Abstract:
A new dry powder inhaler is developed as a pulmonary medicine delivery device for dispersing precise tiny dosages (10 μg-50 mg) of pure carrier-free ultra-fine powdered medicament (&lt;5 μm aerodynamics particle size) into a patient&#39;s lung. The powder is drawn from the blister cell and dispersed through an outlet tube assisted by two air streams. The first air stream goes through a the blister cell from its upstream side, to significantly fluidize the medicament in the dose to flow upward. The second one extracts the fluidized powder from downstream of the blister cell for further deagglomeration and dispersion of the medicament powder by shear force. The rotating multi-dose blister can hold up to 60 doses, which are pre-metered with pure ultra-fine powdered medicament. So that it has higher drug loading capability in small volumes, compared to most current dry powder inhalers, which usually use some excipient. The inhaler efficiently disperse the aerosolized medicament in the air stream to the deep interior of patient&#39;s lung. The fine particle fraction (&lt;4.7 μm) is reported to reach as high as 80% using this inhaler.

Description:
FIELD OF THE INVENTION  
       [0001]     The present invention relates to a method and device delivering fine dry powders, and more particularly the present invention relates to a method and device for pulmonary drug delivery.  
       BACKGROUND OF THE INVENTION  
       [0002]     Pulmonary drug delivery represents a new drug administration method that provides many advantages. It provides direct and fast topical treatments for respiratory and lung diseases. It avoids the first-pass GI (gastrointestinal) metabolism and can provide targeted delivery to heart and brain. Large molecules such as peptides and proteins can be systemically delivered using the pulmonary channel. Pulmonary drug delivery also allows the use of drugs with low solubility. Most peptide and protein drugs are far more stable in the solid rather than liquid state. Antibiotics and even vaccines can be delivered in this manner. Compared to oral in-take, it provides a fast and much more efficient adsorption. Typically, only a few percent of the medication of the oral in-take is required for pulmonary delivery due to that many drugs degrade in the digestive tract before they are absorbed. Compared to intravenous injection, it provides a painless and safer alternative.  
         [0003]     Numerous methods can be employed to generate drug aerosols in therapeutically useful size ranges and concentrations [A. J. Hickey, Inhalation Aerosols: Physical and Biological Basis for Therapy, New York, 1996]. Specifically, these are metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers, that can achieve minimally acceptable characteristics in simple, convenient, inexpensive, and portable format.  
         [0004]     Nebulizers such as jet nebulizers or ultrasonic nebulizers are used for the delivery of aqueous pharmaceuticals and are generally large in design and complex to operate, so that they are more for clinical use. The precision of the dose administered to the patient is highly dependent on a variety of factors such as atmospheric temperature and humidity, as well as the volume and strength of the patient&#39;s breathing. Metered Dose Inhalers (MDI) suspends or dissolves the ultra-fine drug powders into liquid propellants and stores them. When a metered quantity of the propellant is released from the storage canister, the propellant evaporates and expands quickly to disperse the powdered drug or liquid droplet drug into the patients&#39; mouth. The propellant can be a chlorofluorocarbon, a hydrochlorofluorocarbon, or a hydrocarbon, some of which are unfavourable due to environmental concerns. The another key problem with this method is that the quick expansion of the propellant causes the drug to impact in the back of the throat, reducing the amount being inhaled into the lung to about 20-30% [Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Product, U.S. Department of Health and Human Services, 1998]. More recent developments with improvement in design, such as the new SoftMist inhaler, has claimed a high FPF (fraction of fine particles), which suggests a higher lung deposition rate [M. W. Spallek, J. Geser, H. Reincke, and A. Moser, Scale-up and production challenges of bringing Respimat SoftMist inhaler (SMI) to market,  Respiratory Drug Delivery IX,  2004, and R. Dalby, M. W. Spallek, and T. Voshaar, A review of development of Respimat SoftMist Inhaler,  Int. J. Pharmaceutics,  2003]. In general, however, the MDI method needs good breath coordination and it is difficult to predict the amount of drug inhaled if the patients&#39; inhalation does not coincide with the drug releasing.  
         [0005]     Dry powder inhaler (DPI) is similar to a metered dose inhaler in that it also delivers a precisely measured dose medicine into the lungs, but in dry powder form. It is designed to generate a drug powder aerosol onto or via the inspiratory air flow. It has been proved that powder aerosols can carry approximately five times more drug in a single breath than metered dose inhaler (MDI) systems and many more times than liquid or nebulizer systems.  
         [0006]     To facilitate pulmonary delivery, drug powders should normally be less than 5 μm (or equivalent aerodynamic diameter) so that they become airborne during inhalation. However, powders of such small sizes (typical group C powder in the Geldart classification) [D. Geldart, Types of Gas Fluidization,  Powder Technology , Vol. 7, 285-297, 1973] have very strong inter-particle forces that make them agglomerate and very difficult to handle. The agglomeration of powder is normally formed prior to delivery due to the inter-particle forces, and possible moisture absorption. Agglomerated drug powders become difficult to dispense completely from the doses, and/or, is dispensed at least partially as larger agglomerates, thereby significantly reducing the lung deposition efficiency.  
         [0007]     To overcome the inter-particle forces, current industrial practice applies two different methods; one is the suspension of the powder into liquid in Metered Dose Inhalers (MDIs) as described above, and the other involves mixing the ultra-fine drug powders with large amounts of coarser powder. This method uses a large quantity of excipient (filler) particles that are much larger (normally group A or group A-C powders in the Geldart classification). This makes the small-large powder mixture fluidize easily so that they can be handled easily. It also significantly increases the volume of each dosage so that the dispensing and packing becomes more accurate relatively. This is practiced for most dry powder inhaler (DPI) currently on the market. However, only a small fraction of the small drug particles can detach effectively from the large excipient particles during inhalation and the rest stay with the large particles and land in the mouth. This limits the efficiency of final delivery for DPIs to about 6-14%. [I. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today,  Pulmonary Pharmacology  &amp;  Therapeutics  16, 79-95, 2003].  
         [0008]     The current designs of dry powder inhalers (DPIs) can be divided into two types, the pre-metered and the device-metered ones [Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Product, U.S. Department of Health and Human Services, 1998] both of which can be driven by patient inspiration alone (Passive dry powder inhaler) or with some power-assistance (Active dry powder inhaler) [Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Product, U.S. Department of Health and Human Services, 1998] Pre-metered DPIs contain previously measured doses in single or multiple presentations in blisters, capsules, or other cavities that are subsequently inserted into the device during manufacture or by the patient before use. Thereafter, the dose may be inhaled directly from the unit or it may be transferred to a chamber before being inhaled by the patient. Device-metered DPIs have an internal reservoir containing sufficient formulation for multiple doses being metered by the device itself during actuation by the patient.  
         [0009]     Passive dry powder inhalers rely on the aspiratory flow as the sole source of energy for powder fluidization, deagglomeration and inhalation. A number of such inhalers have been developed. These include the Ultrahaler (Aventis), the Clichhaler (Asmabec), Turbuhaler (Astra), and Diskus (GlaxoSmithKline) [I. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today,  Pulmonary Pharmacology  &amp;  Therapeutics  16, 79-95, 2003 and C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998].  
         [0010]     The AstraZeneca Turbulhaler is a multiple dose inhaler with 50, 100 or 200 doses of active drug stored in a reservoir [U.S. Pat. No. 6,257,732, U.S. Pat. No. 6,325,061,1. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today,  Pulmonary Pharmacology  &amp;  Therapeutics  16, 79-95, 2003 and C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998]. The drug is metered into small doses by scrapers inside the inhaler. Air enters the inhaler and passes through the dosing unit, fluidizing the powder by shear force. The turbulence in the narrow inhalation channel, the impaction on the bottom of the mouthpiece, and high shear stress in the swirl nozzle of the mouthpiece help the particle deagglomateration. In this inhaler, it includes two metering and inhalation processes. It is unique in dispensing minute quantity of drug powders without the use of an added carrier.  
         [0011]     The Diskus [I. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today,  Pulmonary Pharmacology  &amp;  Therapeutics  16, 79-95, 2003 and C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998] is a blister pack, unit-dose device. The pack consists of a coiled, double-foil strip of 60 blisters, each containing one dose of drug powder with a lactose carrier. The drug can be in the 50-500 μg range. During inhalation, each blister is moved into place, and its lid-foil is peeled away by a contracting wheel. The inhaled air is drawn through the opened blister, aerosolizing and delivering the dose through the mouthpiece.  
         [0012]     Clickhaler [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998] consists of a metering cone, bulk drug reservoir, and compression spring. It holds 100 or 200 doses of drug. Only one metered dose is present in the inhalation passage at any one time. The inhaler should be held approximately upright during priming and inhalation, and a rapid and deep inhalation is needed for optimal dose delivery.  
         [0013]     Active dry powder inhalers have an additional source of energy than that provided by inhalation to fluidize and disperse the powder. The Nektar Pulmonary Inhaler [U.S. Pat. No. 6,089,228] is a gas-assisted dry powder inhaler. It comprises a relatively large transparent holding chamber with a powder inlet at one end of the feed chamber. The powder inlet has a receptacle where a foiled dosage containing the medicament can be penetrated and a pressurization cylinder providing high pressure air stream extract the powdered medicament from the receptacle to the chamber and disperse in flowing compressed gas to form an aerosol. It is claimed that this kind of inhaler provides an efficient pulmonary delivery of accurate, precise, and repeatable dosages of powdered medicaments. A patient pulls a hand pump to compress a small charge of air, inserts a packet of drug powder into the slot, then presses the firing button to disperse the powder into an aerosol cloud The inhaler generates the aerosol independently of patient inspiratory flow rate, and it is Ideal for large and small molecules with 2-5 mg doses.  
         [0014]     The SPIROS™ (Dura) has a breath activated, motor driven impeller which provides electromechanical energy to disperse the powder [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998]. The Prohaler™ (Valois) is a multi-dose powder inhaler where a built-in pump gives compressed air to facilitate dose metering and powder dispersion [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998].  
         [0015]     The additional energy input decreases or eliminates the dependence of the aerosolization process on the patient&#39;s breathing ability, increases the fine particle fraction in aerosol flow and ensures effective powder dispersion [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols,  KONA,  16, 7-45, 1998]. However, these kinds of inhalers can be big and heavy, are not very convenient for patient use, and also its cost can be much higher than desired. Additionally, breath coordination becomes very important for the active DPIs in most cases, as patient inhalation and aerosolization needs to be synchronized.  
         [0016]     Currently, the most popular formulation of powder for DPIs consists of the drug that is usually blended with a carrier (lactose or glucose) to facilitate flow and dispersion. The suitability of a carrier is dependent on its chemical and physical characteristics, which can have direct effect on the performance of the product such as ease of entrainment of the formulation, energy input necessary for dispersion and aerosolization of the active ingredient from the carrier. It would be ideal if the required small quantity of the fine drug powder could be accurately dispensed alone, without any carrier/incipient. When only the pure drug powder is packaged into the inhaler, if the particle aggregates can be dispersed into primary particles (&lt;5 μm), the delivery efficiency is expected to increase significantly. Considering that many drugs are quite expensive, typically being many times more costly than conventional drugs, it is very critical to be able to efficiently deliver the dry powders to the target region of the lung with minimal loss of the drug.  
         [0017]     There are various types of inhalers for delivering a dry powdered medicament. For example, U.S. Pat. No. 6,116,239 discloses an inhalation device for use in delivering a powdered substance to a user. It comprises a holding portion for holding the powder substance, an air entry passageway having an inlet port open to an exterior of the device to direct air entering it and to fluidize the medicament upon inhalation by the user. A hold-up chamber is for holding the fluidized medicament and maintaining the substance in a fluidized state, then to deliver them to the user through an air exit passageway. The hold-up chamber is cylindrically shaped and has a longitudinally extending axis around which air is inhaled. The powder substance is claimed to be effectively deaggregated almost immediately upon inhalation and form a relatively uniform concentration of powder.  
         [0018]     U.S. Pat. No. 5,975,076 discloses a dry powder inhaler which comprises a reservoir of medicament powder, a dispensing chamber for receiving a charge of powder to be dispensed, an air passage having an inlet terminating at a nozzle directed downwardly into the dispensing chamber. Air is drawn in through the inlet to enter the dispensing chamber as a jet through the nozzle in a direction which is both downwardly onto the medicament and laterally across the chamber with respect to the mouthpiece.  
         [0019]     U.S. Pat. No. 5,921,237 describes a drug powder inhaler including a cover plate pivotally attached to a lid on the inhaler housing. A blister pack disk is rotatably mounted on the housing under the cover plate. An actuator in the housing is most desirably aligned with a lever on the cover plate. When a patient pushes the actuator, it presses to shear open a blister on the blister pack disk and delivers the drug in the dose in the blister into a staging chamber for inhalation by the user.  
         [0020]     In U.S. Pat. No. 6,006,747, a dry powder inhaler has a multi-dosage medicine containing cartridge attached on the top of the housing, and a cartridge ring with apertures for holding dry powder medicine. The housing includes a mixing or aerosolizing chamber. A pressure switch is located in the housing for actuating the mixing process within the chamber. A lid is pivotally attached to the housing and is used to index or advance the cartridge ring to a next aperture for delivery of successive drug dosages. During inhalation, a pressure differential develops across the venturi air passageway and reaches a predetermined level, then the motor is turned on by the pressure switch.  
         [0021]     U.S. Pat. No. 6,055,980 describes a dry powder inhaler comprising: a housing, a mixing chamber in the housing, an impeller within the space of the mixing chamber, a motor linked to the impeller, at least one inlet opening leading into the mixing chamber, and at least one outlet opening leading out of the mixing chamber. The device uses breath-actuation and is generally independent of patient coordination. A motor spins the impeller at high speed. A plunger introduces a dose of powdered medicine into the chamber so that all powder particles are available for intermixing disaggregation and comminution. The drug-laden air flows out of the chamber and into a mouthpiece. It provides a proper mixing of air and powdered drug particles for inhalation by a patient.  
         [0022]     U.S. Pat. No. 6,209,538 describes an inhalation-activated dry powder inhaler, that has a primary inhalation passage extending through the housing, and a secondary inhalation passage disposed in communication with the primary inhalation passage and a source of medicament. As the user&#39;s inhalation reaches a defined rate, the flow inhibiting mechanism restricts flow through the primary inhalation passage and moves the blocking plate to enable airflow through the secondary passage. The medicament is provided through the secondary inhalation passage, thereby optimizing the delivery of medicament to the lungs.  
         [0023]     Most of these dry powder inhalers are ideal for large amount medicament delivery (with 2-5 mg per dose). The formulation of the powder used is usually blended with large particle carriers. There are several problems related to delivery of small quantity of dry powder pharmaceuticals with these inhalers. First, these inhalers all apply an air entry passageway and an air exit passageway on the same side of blister or cartridge. The powder is extracted from its receptacle only by shear force. When the drug receptacle becomes too small drug powder is too cohesive, it becomes difficult to draw entire dry powder completely out from the receptacle and break up the particle aggregates. This will reduce the efficiency of the delivery. Secondly, these devices usually achieve delivery of fine drug particles by a two-step dispersion. It uses a chamber for receiving and maintaining the fluidized drug powder then deliver them to the user. This will cause some waste of expensive drug powder and decrease the accuracy of delivery due to the fine powder stuck on the surface of the chamber. Furthermore, some of the delivery devices are large or expensive, and inconvenient for changing for different medicaments and different dosage sizes.  
         [0024]     There is therefore a need for an inhaler that is capable of accurately delivering small precise amounts of expensive powder drugs with minimal powder handling, in a compact and inexpensive instrument which does not require the need for excipients.  
       SUMMARY OF THE INVENTION  
       [0025]     The present invention addresses the need for a dry powder inhaler that can deliver small accurate volumes of powder. The present invention provides a new method and apparatus for a dry powder inhaler for accurate delivery of powdered medicaments for pulmonary drug delivery. Based on the patented technology, a volumetric metering fluidized bed such as disclosed in (U.S. Pat. No. 6,684,917 B2) can preferably used to precisely dispense a pre-determined amount of pure powdered medicaments (without any excepient) into a receiver such as a described multi-dose blister pack forming part of the dry powder inhaler. This patented device can deliver a powder plume with approximately 90% or more of the inhalable particles (less than 5 μm in diameter or equivalent aerodynamic diameter) in their primary particle form, that is, with less than 10% particle agglomerates for the small inhalable particles. This ensures the accurate and uniform dispensing of the inhalable particles into the blister cells (receptacles) of a blister pack forming part of the dry powder inhaler devices disclosed herein.  
         [0026]     This blister pack with multiple dosages is loaded into the dry powder inhaler. With its flow-through blister cells and an optional dual air flow mechanism, powder inside the blister cells is easily extracted out and excellent dispersion of medicament powder is achieved during inhalation. In particular, there is no need for larger excipient particles which have been used in many existing inhalers to enhance the powder flow and to assist the breakup of and/or to prevent the formation of agglomerates.  
         [0027]     The present invention is most suitable for the very precise delivery of very tiny dosages of pure powdered medicaments, giving the very high delivery efficiency. This is particularly useful for the delivery of very expensive medicaments such as peptide and protein drugs, for which the use of excipient will significantly reduce the delivery efficiency and therefore significantly increase the cost. It is also useful for the systemic delivery or localized delivery of any powdered medicament through the lungs.  
         [0028]     The inhaler can extract and entrain substantially the entire amount of powder within the receptacle. Up to about 90% of drug emitted from a dose of the inhaler is delivered into patient&#39;s respiratory tract. Fine particle fraction of the drug (&lt;4.7 μm) is typically from 60% to 80%, when exiting the inhaler, as measured with the Anderson cascade impactor at 28.3 L/min and the NGI (Next Generation Impactor). It has been reported that most existing dry powder inhalers can only deliver a small fraction (about 10-30%) of the dispensed drug in the correct particle sizes for lung deposition.  
         [0029]     The present invention optionally provides a rotating multi-dose blister with dosages of pre-metered pure drug or drug with either none or a minimum amount of excipient. The blister pack is arranged to have a sufficient number of doses for a patient to use during a convenient long period. The carrier-free inhaler has the advantage of smaller dosage forms and high dosage concentration, which can provide significant savings when using expensive drugs. It is a critical technical challenge to achieve both adequate dispersion and small disperse volumes. Small dosages can also avoid choking during inhalation.  
         [0030]     According to the method of the present invention, the pure powdered medicament is contained in a small pocket of the blister with a porous filter at its bottom. Due to shelf storage, the medicament may have partially reagglomerated and would need to be dispersed during inhalation. The medicament can be drawn out by a negative pressure resulting from the patient&#39;s suction or a positive pressure from a small pressurized gas canister located in the inhaler housing or by the user pressurizing the interior of the inhaler housing in embodiments using telescoping housing sections. Thus extraction and deaggregation of the powder medicament can be achieved by inspiration effort alone, or a combination of inhalation and positive pressure from the bottom side of the blister. The air stream, due to inhalation or pressurized gas, or both, can be divided into two flow streams. The first one pierces into the blister through a bottom plate of a blister pack and filter. It provides sufficiently high air velocity to mobilize, fluidize and deagglomerate the drug powder stored in each individual blister. The second air stream flows to the top of the blister pack through an appropriate positioned channel, and meets the powder dose at the top of the small powder pocket or blister from which the drug powder is to be dispersed. It provides an additional shear fluidization to entrain the fluidized powder in the airflow, then to carry the entrained powder into the mouthpiece of the inhaler, so that the inhaler can break up most of the agglomerates and assure efficient delivery of the powder with minimum losses.  
         [0031]     The present invention has several major advantages. First, the entire amount of drug powder in the blister can be drawn out of the pocket completely. This is because the first stream of fluidization air flows through the small pocket from its bottom and directly blow the powder out of the pocket. This is unlike the commonly used inhalers, where only a tangential flow from the top is used to pick up the powder from the pocket. Secondly, it is easy to break up agglomerates, if any, into individual particles with two streams of airflow. These two airflow streams produce two different dispersion effects on the fine powder. It can significantly reduce the efforts for inhaling the medicine and perfectly aerosolize the ultra-fine powder. Thirdly, the high speed of the second airflow can help break up the agglomerates of particles completely. The ratio of the first airflow and the second airflow is adjustable for different drugs to improve the effect of dispersion. The inhaler eliminates the need for an aerosolized powder holding chamber and directly disperses the powdered drug into the mouthpiece of the inhaler. This reduces the amount of medicament trapped on the surface of the chamber, and further improves the drug delivery efficiency and accuracy. The inhaler also does not depend on the respiratory capacity of the patient even when it is used under negative pressure, because the amount of air required to extract and deliver the medicament is extremely low in comparison with human inhalation capacity. This is clearly an advantage for patients with respiratory diseases. In addition, the inhaler is of simple design which eliminates unnecessary complexity; the device is completely mechanically controlled and extremely compact. It is easy to use, and has very high patient reproducibility.  
         [0032]     Therefore, in one aspect of the invention there is provided a dry powder inhaler for dispensing powder medicament, comprising:  
         [0033]     a) a housing and mounting means for mounting a blister pack in an interior of said housing, said blister pack including a holding plate and a plurality of powder pockets containing a pre-selected amount of powder medicament formed from a plurality of holes extending through the holding plate, said housing including a first gas flow inlet passageway and an outlet flow passageway; and  
         [0034]     b) positioning means for positioning said blister pack to bring each powder pocket into flow communication with said outlet flow passageway and said first gas flow inlet passageway, said first gas flow inlet passageway having an inlet in flow communication with a source of gas and an exit located in said housing on one side of said powder pocket, said outlet flow passageway having an inlet located in said housing on the other side of said powder pocket which is positioned in flow communication with said outlet flow passageway and an outlet on an exterior of said housing, wherein when gas from the source of gas is flowed into said first gas flow inlet passageway it flows into one side of said powder pocket and through the powder pocket to mobilize, fluidize and deagglomerate the powder medicament such that a mixture of powder medicament and gas flows out through the other side of said powder pocket and into said outlet flow passageway and out of said outlet.  
         [0035]     The present invention also provides a method of dispensing a powder medicament contained in a plurality of powder pockets in a blister pack mounted in an inhaler, the method comprising the steps of:  
         [0036]     a) moving the blister pack to bring a powder pocket into flow communication with an outlet flow passageway and a first gas flow inlet passageway in the inhaler, the blister pack including a holding plate and the plurality of powder pockets containing a pre-selected amount of powder medicament formed from a plurality of holes extending through the holding plate, the first gas flow inlet passageway having an inlet in flow communication with a source of gas and an exit located on one side of the powder pocket, said outlet flow passageway having an inlet located on the other side of the powder pocket positioned in flow communication with the outlet flow passageway and an outlet on an exterior of said housing;  
         [0037]     b) fluidizing the powder medicament contained in the powder pocket which is aligned with the first gas flow inlet passageway and the outlet passageway using a first flow of gas from the gas flow inlet passageway which flows into one side of the powder pocket and through the powder pocket to mobilize, fluidize and deagglomerate the powder medicament such that a mixture of powder medicament and gas flows out through the other side of said powder pocket and into said outlet flow passageway and out of said outlet;  
         [0038]     c) withdrawing said fluidized powder out of said inhaler through said outlet passageway; and  
         [0039]     d) repeating steps a), b) and c) as many times as needed to dispense a needed amount of the powder medicament.  
         [0040]     The present invention also provides a method of pulmonary drug delivery of a powder medicament into a user&#39;s respiratory system, comprising the steps of:  
         [0041]     a) filing powder pockets of a blister pack with a fine powder medicament selected from the group consisting of peptides or fragments thereof, proteins or fragments thereof, antibodies or fragments thereof, antibiotics, vaccines and any combination thereof, and loading the blister pack into a dry powder inhaler;  
         [0042]     b) moving the blister pack to bring a powder pocket into flow communication with an outlet flow passageway and a first gas flow inlet passageway in the dry powder inhaler, the first gas flow inlet passageway having an inlet in flow communication with a source of gas and an exit located on one side of the powder pocket, said outlet flow passageway having an inlet located on the other side of the powder pocket positioned in flow communication with the outlet flow passageway and an outlet on an exterior of said housing;  
         [0043]     c) fluidizing the powder medicament contained in the powder pocket which is aligned with the first gas flow inlet passageway and the outlet passageway using a first flow of gas from the gas flow inlet passageway which flows into one side of the powder pocket to mobilize, fluidize and deagglomerate the powder medicament such that a mixture of powder medicament and gas flows out through the other side of said powder pocket and into said outlet flow passageway and out of said outlet through a mouthpiece inserted in a user&#39;s mouth so that powder medicament is expelled out through the mouthpiece and directly into the user&#39;s respiratory system; and  
         [0044]     d) repeating steps b) and c) as many times as needed to dispense a needed amount of the powder medicament.  
         [0045]     Preferably, the fine powder medicament does not contain excipient powder particles. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0046]     The invention will now be described, by way of non-limiting examples only, reference being made to the accompanying drawings, in which:  
         [0047]      FIG. 1   a  is a side view of an embodiment of a blister pack constructed in accordance with the present invention;  
         [0048]      FIG. 1   b  is a top view of the embodiment of the blister pack shown in  FIG. 1   a;    
         [0049]      FIG. 2  is a cross sectional view of an inhaler, which depends on the patient-generated air flow and creates a small airflow from the bottom surface of the blister pack to the mouth piece at the top of the blister;  
         [0050]      FIG. 3  is a cross sectional view of another embodiment of an inhaler, modified from the inhaler shown in  FIG. 2  by having an additional stream of flow assistance air at the access port of the pocket to help the fluidization and deaggoleration of the powder from the pockets;  
         [0051]      FIG. 4  is a cross sectional view of another embodiment of an inhaler similar to the inhaler shown in  FIG. 3 , where both airflow streams are provided by a pressurized air source that is generated by a piston at the bottom of the inhaler;  
         [0052]      FIG. 5   a  is a cross sectional view of another embodiment of a blister pack;  
         [0053]      FIG. 5   b  is a top view of the blister pack of  FIG. 5   a;    
         [0054]      FIG. 6  is a disassembled view of the blister pack of  FIGS. 5   a  and  5   b;    
         [0055]      FIG. 7  is a cross sectional view of another embodiment of a blister pack;  
         [0056]      FIG. 8  is a disassembled view of the blister pack of  FIG. 7 ;  
         [0057]      FIG. 9  shows a cross sectional side view of a blister pack and associated piercing mechanism for piercing the filter retaining the powder in the blister pack of  FIG. 7 ;  
         [0058]      FIG. 10  is a disassembled view of another embodiment of a blister pack that is used to hold multi-doses of a powdered medicament;  
         [0059]      FIG. 11  shows a cross sectional view of another embodiment of an inhaler constructed in accordance with the present invention;  
         [0060]      FIG. 12   a  is a cross sectional view of an alternative embodiment of an inhaler;  
         [0061]      FIG. 12   b  is a cross-sectional top view taken at the A-A plane of the inhaler at  100  in  FIG. 12   a;    
         [0062]      FIG. 12   c  shows an exploded perspective view of the ratchet mechanism for inhalers shown in  FIGS. 12   a , and  120  in  FIG. 13   a;    
         [0063]      FIG. 13   a  shows a cross sectional view of another embodiment of an inhaler;  
         [0064]      FIG. 13   b  shows a cross-section of the inhaler  120  along the line A-A;  
         [0065]      FIG. 13   c  is an exploded perspective view of the inhaler of  FIGS. 13   a  and  13   b;    
         [0066]      FIG. 14   a  shows a cross sectional view of another embodiment of an inhaler;  
         [0067]      FIG. 14   b  is cross-sectional view along the line A-A of the inhaler in  FIG. 14   a;    
         [0068]      FIG. 14   c  showing an exploded perspective view of the inhaler of  FIGS. 14   a  and  14   b;    
         [0069]      FIG. 15   a  is a cross sectional view of another alternative embodiment of an inhaler;  
         [0070]      FIG. 15   b  is a cross-sectional view of the inhaler at  190  in  FIG. 15   a  taken along the line A-A;  
         [0071]      FIG. 15   c  showing an exploded perspective view of the inhaler of  FIGS. 15   a  and  15   b;    
         [0072]      FIG. 16  is a cross sectional view of another embodiment of an inhaler;  
         [0073]      FIG. 17   a  is a side cross sectional view of an alternative embodiment of a blister pack that has a double circle arrangement of blister cells or pockets;  
         [0074]      FIG. 17   b  is a top view of the blister pack of  FIG. 17   a ; and  
         [0075]      FIG. 18  is a cross sectional view of an inhaler that is designed to receive the blister pack of  FIGS. 17   a  and  17   b.   
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0076]     In the following description, like numerals in the different embodiments refer to the same or very similar parts.  FIGS. 1   a  and  1   b  show an embodiment of a blister pack  10  that is used to hold multi-doses of a powdered medicament. The blister pack  10  contains a (holding) plate  12  with multiple powder pockets  14  extending through the plate in which the medicament is contained. The powder pockets  14  formed in the holding plate  12  which contain the powder medicament are also referred to as blisters or blister cells. Powdered medicament is pre-charged into the blisters or blister cells  14  which is then put into an inhaler to be discussed hereinafter. By introducing a gas flow through the blisters  14 , the charged powder medicament will be blown out, to form a powder flow for the pulmonary drug delivery, as will be described in detail hereinafter.  
         [0077]     The blister cells  14  in the holding plate  12  are normally identical in size and have a fixed or pre-selected volume to store a pre-selected amount of powder therein. By changing the holding plates  12  with different pocket diameters and plate thickness, blister packs  10  of different volumes can be obtained. Any number of powder pockets  14  can be arranged in any fashion in the plate  12 , but for easy use in the inhalers it is beneficial that powder pockets  14  are arranged along certain circles on the disk. In the illustrated blister pack of  FIG. 1 , the holding plate  12  is circular and the powder pockets  14  are arranged on the circumference of a circle. However, more powder pockets  14  may be arranged on multiple circles on the plate  12 .  
         [0078]      FIGS. 17   a  and  17   b  shows an embodiment of an alternative blister pack  610  that has a double circle arrangement of pockets. The blister pack  610  contains a holding plate  612  with an inner circle of multiple pockets  614  and an outer circle of pockets  624  arranged in two concentric circles. As before, the powder pockets  614  and  624  in the two circles formed in the holding plate  612  which contain the powder medicament are also referred to as blisters or blister cells. Powdered medicament is pre-charged into the blisters or blister cells  614  and  624  after which the blister pack  610  is inserted into an inhaler. By introducing a gas flow through each of the blisters  614  and  624 , the charged powder medicament will be blown out, to form a powder flow for the pulmonary drug delivery, as will be described in detail hereinafter. The blister cells  614  and  624  in the holding plate  612  are normally identical in size and have a fixed or pre-selected volume to store a pre-selected amount of powder therein. By changing the holding plates  612  with different pocket diameters and plate thickness, blister packs  610  of different volumes can be obtained. Any number of powder blisters  614  and  624  can be arranged in any fashion in the plate  612 , but for easy use in the inhalers it is beneficial that powder blisters  614  and  624  are preferably arranged in two concentric circles on the plate  612 . In the illustrated blister pack of  FIG. 17 , the holding plate  612  is circular and the blisters  614  and  624  are arranged on the circumferences of two concentric circles.  
         [0079]     The blister cells  14  in plate  12  in  FIGS. 1   a  and  1   b , and blister cells  614  and  624  in plate  612  in  FIG. 17   b , may be made of any shape, although a vertical cylindrical shape is preferred since it is the easiest to produce and to align with the powder outlet channel. For example, vertically tapered holes with increasing diameter towards the top surface of plate  12  and  612  would be beneficial for the easy charging and blowing-off of the powder.  
         [0080]     FIGS.  2  to  4  show different embodiments of inhalers constructed in accordance with the present invention. Referring first to  FIG. 2 , an inhaler  20  includes a cylindrical housing  22  which holds a circular disc-shaped blister pack  10  ( FIG. 1 ) which contains several individual blister cells  14 , each containing a known amount of powdered medicament, arranged in one or more circles on the blister pack  10 . Housing  22  includes a gas flow inlet tube  34  which encloses a flow passageway  32  on the bottom of housing  22  and an air flow outlet tube  30  positioned above a blister cell  14  at the top of the blister pack  10  which encloses a flow passageway  36 . The blister pack  10  is sandwiched between, and held in place, by a top seal block  24  and a bottom seal block  26 . With a locking pin  42 , the blister pack  10  is tightly fixed with a ratchet wheel  28 , which can be rotated in steps to align in turn each of the individual pocket holes in the holding plate  12  with the flow passageways  32  and  36 . The ratchet wheel  28  is used to rotate the blister pack  10  and to align and hold in place each blister cell  14  aligned with the passageway  32  (as well as  36 ) through which the powder is to be dispensed. From the top of air flow outlet tube  30 , and in the direction indicated by arrow  44 , a patient can suck the powder contained in the powder blister  14  adjacent to passageway  36  with a gas in passageway  32 .  
         [0081]     The gas flow inlet tube  34  which encloses the flow passageway  32  on the bottom of housing  22  may include an adjustable constriction means for adjusting gas flow in passageway  32  to allow adjustment of the gas flow rate.  
         [0082]      FIG. 18  shows an inhaler arrangement  620  that is designed for holding the blister pack  610  ( FIGS. 17   a  and  17   b ) with two concentric circles of blister pockets. The inhaler  620  includes a cylindrical housing  22  which holds a circular disc-shaped blister pack  610  which contains several individual blisters  614  and  624  ( 624  is not shown on the plane sectioned in  FIG. 18 ), each containing a known amount of powdered medicament, arranged in two circles on the blister pack  610 . Housing  22  includes a gas flow inlet tube  34  which encloses a flow passageway  32  on the bottom of housing  22  and an air flow outlet tube  30  positioned above a blister cell  614  at the top of the blister pack  610  which encloses a flow passageway  36 . The blister pack  610  is sandwiched between, and held in place, by a top seal block  24  and a bottom seal block  26 . The top part of the bottom gas flow inlet tube  34  has a Y shaped branching  632  extending into two directions each pointing to the positions of blisters in the inner and outer circles. Likewise, the bottom part of the top air flow outlet tube  30  also has a Y shaped branching  636  extending into two directions each pointing to the positions of blisters in the inner and outer circles.  
         [0083]     With a locking pin  42 , the blister pack  610  is tightly fixed with a ratchet wheel  28 , which can be rotated in steps to align in turn each of the individual pocket holes  614  and  624  in the holding plate  612  with the flow passageways  32  and  36 . The ratchet wheel  28  is used to rotate the blister pack  610  and to align and hold in place alternatively each blister cell  614  aligned with left branch of Y shape  632  in the passageway  32  and each blister cell  624  aligned with right branch of Y shape  632  in the passageway  32 . Likewise, the left branch of the Y shape  636  is aligned with blisters  614  and the right branch of the Y shape  636  is aligned with blisters  624 , alternatively. Through the gas passageway through either the left branches or the right branches, alternatively, the powder in the blisters on the inner circle or blisters on the outer circle is to be dispensed.  
         [0084]     For the inhalers  20  and  620  shown in  FIGS. 2 and 18 , the powdered medicament can be drawn out by a negative pressure resulting from the patient&#39;s suction from the top of the air flow outlet tube  30  or a positive pressure from the bottom of the gas flow inlet tube  34 . The latter can be provided by connecting a small compressed gas canister with an activation means or by the in-situ compression of a telescope section as shown in  FIG. 4  below.  
         [0085]      FIG. 3  shows a cross sectional view of an alternative embodiment of an inhaler device at  40 . Inhaler device  40  is very similar in structure to device  20  of  FIG. 2  but includes an additional small air flow inlet tube  46 , defining a flow passageway  48 , located just above the holding plate  12  of the blister pack  10 , which is positioned at  90  degrees to outlet tube  30  and which sweeps the top surface of the powder blister  14  adjacent to passageway  36  to entrain the powder out of the powder blister  14  aligned with outlet passageway  36 . With the assistance of this additional air flow through passageway  48 , the dispensing of the powder medicament is easier and more efficient than using the airflow from the inlet tube  32  alone. The relative ratio between the air flow through passageway  32  and the air flow through passageway  48  is determined by the relative flow resistance through the two passageways, mostly by the diameter and the length of the two passageways. A large diameter pipe for passageway  48  would increase the air flow rate which is used for sweeping gas across the top surface of the powder blister  14  and for entraining the powder out of the powder blister  14 . To further adjust the flow ratio, a small screw  49  is set through the top block  24  and ends at the wall of the air inlet tube  46 . To decrease the air flowrate through passageway  48 , the small screw can be advanced into the air inlet tube  46 , creating additional flow resistance inside passageway  48 . It will be understood that all embodiments of the inhalers disclosed herein having the two gas flow passageways may include this adjustable screw  49  to provide gas flow constriction, or any other type of gas flow constriction mechanism may be used.  
         [0086]      FIG. 4  is a cross sectional view of another inhaler  60  which differs from inhaler  40  in that the housing  62  is constructed of a housing in two sections, an upper section  64  and a lower section  66  which move in telescoping relationship to each other for pressurizing the air entering passageway  32  located in the chamber defined by housing sections  64  and  66 . A spring  70  is located between the bottom of housing section  66  and the bottom surface of seal block  26  which acts to bias housing section  66  away from housing section  64 . Housing section  64  includes a shoulder  68  around the periphery of the end portion located within housing section  66  with shoulder  68  extending outwardly to engage the inwardly protruding peripheral edge of section  66  in order to hold the two housing sections  64  and  66  together. At the bottom of housing section  66 , there is a threaded hole which is normally blocked off by a screw  72 . When needed, this screw  72  can be removed to allow airflow through the hole. The flow passageway  48  created by tube  46  as shown in  FIG. 4  is optional and its addition can further help the entrainment of powdered medicament.  
         [0087]     Inhaler  60  as shown in  FIG. 4  provides for the production of a back pressure inside the chamber formed by housing sections  64  and  66  that can be used to disperse the powder from the blister cell aligned with passageway  36 . On the other hand, when the screw  72  is removed, inhaler  60  essentially becomes inhaler  40  of  FIG. 3 . When the screw  72  is threaded into the hole and sealed properly, as a patient squeezes housing sections  64  and  66  together the air in the interior chamber is pressurized thereby producing a compressed air flow up through passageway  32  flowing up through the bottom of the powder blister  14  and in through the small air passageway  48  which sweeps across the top of powder blister cell  14  aligned with passageway  36 . The compressed air flows up through passageway  32  and fluidizes the powder in the blister cell  14  of the blister pack  10 , then entrains and disperses the powder efficiently with the assistance air flow in passageway  48 .  
         [0088]     The blister pack  10  shown in  FIGS. 1   a  and  1   b  may be charged with powdered medicament using the rotating fluidized bed disclosed in U.S. Pat. No. 6,684,917 B2 or other suitable means that can dispense powder accurately into the blister cells. After dispensing powder into the blister cells  14 , the charged blister pack  10  may be covered on one or both sides with protection layers such as aluminum foils or other means, to prevent the powder from falling out and/or prevent moisture from getting into the packed cell with packed powder. Before loading the blister pack  10  into the inhaler  60 , the protective films are removed.  
         [0089]     The blister pack  10  shown in  FIGS. 1   a  and  1   b  is, however, only one embodiment and is likely the simplest embodiment. More complicated blister packs can be made that further ensure the accuracy of final pulmonary drug delivery.  
         [0090]      FIGS. 5   a ,  5   b  and  6  show another embodiment of a blister pack  310  that is used to hold multi-doses of a powdered medicament.  FIG. 6  shows an exploded view of the same blister pack  310 . The blister pack  310  includes a top plate (the holding plate)  312  with multiple blister or blister cells  314  extending through the plate in which the medicament is contained, and a bottom plate  316  with the same number of multiple air passage holes  317  as that of  314  extending through plate  316 , with a filter material  315  clamped in between the top plate  312  and bottom plate  316 . A set screw  318  is used, preferably going through the centre of plates  312  and  316 , to fix the two plates together and to align the pockets  314  in the top holding plate  312  with the holes  317  in the bottom plate  316 . Powdered medicament is pre-charged into the blisters  314  and then the blister pack is put into an inhaler. By introducing a gas flow through the air passage holes  317 , either by inhalation (suction) from the top of the top plate  312  or by apply pressured air to the bottom of the bottom plate  316 , the charged powder medicament will be blown out, to form a powder flow for the pulmonary drug delivery. The main benefit of this embodiment over the blister pack  10  shown in  FIG. 1  is that the filter media supported by the bottom plate helps to hold the powdered medicament in place. If the bottom plate  316  and the filter media  315  are both removed after the powder charging and before the blister pack  310  is put into the inhaler, blister pack  310  shown in  FIGS. 5   a ,  5   b  and  6  reduces to the blister pack  10  shown in  FIG. 1 . Filter media  315  may be any inert porous material such as filter paper, fine mesh screens, membrane sheet, and porous solid materials such as porous Teflon and porous ceramics, to mention just a few. It has a pore size to allow gas to flow through but blocks the medicament powder.  
         [0091]     After dispensing powder into the blister cells  314 , the charged blister pack  310  may be covered on one or both sides with protection layers such as aluminum foils or other protective films to prevent moisture from getting into the blister cells. The film on the top side also helps to hold the powder in the blister cells in place. Before putting the blister pack into the inhaler, the protective films are removed.  
         [0092]     The blister cells  314  in the holding plate  312  are normally identical in size and have a fixed or pre-selected volume to store a pre-selected amount of powder therein. By changing the holding plates  312  with different pocket diameters and plate thickness, blister packs  310  of different volumes can be obtained. Any number of blisters  314  can be arranged in any fashion in the plate  312 , but for easy use in the inhalers it is beneficial that blister cells  314  are arranged along certain circles on the disk. The bottom plate  316  is provided with air passage holes  317  designed to align with each of the blister cells  314  in plate  312 . In the illustrated blister pack of  FIGS. 5   a  and  6 , both top and bottom plates  312  and  316  are circular and the blisters  314  and holes  317  are arranged on the circumference of a circle in each plate of the same diameter. However, more blister cells  314  and holes  17  may be arranged on multiple circles on each plate.  
         [0093]     The blister cells  314  in plate  312  may be made of any shape, although a vertical cylindrical shape is preferred since it is the easiest to produce and to align with the powder outlet and air inlet channels. For example, vertically tapered holes with increasing diameter towards the top surface of plate  312  would be beneficial for the easy charging and blowing-off of the powder, but vertically tapered holes with decreasing diameter towards the top surface of plate  312  would be beneficial for holding the powder in position. The air passage holes  317  in the bottom plate  316  are preferably larger in diameter than the diameter of blister cells  314 , to ensure the complete blow-off of powdered medicament in the blister cells  314  by the gas flow through the bottom holes.  
         [0094]     As discussed above, in operation, the ratchet wheel  28  ( FIG. 2  or  3 ) is used to rotate the blister pack  310  and to align and hold in place each blister cell  314  aligned with the passageway  32  (as well as passageway  36 ) through which the powder is to be dispensed. Holding plate  312 , filter  315  and bottom plate  316  are locked together and move together about the axis of rotation defined by screw  318 .  
         [0095]     Another embodiment of the blister pack is shown generally at  320  in  FIG. 7  and with its exploded view shown in  FIG. 8 . In some cases, the packed powder may not be able to hold together tightly enough so that some particles may easily fall out of the blisters cells. In some other cases, the medicament particles become too sticky that some will stick onto the protective films when peeled before loading into the blisters. Both cases would lead to loss of particles, affecting the accuracy of pulmonary delivery. The embodiment  320  shown in  FIG. 7  is useful in preventing the above problems. The blister pack  320  shown in  FIG. 7  has the lower parts ( 312 ,  314 ,  315 ,  316  and  317 ) identical to the blister pack  310 , but with another top plate  326  on top of the holding plate  312 , with the same number of multiple air passage holes  327  as that of  314  extending through plate  326 , with a filter material  325  clamped in between the top plate  326  and the holding plate  312 . The same blister pack as  310  is first charged with powder medicament and then the top plate and filter media are put on to hold the particles in place. The set screw  328 , in this case, is longer than the screw  318  in  FIG. 5   a  and can be advanced into the top plate  326  after powder loading, so as to fix all three plates together. The holes  327  in the top plate  326  should preferably be equal to, or larger than, the blister holes  314  in the holding plate  312 , for easier and more complete powder dispersing and inhalation.  
         [0096]     With such an arrangement, the powdered medicament is securely held inside the blister cells during transportation. If protection from moisture is also required, protective films can be sealed against the upper surface of the top plate  326  and the lower surface of the bottom plate  316 . Because the protective films are not in direct contact with the medicament particles, there is no potential loss of medicament particles when the films are peeled off before inhalation and usually before loading into the inhalers.  
         [0097]     The above-mentioned blister pack  320  is then loaded into the inhaler, assuming the protective films, if any, have been peeled off. Before inhalation, the top filter media  325  of the blister cell at the position in line with the air inlet passageway  32  and powder outlet passageway  36  must be pierced. This can be realized by a piercing device  322  being pushed into the passageway and onto the filter materials, as shown in  FIG. 9 . After such piercing operation, the air outlet passage way  36  is open and the blister contents are ready for inhalation.  
         [0098]     As discussed above, in operation, the ratchet wheel  28  ( FIG. 2  or  3 ) is used to rotate the blister pack  320  and to align and hold in place each blister cell  314  aligned with the passageway  32  (as well as passageway  36 ) through which the powder is to be dispensed. Ratchet  28  turns the whole sandwiched assembly, including plate  312 /filters  315  and  325 /bottom plate  316  and top plate  326  which move together about the axis of rotation defined by screw  328 . In preferred embodiments of the blister discs the various holding plates and top and/or bottom plates are disc-shaped having an axis of rotation about which the ratchet rotates the blister pack.  
         [0099]     To further decrease the resistance to the air and powder flow during inhalation, it may be beneficial if the bottom filter media  315  is also pierced open. As shown in  FIG. 9 , a similar sharp object  324  to that  322  may be used for this purpose. When both the inlet and outlet passageways are open the flow resistance is minimized and the powdered medicament is more easily fluidized and entrained for more efficient pulmonary drug delivery.  
         [0100]     An alternative arrangement for reducing the flow resistance but avoiding the use of the piercing objective is shown in  FIG. 10 . The modified embodiment of blister pack  330  is essentially the same as the blister pack  320  (both preferably being disc-shaped), but the two filter media  315  and  325  each have a hole  335  and  336  respectively in them and one of the blister cells  334  on a modified holding plate  312 ′ is blocked completed (or alternatively not drilled in the first place). As in the case for blister pack  320 , the top plate and filter are not put on when loading the powdered medicament into the blister pack. At the loading stage, the open hole  335  in the lower filter media  315  and the blocked hole  334  on the holding plate are aligned together. After loading, the top plate  326  and top filter media  325  are assembled onto the lower portion, with the open hole  336  in the top filter media  325  aligned with the blocked hole  334  on the holding plate  312 ′. With such arrangement, the blank blister cell with the blocked hole is exposed to the two openings  336  and  335  on the upper and lower filter media  325  and  315  when the blister pack  330  is in storage and transfer, so that there will be no loss of particles.  
         [0101]     A preferred apparatus for filling the blister packs for use in the inhalers disclosed herein with the powder medicament is a volumetric metering fluidized bed such as disclosed in U.S. Pat. No. 6,684,917 B2, which is incorporated herein by reference in its entirety, which can be used to precisely dispense a pre-determined amount of pure powdered medicaments (without any excepient) into the powder pockets of the multi-dose blister pack forming part of the dry powder inhaler forming part of the present invention. The device disclosed in U.S. Pat. No. 6,684,917 B2 can deliver a powder plume with approximately 90% or more of the inhalable particles (less than 5 μm in diameter or equivalent aerodynamic diameter) in their primary particle form, that is, with less than 10% particle agglomerates for the small inhalable particles. This ensures the accurate and uniform dispensing of the inhalable particles into the blister cells of the blister pack.  
         [0102]     Thus, a preferred method of filling the powder pockets of the blister packs may include producing a fluidized bed in a housing defining an enclosure for containing fine powder medicament where the housing includes a fluid injection mechanism for injecting a fluid into the enclosure for fluidizing the fine powder medicament contained within the housing for forming a dilute phase alone or a dilute phase and a dense phase of fluidized powder medicament. The powder pocket of the blister pack is coupled into flow communication with the enclosure through an outlet passageway for withdrawing pre-selected amounts of the fine powder medicament from housing, and sealing the powder pockets for transporting the pre-filled blister pack.  
         [0103]      FIG. 11  shows an embodiment of an inhaler at  340  which is similar to inhaler  40 , but designed to receive the thicker blister pack  330  shown in  FIG. 10 . In this case, the top plate  326  in  FIG. 10 , with the upper filter material  325  will be secured to the top seal block  24  and the bottom plate  316  with the lower filter material  315  will be secured to the bottom seal block  26  in inhaler  340  in  FIG. 11  so that the ratchet mechanism is configured to move only the holding plate  312  while the top plate  326  and the bottom plate  316  with filters  325  and  315  attached to each respectively remain in the same fixed position while the holding plate  312 ′ rotates. The holding plate  312  is, however, locked with the ratchet wheel  28 . At the initial position, the two openings  335  and  336  on the two filter materials  315  and  325 , and the blank blister  334  on the holding plate  312  are aligned together and also aligned with the inlet and outlet passageways  32  and  36 . Before inhalation, the ratchet wheel  28  will advance the holding plate  312 ′ to its next position so that the next blister (filled with powdered medicament) will be exposed to the inlet and outlet passageways  32  and  36 . Since the passageways are completely open without any filter material in the way, the flow efficiency is greatly increased and the probability for the powdered medicament to be stuck inside the blister is essentially zero. It will be understood that blister pack  330  may be made just using either the bottom plate  316  and filter  315  with the modified holding plate  312 ′ or a combination of both.  
         [0104]     It should be noted that other materials can also be used for the blister pack  330 . For example, the top and bottom plates  326  and  316  may be replaced with solid plates made from porous materials. This eliminates the need for drilling the very small holes in the plates. In addition, membrane sheets with proper pore size can be formed directly onto one surface of the above-mentioned two plates to act as the filter layers  315  and  325 . If the membranes are selected to bond well to the plates, there is no need to use other means to bond the filter layer to the plates. This is particularly useful to ensure membrane layers  315  and  325  stay bound with the top and bottom plates  326  and  316  when the holding plate  312  is rotating with the ratchet wheel  28  being rotated when loaded into the inhaler  340 . Another alternative is to use partially porous media to make the top and bottom plates  326  and  316 , so that the areas marked as holes  327  and  317  are made porous while all the other areas are solid. This eliminates the needs for filter media  315  and  325 .  
         [0105]     Referring now to  FIGS. 12   a  and  12   b , an alternative embodiment of an inhaler shown at  100  includes a housing  102  with two generally cylindrical telescoping sections  104  and  106  with a spring  108  bearing against section  106 . Section  106  functions as a push bottom for activating the inhaler to pressurize the air on the interior of the housing for dispensing powder. The top seal block  24  and bottom seal block  26  serve the same function as in the inhalers  20  and  40  in  FIGS. 2 and 3  for securing blister pack  310  between them. A mouthpiece  114  is mounted on the powder/air outlet passageway  36 .  
         [0106]      FIG. 12   b  is a cross-sectional top view at the A-A plane of the inhaler at  100  in  FIG. 12   a  and shows the ratchet mechanism for rotating the blister pack  310  which includes a ratchet wheel  122  which is turned by handle  118  with the ratchet wheel  122  engaging a tongue  126  pivotally mounted on a block  124  for locking the blister pack  310  in place thereby controlling the position of the blister cells  314  in blister pack  310 . Blister pack rotation handle  118  is connected to the blister pack  310  for rotating the pack into position for dispensing the powder from the different blister cell  314 . Air compressed by pushing housing section  106  up into section  104  compresses the air in the chamber  111  defined by housing  104  and  106  which is forced into entrance  115  and up through passageway  32  into the blister cell  314  thereby forcing the powder to be expelled out through outlet passageway  36  and mouthpiece  114 .  
         [0107]      FIG. 12   c  shows an exploded perspective view of the ratchet mechanism for inhalers  100  and  120  shown in  FIGS. 12   a  and  13   a  but it will be understood that the ratchet mechanisms for the other inhalers are similar. When the handle  118  and lever  121  connected thereto is advanced (counter-clockwise), it turns the ratchet wheel  122  counter-clockwise through a pivotal pin connection  119 . The handle  118  and lever  121  then turn clockwise back to its original position. Since the ratchet wheel  122  is engaged with the tongue  126  pivotally mounted on block  124 , the ratchet wheel  122  cannot turn back but is locked in the position set by the tongue  126  and the block  124 . This locks the blister pack  310  in place thereby controlling the position of the blisters  314 . When the dose of powdered medicament in the air flow passageway is inhaled, the handle  118  is advanced again to turn the ratchet wheel  122  which then turns the blister pack  310  to the next position where the next blister cell is aligned for inhalation.  
         [0108]     It should be noted that although blister pack  310  is used to illustrate the utility of inhaler  100  in  FIG. 12   a , other blister packs such as  320 ,  330  or  10  may also be used in combination with inhaler  100 . It should also be noted that inhaler  100  as shown in  FIG. 12  is a so-called active inhaler where compressed air is used to blow the powdered medicament out of the blister cells. However, inhaler  100  can be easily modified into a passive inhaler where the inhalation force of patient is the sole driving force to lift and then carry the medicament into the patient&#39;s lung for pulmonary drug deposition. This can be done by removing the outer housing  106  and the spring  108  and then shorten the length of housing  104 .  
         [0109]      FIG. 13   a  shows another embodiment of an inhaler shown generally at  120 ,  FIG. 13   b  shows the A-A cross-section of the inhaler  120  and  FIG. 13   c  is an exploded perspective view of the inhaler  120 . Inhaler  120  is similar in structure to inhaler  100  of  FIG. 12   a  but includes an additional secondary air flow passageway  132 . This secondary air flow is separated from the major air flow in passageway  32  and is directed into a hidden passageway inside the shaft  138  for the mechanism that turns the ratchet wheel  122 . A portion of the compressed air from the chamber  111 , other than the portion going through the main air channel  36 , passes through the hollow area of the fixed supporting block  134  and then into a passageway located in the shaft  138  (the shaft is not solid, but hollow), as shown by the arrow  136 . Air comes out of the inner tube  138  then goes to the secondary air flow passageway  132 , as shown by the arrow  112 . Eventually, this secondary air flow makes its way through the flow passageway  132 , to sweep across the top surface of the blister cell  314  aligned with the outlet passageway  32 . This helps to carry the powder out of the pocket into the mouthpiece  114  of the inhaler. The only difference between inhaler  100  and  120  is the presence of this secondary flow passageway  132 .  FIG. 13   b  shows the mechanism for rotating the blister pack  310  which is essentially the same as the mechanism shown in  FIG. 12   b . Also like inhaler  100 , inhaler  120  can also be modified to become a passive inhaler by removing the outer housing  106  and the spring  108  and then shortening the length of housing section  104 .  
         [0110]      FIGS. 14   a  and  14   b  show another alternate embodiment of an inhaler shown generally at  160  with  FIG. 14   c  showing an exploded perspective view of the inhaler  160 . Inhaler  160  differs from the previous embodiments of the inhaler in that the exit passageway  162  is perpendicular to the direction of the button  164  mounted in telescoping relationship with the housing section  166 . Spring  168  returns the button  164  to its rest position. Depressing button  164  acts to compress air within the housing which then enters passageway  170  and exits through exit passageway  162  and mouthpiece  174 . There is a secondary air-flow passageway  178  through top seal block  24 , which introduces air across the top of the blister cell  314  on blister pack  310  positioned adjacent to the exit passageway  162 . Knob  118  and the lever  119  connected thereto is for rotating blister pack  310  to bring the dosages contained in the blisters  314  into alignment with the exit passageway  162  and works the same way as in inhaler  100 .  
         [0111]      FIG. 14   b  is the A-A cross-sectional view of the inhaler at  160  in  FIG. 14   a  and shows the mechanism for rotating the blister pack  310  (similar to  FIGS. 12   b  and  13   b ) which includes ratchet wheel  122  which is turned by handle  118  with the ratchet wheel  122  engaging a tongue  126  pivotally mounted on block  124  for locking the blister pack  310  in place thereby controlling the position of the blister cells  314  in blister pack  310 . Again, inhaler  160  can also be modified to become a passive inhaler by removing the telescoping button  164  and the spring  168  and then leave some openings in place of the button to allow air inflow.  
         [0112]     For inhalers  100 ,  120  and  160 , the blister pack  310  may be centered in the housings as shown for inhaler  160  (see  FIG. 14   b ). However, for the inhalers  100  and  120 , since both have a vertical design, these inhalers have been constructed so that the position of the blister pack  310  is off-centre in the inhaler housing, in order to minimize the required radius while still accommodating the ratchet turning mechanism. For inhaler  160 , because it is of a horizontal design, minimizing the radius is less of a concern than minimizing the total vertical height, the latter being achieved by the positioning the exit passageway  162  perpendicular to the direction of the telescoping housing sections  164  and  166 .  
         [0113]      FIG. 15   a  shows another alternative embodiment of an inhaler shown at  190  which is similar to inhaler  160  of  FIG. 14   a . Inhaler  190  differs from inhaler  160  in that the mouthpiece  194  has been moved to the bottom of the housing so that the main and secondary passageways are shorter with fewer turns. The primary or major air flow passageway  182  directs air to the hole  17  of the blister pack  310 , and into passageway  162  which is located in an elongated housing portion  194  forming the mouthpiece which is inserted into the user&#39;s mouth, and the secondary air flow passes through a small tube  192  which introduces air across the top of the blister cell  314  on blister pack  310  positioned adjacent to the exit passageway  162 .  
         [0114]      FIG. 15   b  shows a view along the line A-A of the inhaler at  190  in  FIG. 15   a  and shows the ratchet mechanism for rotating the blister pack  310  (similar to that shown in  FIGS. 12   b  and  14   b ).  FIG. 15   c  shows an exploded perspective view of inhaler  190 . Inhaler  190  can also be modified to become a passive inhaler by removing the telescoping button  186  and the spring  180  and providing one or more air holes in the stationary housing to allow air inflow.  
         [0115]      FIG. 16  shows another embodiment of an inhaler at  500 . Inhaler  500  is similar in structure to inhaler  120  of  FIG. 13   a  but has the blister pack  310  located concentrically within the housing  104 . All the internal parts in inhaler  500  have the same function as those in inhaler  120 , although their relative positions are adjusted and positioned to accommodate the blister pack being concentric within the housing section  104 . Inhaler  500  can also be modified to become a passive inhaler by removing the section housing  106  and the spring  108  and then providing air vents so that when a user sucks on the mouthpiece  114  air can be drawn into housing  104  and through hole  116  in the blister pack and secondary passageway  132  so that powder within the blister cell aligned with outlet passageway  36  is drawn into the user&#39;s mouth. Optionally the length of housing  104  may be shorted when adapted for the passive mode of operation.  
         [0116]     As mentioned above, the inhaler of the present invention is most suitable for the delivery of very small dosages of pure powdered medicaments, giving the very high delivery efficiency. This is particularly useful for the delivery of very expensive medicaments such as peptide and protein drugs, for which the use of excipient will significantly reduce the delivery efficiency and therefore significantly increase the cost. It is also useful for the systemic delivery or localized delivery of any powdered medicament through the lungs.  
         [0117]     Thus the present invention provides a method of pulmonary drug delivery of a powder medicament into a patient&#39;s respiratory system, which includes filing the powder pockets of a blister pack with a fine powder medicament as discussed above. The fine powder medicament may for example be peptides or fragments thereof, proteins or fragments thereof, antibodies or fragments thereof, antibiotics, vaccines and any combination thereof. The blister pack is loaded into the powder inhaler and the blister pack is moved to bring a powder pocket into flow communication with an outlet flow passageway and a first gas flow inlet passageway, the first gas flow inlet passageway having an inlet in flow communication with a source of gas and an exit located on one side of the powder pocket, said outlet flow passageway having an inlet located on the other side of the powder pocket positioned in flow communication with the outlet flow passageway and an outlet on an exterior of the housing. The powder medicament in the powder pocket which is aligned with the first gas flow inlet and the outlet passageway is fluidized using a first flow of gas from the gas flow inlet passageway which flows into one side of the powder pocket to mobilize, fluidize and deagglomerate the powder medicament such that a mixture of powder medicament and gas flows out through the other side of said powder pocket and into said outlet flow passageway and out of the outlet through a mouthpiece inserted in a user&#39;s mouth so that the medicament is expelled out through the mouthpiece and directly into the user&#39;s respiratory system. The user can repeat this for as many powder pockets as needed.  
         [0118]     This method is very advantageous because the powder medicament does not need to contain any excipient powder particles, but a small amount may be included if desired.  
         [0119]     As used herein, the terms “comprises”, “comprising”, “including” and “includes” are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in this specification including claims, the terms “comprises”, “comprising”, “including” and “includes” and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.  
         [0120]     The foregoing description of the preferred embodiments of the invention has been presented to illustrate the principles of the invention and not to limit the invention to the particular embodiment illustrated. It is intended that the scope of the invention be defined by all of the embodiments encompassed within the following claims and their equivalents.  
                                                           6,546,929   April 2003   Burr, et al.           6,325,061   December 2001   Dagsland           6,257,732   July 2001   Andersson, et al           6,209,538   April 2001   Casper, et al.           6,116,239   September 2000   Volgyesi           6,089,228   July 2000   Smith           6,055,980   May 2000   Mecikalski           6,012,454   January 2000   Hodson, et al.           6,006,747   December1999   Eisele, et al.           5,975,076   November 1999   Yianneskis           5,921,237   July 1999   Eisele, et al.           5,785,049   June 1998   Smith           5,740,794   April 1998   Smith           5,673,685   October 1997   Heide, et al           4,627,432   December 1986   Newel, et al.                      
 
       PUBLICATIONS  
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