Dry powder inhaler

Abstract

To provide a dry powder inhaler including replaceable cartridges containing a dry powder for local or systemic delivery through the pulmonary tract and lungs.SOLUTION: Inhalers 10 are used with inhalable dry powders, including medicament formulations comprising active agents for local or systemic delivery for treatment of pulmonary hypertension, cardiovascular disease, anaphylaxis, diabetes, obesity, cancer and other diseases, or symptoms associated with these and other diseases, such as nausea, vomiting, pain and inflammation.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62 / 289,095, filed on Jan. 29, 2016. The entire contents of this provisional patent application are incorporated herein by reference.

[0002] (Technical Field) The present disclosure relates to a dry powder inhaler comprising an interchangeable cartridge containing a dry powder for delivering an active ingredient to and / or through the lungs, either locally or systemically. The inhaler is used with an inhalable dry powder mainly containing a pharmaceutical formulation including an active agent or an active ingredient for treating diseases such as pulmonary hypertension, cardiovascular diseases, diabetes, obesity and cancer, or symptoms associated with these and other diseases such as nausea, vomiting, pain and inflammation.

[0003] All references cited herein and their references are incorporated herein by reference in their entirety to appropriately explain additional or alternative details, features, and / or technical background.

Background Art

[0004] Drug delivery to lung tissue is achieved using various devices for inhalation, including nebulizers and inhalers such as metered - dose inhalers and dry powder inhalers for treating local diseases or disorders. Dry powder inhalers used to deliver drugs to the lungs typically include a dosing system for a powder formulation, such as bulk supply or hard gelatin capsules or blister packs stored in unit - dose compartments and quantified into individual doses. The bulk container is equipped with a measuring system operated by the patient to separate unit doses from the powder immediately prior to inhalation.

[0005] Dosing reproducibility by an inhaler requires that the drug formulation be uniform and that the dose be delivered to the subject with consistent and reproducible results. Therefore, the dosing system should operate such that all of the formulation is effectively and completely discharged when the patient inhales the amount dosed. However, complete powder discharge from the inhaler is not necessary as long as reproducible dosing can be achieved. In this regard, the flow properties of the powder formulation, as well as the long-term physical and mechanical stability, are more important than the single-dose unit compartments in the bulk container. In unit-dose compartments such as blisters, good moisture protection can be easily achieved. However, the materials used in the manufacture of blisters allow air to enter the drug compartment, and if the formulation being delivered is hygroscopic, the formulation loses viability over long-term storage. The ambient air that penetrates the blister carries moisture that destabilizes the active ingredient. Additionally, dry powder inhalers that use blisters to deliver the drug may cause inconsistencies in dose delivery to the lungs due to geometric changes in the air conduit structure that occur when the blister film is punctured or peeled back.

[0006] A dry powder inhaler can use respiration as a power source or actuation source, and can deliver a drug by transforming drug particles in a carrier into fine dry powder that rides on an air stream and is inhaled by a patient. Drugs delivered using a dry powder inhaler for local pulmonary delivery to treat allergies, asthma, and / or chronic obstructive pulmonary disease (COPD) are contained in multiple-dose inhalers such as, by way of example, FLOVENT® DISKUS, ADVAIR® DISKUS, and PULMICORT® FLEXHALER. Dry powder inhalers are no longer intended to treat only lung diseases and can be used such that a drug is delivered to the lungs and circulates and is absorbed systemically for the treatment of systemic diseases. For example, the AFREZZA® inhaler is a unit-dose dry powder inhaler that delivers a human insulin formulation for the treatment of diabetes in humans. AFREZZA was approved by the U.S. Food and Drug Administration in June 2014 for the treatment of type 1 and type 2 diabetes. AFREZZA is a breath-actuated multi-purpose inhaler that delivers a unit dose of insulin contained in a cartridge to the lungs and circulates and absorbs that insulin for the effective treatment of hyperglycemia associated with diabetes. And accordingly, dry powder inhalers can be used to achieve safe delivery of other active agents by systemic circulation to treat numerous diseases or disorders such as, but not limited to, cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease, and psychosomatic disorders, as well as symptoms of diseases or disorders such as pain, headache, nausea, vomiting, tremors, and infection.

[0007] Dry powder inhalers as described in U.S. Patent Nos. 7,305,986, 7,464,706, 8,499,757, and 8,636,001, which are hereby incorporated by reference in their entirety, can generate primary drug particles or a suitable inhalation plume by deaggregating a single-dose powder formulation contained within a capsule or cartridge during an inhalation operation. During inhalation, the amount of fine powder released from the mouthpiece of the inhaler depends greatly, for example, on the interparticle forces of the powder formulation and the efficiency of the inhaler to separate these particles for inhalation suitability. There are numerous advantages to delivering drugs via the pulmonary circulation, including rapid entry into the arterial circulation, avoidance of drug degradation by hepatic metabolism, and easy and discomfort-free use.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0008] Numerous dry powder inhaler products developed for pulmonary delivery have achieved several successes to date. However, there is room for improvement in terms of lack of practicality and / or manufacturing cost. Some problems existing in prior art inhalers include lack of device durability, dosing inconsistency, device inconvenience, delivery problems when no propellant is used, high manufacturing cost, and / or lack of patient compliance. Accordingly, the inventor has recognized the need to design and manufacture an inhaler with an individual structure that has consistently improved powder transport characteristics, is easy to use, and enables better patient compliance.

MEANS FOR SOLVING THE PROBLEMS

[0009] The present disclosure relates to a dry powder inhaler comprising a replaceable cartridge containing a dry powder for inhalation to be delivered to the lungs for local or systemic delivery to the pulmonary circulation. The dry powder inhaler is a small, reusable or disposable, breath-actuated inhaler having various shapes and sizes, and includes an air flow path conduit system for the effective and rapid delivery of the powder drug to the lungs and the systemic circulation.

[0010] In one embodiment, the dry powder inhaler includes a unit dose cartridge and a dry powder formulation that is aerosolized and delivered to the lung tissue for local tissue action or absorbed into the bloodstream in the lung and delivered by systemic circulation to the target tissue or organ of the subject. In one embodiment, the dry powder can include a pharmaceutically acceptable carrier and excipient, such as a polymer like phospholipid, polyethylene glycol, co-glycolide, carbohydrate, polysaccharide, or diketopiperazine, an active ingredient like a peptide and protein, and a small molecule including a neurotransmitter, and can include carrier molecules.

[0011] In one embodiment, the dry powder inhaler is reusable and is provided with a single-use replaceable cartridge for delivering a single dose using a single inhalation supplied by the patient. In this embodiment, a number of cartridges containing the active ingredient and a specific powder content, for example packaged in a blister pack, can be provided in a single inhaler for multiple uses by the subject. In other embodiments, the cartridge can include a dry powder formulation for treating a variety of conditions, diseases or disorders including bacterial infections such as methicillin-resistant Staphylococcus aureus, pulmonary aspergillosis, lung transplantation, pulmonary arterial hypertension (PHA), osteoporosis, obesity, anaphylaxis or its symptoms, neutropenia, chronic obstructive pulmonary disease (COPD), asthma, allergies, symptoms of diseases or disorders including acute or chronic pain, nausea and vomiting including nausea and vomiting induced by chemotherapy, migraine, dementia, Alzheimer's, depression, Parkinson's, neurological disorders and diseases including multiple sclerosis or its symptoms, etc.

[0012] In one embodiment, the dry inhaler includes a body, a housing, and a mouthpiece formed together with the body. The body includes a mounting area for a cartridge. The body and the housing are movable relative to each other by linear or angular movement. At least a part of the body and the housing are configured to be operable to engage with each other, for example, by insertion, to obtain a closed position and to reconfigure a cartridge disposed in the mounting area to obtain an air flow path for discharging a powder dose contained in the cartridge. In this embodiment, the cartridge is formed of a rigid material and includes a cup and a lid movable relative to each other in translational movement.

[0013] In an exemplary embodiment, a dry powder inhaler is provided that includes a body, a housing, a cartridge, and a mouthpiece. The body of the inhaler includes a mounting area for the cartridge. The cartridge includes a dry powder composition containing fumaryl diketopiperazine and microcrystalline particles of a drug. The housing slides translationally over the body of the inhaler in a proximal to distal direction to open the inhaler or in a distal to proximal direction to close the inhaler. And when the inhaler is closed, the inhaler has one or more rigid air conduits for dispensing the dry powder.

[0014] In another embodiment, the dry powder inhaler comprises a body, a lid, and a mouthpiece. The mouthpiece and the lid are configured as one unit and are movable over the body of the inhaler by angular rotation of the mouthpiece relative to the body. In this and other embodiments, the body includes a distal end, a proximal end, a bottom surface, a top surface, an inner surface, a cartridge mounting region, and an opening in the top surface for connection to the interior of the device and the cartridge mounting region. The mouthpiece has a wing-like structure extending in a plane perpendicular to the mouthpiece air conduit and is configured to form a cover or lid-like structure of a saddle-shaped configuration. When rotated from a perpendicular angle to a horizontal plane, the mouthpiece forms a lid that covers the release region on the top surface to close the inhaler and forms part of the upper surface of the inhaler. In the closed configuration, a cartridge loaded in the cartridge mounting region moves from a storage position to a dosing position, an air conduit is formed through the cartridge, and powder within the cartridge can be discharged from the inhaler during an inhalation operation. In one form of this embodiment, the mouthpiece is formed to have a structure for engaging a cartridge mounting component to reconfigure the cartridge from a storage shape to a dosing shape. In one embodiment, the inner surface of the inhaler has a protrusion in a cartridge mounting region designed to hold a cartridge cup when the cartridge is mounted. In one embodiment, the structure for engaging the cartridge mounting region includes a gear and a rack that pivot the portion of the mouthpiece of the inhaler away from the inhaler body and release the inhaler to a mounting arrangement in a position perpendicular to the inhaler body in a horizontal plane, and also pivot from a vertical plane to a horizontal position to close the inhaler and to a dosing configuration with a cartridge mounted in the inhaler.

[0015] The dry powder comprises an inhalable dry powder comprising a pharmaceutical formulation containing an active ingredient for pulmonary delivery. In some embodiments, the delivery is to the deep lung (i.e., the alveolar region), and in some of these embodiments, for systemic targeting or general use, the active agent or ingredient is absorbed and enters the pulmonary circulation. Dry powder inhalers of unit dose cartridges, and drug delivery formulations, include, for example, diketopiperazine, and active ingredients such as peptides and proteins including parathyroid hormone, insulin, oxyntomodulin and glucagon-like peptide 1. In some embodiments, the active ingredient includes, but is not limited to, treprostinil, salmeterol, epinephrine, tacrolimus, vancomycin, linezolid, filgastrim, fentanyl, cannabinoid, palonosetron, amphotericin B, phosphodiesterase inhibitors including PDE5 inhibitors such as sildenafil, avanafil, vardenafil, tadalafil, prostacyclin (PGI2) and its analogs, neurotransmitter agonists, neurotransmitter antagonists including non-invasive receptors, opioid analgesics such as delta opioid agonists and antagonists, kappa opioid receptor agonists and antagonists, opioid receptor agonists and blockers, including one or more active agents.

[0016] In one embodiment, the dry powder inhaler includes a housing, a movable member, and a mouthpiece. The movable member is operably formed to move a container from a powder storage position to a dosing position. In this and other embodiments, the movable member can be formed as part of a lid component at the proximal end of the inhaler and can form part of a cartridge mounting area. In this embodiment, the mouthpiece is constructed integrally with a lid or cover that covers the housing over the cartridge mounting area when the inhaler is closed. When the mouthpiece moves downward from the horizontal plane, the lid or cover is moved angularly to the vertical position, opening the inhaler, providing access to the interior of the inhaler, and enabling the attachment and detachment of the cartridge. Conversely, when the mouthpiece moves upward from the vertical plane to the horizontal plane, the closure of the inhaler is induced, and an opening in the air path is automatically created between the inhaler and the cartridge mounted in the cartridge mounting area.

[0017] In other embodiments, the dry powder inhaler comprises a body, a housing, and a mouthpiece. The inhaler is structurally formed to have a mechanism that is operable to receive, hold, and reconfigure a cartridge from a storage position to a dispensing, dosing, or dose delivery position as the inhaler moves from an open position, a closed position, and from the open position to the closed position. Also, in a variation of this embodiment, the mechanism can reconfigure the cartridge attached to the inhaler from the dosing position to the storage position after use when the mechanism is opened for removing a used cartridge. In one embodiment, the mechanism can reconfigure the cartridge into a disposable or discarded shape after use.

[0018] In one embodiment, the body of the inhaler includes a proximal portion including a mouthpiece, the body, and a distal portion including a housing that is structurally configured as a slip-on cover over the interior of the inhaler and a portion of the body. The housing includes a distal end and a proximal end, and the proximal end includes an opening for conforming and enclosing a portion of the inhaler body. In one embodiment, the proximal end contacts or abuts the inhaler body to close the inhaler from the external environment. The inhaler is opened by a translational movement in the distal direction on the body to move the upper part of the housing from a closed shape to a mounting position and / or a dismounting position of the inhaler for insertion or removal of the cartridge. With the cartridge attached to the inhaler, when the upper part of the housing is translated from the distal direction to the proximal direction on the body, the cartridge is displaced from the storage arrangement to the dosing arrangement, and the cartridge container is pushed into the dosing arrangement by a protrusion configured inside the housing extending beyond the opening of the proximal end when the inhaler is in the open state. The movement of the top of the housing is achieved by the movement of a lever having a button-like structure at its top, which is attached to the housing and opens and closes the cartridge mounting area of the inhaler. In the closed state, the cartridge attached to the inhaler is reconfigured to form an additional air flow path together with the mouthpiece and the surrounding air and connects to the dry powder in the cartridge in the dosing arrangement during inhalation. In this embodiment and other embodiments, the air flow path of the cartridge in the dosing arrangement has an air inlet and outlet that communicates with the air flow path in the mouthpiece. The mouthpiece itself has an air inlet and outlet.

[0019] In one embodiment, the body of the inhaler comprises a mouthpiece formed at the proximal end of the body, an air duct communicating with the interior of the housing, and can communicate directly with the air outlet of the cartridge attached to the inhaler and the surrounding air. Further, the inhaler body has a cartridge mounting region that is structurally continuous with the mouthpiece and has a distal portion and a proximal portion. The proximal and distal portions form a single unitary part with the mouthpiece and are insertable into the housing. In one embodiment, by separating the body from the housing, a release configuration of the inhaler can be achieved for connection to the internal compartment. In this release configuration, a cartridge containing dry powder can be mounted or attached to the cartridge mounting region of the body, and the body and housing can be pushed or pulled to release or close the inhaler. In one embodiment, the housing is movable on the distal portion of the body from an open configuration to a closed configuration, and together they form an air duct through the cartridge attached to the cartridge mounting region to close the inhaler. In this configuration, the inhaler is in a dosing configuration in which, when orally inhaled by the user through the mouthpiece, the powder in the cartridge is released from the inhaler. In the dosing configuration of this embodiment, the body and the housing abut against each other and are firmly fitted by one or more anti-slip structures to prevent the inhaler from coming apart. Examples of anti-slip features may include snap rings or detents that can generate a sound to warn the user that the inhaler is ready for use.

[0020] In one embodiment, the inhaler has a substantially rectangular shape with a distal side and a proximal side, and the length of the distal side is shorter. The inhaler includes a movable housing portion that covers the distal portion of the inhaler body. The movement of the housing on the body or vice versa is achieved by separating the inhaler body from the housing and exposing the interior of the inhaler. The movement of the housing can be achieved by pulling or pushing the housing on the inhaler body having parallel guide rails or tracks extending outward from the long sides (the first side and the second side) of the inhaler in a longitudinal cross-section. In this embodiment, the inhaler body is designed to have an opening at its distal end so as to fit the opening at the distal end of the housing in order to allow ambient air to flow into and be guided into the internal chamber of the inhaler during inhalation. Also, the housing is configured to fit precisely with grooves or slits for sliding on the guide rails during the opening and closing movement, and further includes a stop end for preventing the disassembly of the inhaler, a positioning for the cartridge in the dosing arrangement after attachment, and a pushing element for closing the inhaler when the housing moves from the distal direction to the proximal direction. The pushing element moves the cartridge cup or container relative to the lid of the cartridge, forms an air flow path through the cartridge, forms an air inlet and outlet, enables aerosolization of the powder in the cup during inhalation, and delivers the aerosolized particles to the mouthpiece of the inhaler and the user. Also, in another embodiment, the pushing element moves the cartridge member to position the lid relative to the inlet opening disposed on the floor of the mouthpiece. In one aspect of this embodiment, the dry powder inhaler includes a housing including a pushing element that positions the cartridge to align with the mouthpiece by converting the housing from a released arrangement covering the inhaler body to a closed arrangement.

[0021] In one embodiment, the dry powder inhaler comprises a housing having a distal end and defining an opening in communication with the surrounding air. In one embodiment, the housing is configured in the shape of a cover that slides over the inhaler body, substantially covering a portion of the inhaler body and translating over the distal portion of the body. The inhaler achieves two configurations, namely a first configuration in which the inhaler is open to connect to its internal compartment, the chamber, and a second configuration in which it abuts against the proximal end to achieve closure of the inhaler. Also, in one embodiment, the distal portion of the housing extends distally and is movable relative to the proximal end in a horizontal plane to allow connection to a cover surrounding the inhaler body and to the internal compartment of the inhaler. In a variation of this embodiment, the distal portion of the housing comprises parallel structures or flanges for engaging a portion of the inhaler body, for example to fix the inhaler body to the housing, fixing the two parts and forming a fixing mechanism for maintaining the dosing arrangement. In one embodiment, the distal portion of the housing has an opening at the distal end for communicating with the interior of the inhaler and comprises an opening configured to slide over the inhaler body. Also, the distal portion of the housing includes an external surface, an internal surface, and a chamber configured to slide over the inhaler body. In one embodiment, the distal portion of the inhaler includes a wing-like structure parallel to its upper surface for directing the air flow towards the mouthpiece during inhalation.

[0022] In another embodiment, the mouthpiece is engaged with the body of the inhaler by various mechanisms including movable members such as hinges, and is integrally formed with a movable member including a rack for moving the lid of the cartridge relative to the cartridge cup or container. The movable member is configured to receive and reconfigure a cartridge attached to the inhaler from a storage position to a dosing position, and can be designed to operate manually or automatically, for example, during the movement of the inhaler components to close the device from an open configuration. In one embodiment, the mechanism for reconfiguring the cartridge comprises a slide tray or thread attached to the mouthpiece and movably attached to the housing. In other embodiments, the mechanism includes a gear mechanism attached or adapted to the inhaler, for example integrally attached within a hinge of the inhaler. In yet another embodiment, the mechanism configured to be operable to receive and reconfigure the cartridge from a storage arrangement to a dosing arrangement comprises a cam capable of reconfiguring the cartridge, for example, upon rotation of the housing or the mouthpiece. In one embodiment, the angular rotation of the mouthpiece from the horizontal plane opens the inhaler and allows attachment or removal of the cartridge, or the angular movement of the mouthpiece from the vertical plane to the horizontal plane achieves closure of the mouthpiece and automatic reconfiguration from the storage position to the dosing position. In one embodiment, the operating gear mechanism positions the lid of the cartridge relative to the inlet opening of the mouthpiece and achieves translation of the cup to the dosing arrangement.

[0023] In yet other embodiments, a dry powder inhaler including a body and a mouthpiece is provided, the inhaler body being designed to have a substantially rectangular shape having an upper portion, a lower portion, a proximal portion, and a distal portion, the upper portion having an opening in the distal half of the inhaler body to be connectable to the internal compartment and the cartridge mounting region of the inhaler. In this embodiment, the mouthpiece of the inhaler comprises two air inlets, one communicating with ambient air at the distal end of the inhaler and one communicating with the outlet portion in the cartridge and the air outlet in the proximal portion of the inhaler for insertion into the subject's mouth. In this embodiment, the body and the mouthpiece are engaged by gears, a rack, and pinion members, and a movable cartridge cup carrier operates by moving the mouthpiece in a horizontal plane from an angle of about 180 degrees parallel to the inhaler body to an angle of about 90 degrees or perpendicular to the inhaler body so that the inhaler is opened and the cartridge can be loaded and unloaded. Moving the mouthpiece back to parallel with the inhaler body up to an angle of 180 degrees closes the inhaler and moves the cartridge cup to create an air flow path between the mouthpiece of the inhaler and the cartridge, and further automatically reconfigures the cartridge disposed in the inhaler into a dosing arrangement by forming an inlet port in the cartridge for ambient air passing through the interior of the cartridge to aerosolize the powder in the cartridge during inhalation.

[0024] In another embodiment, a dry powder inhaler comprises a mouthpiece, a thread, a slide tray or cartridge, a housing, a hinge, and a gear mechanism configured to effect movement of the slide or slide tray. The mouthpiece and the housing are movably attached by a hinge.

[0025] A cartridge for use with a dry powder inhaler can be manufactured to contain any dry powder drug for inhalation. In one embodiment, the cartridge is structurally formed to be compatible with a particular dry powder inhaler and can be formed in any size and shape depending on the size and shape of the inhaler used, for example if the inhaler has a mechanism that allows translational or rotational movement. In one embodiment, the cartridge can be formed with a securing mechanism having an angled edge at the top of the cartridge that corresponds to a matching angled edge within the inhaler such that the cartridge is secured during use. In one embodiment, the cartridge comprises a container and a lid or cover, the container is adapted to the surface of the lid and is movable relative to the lid, or the lid is movable on the container and can achieve various arrangements depending on its position, such as a mounting arrangement, a dosing arrangement, or a post-use arrangement. During inhalation, the cartridge in the dosing position adapted to the inhaler allows air flow to enter the container, mix with the powder, and fluidize the drug. The fluidized drug moves within the container and gradually exits the container through a dispensing opening. The fluidized drug present at the dispensing opening is sheared and diluted by a secondary flow that does not originate within the container. A cartridge for a dry powder inhaler includes, as described, a container formed to hold the drug, at least one inlet port that allows flow into the container, and at least one dispensing port that allows flow out of the container. The at least one inlet port is configured to direct at least a portion of the flow entering the at least one inlet port to at least one dispensing opening within the container depending on a pressure differential.

[0026] In some embodiments, the dry powder formulation is dispensed consistently from the inhaler in less than about 3 seconds, or generally less than 1 second. In some embodiments, the air conduit of the inhaler is designed to produce a high resistance, for example, for an air flow rate value of about 0.065 to about 0.200 (√kPa) / liter / min. Thus, an inhalation system with a peak inhalation pressure drop between 2 and 20 kPa results in a peak flow rate between about 7 and 70 liter / min. These flow rates result in dispensing more than 75% of the contents of the cartridge with a fill mass between 1 and 50 mg. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation operation, producing a cartridge dispense rate of greater than 90%. In certain embodiments, the inhaler and cartridge system are configured to deliver a single dose by discharging the powder from the inhaler as a continuous flow or as one or more pulses of powder delivered to the patient.

[0027] In other embodiments, the inhalation system includes a breath-actuated dry powder inhaler and a cartridge containing a dry powder comprising a drug for delivery to the respiratory tract and lungs. The drug can include, for example, a pharmaceutical formulation for pulmonary delivery, such as a diketopiperazine-containing composition in a self-assembling crystalline form, an amorphous form, and / or a microcrystalline form containing non-self-assembling crystals, or a combination thereof, and an active agent. In other embodiments, the dry powder may be formulated from other carriers and / or excipients other than diketopiperazine, such as sugars including trehalose and an active agent. In some embodiments, the active agent includes peptides and proteins such as insulin, glucagon-like peptide 1, oxyntomodulin, peptide YY, exendin, or any active ingredient, and similar compounds thereof. This inhalation system can be used, for example, in the treatment of diabetes, prediabetes, allergies, infectious diseases including sepsis and urinary and respiratory tract infections, anaphylaxis, lung diseases, kidney diseases, liver diseases, dementia, neurodegenerative diseases, or cardiovascular diseases, blood diseases, cancer, and obesity, and in methods for treating conditions requiring local or systemic delivery of a drug in the treatment of diseases and symptoms associated with these diseases. In one embodiment, the inhalation system includes a kit containing at least one of each component of the inhalation system for treating a disease or disorder.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0029] In the embodiments disclosed in this specification, a dry powder inhaler is disclosed that includes a cartridge for delivering a dry powder, including a pharmaceutical, to a subject by oral inhalation. In one embodiment, the dry powder inhaler is a breath-actuated dry powder inhaler and is designed to contain an inhalable dry powder, including, but not limited to, a pharmaceutical containing an active ingredient, which includes a pharmaceutically active substance and, optionally, a pharmaceutically acceptable carrier.

[0030] Dry powder inhalers are provided in various forms of shape and size, are reusable, easy to use, inexpensive to manufacture, and / or are mass-produced in a simple step using plastic or other acceptable materials. Various forms of dry powder inhalers are provided herein. Generally, the inhalation system includes an inhaler, a powder filling cartridge, and an empty cartridge. This inhalation system can be designed to be used with any type of dry powder. In one embodiment, the dry powder is a relatively cohesive powder that requires optimal deagglomeration conditions. In one embodiment, the inhalation system comprises a reusable small breath-actuated inhaler in combination with a disposable cartridge containing a pre-metered dose of a dry powder formulation.

[0031] As used herein, the term "unit dose inhaler" refers to an inhaler adapted to receive a single cartridge or container containing a dry powder formulation and to deliver a single dose of the dry powder formulation from the single container to the user by inhalation. It should be understood that in some cases, multiple unit doses may be required to supply a specific dosage to the user.

[0032] As used herein, a "cartridge" is a container formed to hold or contain a dry powder formulation or powder enclosed in an enclosed container having a cup or container and a lid. The cartridge is made of a rigid material, and the cup or container is movable relative to the lid in a translational or reverse translational movement.

[0033] As used herein, "powder mass" refers to an agglomerate or aggregate of powder particles having an irregular geometric shape such as width, diameter, and length.

[0034] As used herein, "unit dose" refers to a dry powder formulation that has been pre-measured for inhalation. Alternatively, a unit dose can also be a single container having doses of multiple formulations that can be delivered by inhalation as a measured single amount. A unit dose cartridge / container contains a single dose. Alternatively, it may comprise a plurality of individually accessible compartments, each containing a unit dose.

[0035] As used herein, "about" is used to indicate a value that includes the standard deviation of error in the device or method used to determine that value.

[0036] As used herein, "particles" refers to particles having a diameter of about 0.5 to about 1000 μm, regardless of their exact external or internal structure. Particles having a diameter of about 0.5 to about 10 microns can reach the lungs and can successfully pass through most natural barriers. A diameter of less than about 10 microns is required to pass through the turning part of the throat, and a diameter of about 0.5 μm or more is required to prevent expulsion. To reach the deep lung (or alveolar region) where the most efficient absorption is thought to occur, it is preferable to maximize the proportion of particles included in the "inhalation fraction" (RF). Generally, although used in somewhat different ranges in some references, as measured using standard techniques such as the Anderson Cascade Impactor, these particles are accepted with an aerodynamic diameter of about 0.5 to about 6 μm. Other impactors such as the NEXT GENERATION IMPACTOR (registered trademark) (NGI (registered trademark), MSP Corporation), which defines the inhalation fraction with a similar aerodynamic size of less than 6.4 μm, can be used to measure the aerodynamic particle size. In some embodiments, a laser diffraction device, such as that disclosed in U.S. Patent No. 8,508,732, is used to determine the particle size. The disclosure incorporates the entire theory related to laser diffraction, and the volume median geometric diameter (VMGD) of the particles is measured to evaluate the performance of the inhalation system. For example, in various embodiments, emptying more than 80%, more than 85%, or more than 90% of the cartridge, and the VMGD of the released particles larger than 12.5 μm, larger than 7.0 μm, or larger than 4.8 μm indicates innovatively better aerodynamic performance.

[0037] Inhalation fraction filling (RF / fill) represents the proportion (%) of particles suitable for respiration during the release of the powdered content filled as a dose, which is released from the inhaler. That is, it represents the proportion of particles released in a size suitable for pulmonary delivery during the filled dose and is the measurement result of the aerodynamic performance of fine particles. As described herein, an RF / fill value of 40% or more reflects acceptable aerodynamic performance. In certain embodiments disclosed herein, the inhalation fraction filling may be greater than 50%. In typical embodiments, the inhalation fraction filling is up to about 80%, and about 80% of that filling is released at a particle size up to 5.8 μm as measured using standard techniques.

[0038] As used herein, the term "dry powder" refers to a particulate composition that is not suspended or dissolved in a propellant or other liquid. This does not necessarily mean that all water molecules are completely absent.

[0039] As used herein, "amorphous powder" includes all amorphous powders and refers to a dry powder lacking an ordered repeating form, shape, or structure.

[0040] In the typical embodiments shown herein, the device can be manufactured from several methods and various materials. In one embodiment, the inhaler and cartridge are made using injection molding techniques, thermoforming, blow molding, pressure forming, 3D printing, etc. with various types of plastic materials such as, for example, polypropylene, cyclic olefin copolymer, nylon, and other compatible polymers. In certain embodiments, the dry powder inhaler can be assembled using a component that covers all of the individual components. In some embodiments, the inhaler is generally provided in a compact size of about 1 inch to about 5 inches, for example in dimensions, and the width and height are smaller than the length of the device. In certain embodiments, the inhaler is provided in various shapes including a relatively rectangular body, but can also be provided in other shapes such as cylindrical, elliptical, tubular, square, rectangular, and circular.

[0041] In the embodiments described and illustrated herein, the inhaler effectively fluidizes, deaggregates, or aerosolizes the dry powder formulation by using at least one relatively rigid flow conduit to allow air flow to enter the inhaler. For example, the inhaler is provided with a first air flow path for entering and exiting a cartridge containing the dry powder, and a second air flow path mergeable with the first air flow path exiting the cartridge. The flow conduit can have various shapes and sizes, for example, depending on the shape of the inhaler. In one embodiment, the inhaler has a high resistance inhaler resistance value of, for example, about 0.065 to about 0.200 (√kPa) / litter / min. Therefore, in this system, a peak inhalation pressure drop of 2 to 20 kPa results in a peak flow rate of about 7 to 70 litter / min. These flow rates are greater than 75% of the cartridge contents dispensed with a fill mass of 1 to 50 mg. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation operation to produce a cartridge dispense ratio of greater than 90% of the powder contained in the cartridge.

[0042] Embodiments of the dry powder inhaler 10 are illustrated in FIGS. 1-5. The inhaler 10 includes two elements, a body 12 and a mouthpiece cover 11. In this embodiment, the dry powder inhaler 10 is relatively rectangular, with its long side extending in the longitudinal plane, and is designed to achieve two configurations, namely, a first configuration which is a closed or dosing configuration as shown in FIGS. 1, 3 and 4, and a second configuration which is an open or cartridge mounting / dismounting configuration as shown in FIGS. 2 and 5. As shown in FIGS. 1-5, the dry powder inhaler 10 has a relatively rectangular body 12 manufactured as a single element, including a substantially C-shaped proximal end 14 with a mouthpiece 15 that contacts the user's lips or mouth, and a distal end 16 having a right side 17, a left side 18, an upper side 19, and a lower side 20. The mouthpiece 15 has an outlet 13 and a first inlet 21 that communicates with the chamber or interior of the inhaler body through a second inlet 3 located at the lower part of the mouthpiece in contact with the inhaler body and bypasses the air flowing through the air duct 5 into the interior of the inhaler body. In particular, the second inlet is connected to the outlet port or dispensing port 31 of the cartridge attached to the cartridge mounting area. In FIG. 3, the mouthpiece 15 is shaped to be narrower at the distal end, tapering outwardly towards the proximal end, and is formed with an air duct 5 having a shape similar to the external shape. The mouthpiece 15 is designed as a single element with saddle-shaped or wing-shaped structures 22, 22' that partially extend outwardly to the confluence point on the upper side 19 to form a part of the upper side 19, extend downwardly on the right side 17 and the left side 18, and cover or overlie the right side 17 and the left side 18 of the body 12 to close the inhaler 10 as the mouthpiece cover 11.

[0043] Figures 2 and 5 show the inhaler 10 in an open configuration showing the interior of the body 12. Figure 5 shows the inhaler 10 in the open configuration and Figure 2 shows the inhaler 10 with the cartridge 24 attached to the cartridge attachment member 23. To open it, the mouthpiece 11 is pushed downward from its mouthpiece 15 and by grasping the distal upper portion of the inhaler 12, the entire element 11 is rotated approximately 90° and placed perpendicular to the body 12. The operation of the mouthpiece cover 11 is achieved by providing a rack and pinion in the inhaler that includes a hinge, for example, a shaft 32 connected to a gear having a rack engaged with the rack on the movable cartridge attachment region 23.

[0044] Figure 3 is a central longitudinal sectional view of the inhaler 10 with the cartridge in the dosing arrangement, showing the pushing element 33 of the movable cartridge attachment region 23 that fully positions the cartridge in the dosing arrangement, and an air passage having an air inlet 29 and an air outlet 31 is formed and connected inside the cartridge cup 30. In this embodiment, the inhaler is closed as shown in Figure 1 by moving the mouthpiece cover 11 upward while holding the mouthpiece 15 in a horizontal plane. And during the movement, the movable part of the cartridge member in the cartridge attachment region 23 is pushed distally by a movable element in the proximal part of the cartridge attachment region, as a result, the cartridge lid 28 moves distally beyond the cartridge cup 30, and the cup 30 is held in the attachment region by the rigid protrusions 27, 27' on the inner surface of the lower side surface 20 of the body 12. After use, by opening the inhaler 10, the cartridge is returned to the discard / removal position and a new dosing can be repeated in that cycle. Figure 4 is a central longitudinal sectional view of the inhaler shown in Figure 1, showing the internal relationships of the device in a closed arrangement without the cartridge.

[0045] Figure 5 is a central longitudinal sectional view of the inhaler shown in FIG. 1 in an open configuration without the cartridge. It shows a state in which a rigid protrusion protruding from the lower inner surface 20 of the inhaler body 12 is attached to the cartridge mounting area, and the dosing arrangement is achieved upon movement of the mouthpiece cover 11 to a closed shape by the pushing element 33 of the lid of the movable cartridge mounting area 23 for moving the lid beyond the cup of the cartridge.

[0046] Figures 6 to 10 show another embodiment. The dry powder inhaler 40 includes a main body 42, a mouthpiece 45 having at least two air inlets and one outlet 46, and a mechanism 47 for mounting and reconfiguring a cartridge. Further, the inhaler 40 includes a discontinuous upper surface 51 that can be formed in a partial rib-like structure, and includes a proximal end 48, a distal end 49, and a bottom 42. In this embodiment, the inhaler 40 is in a closed position. The distal half 49 of the upper part of the inhaler body 42 engages with a movable rack 54 within the internal compartment of the inhaler body 42 to accommodate a movable lever 52 within a central longitudinal plane in order to enable movement of the cartridge mounting and reconfiguring mechanism 47, and includes a rack having a pushing element for moving the cartridge lid over the cup or moving the cup under the fixed lid of the cartridge. In this embodiment, when the lever 52 is manually moved in the distal direction, the inhaler is configured in a cartridge mounting position. FIG. 7 shows the inhaler 40 in an open configuration with a cartridge attached or mounted in the cartridge mounting area 55. When preparing a dose for pulmonary inhalation, the user can place or install a cartridge 56 within the inhaler as shown in FIG. 7. After the cartridge 56 is attached or mounted in the cartridge mounting area 55, the lever 52 moves proximally until it can no longer move. FIG. 8 shows a central longitudinal cross-sectional view of the inhaler 40 in a closed or dosing configuration with a cartridge attached in the cartridge attachment or reconfiguration area 55, and shows a pushing element 66 for moving the cup 58 under the lid 59 in the dosing configuration. While the lever 52 is moving, a pushing element 66 inside the inhaler engaged with the lever 52 actuates the pushing element 66 of the rack to move the cartridge 56, reform its lid, form an air conduit together with the air inlet 64, and form an air outlet 65 in communication with a second inlet 63 of the mouthpiece 45 to deliver powder to the air conduit 61 and the outlet 46 of the mouthpiece during inhalation. The intake of air through the first inlet 62 bypasses the cartridge compartment during inhalation. The discontinuous area on the upper surface 51 of the inhaler allows access to the cartridge mounting area 55. Also, FIG. 8 shows the lever 52 engaged with the shaft 60 of the reconfiguring mechanism 47.

[0047] Figure 9 shows a closed inhaler 40 which is similar to Figure 8, except that it does not include a cartridge disposed at the proximal end of the inhaler body 42. In the shape shown in Figure 9, during inhalation of the powder dose, in order to achieve the deaggregation of the powder by shear force, the close proximity of the rack 54 including the pushing element 66 and the horizontal first inlet 62 is related in an approximately vertical shape by the second inlet 63 of the mouthpiece 45. Figure 10 shows the inhaler 40 shown in Figure 9 in a state without a cartridge in an open arrangement through a central longitudinal section, showing the positions of the lever 52 and the rack 54 for holding the cartridge, and the position of the central part of the inhaler body 42 at the end inside the inhaler. Also, Figure 10 shows the rack 54 integrally engaged with the movable mechanism for mechanically pushing the rack 54, as indicated by the shaft 60 contacting the lever 52.

[0048] Figures 11 to 15 show yet another inhaler, which is connected inside the main body 72 and allows the cartridge to be detachably attached. A gear mechanism 85 that rotates horizontally on a horizontal plane at an angle of approximately 90° from the longitudinal axis A of the inhaler 70 is shown, and the mouthpiece 71 is movable relative to the inhaler main body 72. Further, the mouthpiece 71 includes an air inlet 74, an air outlet 73, and a second air inlet communicating with the inside of the main body 72 of the inhaler. Figure 11 shows the closed or dosing arrangement of the inhaler 70. Figure 12 shows the inhaler 70 in an open arrangement for attaching or mounting the cartridge, as illustrated by the cartridge 76. The inhaler 70 is designed to have a substantially rectangular main body 72 with a proximal end 75, a distal end 77, a bottom 78, a right side 79, a left side 80, and a top 81 that is closed at one end and open at its distal end. Also, the mouthpiece 71 has a side extension 82 formed as a single part extending from the central air duct and covering the top surface 81 of the inhaler main body. The top surface 81 includes a stop end 83 formed to prevent the mouthpiece 71 from rotating beyond a plane perpendicular to the inhaler main body 72. By rotating the mouthpiece 71 to the open position, as shown in Figure 12, the attachment or reconfiguration mechanism is actuated so as to provide access to the open area of the top surface 81 of the main body 72. Figures 13 and 14 show a central longitudinal sectional view of the inhaler 70, where Figure 13 shows the state with the cartridge to show the movement of the rack 86 in the closing or dosing mechanism by the gear mechanism 90, and Figure 14 shows the situation without the cartridge. The movement of the mouthpiece 71 from the right side 79 to the left side 80 in the horizontal direction relative to the inhaler main body actuates the gear mechanism, causing the cup 92 to move relative to the lid 93 by a translational movement in the proximal direction, forming an air flow path through the inside of the cup together with the air inlet 94 and the air outlet 95, and connecting the inlet 89 of the inhaler 70 and the air duct 96 for discharging the powder contained in the cup 92. In this embodiment, the attachment and reconfiguration mechanism includes a shelf structure 99 constructed within the top surface of the mounting area 91 for placing the lid 93 of the cartridge that extends outward from the cup 92 and is placed on the fixed shelf structure 99. The cup 92 is received in the rack 86, and the cartridge is in a powder-containing shape.

[0049] Further, other forms of dry powder inhalers are shown in FIGS. 16 to 20. The inhaler 100 includes a two-part member, an inhaler body 101, and a housing or cover 102 that covers a part of the inhaler body 101. In one embodiment shown in FIG. 16, the inhaler 100 includes a proximal end 103 with a mouthpiece 104 and a distal end 105 with an inhaler body 101 that includes a housing 102 structurally formed as a slip-on cover over the inhaler body and internal parts. The housing 102 shown in FIG. 17 includes a distal end 107 and a proximal end 106. The proximal end 106 includes an opening for adapting and encapsulating a part of the inhaler body 105, and also includes a protrusion 113 protruding from its upper surface to allow a direct air flow to enter the air conduit 115 of the mouthpiece 104 during inhalation. In one embodiment, as shown in FIG. 16, the proximal end 106 contacts or abuts the inhaler body 101 so as to close the inhaler 100 from the external environment. The inhaler 100 is opened by moving the housing 102 in a translational motion in the distal direction on the body 105 from a closed position to achieve a mounting and / or dismounting position in the inhaler for attaching and removing the cartridge. FIG. 17 shows the inhaler 100 in an open position where the housing 102 is pulled away distally to allow access to the distal part 105 of the inhaler body. In this and other embodiments, as shown in FIG. 17, a cartridge 108 is attached to the cartridge mounting area 109 of the inhaler 100, and a lid and outlet port 110 communicating with an air conduit in the mouthpiece extending through a second inlet of the mouthpiece 104 to the inlet 111 and outlet 112 are shown. The mounting area 109 is formed to fit exactly the shape of the cartridge 108 and is formed to visually indicate the proper orientation of the cartridge to the user during mounting.

[0050] Also, FIG. 18 shows a central longitudinal sectional view of the inhaler 100 in a closed dosing arrangement showing the position of the cartridge cup 116 relative to the lid 117 during the translational movement of the housing 102 on the body 105 from the distal direction to the proximal direction, causing the movement of the cartridge 108 from the storage arrangement to the dosing arrangement. The cup 116 of the cartridge container is pushed into the dosing arrangement at the proximal end 106 in the horizontal plane by a protruding rigid element at the bottom inside the housing 102 extending beyond the opening 106. Also, the protruding rigid element 118 can include one or more vertical protrusions to facilitate removal of the cartridge 108 after use. Further, in the closed arrangement, the cartridge attached to the inhaler 100 is reconfigured to form an additional air flow path through the cartridge cup 116 at the air inlet 119 and the air outlet 120, and in the dosing arrangement, using the mouthpiece for ambient air, accesses the dry powder in the cartridge 108 during inhalation. In this and other embodiments, when inhaled, air enters the air flow path of the cartridge 108 in the dosing arrangement through the air inlet 119, the dry powder particles are aerosolized and entrained in the air, and are discharged from the air inlet in the air conduit 115 of the mouthpiece 104 and the air outlet 120 communicating with the air flow path of the mouthpiece 104, and further shearing of the powder occurs before the powder is discharged through the outlet 112 of the mouthpiece.

[0051] In one embodiment, the main body 101 of the inhaler includes a mouthpiece integrally formed at the proximal end of the main body 101, and includes an air duct 115 communicating with the interior of the main body 101 and the housing 102, and can directly communicate with the air inlet 120 of the cartridge 108 attached to the inhaler 100 and the ambient air. Further, the inhaler main body 101 includes a cartridge mounting region 121 that is structurally continuous with the mouthpiece and has a distal portion 105 and a proximal portion 103. The proximal portion 103 and the distal portion 105 form a single component together with the mouthpiece 104, and the distal portion 105 can be inserted into the housing 102. In one embodiment, as shown in FIGS. 17 and 20, the main body 101 and the housing 102 can be manually separated to obtain an inhaler opening arrangement for accessing the internal compartments. In this form of the opening arrangement, the cartridge 108 containing the dry powder is mounted or attached in the cartridge mounting region of the main body portion 105 in an appropriate orientation as indicated by a visual cue, and the main body 101 and the housing 102 can be pushed or pulled to open and close the inhaler 100. In one embodiment, the housing is movable over the distal portion 105 of the main body 105 to move from the open arrangement to the closed arrangement, and when they contact each other, the inhaler 100 is closed.

[0052] Figures 18 and 19 show the inhaler 100 in the closed or dosing configuration. The closing operation achieves the movement of the cartridge 108 to the dosing position. Further, the cartridge cup is pushed by the protrusion 118 and reconfigured independently of the lid 117, showing a state of forming an air duct passing through the cartridge 108 attached to the cartridge mounting area 109. In this shape, the inhaler achieves the dosing shape so that the powder in the cup 116 is released from the inhaler during oral inhalation by the user through the mouthpiece 104. In this embodiment and dosing arrangement shown in Figure 18, the body and the housing are in contact with each other and are closely fitted by one or more anti-slip structures to prevent the disassembly of the inhaler. Some examples of the anti-slip structures include a snap ring that can generate a sound to warn the user that the inhaler is ready for use, or a detent. Figures 17 and 20 show the inhaler 100 in the release shape. In this embodiment, the inhaler 100 is substantially rectangular, with the lengths of the distal and proximal sides being smaller. By pulling or pushing the body part 105, the movement of the housing 102 on the body part 105 is achieved, and vice versa. The movement is facilitated by a body including guide rails and tracks 123 that extend outward from the long sides (the first side and the second side) of the inhaler body 105 in the longitudinal plane. In this embodiment, the inhaler body 105 is designed to have an opening at its distal end so as to coincide with the opening at the distal end of the housing, guiding and introducing ambient air into the internal chamber of the inhaler 100 during inhalation. Also, the housing 102 of the inhaler is precisely formed to have grooves or slots 124 for sliding on the guide rails 123 during movement, and is provided with one or more stop ends to prevent the disassembly of the inhaler 100. The push or protrusion 118 is designed to position the cartridge in dosing after attachment and closing of the inhaler 100. The push or protrusion 118 moves the cartridge cup or container 116 relative to the cartridge lid 117, forms an air flow path through the cartridge, forms an air inlet 119 and an air outlet 120, enables the aerosolization of the powder in the cup during inhalation, and delivers the aerosolized particles to the mouthpiece air duct 115 of the inhaler and the user.

[0053] In the description of the inhaler 100, the distal portion of the housing includes a parallel structure and a flange for engaging a part of the inhaler body, for example, fixing the inhaler body to the housing to form a fixing mechanism for fixing the two parts and maintaining the dosing arrangement. In one embodiment, the distal portion 107 of the housing 102 has an opening at its distal end for communicating with the interior of the inhaler 100 and an opening 106 formed to slide over the inhaler body 105. Further, the distal portion 107 of the housing 102 includes an outer surface, an inner surface and a chamber formed to enclose the inhaler body 105. In one embodiment, the housing 102 includes a wing-like structure 113 parallel to its upper surface for directing an air flow towards the mouthpiece 104 during inhalation. The inhaler body portion 105 can be designed with a groove in its central longitudinal plane for fitting an extrusion or a protrusion 118, for example, to push and slide the cartridge or to prevent the disassembly of the housing. Also, the inhaler body portion 105 may be formed to include a detent at its distal end for engaging the housing 102 and fixing the two parts of the inhaler.

[0054] The form of the cartridge for use with an inhaler is described in U.S. Patent No. 8,424,518, the disclosure of which is incorporated herein by reference in its entirety. Briefly, the cartridge for use in the inhaler embodiments disclosed herein includes two parts, although other embodiments may be envisioned. The cartridge is formed such that the dry powder during storage is contained in a sealed or enclosed position and can be reconstituted within the inhaler from a powder storage position to an inhalation or dosing arrangement. In certain embodiments, the cartridge comprises a lid and a cup having one or more openings, a storage arrangement, and a dosing arrangement, an outer surface, and an inner surface defining an inner volume. The storage arrangement restricts communication to the inner volume, and the dispensing arrangement forms an air passage through the inner volume to allow air flow to enter and exit the inner volume in a predetermined manner. For example, the air flow entering the air inlet of the cartridge can be directed to cross the air outlet within the inner volume, and the container of the cartridge can be formed to meter the drug exiting the cartridge such that the rate of powder outflow is restricted. The air flow within the cartridge can be substantially perpendicular to the flow direction of the air outlet and can mix and fluidize the powder within the inner volume before exiting through the dispensing opening. The cartridge for use with an immediate inhaler can be supplied in individual blisters or grouped in blisters depending on the patient's needs or the hygroscopicity of the formulation with respect to the stability of the powder and / or active ingredient.

[0055] In the embodiments described herein, the dry powder inhaler and the cartridge can be structurally formed to form an inhalation system and achieve a distributable or defined airflow resistance. This can be achieved by changing the cross-sectional area or arrangement of the air conduit in some parts of the flow path of the system. In one embodiment, the arrangement of the air conduit of the dry powder inhaler system can achieve an airflow resistance value of from about 0.065 to about 0.200 (√kPa) / liter / min. In other embodiments, a check valve can be used to prevent air flow through the inhaler until a desired pressure drop, such as 4 kPa, is achieved, at which point the desired resistance value reaches a value within the range indicated herein.

[0056] In yet another embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided. The system has an inhaler that includes a container receiving region formed to receive a container, and a mouthpiece having at least two inlet openings and at least one outlet opening. One of the at least two inlet openings is in fluid communication with the container region, and one of the at least two inlet openings is in fluid communication with the at least one outlet opening via a flow path formed to bypass the container region to deliver the dry powder formulation to the patient. The flow conduit is formed to bypass the container region so as to deliver 30% to 90% of the total amount flowing through the inhaler during inhalation.

[0057] In other embodiments, an inhalation system for delivering a dry powder formulation to a patient is provided. The system includes a dry powder inhaler that includes a cartridge mounting and reconfiguration region. The combination of the dry powder inhaler and the cartridge is formed to have at least two flow paths that are rigid conduits in the dosing arrangement, and a plurality of structural regions that provide a mechanism for powder deaggregation of the inhalation system during use. At least one of the plurality of mechanisms for deaggregation is the size of an aggregate that closes an opening in a container region having a minimum dimension of 0.5 mm to 3 mm.

[0058] In the embodiments disclosed herein, the dry powder formulation consists of crystalline powder, amorphous powder, or a combination thereof, and the powder is consistently dispensed from the inhaler in less than about 2 seconds. The inhalation system of the present application exhibits a high resistance value of about 0.065 to about 0.200 kPa / liter / min. Therefore, in a system including a cartridge, a peak inhalation pressure drop applied between 2 and 20 kPa results in a peak flow rate through the system of about 7 to 70 liters / min. These flow rates result in more than 75% of the cartridge contents being dispensed with a powder fill mass of 1 to 30 mg, or up to 50 mg. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation operation, generating a cartridge dispense rate of more than 90%. In certain embodiments, the inhaler and cartridge system are configured to deliver a single dose by releasing the powder from the inhaler as a continuous flow or as one or more pulses of powder delivered to the patient. In one embodiment, an inhalation system for delivering a dry powder formulation to a patient's lungs is provided and is formed to include a flow conduit having a total resistance value for flow up to a value of about 0.065 to about 0.200 (√kPa) / liter / min in a dosage form. In this and other embodiments, the total resistance value for flow of the inhalation system is relatively constant over a pressure difference range between 0.5 kPa and 7 kPa.

[0059] The structural configuration of the inhaler enables the disintegration mechanism to produce an inhalation fraction greater than 50% and particles less than 5.8 μm. The inhaler can release more than 85% of the powder formulation contained within the container during an inhalation operation. Generally, the inhalers disclosed herein can release more than 90% of the contents of the cartridge or the container in less than 3 seconds with a pressure difference of 2 to 5 kPa and a fill mass of 30 mg to 50 mg.

[0060] The inhaler of the present invention mainly uses breathing as the power source. However, in some embodiments, it can be provided with a power source to generate the pressure difference required for the deaggregation and delivery of dry powder formulations. For example, the inhaler can be adapted to a gas power source such as a compressed gas storage energy source like a nitrogen cylinder that can be provided at the air inlet. Also, a spacer for obtaining a plume can be provided so that the patient can inhale in a comfortable space.

[0061] In the embodiments described herein, the inhaler is supplied as a reusable inhaler for delivering a single unit dose. The reusable inhaler can be used a plurality of times as predetermined by the formulation to be delivered and is disposed of when the maximum usage amount is reached.

[0062] These devices and systems of the present invention are useful for the pulmonary delivery of powders having a wide range of properties. Embodiments include an inhaler and a system including an integrated or mountable unit dose cartridge containing a desired powder dose. Pulmonary delivery of powders includes carriers and excipients that have been proven safe and effective in commercially available products. Also, in an exemplary embodiment, 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; fumarildiketopiperazine known as FDKP. FDKP can produce fine particles that can form self-organized aggregates of crystal plates in suspension and can be produced as amorphous powder or its combination according to the process, as disclosed in U.S. Patent Nos. 7,820,676, 7,709,639, and 8,551,528, which are incorporated herein by reference. Dry powders produced using diketopiperazine can be produced by freeze-drying, spray-drying solutions or suspensions of various desired formulations. DKP crystal fine particles having a specific surface area (SSA) of about 35 to about 67 m 2 / g exhibit properties beneficial for drug delivery to the lungs, such as improved aerodynamic performance and improved drug adsorption. In some embodiments, high-volume crystalline FDKP fine particles for use in peptide-containing formulations are, for example, 35 m 2having a specific surface area of less than / g, and depending on the amount of the activator, the specific surface area of the particles is about 19 m 2 / g to about 30 m 2 / g, about 28 m 2 / g to about 71 m 2 / g, or about 19 m 2 / g to about 57 m 2 / g. In some embodiments, the microparticles of FDKP having a peptide activator such as insulin exemplified have a specific surface area in the range of about 4 m 2 / g to about 30 m 2 / g and have improved aerodynamic properties as measured by flyability and fluidity.

[0063] In one embodiment, the dry powder formulation may contain, for example, diketopiperazine and a pharmaceutical active ingredient. In this embodiment, the pharmaceutical active ingredient or activator can be of various types depending on the disease or condition to be treated. In other embodiments, diketopiperazine can include symmetric molecules and asymmetric diketopiperazines that are useful for forming particles, microparticles, etc. that are used as carrier systems for delivering the activator to a target site in the body. As used herein, the term "activator" refers to a therapeutic agent, or a molecule such as a protein or peptide or biomolecule, and a small molecule that is encapsulated or bound or mixed within the diketopiperazine formulation or adsorbed onto the diketopiperazine formulation. It can be combined with diketopiperazine in any form of the activator. The drug delivery system can be used to deliver a biological activator having therapeutic, prophylactic, or diagnostic activity.

[0064] Fumaryl diketopiperazine 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP) is one of the preferred diketopiperazines for pulmonary applications.

[0065]

Chemical Structure

[0066] Particles for pulmonary delivery having a diameter between about 0.5 and about 10 μm can reach the lungs, reach the systemic circulation, and deliver an active agent. To move through the turning part of the larynx, a diameter of less than about 10 μm is required, and to prevent being expelled, a diameter of about 0.5 μm or more is required. Generally, particles having a diameter greater than 10 μm or greater than 20 μm are useful for local delivery to the airways and lungs.

[0067] Particles having a diameter between about 0.5 and about 10 microns can reach the lungs and can successfully pass through most natural barriers. To move through the turning part of the larynx, a diameter of less than about 10 microns is required, and to prevent being expelled, a diameter of about 0.5 microns or more is required. In the embodiments disclosed herein, about 4 to about 71m 2 Particles having a specific surface area (SSA) of about 4 to about 71 m² / g exhibit beneficial properties for drug delivery to the lungs, such as improved aerodynamic performance and improved drug adsorption. Along with this, in some embodiments, compositions are provided that include crystalline fumarildiketopiperazine (FDKP) particles having a specific trans isomer content of about 35 to about 65%, 45 to about 63%, or 45 to about 60%.

[0068] In certain embodiments, a diketopiperazine - based composition for pulmonary delivery is provided with an active agent, and the diketopiperazine is fumarildiketopiperazine, comprising a plurality of microcrystalline particles formed substantially uniformly, the particles having a hollow spherical structure and comprising a shell containing microcrystals of diketopiperazine that do not self - assemble, and the volume - average geometric diameter of the particles is less than 5 μm. The particles are formed by a method that includes combining diketopiperazine in solution with an acetic acid solution without using a surfactant and simultaneously homogenizing under high pressure up to 2000 psi in a high - shear mixer to form a precipitate. Then, the precipitate is washed with a suspension of deionized water, the suspension is concentrated, and the suspension is dried in a spray - drying apparatus.

[0069] In some embodiments, the diketopiperazine-based composition for pulmonary delivery is provided with an active agent, and the diketopiperazine is a salt of fumarildiketopiperazine containing sodium and magnesium, and the composition contains an amorphous powder.

[0070] Also, a delivery system for inhalable dry powder comprises: a) a dry powder containing a drug, and b) an inhaler containing the powder included in a cartridge. The cartridge includes a gas inlet, a gas outlet, and a housing for fixing the cartridge, defines two flow paths, the first flow path enables gas to enter the gas inlet of the cartridge, and the second flow path enables gas to bypass to the gas inlet of the container. Further, a pressure drop of 2 kPa or more beyond the inhaler plume is applied so that particles are released from the mouthpiece, 50% of the released particles have a VMAD of 10 μm or less, and the flow bypassing the gas inlet of the cartridge is substantially perpendicular to the flow direction of the gas inlet and affects the outflowing flow.

[0071] The active agents used in the compositions and methods described herein can include any pharmaceutical. These include, for example, organic synthetic compounds, proteins and peptides, polysaccharides and other sugars, lipids, inorganic compounds, and nucleic acid sequences, and include therapeutic, prophylactic, or diagnostic activities. Peptides, proteins, and polypeptides are all amino acid chains linked by peptide bonds.

[0072] The active agents delivered to a target or site in the body using diketopiperazine include, for example, hormones, anticoagulants, immunomodulators, vaccines, cytotoxic drugs, neurotransmitter agonists and antagonists, antibiotics, vasoactive substances, neuroactive agents, anesthetics and sedatives, steroids, decongestants, antiviral agents, antisense, antigens, and antibodies. In particular, these compounds include insulin, heparin (including low molecular weight heparin), calcitonin, felbamate, sumatriptan, parathyroid hormone and its active fragments, growth hormone, erythropoietin, AZT, DDI, granulocyte-macrophage colony-stimulating factor (GM-CSF), lamotrigine, gonadotropin-releasing factor, luteinizing-releasing hormone, β-galactosidase, exendin, vasoactive intestinal peptide, argatroban. Antibodies and their fragments may include, but are not limited to, anti-SSX-241-49 (synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor-related antigen), anti-FRAME (melanoma antigen preferentially expressed), anti-PSMA (prostate-specific membrane antigen), anti-melan-A (melanoma tumor-related antigen), and anti-tyrosinase ((melanoma tumor-related antigen).

[0073] In certain embodiments, the dry powder formulation delivered via the pulmonary circulation comprises an active ingredient or agent, including a peptide, protein, hormone, analog thereof, or a conjugate thereof. The active ingredient is insulin, calcitonin, growth hormone, erythropoietin, granulocyte macrophage colony-stimulating factor (GM-CSF), gonadotropin-releasing hormone, luteinizing hormone-releasing hormone, follicle-stimulating hormone, vasoactive intestinal peptide, parathyroid hormone (including bovine PTH), parathyroid hormone-related protein, glucagon-like peptide-1 (GLP-1), exendin, oxyntomodulin, peptide YY, interleukin 2-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1 (IRE1) or the like, an active fragment, a PC-DAC-modified derivative, or an O-glycosylated form thereof. In certain embodiments, the pharmaceutical composition or dry powder formulation comprises fumarildiketopiperazine, and the active ingredient is insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin, adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, brain natriuretic peptide (BNP), atrial natriuretic peptide, IGF-1, growth hormone-releasing factor (GHRF), integrin beta-4 precursor (ITB4) receptor antagonist, nociceptin, nocistatin, orphanin FQ2, calcitonin, CGRP, angiotensin, substance P, neurokinin A, tetrahydrocannabinol, cannabinoids including cannabidiol, pancreatic polypeptide, neuropeptide Y, delta-sleep-inducing peptide, vasoactive intestinal peptide, one or more conjugates of the active agent and / or an analog thereof, and is one or more selected from the above.

[0074] Other active agents that can be used in dry powders for pulmonary delivery include treprostinil, salmeterol, epinephrine, tacrolimus, vancomycin, linezolid, filgastrim, fentanyl, cannabinoids including cannabidiol and tetrahydrocannabinol, paroxetine, amphotericin B, phosphodiesterase inhibitors including PDE5 inhibitors such as sildenafil, avanafil, vardenafil, and tadalafil, prostaglandins including prostacyclin, delta opioid agonists and antagonists, kappa opioid receptor agonists and antagonists, mu opioid receptor agonists and antagonists, and / or neurotransmitter agonists including opioid analgesics such as one or more conjugates of the foregoing active agents, and neurotransmitter antagonists.

[0075] Also, the present disclosure provides improved microcrystalline particles, compositions, methods of making the particles, and methods of enabling improved drug delivery to the lungs for treating diseases and disorders of a subject. The embodiments disclosed herein achieve improved delivery by providing a microcrystalline diketopiperazine composition containing microcrystalline diketopiperazine particles having a high capacity for drug adsorption that results in a powder with a high drug content of one or more active agents. The powder produced with the present microcrystalline particles can deliver the drug content with a lower powder dose and can facilitate drug delivery to a patient. It can be produced by various methods including using a surfactant-free solution or a solution containing a surfactant depending on the starting materials.

[0076] In other embodiments disclosed herein, it is possible to include a dry powder for inhalation comprising a plurality of substantially uniform microcrystalline particles, the microcrystalline particles can have a substantially hollow spherical structure, and can include a porous shell containing crystals of diketopiperazine that do not self-assemble in a suspension or solution. In certain embodiments, the microcrystalline particles can be substantially hollow spherical and substantially solid particles containing crystals of diketopiperazine, depending on the drug and / or drug content provided and other factors in the powder manufacturing process. In one embodiment, the microcrystalline particles are relatively porous and have an average pore volume of about 0.43 cm 3 / g, about 0.4 cm 3 / g to about 0.45 cm 3 / g and an average pore size of about 23 nm to about 30 nm or about 23.8 nm to 26.2 nm as determined by BJT adsorption, and include particles having such characteristics.

[0077] In certain embodiments disclosed herein, it includes a powder comprising a large number of substantially uniform microcrystalline particles, the particles having a substantially spherical structure including a shell that can be porous, containing crystals of diketopiperazine that do not self-assemble in a suspension or solution, and having a geometric diameter in volume of less than 5 μm, or less than 2.5 μm.

[0078] In certain embodiments herein, up to about 92% of the microcrystalline particles have a geometric diameter in volume of 5.8 μm. In one embodiment, the shell of the particle is assembled from interlocking diketopiperazine microparticles having one or more drugs adsorbed on its surface. In some embodiments, the particles can encapsulate the binding of drugs in the internal void volume and / or drugs adsorbed on the crystal surface and drugs encapsulated in the internal void volume of the sphere.

[0079] In certain embodiments, the diketopiperazine composition comprises a large number of microcrystalline particles formed substantially uniformly, the particles having a substantially hollow spherical structure and comprising a shell containing non-self-assembling diketopiperazine crystals. The particles are formed by a method that combines diketopiperazine in solution and in acetic acid solution, in the absence of a surfactant, and simultaneously homogenizes in a high-shear mixer at a high pressure up to 2000 psi to form a precipitate. The precipitate is then washed in suspension with deionized water, the suspension is concentrated, and the suspension is dried in a spray dryer.

[0080] Furthermore, the method includes the step of adding, with mixing, a solution containing an active agent or active ingredient, such as a drug or bioactive agent, prior to the spray drying step, and the active agent or active ingredient is adsorbed and / or encapsulated on or in the particles. The particles produced in this process can be in the submicron size range.

[0081] In certain embodiments, the diketopiperazine composition comprises a large number of microcrystalline particles formed substantially uniformly, the particles having a substantially hollow spherical structure and comprising a shell containing non-self-assembling diketopiperazine crystals, and having a volume average geometric diameter of less than 5 μm. The particles are formed by a method that combines diketopiperazine in solution and in acetic acid solution, in the absence of a surfactant, and simultaneously homogenizes in a high-shear mixer at a high pressure up to 2000 psi to form a precipitate. The precipitate is then washed in suspension with deionized water, the suspension is concentrated, and the suspension is dried in a spray dryer.

[0082] Furthermore, the method includes the step of adding, with mixing, a solution containing an active agent or active ingredient, such as a drug or bioactive agent, prior to the spray drying step, and the active agent or active ingredient is adsorbed and / or encapsulated on or in the particles. The particles produced in this process can be in the submicron size range.

[0083] In certain embodiments, the diketopiperazine composition comprises a plurality of microcrystalline particles formed substantially uniformly, the microcrystalline particles having a substantially hollow spherical structure and comprising a shell containing crystals of diketopiperazine that do not self-assemble, and having a volume average geometric diameter of less than 5 μm. The particles are formed by a method that includes combining diketopiperazine in solution and in acetic acid solution in the absence of a surfactant and simultaneously homogenizing in a high shear mixer at a high pressure up to 2000 psi to form a precipitate. The precipitate is then washed in suspension with deionized water, the suspension is concentrated, and the suspension is dried in a spray dryer.

[0084] In certain embodiments where the starting material containing the active ingredient is an extract showing a high degree of viscosity or a substance having honey-like viscosity, the microcrystalline particles are formed by washing them using tangential flow filtration before binding with the above and the extract or viscous material. After washing in water, the resulting particle suspension is lyophilized to remove moisture and resuspended in an alcohol solution, suspension, or solution containing ethanol or methanol before adding the active ingredient as a solid. In one embodiment, in the method of manufacturing the composition, leucine, isoleucine, norleucine, methionine, or one or more phospholipids such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), etc., are added as additional excipients containing one or more amino acids, either simultaneously with the active ingredient or after adding the active ingredient and before spray drying. In certain embodiments, the formation of the composition includes a step in which the extract containing the desired active ingredient is optionally filtered or winterized to remove and separate layers of unwanted materials such as lipids that increase solubility.

[0085] Furthermore, this method includes the step of adding while mixing the solutions, and the mixing may or may not be homogenized with a high shear mixer as required. The solution contains an active agent or active ingredient such as a drug or a bioactive agent before the spray drying process, and the active agent or active ingredient is adsorbed and / or encapsulated on or in the particles. The particles produced in this process can be in the submicron size range before spray drying, or the particles can be formed from the solution during spray drying.

[0086] In some embodiments associated therewith, the drug content can be delivered onto the crystalline powder using FDKP and is lyophilized or spray dried at a content of about 10%, about 20%, or about 30% or more. In embodiments where crystalline particles formed from FDKP or disodium FDKP salt are used and the particles do not self-assemble and are submicron-sized particles, the drug content may typically be greater than 0.01% (w / w). In one embodiment, the drug content delivered with the microcrystalline particles depends on the drug being delivered and is from about 0.01% (w / w) to about 75% (w / w), from about 1% (w / w) to about 50% (w / w), from about 10% (w / w) to about 25% (w / w), from about 10% (w / w) to about 20% (w / w), from about 5% to about 30%, or greater than 25%. In an exemplary embodiment where the drug is a peptide such as insulin, the microparticles of the present invention typically contain from about 10% to 45% (w / w), or from about 10% to 20% (w / w) of insulin. In certain embodiments, the drug content of the particles may vary depending on the shape and size of the drug being delivered.

[0087] In one embodiment, the composition delivered by the inhaler herein may include fumarildiketopiperazine crystal particles and an active agent such as tetrahydrocannabinol (THC) and / or a cannabinoid including cannabidiol, treprostinil, palonosetron, parathyroid hormone, sildenafil, or epinephrine. In a composition where a cannabinoid is used as the active agent, the content of the cannabinoid (including its derivatives and / or analogs) may be 40% (w / w) even in powder delivery where it is greater than 40% of the content of the inhaler. In some embodiments, the content of the cannabinoid in the composition may be about 1% to about 30%, about 5% to about 25% (w / w) of the powder content. Also, the composition herein may include one or more excipients including amino acids such as leucine, isoleucine, and methionine, and one or more phospholipids such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in an amount of up to about 25% (w / w), about 1% (w / w) to about 25% (w / w), 2.5% to 20% (w / w), or 5% to 15% (w / w). In this embodiment, the inhaler can release about 50% to 100% of the composition in a single inhalation. In this embodiment, the composition can be administered to a patient in need of treatment as required.

[0088] In embodiments where epinephrine is used as an active agent, the content of the epinephrine composition includes up to about 30% (w / w) of the powder content and ranges from about 1% to about 35%. In certain embodiments, the composition containing microcrystalline particles can include from about 2% to about 30% or from about 0.1% to about 20% (w / w) of epinephrine. In this embodiment, the epinephrine powder can be delivered with a delivery L efficiency of more than 50% of the dosing content using the inhaler described herein. In this embodiment, it can be used as a method for treating the symptoms of an allergic reaction prior to the onset of anaphylaxis caused by allergens such as nuts containing peanut allergens, antibiotics such as penicillin, and other substances. This method includes providing an inhaler containing a dose of from about 1 mg to about 15 mg of a composition effective to prevent the onset of anaphylaxis to a patient who needs to treat the symptoms of an allergic reaction and exhibits the initial symptoms of anaphylaxis, and providing an inhaler containing a dosage of a composition containing an amount of epinephrine sufficient to prevent the onset of anaphylaxis to the patient.

[0089] In embodiments where treprostinil is used as an active agent, the dry powder composition includes microcrystalline particles of fumaryl diketopiperazine, treprostinil is absorbed into the particles, and the content of treprostinil in the composition includes up to about 20% (w / w) of the powder content and ranges from about 0.5% to about 10% (w / w), or from about 1% to about 5% (w / w). In one embodiment, the composition herein can include other excipients suitable for inhalation, such as amino acids including methionine, isoleucine, and leucine. In this embodiment, the treprostinil composition can be used for the prevention and treatment of pulmonary hypertension by self-administering an effective amount containing from about 1 mg to about 15 mg of the dry powder composition containing microcrystalline particles of fumaryl diketopiperazine and treprostinil in a single inhalation.

[0090] In an embodiment where paroxetine is used as an active agent for an inhaled powder, the content of the paroxetine dry powder in the composition can range from about 20% (w / w) of the dry powder content, and from about 0.1% to about 20%, or from 0.1% to about 10% (w / w). In one embodiment, the paroxetine composition can be manufactured to include excipients such as crystalline synthetic particles of fumarildiketopiperazine disodium salt or fumarildiketopiperazine, and amino acids such as leucine, isoleucine, and methionine to improve the storage stability of the composition. In this embodiment, the paroxetine inhalation composition can be used for the treatment and prevention of chemotherapy-induced nausea and vomiting by self-administration in a single inhalation using this inhaler, before or simultaneously with receiving chemotherapy dosing, by dosing the composition for about 5 minutes to 30 minutes and preferably about 5 minutes to about 15 minutes.

[0091] In another embodiment, the pharmaceutically acceptable carrier for manufacturing the dry powder may include any carrier or excipient useful for manufacturing the dry powder and suitable for pulmonary delivery. Examples of suitable carriers and excipients include sugars and polysaccharides such as lactose, mannose, sucrose, mannitol, trehalose, amino acids such as glycine, L-leucine, isoleucine, trileucine, tartrate, methionine, vitamins such as vitamin A, vitamin E, zinc citrate, sodium citrate, zinc chloride, phospholipids such as polyvinylpyrrolidone, polysorbate 80, phosphatidylcholine, and citric acid.

[0092] In one embodiment, a method is provided for self-administering a dry powder formulation to one's own lungs using a dry powder inhaler. The method includes obtaining a dry powder inhaler in a closed state and equipped with a mouthpiece; obtaining a cartridge containing a pre-metered dose of the dry powder formulation; opening the dry powder inhaler to attach the cartridge; moving the cartridge to the dosing position and closing the inhaler; placing the mouthpiece in the mouth and taking a single deep inhalation to deliver the dry powder formulation.

[0093] In a further embodiment, methods for treating obesity, hyperglycemia, insulin resistance, pulmonary hypertension, anaphylaxis, and / or diabetes are disclosed. The methods include, for example, administration of an inhalable dry powder composition or formulation comprising a diketopiperazine including, for example, 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, where X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaroyl. In this embodiment, the dry powder composition can include a diketopiperazine salt. In yet another embodiment, a dry powder composition or formulation is provided wherein the diketopiperazine is 2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine, with or without a pharmaceutically acceptable carrier or excipient.

[0094] An inhalation system for delivering a dry powder formulation to a patient's lungs is provided, the system having a dry powder inhaler configured to include a flow conduit having a total resistance value in the range of 0.065 to about 0.200 (√kPa) / liter / minute in a dosing configuration.

[0095] In one embodiment, a dry powder inhalation kit is provided that includes the dry powder inhaler described above and one or more drug cartridges containing a dry powder formulation for treating disorders or diseases such as airway and lung diseases, diabetes, and obesity.

[0096] Also provided is a method for treating a patient's disease or disorder in the form of the dry powder inhaler disclosed herein. The treatment method includes providing a dry powder inhaler containing a cartridge containing a dose of an inhalable formulation comprising an active ingredient selected from the group described above and a pharmaceutically acceptable carrier and / or excipient, as needed for the treatment of the patient. The method also includes delivering the dose by having the patient inhale through the dry powder inhaler for about 3 to 4 seconds. In this method, the patient can then resume normal breathing.

[0097] The following examples show some processes for manufacturing dry powders suitable for use in the inhalers described herein, and data obtained from experiments using such dry powders.

[0098] (Example 1) Preparation of surfactant-free dry powder containing FDKP microparticle powder for use with an inhaler In an exemplary embodiment, a surfactant-free dry powder containing FDKP microcrystalline particles was prepared. Using a dual-feed high-shear mixer, approximately equal masses of an acetic acid solution (Table 1) and an FDKP solution (Table 2) maintained at about 25 °C ± 5 °C were introduced at 2000 psi through a 0.001-in2 orifice and homogenized to form a precipitate. The precipitate was collected in deionized (DI) water at approximately the same temperature. The content, expressed as mass % of FDKP microcrystals in the suspension, was about 2 - 3.5%. The concentration of FDKP in the suspension can be analyzed by the oven-drying method for solid content. The suspension of FDKP microcrystals can be washed, if necessary, by tangential flow filtration using deionized water. The FDKP microcrystals can be separated, if necessary, by filtration, centrifugation, spray drying, or freeze drying.

[0099] Composition of the FDKP solution

Table 1

[0100] Composition of the acetic acid solution

Table 2

[0101] Dry powders (A, B, C, and D) containing microcrystalline particles produced by the above method were tested for various properties including surface area, water content, and porosity measurements. Four types of powders were used in this test. All powders tested had a residual moisture of 0.4%. Table 2a shows the data obtained from this test.

[0102]

Table 2a

[0103] The data in Table 2a indicate that the surface area of the spray-dried bulk dry powder containing the microcrystalline particles of the tested sample is in the range of 59 m 2 / g to 63 m 2 / g. The porosity data indicate that the microcrystalline particles are relatively porous, with an average pore volume determined by BJH adsorption of about 0.43 cm 3 / g and an average pore size in the range of about 23.8 nm to 26.2 nm. The porosity measurement data indicate that these particles are different from the conventional FDKP microcrystals having an average pore volume of about 0.36 cm 3 / g and an average pore size in the range of about 20 nm to about 22.6 nm.

[0104] (Example 2) Preparation of a dry powder containing microcrystalline FDKP particles containing epinephrine A solution of about 5 wt% epinephrine in an aqueous acetic acid solution of about 5% was added to the suspension of FDKP microcrystals obtained as described in Example 1. Also, leucine was added to the suspension of FDKP microcrystals as needed. The mixture was spray-dried using a Buchi B290 spray dryer equipped with a high-efficiency cyclone. Nitrogen was used as the process gas (60 mm). The mixture was dried at a pump capacity of 10 - 20%, a suction rate of 90 - 100%, and an inlet temperature of 170 - 190 °C. The weight % concentrations of epinephrine and leucine in the resulting powder were 2 - 30% and 0 - 20%, respectively. The delivery efficiency of these powders after discharge from the spray dryer was in the range of about 50% to 80%.

[0105] (Example 3) Preparation of a dry powder containing microcrystalline FDKP particles containing paroxetine A solution of about 5% by weight of paracetamol in DI water was added to the suspension of FDKP microcrystals obtained as described in Example 1. Also, leucine and methionine in deionized (DI) water were added as needed. The mixture was titrated to pH 6.5 ± 0.5 with ammonium hydroxide. The mixture was spray-dried using a Buchi B290 spray dryer equipped with a high-efficiency cyclone. Nitrogen was used as the process gas (60 mm). The mixture was dried at a pump capacity of 10 - 12%, a suction rate of 90 - 100%, and an inlet temperature of 170 - 190°C. The weight % concentrations of paracetamol, leucine, and methionine in the resulting powder were 5%, 0 - 20%, and 0 - 10% respectively. The delivery efficiency of these powders after discharge from the spray dryer was in the range of about 50% - 70%.

[0106] (Example 4) Preparation of a dry powder containing microcrystalline FDKP particles containing treprostinil 0.2 - 1.0 wt% of treprostinil in ethyl alcohol was added to the suspension of FDKP microcrystals obtained as described in Example 1. The mixture was spray-dried using a Buchi B290 spray dryer equipped with a high-efficiency cyclone. Nitrogen was used as the process gas (60 mm). The mixture was dried at a pump capacity of 10 - 12%, a suction rate of 90 - 100%, and an inlet temperature of 170 - 190°C. The weight % concentration of treprostinil in the resulting powder was 0.5 - 10%. The delivery efficiency of these powders after discharge from the spray dryer was in the range of about 50% - 70%.

[0107] (Example 5) Preparation of a dry powder containing microcrystalline FDKP particles containing Δ9-THC or CBD The separated FDKP microcrystalline particles prepared in the same manner as in Example 1 were suspended in ethyl alcohol. A solution of approximately 1-4% by weight of a cannabis extract containing either Δ9-THC or CBD was added to the ethanol and ethanol suspension of the FDKP microcrystals. If necessary, a solution of an additive dissolved in ethanol was also added. The mixture was spray-dried using a Buchi B290 spray dryer equipped with a high-efficiency cyclone. Nitrogen was used as the process gas (60 mm). The mixture was dried at a pump capacity of 12-15%, a suction rate of 70-100%, and an inlet temperature of 110-140 °C. The weight percentage concentrations of Δ9-THC and the additive are shown in Table 3. The delivery efficiency of these powders after discharge from the spray dryer was in the range of approximately 50% to 70%.

[0108] Composition of microcrystalline FDKP particles containing Δ9-THC or CBD

Table 3

[0109] The dry powder produced by the above method was tested using a substantially anatomically correct airway (ACA) system as described in U.S. Patent No. 9,016,147. The dry powder showed a significant degree of stability at room temperature. For example, after one month of storage, more than 90% of THC or CBD maintained its activity, and this method showed a delivery efficiency in the range of approximately 35% to approximately 75%.

[0110] The above disclosure is an exemplary embodiment. It should be understood by those skilled in the art that the apparatuses, techniques, and methods disclosed herein are illustrative of representative embodiments that function well in the practice of this disclosure. However, those skilled in the art will understand that, in light of this disclosure, many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention, and similar or analogous results can be obtained.

[0111] Unless otherwise indicated, all numbers expressing quantities of ingredients, molecular weights, reaction conditions, and other properties used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and the application of ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth broad ranges of values are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in the respective testing measurements.

[0112] (Especially in the context of the claims) The terms "a," "an," "the," and similar references used in the context of describing the invention herein are to be construed to include both the singular and the plural unless otherwise specified herein or clearly contradicted by the context. The numerical ranges recited herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by the context. Any and all examples, or exemplary language (e.g., "such as") provided herein are intended merely to better illustrate the invention and are not intended to limit the scope of the claims. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0113] The term "or" as used in the claims means "and / or" unless explicitly indicated to refer to only the alternative(s), or is used and defined to refer to only the alternative(s) and "and / or", except when the alternatives are mutually exclusive of each other.

[0114] The grouping of alternative elements or embodiments disclosed herein is not to be construed in a limiting sense. Elements of each group may be referred to and claimed individually, or in any combination with other elements in the group or other elements disclosed herein. For reasons of convenience and / or patentability, it is contemplated that one or more elements of a group may be included in or deleted from the group. When such inclusion or deletion occurs, the specification is considered to include the modified group and thus to satisfy all descriptions of all Markush groups used in the claims.

[0115] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for practicing the invention. It will of course be apparent to those skilled in the art that variations of the preferred embodiments described above will become apparent upon reading the foregoing description. The inventors expect such variations to be made by those skilled in the art and intend the invention to be practiced otherwise than as specifically described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Further, unless otherwise specified herein or clearly precluded by context, any combination of the above-described elements in all possible variations is included in the invention.

[0116] The specific embodiments disclosed herein may be further limited in the claims using the language "comprising" or "consisting essentially of." When used in a claim, whether submitted or added by amendment, the language "comprising" excludes other elements, steps, or components not recited in the claim. The language "consisting essentially of" limits the scope of the claim to the specified materials or steps and does not materially affect the basic or novel characteristics. As such, the embodiments described in the claims are effective whether consisting essentially of or explicitly recited.

[0117] Further, throughout this specification, numerous references are cited as patents and publications. Each of the above references and printed publications is hereby incorporated by reference in its entirety into this specification, individually.

[0118] Furthermore, it should be understood that the embodiments disclosed herein are to disclose the principles of the present invention. Other variations may be employed within the scope of the present invention. Thus, by way of example and not limitation, another configuration may be utilized in accordance with the disclosure herein. Therefore, the present invention is not precisely limited to that shown and described.

[0119] (Appendix) (Appendix 1) A housing, A body comprising a mouthpiece integrally formed with the body, Comprising, The body has a mounting area for a cartridge, and the body and the housing are linearly movable relative to each other and are configured to be operable to reconfigure the cartridge by engaging with each other by insertion to obtain an air flow path for discharging a powder dosage during inhalation. Dry powder inhaler.

[0120] (Appendix 2) The mouthpiece has an air inlet communicating with an internal compartment of the inhaler body. The dry powder inhaler according to Appendix 1.

[0121] (Appendix 3) By shifting the housing on the inhaler body from the open position to the closed position, the housing reconfigures the cartridge attached to the inhaler. The dry powder inhaler according to Appendix 1.

[0122] (Appendix 4) The movement of the housing relative to the body is configured along the longitudinal axis and is facilitated by guide rails extending from the right side and / or left side of the inhaler body. The dry powder inhaler according to Appendix 1.

[0123] (Appendix 5) Configured to obtain an open or attached position and a closed or dosing position. The dry powder inhaler according to Appendix 1.

[0124] (Appendix 6) The housing further includes a protruding rigid element that pushes the cartridge from the storage position to the dosing position. The dry powder inhaler according to Appendix 1.

[0125] (Appendix 7) Furthermore, it is configured to have a rigid flow conduit. The dry powder inhaler according to Appendix 1.

[0126] (Appendix 8) The housing includes a cover that covers a part of the inhaler body. The dry powder inhaler according to Appendix 1.

[0127] (Appendix 9) Furthermore, the mouthpiece has an internal volume extending from a first inlet port to an outlet port. The internal volume is greater than 0.2 cubic centimeters. The dry powder inhaler according to Appendix 1.

[0128] (Appendix 10) In the assembled inhaler, the inhaler body is provided with a detent to prevent the body from separating from the housing. The dry powder inhaler according to Addendum 1.

[0129] (Addendum 11) Upon transition of the housing on the inhaler body from an open configuration to a closed configuration, the housing positions the cartridge so as to be aligned with the mouthpiece. The dry powder inhaler according to Addendum 1.

[0130] (Addendum 12) Furthermore, it contains dry powder. The dry powder inhaler according to Addendum 1.

[0131] (Addendum 13) The dry powder is a pharmaceutical composition for inhalation. The dry powder inhaler according to Addendum 12.

[0132] (Addendum 14) The dry powder contains 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine. The dry powder inhaler according to Addendum 12.

[0133] (Addendum 15) The dry powder contains a cannabinoid in an amount of 1% to 40% (w / w). The dry powder inhaler according to Addendum 14.

[0134] (Addendum 16) The cannabinoid is tetrahydrocannabinol or cannabidiol. The dry powder inhaler according to Addendum 15.

[0135] (Addendum 17) Furthermore, the dry powder contains a phospholipid selected from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-3-phosphocholine. The dry powder inhaler according to Supplementary Note 14.

[0136] (Supplementary Note 18) A dry powder inhaler comprising a main body, a housing, a cartridge, and a mouthpiece, wherein the main body has a mounting area for the cartridge, the cartridge contains a dry powder composition comprising fumaryl diketopiperazine and fine crystalline particles of a drug, the housing slides translationally on the main body from the proximal direction to the distal direction to open the inhaler, or slides translationally on the main body from the distal direction to the proximal direction to close the inhaler, when the inhaler is closed, the inhaler is provided with one or more rigid air conduits for dispensing the dry powder, Dry powder inhaler.

[0137] (Supplementary Note 19) The drug is tetrahydrocannabinol or cannabidiol, The dry powder inhaler according to Supplementary Note 18.

[0138] (Supplementary Note 20) Furthermore, the dry powder contains a phospholipid selected from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-3-phosphocholine. The dry powder inhaler according to Supplementary Note 18.

Claims

1. 1. A system for use in treating pulmonary hypertension, comprising: a dry powder inhaler comprising a replaceable cartridge containing 1 mg to about 15 mg of a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and an active agent; The active agent is present in an amount of up to about 20% (w / w) of the dry powder composition. system.

2. The dry powder composition is administered in a single dose. The system of claim 1 .

3. The active agent is treprostinil. The system of claim 1 .

4. The content of treprostinil is from about 0.5% (w / w) to about 10% (w / w). The system of claim 3 .

5. The dry powder inhaler, in a dosing configuration, is configured with a flow conduit having a total resistance to flow ranging from 0.065 to about 0.200 (kPa) / liter per minute. The system of claim 2 .

6. The dry powder composition is administered orally. The system of claim 1 .

7. The dry powder composition is administered by inhalation. The system of claim 1 .

8. The dry powder inhaler comprising: a housing and a body; the body including a mounting area for a cartridge containing the dry powder composition; the body and the housing are linearly movable relative to one another and are operably configured to bayonetically engage one another to provide an air flow path for expelling a powder dose upon inhalation; The system of claim 1 .

9. A system comprising a dry powder inhaler containing a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and an active agent, The dry powder composition is formed by spray drying a suspension of microcrystals of fumaryl diketopiperazine and a solution containing from about 0.2% (w / w) to about 5% (w / w) of the active agent in ethyl alcohol. system.

10. The active agent is a small molecule.

10. The system of claim 1 or 9.

11. The active agent is an antibiotic.

10. The system of claim 1 or 9.

12. The active agent is treprostinil. The system of claim 9.

13. A system comprising a dry powder inhaler including a body and a housing, the body including a mouthpiece integrally formed with the body and a mounting area for a cartridge; the body and the housing are operably configured to be linearly movable relative to one another and to bayonetically engage one another to reform a cartridge and provide an airflow path for expelling a powder dose upon inhalation; the dry powder inhaler having a relatively rectangular body manufactured as a single element, the body further having a substantially C-shaped proximal end; The dry powder inhaler further comprises treprostinil. system.

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