HK1258955B - Dry powder inhaler - Google Patents

Description

Dry powder inhaler

Cross Reference to Related Applications

The present application claims the benefit of united states provisional patent application No. 62/289,095 filed 2016, 1, 29, each and the contents of which are incorporated herein by reference in their entirety, in accordance with 35 u.s.c. § 119 (e).

Technical Field

The present disclosure relates to dry powder inhalers with replaceable cartridges comprising dry powders for local or systemic delivery of active ingredients to and/or through the lungs. The inhaler is used with inhalable dry powders that contain mainly medicinal preparations comprising active agents or active ingredients for the treatment of diseases such as pulmonary hypertension, cardiovascular diseases, diabetes, obesity and cancer or symptoms associated with these or other diseases such as nausea, vomiting, pain and inflammation.

All references cited in this specification, and references to such references, are hereby incorporated by reference in their entirety where the teachings of additional or alternative details, features, and/or technical background are applicable.

Background

Drug delivery to lung tissue to treat local diseases or disorders has been accomplished using a variety of devices for inhalation, including nebulizers and inhalers, such as metered dose inhalers and dry powder inhalers. Dry powder inhalers for delivering medicament to the lung include a dosing system of powder formulations that are typically supplied in bulk or are quantified as individual doses stored in a unit dose chamber (e.g. hard capsule or blister pack). The bulk container is fitted with a patient-operated metering system to separate a single dose from the powder prior to inhalation.

The repeatability of dosing using an inhaler requires that the drug formulation be uniform and that the dose be consistently and repeatably delivered to the patient. Thus, the medicated system should ideally operate to effectively expel the entire amount of drug completely during the inspiratory maneuver when the patient is taking a dose. However, complete discharge of the powder from the inhaler is generally not required as long as reproducible dosing can be achieved. With bulk containers, the flowability and long-term physical and mechanical stability of the powder formulation are more critical for bulk containers than for single unit dose containers. Good moisture protection is more easily achieved for unit dose compartments such as blisters. However, the materials used to make the blister allow air to enter the medication chamber and thereafter the medication fails with long term storage, especially if the formulation to be delivered is hygroscopic. Ambient air that permeates through the blister entrains moisture, which destabilizes the active ingredient. In addition, dry powder inhalers that utilize blisters to deliver a drug by inhalation suffer from incoherence of the drug administration to the lung due to changes in the geometry of the air conduit structure created by the piercing film (piercing film) or the peel-off film of the blister.

The dry powder inhaler may be breath activated or breath actuated and may be actuated by attaching a carrierThe drug particles in (a) are converted to a fine dry powder to deliver the drug, which is entrained in the air stream and inhaled by the patient. Medicaments for topical pulmonary delivery using dry powder inhaler delivery to treat allergy, asthma and/or Chronic Obstructive Pulmonary Disease (COPD) include multi-dose inhalers, such as, for exampleDISKUS、DISKUS andFLEXHALER. Dry powder inhalers are no longer used only for treating pulmonary diseases, but can also be used for treating systemic diseases, so that the drug is delivered to the lungs and absorbed into the systemic circulation. For example,the inhaler is a unit dose dry powder inhaler that delivers a human insulin formulation for the treatment of diabetes in humans. Afreza was approved by the U.S. food and drug administration for the treatment of type I and type II diabetes 6 months 2014. The AFREZZA inhaler is a breath-activated multi-purpose inhaler that delivers a single dose of insulin contained in a drug cartridge to the lungs, where the insulin is absorbed into the circulatory system to effectively treat hyperglycemia associated with diabetes. Accordingly, dry powder inhalers can be used to achieve safe delivery of other active agents to the systemic circulation to treat a wide variety of diseases and disorders (including, but not limited to, cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease or disorder, etc.) and symptoms of such diseases and disorders (including, but not limited to, pain, headaches, nausea, vomiting, tremors, infections, etc.).

Dry powder inhalers, such as those described in us patent nos. 7,305,986, 7,464,706, 8,499,757 and 8,636,001, the disclosures of which are incorporated herein by reference in their entirety, can produce primary drug particles or a suitable inhalation plume (inhalation plume) during the inspiratory action by deagglomerating the powder formulation within a capsule or cartridge containing a single dose. The amount of fine powder discharged from the mouth (mouthpiece) of the inhaler during inhalation depends largely on, for example, the interparticle cohesion in the powder formulation and the efficiency with which the inhaler separates those particles to make them suitable for inhalation. The benefits of delivering drugs via the pulmonary circulation are numerous and may include rapid access to the arterial circulation, avoidance of liver metabolic drug degradation, ease of use without discomfort.

Several dry powder inhalers have been developed for pulmonary administration to date with several efficacy. However, there is still room for improvement due to lack of practicality and/or manufacturing costs. Some long-term problems with prior art inhalers include lack of durability of the device, inconsistent dosing, inconvenience of the device, poor deaggregation, delivery problems in terms of separation from the propellant use, high production costs and/or lack of patient compliance. Accordingly, the present inventors have identified a need to design and manufacture inhalers with consistently improved powder delivery performance, ease of use, and discrete (discrete) configurations that allow for better patient compliance.

Disclosure of Invention

This document is directed to a dry powder inhaler having a replaceable cartridge that includes a housing for inhalation for delivery to the lungs for local or systemic administration to the pulmonary circulation. Dry powder inhalers are breath actuated inhalers that are compact, reusable or disposable, have a variety of shapes and sizes, and include an airflow conduit pathway system for efficient and rapid delivery of the powdered medicament to the lungs and systemic circulation.

In one embodiment, a dry powder inhaler includes a unit dose cartridge and a dry powder formulation to be aerosolized and delivered to lung tissue for local tissue effect or absorption into the bloodstream of the lungs and delivered to a target tissue or organ of a subject through the systemic circulation. In an embodiment, the dry powder may comprise carrier molecules including pharmaceutically acceptable carriers and excipients, such as phospholipids, polymers (such as polyethylene glycol, glycolide, sugars, polysaccharides or diketopiperazine) and active ingredients (such as polypeptides and proteins and small molecules, including neurotransmitters).

In one embodiment, the dry powder inhaler is reusable and is provided with a replaceable cartridge for single use to deliver a single dose with a single inhalation provided by the subject. In this embodiment, a plurality of cartridges containing the active ingredient and, for example, a specific powder content packaged in a blister pack may be provided with a single inhaler for multiple uses by a subject. In this and other embodiments, the kit may include a dry powder formulation for treating various conditions, diseases or disorders including bacterial infections (such as methicillin-resistant staphylococcus aureus infections), pulmonary aspergillosis, lung transplantation, Pulmonary Arterial Hypertension (PAH), osteoporosis, obesity, allergies 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; neurological disorders and diseases including dementia, alzheimer's disease, depression, parkinson's disease, multiple sclerosis or symptoms thereof and the like.

In one embodiment, the dry powder inhaler comprises a body, a housing and a mouthpiece configured with the body, wherein the body comprises a mounting region for the cartridge and the body and the housing are movable in a linear or angular motion relative to each other, and at least a portion of the body and the housing are operably configured to obtain an air flow path for expelling a powder dose contained in the cartridge, e.g. by insertion into engagement with each other to obtain a closed position and effect reconfiguration of a cartridge positioned in the mounting region. In an embodiment along with this, the cartridge is made of a rigid material and comprises a cup and a lid that are movable relative to each other in a translational movement.

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

In another embodiment, a dry powder inhaler comprises a body, a cap, and a mouthpiece; wherein the mouthpiece and the cover are configured as a unit and are movable on the inhaler body by angular rotation of the mouthpiece relative to the body. In this and other embodiments, the body comprises a distal end, a proximal end, a bottom surface, a top surface, an inner surface, a cartridge mounting region, and an opening in the top surface for accessing the device interior and the cartridge mounting region; wherein the mouthpiece is configured to have a wing structure extending in a vertical plane to the air conduit of the mouthpiece to form a saddle-like structure shaped hood or lid like structure, the mouthpiece forming a lid over the open area of the top surface when rotated from a vertical angle to a horizontal plane to effect closing of the inhaler and form part of the top portion of the inhaler. In the closed configuration, the cartridge loaded onto the cartridge mounting area is translated from the containment position to the dosing position such that an air conduit is formed through the cartridge and powder in the cartridge can be expelled from the inhaler upon inhalation operation. In one aspect of this embodiment, the mouthpiece is configured with a mechanism for engaging the cartridge mounting assembly to effect reconfiguration of the cartridge from the containment configuration to the administration configuration. In one embodiment, the inner surface of the inhaler comprises a protrusion at the cartridge mounting area designed to hold the cartridge cup when the cartridge is loaded. In one embodiment, the mechanism for engaging the cartridge mounting area comprises a gear and rack that pivot a mouth portion of the inhaler away from the inhaler body and into a vertical position with the inhaler body in a horizontal plane to open the inhaler into a loading configuration and into a horizontal position relative to the vertical plane to close the inhaler into a dosing configuration that loads the cartridge into the inhaler.

Dry powders include inhalable dry powders containing a pharmaceutical formulation that includes an active ingredient for pulmonary administration. In some embodiments, delivery will reach the deep lung (i.e., to the alveolar region), and in some such embodiments, the active agent or active ingredient is absorbed into the pulmonary circulation for body-directed or general use. The dry powder inhaler has a unit dose kit and the drug delivery formulation includes active ingredients such as diketopiperazines and peptides and proteins including parathyroid hormone, insulin, oxyntomodulin and glucagon-like peptide 1. In some embodiments, the active ingredient includes one or more active agents including, but not limited to, treprostinil, salmeterol, epinephrine, tacrolimus, vancomycin, linezolid, filgrastim, fentanyl, cannabinoid, palonosetron, amphotericin B, phosphodiesterase inhibitors (including PDE5 inhibitors such as sildenafil, avanafil, vardenafil (verdenafil), and tadalafil), prostaglandins (including prostacyclin (PG 12) and derivatives thereof), neurotransmitter agonists, neurotransmitter antagonists (including analgesics, narcotic analgesics such as delta opioid agonists and antagonists, opioid receptor agonists and antagonists).

In one embodiment, a dry powder inhaler includes a housing, a movable member, and a mouthpiece, wherein the movable member is operably configured to move a container from a powder containment position to a dosing position. In this and other embodiments, the movable member may be configured as a component of the cap assembly at the proximal end of the inhaler and form part of the cartridge mounting region. In this embodiment, the mouthpiece is constructed integrally with a cover or lid portion that covers the housing over the cartridge mounting area when the inhaler is closed. Movement of the mouthpiece from the horizontal in a downward direction moves the cover or shroud in an angular direction to an upright position and opens the inhaler to form a channel into the inhaler to allow loading and unloading of the cartridge. Instead, the mouthpiece moves in an upward direction from a vertical plane to a horizontal plane, causing closure of the inhaler and automatically creating an opening of the air path between the inhaler and the cartridge loaded onto the cartridge mounting area.

In another embodiment, a dry powder inhaler comprises a body, a housing, and a mouthpiece; an inhaler; the inhaler is structurally configured to have an open position, a closed position, and a mechanism operably configured to receive, retain, and reconfigure a cartridge from a containment position to a dispensing, dosing, or drug delivery position when the inhaler is moved from the open position to the closed position. In a version of this embodiment, the mechanism may also reconfigure a cartridge installed in the inhaler from a dosing position to a containment position when the inhaler is opened to unload a used cartridge after use. In one embodiment, the mechanism may reconfigure the cartridge to a disposable or discard configuration after use.

In one embodiment, the body of the inhaler comprises a proximal portion comprising the mouthpiece, a body and a distal portion comprising a housing structurally configured as a sliding closure over a portion of the body and internal components of the inhaler; wherein the housing comprises a distal end and a proximal end, and the proximal end has 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 to the external environment. The inhaler is opened from the closed configuration to obtain an inhaler loading and/or unloading position for inserting or removing a cartridge by the upper portion of the housing being moved in a distal direction in a translational motion over the body. With the cartridge mounted in the inhaler, translational movement of the housing upper portion over the body in a distal-to-proximal direction causes the cartridge to be displaced from a containment configuration to a dosing configuration, wherein the cartridge container is urged to an oriented configuration by a protrusion configured inside the housing, which protrusion extends at the proximal end beyond the opening when the inhaler is in an open configuration. The movement of the top part of the housing is achieved by a lever having a button-like structure at the top end and attached to the housing, and opening and closing a cartridge mounting area of the inhaler. In the closed configuration, the cartridge installed in the inhaler is reconfigured to form an additional air channel with the mouth and ambient air to access the dry powder in the cartridge in the on-inhalation dosing configuration. In this other embodiment, the air channel of the drug cassette in the dosing configuration has an air inlet air outlet which communicates with the air channel in the mouth, where the mouth has its own air inlet and air outlet.

In one embodiment, the body of the inhaler includes a mouthpiece formed at the proximal end of the body and has an air conduit communicating with the interior of the housing and may be in direct communication with the air outlet of a cartridge mounted in the inhaler and with ambient air. The inhaler body further comprises a cartridge mounting region structurally contiguous with the mouth and having a distal component and a proximal component; wherein the proximal and distal members form a single piece with the mouth and are insertable into the housing. In one embodiment, the body and housing may be pulled apart to obtain an open inhaler configuration to access the interior compartment. In the open configuration of this embodiment, a cartridge comprising dry powder may be loaded or mounted in the cartridge mounting region of the body, and the body and housing may be pushed or pulled to open or close the inhaler. In one embodiment, the housing is movable over the distal part of the body from an open configuration to a closed configuration and together they close the inhaler and enable the formation of an air conduit through a cartridge mounted in the cartridge mounting area. In this configuration, the inhaler attains a dosing configuration to expel powder from the cartridge when the user inhales orally through the mouth. In this embodiment of the dosing arrangement, the body and the housing abut each other and are tightly fitted together by one or more anti-slip structures to prevent disassembly of the inhaler. Examples of anti-slip features may include a snap ring or detent (detent) that may generate a sound to alert the user that the inhaler is ready for use.

In one embodiment, the inhaler is substantially rectangular in shape having a distal side and a proximal side, and the distal length is shorter; wherein the inhaler comprises a movable housing portion covering a distal portion of the inhaler body; movement of the housing over the body or movement of the body over the housing is achieved by separating the inhaler from the housing to expose the interior of the inhaler; the movement of the housing may be a pulling or pushing action of the housing over the inhaler body having parallel rails or tracks extending outwardly from the longer sides (first and second sides) of the inhaler along the longitudinal plane. In this embodiment, the inhaler body is designed with an opening at its distal end to match the opening at the distal end of the housing to allow and direct ambient air into the interior chamber of the inhaler upon inhalation. The housing is also fittingly configured with a groove or slot for sliding over the guide rail during opening and closing movements, and further comprises a stop end preventing disassembly of the inhaler and a push element for positioning the cartridge in the dosing configuration after mounting and closing the inhaler when the housing is moved in the distal to proximal direction. The pushing element moves the cartridge cup or container relative to the cartridge lid to create an air channel through the cartridge and create an air inlet and an air outlet, and allows the powder in the cup to aerosolize during inhalation to deliver aerosolized particles to the inhaler mouthpiece and into the user. In another embodiment, the pushing element also moves the cartridge assembly to position the cap relative to the access opening in the base plate of the mouthpiece. In one aspect of this embodiment, the dry powder inhaler comprises a housing comprising a pushing element, wherein the housing positions the cartridge in alignment with the mouthpiece by translating the housing on the inhaler body from an open configuration to a closed configuration.

In one embodiment, a dry powder inhaler includes a housing having a distal end and configured with an opening for communication with ambient air. In one embodiment, the housing is configured in the shape of a shroud that slides over the inhaler body to substantially enclose a portion of the inhaler body, the housing moving translationally over the distal portion of the body; among these, the inhaler can obtain two configurations: a first position in which the inhaler is opened to access its internal compartment, i.e. chamber; and a second position abutting the proximal end to obtain closing of the inhaler. In one embodiment, the distal portion of the housing is also movable relative to the proximal end along a horizontal plane to extend distally and allow access to the interior compartment of the inhaler and the shroud surrounding the inhaler body. In a version of this embodiment, the distal portion of the housing comprises parallel structures or flanges for engaging portions of the inhaler body and forming a fastening mechanism, for example for locking the inhaler body and the housing to fasten the two components together and maintain the dosing configuration. In an embodiment, the distal portion of the housing has an opening at its distal end for communicating with the interior of the inhaler and an opening configured to slide over the inhaler body. The distal portion of the housing further includes an outer surface, an inner surface, and a chamber configured to slide over the inhaler body. In one embodiment, the distal portion of the inhaler includes parallel wing structures on its upper surface to direct the airflow into the mouth during inhalation.

In alternative embodiments, the mouthpiece is engaged with the body of the inhaler by various mechanisms including a moveable member (such as a hinge), and the moveable component is integral with the moveable component and comprises a rack for moving the cartridge lid relative to the cartridge cup or container. The movable assembly is configured to receive a cartridge mounted in the inhaler and reconfigure it from a containment position to a dosing position, and may be designed to operate manually or automatically upon movement of the inhaler components, for example by closing the device from an open configuration. In one embodiment, the mechanism for reconfiguring the cartridge includes a sliding tray or sled attached to the mouth and movably attached to the housing. In another embodiment, the mechanism is mounted or adapted to the inhaler and comprises a gear mechanism integrally mounted within, for example, a hinge of the inhaler device. In yet another embodiment, the mechanism operably configured to receive and reconfigure the cartridge from the containment position to the administration position comprises a cam that can reconfigure the cartridge when, for example, the housing or mouth is rotated. In one embodiment, angular rotation of the mouthpiece from the horizontal opens the inhaler to allow installation or removal of the cartridge, and angular movement of the mouthpiece from the vertical plane to the horizontal plane effects closure of the mouthpiece and automatic reconfiguration of the cartridge from the containment position to the dosing position. In an embodiment, the gear mechanism positions the cartridge cover relative to the access opening in the mouth and effects translation of the cup body to the dosing configuration during actuation.

In yet another embodiment, a dry powder inhaler is provided comprising a body and a mouthpiece, wherein the inhaler body is designed with a substantially rectangular body having a top portion, a bottom portion, a proximal portion and a distal portion, and the top portion has an opening in the distal half of the inhaler body to allow access to the interior compartment of the inhaler and the cartridge mounting area. In this embodiment, the inhaler mouthpiece comprises two air inlets, one for communicating with ambient air at the distal end of the inhaler, one for communicating with the cartridge outlet, and an air outlet at the proximal portion of the inhaler for insertion into the subject's mouth. In this embodiment, the body and mouthpiece are joined together by a gear and rack and pinion assembly, wherein the movable cartridge cup carrier is configured to be actuated by movement of the mouthpiece along a horizontal plane from an angle of about 180 ° parallel to the inhaler body to an angle of about 90 ° or perpendicular to the inhaler body, which opens the inhaler to load and/or unload a cartridge. Movement of the mouthpiece back 180 ° and parallel to the inhaler body closes the inhaler and reconfigures a cartridge placed into the inhaler to a dosing configuration by displacing the cartridge cup to create an air channel between the inhaler mouthpiece and the cartridge, and further the cartridge inlet to pass ambient air through the cartridge interior to aerosolize powder in the cartridge upon inhalation.

In another embodiment, a 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 sled or sliding tray; wherein the mouth and the housing are movably attached together by a hinge.

A carriage for use with a dry powder inhaler may be manufactured to contain any dry powder medicament for inhalation. In one embodiment, the cartridge is structurally configured to fit a particular dry powder inhaler and can be made in any size and shape depending on the size and shape of the inhaler to be used together, for example, if the inhaler has a mechanism that allows translational or rotational movement. In one embodiment, the cartridge may be configured with a gold-stranded mechanism, e.g., having a beveled edge on the top of the cartridge that corresponds to a matching beveled edge in the inhaler, so that the cartridge is secured during use. In one embodiment, the cartridge comprises a container and a lid or cover, wherein the container may be adapted to the surface of the lid and may be movable relative to the lid, or the lid may be movable on the container and may attain various configurations depending on its position, such as a containment configuration, a dosing configuration or a post-use configuration. During inhalation, a cartridge adapted to the inhaler in the dosing position allows an air flow into the housing and mixes with the powder to liquefy the medicament. The liquefied medicament moves within the enclosed space such that the medicament gradually exits the housing through the dispensing aperture, wherein the liquefied medicament exiting the dispensing aperture is sheared and diluted by a secondary flow not from within the housing. A cartridge for a dry powder inhaler is described, comprising: a housing configured to hold a medicament; at least one inlet port for allowing airflow into the housing and at least one dispensing port for allowing airflow out of the housing; the at least one inlet is configured to direct at least a portion of the airflow entering the at least one inlet at the at least one distribution opening within the enclosure in response to the pressure differential.

In some embodiments, the dry powder formulation is consistently dispensed from the inhaler in less than about three (3) seconds, or typically less than one (1) second. In some embodiments, the inhaler air conduit is designed to produce a high resistance to air flow values, for example approximately 0.065 to approximately 0.200(√ kPa)/liter per minute. Thus, in an inhalation system, a peak inhalation pressure drop of between 2kPa and 20kPa results in a resulting peak flow rate of between about 7 and 70 liters per minute. These flow rates resulted in greater than 75% of the cartridge contents being dispensed in a fill block of between 1 and 50 mg. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation maneuver to produce a dispense percentage of greater than 90%. In certain embodiments, the inhaler and cartridge system is configured to provide a single dose by discharging powder from the inhaler as a continuous stream or one or more pulses of powder delivered to the patient.

In another embodiment, the inhalation system comprises a breath actuated dry powder inhaler, a kit containing a dry powder for pulmonary delivery to the pulmonary respiratory tract and lungs, the dry powder comprising a medicament, wherein the medicament may comprise, for example, a pharmaceutical formulation for pulmonary delivery such as a composition comprising a diketopiperazine in a self-assembled crystalline form, an amorphous form and/or a microcrystalline form comprising non-self-assembled crystallites or a combination thereof, and an active agent. In alternative embodiments, the dry powder may be formulated with other carriers and/or excipients and active agents besides diketopiperazines, such as sugars, including trehalose. In some embodiments, the active agent includes polypeptides and proteins, such as insulin, glucagon-like peptide 1, oxyntomodulin, casein, or any of the aforementioned active ingredients, derivatives thereof, and the like. The inhalation system can be used, for example, in methods of treating conditions requiring local or systemic delivery of agents, such as methods of treating diabetes, prediabetic conditions, allergies, infections (including sepsis, urinary and respiratory tract infections), allergic reactions, pulmonary diseases, renal, hepatic, cognitive, neurological or cardiovascular diseases, blood disorders, cancer and obesity and the symptoms associated with these diseases. In one embodiment, the inhalation system comprises a kit comprising at least one of the components of the inhalation system for treating a disease or disorder.

Drawings

Fig. 1 shows a perspective view of an embodiment of a dry powder inhaler in the closed ready to use position.

Fig. 2 depicts a perspective view of the dry powder inhaler of fig. 1, showing the dry powder inhaler in a fully open cartridge loading/unloading position and having a cartridge mounted in a cartridge mounting area, wherein the cartridge is in a powder containment configuration.

Fig. 3 depicts a cross-sectional view through the middle longitudinal axis of the dry powder inhaler of fig. 1, showing the inhaler containing a cartridge mounted in the inhaler and in a powder delivery configuration showing an airflow path formed through the cartridge chamber.

Figure 4 shows a cross-sectional view through the middle longitudinal axis of the inhaler of figure 1, similar to figure 3, but without the cartridge.

Figure 5 shows a cross-sectional view through the middle longitudinal axis of the inhaler of figure 1, similar to figure 4, but without the cartridge, and in an open configuration.

Fig. 6 depicts a perspective view of an alternative dry powder inhaler embodiment shown in a closed position.

Fig. 7 depicts a perspective view of the dry powder inhaler of fig. 6 in an open cartridge loading/unloading position and with a cartridge installed in a cartridge mounting area, wherein the cartridge is in a powder containment configuration.

Fig. 8 depicts a cross-sectional view through the middle longitudinal axis of the dry powder inhaler of fig. 6 showing the inhaler containing the cartridge in a powder administration configuration showing the inhaler airflow path formed through the cartridge chamber and in the powder administration configuration.

Figure 9 shows a cross-sectional view through the middle longitudinal axis of the inhaler of figure 6, similar to figure 8, but without the cartridge.

Figure 10 shows a cross-sectional view through the middle longitudinal axis of the inhaler of figure 6, similar to figure 9, but without the cartridge, and in an open configuration.

Fig. 11 shows a perspective view of yet another alternative embodiment of a dry powder inhaler in the closed or inhalation position.

Fig. 12 depicts the dry powder inhaler of fig. 11 in an open cartridge loading/unloading position and with a cartridge installed in a cartridge mounting area, wherein the cartridge is in a powder containment configuration.

Fig. 13 depicts a cross-sectional view through the middle longitudinal axis of the dry powder inhaler of fig. 11 showing the inhaler containing the cartridge in a powder administration configuration showing the inhaler airflow path formed through the cartridge chamber and in the powder administration configuration.

Fig. 14 shows a cross-sectional view through the middle longitudinal axis of the inhaler of fig. 11, similar to fig. 13, but without the cartridge.

Figure 15 shows a cross-sectional view through the middle longitudinal axis in the vertical plane of the inhaler of figure 12, similar to figure 14, but without the cartridge, and in an open configuration.

Fig. 16 depicts a perspective view of another alternative dry powder inhaler embodiment ready for use in a closed position.

Fig. 17 depicts the embodiment of fig. 16 in an open cartridge loading/unloading position and with a dry powder inhaler having a cartridge mounted in a cartridge mounting area, wherein the cartridge is in a powder containment configuration.

Fig. 18 depicts a cross-sectional view through the middle longitudinal axis of the dry powder inhaler of fig. 16 showing the inhaler containing the cartridge in a powder dosing configuration showing the inhaler airflow path formed through the cartridge chamber and in the powder dosing configuration.

Figure 19 shows a cross-sectional view through the middle longitudinal axis of the inhaler of figure 16, similar to figure 18, but without the cartridge.

Figure 20 shows a cross-sectional view through the middle longitudinal axis in the vertical plane of the inhaler of figure 17, similar to figure 19, but without the cartridge, and in an open configuration.

Detailed Description

In embodiments disclosed herein, a dry powder inhaler is described that includes a cartridge for delivering a dry powder to a subject by oral inhalation, the dry powder including a medicament. In one embodiment, the dry powder inhaler is a breath actuated dry powder inhaler and the cartridge is designed to contain an inhalable dry powder including, but not limited to, a pharmaceutical formulation containing an active ingredient comprising a pharmaceutically active substance and optionally a pharmaceutically acceptable carrier.

Dry powder inhalers come in a variety of shapes and sizes of embodiments and may be reusable, easy to use, inexpensive to manufacture and/or produce in large quantities in simple steps using plastic or other acceptable materials. Various embodiments of dry powder inhalers are provided herein, and in general, inhalation systems include an inhaler, a powder-filled cartridge, and an empty cartridge. The present inhalation system can be designed for use with any type of dry powder. In one embodiment, the dry powder is a relatively cohesive powder requiring optimal deagglomeration conditions. In one embodiment, the inhalation system provides a reusable miniature breath actuated inhaler in combination with a single use cartridge containing a pre-metered dose of a dry powder formulation.

As used herein, the term "unit dose inhaler" refers to an inhaler adapted to receive a single cartridge or container comprising a powder formulation and deliver a single dose of the dry powder formulation by inhalation from the single cartridge to a user. It will be appreciated that in some instances, multiple unit doses will be required to provide a user with a given dosage.

As used herein, a "cartridge" is a housing configured to hold or contain a dry powder formulation, i.e., a dry powder containing housing, having a cup or container and a lid. The cartridge is supported by a rigid material and the cup or container can be moved in a translational movement relative to the lid, or vice versa.

As used herein, "powder agglomerates" refer to agglomerates of powder particles or agglomerates having irregular geometric shapes such as width, diameter, and length.

As used herein, "unit dose" refers to a pre-metered amount of a dry powder formulation for inhalation. Alternatively, the unit dose may be a single container of formulation having multiple doses that can be delivered by inhalation as a metered, single quantity. The unit dose cartridge/container contains a single dose. Alternatively, it may comprise a plurality of individually accessible compartments, each compartment containing a unit dose.

The term "about" is used herein to indicate that a numerical value includes the standard deviation of error for the device or method used to determine the value.

The term "microparticle" as used herein refers to a particle having a diameter of about 0.5 to about 1000 μm, regardless of the precise external or internal structure. Microparticles having a diameter between about 0.5 and about 10 microns can successfully pass through most natural barriers to the lungs. A diameter of less than about 10 microns is required to cope with throat turns and a diameter of about 0.5 μm or more is required to avoid volatilization. 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 "respirable fraction" (RF), generally accepted as those particles having an aerodynamic diameter of about 0.5 to about 6 μm, although some references use slightly different ranges as measured using standard techniques, such as the anderson cascade impactor. Other IMPACTORs may be used to measure aerodynamic particle size, such as NEXT GENERATION impact actuator^TM(NGI^TMMSP company) for which the respirable fraction is defined by similar aerodynamic dimensions, e.g.<6.4 μm. in some embodiments, a laser diffraction device is used to determine particle size, e.g., 8,508732, which is incorporated herein in its entirety for its relevant teachings relating to laser diffraction, wherein the volume median geometric figure diameter (VMGD) of the particles is measured to assess the performance of the inhalation system. For example, in various embodiments, ≧ 80%, 85% or 90% of the drug cassettes are empty and<12.5μm、<7.0 μm or<A 4.8 μm exit particle VMGD may represent progressively better aerodynamic performance.

The respirable fraction ratio (RF/fill) relative to the fill represents the proportion (%) of powder suitable for inhalation in a dose expelled from an inhaler when expelling powder content filled for dose use, i.e. the proportion of particles in the fill dose expelled in a size suitable for pulmonary delivery, the respirable fraction ratio relative to the fill being a measure of the aerodynamic performance of the microparticles. As described herein, RF/fill values of 40% or greater than 40% reflect acceptable aerodynamic performance characteristics. In certain embodiments disclosed herein, the respirable fraction ratio relative to the loading may be greater than 50%. In exemplary embodiments, the respirable fraction ratio relative to the fill may be up to about 80%, wherein about 80% of the fill is discharged at a particle size of <5.8 μm measured using standard techniques.

The term "dry powder" as used herein refers to a fine particulate ingredient that is not suspended or dissolved in a propellant or other liquid. This is not necessarily meant to imply the complete absence of any water molecules.

As used herein, "amorphous powder" refers to dry powders, including non-crystalline powders, that lack a defined repeating morphology, shape, or structure.

In the same exemplary embodiment, the present device can be made of various materials by several methods. In one embodiment, the inhaler and the cartridge are made using various types of plastic materials, including polypropylene, cyclic olefin copolymers, nylon and other compatible polymers, and the like, for example, by injection molding techniques, thermoforming, blow molding, crimping, 3D printing, and the like. In certain embodiments, the dry powder inhaler may be assembled using a top-down assembly of the various components. In some embodiments, inhalers are typically provided in compact sizes, for example from about 1 inch to about 5 inches in size, and typically the width and height of the device is less than the length. In some embodiments, the inhaler is provided in a variety of shapes, including a relatively rectangular body, however other shapes are possible, such as cylindrical, oval, tubular, square, rectangular, and circular.

In the embodiments described and exemplified together, the inhaler effectively liquefies, de-polymerizes or aerosolizes the dry powder formulation by using at least one relatively rigid flow path for allowing airflow into the inhaler. For example, the inhaler is provided with a first airflow path for accessing a cartridge containing the dry powder and a second airflow path that can merge with the first airflow path exiting the cartridge. The flow channel may have various shapes and sizes, for example, depending on the inhaler configuration. In one embodiment, the inhaler air conduit is a high resistance inhalation tube with a resistance value of, for example, approximately 0.065 to approximately 0.200(√ kPa)/liter per minute. Thus, in this system, a peak suction pressure drop of between 2kPa and 20kPa produces a resulting peak flow rate of between about 7 and 70 liters per minute. These flow rates resulted in greater than 75% of the cartridge contents being dispensed in a fill block of between 1 and 50 mg. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation operation to produce a dispense percentage of greater than 90% of the powder contained by the cartridge.

An embodiment of a dry powder inhaler 10 is illustrated in fig. 1-5. The inhaler 10 comprises two elements, a body 12 and a mouthpiece 11. In this embodiment, the dry powder inhaler 10 is relatively rectangular with the longer sides extending along the longitudinal plane and is designed to obtain two configurations, namely a first configuration, which is a closed or dosing configuration as shown in fig. 1, 3 and 4, and a second configuration, or an open or cartridge loading/unloading configuration, as shown in fig. 2 and 5. As shown in fig. 1-5, the dry powder inhaler 10 has a relatively rectangular body 12, the body 12 being manufactured as a single element and having a proximal end 14 and a distal end 16, the proximal end generally C-shaped including a mouth 15 for contacting the lips or mouth of a user, and a right side 17, a left side 18, a top side 19, and a bottom side 20. The mouthpiece 15 has an outlet 13 and a first inlet 21 to allow bypass air to flow through the air conduit 5, the air conduit 5 being external to the interior of the inhaler body 12 but communicating with the chamber or interior of the inhaler body through the mouthpiece second inlet 3, which is located in the bottom portion of the mouthpiece which is in contact with the inhaler body 12. The second inlet is in particular intended to contact an outlet or dispensing opening 31 of a cartridge mounted in the cartridge mounting area. Fig. 3 shows that the mouth 15 is narrower in shape at its distal end and tapers outwardly towards the proximal end and is provided with an air duct 5 similar to its external shape. The mouthpiece 15 is designed as a single element with saddle or wing like structures 22, 22 ', which saddle or wing like structures 22, 22' extend partly outwards to the point of connection between the top sides 19 and downwards over the right and left sides 17, 18, forming part of the top side 19 and covering or resting over the right and left sides 17, 18 of the inhaler body 12 for closing the inhaler 10 as a mouthpiece 11. To prevent movement of the mouthpiece 10 during use, a locking mechanism may be provided, comprising a snap-in fitting, detent (such as detent 25 fitted to element 26).

Fig. 2 and 5 illustrate the inhaler 10 in an open configuration, showing the interior of the body 12. Fig. 5 depicts inhaler 10 in an open configuration, while fig. 2 represents inhaler 10 with cartridge 24 installed in cartridge mounting assembly 23. To obtain the open configuration, the mouthpiece 11 is pushed down from the mouthpiece 15 and grips the distal top portion of the inhaler 12, which actuates the entire element 11 to rotate angularly by approximately 90 ° to be perpendicular to the body 12. The movement of the mouthpiece 11 is achieved by providing the inhaler with a hinge, e.g. a rack and pinion comprising an axle 32 connected to a gear having a rack which engages the rack on the movable cartridge mounting region 23.

Fig. 3 is a middle longitudinal section of the inhaler 10 with the cartridge mounted in the dosing position and shows the push element 33 fully positioning the cartridge in the movable cartridge mounting region 23 in the dosing configuration, wherein a channel with an air inlet 29 and an air outlet 31 into the interior of the cartridge cup 30 is created. In this embodiment, upward movement of the mouthpiece 11 when holding the mouth 15 in the horizontal closes the inhaler (as shown in fig. 1) and, when moved, the portion of the movable part of the cartridge assembly in the cartridge mounting region 23 is pushed distally by the movable element in the proximal part of the cartridge mounting region, causing the cartridge cap 28 to move distally over the cartridge cup 30, the cup 30 being held at the mounting region by the rigid projections 27, 27' from the inner surface of the bottom side 20 of the body 12. After use, by opening the inhaler 10, the cartridge is returned to the discharge/unload position and the cycle can be repeated for a new dose. Figure 4 shows a middle longitudinal section of the inhaler of figure 1 without cartridge in closed configuration, illustrating the relationship inside the device.

Fig. 5 shows the inhaler 10 without a cartridge in an open configuration by means of a middle longitudinal section of the inhaler of fig. 1. The cartridge mounting area is shown with its rigid protrusion protruding from the inner bottom surface 20 of the inhaler body 12, and the cartridge cover pushing element 33 of the movable cartridge mounting area 23 translates the cover over the cup of the cartridge to obtain a dosing configuration when the mouthpiece cover 11 is moved to the closed position.

Fig. 6-10 illustrate an alternative embodiment in which a dry powder inhaler 40 includes a body 42, a mouthpiece 45 having at least two air inlets and one outlet 46, and a cartridge mounting and reconfiguration mechanism 47. The inhaler 40 also includes a discontinuous top side 51, a proximal end 48, a distal end 49, and a bottom portion 42, the bottom portion 42 may be configured with a segmented rib-like structure. In this embodiment, the inhaler 40 is in the closed position. The distal half of the top portion 49 of the inhaler body 42 has an opening or slot 53 along a medial longitudinal plane that receives a movable rod 52 to engage a movable rack 54 in the interior compartment of the inhaler body 42 to effect movement of the cartridge mounting and reconfiguring mechanism 47, the cartridge mounting and reconfiguring mechanism 47 including a rack with a pushing element to translate the lid of the cartridge above the cup or to translate the cup below the fixed lid of the cartridge. In this embodiment, the inhaler is configured in the cartridge loading position upon manual actuation of the lever 52 distally. Fig. 7 depicts the inhaler 40 in an open configuration with a cartridge mounted or disposed in the cartridge mounting area 55. In preparing a dose for pulmonary inhalation, the user may place or install the drug cassette 56 in the inhaler, as shown in fig. 7. After cartridge 56 is installed or loaded into cartridge installation area 55, rod 52 moves proximally until it cannot move further. Fig. 8 shows a middle longitudinal section through the inhaler 40 in the closed or dosing configuration, in which the cartridge is mounted in the cartridge mounting and reconfiguration region 55, which shows the cup 58 displaced under the lid 59 by the pushing element 66 in the dosing configuration. As the lever 52 moves, a push element 66 inside the inhaler that engages the lever 52 actuates the push element 66 of the rack to move the cartridge 56 and reconfigure its cover to create an air conduit having an air inlet 64 and an air outlet 65 that communicate with the second inlet 63 of the mouthpiece 45 to deliver powder to the mouthpiece air conduit 61 and outlet 46 during inhalation. Intake air through the first inlet 62 bypasses the cartridge compartment upon inhalation. A discontinuity on the top side 51 of the inhaler allows access to the cartridge mounting area 55. Fig. 8 also shows the lever 52 engaged with the axle 60 of the reconfiguration mechanism 47.

Fig. 9 illustrates the inhaler 40 closed, similar to fig. 8 except without the cartridge, and at the proximal end of the inhaler body 42. In this configuration, fig. 9 depicts the relationship between the rack 54 comprising the pushing element 66 and the closed proximity of the horizontal first inlet 62, the horizontal first inlet 62 forming almost a right angle with the second inlet 63 of the mouth 45 to achieve deaggregation of the powder by shear forces during inhalation of a powder dose. Fig. 10 shows the inhaler 40 without a cartridge in an open configuration shown in fig. 9 in a middle longitudinal section, showing the position of the lever 52 and the rack 54 for holding the cartridge and the position in the central part of the inhaler body 42, i.e. the end inside the inhaler. Fig. 10 also shows the rack gear 54 integrally engaged with a movable mechanism, depicted as an axle 60, that contacts the rod 52 to mechanically push the rack gear 54.

Fig. 11-15 illustrate yet another alternative inhaler, namely inhaler 70, in which mouthpiece 71 is movable relative to inhaler body 72 by a gear mechanism 85, gear mechanism 85 being moved laterally by rotation in a horizontal plane to an angle of about 90 ° from the longitudinal axis a of inhaler 70 to allow access to the interior of inhaler body 72 for mounting or dismounting the cartridge. The mouthpiece 71 further comprises an air inlet 74, an air outlet 73 and a second air inlet communicating with the interior of the inhaler body 72. Fig. 11 shows the inhaler 70 in a closed or dosing configuration. Fig. 12 depicts inhaler 70 in an open configuration to mount or load a drug cassette (as exemplified by drug cassette 76). Inhaler 70 is designed with a substantially rectangular body 72, body 72 having a proximal end 75, a distal end 77, a bottom 78, a right side 79, a left side 80, and a top 81, body 72 being closed at one end and open at its distal end. The mouthpiece 71 further comprises a lateral extension 82, the lateral extension 82 spanning the central air conduit and being configured as a single piece covering the inhaler body top surface 81. The top surface region 81 includes a stop end 83, the stop end 83 being configured to prevent the mouthpiece 71 from rotating past a plane perpendicular to the inhaler body 72. Movement of the mouth 71 to rotate to the open position actuates the mounting and reconfiguration mechanism to be accessible at an open area 81 of the top surface 81 of the body 72, as shown in fig. 12. Figures 13 and 14 show intermediate longitudinal sections of the inhaler 70 with (figure 13) and without (figure 14) the cartridge, respectively, to illustrate the movement of the rack 86 in the closed or dosing configuration under the action of the gear mechanism 90. Movement of the mouthpiece 71 from the right side 79 to the left side 80 in a horizontal plane relative to the inhaler body actuates the gear mechanism, causing the cup 92 to move relative to the lid 93 by translational movement in a proximal direction to create an air flow path through the interior of the cup having an air inlet 94 and an air outlet 95, which air flow path communicates with the inlet 89 and the air conduit 96 of the inhaler 70 to discharge the powder contained in the cup 92. In this embodiment, the mounting and reconfiguration mechanism includes a shelf structure 99 built into the top surface of the mounting area 91 to position the cartridge cover 93, the cartridge cover 93 extending outwardly from the cup 92 and seated on the shelf structure 99 to be secured, while the cup 92 is seated in the rack 86 and the cartridge is in the powder containing configuration.

In yet another embodiment of a dry powder inhaler shown in fig. 16-20, an inhaler 100 is provided, the inhaler 100 comprising two component parts, an inhaler body 101 and a housing or cover 102, the housing or cover 102 encasing a portion of the inhaler body 101. In one embodiment shown in fig. 16, inhaler 100 comprises inhaler body 101 and housing 102, inhaler body 101 comprising proximal portion 103 and distal portion 105, proximal portion 103 comprising mouthpiece 104, housing 102 structurally configured as a snap-fit over a portion of the body and internal components of the inhaler; therein, the housing 102 shown in fig. 17 comprises a distal end 107 and a proximal end 106, and the proximal end 106 has an opening for fitting and enclosing a portion of the inhaler body 105, and further comprises a protrusion 113 from its upper surface, the protrusion 113 guiding the air flow into the air duct 115 of the mouthpiece 104 upon inhalation. In an embodiment, as shown in fig. 16, the proximal end 106 contacts or abuts the inhaler body 101 in order to close the inhaler 100 to the external environment. By the housing 102 being moved in a distal direction in a translational movement over the body 105, the inhaler 100 is opened from the closed configuration to obtain an inhaler loading and/or unloading position for inserting or removing a cartridge. Fig. 17 illustrates the inhaler 100 in an open configuration, in which the housing 102 has been pulled distally to allow access to the distal portion 105 of the inhaler body. In this and other embodiments, fig. 17 depicts a cartridge 108 mounted in a cartridge mounting area 109 of inhaler 100, and shows a cover and an outlet 110, the outlet 110 communicating with an air conduit in the mouth, spanning inlet 111 and outlet 112, through a secondary inlet in the mouth 104. The mounting area 109 is configured in the shape of the cartridge 108 to fit properly and is configured to display a visual cue to the user to properly position the cartridge during installation.

Fig. 18 also depicts a mid longitudinal section of the inhaler 100 in a closed dosing configuration, illustrating the position of the cartridge cup 116 relative to the lid 117 when the housing 102 is moved in a distal-to-proximal direction over the body 105, which causes the cartridge 108 to be displaced from a containment configuration to a dosing configuration, wherein the cartridge containment cup 116 is pushed to the dosing configuration by a protruding rigid element in an inner bottom portion of the housing 102, which extends in a horizontal plane over the opening 106 at the proximal end 106. Raised rigid member 118 may also include one or more vertical protrusions to facilitate removal of cartridge 108 after use. Further, in the closed configuration, the cartridge installed in the inhaler 100 is reconfigured to form an air passage with the mouth through the cup 116 from the air inlet 119 and the air outlet 120 so that ambient air enters the dry powder in the cartridge 108 in the administration configuration upon inhalation. In this and other embodiments, inhalation air enters the air channel of the cartridge 108 in the dosing configuration through the air inlet 119 and aerosolizes the dry powder particles to become entrained in the air, and the aerosolized powder then exits through the air outlet 120 which communicates with the air inlet in the air conduit 115 of the mouthpiece 104, and in the mouthpiece 104, further shearing of the powder by the air channel occurs before the powder exits through the mouthpiece outlet 112.

In one embodiment, the body 101 of the inhaler comprises a mouthpiece integrally formed at the proximal end of the body 101 and an air conduit 115, the air conduit 115 communicating with the interior of the body 101 and the housing 102 and may be in direct communication with the air outlet 120 of the cartridge 108 mounted in the inhaler 100 and with ambient air. Inhaler body 101 further comprises a cartridge mounting region 121, cartridge mounting region 121 being structurally continuous with the mouth and having a distal part 105 and a proximal part 103; wherein the proximal part 103 and the distal part 105 form one single piece with the mouth 104 and the distal part 105 can be inserted into the housing 102. In one embodiment shown in fig. 17 and 20, the body 101 and housing 102 may be pulled apart manually to obtain an open inhaler configuration to access the interior compartment. In the open configuration of the present embodiment, the cartridge 108 containing the dry powder may be loaded or mounted in the cartridge mounting area of the body member 105 in the appropriate orientation (shown by the visual cue) and the body 105 and housing 102 may be pushed or pulled to open or close the inhaler 100. In one embodiment, the housing is movable from an open configuration to a closed configuration over the distal member 105 of the body 101, and together they close the inhaler 100 when in contact with each other.

Fig. 18 and 19 show the inhaler 100 in a closed or dosing configuration, wherein the closing action effects movement of the cartridge 108 to the dosing configuration, and wherein the cartridge cup is further urged by the protrusion element 118 to reconfigure independently of the cover 117 to form an air conduit through the cartridge 108 mounted in the cartridge mounting area 109. In this configuration, the inhaler attains a dosing configuration to discharge powder from the cup 116 upon oral inhalation by the user through the mouth 104. In this embodiment of the dosing arrangement shown in figure 18, the body and housing abut each other and are tightly fitted together by one or more anti-slip structures to prevent the inhaler from being disengaged. Examples of anti-slip features may include a snap ring or detent that may produce a sound to alert the user that the inhaler is ready for use. Fig. 17 and 20 illustrate the inhaler 100 in an open configuration. In the present embodiment, the inhaler 100 is generally rectangular in shape with a proximal side and a distal side of smaller length; wherein the movement of the housing 102 over the body part 105 is achieved by pulling or pushing the inhaler body 105, or vice versa, facilitated by a body comprising a guide rail or track 123, which guide rail or track 123 extends outwardly from the longer sides (first and second sides) of the inhaler body 105 along 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 housing distal end to allow and direct ambient air into the interior chamber of the inhaler 100 upon inhalation. The inhaler housing 102 is also suitably configured with a groove or slot 124 for sliding over the guide rail 123 during movement, and also includes one or more stop ends that prevent disassembly of the inhaler 100. The push or protrusion element 118 is designed to position the cartridge in the dosing configuration after the inhaler 100 is installed or closed. A projection or push member 118 moves the cartridge cup or container 116 relative to the cartridge cap 117 to create an air passageway through the cartridge and create an air inlet 119 and an air outlet 120, allowing powder in the cup to aerosolize during inhalation to deliver aerosolized particles to the inhaler mouthpiece air conduit 115 and into the user.

In a version of the inhaler 100, the distal portion of the housing comprises parallel structures or flanges for engaging a portion of the inhaler body to form a fastening mechanism, for example for locking the inhaler body and the housing to fasten the two components together and maintain the dosing configuration. In an embodiment, the distal portion 107 of the housing 102 has an opening at its distal end for communicating with the interior of the inhaler 100 and an opening 106 configured to slide over the inhaler body 105. The distal portion 107 of the housing 102 also includes an outer surface, an inner surface, and a cavity configured to slide over the inhaler body 105. In one embodiment, the housing 102 includes parallel wing structures 113 on its upper surface to direct the airflow into the mouth 104 during inhalation. The inhaler body part 105 is designed with a groove along its middle longitudinal plane to accommodate the sliding of the protrusion or pushing element 18 to push the cartridge or to prevent disassembly of the housing. The inhaler body part 105 is also configured with a detent at its distal end for engaging with the housing 102 and securing the two inhaler parts.

An example of a cartridge for use with an inhaler is described in U.S. patent No. 8,424,518, the disclosure of which is incorporated herein by reference in its entirety. In summary, the cartridge disclosed together with the inhaler embodiment comprises two parts, however other embodiments are also contemplated. The cartridge is configured to contain the dry powder medicament in a storage, tightly sealed or contained position and is reconfigurable within the inhaler from the powder containing position to an inhalation or administration configuration. In certain embodiments, a cartridge includes a lid and a cup having one or more apertures, a containment configuration and a dosing configuration, an exterior surface, an interior surface defining an interior space; and the receiving arrangement restricts communication with the interior space, while the dispensing arrangement forms a gas passage that runs through the interior space to allow gas flow to enter and exit the interior space in a predetermined manner. For example, the cartridge container may be configured such that an airflow entering the cartridge air inlet is directed through the air outlet to the interior space to meter medicament out of the cartridge such that the rate of expulsion of powder is controlled; and wherein the airflow in the cartridge may tumble substantially perpendicular to the direction of flow of the air outlet, causing the powder in the interior space to mix and liquefy before exiting the dispensing aperture. The cartridges for use with current inhalers can be provided in separate blisters or be polymerized in one blister, depending on the needs of the subject or the water absorption of the formulation with respect to the stability of the powder and/or the active ingredient.

In the embodiments described herein, the dry powder inhaler and cartridge form an inhalation system that may be structurally configured to achieve adjustable or modular airflow resistance, as this may be achieved by varying the cross-sectional area or geometry of the air conduit at any part of the airflow path of the system. In one embodiment, the geometry of the air conduit of the dry powder inhaler system may produce a resistance to airflow value of from about 0.065 to about 0.200(√ kPa)/liter per minute. In other embodiments, a check valve may be employed to prevent airflow through the inhaler until a desired pressure drop, such as 4kPa has been achieved, at which point the desired resistance reaches a value within a given range together.

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 region configured to receive a container and a mouthpiece having at least two inlet apertures and at least one exit aperture; wherein one of the at least two inlet apertures is in fluid communication with the container region and one of the at least two inlet apertures is in fluid communication with the at least one exit aperture via a flow path configured to bypass the containment region to deliver the dry powder formulation to the patient; wherein the airflow conduit configured to bypass the reservoir region delivers 30% to 90% of the total flow through the inhaler at the inhalation device.

In another embodiment, a dry powder inhalation system for delivering a dry powder formulation to a patient is also provided. The system includes a dry powder inhaler including a mounting and reconfiguration area for a cartridge; the combined dry powder inhaler and cartridge is configured to have at least two airflow paths as rigid airflow conduits in a dosing configuration and a plurality of mechanism regions providing a mechanism for deagglomerating powder of an inhalation system in use; wherein at least one of the plurality of means for deagglomeration is a lump-sized drainage hole in the container region having a minimum dimension of between 0.5mm and 3 mm.

In the embodiments described herein, the dry powder formulation may contain a crystalline powder, an amorphous powder, or a combination thereof, wherein the powder is consistently dispensed from the inhaler in less than about 2 seconds. The present inhaler system has a high resistance value of approximately 0.065 to approximately 0.200(√ kPa)/liter per minute. Thus, in a system including a cartridge, applying a peak inhalation pressure drop of between 2kPa and 20kPa results in a resulting peak flow rate of between about 7 and 70 liters per minute. These flow rates resulted in more than 75% of the cartridge contents being dispensed in a fill block of between 1 and 30mg or up to 50mg of powder. In some embodiments, these performance characteristics are achieved by the end user in a single inhalation maneuver to produce a dispense percentage of greater than 90%. In certain embodiments, the inhaler and cartridge system is configured to provide a single dose by discharging powder from the inhaler as a continuous stream or one or more pulses of powder delivered to the patient. In an embodiment, an inhalation system for delivering a dry powder formulation to the lungs of a patient is provided, comprising a dry powder inhaler configured with an airflow conduit having a total resistance to flow in a dosing configuration in the range of values of 0.065 to about 0.200(√ kPa)/liter per minute. In this and other embodiments, the total resistance to flow of the aspiration system is relatively constant over a pressure differential range of between 0.5kPa and 7 kPa.

The structural configuration of the inhaler allows the ending mechanism to produce an inhalation fraction of greater than 50% and particles of less than 5.8 μm. The inhaler may discharge more than 85% of the powdered medicament contained in the container during an inhalation operation. In summary, the inhaler described herein can expel more than 90% of the cartridge content or container content in less than 3 seconds at a pressure differential of between 2 and 5kPa, with a fill block range of up to 30mg or 50 mg.

Although the present inhaler is primarily described as being breath actuated, in some embodiments the inhaler may be provided with a source for generating the pressure differential required to deagglomerate and deliver the dry powder formulation. For example, the inhaler may be adapted to a gas driven source, such as an energy source storing compressed gas, such as from a nitrogen tank which may be provided at the air inlet. A pad may be provided to catch the plume so that the patient may inhale at a comfortable rate.

In the embodiments described together, the inhaler may be provided as a reusable inhaler for delivering a single unit dose. A reusable inhaler means that it can be used multiple times, which can be predetermined according to the formulation to be delivered and discarded once the inhaler has reached its maximum number of uses.

These devices and systems are used for pulmonary delivery of powders and have a wide range of features. Embodiments include a system, the systemThe system includes an inhaler, an integral or mountable unit dose cartridge containing the desired powder dose. Pulmonary delivery of powders includes carriers and excipients, the safety and efficacy of which have been demonstrated in commercial products. An exemplary embodiment is fumaryl diketopiperazine, also known as 3, 6-bis (N-fumaryl-4-aminobutyl) -2, 5-diketopiperazine, FDKP. FDKP produces microparticles that can be self-assembled aggregates of suspended crystal plates according to the process disclosed in U.S. patent nos. 7,820,676, 7,709,639, and 8,551,528; may be manufactured as an amorphous powder or a combination thereof, the above-mentioned U.S. patents being incorporated herein by reference for their related subject matter. Dry powders made using diketopiperazines can be made by lyophilizing or spray drying solutions or suspensions of the various desired formulations. Having a diameter of about 35 to about 67m²DKP crystalline particles of Specific Surface Area (SSA) between/g exhibit characteristics favorable for drug delivery to the lung, such as improved aerodynamic performance and improved drug absorption. In some embodiments, the large capacity crystalline FDKP microparticles used in polypeptide-containing formulations, for example, have a particle size of less than 35m²A specific surface area per gram, and depending on the amount of active agent, the specific surface area of these particles may range from about 19m²G to about 30m²A/g or about 28m²G to about 71m²In terms of/g, or about 19m²G to about 57m²(ii) in terms of/g. In some embodiments, FDKP microparticles with a peptide active agent (e.g., insulin) may have a range from about 4m²G to about 30m²Specific surface area in g and has improved aerodynamic properties in terms of flyability and flowability.

In one embodiment, the dry powder medicament may include, for example, a diketopiperazine and a pharmaceutically active ingredient. In this embodiment, the pharmaceutically active ingredient or agent may be of any type, depending on the disease or condition to be treated. In another embodiment, the diketopiperazines can include, for example, symmetric molecules and asymmetric diketopiperazines that have the function of forming particles, microparticles, etc., which can be used as a carrier system to deliver an active agent to a target in the body. The term "active agent" is referred to herein as therapeutic agents or molecules (such as proteins or peptides or biomolecules) and small molecules (including neurotransmitters that can be encapsulated, linked, conjugated, complexed or entrapped within or adsorbed onto diketopiperazine formulations). Any form of the active agent can be combined with the diketopiperazine. The drug delivery system may be used to biodegrade bioactive agents having therapeutic, prophylactic or diagnostic functionality.

Fumaryl diketopiperazines (3, 6-bis (N-fumaryl-4-aminobutyl) -2, 5-diketopiperazine; FDKP) is one preferred diketopiperazine for pulmonary use.

Microparticles for pulmonary delivery having a diameter of about 0.5 to about 10 microparticles μm can reach the lungs and can reach the systemic circulation and deliver the active agent. A diameter of less than about 10 μm is required to cope with throat turns and a diameter of about 0.5 μm or more is required to avoid volatilization. Typically, microparticles having a diameter greater than 10 μm or greater than 20 μm are used for delivery to the respiratory tract and lungs.

Microparticles having a diameter between about 0.5 and about 10 microns can successfully pass through most natural barriers to the lungs. A diameter of less than about 10 microns is required to cope with throat turns and a diameter of about 0.5 microns or more is required to avoid volatilization. The embodiments disclosed herein are shown to have about 4 to about 71m²DKP crystalline particles of Specific Surface Area (SSA) between/g exhibit characteristics favorable for drug delivery to the lung, such as improved aerodynamic performance and improved drug absorption. Together, in some embodiments, there is provided microparticles comprising crystalline Fumaryl Diketopiperazine (FDKP) having a specific trans isomer content of from about 35% to about 65%, or from 45% to about 63%, or from 45% to about 60%.

In certain embodiments, a diketopiperazine-based composition for pulmonary delivery is provided with an active agent, wherein the diketopiperazine is fumaryl diketopiperazine and comprises a plurality of substantially uniformly formed microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystals of the diketopiperazine that do not self-assemble, and the particles have a volume geometric mean diameter of 5 μ ι η or less; wherein the particles are formed by a process comprising combining diketopiperazine in a surfactant-free acetic acid solution and simultaneously homogenizing in a high shear mixer at high pressures up to 2000 psi; washing the precipitate in the suspension by using deionized water; the suspension is concentrated and dried in a spray drying apparatus.

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

Also provided is a system for delivering an inhalable dry powder, comprising: a) a dry powder comprising a medicament, and b) an inhaler comprising a powder containing cartridge and a housing, the cartridge comprising a gas inlet and a gas outlet, the housing mounting the cartridge therein and defining two gas flow paths, a first gas flow path allowing a gas thereof to enter the gas inlet of the cartridge and a second gas flow path allowing the gas to bypass the housing gas inlet, and a mouth, and discharging a plume of particles from the mouth when a pressure drop of ≧ 2kPa is applied in the inhaler, wherein 50% of said discharged particles have a VMAD ≦ 10 μm, wherein the gas flow bypassing the cartridge gas inlet is directed to impinge on the gas flow exiting the housing substantially perpendicular to the gas outlet flow direction.

The active agent used in the compositions and methods described herein may include any pharmaceutical agent. These may include, for example, synthetic organic compounds, proteins and polypeptides, polysaccharides and other carbohydrates, liquids, inorganic compounds, and nucleic acid sequences having therapeutic, prophylactic, or diagnostic activity. Peptides, proteins and polypeptides are chains of amino acids linked by peptide bonds.

Examples of target or target active agents that can be delivered into the body using diketopiperazine formulations include hormones, anticoagulants, immunomodulators, vaccines, cytotoxic agents, neurotransmitter agonists and anti-caking agents, antibiotics, vasoactive agents, neurostimulators, anesthetics or sedatives, steroids, decongestants, antivirals, antiretrovirals, antigens and antibodies. More specifically, these complexes include insulin, heparin (including low molecular weight heparins), calcitonin, felbamate, sumatriptan, parathyroid hormone and active fragments thereof, growth hormone, erythropoietin, AZT, DDI, granulocyte macrophage colony stimulating factor (GM-CSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β -galactosidase, agonist peptides, vasoactive intestinal peptide, and argatroban. Antibodies and fragments thereof may include, in a non-limiting manner, SSX-241-49 antigen (synovial sarcoma, X breakpoint 2), NY-ESO-1 antigen (esophageal tumor-associated antigen), PRAME antigen (preferably expressing melanoma antigen), PSMA antigen (prostate specific membrane antigen), melanoma antigen (melanoma-associated antigen), and tyrosinase antigen (melanoma-associated antibody).

In certain embodiments, dry powder formulations for delivery to the pulmonary circulation include an active ingredient or agent, including peptides, proteins, hormones, analogs thereof, or combinations thereof, wherein the active ingredient is insulin, calcitonin, growth hormone, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), chorionic gonadotropin releasing factor, luteinizing hormone releasing hormone, Follicle Stimulating Hormone (FSH), vasoactive intestinal peptide, parathyroid hormone (including black bear PTH), parathyroid hormone related protein, glucagon-like peptide 1(GLP-1), agonist peptide, oxyntomodulin, casein, interleukin 2 induced tyrosine kinase, Bruton tyrosine protein kinase (BTK), inositol essential enzyme-1 (IRE1) or an analogue, an active fragment, a PC-DAC modified derivative or an O-glycosylated form thereof. In particular embodiments, the pharmaceutical ingredient or dry powder formulation comprises fumaryl diketopiperazine and the active ingredient is one or more selected from the group consisting of: insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, casein, heparin, adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, Brain Natriuretic Peptide (BNP), Atrial Natriuretic Peptide (ANP), IGF-1, Growth Hormone Releasing Factor (GHRF), integrin beta 4 antibody (ITB4) receptor antagonists, nociceptin 2, calcitonin, CGRP, angiotensin, substance P, neurokinin A, cannabinoids (including tetrahydrocannabinol, cannabidiol), pancreatic polypeptide, neuropeptide Y, delta sleep-inducing peptide, vasoactive intestinal peptide, combinations of one or more of these agents, and/or analogs thereof.

Other active agents that may be used in dry powders for pulmonary delivery include: treprostinil, salmeterol, epinephrine, tacrolimus, vancomycin, linezolid, filgastrin, fentanyl, cannabinoids (including cannabidiol and tetrahydrocannabinol), palonosetron, amphotericin B, phosphodiesterase inhibitors (including PDE5 inhibitors such as sildenafil, avanafil, vardenafil and tadalafil), prostaglandins (including prostacyclins), neurotransmitter agonists, neurotransmitter antagonists (including analgesics, narcotic analgesics such as delta opioid agonists and antagonists, kappa opioid agonists and antagonists, mu opioid agonists and antagonists) and/or combinations of one or more of the foregoing active agents.

Also provided herein are improved microcrystalline particles, compositions, methods of making microcrystalline particles, and methods that allow for improved delivery of drugs to the lung for treatment of diseases and disorders in a subject. Embodiments disclosed herein achieve improved delivery by providing a crystalline diketopiperazine composition that includes microcrystalline diketopiperazine particles that have a large capacity for drug adsorption such that the powder has a large drug capacity for one or more active agents. Powders made with the microcrystalline particles can deliver more drug content in a smaller amount of powder dose, which can facilitate delivery of the drug to the patient. The powder can be produced by various methods including a method of using a surfactant-free solution or a surfactant-containing solution depending on the raw material.

Alternative embodiments disclosed herein may include a dry powder for inhalation comprising a plurality of substantially uniform microcrystalline particles, wherein the microcrystalline particles may have a substantially hollow spherical structure and comprise a shell which may be porous, the shell comprising diketopiperazine crystals which are not self-assembled in suspension or solution. In some casesIn embodiments, the microcrystalline particles may be substantially hollow spherical and substantially solid particles comprising diketopiperazine crystals, depending on the drug and/or drug content provided and other factors in the process of making the powder. In one embodiment, the microcrystalline particles comprise relatively porous particles having about 0.43cm³Average pore volume in the range of from about 0.4 cm/g³G to about 0.45cm³(ii)/g, and pore size ranges from about 23nm to about 30nm, or from about 23.8nm to 26.2nm, as determined by BJH adsorption.

Certain embodiments disclosed herein include powders comprising a plurality of substantially uniform microcrystalline particles, wherein the particles have a substantially spherical structure comprising a shell that may be porous, and the particles comprise diketopiperazine crystals that are not self-assembled in suspension or solution and the volume median geometric diameter of the particles is less than 5 μm; or less than 2.5 μm.

In particular embodiments herein, up to about 92% of the crystallite particles have a volume median geometric diameter of 5.8 μm. In one embodiment, the shell of the particle is composed of linked diketopiperazine crystallites having one or more drugs adsorbed on their surface. In some embodiments, the particles may trap the drug in their internal pore space and/or adsorb a combination of drugs to the surface of the crystal to trap the drug in the internal pore space of the sphere.

In certain embodiments, diketopiperazine compositions are provided that include a plurality of substantially uniformly formed microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising non-self-assembled diketopiperazine crystals; wherein the particles are formed by a process comprising combining diketopiperazine having a trans isomer content ranging from about 45% to 65% in a surfactant-free acetic acid solution and simultaneously homogenizing in a high shear mixer at high pressures up to 2000 psi; washing the precipitate in the suspension by using deionized water; the suspension is concentrated and dried in a spray drying apparatus.

The method may further comprise the step of adding a step of mixing a solution comprising an active agent or active ingredient (such as a drug or bioactive agent) prior to the step of spray drying such that the active agent or active ingredient is adsorbed and/or trapped on or within the particles. Particles made by this process can reach the submicron size range before spray drying.

In certain embodiments, diketopiperazine compositions are provided comprising a plurality of substantially uniformly formed microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising non-self-assembled diketopiperazine crystals, and the particles have a volume geometric mean diameter of 5 μm or less; wherein the particles are formed by a process comprising combining diketopiperazine in a surfactant-free acetic acid solution and simultaneously homogenizing in a high shear mixer at high pressures up to 2000 psi; washing the precipitate in the suspension by using deionized water; the suspension is concentrated and dried in a spray drying apparatus.

The method may further comprise the step of adding agitation to the solution comprising the active agent or active ingredient (such as a drug or bioactive agent) prior to the step of spray drying, such that the active agent or active ingredient is adsorbed and/or trapped on or within the particles. Particles made by this process can reach the submicron size range before spray drying.

In certain embodiments, a diketopiperazine-based composition for pulmonary delivery is provided with an active agent, wherein the diketopiperazine is fumaryl diketopiperazine and comprises a plurality of substantially uniformly formed microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystals of the diketopiperazine that do not self-assemble, and the particles have a volume geometric mean diameter of 5 μ ι η or less; wherein the particles are formed by a process comprising incorporating diketopiperazines in a surfactant-free and active-free acetic acid solution and simultaneously homogenizing in a high shear mixer at high pressures up to 2000 psi; washing the precipitate in the suspension by using deionized water; the suspension is concentrated and dried in a spray drying apparatus.

In certain embodiments, wherein the raw material comprising the active ingredient is an extract exhibiting a high viscosity or a material having a syringy viscous appearance, the microcrystalline particles are formed as above by washing the microcrystalline particles in water using tangential flow filtration prior to combining with the extract or viscous material. After washing in water, the resulting suspension of particles is lyophilized to remove the water and resuspended in an alcoholic solution comprising ethanol or methanol before adding the active ingredient as a solid or in suspension or in solution. In one embodiment, optionally, the method of making the composition comprises the step of adding any additional excipients including one or more amino acids (such as leucine, isoleucine, norleucine, methionine) or one or more phospholipids (e.g., Dipalmitoylphosphatidylcholine (DPPC) or Distearoylphosphatidylcholine (DSPC)) simultaneously with the active ingredient or after the addition of mars prior to spray drying. In certain embodiments, the formation of the composition includes a step in which the extract including the desired active agent is optionally filtered or frozen to separate and remove layers of unwanted material (such as grease) to increase its solubility.

The method may further comprise the step of adding a stirring solution prior to the step of spray drying, the stirring optionally being performed with or without homogenization in a high shear mixer, the solution comprising an active agent or active ingredient, such as a drug or a biologically active agent, such that the active agent or active ingredient is adsorbed and/or entrapped on or within the particles. Particles made by this process can reach the submicron size range prior to spray drying, or these particles can be formed from solution during spray drying.

In some embodiments together, the drug content may be delivered using FDKP on a bulk powder that is lyophilized or spray dried to a content of about 10% or about 20% or about 30% or more. In embodiments using microcrystalline particles formed from FDKP or FDKP disodium salt and wherein the particles are not self-assembled and comprise submicron sized particles, the drug content may typically be greater than 0.01% (w/w). In one embodiment, the drug content to be delivered by the microcrystalline particles is from about 0.01% (w/w) to about 75% (w/w), depending on the drug to be delivered; from about 1% to about 50% (w/w), from about 10% (w/w) to about 25% (w/w), or from about 10% to about 20% (w/w), or from 5% to about 30%, or greater than 25%. In an exemplary embodiment where the drug is a peptide such as insulin, the current microparticles typically comprise approximately 10% to 45% (w/w) or from about 10% to about 20% (w/w) insulin. In certain embodiments, the drug content of the particles may vary depending on the morphology and size of the drug to be delivered.

In embodiments, the ingredients for delivery by the inhalers herein may include fumaryl diketopiperazine crystal particles and an active agent, such as a cannabinoid (including Tetrahydrocannabinol (THC) and/or cannabidiol), treprostinil, palonosetron, parathyroid hormone, sildenafil, or epinephrine. In ingredients using cannabinoids as active agents, cannabinoids (including derivatives and/or analogues thereof) may be up to 40% (w/w), with powder delivery of more than 40% of the inhaler contents. In some embodiments, the cannabinoid content in the ingredient can range from about 1% to about 30%, from about 5% to about 25% (w/w) of the powder contents. The compositions herein may also include one or more excipients (including amino acids such as leucine, isoleucine, methionine, and the like) and one or more phospholipids (e.g., Dipalmitoylphosphatidylcholine (DPPC) or Distearoylphosphatidylcholine (DSPC)) in an amount of up to about 25% (w/w), ranging from about 1% (w/w) to about 25%, or from 2.5% to 20% (w/w), or from 5% to 15% (w/w), prior to spray drying. In this embodiment, the inhaler can expel from about 50% to 100% of the composition in a single inhalation. In this embodiment, the composition may be delivered to the subject as needed for treatment.

In embodiments using epinephrine as the active agent, the content of epinephrine component constitutes up to about 30% (w/w) of the powder content; and ranges from about 1% to about 35%. In certain embodiments, the ingredients comprising microcrystalline particles may contain from about 2% to about 30% or from about 0.1% to about 20% (w/w) epinephrine. In this embodiment, epinephrine may be delivered by the inhaler described herein with a powder delivery efficiency of greater than 50% of the dose content. In this example, the composition is used in a method of treating symptoms of an allergic reaction prior to the onset of the allergic reaction caused by an allergen (such as nuts including peanut allergen, antibiotics such as penicillin, and other substances). The method comprises providing a subject in need of treatment for symptoms of an allergic reaction and exhibiting symptoms of an early allergic reaction with an inhaler comprising a dose of about 1mg to about 15mg of a composition effective to prevent the onset of the allergic reaction and to cause the subject to inhale the dose of the composition, the dose of the composition comprising an amount of epinephrine sufficient to prevent the onset of the allergic reaction in the subject.

In embodiments using treprostinil as an active agent, the dry powder formulation comprises microcrystalline granules of fumaryl diketopiperazine, wherein the treprostinil is adsorbed to the granules, and wherein the content of treprostinil in the formulation constitutes up to about 20% (w/w) and ranges from about 0.5% to about 10% (w/w) or from about 1% to about 5% (w/w) of the dry powder. In one embodiment, the compositions herein may include other excipients for inhalation, such as amino acids, including methionine, isoleucine, and leucine. In this example, treprostinil composition may be used to prevent and treat pulmonary hypertension by self-feeding an effective dose comprising about 1mg to 15mg of a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and treprostinil in a single inhalation.

In embodiments using palonosetron as the active agent for the inhalation dry powder, the dry powder content of palonosetron in the composition comprises up to about 20% (w/w) of the dry powder content; and ranges from about 0.1% to about 20%, or from 0.1% to about 10% of the dry powder content. In one embodiment, the palonosetron component can be prepared as crystalline component particles comprising fumaryl diketopiperazine disodium salt or fumaryl diketopiperazine with an excipient comprising an amino acid (such as leucine, isoleucine, or methionine) to improve the storage stability of the component. In embodiments, the inhalable composition of palonosetron may be used to prevent and treat chemotherapy nausea and vomiting by self-administering a dose of the composition in a single inhalation using the inhaler herein about 5 to 30 minutes and preferably about 5 to 15 minutes or simultaneously before a patient receives a chemotherapy medication.

In alternative embodiments, the medically acceptable carrier for the manufacture of the dry powder may comprise any carrier or excipient that may be used in the manufacture of the dry powder and that is suitable for pulmonary delivery. Examples of suitable carriers and excipients include sugars (including carbohydrates and polysaccharides such as lactose, mannose sucrose, mannitol, trehalose), citrate, amino acids (such as glycine, L-leucine, isoleucine, trileucine, tartrate, methionine), vitamin a, vitamin E, zinc citrate, trisodium citrate, zinc chloride, polyvinylpyrrolidone, polysorbate 80, phospholipids (including phosphorylcholine), and the like.

In one embodiment, a method for self-administering a dry powder formulation to the lungs via a dry powder inhalation system is also provided. The method comprises the following steps: obtaining a dry powder inhaler in a closed position and having a mouthpiece; obtaining a cartridge comprising a pre-metered dose of a dry powder formulation in a containment configuration; opening the dry powder inhaler to install the cartridge; closing the breast pump to effect movement of the cartridge to the dosing position; the mouth is placed in the patient's mouth and one deep inhalation delivers the dry powder formulation.

In yet another embodiment, a method of treating obesity, hyperglycemia, insulin resistance, pulmonary hypertension, allergic reactions, and/or diabetes is disclosed. The method comprises administering an inhalable dry powder formulation or formulation comprising, for example, a compound having 2, 5-diketo-3, 6-di (4-X-aminobutyl) piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder formulation may include a diketopiperazine salt. In yet another embodiment, a dry powder formulation or preparation is provided wherein the diketopiperazine is 2, 5-diketo-3, 6-bis (4-fumaryl-aminobutyl) piperazine with or without a pharmaceutically acceptable carrier or excipient.

An inhalation system for delivering a dry powder formulation to the lungs of a patient is provided, the system comprising a dry powder inhaler configured with an airflow conduit having a total resistance to flow in a dosing configuration in the range of values of 0.065 to about 0.200(√ kPa) per liter per minute.

In one embodiment, a dry powder inhalation kit is provided comprising a dry powder inhaler as described above, one or more medicament kits comprising a dry powder formulation for the treatment of disorders or diseases, such as respiratory and pulmonary diseases, diabetes and obesity.

Also provided are methods of treating a disease or disorder in a patient by embodiments of the dry powder inhaler disclosed herein. The method of treatment comprises providing a patient in need of treatment with a dry powder inhaler comprising a kit containing a dose of an inhalable formulation comprising an active ingredient selected from the group described above and a pharmaceutically acceptable carrier and/or excipient; and allowing the patient to inhale deeply through the dry powder inhaler for about 3 to 4 seconds to deliver the dose. In the present method, the patient may thereafter resume the normal breathing mode.

The following examples illustrate some processes for manufacturing dry powders suitable for use with the inhalers described herein and data obtained from experiments using the dry powders.

Example 1

Preparation of a surfactant-free dry powder for use in an inhaler comprising FDKP raw powder: in an exemplary embodiment, a surfactant-free dry powder comprising FDKP crystallite particles is prepared. Approximately equal masses of acetic acid solution (table 1) and FDKP solution (table 2) maintained at approximately 25 ℃ ± 5 ℃ were fed through 0.001-in2 orifices at 2000psi using a two-wire fed high shear mixer to form a precipitate by homogenization. The precipitate was collected in Deionized (DI) water at about equal temperature. The suspension has a weight percent FDKP crystallite content of about 2-3.5%. The suspension may be analyzed for FDKP concentration for solids content by a drying process. The FDKP crystallite suspension may optionally be washed by tangential flow filtration using deionized water. FDKP microcrystals can optionally be isolated by filtration, concentration, spray drying or lyophilization.

TABLE 1 composition of FDKP solution

Composition (I)	Component range (% by weight)
		FDKP	2.5–6.25
30% NH4OH solution	1.6–1.75
		Deionized water	92–95.9

TABLE 2 composition of acetic acid solution

Composition (I)	Component range (% by weight)
		Acetic acid	10.5–13.0
Deionized water	87.0–89.5

Dry powders (A, B, C and D) comprising microcrystalline particles made by the above method were tested for various characteristics including surface area, water content and porosity measurements. Four different powders were used in this experiment. All powders tested had a residual water content of 0.4%. Table 2a shows the data obtained from the experiment.

TABLE 2a

The data in table 2a shows that the bulk dry powder comprising microcrystalline particles of the tested samples had a surface area after spray drying ranging from 59m²G to 63m²(ii) in terms of/g. The porosity data indicated that the microcrystalline particles were relatively porous, as determined by BJH inhalation, having about 0.43cm³An average void volume per gram and an average pore size in the range of about 23.8nm to 26.2 nm. The porosity measurement data indicates that these particles are different from prior art FDKP microparticles, which have been shown to have about 0.36cm³An average pore volume per gram and an average pore size of about 20nm to about 22.6 nm.

Example 2

Preparation of a dry powder comprising microcrystalline FDKP granules comprising epinephrine. To the suspension of FDKP crystallites obtained as described in example 1 was added approximately 5% by weight of epinephrine in an approximately 5% aqueous acetic acid solution. Optionally, leucine is also added to the FDKP crystallite suspension. The mixture was spray dried using a Buchi B290 spray dryer equipped with a high efficiency cyclone. Nitrogen was used as process gas (60 mm). The mixture was dried using a 10% -20% pump flow rate, 90% -100% suction rate, and an inlet temperature of 170 ℃ and 190 ℃. The resulting powder had concentrations of epinephrine and leucine in the range of 2% to 30% and 0% to 20% by weight, respectively. The delivery efficiency of these powders after discharge from a dry powder inhaler ranges between approximately 50% to 80%.

Example 3

The preparation of a dry powder comprising microcrystalline FDKP granules comprising palonosetron. To the suspension of FDKP crystallites obtained as described in example 1 was added a DI solution of approximately 5% by weight palonosetron hydrochloride. Optionally, a deionized water (DI) solution of leucine and methionine. The mixture was titrated to pH 6.5. + -. 0.5 using ammonium hydroxide. The mixture was spray dried using a Buchi B290 spray dryer equipped with a high efficiency cyclone. Nitrogen was used as process gas (60 mm). The mixture was dried using a 10% -12% pump flow, 90% -100% suction rate and an inlet temperature of 170 ℃ and 190 ℃. The resulting powder had palonosetron, leucine and methionine concentrations of 5%, 0-20% and 0-10% by weight, respectively. The delivery efficiency of these powders after discharge from a dry powder inhaler ranges between approximately 50% to 70%.

Example 4

Comprising the preparation of a dry powder of microcrystalline FDKP granules containing treprostinil. To the FDKP crystallite suspension obtained as described in example 1, an ethanol solution containing 0.2-1.0% by weight of treprostinil was added. The mixture was spray dried using a Buchi B290 spray dryer equipped with a high efficiency cyclone. Nitrogen was used as process gas (60 mm). The mixture was dried using a 10% -12% pump flow, 90% -100% suction rate and an inlet temperature of 170 ℃ and 190 ℃. The treprostinil concentration in the resulting powder is 0.5% -10% by weight. The delivery efficiency of these powders after discharge from a dry powder inhaler ranges between approximately 50% to 70%.

Example 5

The preparation of a dry powder comprising microcrystalline FDKP granules comprising Δ 9-THC or CBD. Isolated FDKP crystallite particles prepared as in example 1 were suspended in ethanol. An approximately 1% -4% by weight solution of cannabis extract (mainly comprising. DELTA.9-THC or CBD) in ethanol and a suspension of FDKP in microcrystalline ethanol were added. Optionally, a solution of the additive dissolved in ethanol is added. The mixture was spray dried using a Buchi B290 spray dryer equipped with a high efficiency cyclone. Nitrogen was used as process gas (60 mm). The mixture was dried using a 12% -15% pump flow, 70% -100% suction rate, and an inlet temperature of 110 ℃ and 190 ℃. The weight percent concentrations of Δ 9-THC and additional additives are provided in Table 3. The delivery efficiency of these powders after discharge from a dry powder inhaler ranges between approximately 50% to 70%.

TABLE 3 composition of microcrystalline FDKP granules containing Δ 9-THC or CBD

Composition (I)	Ingredient Range (wt.%)
		Delta 9-THC and/or CBD	10–40
DPPC	5–15
		DSPC	5–15
PVP	0.5–5
		PEG	2
PS-80	2

The dry powder produced by the above method was tested using the basic Anatomically Correct Airway (ACA) system described in U.S. patent No. 9,016,147. Dry powders exhibit significant stability at room temperature, for example greater than 90% THC or CBD remains active at one month of storage, with delivery efficiencies using this approach ranging from about 35% to about 75%.

The foregoing disclosure is an exemplary embodiment. It should be apparent to those skilled in the art that the apparatus, techniques, and methods disclosed herein are illustrative of representative embodiments that function well in the practice of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope 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.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

The use of the term "or" in the claims, although the present disclosure supports the recitation of substitutes and definitions of "and/or" only, is used to mean "and/or" unless expressly indicated to the contrary.

Groupings of alternative components or embodiments disclosed herein are not to be construed as limiting. Each group of components may be referred to and claimed individually or in any combination with other components of the group or other assemblies found herein. It is contemplated that one or more components of a group may be included in, or deleted from, a group for convenience and/or patentability. When such inclusion or deletion occurs, the specification is considered herein to contain the group as modified to implement the written specification of all markush groups used in the claims.

Preferred embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for 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 appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in various possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

The specific embodiments disclosed herein may be further defined in the claims with inclusion or inclusion of language. As used in the claims, the transitional term excludes any element, step, or component not recited in the claims, whether as a filing or as a supplement to each amendment. The transitional term "consisting essentially of" limits the scope of the claims to specific materials or steps, as well as materials and steps that do not materially affect the basic and novel characteristics. Such required embodiments are described and enabled herein either explicitly or explicitly.

In addition, patent and printed publications are cited multiple times throughout the specification. Each of the above-cited documents and printed publications is herein incorporated by reference in its entirety.

In addition, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications may be employed within the scope of the invention. Thus, by way of example, and not limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the invention is not limited to the exact descriptions shown and described.

Claims (19)

1. A dry powder inhaler comprising:

a housing, and

a body including a mouth integrally configured with the body,

wherein the body comprises a mounting region for a cartridge and the body and housing are linearly movable relative to each other and operatively configured to engage each other by insertion to effect reconfiguration of the cartridge to obtain an airflow path for expelling powder on inhalation;

wherein the dry powder inhaler has a relatively rectangular body manufactured as a single element, and the body further has a proximal end that is generally C-shaped; and is

Wherein the dry powder inhaler further comprises a dry powder comprising a diketopiperazine, a cannabis component, and a phospholipid.

2. The dry powder inhaler of claim 1, wherein the mouthpiece has an air inlet for communicating with an interior compartment of the inhaler body.

3. The dry powder inhaler of claim 1, wherein the housing reconfigures the cartridge mounted in the inhaler by translating the housing on the inhaler body from an open configuration to a closed configuration.

4. The dry powder inhaler of claim 1, wherein movement of the housing relative to the body is facilitated by a guide track configured along a longitudinal axis and extending from a right side and/or a left side of the inhaler body.

5. The dry powder inhaler of claim 1, wherein the dry powder inhaler is configured to reach an open or loading position and a closed or dosing position.

6. The dry powder inhaler of claim 1, wherein the housing further comprises a protruding rigid element that urges the cartridge from a containment configuration to a dosing position.

7. The dry powder inhaler of claim 1, wherein the inhaler is further configured with a rigid flow channel.

8. The dry powder inhaler of claim 1, wherein the housing comprises a cover that encases a portion of the inhaler body.

9. The dry powder inhaler of claim 1, wherein the mouthpiece further has an interior space extending from the first inlet to the outlet, wherein the interior space is greater than 0.2 cubic centimeters.

10. The dry powder inhaler of claim 1, wherein the inhaler body comprises a detent that prevents the body from separating from the housing in an assembled inhaler device.

11. The dry powder inhaler of claim 1, wherein the housing positions the cartridge in alignment with the mouthpiece by translating the housing on the inhaler body from an open configuration to a closed configuration.

12. The dry powder inhaler of claim 1, wherein the dry powder is a pharmaceutical composition for inhalation.

13. The dry powder inhaler of claim 12, wherein the dry powder comprises 3, 6-bis (N-fumaryl-4-aminobutyl) -2, 5-diketopiperazine.

14. The dry powder inhaler of claim 13, wherein the dry powder comprises a cannabis ingredient in an amount of 1-40% (w/w).

15. The dry powder inhaler of claim 14, wherein the cannabis component is tetrahydrocannabinol or cannabidiol.

16. The dry powder inhaler of claim 13, wherein the phospholipid is selected from 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine and 1, 2-distearoyl-sn-propanetriyl-3-phosphocholine.

17. A dry powder inhaler comprising a body, a housing, a cartridge, and a mouthpiece, the body having a mounting area for the cartridge, and the cartridge comprising a dry powder formulation, and wherein the housing slides translationally over the body in a proximal-to-distal direction to open the inhaler or in a distal-to-proximal direction to close the inhaler, wherein when the inhaler is closed the inhaler has one or more rigid air conduits for dispensing the dry powder, the dry powder formulation comprising microcrystalline particles of fumaryl diketopiperazine, a cannabis formulation, and a phospholipid, and wherein the dry powder inhaler has a relatively rectangular body manufactured as a single element, and the body further has a proximal end that is generally C-shaped.

18. The dry powder inhaler of claim 17, wherein the cannabis component is tetrahydrocannabinol or cannabidiol.

19. The dry powder inhaler of claim 17, wherein the phospholipid is selected from 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine and 1, 2-distearoyl-sn-propanetriyl-3-phosphocholine.