered drugs through inhalers that compress a canister or puncture a capsule. In such embodiments, the patient or test subject must inhale deeply in order to receive the required amount of dry powder to treat their ailment. In order for the patient or test subject to receive such dosage, the patient or test subject must make a conscious effort to inhale deeply at the appropriate moment in which the dry powder aerosol is ready to be delivered. However, for certain patients and test subjects, the ability to inhale deeply at the appropriate moment is not always controllable. For example, when delivering aerosols to certain test animals, a researcher cannot coax the animal or communicate with the animal being tested to make it inhale at the correct moment. Therefore, when testing animals with dry powder inhalation drugs, a low efficiency of deposition of the drug within the animal's respiratory tract often occurs. A similar problem occurs when trying to coax children to inhale at the proper moment.

When testing animals, direct insufflations may be used to deposit the drugs within the respiratory tract of the animal. However, this approach requires anesthesia and can cause untoward health problems in the animals and is not feasible for chronic treatment.

A variety of nebulizers and methods for using nebulizers have been employed to deliver drugs to the respiratory tracts of test subjects and patients. Such nebulizers do not require special breathing patterns. Nebulizers create a mist that is delivered in proximity to the mouth and nose of the patient or test subject. Nebulizers, however, require the use of a large amount of the drug in liquid form. The amount necessary to deliver an effective dosage to the patient or test subject is much larger than the amount deposited within the respiratory tract of the patient. A large majority of the drug being tested escapes into the surrounding environment. Therefore, much of the drug is wasted during a dosage session using a nebulizer. When testing drugs on small animals, the use of a nebulizer can waste large amounts of the drug being tested. These drugs are often times very expensive and time-consuming to make. Also, with experimental drugs, only small amounts of the drug may be available at any given time. Therefore, it is preferred that such nebulizing systems not be used for experimental drugs to conserve the drug for test purposes.

Therefore, a need exists for an improved delivery system of dry powdered aerosol drugs to test subjects that cannot consciously inhale deeply upon command to facilitate proper delivery of the drugs within the respiratory tract of the patient or test subject.

SUMMARY

According to certain aspects of the present subject matter, a dry powder aerosol generator is provided. The dry powder aerosol generator includes a dispersion chamber having sidewalls, a top and bottom. The dispersion chamber has an inner surface that defines an internal cavity within the chamber. The dispersion chamber also defines at least one dosing port in the sidewalls that is in communication with the internal cavity. The dry powder aerosol generator also includes a dosing chamber having a porthole end that is insertable in the at least one dosing port within the dispersion chamber. The dosing chamber defines an opening within the porthole end. The dry powder aerosol generator includes an impeller disposed within the internal cavity of the dispersion chamber. The impeller is capable of rotating at speeds that create an airflow that fluidizes a powdered drug introduced into the dispersion chamber. Further, the dry powder aerosol generator includes a controller in communication with the impeller for controlling the impeller.

According to another aspect of the present subject matter, a method for dosing an animal through the animal's respiratory tract is provided. The method includes providing a dry powder aerosol generator having a dispersion chamber with an internal cavity and at least one dosing port in communication with the internal cavity and at least one removable dosing chamber. The method also includes placing a test animal into the at least dosing chamber. The method also includes attaching the at least one dosing chamber to the at least one dosing port such that the at least one dosing chamber is in communication with the internal cavity. A dry powdered drug may be inserted into the internal cavity of the dispersion chamber. An airflow is created within the internal cavity of the dispersion chamber that fluidizes the dry powdered drug within the internal cavity so that the dry powdered drug migrates into the dosing chamber wherein the test animal may breathe in the dry powdered drug during its normal breathing process.

Some of the advantages of present subject matter have been stated hereinabove. Other advantages will become evident as the description proceeds when taken in connection with the accompanying drawings as best described herein below.

DETAILED DESCRIPTION

Reference will now be made in detail to presently preferred embodiments of the present subject matter, one or more examples of which are shown in the figures. Each example is provided to explain the subject matter and not as a limitation of the subject matter. In fact, features illustrated or described as part of one embodiment can be used in another embodiment to yield still another embodiment. It is intended that the present invention covers such modifications and variations.

FIG. 1illustrates a schematic view of a dry powder aerosol generator, generally designated as10. The dry powder aerosol generator10includes a dispersion chamber, generally designated as12, which has a top14, a bottom16and sidewalls18. Sidewalls18, top14, and bottom16define an internal cavity, generally designated as20. Dispersion chamber12can define dosing ports22that are in communication with internal cavity20. An impeller30may reside within internal cavity20of dispersion chamber12. Impeller30may reside near the bottom16of dispersion chamber12. Impeller30may be secured to a motor (not shown) that rotates impeller30in order to create an airflow within dispersion chamber12. Impeller30can have a plurality of blades32that can rotate around an axis34in order to create an airflow within dispersion chamber12. For example, two impeller blades can form an impeller. In other embodiments as shown inFIG. 1, three or more blades may be used to form impeller30. The size of impeller blades32are such that they may freely rotate within internal cavity20of dispersion chamber12. The impeller can be centered along an axis of internal cavity20. In such embodiments, the blades32may extend from axis34proximal to an inner surface24of dispersion chamber12which forms internal cavity20. In such embodiments, the airflow created within the internal cavity20is generated from across a major portion of bottom16of dispersion chamber12.

Impeller30may be rotated by a controller40which may include a motor (not shown) to which impeller30is attached. Controller40may permit a turning on and turning off of impeller30such that impeller30spins about axis34when the controller is at an ON position and comes to rest when the controller40is turned to an OFF position. Controller40may be a variable speed controller as shown inFIG. 1that permits impeller30to rotate at different speeds, thereby creating different airflows and airflow velocities within dispersion chamber12. For example, controller40may include a knob42which can be turned about a speed-setting dial44. As shown inFIG. 1, speed-setting dial44can include an OFF position46and variable speed positions48at which impeller30may be rotated. Alternatively, controller40can be an infinite speed control that allows for incremental adjustment in speeds. Different speeds may be used with different drugs depending on variables such as particle size, adhesiveness of the particles, the cohesiveness of the particles, and the like. Further, the type of animal to be tested may affect the speed at which the airflow is created. When a drug in powder form is introduced into dispersion chamber12, impeller30is rotated causing the drug in powder form to become airborne such that the drug is fluidized and may reach the ports in which individual animals can inhale the drug during their normal breathing states.

Such a dry powder aerosol generator10can be particularly useful for large porous particles that have a density that is conducive for being suspended within the dispersion chamber12of the dry powder aerosol generator10. Large porous particles have large geometric diameters, but due to their porosity and low density they have the mass and aerodynamic properties of much smaller particles. The large geometric diameter, however, reduces the interparticulate forces and the tendency of small particles to adhere to surfaces and to each other (aggregation). An example of such large porous particles is Dipalmitoylphosphatidylcholine (“DPPC”). DPPC is manufactured at Harvard University, located in Cambridge, Mass. DPPC can be mixed with drug compounds to form large porous particles that contain the drug compounds. Such large porous particles can be easily suspended in dispersion chamber12.

Dry powder aerosol generator10can also include dosing chambers50. Dosing chamber50may have an entrance end52and a porthole end54. The dosing chamber50may include an opening56within entrance end52and an opening58within porthole end54. The porthole end54of the dosing chamber50should fit snugly within dosing ports22within dispersion chamber12. For example, the porthole end54may be equipped such that, when dosing chamber50and its porthole end54are placed within dosing port22, an airtight seal may be created between porthole end54and the rim of dosing port22to prevent dry powdered drugs from escaping and external air from being introduced into the dispersion chamber12. Alternatively, the connection between a dosing port22and a porthole end54of a dosing chamber50may not be airtight.

In embodiments in which small animals such as guinea pigs, rats, mice, or the like are tested, the opening58within porthole end54may be sized such that the fluidized drug in powder form may enter the dosing chamber allowing for the animal within the dosing chamber to receive an effective amount of the drug through normal breathing. The dosing chamber50may have a tapered shape. In particular, the internal cavity within the dosing chamber50may be tapered. Thereby, opening56of entrance end52may have a larger cross-section than opening58of porthole end54. For example, dosing chamber50may have a truncated conical shape with entrance end52having a larger circular cross-section than porthole end54. The internal cavity of dosing chamber50may be long and have a small diameter sized to direct the animal's head toward opening58of porthole end54, while not providing enough room for the animal to move its head away from opening58of porthole end54.

To help minimize any loss of drug in powder form, dosing chamber50may include a stopper60that is designed to fit in and close off opening56within entrance end52. Stopper60may prevent the retreat of an animal being tested within dosing chamber50as well as prevent leakage of the powdered drug from the closed environment within dispersion chamber12and dosing chamber50. Stopper60may include a prod62which extends through stopper60to prod the animal to be tested toward opening58within porthole end54. Prod62may comprise a stem64and a head66. Stem64of prod62may extend through an aperture68within stopper60. The aperture68may be of a size that creates a frictional seal between the stem64and the stopper60that prevents, or at least minimizes, the loss of air and powdered drug from dosing chamber50through aperture68. Head66of prod62resides within dosing chamber50. Head66is firmly attached to stem64of prod62. Stem64may be moved back and forth such that head66of prod62may be moved likewise within dosing chamber50.

In use, an animal may be placed within dosing chamber50before the powdered drug is fluidized by impeller30within internal cavity20of dispersion chamber12. Once the animal is placed within the dosing chamber, stopper60may be placed within opening56of entrance end52with head66residing within dosing chamber50. Stem64of prod62may then be pushed forward to encourage the animal to move towards opening58of porthole end54so that when the controller40is turned on and impeller30rotates to fluidize the dry powdered drug, the animal will be in an optimal position to breathe the dry powdered drug into its respiratory tract.

As previously noted, dispersion chamber12includes inner surface24that defines internal cavity20. Dispersion chamber12may have a cylindrical inner surface24such that the internal cavity20is cylindrical in shape. Such embodiments are conducive to having impellers30which extend close to inner surface24, thereby creating an airflow from across the entire bottom16of dispersion chamber12. However, other shapes may be used for the internal cavity. For example, the internal cavity may have a hexagonal cross-section, an elliptical cross-section, a rectangular or square cross-section, and the like in which multiple impellers are used. Further, the internal cavity may have a nonsymmetrical cross-section as well. However, minimizing the number of corners created within the chamber may be preferred to decrease the areas where airflow is slowed and particles would preferentially accumulate. Similarly, multiple impellers30may be used to provide the airflow that creates the fluidization of the dry powdered drug. For example, in an internal cavity having an elliptical cross-section, two impellers30can be used.

Dispersion chamber12may be made of wood, plastic, metal or the like. For example, dispersion chambers made of metal can help to dissipate the charge of the particles, thus reducing particle adhesion to inner surface24of dispersion chamber12. The dispersion chamber can be made up of a composition of different materials. For example, the sidewalls may be comprised of metal while the top and bottom comprise a plastic material. Similarly, the dosing chambers50may be constructed of any material or combination of materials, such as wood, plastic or metal. For example, a clear plastic may be used to allow the researchers to monitor the animals during tests to ensure that they are in a proper position to permit breathing of the dry powdered drug during testing. The material used in the dispersion chambers and dosing chambers should provide a smooth surface either naturally or through proper treatment of the material to minimize the likelihood of the particles adhering to the surfaces within the chamber. In particular, inner surface24of dispersion chamber12may be smooth to minimize the attachment of drug particles to inner surface24of dispersion chamber12. For example, inner surface24of dispersion chamber12may be finished and polished to reduce the amount of powdered drug deposited on and adhering to inner surface24of dispersion chamber12.

Sidewalls18as discussed above may have at least one dosing port22. However, multiple ports may be defined within sidewalls18of dispersion chamber12. For example, three dosing ports24may be positioned along the sidewalls. In other embodiments, six ports may be positioned along the sidewalls of dispersion chamber12. If multiple dosing ports22are defined within sidewalls18of dispersion chamber12, then they may be placed at equal distance from one another. For example, if dispersion chamber12has a cylindrical outer surface, then three dosing ports22may be positioned at 120° from one another around the cylindrical sidewalls18. Similarly, if six ports are used around cylindrical sidewalls18, then the six dosing ports22may be positioned at 60° from one another around the sidewalls18.

Top14of dispersion chamber12may be a lid, generally designated as70, which is removable from dispersion chamber12. Lid70can permit the introduction of the dry powder into the internal cavity20of dispersion chamber12. Lid70may be lifted to allow the dry powdered drug to be poured in before impeller30is rotated. Lid70may be closed in order to keep dispersion chamber12self-contained and keep dry powder aerosol generator10as a relatively closed system. In some embodiments, the dry powdered drug may be introduced through other means such as a door, pluggable hole or the like.

The volume of the internal cavity20created by dispersion chamber12can be small and fixed. For example, the embodiment shown inFIG. 1having a cylindrical internal cavity can have a height of about 20 cm and an internal diameter of about 10 cm. However, smaller or larger chambers can be expected to work as well and can depend on the size and nature of the test subjects and the amount of dry powder drug to be dispersed. Therefore, the exact dimensions can vary. The size range of the dry powder aerosol generator10can be such that it should provide a large enough volume for adequate fluidization without being significantly effected by the walls of the dispersion chamber, but small enough that the concentration of particles is sufficiently high for adequate exposure.

The dosing ports22may be positioned adjacent to top14of dispersion chamber12. Such a construction can give high drug concentrations in small volumes with very little additional air added. When impellers30are rotated at sufficient speeds, a standing cloud is produced of the dry powdered drug which allows the fluidized drug to migrate toward the top and into the dosing chambers50. For example, in the embodiment shown, the centers of the ports are positioned about 5 cm from the top of dispersion chamber12. However, the location of the dosing ports along sidewalls18should be at the optimal level where the standing cloud of dry powder resides. Such location can be dependent on the volume size and volumetric shape of the internal cavity20, the type of powdered drug used, and the force of the airflow created by the impeller30.

In practice, if multiple dosing ports22are employed then one or multiple dosing chambers50may be used. If the total number of dosing chambers50used is less than the total number of dosing ports22, then the dosing ports can be closed by a suitable stopper (not shown) which can be inserted into the dosing ports22.

FIG. 2illustrates the dry powder aerosol generator, generally designated as10, shown inFIG. 1. Dry powder aerosol generator10includes a dispersion chamber, generally designated as12, having sidewalls18, a top14and bottom16to define an internal cavity, generally designated as20. The dispersion chamber12may have a cylindrical inner surface24which forms the internal cavity20. An impeller30may be disposed within internal cavity20. Impeller30may be controlled by a controller40. Controller40may be a variable speed controller which allows an operator to control the rotation of impeller30through a control panel44.

At least one dosing port22may be defined within sidewalls18of dispersion chamber12such that each dosing port22is in communication with internal cavity20of dispersion chamber12. Dosing chamber50as described above may engage dosing port22such that a porthole end54of dosing chamber50is securable within dosing port22.

As shown inFIG. 2, a test animal TA may be placed within an entrance end52of dosing chamber50. Opening56of entrance end52may then be closed by a stopper60which has a prod62extending therethrough. The head portion66of prod62may be attached to a stem portion64that extends through stopper60. The stem portion64may be pushed forward such that head portion66of prod62encourages the animal TA within dosing chamber50toward opening58of porthole end54of dosing chamber50. A lid, generally designated as70, which forms the top14of dispersion chamber12may be lifted to add a dry powdered drug into internal cavity20of dispersion chamber12before impeller30is turned on. Lid70may be placed back on dispersion chamber12. Lid70can form an airtight seal to prevent escape of air and drug from internal cavity20. However, in some embodiments, lid70may not form an airtight seal. Similarly, stopper60can form an airtight seal with dosing chamber50to prevent air and drug from escaping the closed system of dry powder aerosol generator10. Again, in some embodiments, however, stopper60may not form an airtight seal.

Once knob42of speed-setting panel44of controller40is turned to a speed setting48, impeller30begins to rotate thereby creating an airflow within internal cavity20. This airflow lifts the particles of the dry powdered drug in dispersion chamber12to create a standing cloud within internal cavity20of dispersion chamber12. Portions of the standing cloud migrate into dosing chamber50such that test animal TA can inhale the dry powdered drug into its respiratory tract during its normal breathing functions.

In order to keep the particles of the dry powdered drug circulating to maximize the amount of dry powdered drug within the standing cloud in the airflow created by impeller30, strategic jets of air may be directed into internal cavity20of the dispersion chamber12so as to remove adhered powder from the inner surface24of dispersion chamber12. These particles of the dry powdered drug are thereby re-circulated back into the airflow created by impeller30. Such jets of air may come from a directable air supply, generally designated as80. For example, the directable air supply80may be a canister82of compressed air having a long-nosed nozzle84which can be inserted into a nozzle port86. Nozzle port86can be formed in sidewalls18and may have a diameter large enough to allow nozzle84of canister82to be directed in different directions within internal cavity20to allow short discrete jets of compressed air to be directed along sidewalls18, the bottom16and lid70of dispersion chamber12. Further, nozzle port86can be a size that minimizes loss of air and dry powdered drug therethrough when the nozzle84of the canister82is placed through the nozzle port86.

In the embodiment shown inFIG. 2, nozzle port86may be disposed within a stopper23used to seal a dosing port22within sidewalls18. Further, nozzle port86may be a stand-alone port that may be filled with a stopper when not in use. Multiple nozzle ports86may be placed around dispersion chamber12at different locations including the top14, or lid70, as well as along the expanse of the sidewalls18. Further, nozzle ports86may also be placed along the bottom16of dispersion chamber12.

Instead of using a nozzle port86, a regular dosing port22which does not have a dosing chamber secured therein may be used to insert nozzle84of the canister82to supply the short and discrete jets of compressed air within internal cavity20. The stopper, which may be placed within dosing port22, can be removed during the time that nozzle84is inserted in dosing port22. After the release of the short and discrete jets of compressed air, nozzle84can be removed and the stopper placed back in dosing port22. In such embodiments, the stoppers within dosing port22help minimize the loss of air and powder from the internal cavity22. However, when the nozzle is inserted to supply short and discrete jets of compressed air some air and dry powdered drug may escape from internal cavity20of dispersion chamber12.

Canister82can be a commercial office-type compressed air canister that may be bought off the shelf at office supply stores. For example, the canister may be a canister of compressed air sold under the trademark DUST-OFF® and manufactured by Falcon Safety Products, Inc. of Branchburg, N.J.

The short and discrete jets of compressed air can introduce approximately 8 c.c. of air at a high linear velocity that easily detaches most of the adhered dry powdered drug from inner surface24within internal cavity20. Such small introduction of air can change the pressure within dispersion chamber12if enough short, discrete jets are provided during the testing. However, in the embodiment shown inFIG. 2, nozzle port86can be such a size that it allows air to escape dispersion chamber12. If such nozzle ports86are used, or when a dosing port22is used to insert nozzle84of canister82, enough air escapes to equalize the pressure within dispersion chamber12. Further, dispersion chamber12may not be absolutely airtight, allowing for the pressure within dispersion chamber12to remain at atmospheric pressure. In embodiments where nozzle ports86and dispersion chamber12are airtight, a pressure equalization valve may be used to equalize the pressure in the dispersion chamber12to the atmospheric pressure surrounding chamber12.

FIGS. 3 and 4illustrate a further embodiment of a dry powder aerosol generator, generally designated as110. Dry powder aerosol generator110includes a dispersion chamber, generally designated as112, having a top114, a bottom116and sidewalls118which define an internal cavity, generally designated as120. Dosing ports122may be defined within sidewalls118such that dosing ports122are in communication with the internal cavity120. An impeller130may be disposed within internal cavity120of dispersion chamber112. Impeller130can be controlled by a controller140. Controller140may be a variable speed controller as described above.

Dosing chambers, generally designated as150, may be provided which are insertable into the plurality of dosing ports122. Dosing chambers150provide a portion of the closed system in which an animal may be placed to be tested. The number of dosing chambers150may correspond to the number of dosing ports122disposed along sidewalls118of dispersion chamber112. Dosing chamber150may include a porthole end154and an entrance end152. Entrance end152may provide an opening in which to place an animal to be tested. Porthole end154may include an opening158that provides access to internal cavity120of dispersion chamber112once porthole end154of a dosing chamber150is placed within a dosing port122. An airtight seal may be formed between dosing port122and porthole end154of dosing chamber150. A stopper160may be placed within opening156of the entrance end152once an animal is placed within dosing chamber150. Stopper160may include a prod162having a stem portion164and a head portion166, which is used to prod the animal toward opening158of porthole end150of dosing chamber150. The top114may be a lid, generally designated as170, which can be lifted to allow introduction of the dry powdered drug into the internal chamber120of dispersion chamber112. Impeller130may then be rotated at a speed that produces an airflow that suspends the dry powdered drug in a cloud which may migrate through dosing ports122and opening158of dosing chamber150to allow the test animal (not shown) disposed within dosing chamber150to receive the dry powdered drug into its respiratory tract through its normal breathing process.

The dry powder aerosol generator110may also include an air supply system, generally designated as180, used to help keep dry powdered drug off the inner surface125of dispersion chamber112. Air supply system180may include a compressed air source182and an air supply controller, generally designated as184. The air supply controller may include a regulator186and a switch mechanism188which may direct air to different air lines192,194,196, and198. Switch mechanism188can include a plurality of buttons190with each button190controlling the flow of air through one of the air lines192,194,196, and198, respectively.

The dispersion chamber112may have at least one jet port defined within dispersion chamber112. One or more jet ports200,202,204,206can be defined within sidewalls118of dispersion chamber112. These jet ports200,202,204,206can be tangential to the circumference of inner surface124of dispersion chamber112to create an airflow around inner surface124of dispersion chamber112to blow off and re-suspend dry powdered drug that has been deposited on sidewalls118.

As shown inFIG. 3, jet ports200,202,204,206can be placed at different heights along sidewalls118. For example, jet port200can be at a height H1as measured from the bottom116of dispersion chamber112, while jet port206may be at a height H2that is less than height H1as measured from the bottom116of dispersion chamber112. By providing multiple jet ports200,202,204,206within sidewalls118that are located at different heights along sidewalls118, short discrete jets of air may be supplied through air supply system180that blow off and re-suspend dry powdered drug that is deposited at different locations on inner surface124of dispersion chamber112. These short, discrete jets along different heights and positions of sidewalls118thereby ensure that most of the dry powdered drug that has been deposited on inner surface124of dispersion chamber112is re-suspended within the airflow created by impeller130. Summarily, in the embodiment shown inFIG. 3, lines192,194,196, and198are attached to jet ports200,202,204,206, respectively. Each jet port200,202,204,206is at a different height of dispersion chamber112and at a different position around inner surface124of dispersion chamber112. The different heights and different positions at which jet ports can be defined in sidewalls118can be determined to optimize removal and re-suspension of dry powdered drug into the airflow created by impeller130.

Switch mechanism188controls the supply of air through the respective air lines192,194,196, and198to provide short, discrete jets of air to dispersion chamber112through the respective jet ports200,202,204,206. Switch mechanism188can be controlled manually through buttons190. In some embodiments, switch mechanism188can be controlled through an automated process using a suitable computer, mini-computer, programmable logic controller, internal hardware or software or the like as a matter of design choice.

FIG. 4illustrates an airflow pathway created by jet port200that is defined within dispersion chamber112through outer surface125and through inner surface124such that the jet port200is tangential to inner surface124. Inner surface124has a cylindrical shape and jet port200is tangential to the circular cross-section of inner surface124along a plane in which jet port200resides. Therefore, when an air line192supplies a jet of air through jet port200, air flow travels in a direction of arrows A shown inFIG. 4. Further, as the jet of air expands after exit from jet port200, a greater surface area around inner surface124may be affected by the air, thereby re-suspending more dry powdered drug deposited therealong. The expansion of the jets of air along inner surface124can be taken into consideration when determining the optimum number of jet ports for sidewalls118and the optimum placement of the jet ports.

A screen210(seeFIG. 3) may also be provided within internal cavity120of dispersion chamber112. Screen210may be placed across the diameter of inner surface124and above impeller130. Screen210can be made of a fine mesh or tight woven fabric which minimizes the amount of dry powdered drug that falls below impeller130. Screen210can be constructed such that it prevents large particle powders having aerodynamic diameters in the micron range from passing through screen210. At the same time, screen210allows an airflow generated from impellers130to pass through screen210to suspend the dry powder particles in a cloud that can enter dosing chamber150in which test animals reside. A screen size of approximately 100 micrometers may suffice.

FIG. 5illustrates a further embodiment of a dry powder aerosol generator, generally designated as310, similar to the embodiment shown inFIGS. 3 and 4. Dry powder aerosol generator310as described above can include a dispersion chamber, generally designated as312, having a top314, a bottom316and sidewalls318forming an internal cavity, generally designated as320. As described above, the top314may be a lid, generally designated as315, that allows introduction of the dry powdered drug into internal cavity320of dispersion chamber312. Sidewalls318of dispersion chamber312can define a plurality of dosing ports322. Impeller330may be controlled by controller340so that impeller330creates an airflow within dispersion chamber312to suspend the dry powdered drug. Dosing chambers350having an entrance end352and a porthole end354that define an opening356and an opening358, respectively, provide passages in which to place animals to be tested. Porthole end354of a dosing chamber350with its opening358may be secured within a dosing port322defined within sidewalls318to allow a fluidized dry powdered drug to enter dosing chamber350and permit the test animal disposed therein (not shown) to receive the dry powdered drug within its respiratory tract through its normal breathing process. As described above, a stopper360may be provided for closing off opening356of entrance end352. Stopper360can include a prod362for positioning the test animal near opening358of porthole end354and dosing port322.

A support beam370(seeFIG. 5) may be provided proximal to each dosing port322defined within sidewalls318. Each support beam370is provided to help hold a corresponding dosing chamber350in its appropriate position within its corresponding dosing port322. Support beams370allow larger animals to be placed in dosing chambers350. Support beams370can provide the necessary support to hold corresponding dosing chambers350in the appropriate position for receiving the fluidized dry powdered drug to permit the dosing of the test animal contained therein.

Dry powder aerosol generator310may include an air supply system, generally designated as380, that includes a compressed air source382and air supply controller, generally designated as384. Air supply controller384may be configured in a similar manner as described above, with a regulator386and a switch mechanism388. Further, the regulator386and the switch mechanism388can be a single solitary controller384used to control the supply of air to dispersion chamber312. Switch mechanism388can be automated using a suitable computer, mini-computer, programmable logic controller, internal hardware or software, or the like as a matter of design choice. Such a switch mechanism can direct jets of air to different jet ports defined within dispersion chamber312at different times and at different intervals. For example, each jet port may be provided with a 0.1 second jet of compressed air at 30 p.s.i. at staggered intervals of 15 seconds.

In the embodiment shown inFIG. 5, dispersion chamber312includes a jet port400disposed at a center point within lid315. Further, a jet port402can be defined in sidewalls318such that jet port402is tangential to the circumferential cross-section of the inner surface of dispersion chamber312. Further, a jet port404can be defined within sidewalls318which directs air toward impeller330thereby helping to prevent buildup of dry powder particles on impeller330as well as underneath impeller330on the bottom of dispersion chamber312.

Air jets supplied by the air supply system380may be sent through the different jet ports400,402, and404. Airlines392,394, and396, from air supply system380provide the jets of air through jet ports400,402, and404into internal cavity320. Airline392is secured to jet port400within the center of lid315and can provide an air blast forcing the cloud downward towards dosing chambers350contained within dosing ports322. Alternatively, as shown inFIG. 5, airline392may have a portion398(shown in dotted line) that extends through jet port400and into internal cavity320. The portion398can undulate when the air is sent through air line392. This undulation can cause the jet of air to be randomly directed in different directions. Further, the portion398can be rigid and be directed at a specific location in internal cavity320.

Airline394supplies air to jet port402that provides jets of air within the internal cavity320as described in relation toFIGS. 3 and 4. Airline396provides jets of air to jet port404, which directs the jets of air downward towards impeller330in the bottom316of dispersion chamber312. Air supply controller384can selectively supply air to different jet ports at different times by providing short, discrete jets to facilitate and maintain the dry powdered drug within the airflow created by impeller330. In an airtight closed system, the pressure within internal chamber320may be maintained at atmospheric pressure through a pressure equalization valve408. Pressure equalization valve408can be secured to dispersion chamber312to allow the release of pressure that builds up due to the insertion of pressure through the air jets from air supply system380. Pressure equalization valve408, for example, may be located in the lid to allow the pressure to be equalized between the surrounding pressure outside dispersion chamber312and the pressure within dispersion chamber312.

In Vitro Testing

An embodiment similar to those illustrated inFIGS. 1 and 2was tested to determine the delivery efficiency of the dry powdered aerosol generator for large porous particles. As shown inFIG. 6, a liquid impinger LI with tubing TB connected to a dosing port22of a dispersion chamber12of dry powder aerosol generator10was used to determine the amount of dry powdered particles P that were being received within a dosing chamber. Liquid impingers are commonly known particle collection devices in the art and will not be explained further in detail. Liquid impinger LI includes a vacuum V which operated at 2500 ml/min. as shown inFIG. 6. Compressed air from a canister82having a nozzle84was introduced through another dosing port22in short, discrete jets at regular intervals. The compressed air was used to remove dry particles P from the inner surface of dispersion chamber12and to re-suspend the particles P in the airflow created by impeller30during testing. The liquid impinger LI would catch particles P that pass through the dosing port to which it was connected and travel down the tubing TB and into the liquid L in the liquid impinger LI. The amount of particles P contained within the liquid L after testing was then measured.

Large porous particles containing capreomycin or capreomycin large porous particles (“CLPP”) were tested using the liquid impinger LI. The CLPP was introduced into the chamber12. Impeller30created a fluidization of the dry powdered drug. Short discrete jets of compressed air of approximately 8 c.c. were introduced every 15 seconds while suspending the CLPP over a 6 minute period. The amount of CLPP captured on the liquid of the liquid impinger was then measured. The test results showed a delivery efficiency of approximately of 8%, i.e., 8% of the drug loaded into chamber was recovered from the liquid in the liquid impinger.

To determine how well a dry powder aerosol generator similar to those depicted inFIGS. 1 and 2disperses particles, experiments were set up to characterize particles P that are delivered to the animal ports. Tubing TB was introduced into a dosing port of a chamber12of a dry powder aerosol generator, generally designated as10, as shown inFIG. 7and strictly maintained in the dosing port. Tubing TB was connected to a measuring zone compartment MZ which was intersected by the laser of a MALVERN sizer, manufactured by Malvern Instruments, Ltd., located in Worcestershire, United Kingdom. On the other side of the measuring zone compartment MZ, the tubing TB was continue through a liquid impinger and connected to a pump which drew air at approximately 30 liters per minute. The other dosing ports were closed off.

The first large particles tested were made from leucine and DPPC manufactured at Harvard University, located in Cambridge, Mass. These large particles have aerodynamic diameters in the micron range but smaller cohesive properties due to the increased size. Dispersion was assessed quantitatively.

Twenty milligrams of DPPC particles were loaded into the chamber, and the impeller was rotated. Measurements of dispersion were taken for several particles. Resulting particle diffraction data is shown inFIG. 8. The dark diamonds show an accumulative geometric particle size distribution of luceine: DPPC large pore particles sampled from the animal ports after suspension inside the dry powder aerosol generator10. The light square points illustrate interval geometric particle size distribution.FIG. 8shows that the dry powder aerosol generator successfully suspended particles and made them available for inhalation to the animals. As shown inFIG. 8, the dry powder aerosol generator fluidizes and disperses the particles sufficiently so that particles are delivered into the ports and are available for inhalation by the resident animal.

In Vivo Testing

Once a dispersability testing was conducted and delivery efficiency was determined using a liquid impinger, in vivo experiments were conducted to assess the actual amount deposited in the lung of an animal. The tests were performed in a dry powder aerosol generator similar to those described inFIGS. 1 and 2. Two healthy animals, in the form of guinea pigs, were prepared for pharmacokinetics studies. The guinea pigs were placed in the dry powdered dosing chamber, as shown inFIG. 2, and dosed with dispersed capreomycin (“CLPP”). About 30 mg of CLPP were loaded into the chamber every four minutes for 32 minutes for a total of about 240 mg. It was estimated that each guinea pig inhaled about 10 mg of the CLPP based on tidal volume, length of exposure, and a delivery efficiency of approximately 8%. Particles dispersion was aided by compressed air as described above in the In vitro testing.

After dosing, blood samples were collected for predetermined periods of time (PK Studies). The plasma was separated from the blood and analyzed for CLPP concentrations by high performance liquid chromatography (“HPLC”). Capreomycin plasma concentrations versus time curves for these two guinea pigs are shown inFIG. 9. Capreomycin plasma concentration curves of animals receiving aerosolize particles were different from each other. For Animal 1 (“Aero 1”) plasma concentrations were between approximately 5 μg/ml of plasma and about 0.5 μg/ml of the plasma over a 4 hour period. In contrast, the plasma concentration versus time curves for Animal 2 (“Aero 2”) produced a capreomycin level between about 1 μg/ml of plasma and about 0.5 μg/ml of plasma over a 5 hour period. Exposure, measured as areas of the plasma concentration-time curve (“AUC”), was calculated by nonlinear methods for Aero 1 and Aero 2 and the fraction delivered by the aerosol was calculated. This delivery fraction equaled about 34.7% and 13.8% for Aero 1 and Aero 2, respectively.

In order to calculate the actual dose delivery to each animal, the following equation was employed:

Where F is the absolute bioavailability, AUCLUNGand DLUNGare the area under the curve and dose, respectively, for drug administration through the lung. AUCIVand DIVare areas under the curve and dose, respectively, of drug administered intravenously. From internal PK Studies performed, it is known that F equals 0.54 for capreomycin particles administered through the lungs, AUCIVequals 48.47 μgh/ml, and DIVequals 20 mg/kg.

Dosage received depends on the body weight of the animal being tested as well. This is shown through the equation provided below:
Dosage received=(GPbody weight)(DLUNG)  EQ (2)

Body weights of Aero1 and Aero2 guinea pigs were 606 g and 750 g, respectively. Thus, the actual dose received by Aero1 was 2.74 mg and by Aero 2 was 1.33 mg. Finally, the efficiency of the delivery expressed as a fraction of the dosage received was calculated by the following equation:
% Efficiency of delivery=[(dose received)+(dose delivered)]×100  EQ (3)

If the total dose loaded into the chamber was 100 mg of capreomycin particles for three animals, the percent of efficiency of delivery of Aero 1 was approximately 8.22% and for Aero 2 was 3.99%.

The embodiments of the present disclosure shown in the drawings and described above are exemplary of numerous embodiments that can be made within the scope of the appending claims. It is contemplated that the configurations of the dry powdered aerosol generator and the methods of making a dry powdered aerosol comprising numerous configurations other than those specifically disclosed. Thus, it is applicants' intention that the scope of the patent issuing herefrom will only be limited by the scope of the appending claims.