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 Jan. 29, 2016, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) The present disclosure relates to a dry powder inhaler with a replaceable cartridge containing a dry powder for local or systemic delivery of an active ingredient to and / or through the lungs, the inhaler being used with an inhalable dry powder that primarily comprises a pharmaceutical formulation containing an active agent or ingredient for treating diseases such as pulmonary hypertension, cardiovascular disease, 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 the references therein are hereby incorporated by reference in their entirety to adequately describe additional or alternative details, features, and / or technical background. [Background technology]

[0004] Drug delivery to pulmonary tissue is accomplished using a variety of devices for inhalation, including nebulizers and inhalers, such as metered dose inhalers and dry powder inhalers for treating localized diseases or disorders. Dry powder inhalers used to deliver drugs to the lungs usually include a bulk supply or dispensing system of powder formulations, such as hard gelatin capsules or blister packs, stored in unit dose compartments and metered into individual doses. The bulk container is equipped with a metering system operated by the patient to separate the unit dose from the powder immediately prior to inhalation.

[0005] Dosing reproducibility by an inhaler requires that the drug formulation is uniform and that the dose is delivered to the subject with consistent and reproducible results. Therefore, the dosing system should operate such that all the formulation is effectively completely expelled when the patient takes the dose by inhalation. However, complete powder expulsion from the inhaler is not necessary as long as reproducible dosing can be achieved. In this respect, the flow characteristics and long-term physical and mechanical stability of the powder formulation are more important than in single unit dose compartments in bulk containers. In unit dose compartments such as blisters, good moisture protection can be easily achieved. However, the materials used to manufacture the blisters introduce air into the drug compartment, so that the formulation loses viability upon long-term storage, especially if the formulation delivered is hygroscopic. The ambient air penetrating the blister carries moisture that destabilizes the active ingredient. Furthermore, dry powder inhalers that use blisters to deliver medication by inhalation can experience inconsistencies in dose delivery to the lungs due to geometric changes in the air channel structure caused by puncturing or peeling the blister film.

[0006] Dry powder inhalers can be breath-powered or actuated, and deliver drugs by transforming drug particles in a carrier into a fine dry powder that is entrained in the airflow and inhaled by the patient. Drugs delivered using dry powder inhalers for localized pulmonary delivery to treat allergies, asthma, and / or chronic obstructive pulmonary disease (CDPD) are contained in multi-dose inhalers such as FLOVENT® DISKUS, ADVAIR® DISKUS, and PULMICORT® FLEXHALER, to name a few. Dry powder inhalers are no longer intended to treat only pulmonary diseases, but can be used to treat systemic diseases, with drugs delivered to the lungs for absorption in the systemic circulation. 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 for absorption into the circulation for effective treatment of hyperglycemia associated with diabetes, and accordingly, dry powder inhalers can be used to achieve safe delivery of other active agents through the systemic circulation to treat numerous diseases or disorders, including, but not limited to, cancer, diabetes, obesity, cardiovascular disease, neurodegenerative diseases and mental and physical disorders, as well as symptoms of diseases or disorders, such as pain, headache, nausea, vomiting, tremors, infections, etc.

[0007] Dry powder inhalers, such as those described in U.S. Patent Nos. 7,305,986, 7,464,706, 8,499,757, and 8,636,001, the entirety of which are incorporated herein by reference, can deagglomerate a single dose of powder formulation contained in a capsule or cartridge during an inhalation maneuver to generate primary drug particles or a suitable inhalation plume. During inhalation, the amount of fine powder emitted from the mouthpiece of the inhaler depends largely on, for example, the interparticle forces of the powder formulation and the efficiency of the inhaler to separate these particles suitable for inhalation. The advantages of delivering drugs via the pulmonary circulation are numerous, including rapid entry into the arterial circulation, avoidance of drug degradation by liver metabolism, and ease of use without discomfort. Summary of the Invention [Problem to be solved by the invention]

[0008] A number of dry powder inhaler products developed for pulmonary delivery have been met with some success to date. However, there is room for improvement in terms of lack of practicality and / or manufacturing costs. Some problems present in prior art inhalers include lack of device durability, dosage inconsistency, device inconvenience, delivery problems without the use of propellants, high manufacturing costs, and / or lack of patient compliance. Thus, the present inventors have identified a need to design and manufacture an inhaler with consistently improved powder transport properties, ease of use, and individualized structure that allows for better patient compliance. [Means for solving the problem]

[0009] The present disclosure relates to dry powder inhalers with replaceable cartridges containing dry powder for inhalation to be delivered to the lungs for local or systemic delivery to the pulmonary circulation. Dry powder inhalers are small, reusable or disposable, breath-actuated inhalers of various shapes and sizes that contain an airflow conduit system for effective and rapid delivery of powdered medicament to the lungs and 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 pulmonary tissue for local tissue action or absorbed into the bloodstream in the lungs and delivered via the systemic circulation to a target tissue or organ of interest. In one embodiment, the dry powder can include pharma- ceutically acceptable carriers and excipients, such as polymers, such as phospholipids, polyethylene glycols, co-glycolides, carbohydrates, polysaccharides, or diketopiperazines, active ingredients, such as peptides and proteins, and carrier molecules, including small molecules, including neurotransmitters.

[0011] In one embodiment, the dry powder inhaler is reusable and is equipped with a single-use replaceable cartridge for use in a single inhalation and for delivering a single dose with a single inhalation provided by the patient. In this embodiment, multiple cartridges containing a specific powder content containing the active ingredient, e.g., packaged in a blister pack, can be equipped with a single inhaler for multiple uses by the subject. In other embodiments, the cartridges can contain dry powder formulations 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 symptoms thereof, neutropenia, chronic obstructive pulmonary disease (COPD), asthma, allergies, symptoms of diseases or disorders including acute or chronic pain, nausea and vomiting including chemotherapy-induced nausea and vomiting, migraine headaches, dementia, Alzheimer's, depression, Parkinson's, nervous system disorders and diseases or symptoms thereof including multiple sclerosis, and the like.

[0012] In one embodiment, the dry inhaler comprises a body, a housing and a mouthpiece formed with the body, the body comprising a mounting area for a cartridge, the body and the housing being movable relative to each other in a linear or angular motion. At least a portion of the body and the housing are operable to engage with each other, e.g. by plugging, to obtain a closed position and reconfigure the cartridge disposed in the mounting area to obtain an air flow path for releasing a powder dose contained in the cartridge. In this embodiment, the cartridge is formed of a rigid material and comprises a cup and a lid movable relative to each other in a translational motion.

[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 contains a dry powder composition including fumaryl diketopiperazine and microcrystalline particles of drug. The housing slides translationally over the body of the inhaler from a proximal to a distal direction to open the inhaler, or from a distal to a 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 lid are configured as one unit and are movable on 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 interior surface, a cartridge mounting area, and an opening in the top surface for connecting to the interior of the device and the cartridge mounting area, and the mouthpiece has a wing-like structure extending in a plane perpendicular to the mouthpiece air conduit and configured to form a cover or lid-like structure in the shape of a saddle-like structure. When rotated from a vertical angle to a horizontal plane, the mouthpiece forms a lid that covers an open area in 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 area is moved from a storage position to a dispensing position, an air conduit is formed through the cartridge, and powder in the cartridge can be released from the inhaler during an inhalation maneuver. In one form of this embodiment, the mouthpiece is formed with structure for engaging the cartridge mounting components to reconfigure the cartridge from the stored configuration to the dispensing configuration. In one embodiment, the inner surface of the inhaler includes a protrusion in the cartridge mounting area designed to hold the cartridge cup when the cartridge is mounted. In one embodiment, the structure for engaging the cartridge mounting area includes a gear and rack that pivots a portion of the mouthpiece of the inhaler away from the inhaler body to a position vertical to the inhaler body in a horizontal plane to release the inhaler to a mounted configuration, and pivots from the vertical plane to a horizontal position to close the inhaler and to a dispensing configuration with the cartridge mounted in the inhaler.

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

[0016] In one embodiment, the dry powder inhaler includes a housing, a movable member, and a mouthpiece. The movable member is operably configured to move the container from a powder storage position to a dispensing position. In this and other embodiments, the movable member can be formed as part of a lid piece at the proximal end of the inhaler and can form part of the cartridge mounting area. In this embodiment, the mouthpiece is integrally constructed 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 a horizontal plane, it moves the lid or cover angularly to a vertical position, opening the inhaler and providing access to the interior of the inhaler and allowing the loading and unloading of the cartridge. Conversely, when the mouthpiece moves upward from a vertical plane to a horizontal plane, it triggers the closing of the inhaler and automatically creates an opening of the air path between the inhaler and a cartridge mounted in the cartridge mounting area.

[0017] In another embodiment, the dry powder inhaler comprises a body, a housing, and a mouthpiece. The inhaler is structurally configured to have a mechanism operably configured to accept, 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 is capable of reconfiguring a cartridge attached to the inhaler from a dosing position to a storage position after use when the inhaler is opened to remove a used cartridge. In one embodiment, the mechanism is capable of reconfiguring a cartridge to a disposable or disposal configuration after use.

[0018] In one embodiment, the body of the inhaler includes a proximal portion including a mouthpiece, a body, and a distal portion including a housing 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, the proximal end having an opening for fitting 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 outside environment. The inhaler is opened by moving the top of the housing in a translational motion in a distal direction on the body to a loading and / or unloading position of the inhaler for insertion or removal of the cartridge. With the cartridge attached to the inhaler, translating the top of the housing in a distal to proximal direction on the body displaces the cartridge from a storage configuration to a dosing configuration, and the cartridge receptacle is pushed into the dosing configuration by a protrusion configured on the interior of the housing that extends beyond the opening of the proximal end when the inhaler is in the open configuration. Movement of the top of the housing is accomplished by movement of a lever having a button-like structure on the 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 reconfigures to form an additional air flow path with the mouthpiece and ambient air that connects with the dry powder in the cartridge in the dosing configuration upon inhalation. In this and other embodiments, the air flow path of the cartridge in the dosing configuration has an air inlet / outlet that communicates with the air flow path in the mouthpiece. The mouthpiece has its own air inlet / outlet.

[0019] In one embodiment, the inhaler body includes a mouthpiece formed at a proximal end of the body, with an air conduit communicating with the interior of the housing, and can communicate directly with the air outlet of a cartridge attached to the inhaler and with the ambient air. The inhaler body also includes a cartridge mounting area that is structurally continuous with the mouthpiece and has a distal portion and a proximal portion. The proximal portion and the distal portion form one single piece with the mouthpiece and are pluggable into the housing. In one embodiment, the body and the housing can be pulled apart to provide an open configuration of the inhaler for connection to the internal compartment. In this form of open configuration, a cartridge containing dry powder can be mounted or attached to the cartridge mounting area of ​​the body, and the body and the housing can be pushed or pulled to open or close the inhaler. In one embodiment, the housing is movable from an open configuration to a closed configuration on the distal portion of the body, which together close the inhaler and form an air conduit through the cartridge attached to the cartridge mounting area. In this configuration, the inhaler is in a dispensing configuration in which the powder in the cartridge is released from the inhaler when orally inhaled by a user through the mouthpiece. In the dosing arrangement of this embodiment, the body and housing abut one another and are tightly fitted with one or more anti-slip features to prevent the inhaler from coming apart. Examples of anti-slip features may include a snap ring or detent that can generate a sound to alert the user that the inhaler is ready for use.

[0020] In one embodiment, the inhaler is substantially rectangular in shape with a distal side and a proximal side, the distal side being shorter in length. The inhaler includes a movable housing part that covers the distal part 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, exposing the interior of the inhaler. The movement of the housing can be achieved by a pulling or pushing action of the housing on the inhaler body, which has parallel guide rails or tracks that extend outward from the long sides (first side and 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 to fit into the opening at the distal end of the housing to guide and admit ambient air into the internal chamber of the inhaler during inhalation. The housing is also fitted with grooves or slits for sliding on the guide rails during opening and closing movement, and includes stops to prevent disassembly of the inhaler, and a pusher element for positioning the cartridge in a dosing configuration after installation and for closing the inhaler when the housing is moving from a distal to a proximal direction. The pusher element moves the cartridge cup or container against the cartridge lid to form an air flow path through the cartridge, form an air inlet and outlet, allow aerosolization of the powder in the cup during inhalation, and deliver the aerosolized particles to the inhaler mouthpiece and the user. In another embodiment, the pusher element moves the cartridge member to position the lid against an inlet opening located in the floor of the mouthpiece. In one aspect of this embodiment, the dry powder inhaler includes a housing including a pusher element that positions the cartridge in alignment with the mouthpiece by transforming the housing over the inhaler body from an open configuration to a closed configuration.

[0021] In one embodiment, the dry powder inhaler comprises a housing having a distal end and constituting an opening communicating with the surrounding air. In one embodiment, the housing is configured in the form of a cover that slides over the inhaler body, substantially covering a portion of the inhaler body and moving translationally over the distal portion of the body. The inhaler achieves two configurations, a first position that opens the inhaler and connects it to its internal compartment, the chamber, and a second position that abuts the proximal end to achieve closure of the inhaler. Also, in one embodiment, the distal portion of the housing is movable relative to the proximal end in a horizontal plane to extend distally and allow connection to the cover surrounding the inhaler body and 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 with a portion of the body of the inhaler, for example to fix the body of the inhaler to the housing, forming a fixing mechanism for fixing the two portions and maintaining the dosing arrangement. In one embodiment, the distal portion of the housing has an opening at its distal end for communicating with the interior of the inhaler and configured to slide over the inhaler body. The distal portion of the housing also includes an exterior surface, an interior surface, and a chamber configured to slide over the inhaler body. In one embodiment, the distal portion of the inhaler includes parallel wing-like structures on its upper surface for directing airflow towards the mouthpiece upon inhalation.

[0022] In another embodiment, the mouthpiece is engaged with the body of the inhaler by various mechanisms including a movable member such as a hinge 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 reconstitute the cartridge attached to the inhaler from a storage position to a dispensing position and can be designed to operate manually or automatically upon movement of the inhaler components to close the device from an open configuration, for example. In one embodiment, the mechanism for reconstituting the cartridge comprises a sliding tray or sled attached to the mouthpiece and movably attached to the housing. In another embodiment, the mechanism comprises 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 operably configured to reconstitute the cartridge from a storage configuration to a dispensing configuration comprises a cam that can reconstitute the cartridge upon rotation of, for example, the housing or the mouthpiece. In one embodiment, angular rotation of the mouthpiece out of the horizontal plane opens the inhaler and allows for installation or removal of the cartridge, or angular movement of the mouthpiece from a vertical plane to a horizontal plane accomplishes closing of the mouthpiece and automatic reconfiguration from the retracted position to the dosing position. In one embodiment, a working gear mechanism positions the cartridge lid relative to the mouthpiece inlet opening and accomplishes translation of its cup into the dosing configuration.

[0023] In yet another embodiment, a dry powder inhaler is provided that includes a body and a mouthpiece, the inhaler body is designed to have a substantially rectangular shape with a top, a bottom, a proximal portion and a distal portion, and the top portion has an opening in the distal half of the inhaler body to allow connection to the interior compartment of the inhaler and the cartridge mounting area. In this embodiment, the inhaler mouthpiece has two air inlets, one communicating with the ambient air at the distal end of the inhaler and one communicating with the outlet portion in the cartridge and an air outlet at the proximal portion of the inhaler for insertion into the mouth of a subject. In this embodiment, the body and mouthpiece are engaged by a gear, rack and pinion member, and the movable cartridge cup carrier is configured to be actuated 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, opening the inhaler to load and unload the cartridge. Moving the mouthpiece back to a 180 degree angle parallel to the inhaler body closes the inhaler and automatically reconfigures the cartridge placed in the inhaler to a dosing configuration by moving the cartridge cup to create an air flow path between the inhaler mouthpiece and the cartridge, and further by creating an inlet port in the cartridge for ambient air to pass through the interior of the cartridge to aerosolize the powder in the cartridge upon inhalation.

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

[0025] The cartridge used with the dry powder inhaler can be manufactured to contain any dry powder medicament for inhalation. In one embodiment, the cartridge is structurally configured to fit into a particular dry powder inhaler and can be formed in any size and shape depending on the size and shape of the inhaler to be used, for example if the inhaler is equipped with a mechanism that allows translational or rotational movement. In one embodiment, the cartridge can be formed with a locking mechanism, for example with a slanted edge on the top of the cartridge that corresponds to a matching slanted edge in the inhaler so that the cartridge is fixed during use. In one embodiment, the cartridge comprises a container and a lid or cover, where the container fits onto the surface of the lid and is movable relative to the lid, or the lid is movable on the container, and can achieve various configurations depending on its position, for example, an installation configuration, a dosing configuration, or a post-use configuration. During inhalation, the cartridge in a dosing position fitted to the inhaler allows airflow to enter the container and mix with the powder, fluidizing the medicament. The fluidized medicament moves through the container and gradually exits the container through the dispensing opening. The fluidized medicament present at the dispensing opening is sheared and diluted by a secondary flow not originating from within the container. A cartridge for a dry powder inhaler, as described, includes a container configured to hold the medicament, at least one inlet port allowing flow into the container, and at least one dispensing port allowing 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 orifice in the container in response to a pressure differential.

[0026] In some embodiments, the dry powder formulation is consistently dispensed from the inhaler in less than about 3 seconds, or typically less than 1 second. In some embodiments, the air conduit of the inhaler is designed to provide high resistance to air flow values, for example, between about 0.065 and about 0.200 (√kPa) / liter / min. Thus, in an inhalation system, a peak inhalation pressure drop of between 2 and 20 kPa results in a peak flow rate of between about 7 and 70 liters / min. These flow rates result in dispensing greater than 75% of the cartridge contents with a fill mass of between 1 and 50 mg. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation maneuver, producing a cartridge dispensing rate of greater than 90%. In certain embodiments, the inhaler and cartridge system is configured to deliver a single dose by releasing the powder from the inhaler as a continuous stream 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 containing a medicament for delivery to the pulmonary tract and lungs. The medicament can include a drug formulation for pulmonary delivery, such as a composition including a diketopiperazine, in a self-assembled crystalline form, an amorphous form, and / or a microcrystalline form including crystals that do not self-assemble, or a combination thereof, and an active agent. In other embodiments, the dry powder can be formulated with other carriers and / or excipients other than the 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 analogs thereof. The inhalation system can be used in methods for treating conditions requiring local or systemic delivery of a drug, for example, in methods for treating diabetes, pre-diabetic conditions, allergies, infections including sepsis and infections of the urinary and respiratory tract, anaphylaxis, pulmonary disease, kidney disease, liver disease, dementia, neurodegenerative diseases, or cardiovascular disease, blood disorders, cancer and obesity, and conditions associated with these diseases. In one embodiment, the inhalation system comprises a kit including at least one of each of the components of the inhalation system for treating a disease or disorder. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 is a perspective view of a configuration of a dry powder inhaler in a closed configuration ready for use. [Diagram 2] FIG. 2 is a perspective view of the dry powder inhaler shown in FIG. 1 with the cartridge loading / unloading position fully open and with a powder-containing cartridge attached to the cartridge loading area. [Diagram 3] FIG. 2 is a cross-sectional view of the dry powder inhaler shown in FIG. 1 taken along its central longitudinal axis, showing the inhaler including a cartridge attached to the inhaler and a powder dosage configuration showing the air flow path formed through the chamber of the cartridge. [Figure 4]4 is a cross-sectional view of an inhaler similar to that shown in FIG. 3, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 1, without a cartridge. [Diagram 5] 5 is a cross-sectional view of an inhaler similar to that shown in FIG. 4, without a cartridge, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 1, in an open configuration. [Figure 6] FIG. 1 is a perspective view of another embodiment of a dry powder inhaler in a closed configuration. [Figure 7] FIG. 7 is a perspective view of the dry powder inhaler shown in FIG. 6 with the cartridge loading / unloading position open and with a powder-containing cartridge mounted in the cartridge loading area. [Figure 8] FIG. 7 is a cross-sectional view of the dry powder inhaler shown in FIG. 6 in a closed configuration, taken along a longitudinal axis through the center, showing the inhaler including a cartridge in a powder dosing configuration with the inhaler's air flow path formed through the chamber of the cartridge. [Figure 9] 9 is a cross-sectional view of an inhaler similar to that shown in FIG. 8, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 6, without a cartridge. [Figure 10] 10 is a cross-sectional view of an inhaler similar to that shown in FIG. 9, but without a cartridge, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 6, in a released position. [Figure 11] FIG. 13 is a perspective view of yet another embodiment of a dry powder inhaler in a closed or inhalation position. [Figure 12] 12 shows the dry powder inhaler shown in FIG. 11 with the cartridge loading / unloading position open and with a powder containing cartridge attached to the cartridge loading area. [Figure 13] FIG. 12 is a cross-sectional view of the dry powder inhaler shown in FIG. 11 in a closed configuration, taken along a longitudinal axis through the center, showing the inhaler including a cartridge in a powder dosage configuration with the inhaler's air flow path formed through the chamber of the cartridge. [Figure 14] 14 is a cross-sectional view of an inhaler similar to that shown in FIG. 13, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 11, without a cartridge. [Figure 15] 15 is a cross-sectional view of an inhaler similar to that shown in FIG. 14, but without a cartridge, in an open configuration, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 12. [Figure 16] FIG. 1 is a perspective view of yet another dry powder inhaler configuration in a closed, ready-to-use configuration. [Figure 17] 17 shows the dry powder inhaler shown in FIG. 16 with the cartridge loading / unloading position in the open position and with a powder containing cartridge attached to the cartridge loading area. [Figure 18] FIG. 17 is a cross-sectional view of the dry powder inhaler shown in FIG. 16 in a closed configuration, taken along a longitudinal axis through the center, showing the inhaler including a cartridge in a powder dosage configuration with the inhaler's air flow path formed through the chamber of the cartridge. [Figure 19] 19 is a cross-sectional view of an inhaler similar to that shown in FIG. 18, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 16, without a cartridge. [Figure 20] 19 is a cross-sectional view of an inhaler similar to that shown in FIG. 19, without a cartridge, taken along a longitudinal axis through the centre of the inhaler shown in FIG. 17, in an open configuration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] In embodiments disclosed herein, a dry powder inhaler is disclosed that includes a cartridge for delivering a dry powder containing a pharmaceutical product to a subject via oral inhalation. In one embodiment, the dry powder inhaler is a respiratory dry powder inhaler that is designed to contain an inhalable dry powder that contains a pharmaceutical product that includes an active ingredient, including but not limited to a pharmaceutical agent and optionally a pharma- ceutical acceptable carrier.

[0030] Dry powder inhalers come in a variety of shapes and sizes, are reusable, easy to use, inexpensive to manufacture, and / or mass-produced in simple steps using plastic or other acceptable materials. Various forms of dry powder inhalers are provided herein, and generally, the inhalation system includes an inhaler, a powder-filled cartridge, and an empty cartridge. The 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 is provided by combining a reusable miniature respiratory inhaler with a disposable cartridge containing a pre-metered dose of the dry powder formulation.

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

[0032] As used herein, a "cartridge" is a container configured to hold or contain a dry powder formulation or powder enclosed in an enclosure with 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 motion or vice versa.

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

[0034] As used herein, "unit dose" refers to a dry powder formulation that is pre-measured for inhalation. Alternatively, a unit dose may be a single container with multiple doses of the formulation that can be delivered by inhalation as a single measured amount. A unit dose cartridge / container contains a single dose. Alternatively, it may comprise multiple 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 for the device or method being employed to determine the value.

[0036] As used herein, "fine particles" refers to particles with a diameter of about 0.5 to about 1000 μm, regardless of the exact external or internal structure. Fine particles with a diameter of about 0.5 to about 10 microns are able to reach the lungs and successfully pass most natural barriers. A diameter of less than about 10 microns is necessary to pass through the throat turnover, and a diameter of about 0.5 μm or more is necessary to prevent exhalation. To reach the deep lung (or alveolar region) where most efficient absorption is believed to occur, it is preferable to maximize the proportion of particles contained in the "inhaled fraction" (RF), and generally these particles are accepted with an aerodynamic diameter of about 0.5 to about 6 μm, although some references use somewhat different ranges, as measured using standard techniques such as the Anderson Cascade Impactor. Other impactors, such as the NEXT GENERATION IMPACTOR® (NGI®, MSP Corporation), which define the inhaled fraction at a similar aerodynamic size, such as 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. Pat. No. 8,508,732, is used to determine particle size, 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 80% or more, 85% or more, or 90% or more of the cartridge and a VMGD of the emitted particles greater than 12.5 μm, greater than 7.0 μm, or greater than 4.8 μm indicates progressively better aerodynamic performance.

[0037] The inhaled fraction fill (RF / fill) represents the percentage of respirable particles emitted from the inhaler upon release of the dose-filled powder contents. That is, it represents the percentage of particles emitted in the filled dose that are suitable for pulmonary delivery, and is a measure of particulate aerodynamic performance. As described herein, an RF / fill value of 40% or greater reflects acceptable aerodynamic performance. In certain embodiments disclosed herein, the inhaled fraction fill may be greater than 50%. In typical embodiments, the inhaled fraction fill is up to about 80%, and about 80% of the fill is emitted in particle sizes 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, which does not necessarily imply a complete lack of all water molecules.

[0039] "Amorphous powder," as used herein, includes all non-crystalline powders and refers to dry powders that lack an ordered, repeating form, shape, or structure.

[0040] In the exemplary embodiments shown herein, the device can be manufactured by several methods and from various materials. In one embodiment, the inhaler and cartridge are made using various types of plastic materials, such as, for example, polypropylene, cyclic olefin copolymer, nylon, and other compatible polymers, by injection molding techniques, thermoforming, blow molding, pressure forming, 3D printing, and the like. In certain embodiments, the dry powder inhaler can be assembled using parts that cover all of the individual components. In some embodiments, the inhaler is generally provided in a compact size, for example, in dimensions of about 1 inch to about 5 inches, with the width and height being less than the length of the device. In certain embodiments, the inhaler is provided in a variety of shapes, including a relatively rectangular body, but can 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, deagglomerates, or aerosolizes the dry powder formulation by using at least one relatively rigid flow conduit to allow airflow to enter the inhaler. For example, the inhaler is provided with a first air flow path to enter and exit the cartridge containing the dry powder, and a second air flow path that can merge with the first air flow path exiting the cartridge. The flow conduit can have a variety of shapes and sizes, for example, depending on the shape of the inhaler. In one embodiment, the inhaler has a high resistance inhaler resistance, for example, about 0.065 to about 0.200 (√kPa) / liter / min. Thus, in this system, a peak inhalation pressure drop of 2 to 20 kPa results in a peak flow rate of about 7 to 70 liters / min. These flow rates are greater than 75% of the cartridge contents dispensed at a fill mass of 1 to 50 mg. In some embodiments, these performance characteristics are achieved by an end user in a single inhalation act to produce a cartridge dispensing fraction of greater than 90% of the powder contained in the cartridge.

[0042] An embodiment of a dry powder inhaler 10 is illustrated in Figures 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 a long side extending in a longitudinal plane and is designed to achieve two configurations: a first configuration which is a closed or dosing configuration as shown in Figures 1, 3 and 4, and a second configuration which is an open or cartridge loading / unloading configuration as shown in Figures 2 and 5. As shown in Figures 1-5, the dry powder inhaler 10 has a relatively rectangular body 12 manufactured as a single element and includes a substantially C-shaped proximal end 14 including a mouthpiece 15 which contacts the lips or oral cavity of the user, 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 which diverts air flowing through the air conduit 5 to the interior of the inhaler body 12 but communicates with the chamber or interior of the inhaler body through a second inlet 3 located in the lower part of the mouthpiece in contact with the inhaler body 12. In particular, the second inlet connects with an outlet or dispensing port 31 of a cartridge which is attached to the cartridge mounting area. In Figure 3, the mouthpiece 15 is formed with an air conduit 5 which is narrowed at the distal end and tapers outwardly towards the proximal end, similar to the external shape. The mouthpiece 15 is designed as a single element having saddle or wing-like structures 22, 22' that extend partially outwardly to the junction of the upper side 19 to form part of the upper side 19, and extend downwardly over the right side 17 and left side 18 to cover or slip over the right side 17 and left side 18 of the body 12 to close the inhaler 10 as a 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 a cartridge 24 mounted on the cartridge mounting member 23. To achieve the open configuration, the mouthpiece 11 is pushed downwards from its mouthpiece 15 and the entire element 11 is rotated approximately 90° by grasping the distal top of the inhaler 12, placing it vertically relative to the body 12. Movement of the mouthpiece cover 11 is achieved by providing the inhaler with a hinge, for example a rack and pinion including an axle 32 connected to a gear having a rack engaged with a rack on the movable cartridge mounting area 23.

[0044] FIG. 3 is a central longitudinal section of the inhaler 10 with the cartridge mounted in the dosing configuration, showing the pushing element 33 of the movable cartridge mounting area 23 which fully positions the cartridge in the dosing configuration, and an air passage with an air inlet 29 and an air outlet 31 is formed and connects to the interior of the cartridge cup 30. This embodiment closes the inhaler as shown in FIG. 1 by moving the mouthpiece cover 11 upwards while holding the mouthpiece 15 on a horizontal surface. Then, during the movement, the movable part of the cartridge member in the cartridge mounting area 23 is pushed distally by the movable element in the proximal part of the cartridge mounting area, so that the cartridge lid 28 moves distally beyond the cartridge cup 30, which is held in the mounting area by the rigid projections 27, 27' on the inner surface of the lower side 20 of the body 12. After use, by opening the inhaler 10, the cartridge is returned to the discard / removal position, and the cycle can be repeated with a new dose. FIG. 4 is a central longitudinal section of the inhaler shown in FIG. 1, showing the internal relationships of the device in the closed configuration without the cartridge.

[0045] Figure 5 is a central longitudinal section of the inhaler shown in Figure 1 in an open configuration without a cartridge. The cartridge mounting area is shown fitted with a rigid protrusion projecting from the inner underside 20 of the inhaler body 12, with the dosing position being achieved upon movement of the mouthpiece cover 11 to the closed configuration by a cartridge lid pusher element 33 in the movable cartridge mounting area 23 for moving the lid over the cartridge cup.

[0046] 6-10 show another embodiment, in which the dry powder inhaler 40 comprises a body 42, a mouthpiece 45 having at least two air inlets and one air outlet 46, and a mechanism 47 for loading and reconstituting the cartridge. The inhaler 40 also comprises a discontinuous upper surface 51, which may be formed of a partially ribbed structure, a proximal end 48, a distal end 49, and a bottom 42. In this embodiment, the inhaler 40 is in a closed position. The upper distal half 49 of the inhaler body 42 has an opening or slot 53 for receiving a movable lever 52 in a central longitudinal plane to engage with a movable rack 54 in the internal compartment of the inhaler body 42 to allow movement of the cartridge loading and reconstituting mechanism 47, and the rack includes a pusher element for transferring the lid of the cartridge onto the cup or the cup under the fixed lid of the cartridge. In this embodiment, manual movement of the lever 52 in a distal direction configures the inhaler in a cartridge loading position. FIG. 7 shows the inhaler 40 in an open configuration with a cartridge attached or mounted in the cartridge mounting area 55. In preparing a dose for pulmonary inhalation, the user can place or install the cartridge 56 in 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 cannot move any further. FIG. 8 shows a central longitudinal section of the inhaler 40 in a closed or dosing configuration with a cartridge attached in the cartridge mounting or reconfiguration area 55, showing the pushing element 66 that moves the cup 58 under the lid 59 in the dosing configuration. During the movement of the lever 52, the pushing element 66 inside the inhaler engaged with the lever 52 activates the pushing element 66 of the rack to move the cartridge 56 and reform its lid, forming an air conduit with the air inlet 64 and an air outlet 65 that communicates with the second inlet 63 of the mouthpiece 45 for delivering powder to the air conduit 61 and outlet 46 of the mouthpiece during inhalation. Air intake through first inlet 62 bypasses the cartridge compartment during inhalation. A discontinuous area on the top surface 51 of the inhaler allows access to the cartridge mounting area 55. Figure 8 also shows lever 52 engaged with shaft 60 of reconstitution mechanism 47.

[0047] FIG. 9 shows the closed inhaler 40, which is similar to FIG. 8, except that it does not include a cartridge located at the proximal end of the inhaler body 42. In the configuration shown in FIG. 9, the rack 54 including the pushing element 66 and the horizontal first inlet 62 are in close proximity with the second inlet 63 of the mouthpiece 45 in a substantially vertical configuration to achieve deagglomeration of the powder by shear forces during inhalation of a powder dose. FIG. 10 shows the inhaler 40 shown in FIG. 9 without a cartridge in an open configuration through a central longitudinal section, showing the position of the lever 52 and rack 54 for holding the cartridge, and the position of the central part of the inhaler body 42 at the inner end of the inhaler. FIG. 10 also shows the rack 54 integrally engaged with a movable mechanism for mechanically pushing the rack 54, as shown by the shaft 60 contacting the lever 52.

[0048] 11-15 show yet another inhaler, in which a cartridge can be attached and detached to the interior of the body 72, and a mouthpiece 71 can be moved relative to the inhaler body 72 by a gear mechanism 85 that rotates laterally in a horizontal plane at an angle of about 90° from the longitudinal axis A of the inhaler 70. The mouthpiece 71 further includes an air inlet 74, an air outlet 73, and a second air inlet that communicates with the interior of the inhaler body 72. FIG. 11 shows the inhaler 70 in a closed or dosing configuration. FIG. 12 shows the inhaler 70 in an open configuration for mounting or attaching a cartridge, as exemplified by the cartridge 76. The inhaler 70 is designed to have a substantially rectangular 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. The mouthpiece 71 also has side extensions 82 extending from the central air conduit and formed as one piece over a top surface 81 of the inhaler body. The top surface 81 includes a stop 83 formed to prevent the mouthpiece 71 from rotating beyond a plane perpendicular to the inhaler body 72. Rotating the mouthpiece 71 to an open position activates the attachment or reconfiguration mechanism so that the open area of ​​the top surface 81 of the body 72 is accessible, as shown in Figure 12. Figures 13 and 14 show central longitudinal sections of the inhaler 70, with Figure 13 showing it with a cartridge and Figure 14 showing it without a cartridge, to illustrate the movement of the rack 86 in the closing or dispensing mechanism by the gear mechanism 90. Movement of mouthpiece 71 from right side 79 to left side 80 in a horizontal direction relative to the inhaler body actuates a gear mechanism to move cup 92 relative to lid 93 in a proximal translational motion to form an air flow path through the interior of the cup with air inlet 94 and air outlet 95 communicating inlet 89 and air conduit 96 of inhaler 70 for releasing powder contained in cup 92. In this embodiment, the mounting and reconfiguring mechanism includes a shelf structure 99 extending outwardly from cup 92 and constructed within the top surface of mounting area 91 for receiving lid 93 of a cartridge that rests on shelf structure 99 which is secured thereto, with cup 92 received in rack 86 and cartridge in powder containing configuration.

[0049] Yet another dry powder inhaler configuration is shown in Figures 16-20, in which the inhaler 100 comprises a two-part member, an inhaler body 101, and a housing or cover 102 which covers a portion of the inhaler body 101. In one embodiment shown in Figure 16, the inhaler 100 comprises an inhaler body 101 having a proximal end 103 with a mouthpiece 104, and a distal end 105 with the housing 102 which is structurally formed as a slip-on cover over the body and interior portions of the inhaler. The housing 102 shown in Figure 17 comprises a distal end 107 and a proximal end 106, the proximal end 106 having an opening to accommodate and encapsulate a portion of the inhaler body 105, and a protrusion 113 protruding from its upper surface to allow a direct airflow into the air conduit 115 of the mouthpiece 104 upon inhalation. In one embodiment, as shown in Figure 16, the proximal end 106 contacts or abuts the inhaler body 101 to close the inhaler 100 from the outside environment. From the closed configuration, the inhaler 100 is opened by translating the housing 102 distally over the body 105 to achieve a loading and / or unloading position on the inhaler for loading and unloading a cartridge. Figure 17 shows the inhaler 100 in an open configuration with the housing 102 pulled distally away to allow access to the distal portion 105 of the inhaler body. In this and other embodiments, as shown in Figure 17, the cartridge 108 is mounted in the cartridge mounting area 109 of the inhaler 100, which shows a lid and outlet port 110 that communicates with an air conduit in the mouthpiece that extends through a second inlet portion of the mouthpiece 104 to an inlet 111 and an outlet 112. The mounting area 109 is contoured to closely match the shape of the cartridge 108 and to visually indicate to the user the proper orientation of the cartridge during mounting.

[0050] Also, in Fig. 18, a central longitudinal section of the inhaler 100 in the closed dispensing configuration is shown showing the position of the cartridge cup 116 relative to the lid 117 upon translational movement of the housing 102 on the body 105 in the distal to proximal direction, causing the cartridge 108 to move from the storage configuration to the dispensing configuration, the cartridge receptacle cup 116 is pressed into the dispensing configuration by a protruding rigid element at the bottom of the interior of the housing 102 that extends beyond the opening 106 at the proximal end 106 in the horizontal plane. Also, the protruding rigid element 118 may include one or more vertical protrusions to facilitate removal of the cartridge 108 after use. Furthermore, in the closed configuration, 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 dispensing configuration, the mouthpiece for ambient air is used to access the dry powder in the cartridge 108 upon inhalation. In this and other embodiments, upon inhalation, air enters the air flow path of the cartridge 108 in the dosing configuration through the air inlet 119, and the dry powder particles are aerosolized and entrained in the air and exit through the air inlet in the air conduit 115 of the mouthpiece 104 and the air outlet 120 which communicates with the air flow path of the mouthpiece 104, where further shearing of the powder occurs before the powder is expelled through the outlet 112 of the mouthpiece.

[0051] In one embodiment, the inhaler body 101 includes a mouthpiece integrally formed at the proximal end of the body 101 and includes an air conduit 115 in communication with the interior of the body 101 and housing 102, and can directly communicate with an air inlet 120 of a cartridge 108 attached to the inhaler 100 and with the ambient air. The inhaler body 101 also includes a cartridge mounting area 121 that is structurally continuous with the mouthpiece and has a distal portion 105 and a proximal portion 103. The proximal portion 103 and distal portion 105 form a single piece with the mouthpiece 104, and the distal portion 105 is pluggable into the housing 102. In one embodiment, as shown in Figures 17 and 20, the body 101 and housing 102 can be manually pulled apart to obtain an inhaler open configuration for accessing the internal compartment. In this form of open configuration, a cartridge 108 containing dry powder is mounted or attached in a cartridge mounting area of ​​the body portion 105 in the appropriate orientation as indicated by visual cues, and the body 101 and housing 102 can be pushed or pulled to open and close the inhaler 100. In one embodiment, the housing is movable on the distal portion 105 of the body 105 from the open configuration to a closed configuration, which closes the inhaler 100 when they contact each other.

[0052] 18 and 19 show the inhaler 100 in a closed or dispensing configuration, where the closing action accomplishes the movement of the cartridge 108 to the dispensing position, and the cartridge cup is pushed by the protrusion 118 to reconfigure independently of the lid 117 to form an air conduit through the cartridge 108 attached to the cartridge mounting area 109. In this configuration, the inhaler achieves a dispensing configuration such that the powder in the cup 116 is released from the inhaler upon oral inhalation by the user through the mouthpiece 104. In this embodiment and the dispensing configuration shown in FIG. 18, the body and the housing abut against each other and are closely fitted by one or more anti-slip structures to prevent disassembly of the inhaler. Some examples of anti-slip structures are snap rings or detents that can generate sounds to alert the user that the inhaler is ready for use. FIGS. 17 and 20 show the inhaler 100 in an open configuration. In this embodiment, the inhaler 100 is substantially rectangular with smaller lengths on the distal and proximal sides. Movement of the housing 102 on the body 105 is accomplished by pulling or pushing the body 105, and vice versa. The movement is facilitated by the body including guide rails and tracks 123 extending outwardly from the long sides (first and second sides) of the inhaler body 105 in a longitudinal plane. In this embodiment, the inhaler body 105 is designed with an opening at its distal end to match the opening at the distal end of the housing to direct and guide ambient air into the internal chamber of the inhaler 100 during inhalation. The inhaler housing 102 is also closely formed with a groove or slot 124 for sliding on the guide rails 123 during movement, and includes one or more stop ends to prevent disassembly of the inhaler 100. The push-in or protrusion 118 is designed to position the cartridge in the dose after installation and closing of the inhaler 100. The indentation or protrusion 118 moves the cartridge cup or container 116 relative to the cartridge lid 117, creating an air flow path through the cartridge and creating an air inlet 119 and an air outlet 120 to allow aerosolization of the powder in the cup during inhalation and delivery of the aerosolized particles to the inhaler mouthpiece air conduit 115 and the user.

[0053] In the description of the inhaler 100, the distal part of the housing includes parallel structures and flanges for engaging with a portion of the inhaler body, for example, to secure the inhaler body to the housing, forming a locking mechanism for locking the two parts together and maintaining the dosing arrangement. In one embodiment, the distal part 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. The distal part 107 of the housing 102 also includes an outer surface, an inner surface and a chamber formed to encase the inhaler body 105. In one embodiment, the housing 102 includes parallel wing-like structures 113 on its upper surface to direct the airflow to the mouthpiece 104 during inhalation. The inhaler body part 105 can be designed with grooves in its central longitudinal plane to fit the push-out or protrusions 118 to push out and slide the cartridge or to prevent disassembly of the housing. The inhaler body 105 may also be formed with a detent at its distal end to engage the housing 102 and secure the two inhaler portions together.

[0054] The configuration of the cartridge for use with the inhaler is described in U.S. Pat. No. 8,424,518, the disclosure of which is incorporated herein by reference in its entirety. In summary, the cartridge for use with the embodiments of the inhaler disclosed herein includes two parts, although other embodiments may be envisioned. The cartridge is formed to contain the dry powder in storage in an enclosed or containment position, and can be reconfigured within the inhaler from the powder storage position to an inhalation or dispensing position. In certain embodiments, the cartridge comprises a lid and a cup having one or more openings, a storage position, and a dispensing position, an outer surface, an inner surface defining an interior volume. And the storage position limits communication to the interior volume, and the dispensing position forms an air passage through the interior volume, allowing air flow to enter and exit the interior volume in a predetermined manner. For example, the container of the cartridge can be formed such that air flow entering the air inlet of the cartridge is directed across an air outlet within the interior volume, and the rate of powder spillage is limited by calculating the medicament exiting the cartridge. The air flow within the cartridge can be substantially perpendicular to the flow direction of the air flow outlet, mixing and fluidizing the powder within the internal volume before exiting through the dispensing opening. Cartridges for use with instant inhalers can be supplied in individual blisters or grouped together in blisters depending on the patient's needs or the hygroscopic nature 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 cartridge form an inhalation system and can be structurally configured to achieve a distributable or prescribed airflow resistance. This can be achieved by varying the cross-sectional area or arrangement of the air conduits in some parts of the system's flow path. In one embodiment, the arrangement of the air conduits in the dry powder inhaler system can achieve an airflow resistance value of 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 ranges shown herein.

[0056] In yet another embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided. The system includes an inhaler including a container mounting area configured 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 area, and one of the at least two inlet openings is in fluid communication with the at least one outlet opening via a flow path configured to bypass the container area to deliver the dry powder formulation to the patient. The flow conduit is configured to bypass the container area to deliver 30% to 90% of the total amount flowing through the inhaler upon inhalation.

[0057] In another embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided. The system includes a dry powder inhaler including a cartridge mounting and reconstitution area. The dry powder inhaler and cartridge combination is formed to have at least two flow paths that are rigid flow conduits in a dosing configuration and a plurality of structural areas that provide a mechanism for powder deagglomeration of the inhalation system during use. At least one of the plurality of mechanisms for deagglomeration is the size of the agglomerates that close an opening in a container area having a minimum dimension of 0.5 mm to 3 mm.

[0058] In embodiments disclosed herein, the dry powder formulation comprises a crystalline powder, an 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. Thus, 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 greater than 75% of the cartridge contents being dispensed, with a fill mass of 1 to 30 mg, or even up to 50 mg of powder. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation maneuver, producing a cartridge dispensing rate of greater than 90%. In certain embodiments, the inhaler and cartridge system is configured to deliver a single dose by releasing the powder from the inhaler as a continuous stream 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 the lungs of a patient is provided and configured with a flow conduit having a total resistance to flow of from about 0.065 to about 0.200 (√kPa) / liter / min in a dosage form. In this and other embodiments, the total resistance to flow of the inhalation system is relatively constant over a pressure differential range between 0.5 kPa and 7 kPa.

[0059] The structural configuration of the inhaler allows the deagglomeration mechanism to produce an inhaled fraction of greater than 50% and particles less than 5.8 μm. The inhaler is capable of releasing greater than 85% of the powder formulation contained in the container during an inhalation maneuver. In general, the inhalers disclosed herein are capable of releasing greater than 90% of the contents of the cartridge or container in less than 3 seconds at a pressure difference of 2 to 5 kPa with a fill mass of 30 mg to 50 mg.

[0060] Although the inhaler of the present invention is primarily powered by breath, in some embodiments, it can be equipped with a power source to generate the pressure differential necessary for deagglomeration and delivery of the dry powder formulation. For example, the inhaler can accommodate a gas power source, such as a compressed gas stored energy source, such as a nitrogen canister, which can be equipped at the air inlet. It can also be equipped with a spacer to capture the plume so that the patient can inhale in a comfortable space.

[0061] In the embodiments described herein, the inhaler is provided as a reusable inhaler that delivers a single unit dose, the reusable inhaler allows for a predetermined number of uses depending on the formulation delivered, and is disposed of once a maximum usage has been reached.

[0062] These subject devices and systems are useful for pulmonary delivery of powders with a wide range of properties. Embodiments include systems including an inhaler and an integrated or mountable unit dose cartridge containing the desired powder dose. For pulmonary delivery of powders, carriers and excipients with proven safety and efficacy in commercially available products are included. Also, in exemplary embodiments, fumaryl diketopiperazine, known as 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP. FDKP produces fine particles that can become self-assembled aggregates of crystalline plates in suspension and can be produced as amorphous powders or combinations thereof, depending on the process, as disclosed in U.S. Pat. Nos. 7,820,676, 7,709,639 and 8,551,528, which are incorporated herein by reference. Dry powders produced using diketopiperazines can be produced by freeze drying, spray drying solutions or suspensions of various desired formulations. Approximately 35 to about 67 m 2 DKP crystalline microparticles having a specific surface area (SSA) of 1000 μg / g exhibit beneficial properties for pulmonary drug delivery, such as improved aerodynamic performance and improved drug adsorption. In some embodiments, high volume crystalline DKP microparticles for use in peptide-containing formulations can be prepared in a volume of 1000 μg / g, e.g., 35 m 2 / g, and the amount of activator increases the specific surface area of ​​the particles to approximately 19 m 2 / g ~ approx. 30m 2 / g, approx. 28m 2 / g ~ approx. 71m 2 / g, or about 19m 2 / g ~ approx. 57m 2 In some embodiments, the microparticles of FDKP with a peptide active agent, such as insulin, can range from about 4 m / g. 2 / g ~ approx. 30m 2 / g range and have improved aerodynamic properties as measured by flight and flow properties.

[0063] In one embodiment, the dry powder formulation may include, for example, a diketopiperazine and a pharmacoactive ingredient. In this embodiment, the pharmacoactive ingredient or active agent may be of various types depending on the disease or condition being treated. In other embodiments, the diketopiperazine may include symmetrical and asymmetrical diketopiperazine molecules that are useful for forming particles, microparticles, etc., that are used as carrier systems to deliver active agents to target sites in the body. The term "active agent" as used herein refers to therapeutic agents or molecules such as proteins or peptides or biomolecules and small molecules that are encapsulated or bound or mixed within or adsorbed onto the diketopiperazine formulation. Any form of active agent may be combined with the diketopiperazine. The drug delivery system may be used to deliver biologically active agents that have 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] [ka]

[0066] Pulmonary delivery microparticles having diameters between about 0.5 and about 10 μm can reach the lungs and also reach the systemic circulation to deliver the active agent. A diameter of less than about 10 μm is necessary to traverse the throat turnover, and a diameter of about 0.5 μm or greater is necessary to prevent exhalation. In general, microparticles having diameters greater than 10 μm or greater than 20 μm are useful for local delivery to the airways and lungs.

[0067] Particulates having diameters of about 0.5 to about 10 microns can reach the lungs and successfully pass through most natural barriers. A diameter of less than about 10 microns is necessary to traverse the pharyngeal turn, and a diameter of about 0.5 microns or greater is necessary to prevent exhalation. In the embodiments disclosed herein, the diameters range from about 4 to about 71 microns. 2 Microparticles having a specific surface area (SSA) of about 100 / g exhibit beneficial properties for pulmonary drug delivery, such as improved aerodynamic performance and improved drug adsorption. In accordance with this, in some embodiments, compositions are provided that include crystalline fumaryl diketopiperazine (FDKP) microparticles 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, the diketopiperazine being fumaryl diketopiperazine, and comprising a plurality of substantially uniformly formed microcrystalline particles, the particles being hollow spherical structures and comprising a shell comprising non-self-assembled microcrystals of diketopiperazine, and the volume average geometric diameter of the particles is less than 5 μm. The particles are formed by a method comprising combining diketopiperazine in solution without the use of surfactants with an acetic acid solution, and simultaneously homogenizing in a high shear mixer under high pressure up to 2000 psi to form a precipitate. The precipitate is then washed with a suspension of deionized water, the suspension is concentrated, and the suspension is dried in a spray dryer.

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

[0070] A system for delivery of an inhalable dry powder is also provided, comprising: a) a dry powder comprising a medicament; and b) an inhaler comprising the powder contained in a cartridge, the cartridge including a gas inlet, a gas outlet, and a housing that secures the cartridge and defines two flow paths, a first flow path that allows gas to enter the gas inlet of the cartridge and a second flow path that allows gas to be bypassed to the gas inlet of the container, and a pressure drop of 2 kPa or more over the inhaler plume is applied to cause particles to be emitted from the mouthpiece, 50% of the emitted particles having a VMAD of 10 μm or less, the flow bypassing the gas inlet of the cartridge being substantially perpendicular to the flow direction of the gas inlet and influencing the outgoing flow.

[0071] Active agents used in the compositions and methods described herein can include any pharmaceutical agent, including, for example, organic synthetic compounds, proteins and peptides, polysaccharides and other sugars, lipids, inorganic compounds, and nucleic acid sequences, that contain therapeutic, prophylactic, or diagnostic activity. Peptides, proteins, and polypeptides are all chains of amino acids linked by peptide bonds.

[0072] Active agents that can be delivered to targets or sites in the body using diketopiperazines include, for example, hormones, anticoagulants, immunomodulators, vaccines, cytotoxic drugs, neurotransmitter agonists and antagonists, antibiotics, vasoactive agents, neuroactive agents, anesthetics and sedatives, steroids, decongestants, antivirals, 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, DDIs, granulocyte monocyte colony stimulating factor (GM-CSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β-galactosidase, exendin, vasoactive intestinal peptide, and argatroban. Antibodies and fragments thereof may include, but are not limited to, anti-SSX-241-49 (synovial sarcoma, X-breakpoint 2), anti-NY-ESO-1 (esophageal tumor associated antigen), anti-FRAME (preferentially expressed antigen in melanoma), anti-PSMA (prostate specific membrane antigen), anti-Melan-A (melanoma tumor associated antigen), and anti-tyrosinase (melanoma tumor associated antigen).

[0073] In certain embodiments, the dry powder formulation delivered to the pulmonary circulation comprises an active ingredient or agent, including a peptide, protein, hormone, analog or conjugate thereof, such as insulin, calcitonin, growth hormone, rythropoietin, granulocyte-monocyte colony-stimulating factor (GM-CSF), chorionic gonadotropin-releasing factor, luteinizing releasing hormone, follicle-stimulating hormone, vasoactive intestinal peptide, parathyroid hormone (including black bear 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, active fragments, PC-DAC-modified derivatives, or O-glycosylated forms thereof. In certain embodiments, the pharmaceutical composition or dry powder formulation comprises fumaryl diketopiperazine, and the active ingredient is one or more selected from insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin, adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, cerebral 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, cannabinoids including tetrahydrocannabinol, cannabidiol, pancreatic peptide, neuropeptide Y, delta-sleep-containing peptide, vasoactive intestinal peptide, one or more combinations of active agents thereof and / or analogs thereof.

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

[0075] The present disclosure also provides improved microcrystalline particles, compositions, methods of making the particles, and methods that allow for improved drug delivery to the lungs to treat diseases and disorders of a subject. The embodiments disclosed herein achieve improved delivery by providing microcrystalline diketopiperazine compositions containing microcrystalline diketopiperazine particles that have a high capacity for drug adsorption resulting in powders with high drug loading of one or more active agents. Powders made with the microcrystalline particles can deliver drug loading at lower powder doses, facilitating drug delivery to patients. They can be made by a variety of methods, including methods utilizing surfactant-free solutions or solutions that include surfactants depending on the starting materials.

[0076] Other embodiments disclosed herein can include dry powders for inhalation comprising a plurality of substantially uniform microcrystalline particles, which can have a substantially hollow spherical structure and can include a porous shell comprising crystals of diketopiperazine that do not self-assemble in suspension or solution. In certain embodiments, the microcrystalline particles can be substantially hollow spherical and substantially solid particles comprising crystals of diketopiperazine, depending on the drug and / or drug load provided and other factors in the powder manufacturing process. In one embodiment, the microcrystalline particles are relatively porous and have a size of about 0.43 cm. 3 / g, approx. 0.4cm 3 / g ~ approx. 0.45cm 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.

[0077] Certain embodiments disclosed herein include powders comprising a multiplicity of substantially uniform microcrystalline particles, the particles having a substantially spherical structure with a shell which may be porous, comprising crystals of diketopiperazine that do not self-assemble in suspension or solution, and having a volumetric geometric diameter 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 volumetric geometric diameter of 5.8 μm. In one embodiment, the shell of the particle is constructed from interlocking diketopiperazine microparticles having one or more drugs adsorbed on their surface. In some embodiments, the particle can encapsulate a drug in the interior void volume and / or a combination of a drug adsorbed on the crystalline surface and a drug encapsulated in the interior void volume of the sphere.

[0079] In certain embodiments, the diketopiperazine composition comprises a multiplicity of substantially uniformly formed microcrystalline particles, the particles having a substantially hollow spherical structure and including a shell comprising non-self-assembled crystals of diketopiperazine, the particles being formed by a process comprising combining diketopiperazine having a trans-isomer content of about 45% to 65% in solution and in an acetic acid solution without the presence of a surfactant, simultaneously homogenizing in a high shear mixer at high pressures of up to 2000 psi to form a precipitate, washing the precipitate in a suspension with deionized water, concentrating the suspension, and drying the suspension in a spray dryer.

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

[0081] In certain embodiments, the diketopiperazine composition comprises a multiplicity of substantially uniformly formed microcrystalline particles, the particles having a substantially hollow spherical structure, a shell comprising non-self-assembled crystals of diketopiperazine, and a volume average geometric diameter of less than 5 μm. The particles are formed by a process comprising combining diketopiperazine in solution and in acetic acid solution without the presence of a surfactant, and simultaneously homogenizing in a high shear mixer at high pressures 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] Additionally, the method includes the step of adding, with mixing, a solution containing an active agent or ingredient, such as a drug or bioactive agent, prior to the spray drying process, where the active agent or ingredient is adsorbed and / or encapsulated onto or within the particles. The particles produced by this process can be in the submicron size range.

[0083] In certain embodiments, the diketopiperazine composition comprises a multiplicity of substantially uniformly formed microcrystalline particles, the microcrystalline particles having a substantially hollow spherical structure, a shell comprising non-self-assembled crystals of diketopiperazine, and a volume average geometric diameter of less than 5 μm. The particles are formed by a process comprising combining diketopiperazine in solution and in acetic acid solution without the presence of a surfactant, and simultaneously homogenizing in a high shear mixer at high pressures 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 a highly viscous extract or a material with a honey-like consistency, microcrystalline particles are formed as above and by washing them using tangential flow filtration before binding with the extract or viscous material. After washing in water, the resulting particle suspension is lyophilized to remove water and resuspended in an alcoholic solution, or suspension, or solution, including ethanol or methanol, before adding the active ingredient as a solid. In one embodiment, if desired, the method of making the composition includes the step of adding additional excipients including one or more amino acids, such as leucine, isoleucine, norleucine, methionine, or one or more phospholipids, e.g., 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), simultaneously with the active ingredient or after adding the active ingredient, but before spray drying. In certain embodiments, formation of the composition includes a step in which the extract containing the desired active ingredients is filtered or wintered, if necessary, to remove and separate layers of unwanted materials, such as lipids that increase solubility.

[0085] The method further includes adding with mixing a solution, optionally homogenized or not homogenized with a high shear mixer, containing an active agent or ingredient, such as a drug or bioactive agent, prior to the spray drying process, which is adsorbed and / or encapsulated on or within the particles. The particles produced by this process can be in the submicron size range prior to spray drying, or the particles can be formed from the solution during spray drying.

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

[0087] In one embodiment, the compositions delivered by the inhaler herein may include fumaryl diketopiperazine crystalline particles and an active agent such as a cannabinoid, including tetrahydrocannabinol (THC) and / or cannabidiol, treprostinil, palonosetron, parathyroid hormone, sildenafil, or epinephrine. In compositions in which a cannabinoid is used as the active agent, the cannabinoid (including derivatives and / or analogs thereof) content may be 40% (w / w) with powder delivery being greater than 40% of the inhaler content. In some embodiments, the cannabinoid content in the composition may be about 1% to about 30%, about 5% to about 25% (w / w) of the powder content. The compositions herein may also 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 amounts 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 needed.

[0088] In embodiments where epinephrine is used as the active agent, the epinephrine composition content includes up to about 30% (w / w) and from about 1% to about 35% of the powder content. In certain embodiments, the composition including the 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 using the inhalers described herein with a powder delivery efficiency of greater than 50% of the dosage content. In this embodiment, it can be used as a method to treat the symptoms of an allergic reaction prior to the onset of anaphylaxis caused by allergens such as nuts, including peanut allergens, antibiotics such as penicillin, and other substances. The method includes providing to a patient in need of treatment for the symptoms of an allergic reaction and who is exhibiting early symptoms of anaphylaxis an inhaler containing a dose of from about 1 mg to about 15 mg of a composition effective to prevent the onset of anaphylaxis, and providing to the patient an inhaler containing a dose of a composition comprising epinephrine in an amount sufficient to prevent the onset of anaphylaxis.

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

[0090] In embodiments where palonosetron is used as the active agent for the inhalation powder, the content of palonosetron dry powder in the composition includes up to about 20% (w / w), and about 0.1% to about 20%, or 0.1% to about 10% (w / w) of the dry powder content. In one embodiment, the palonosetron composition can be prepared with fumaryl diketopiperazine disodium salt or crystalline synthetic particles of fumaryl diketopiperazine, and excipients including amino acids such as leucine, isoleucine, and methionine to improve the storage stability of the composition. In this embodiment, the palonosetron inhalation composition can be used for the treatment and prevention of nausea and vomiting inducing chemotherapy by self-administration with a single inhalation using the inhaler, by administering the composition about 5 minutes to 30 minutes, and preferably about 5 minutes to about 15 minutes, before or simultaneously with receiving a chemotherapy dose.

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

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

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

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

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

[0096] Also provided is a method for treating a disease or disorder in a patient in the form of a dry powder inhaler as disclosed herein. The method of treatment includes providing a patient in need of treatment with a dry powder inhaler that includes a cartridge containing a dose of an inhalable formulation, the inhalable formulation including an active ingredient selected from the group set forth above, and a pharma- ceutically acceptable carrier and / or excipient. The method also includes having the patient inhale for about 3-4 seconds through the dry powder inhaler to deliver the dose, after which the patient can resume normal breathing.

[0097] The following examples provide several processes for producing dry powders suitable for use in the inhalers described herein, and data obtained from experiments with the dry powders.

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

[0099] Composition of FDKP solution [Table 1]

[0100] Acetic acid solution composition [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, moisture content and porosity measurements. Four types of powders were used in this study. All powders tested had a residual moisture of 0.4%. Table 2a shows the data obtained in this study.

[0102] [Table 2a]

[0103] The data in Table 2a show that the surface area of ​​the spray-dried bulk dry powder containing microcrystalline particles of the tested sample is 59 m 2 / g~63m 2 Porosity data indicates that the microcrystalline particles are relatively porous, with an average pore volume of approximately 0.43 cm3 as determined by BJH adsorption. 3 / g, with an average pore size ranging from about 23.8 nm to 26.2 nm. Porosimetry data indicate that these particles have a pore size of about 0.36 cm 3 This indicates that the FDKP microcrystals are different from conventional FDKP microcrystals, which have an average pore volume of 1 / g and an average pore size ranging from about 20 nm to about 22.6 nm.

[0104] Example 2 Preparation of dry powder containing microcrystalline FDKP particles containing epinephrine A solution of about 5% by weight epinephrine in about 5% aqueous acetic acid was added to the suspension of FDKP microcrystals obtained as described in Example 1. Leucine was also added to the suspension of FDKP microcrystals, if necessary. 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 10-20% pump capacity, 90-100% suction speed, and 170-190°C inlet temperature. The weight percent concentrations of epinephrine and leucine in the resulting powders were 2-30% and 0-20%, respectively. The delivery efficiency of these powders after release from the spray dryer ranged from about 50% to 80%.

[0105] Example 3 Preparation of a dry powder containing microcrystalline FDKP particles containing palonosetron A solution of about 5% by weight of palonosetron hydrochloride in DI water was added to the suspension of FDKP microcrystals obtained as described in Example 1. Leucine and methionine in deionized (DI) water were also added as required. 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 10-12% pump capacity, 90-100% suction speed, and 170-190°C inlet temperature. The weight percent concentrations of palonosetron, leucine, and methionine in the resulting powders were 5%, 0-20%, and 0-10%, respectively. The delivery efficiency of these powders after release from the spray dryer ranged from about 50% to 70%.

[0106] Example 4 Preparation of dry powder containing microcrystalline FDKP particles containing treprostinil Treprostinil at 0.2-1.0 wt% in ethyl alcohol was added to a 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 10-12% pump capacity, 90-100% suction speed, and 170-190°C inlet temperature. The weight percent concentration of Treprostinil in the resulting powder was 0.5-10%. The delivery efficiency of these powders after release from the spray dryer ranged from about 50% to 70%.

[0107] Example 5 Preparation of dry powders containing microcrystalline FDKP particles containing Δ9-THC or CBD Separated FDKP microcrystal particles prepared as in Example 1 were suspended in ethyl alcohol. Approximately 1-4 wt% solutions of cannabis extracts containing primarily either Δ9-THC or CBD were added to the ethanol and ethanol suspension of FDKP microcrystals. If necessary, solutions of additives dissolved in ethanol were 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 12-15% pump capacity, 70-100% suction speed, and 110-140°C inlet temperature. The wt% concentrations of Δ9-THC and additives are shown in Table 3. The delivery efficiency of these powders after release from the spray dryer ranged from about 50% to 70%.

[0108] Composition of microcrystalline FDKP particles containing Δ9-THC or CBD [Table 3]

[0109] Dry powders produced by the above method were tested using a substantially anatomically correct airway (ACA) system as described in U.S. Patent No. 9,016,147. The dry powders demonstrated a significant degree of stability at room temperature, e.g., over 90% of the THC or CBD remained active upon one month of storage, and demonstrated delivery efficiencies ranging from about 35% to about 75% using this method.

[0110] The above disclosure is of exemplary embodiments. It should be appreciated by those skilled in the art that the devices, techniques, and methods disclosed herein set forth representative embodiments that work well in the practice of the present disclosure. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain like or similar results without departing from the spirit and scope of the invention.

[0111] Unless otherwise indicated, all numbers expressing properties such as amounts of ingredients, molecular weights, reaction conditions, and the like used in the specification and claims should be understood to be 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 on 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 be construed in accordance with, at the very least, the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth broad ranges are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0112] The terms "a", "an", "the" and similar references used in the context of describing the invention (particularly in the context of the claims) are intended to encompass both the singular and the plural, unless otherwise specified herein or clearly contradicted by context. Numerical ranges described herein are merely intended to serve as a shorthand method of referring individually to each individual value falling within the range. Unless otherwise specified herein, each individual value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise specified herein or clearly contradicted by context. Any and all examples or exemplary language (e.g., "etc.") 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 essential to the practice of the invention.

[0113] The term "or" as used in the claims means "and / or" unless expressly indicated to refer only to other alternatives, or where only alternatives and "and / or" are mentioned and defined but the alternatives are mutually exclusive.

[0114] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limiting. The elements of each group may be referenced and claimed individually or in any combination with other elements in the group or other elements disclosed herein. It is anticipated that for reasons of convenience and / or patentability, one or more elements of a group may be included in or deleted from a group. When such inclusion or deletion occurs, the specification is considered to include the modified group, and thus to satisfy the description of all Markush groups used in the claims.

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

[0116] Certain embodiments disclosed herein may be further limited in the claims using the language consisting of or consisting essentially of. When used in the claims, whether submitted in an amendment or added, the language consisting of excludes other elements, steps, or ingredients not recited in the claim. The language consisting essentially limits the scope of the claim to certain materials or steps without materially affecting the basic or novel characteristics. As such, the claimed embodiments are operative as essentially or explicitly recited.

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

[0118] Moreover, it is to be understood that the embodiments disclosed herein disclose the principles of the invention. Other modifications may be adopted within the scope of the invention. Thus, by way of example, and not of limitation, other configurations may be utilized in accordance with the disclosure herein. Accordingly, the invention is not limited to that precisely as shown and described.

[0119] (Additional Note) (Appendix 1) Housing and a body having a mouthpiece integrally formed with the body; Equipped with the body having a mounting area for a cartridge, the body and the housing being linearly movable relative to one another and configured to be operatively configured to reconfigure the cartridge to interlockingly engage one another to provide an airflow path for expelling a powder dose upon inhalation; Dry powder inhaler.

[0120] (Appendix 2) The mouthpiece has an air inlet in communication with an interior compartment of the inhaler body. 2. A dry powder inhaler as described in claim 1.

[0121] (Appendix 3) transition of the housing on the inhaler body from an open configuration to a closed configuration causes the housing to reconfigure the cartridge for installation in the inhaler. 2. A dry powder inhaler as described in claim 1.

[0122] (Appendix 4) Movement of the housing relative to the body is facilitated by guide rails configured along a longitudinal axis and extending from the right and / or left side of the inhaler body. 2. A dry powder inhaler as described in claim 1.

[0123] (Appendix 5) configured to have an open or loading position and a closed or dispensing position; 2. A dry powder inhaler as described in claim 1.

[0124] (Appendix 6) The housing further includes a protruding rigid element that urges the cartridge from the storage position to the dispensing position. 2. A dry powder inhaler as described in claim 1.

[0125] (Appendix 7) and further configured to have a rigid flow conduit. 2. A dry powder inhaler as described in claim 1.

[0126] (Appendix 8) The housing includes a cover that covers a portion of the inhaler body. 2. A dry powder inhaler as described in claim 1.

[0127] (Appendix 9) Further, the mouthpiece has an interior volume extending from the first inlet port to the outlet port; the internal volume is greater than 0.2 cubic centimeters; 2. A dry powder inhaler as described in claim 1.

[0128] (Appendix 10) the inhaler body includes a detent that prevents separation of the body from the housing in the assembled inhaler; 2. A dry powder inhaler as described in claim 1.

[0129] (Appendix 11) a transition of the housing on the inhaler body from an open to a closed configuration positions the cartridge such that the housing is aligned with the mouthpiece; 2. A dry powder inhaler as described in claim 1.

[0130] (Appendix 12) Further, the dry powder comprises 2. A dry powder inhaler as described in claim 1.

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

[0132] (Appendix 14) The dry powder comprises 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine, 13. A dry powder inhaler according to claim 12.

[0133] (Appendix 15) The dry powder contains cannabinoids in an amount of 1% to 40% (w / w); 15. A dry powder inhaler according to claim 14.

[0134] (Appendix 16) The cannabinoid is tetrahydrocannabinol or cannabidiol; 16. A dry powder inhaler according to claim 15.

[0135] (Appendix 17) The dry powder further comprises a phospholipid selected from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-3-phosphocholine. 15. A dry powder inhaler according to claim 14.

[0136] (Appendix 18) A main body, a housing, a cartridge, a mouthpiece, 1. A dry powder inhaler comprising: the body having a mounting area for the cartridge; the cartridge contains a dry powder composition comprising fumaryl diketopiperazine and microcrystalline particles of a drug; the housing slides translationally from a proximal direction to a distal direction on the body to open the inhaler, or slides translationally from a distal direction to a proximal direction on the body to close the inhaler; the inhaler comprising one or more rigid air conduits for dispensing the dry powder when the inhaler is closed; Dry powder inhaler.

[0137] (Appendix 19) The drug is Tetrahydrocannabinol or cannabidiol, 19. The dry powder inhaler of claim 18.

[0138] (Appendix 20) The dry powder further comprises a phospholipid selected from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-3-phosphocholine. 19. The dry powder inhaler of claim 18.

Claims

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

Images