HK1208389B - A dry powder inhaler and system for drug delivery - Google Patents

Description

Dry powder inhalers and systems for drug delivery

The present application is a divisional application based on application number 200980000440.4, filed on June 12, 2009, and filed by Mankind Corporation, entitled "Dry Powder Inhaler and System for Drug Delivery."

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Serial No. 61/157,506, filed on March 4, 2009, and U.S. Provisional Patent Application Serial No. 61/061,551, filed on June 13, 2008, the contents of each of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to a dry powder inhaler, a tube for a dry powder inhaler, and a system for rapidly delivering medicine to the pulmonary trachea, comprising a dry powder drug formulation for the inhaler comprising an activating agent for treating diseases such as diabetes and obesity. Specifically, the system may comprise a dry powder inhaler with or without a unit dose tube, and a drug delivery formulation comprising, for example, a diketopiperazine and an activating agent such as a peptide and protein (comprising insulin and glucagon-like peptide 1).

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

Background Art

There are numerous drug delivery systems for introducing active ingredients into the circulatory system for the treatment of diseases, including oral, dermal, inhalation, subcutaneous, and intravenous administration. Drugs delivered by inhalation are typically delivered using positive pressure relative to atmospheric pressure and a propellant. Such drug delivery systems deliver drugs in the form of suspended particles, mist, or vapor. In recent years, dry powder inhalers have been used to deliver drugs to lung tissue. Dry powder inhalers can be activated or powered by breathing and can deliver drugs by converting drug particles in a carrier into a fine dry powder that is entrained in an airflow and inhaled by the patient. The use of dry powder inhalers to deliver drugs is no longer just for the treatment of lung diseases, and specific drugs can be used to treat many conditions, including diabetes and obesity.

Dry powder inhalers are used to deliver medication to the lungs and include a dosing system for a powder formulation, which is either supplied in bulk or quantified into individual doses stored in unit-dose chambers (such as hard gel capsules or blisters). The bulk container is equipped with a patient-operated metering system to separate the individual doses from the powder immediately prior to inhalation. Dosage reproducibility requires that the drug formulation be uniform and that the dose be delivered to the patient with consistent and reproducible results. Therefore, ideally, the dosing system works to effectively expel all of the formulation during the inhalation process while the patient is taking their dose. However, complete expulsion is not required as long as reproducible dosing is achieved. In this regard, the flow properties and long-term physical and mechanical stability of the powder formulation are more critical for bulk containers than for individual unit-dose chambers. Good moisture protection is easier to achieve with unit-dose chambers such as blisters, but if the materials used to make the blisters allow air to enter the medication, the formulation can subsequently lose effectiveness due to long-term storage. Additionally, dry powder inhalers that use blisters to deliver medication by inhalation can experience inconsistencies in the dose delivered to the lungs due to variations in the air passage structure caused by puncturing or peeling of the blister membrane.

The dry powder inhaler of describing in U.S. Patent No. 7,305,986 and 7,464,706 (the disclosure of these two patents is fully combined in this by reference) can produce basic medicine particle or suitable inhalation flow by the powder formulation in disintegrating capsule during inhalation operation.The fine powder amount discharged from the mouthpiece of inhaler during inhalation process for example mainly depends on the force between particles in powder formulation and the efficiency that inhaler separates these particles and makes particles suitable for inhalation.The benefit of delivering medicine via pulmonary circulation is many, and comprises that enters arterial circulation quickly, avoids being metabolized by liver and makes medicine deteriorate, is easy to use (that is, does not have the discomfort of management that other management routes cause).

Dispersible powder inhalers developed for pulmonary delivery have had limited success to date, and this is because lacking practicality and/or manufacturing cost. Some lasting problems of the inhalers of the prior art comprise the durability that lacks device, the pusher that is used to deliver powder, the consistency of dosage, the inconvenience of equipment, poor disintegration and/or lack patient's compliance. Thus, the inventor has recognized that design and manufacture have constant powder delivery characteristics, comfortable and easy to use and allow the inhaler of higher patient's compliance discrete inhaler structure.

Summary of the Invention

Disclosure of the invention relates to Diskus, the tube that is used for Diskus and the system that is used to deliver medicine to the lung trachea quickly, comprise the dry powder with the activating agent that is used to treat disease (comprising diabetes and obesity).Diskus can be that breathing provides power, compact, reusable or can be disposed of arbitrarily, and has various shapes and sizes, and comprises the system that is used for the air flow duct path of effective and fast delivery powder medicine.In one embodiment, inhaler can be unit dose, reusable or can be disposed of arbitrarily, it can with or not use together with tube.When not using together with tube, we refer to the system that tubular structure and inhaler are one, and this and tube are for example installed by the system of using contrary by user.In another embodiment, inhaler can be multi-metered inhaler, can be disposed of arbitrarily or can be used, and use together with the tubular structure of the part that is installed in the unit metering cylinder in the inhaler or built-in or structural configuration as inhaler.

The dry powder inhalation system comprises a dry powder inhalation device or an inhaler with or without a tube, and comprises a pharmaceutical formulation for the active ingredient of pulmonary delivery. In certain embodiments, it is delivered to deep lungs (that is, alveolar regions), and in some of these embodiments, activating agent is absorbed into the pulmonary circulation and is systemically delivered. The system also comprises a dry powder inhaler with or without a unit dose tube, and comprises a drug delivery formulation of, for example, a diketopiperazine and an active ingredient such as a peptide and protein (comprising insulin and glucagon-like peptide 1).

In one embodiment, Diskus comprises housing, movable member and the mouth of pipe, and wherein, movable member is operably configured to container is moved to quantitative position from powder holding position.In this and other embodiments, movable member can be slide plate, sliding plate or the carriage moved by various mechanisms.

In another embodiment, the Diskus comprises that housing and structure are configured to the mouth of pipe with open position and closed position and operably configured to when described inhaler moves to closed position from open position tube is received, kept and reconfigured to the mechanism of distributing quantitative or dosage delivery position from accommodating position.In the various forms of this embodiment, when opening the employed tube of inhaler unloading, mechanism can also be reconfigured to the accommodating position from the quantitative position with the tube that is installed in the inhaler after use. In one embodiment, mechanism can be reconfigured to the structure that can dispose of or discard with the tube after use. In this embodiment, the structure of housing is configured to be movably installed to the mouth of pipe by various mechanisms such as hinge. Be configured to the mechanism that the tube that is installed in the inhaler is received and is reconfigured to the quantitative position from the accommodating position and can be designed to manually or automatically work when for example by making each component motion of inhaler from opening structure closing device. In one embodiment, the mechanism that is used to reconfigure tube comprises the sliding plate or the slide plate that is installed to the mouth of pipe and movably installed to housing. In another embodiment, mechanism is installed to or is adapted to inhaler, and comprises the gear mechanism that is for example installed in the hinge of inhaler device. In another embodiment, the mechanism operably configured to receive the cartridge and reconfigure the cartridge from the containment position to the dosing position includes a cam that reconfigures the cartridge upon rotation of, for example, the housing or the spout.

In optional embodiment, Diskus can be manufactured into the inhaler that single use, unit dose can be disposed of arbitrarily, it is provided with the powder container that is configured to keep powder medicine, and wherein, inhaler can have wherein first configuration is to hold structure and second configuration is the first and second configurations of quantitative or distribution structure.In this embodiment, inhaler can be provided with or do not have the mechanism that is used to reconstruct powder container.According to the various aspects of the latter's embodiment, container can be directly reconstructed by the user.

In another embodiment, the inhaler includes a container mounting area configured to receive a container and a mouthpiece having at least two inlet openings and at least one outlet opening; wherein one of the at least two inlet openings is in fluid communication with the container area, and one of the at least two inlet openings is in fluid communication with the at least one outlet opening via a flow path configured to bypass the container area.

In one embodiment, the inhaler has the proximal and distal opposite ends such as being used to contact user's lips or mouth, and comprises the mouth of pipe and medicine container; Wherein, the mouth of pipe comprises top surface and bottom surface or lower surface.The mouth of pipe lower surface has the first area that is configured to be relatively flat so that container is remained on sealing or accommodating structure and the second area that is adjacent to the first area and protrudes relative to the first area. In this embodiment, container can be moved to quantitative structure from accommodating structure, and vice versa, and in quantitative structure, the second raised area of the mouth of pipe lower surface and the container form or limit the inner space that allows ambient air container or the inner space of container is exposed to the inlet passage of ambient air. In one embodiment, the mouth of pipe can have a plurality of perforations, for example, inlet, outlet or at least one mouth that is communicated with the medicine container that is in distribution or quantitative position, and be configured to have the integral panel of the flange that extends from the bottom surface side of inhaler and protrudes towards the center of the inhaler mouth of pipe, flange is used as track and container is supported on the mouth of pipe so that container can move to distribution or quantitative position from accommodated position along track, and if expectation returns to accommodated position. In one embodiment, the drug container is configured with wing-like protrusions or winglets extending from the top edge to fit over flanges on the nozzle panel. In one embodiment, the drug container can be manually moved from the containing position to the dosing position by the user or by means of a slide, a sliding tray, or a carriage, and returned to the containing position after dosing.

In another embodiment, the disposable inhaler of single use, unit dose can be configured to have combination and be operatively configured to the slide plate of the mouth of pipe.In this embodiment, the bridge on the slide plate can abut or rely on on the zone of the medicine container so that container is moved to distribution or quantitative position along the mouth of pipe panel track from accommodating position.In this embodiment, slide plate can be manually operated to move container on the mouth of pipe track.

In one embodiment, the dry powder inhaler includes one or more air inlets and one or more air outlets. When the inhaler is closed, at least one air inlet allows airflow into the inhaler, and at least one air inlet allows airflow into the barrel chamber or interior of a barrel or container suitable for inhalation. In one embodiment, the inhaler has an opening that is structurally configured to communicate with the barrel placement area and the barrel outlet when the barrel container is in a quantitative position. The airflow entering the barrel interior can exit the barrel through the outlet or distribution port; or the airflow entering the inhaler's container can exit through at least one distribution opening. In this embodiment, the barrel inlet is configured so that all or part of the airflow entering the interior of the barrel is guided at the outlet or distribution port. The medicament container is configured to have two opposite, relatively curved sides that can guide the airflow. In this embodiment, the airflow entering the air inlet can circulate around an axis relatively perpendicular to the axis of the distribution port inside the container during inhalation, thereby causing the airflow to rise, tumble, and effectively fluidize the powdered medicament contained in the barrel. In this and other embodiments, the fluidized powder in the air duct can be further broken down into fine powder particles by changes in the direction or velocity (i.e., acceleration or deceleration) of the particles in the flow path. In some embodiments, the change in acceleration or deceleration is accomplished by changing, for example, the angle and geometry of the dispensing opening, the nozzle conduit, and/or its inner surface. In the inhaler described herein, the mechanism for fluidizing and accelerating the particles as they travel through the inhaler is a method for performing the disintegration and delivery of the dry powder formulation.

In a specific embodiment, a method for disintegrating and dispensing a dry powder formulation includes one or more steps such as: tumbling within the main container area is initiated and increased by the air flow entering the container; rapidly accelerating the powder flow out of the container through the dispensing port; accelerating the powder as it leaves the dispensing port by a change in direction or speed, wherein the flow at the top of the particles is faster than the flow at the bottom of the particles; causing the flow to slow due to an expansion of the cross-section within the nozzle air duct; and expansion of air trapped within the particles due to the movement of the particles from a higher pressure area to a lower pressure area or collisions between the particles and the flow duct wall at any point in the flow channel.

In another embodiment, a dry powder inhaler includes a mouthpiece; a slide, a tray or a carriage, a housing, a hinge and a gear mechanism configured to perform movement of the slide or tray; wherein the mouthpiece and the housing are movably mounted by the hinge.

The tube that is used for Diskus can be configured to hold any dry powder medicine that is used to suck.In one embodiment, if inhaler has the mechanism that allows translational movement or rotational movement, then the structure of tube is configured to be adapted to specific Diskus and can be made into any size and shape, and this depends on the size and shape of used inhaler.In one embodiment, tube can be configured with fastening mechanism, for example it has bevel edge at the tube top corresponding to the matching bevel edge in the inhaler, so that tube is fastened in use.In one embodiment, tube comprises container and lid or cover, wherein, container can be adapted to the surface of lid, and can move or lid can move on container and can depend on its position and arrive various structures, for example, hold structure, quantitative structure or the structure after use with respect to lid.Alternatively, lid is detachable.Exemplary embodiment comprises the shell that keeps medicine, and is configured to guide a part of airflow in response to pressure gradient at the distribution opening place or at the granule near the distribution opening in the shell.Distribution opening and air inlet opening each independently have such as oval, rectangle, triangle, square and egg-shaped shape, and can approach each other. In the inhalation process, the tube that is adapted to the inhaler in the quantitative structure allows air flow to enter the shell and mix with powder so that the medicine fluidizes.The fluidized medicine moves in the shell so that the medicine gradually leaves the shell by the distribution opening, wherein, the fluidized medicine that leaves the distribution opening is not sheared and diluted by the auxiliary air flow from the shell. In one embodiment, the flow of air in the inner space rotates in a circular manner to promote powder medicine in container or shell, and in the inner space of the container, the powder particles or powder cakes of the recirculation tape are recirculated to promote air flow tumbling before particles leave the distribution opening of the container or the inhaler inlet or the air outlet or the distribution opening, and wherein, the recirculated air flow can cause tumbling, or the non-vortex flow of air in the inner space is used for medicine disintegration. In one embodiment, the axis of rotation is almost perpendicular to the center of gravity. In another embodiment, the axis of rotation is roughly parallel to the center of gravity. Not that the auxiliary air flow from the shell is further used for medicine disintegration. In this embodiment, a pressure difference is formed by the user's breathing.

A cartridge for a dry powder inhaler comprises a housing configured to hold a medicament; at least one inlet for permitting airflow into the housing and at least one dispensing port for permitting airflow out of the housing; the at least one inlet configured to direct at least a portion of an airflow entering the at least one inlet to the at least one dispensing port within the housing in response to a pressure differential.

A unit dose cartridge for an inhaler comprises: a cartridge top of generally flat, arrow-shaped configuration having one or more inlet openings, one or more dispensing apertures, and two downwardly extending side panels, each side panel having a track; and a container movably engaged to the tracks of the side panels of the cartridge top, and comprising an inner surface configured to have a relatively cup-like shape and having two relatively flat and parallel sides and a relatively circular bottom, and defining an interior space; the container being configurable to reach a receiving position and a metered position at the cartridge top; wherein, during use of the dry powder inhaler, during inhalation, an airflow into the interior space diverges as it enters the interior space, with a portion of the airflow flowing out of the one or more dispensing apertures and a portion of the airflow rotating within the interior space and lifting powder in the interior space before exiting the dispensing apertures.

In one embodiment, an inhalation system for pulmonary drug delivery is provided, comprising a dry powder inhaler having a housing and a nozzle with an inlet and an outlet, an air duct between the inlet and the outlet, and an opening structured to receive a cartridge; a cartridge mounting mechanism such as a slide; a cartridge configured to fit within the dry powder inhaler and containing a dry powder medicament for inhalation; wherein the cartridge comprises a container and a cap having one or more inlets or one or more dispensing ports; and the dry powder inhalation system having, during use, a predetermined balanced distribution of airflow through the cartridge relative to the total flow delivered to the patient.

In the embodiment disclosed herein, the dry powder inhalation system comprises a predetermined mass flow balance in the inhaler.For example, leave the inhaler and enter approximately 10% to 70% flow balance of the patient's total flow rate and be carried or through tube by the distribution openings, and approximately 30% to 90% produce from other pipelines of the inhaler.In addition, the bypass flow or the flow energy that does not enter and leave the tube and the distribution openings that leave the tube in the inhaler are recombined to dilute, accelerate and finally disintegrate fluidized powder before leaving the mouth of pipe.

In the embodiments described herein, the dry powder inhaler is provided with a relatively rigid air duct or tubing system and a high flow resistance level to maximize the disintegration of the powdered medicament and promote delivery. Thus, because the inhaler is provided with air duct geometry that remains the same and cannot be changed, the effectiveness and consistency of the powdered medicament discharge are obtained from the inhaler after repeated use. In certain embodiments, the dry powdered medicament is uniformly dispensed from the inhaler in less than about 3 seconds or typically less than 1 second. In certain embodiments, the inhaler system can have a high resistance value of, for example, about 0.065 to about 0.200 (kPa)/liter per minute. Thus, in the system, the peak inhalation pressure drop between 2 and 20 kPa produces a synthetic peak flow rate of about 7 and 70 liters per minute. These outflows cause more than 75% of the contents of the dispensed cartridge with a fill mass of 1 and 30 mg. In certain embodiments, these performance characteristics are realized by the cartridge dispense percentage producing more than 90% in a single inhalation operation by the final use. In certain embodiments, the inhaler and cartridge system are configured to provide a single dose by discharging honey from the inhaler as a continuous stream or as one or more pulses of powder delivered to the patient.

In one embodiment, a method for effectively disintegrating a dry powder formulation in a dry powder inhaler during inhalation is provided. The method can include the following steps: providing a dry powder inhaler comprising a container having an air inlet, a dispensing port communicating with a nozzle air duct, and containing and delivering the formulation to a subject upon request; generating airflow in the inhaler through the subject's breathing such that about 10 to about 70% of the airflow entering the inhaler enters and exits the container; allowing the airflow to enter the container inlet, circulate and tumble the formulation in an axis perpendicular to the dispensing port to fluidize the formulation, thereby producing a fluidized formulation; accelerating the metered fluidized formulation through the dispensing port and in the air duct, and decelerating the airflow containing the fluidized formulation in the nozzle air duct of the inhaler before reaching the subject.

In another embodiment, a method for disintegrating and dispensing a dry powder formulation for inhalation is provided, comprising the steps of: generating an airflow within a dry powder inhaler comprising a mouthpiece and a container having at least one inlet and at least one dispensing port, the container containing the dry powder formulation; forming an air passage within the container between the at least one inlet and the at least one dispensing port, wherein the inlet directs a portion of the airflow entering the container to the at least one dispensing port; allowing the airflow to tumble the powder within the container on an axis generally perpendicular to the at least one dispensing port to lift and mix the dry powder medicament in the container to form an airflow medicament mixture; and accelerating the airflow exiting the container through the at least one dispensing port. In one embodiment, the inhaler mouthpiece is configured with a gradually expanding cross-section to decelerate the flow, minimize powder deposition within the inhaler, and promote maximum powder delivery to the patient. In one embodiment, for example, the cross-sectional area of the oral cavity placement region of the inhaler ranges from about 0.05 ^cm² to about 0.25 ^cm² over an approximate length of about 3 cm. These dimensions depend on the type of powder used in the inhaler and the size of the inhaler itself.

A cartridge for a dry powder inhaler comprises a cartridge top and a container defining an interior space, wherein the cartridge top has a lower surface extending above the container; the lower surface is configured to fit the container and includes an area containing the interior space and an area exposing the interior space to ambient air.

In an alternative embodiment, a method for delivering particles through a dry powder device is provided, wherein a cartridge for containing and dispensing particles is inserted into the delivery device, the cartridge comprising a shell for containing the particles, a dispensing opening, and an air inlet opening; wherein the shell, the dispensing opening, and the air inlet opening are positioned such that when air enters the air inlet opening, the particles are disintegrated by at least one mode of disintegration as described above to separate the particles, and the particles are dispensed through the dispensing opening with a portion of the air; simultaneously, air is forced through a delivery conduit connected to the dispensing opening, thereby forcing the air into the air inlet opening, disintegrating the particles, and dispensing the particles through the dispensing opening along with a portion of the air; and the particles are delivered through the delivery conduit of the device, such as in an inhaler nozzle. In the embodiments described herein, to effect powder disintegration, the dry powder inhaler is constructed and provided with one or more powder disintegration regions, wherein the disintegration regions are capable of promoting tumbling of the powder by airflow entering the inhaler, decelerating the airflow containing the powder, decelerating the airflow containing the powder, shearing the powder particles, and causing air trapped in the powder particles to expand, and/or combinations thereof.

In another embodiment, the inhalation system comprises a breath-powered dry powder inhaler, a cartridge containing a drug, wherein the drug, for example, comprises a pharmaceutical formulation for pulmonary delivery, such as a composition of a diketopiperazine and an active agent. In certain embodiments, the active agent comprises peptides and proteins, such as insulin, glucagon-like peptide, oxyntomodulin, peptide YY, insulin secretagogue peptide, its analogs, etc. The inhalation system of the present invention can be used, for example, in methods for treating symptoms requiring localized or systemic delivery of a drug, for example, in methods for treating diabetes, pre-diabetic obesity symptoms, respiratory infections, lung diseases, and obesity. In one embodiment, the inhalation system comprises a kit comprising at least one of each component of the inhalation system for treating a disease or disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a perspective view of an embodiment of a dry powder inhaler in a closed position.

2 depicts a perspective view of the dry powder inhaler of FIG. 1 , showing the dry powder inhaler in a partially open position.

3 depicts a perspective view of the dry powder inhaler of FIG. 1 , showing the dry powder inhaler in a fully open loading/unloading cartridge position, and depicting the interior chamber of the inhaler.

Fig. 4 A has been described the stereoscopic view of the Diskus of Fig. 1, and shows the Diskus that is in the position of opening the loading/unloading tube fully, and has described the inner surface that comprises the inner surface of the inhaler mouth of pipe. Fig. 4 B has been described the stereoscopic view of the Diskus of Fig. 4 A, and shows the inhaler that is in the position of opening the loading/unloading tube fully and the tube that is configured to be placed in the inhaler. Fig. 4 C is the inhaler shown in Fig. 4 A and Fig. 4 B and has shown the tube that is loaded onto the tube support.

5 depicts the dry powder inhaler of FIG. 1 with the cartridge in a fully open position shown in a middle longitudinal section and containing the cartridge in a cradle with the cartridge container in a contained position.

6 depicts the dry powder inhaler of FIG. 1 with the cartridge in a partially open position shown in a central longitudinal section and containing the cartridge in a holder in a contained position.

7 depicts the dry powder inhaler of FIG. 1 with the cartridge in a closed position shown in a central longitudinal section and containing the cartridge in a holder, wherein the cartridge is in a dosing position.

8 depicts a top view of the dry powder inhaler of FIG. 1 in a fully open configuration and showing the internal chamber components of the inhaler.

FIG. 9 depicts a perspective view of an alternative embodiment of a dry powder inhaler in a closed or inhalation position.

10 depicts the dry powder inhaler of FIG. 9 in an open position and shows the cartridge mounted in the cartridge holder, wherein the cartridge is in a contained position.

11A and 11B depict the dry powder inhaler embodiment of FIG. 9 in open ( FIG. 11A ) and closed ( FIG. 11B ) positions shown in intermediate longitudinal cross-section, with the cartridge in the cartridge holder in the receiving and dosing positions, respectively.

FIG. 12 depicts a perspective view of an alternative embodiment of a dry powder inhaler in a closed position.

13 depicts a perspective view of the dry powder inhaler embodiment of FIG. 12 in an open position and illustrating the interior chamber of the inhaler.

14 depicts the embodiment of FIG. 12 in an open loading/unloading position with the cartridge mounted in the cradle in a contained position.

Figure 15 A has described the embodiment of Figure 12, and shows the cross section of the process longitudinal axis of the Diskus in the closed position.Can see the gear mechanism that is used to open and close tube and open and close inhaler.Figure 15 B has described the embodiment of Figure 12, and shows the cross section of the process middle longitudinal axis of the Diskus in the closed position.

Figure 15 C has described the optional embodiment of the inhaler of Figure 12, and has shown the positive isometric drawing that is in the closed position.Figure 15 D, 15E, 15F and 15G and 15H have described the side view, top view, upward view, close-up view and the remote view of the inhaler of Figure 15 C respectively.Figure 15 I has described the stereoscopic view of the inhaler among the Figure 15 C that opens in the structure and has shown corresponding tube and mouth of pipe lid.Figure 15J has described the positive isometric drawing that is in the inhaler of Figure 15 I that opens in the structure and tube is installed in the support.Figure 15K has described the inhaler through the middle longitudinal axis of Figure 15 C, and wherein tube is installed in the tube support and is in the quantitative structure and in the closed structure.

16 illustrates a perspective view of an alternative embodiment of a dry powder inhaler in a closed position.

FIG. 17 illustrates the embodiment of FIG. 16 in an open loading/unloading position with a cartridge mounted in a cartridge holder.

FIG. 18 illustrates the embodiment of FIG. 16 in a closed inhalation position with the cartridge mounted in the cartridge holder and in a dosing configuration.

19 illustrates a perspective view of an alternative embodiment of a single-use dry powder inhaler, showing the container in a contained configuration.

20 illustrates a perspective view of the inhaler shown in FIG. 19 , wherein the inhaler is in a dosing configuration allowing air to flow through the interior of the powder containing cup.

FIG. 21 illustrates a perspective view of a mid-longitudinal section of the inhaler shown in FIG. 19 , wherein the inhaler is in a contained configuration.

FIG. 22 illustrates a perspective view of a mid-longitudinal section of the inhaler shown in FIG. 20 , wherein the inhaler is in a metered dose configuration.

23 depicts a bottom view of the embodiment of FIG. 19 and illustrates the underside of the dry powder inhaler components.

24 illustrates a perspective view of another embodiment of a single-use dry powder inhaler and shows a contained configuration.

25 illustrates a perspective view of the inhaler of FIG. 23 showing a dosing configuration that allows air to flow through the interior of the medicament container.

FIG. 26 illustrates a perspective view of a mid-longitudinal section of the inhaler shown in FIG. 24 , wherein the medicament container is shown in a contained or closed position.

FIG. 27 illustrates a perspective view of a mid-longitudinal section of the inhaler shown in FIG. 24 , wherein the medicament container is shown in a dosing position.

28 is a perspective view and a bottom view of the inhaler of FIG. 24 showing a lower surface component of the inhaler.

29 illustrates a perspective view of another embodiment of a dry powder inhaler showing a contained configuration.

30A and 30B illustrate perspective views of the inhaler of FIG. 29 in an open position and showing the cartridge installed in a contained or closed position.

FIG. 31 shows a perspective view of a middle longitudinal section of the inhaler shown in FIG. 30 in an open configuration, wherein the medicament container is shown in a contained position.

FIG. 32 illustrates a perspective view of a mid-longitudinal section of the inhaler shown in FIG. 31 , wherein the medicament container is shown in a contained position and the mouthpiece portion has been fastened to the housing.

Figure 33 illustrates a perspective view of the inhaler shown in Figure 29 and showing the inhaler in a metered position.

FIG. 34 illustrates a perspective view of a mid-longitudinal section of the inhaler shown in FIG. 33 , wherein the medicament container is shown in a dosing position.

35 illustrates a perspective view of an embodiment of a cartridge for use with the inhaler of FIG. 1 , which embodiment of the cartridge is also shown in FIG. 4B depicting the cartridge in a contained configuration.

36 illustrates a top view of the cartridge embodiment of FIG. 35 and shows the component structures of the cartridge top surface.

37 illustrates a bottom view of the cartridge embodiment of FIG. 35 and shows the component structures of the cartridge's lower surface.

Figure 38A illustrates a perspective view of a medial longitudinal cross-section and a contained configuration of the embodiment of the cartridge of Figure 35. Figure 38B illustrates a perspective view of a medial longitudinal cross-section and a dosing configuration of the embodiment of the cartridge of Figure 35.

Figure 39 A has described the three-dimensional view of the optional embodiment of the tube that is in the structure of accommodating.Figure 39B to 39F has described the top view, bottom view, close-up view, far view and the side view of the tube embodiment shown in Figure 39 A respectively.Figure 39G has described the three-dimensional view of the tube embodiment shown in Figure 39 A that is in the quantitative structure.Figure 39H and 39I are respectively the cross sections of the longitudinal axis of the tube embodiment through Figure 39 A and Figure 39G.

40 illustrates a perspective view of a cartridge embodiment for use with the inhaler of FIG. 29 , showing the cartridge in a contained configuration.

41 illustrates an exploded view of the cartridge embodiment of FIG. 40 and shows the cartridge's component parts.

42 illustrates a perspective view of a medial longitudinal cross-section of the containment configuration of the cartridge embodiment of FIG. 40 .

43 illustrates a perspective view of the cartridge embodiment of FIG. 40 in a dosing configuration.

44 illustrates a perspective view of a mid-longitudinal cross-section of the cartridge embodiment of FIG. 38 in a dosing configuration.

45 illustrates a perspective view of an alternative cartridge embodiment for a dry powder inhaler, showing the cartridge in a contained configuration.

46A illustrates a perspective view of the cartridge embodiment of FIG. 45 for use with a dry powder inhaler, and shows the cartridge in a dosing configuration.

46B illustrates a perspective view of a mid-longitudinal cross-section of the dosing configuration of the cartridge embodiment of FIG. 45 .

47A illustrates a perspective view of an alternative cartridge embodiment for a dry powder inhaler, showing the cartridge in a dosing configuration.

47B illustrates a perspective view of the cartridge embodiment of FIG. 47A for use with a dry powder inhaler, and shows the cartridge in a dosing configuration.

48 illustrates a perspective view of an alternative embodiment of a dry powder inhaler showing an open configuration.

49 illustrates an exploded view of the inhaler embodiment of FIG. 48 and shows the inhaler components.

50 illustrates a perspective view of the inhaler of FIG. 48 in an open configuration and showing the type and orientation of the cartridge to be installed in the inhaler holder.

Figure 51 illustrates a perspective view of the inhaler of Figure 50 in an open configuration and showing the cartridge installed in the inhaler.

52 illustrates a mid-longitudinal section of the inhaler depicted in FIG. 51 and showing the cartridge container in a contained configuration and in contact with the slide and the gear mechanism in contact with the slide.

53 illustrates a perspective view of the inhaler of FIG. 50 in a closed configuration with the cartridge in the holder.

54 illustrates a mid-longitudinal section of the inhaler depicted in FIG. 53 and showing the cartridge container in a dosing configuration and the air flow path established through the container.

Figure 55 shows a schematic representation of the flow within the powder containment area of a dry powder inhaler indicated by the arrows.

56 is a schematic representation of an embodiment of a dry powder inhaler showing the flow paths and the direction of flow through the inhaler indicated by arrows.

57 illustrates a perspective view of a multi-dose embodiment of a dry powder inhaler.

58 illustrates an exploded view of the inhaler embodiment of FIG. 57 and shows the component parts of the inhaler.

FIG. 59 illustrates a perspective bottom view of component 958 of the inhaler depicted in FIG. 58 .

FIG. 60 illustrates a perspective top view of the assembled components of the inhaler depicted in FIG. 58 .

FIG. 61 illustrates a perspective top view of component 958 of the inhaler depicted in FIG. 58 .

FIG. 62 illustrates a perspective top view of the components of the housing assembly of the inhaler depicted in FIG. 58 .

FIG. 63 illustrates a perspective view of the cartridge-disc system of the inhaler depicted in FIG. 58 .

FIG. 64 illustrates a perspective view of a cross section of the cartridge-disc system illustrated in FIG. 63 .

FIG. 65 illustrates a perspective top view of the housing assembly of the inhaler depicted in FIG. 57 and FIG. 58 .

FIG. 66 illustrates a perspective cross-sectional view of the components of the inhaler depicted in FIG. 58 .

FIG. 67 illustrates a perspective view of a cross section of the inhaler depicted in FIG. 57 .

FIG. 68 illustrates a perspective view of an alternative embodiment of a multi-meter dry powder inhaler.

FIG. 69 illustrates a perspective bottom view of the inhaler depicted in FIG. 68 .

70 illustrates a top view of the inhaler embodiment of FIG. 68 and showing the inhaler body and mouthpiece.

FIG. 71 illustrates a front view of the inhaler depicted in FIG. 68 .

FIG. 72 illustrates a side view of the inhaler depicted in FIG. 68 .

Figure 73 shows a perspective view with the bottom cartridge tray removed and not all components shown.

Figure 74 illustrates an exploded view of the inhaler depicted in Figure 68 and showing the gear drive system.

FIG. 75 illustrates an exploded view of the cartridge-disc system of the inhaler depicted in FIG. 68 .

FIG. 76 illustrates a rear view of the cartridge-disc system of the inhaler depicted in FIG. 68 .

FIG. 77 illustrates a front view of the cartridge-disc system of the inhaler depicted in FIG. 68 .

FIG. 78 illustrates a bottom view of the cartridge-disc system of the inhaler depicted in FIG. 68 .

FIG. 79 illustrates a top view of the sealing disc of the inhaler depicted in FIG. 68 .

80 illustrates a measured graph of flow and pressure relationships based on the Bernoulli principle for an exemplary embodiment of flow resistance of an inhaler.

Figure 81 depicts particle size distribution obtained using laser diffraction equipment using an inhaler and a cartridge containing a dry powder formulation for inhalation, wherein the formulation includes insulin and fumaryldiketopiperazine particles.

DETAILED DESCRIPTION

In the embodiment disclosed herein, disclose a kind of Diskus, the tube that is used for Diskus and the suction system that is used for medicine via suction delivery to patient.In one embodiment, the suction system comprises breathing electric Diskus and the tube that comprises pharmaceutical formulation, and this tube comprises pharmaceutical active substance or active ingredient and medicine receiving carrier.Diskus is arranged into various shapes and sizes, and can be reused or be used for single use, easy to use, and cheaply manufacture, and can use plastics or other acceptable materials to be produced in large quantities in the tube single step. Except complete system, inhaler, the tube of filling and empty tube constitute other embodiments disclosed herein.This suction system can be designed to be used for any type of dry powder.In one embodiment, dry powder is relatively sticky powder, and it requires optimal disintegration condition.In one embodiment, the suction system provides reusable, miniature breathing electric inhaler, and it combines with the single use tube of the dosage that comprises pre-metered dry powder formulation.

As used herein, "unit dose inhaler" refers to an inhaler that is suitable for receiving a single container containing a dry powder formulation, and a single dose of the dry powder formulation is delivered to the user from the container by inhalation. It should be understood that in some cases, multiple unit doses are needed to provide the dose specified to the user.

As used herein, the term "multi-dose inhaler" refers to an inhaler having multiple reservoirs, each reservoir containing a pre-dose of dry powder medicament, and the inhaler delivers individual doses of medicament powder simultaneously by inhalation.

As used herein, a "container" is a housing configured to hold or contain a dry powder formulation, a housing that holds the powder, and can be configured with or without a lid.

As used herein, "powder agglomerate" refers to an agglomeration of powdered particles or an agglomerate having an irregular geometry, such as width, diameter, and length.

As used herein, the term "microparticles" refers to particles having a diameter of about 0.5 to 1000 μm, regardless of the precise external or internal structure. However, microparticles smaller than 10 μm are generally desired for pulmonary delivery, particularly microparticles having an average particle diameter of less than about 5.8 μm.

As used herein, "unit dose" refers to a pre-metered dry powder formulation for inhalation. Alternatively, a unit dose can be a single container with a multi-dose formulation that can be delivered as a metered single amount by inhalation. A unit dose cartridge/container contains a single dose. Alternatively, it can include multiple, individually accessible chambers, each chamber containing a unit dose.

As used herein, the term "about" is intended to indicate a value that includes the standard deviation of error for the device or method employed to determine the value.

This device can be manufactured by some methods.Yet, in one embodiment, for example, by injection molding technology, heat forming, use various types of material (comprising polypropylene, cyclic olefin (cyclicolephin) copolymer, nylon and other compatible polymers etc.) to make inhaler and tube.In certain embodiments, can use the up and down assembly method of each component to assemble Diskus.In certain embodiments, inhaler is arranged to compact size, such as from approximately 1 inch to approximately 5 inches size, and width and height are less than the length of device usually.In certain embodiments, inhaler is arranged to various shapes, comprises relative rectangular body, column, oval, tubular, square, rectangular and circle.

In the embodiment of describing and giving an example here, inhaler makes dry powder formulation fluidize, disintegrate or become aerosol shape effectively by using at least one relatively rigid flow duct path, and wherein this flow duct path is used for allowing the gas such as air to enter inhaler.For example, inhaler is provided with first air/gas path that is used to enter and leave the tube that comprises dry powder, and second air path that can merge with the first air flow path that leaves tube.Flow duct depends on that the structure of inhaler for example can have various shapes and sizes.

In Fig. 1 to Fig. 8, cite the embodiment of Diskus.In this embodiment, Diskus has three structures, that is, the closed structure illustrated in Fig. 1 and Fig. 7, the structure of the partially opened illustrated in Fig. 2 and the open structure illustrated in Fig. 3 to Fig. 5 and Fig. 8. The Diskus 100 of describing in Fig. 1 to Fig. 8 has relative rectangular body, and rectangular body has the near-end and the distal end that are used to contact the lip or oral cavity of user, and has end surface and bottom surface, housing 120, mouth of pipe 130 and tube, sliding plate or slide plate 117. Fig. 1 illustrates the Diskus under the closed condition, and wherein the mouth of pipe 130 comprises main body 112, and has one or more air inlet 110 (also referring to Fig. 5 and Fig. 7) and the oral cavity placement part with outlet 135. Air conduit extends to outlet 135 from air inlet 110 along the length of the mouth of pipe 130 of inhaler. The mouth of pipe 130 can be configured to have the narrow part of hourglass shape in the approximate middle of distal part so that air-flow is accelerated, is configured to wider diameter so that air-flow is slowed down towards outlet or opening 135 (common Fig. 7) at its proximal end or oral cavity placement part place then.Air conduit 140 (Fig. 4 A) has the zone that is used to be adapted to tube top 156 or the opening 155 of boss 126, and communicates (Fig. 6 and Fig. 7) with the tube 150 that installs in the inhaler under the condition of sealing.When inhaler was in closing or suction position as shown in Figure 1, body 112 surrounded the part of the housing 100 of inhaler 100. Fig. 1 still has the tube holder 115 that extends downwards from the inhaler body.In the embodiment of Fig. 1, the structural configuration of housing 120 is shaped as relatively rectangular, and has diagonal wall 123, sidewall 124 and is convenient to the rib projection 125 that stably grasps in order to open and close inhaler 100.

Fig. 2 is the Diskus embodiment described in Fig. 1, shows the inhaler that is in the local opening accommodated position, and wherein, the mouth of pipe 130 shows the part that housing 120 slightly protrudes outwards.In this position, the mouth of pipe 130 can be pivoted to the opening structure that is used for the loading tube by angular rotation, if perhaps tube is contained in the support then can be closed to quantitative structure, perhaps is used to store.In Fig. 2, the tube that is installed in the tube support 115 is in the structure that closes and holds powder.The three-dimensional view of the Diskus of Fig. 3 diagrammatic diagram 1 shows the inhaler that is in the position that opens the loading/unloading tube fully, and has described the inner chamber area of inhaler.As seen from Figure 3, the mouth of pipe 130 that is in the inhaler fully open position can relatively move approximately 90 ° to horizontal plane X-Z from vertical plane Y-Z. As the nozzle 130 is rotated from the open position to the closed position, the opening 155 ( FIG. 4A ) can engage the cartridge boss 126 ( FIG. 4B ) to allow the outlet or dispensing port 126 to be in communication and within the floor of the flow conduit 140 when the cartridge is fitted in the inhaler.

As shown in Figure 3, housing 120 comprises the bottom of inhaler main body, it comprises the tube support 115 of cup shape, inhaler is fastened to the fastening mechanism (such as, buckle) and the air inlet perforate 118 in the closed position, in the closed position of inhaler, opening 155 is in the mouth of pipe base plate and tube is not communicated with the mouth of pipe air duct 140 under the situation in the support 115.Tube is installed in the inhaler and in the situation of the closed position, when tube 150 was in the quantitative structure (referring to Fig. 7), inlet perforate 118 was communicated with tube inlet support 119.In the closed position of inhaler, slide plate 117 is configured to the air inlet perforate 118 corresponding to housing 120 at its far-end shape, makes that the position air inlet of the closing of inhaler is not hindered.In this embodiment, the motion of the mouth of pipe 130 from the position of partial opening to the closed position is finished by the sliding motion in the X-Z plane, and the motion of the mouth of pipe 130 from the partial opening to the fully opened structure is the angular rotation around the Z axis. In order to realize the complete closure of inhaler, the mouth of pipe 130 can move on horizontal axis X, and moves or slides distally with respect to housing 120. In this way, sliding plate or slide plate 117 are against the tube top 156 horizontal movement of the tube 150 that remains on tube container 115 (referring to Fig. 4), and boss 126 is placed on the tube container, makes tube container 151 be in the below of distribution openings 127 and align with the mouth of pipe opening 155.This horizontal movement also tube 150 is configured to form opening or the air inlet 119 that enters container 151.Then under the situation of air duct 140 and inlet by distribution openings 127, set up flow path.The structure of tube boss 126 is configured to opening 155 (Fig. 4 A) corresponding to and be assembled in the waist of the air duct 140 of mouth of pipe 130, makes it in the inwall of air conduit 140.

Fig. 4 A-4C has described the stereogram of the Diskus of Fig. 1, shows the inhaler that is in the fully opening loading/unloading tube position.Fig. 4 A is the elevation view of the inhaler that has shown the mouth of pipe 130, perforate 155, air inlet 110 and air outlet 135, this mouth of pipe 130 comprises the top of the body of inhaler, perforate 155 is positioned at the relative center of the mouth of pipe inner surface, and communicates with air conduit 140, and air inlet 110 and air outlet 135 communicate with the air conduit 140 of inhaler 100.Housing 120 forms the bottom of inhaler body, and comprises tube support 115 and keeps sliding plate or the slide plate 117 that moves with respect to housing 120.The hinge 160 (Fig. 4 A) that is formed by hasp and rod cooperates sliding plate or slide plate 117 with the mouth of pipe 130.Fig. 4 B illustrates the inhaler of Fig. 4 A and the tube 150 that is configured to be adapted to inhaler 100. Housing 120 comprises air opening or inlet 118, and sliding plate or slide plate 117 cooperate with the mouth of pipe 130 with opening 155 and air inlet 110.Tube 150 comprises medicine container 151 and comprises the top 156 of boss 126 with distribution 127.Tube top 156 comprises first zone 154, and first zone 154 is recessed so that its dike contact container 151 top boundaries, and seals the container 151 that is in the accommodated position.In the present embodiment, first zone 154 is recessed for easy manufacturing, and first zone 154 can have optional design, as long as it forms the acceptable sealing that is used to hold dry powder. Fig. 4 B shows the tube 150 that is in the accommodated position, and this accommodated position is that tube is closed and does not allow to set up the position of the flow path through its inner chamber.As seen in Fig. 4 C, tube 150 is installed in the inhaler 100, and inhaler is in the open structure.

FIG5 also depicts the dry powder inhaler of FIG4C in a fully open position, showing a mid-longitudinal cross-section and the receiving cartridge 150 in the holder, wherein the cartridge container 151 is in the received position and assembled with the cartridge holder 115. The cartridge top 156 and the recessed area 154 are clearly depicted as forming a tight seal with the container 151. It can be seen that the area of the cartridge top 156 below the boss is concave in shape and is raised compared to the area 154.

Fig. 6 has described the Diskus inhaler of Fig. 4 A in the partial open position, is in middle longitudinal section and comprises tube 150, and tube container 151 is installed in tube holder 115.In this embodiment, tube container 151 is in accommodating position; Boss 126 is assembled in the perforation 155 of air duct 140 concealedly, and wherein air duct 140 allows distribution opening 127 to be communicated with air duct 140 fluids.As seen from Fig. 6, slide plate or sliding plate 117 are against tube top 156, and the mouth of pipe and sliding plate 117 can move as unit, so that the tube top can move to the position of distribution above container 151 when device is closed.In closing or distribution position, housing 120 and the mouth of pipe are matched securely by the illustrated fastening mechanism of buckle (Fig. 3).In this embodiment, by releasing buckle and above housing 120, move the mouth of pipe 130 in opposite directions to reach the structure of partial opening, housing 120 can break away from the mouth of pipe, and wherein the partial opening structure makes tube 150 be reconfigured into and hold structure from quantitative position.

When inhaler unit is reconfigured to closed position as shown in Figure 7, tube 150 can be movably configured to quantitative position from accommodating position.In quantitative position, tube container 151 is aligned with boss 126, and forms air inlet 119 by tube container 151 and tube top 156, tube top 156 communicates with dispensing opening 127, sets up the air duct by tube 150.

Fig. 7 has also been described in the closed position and is ready to suck and in the middle longitudinal section of the Diskus of Fig. 1 that comprises tube 150 in support 115, and wherein tube container 151 is in the quantitative position.As seen in Fig. 7, the structural configuration of tube boss 126 is to be assembled in the inhaler perforation 155, makes to enter the air flow path that enters air duct at 100 by distributing or outlet 127 leaving the air flow of tube.Fig. 7 also illustrates the tube air inlet 119 that forms by tube top 156 and the tube container 151 that is in quantitative structure, and wherein air inlet 119 is near distribution openings 127.In one embodiment, the boss 126 with distribution openings 127 is positioned at the narrowest part of the air duct 140 of the mouth of pipe 130.

Fig. 8 has been described the top view of the Diskus that is in Fig. 1 of opening structure fully, and has shown the inner chamber parts of inhaler.As seen from Figure 8, the mouth of pipe 130 is movably installed or is pivoted to housing 120 via sliding plate or slide plate 117 by hinge assembly 160, and wherein sliding plate or slide plate 117 can be cooperatively connected to the mouth of pipe 130 and be connected to the inside of housing 120 by hinge 160,161.Slide plate 117 is movable in the horizontal plane of housing 120, and is prevented from further moving on the direction of the mouth of pipe by the flange 134 that outwards protrudes, and is stopped by the recess 137 of housing 134.Tube container support 115 is integrally formed in the dike of housing 120, and dike has the perforate 118 that allows ambient air to enter inhaler to the tube supply air flow that is in the quantitative position.Slide plate 117 remains in the housing by for example extending to the projection or the flange 133 in its inner space from the sidewall of housing.

In another embodiment, Diskus is provided with relative columnar shape. Fig. 9 to Figure 11B illustrates this embodiment, and wherein inhaler comprises housing 220 and slide plate or the sliding plate 217 that are installed to the mouth of pipe 230 as a whole.In Fig. 9 and Figure 10, slide plate 217 is described as and comprises shell 257, and shell 257 is with telescopic arrangement, and concentric positioning, and local covering housing 220. Slide plate 217 also comprises the gripping mechanism such as rib 255 on the outer surface of shell 257, is used for firmly gripping the inhaler slide plate when slide plate slides on housing 220 to open and close device.Slide plate 217 also comprises groove 221 at the end of its inner surface facing the mouth of pipe, for the buckle ring 224 parts that can be installed with the mouth of pipe 230 cooperatively, so that inhaler is fastened in the closed structure.

As seen from Figure 11 A, slide plate 217 also comprises the tube holder 215 that is configured to receive tube 250.Tube holder 215 is integrally constructed with shell 257, makes when closing inhaler, shell 257 moves tube holder.Figure 11 A also illustrates tube 250 and is positioned in the inhaler, and wherein tube can be seen to have top 256, boss 226, distribution openings 227 and the container 251 that is in the accommodated position.In this embodiment, the motion of slide plate 217 has been finished tube container 251 and distribution openings 227 and is translated to the quantitative position in alignment, the structure of visible inlet 219 in Figure 11 B.

In this embodiment, housing 220 is a tubular shape, and its structure is configured to have inlet 210, and inlet 210 has one or more air ducts, for example such as the air ducts of air duct 245,246. Surface protrusion or rib 225 from the outer surface protrusion of slide plate housing 257 allow to easily grasp in use inhaler device 200. In Fig. 9, as seen, inhaler comprises mouth of pipe part 230 and housing 220, air inlet 210 and air outlet 235. As shown in Figure 10, inhaler 200 can be constructed to the open position, and wherein the user can load and/or unload tube. By grasping rib 222 and 225, slide plate housing 257 can move away from the mouth of pipe 230, and then can be near the tube support. Figure 10 shows the inhaler 200 that is in opening the load/unload tube position, and describes the slide plate 217 that is fully contracted to allow to enter the inner chamber to load or unload tube from the mouth of pipe 230. FIG10 also illustrates a cartridge 250 mounted in the cartridge holder 215 of a slide 217 and a mechanism, such as a housing 257, for actuating and opening the cartridge to the airflow path, placing the device in a closed or inhalation position, when the slide housing 257 engages the snap ring 224 of the nozzle. Closing of the device is accomplished by translation of the slide 217 on the housing 220 and engagement of the slide 217 with the nozzle 230 along the horizontal axis X. As can be seen in FIG11 , the closing action of the slide 217 moves the cartridge 250 until the cartridge top 256 abuts the nozzle recessed surface 223. Continued movement of the slide 217 to the closed position thereafter moves the container 251 portion of the cartridge 250 from the receiving position to the opposite side of the cartridge cover 256, aligning the dispensing opening 227 relative to the container or cup 251. An air inlet passage is then formed between the container 251 and the cartridge top 256, with the air inlet of the cartridge top 256 communicating with the outlet or dispensing opening 227 of the container 251 and the boss 226.

Figure 11A is the stereoscopic view of the middle longitudinal section of the embodiment of Figure 10 that is in the open structure. Figure 11B is the stereoscopic view of the middle longitudinal section of the embodiment of Figure 10 that is in the closed quantitative structure.As seen in Figure 11A and Figure 11B, inhaler comprises the mouth of pipe 230 with frustum cone shape, is reduced to the air duct 240 that cooperates with the tube boss 226 on the tube top 256 of the tube 250 that is in the closed position.The mouth of pipe 230 also comprises air outlet 235.Figure 10 and Figure 11 also show that housing 220 can be installed to the mouth of pipe 230 in one piece, and comprise the buckle ring part 224 that is used to cooperate the slide plate 217 that is in the closed position.Figure 11B shows the inhaler 200 that is in the quantitative structure and has the airway 240 that is communicated with tube 250 by distribution openings 227 and tube inlet 219. In the closed configuration, the inhaler housing 220 protrudes beyond the slide plate 217 and the cartridge container is remotely positioned into a dosing position below the boss 126 .

In an optional embodiment, a kind of dry powder inhaler 300 is provided, and it comprises mouth of pipe, slide plate or sliding plate mechanism and housing.In the illustrated embodiment of Figure 12 to Figure 15, the shape of inhaler is relatively rectangular, and mouth of pipe 330 comprises the top of inhaler body 305; Oral cavity placement portion 312; Air inlet 310; The air conduit 340 that extends from air inlet 310 to air outlet 335. Figure 12 illustrates the inhaler in the closed position, and shows the various features of the outside of inhaler 300, and this inhaler 300 comprises the air channel 311 that can guide air into inlet 375.The zone 325 that is used to keep inhaler is constructed in inhaler body 305 with easy use, and also serves as pushing or squeezing to discharge the surface of door latch 380.

Figure 13 illustrates the three-dimensional view of the embodiment of Figure 12 that is in the open structure or in the loading and unloading tube position.As shown in Figure 13, the mouth of pipe 330 can be installed to housing 320 cooperatively by the hinge that is installed to gear mechanism 360,363.The mouth of pipe 330 has the perforate 355 that is communicated with air duct 340 fluids; Air outlet 335 and flange 358 limit the rectangular structure that surrounds perforate 355.Figure 13 has also been described that housing 230 comprises tube support 315; The part of slide plate 317, it illustrates by the tube container placement area; Be used to keep the projection 353 of tube top 356 in the position that is suitable for and the hasp 380 of the body portion that is used to close the inhaler mouth of pipe.

Figure 14 illustrates the stereoscopic view of the embodiment of Figure 13 in the open structure, and wherein, tube can be loaded or unloaded to tube support.Figure 14 illustrates inhaler and comprises mouth of pipe 330, and mouth of pipe 330 comprises the top of the body 305 of inhaler and has the perforate 355 that is positioned at the relative center of body and is surrounded by flange 368; Mouth of pipe oral cavity placement portion 312 is configured to extend from inhaler body and has the air outlet that is used for placing the oral cavity of patient when quantitative.Inhaler also comprises housing 320, and housing 320 can be mounted to mouth of pipe 330 cooperatively by gear mechanism.In the present embodiment, gear mechanism is for example rack and pinion 363 (also referring to Figure 15 A), and it allows the mouth of pipe to move with respect to housing angle.When inhaler was in the closed position, rack mechanism 363 was coupled to slide plate 317 to carry out the motion of the container 351 of tube 350 to slidably move below the tube top and below tube boss 326. Figure 14 also illustrates the position of the tube 350 that is installed in the support 115, and shows interior chamber parts, comprises the boss 326 with dispensing opening 327; Gear mechanism 360,363 and auxiliary device are remained on the buckle 380 in the closed structure.As seen in Figure 13, mouth of pipe 330 forms the inhaler body top, and comprises the oral cavity placement part 312 with air duct 340, air inlet 310 and air outlet 335.

Figures 15A and 15B have described the embodiment of Figure 12, and show the cross section through the longitudinal axis of the dry powder inhaler in the closed/inhalation position, wherein the tube 350 in the metered position is in the tube holder 315 of the housing 320. Figure 15A illustrates a gear mechanism 362, 362, which is cooperatively connected to the slide plate for opening and closing the inhaler and simultaneously moves the tube holder to the metered or dispensing position when the device is closed.

Figure 15 B has described the embodiment of Figure 12, and shows the cross section through the middle longitudinal axis of the Diskus in the closing/inhalation position.Can see that tube 350 is in the quantitative position, and wherein, boss 326 assembles or cooperates with the perforate 355 of air duct 340, to allow to flow out tube 350 from distribution opening 327, and enter the flow path in the pipeline 340.Figure 14 also shows the tube top 359 that is firmly remained in the position that is suitable for by the projection in the tube placement area.Figure 15 A and Figure 15 B show the tube container 351 that is configured to be in the quantitative position and has the close distribution opening 327 and is communicated with distribution opening 327.Slide plate 317 is against the tube container to be remained on the position that is suitable for and sucks.In this embodiment, the air inlet 375 that leads to tube inlet 319 is configured to below air duct 340 and extends parallel to air duct 340.The motion of tube is carried out by opening and closing the mouth of pipe 330 with respect to housing in this embodiment, and wherein, gear mechanism opens and closes tube by the translational motion of slide plate 317. As shown in Figure 15 B, in use, air-flow enters inhaler by air inlet 310, and enters air inlet 375 simultaneously, and enters in the tube 350 by air inlet 319.In an illustrative embodiment, the internal volume extending to outlet 335 from inlet 310 is greater than approximately 0.2cm ^3.In other illustrative embodiments, the approximately 0.3cm ³ of internal volume or approximately 0.3cm ³ or 0.4cm ³ or 0.5cm ^3.In another illustrative embodiment, this is greater than 0.2cm ³ internal volume be the internal volume of the mouth of pipe.The powder fluidization that is contained in the tube container 351 or forms the air flow that enters tube by the tumbling of powder.The fluidized powder flows out into the mouth of pipe air duct 340 gradually by distribution openings 327 then, and further disintegrates and before flowing out outlet 335, dilutes with the air flow that enters at air inlet 3410 places.

Figure 15 C-Figure 15K has described the optional embodiment 302 of the inhaler 300 that in Figure 12-15B, describes.Inhaler comprises housing 320, mouth of pipe 330, gear mechanism and slide plate, and uses the mode of for example four parts assembling up and down to manufacture.The mouth of pipe 330 also comprises and is configured to extend along the longitudinal axis of inhaler and has oral cavity placement part 312, air inlet 310 and is configured to have the air outlet 335 on the surface that angles or tilts with respect to the longitudinal axis of air line and with housing 320 and/or be installed in the tube fluid in the housing 320 to allow in use, air-flow from housing or from the tube that is installed in the inhaler to enter the barrel mouth opening 355 of air line 340. Figure 15 C illustrates the isometric view of the inhaler 302 in the closed position, and it has the thinner body 305 of the inhaler 300 that forms than the cover part 308 by housing 320 and the mouth of pipe 330, and wherein the cover part 308 extends on housing 320 and cooperates with housing 320 by the locking mechanism 312 of for example projection.Figure 15 D, 15E, 15F, 15G and 15H have described the side view, top view, side view, close-up view and the far view of the inhaler of Figure 15 C respectively.As seen in these figures, inhaler 302 comprises the mouth of pipe 330 with oral cavity placement part 312, is constructed as the extension that is installed to the lid 308 of housing 320 at least one position shown in Figure 15 J.The mouth of pipe 330 can be pivoted to and opened from the proximal position shown in Figure 15 J via hinge mechanism 313 by the user's hand on the angled direction. 317 can be configured with the mouth of pipe that cooperates with housing 320 as a part of hinge mechanism, and wherein housing 320 is also configured to cooperate with slide plate 317.In this embodiment, slide plate 317 is configured with the rack that cooperates with the gear that is configured on hinge mechanism.Hinge mechanism 363 allows the mouth of pipe 330 to move to the opening of inhaler 302 or the structure of loading tube and the structure or the position of closing along the direction that angles.When inhaler opens and closes by the part that is integrally configured to gear mechanism 363, the gear mechanism 363 in inhaler 300,302 can actuate slide plate to allow slide plate 317 to move simultaneously in housing 330.Under the situation that uses tube, the gear mechanism 363 of inhaler can be configured tube again by the motion of slide plate 317 in the process that inhaler closes, is installed in the tube after on the inhaler housing from tube and holds the quantitative structure that is configured to when inhaler closes, perhaps to the quantitative structure that can use arbitrarily after finishing at the dry powder formulation. In the embodiment illustrated here, the hinge and gear mechanism is provided at the proximal end of the inhaler, however, other configurations can be provided, such that the inhaler opens and closes to load or unload the cartridge as a clam.

In one embodiment, housing 320 comprises one or more parts, for example, top 316 and bottom 318.Top and bottom are configured to adapt each other with tight seal, form the shell that holds slide plate 317 and hinge and/or gear mechanism 363.Housing 320 is also configured to have one or more openings 309 to allow air-flow to enter the inside of housing, and also has the locking mechanism such as projection or snap ring, and it cooperates and fastens the mouth of pipe cover part 308 in the position of closing of inhaler 302.Housing 320 is also configured to have tube support or tube mounting area 315, and it is configured to the type corresponding to the tube that is used for inhaler.In this embodiment, tube placement area or support are the opening in the top of housing 320, and in case tube is installed in the inhaler 302, this opening also allows tube bottom or container to be on slide plate 317.Housing also comprises gripping area 304,307, and its user that is configured to auxiliary inhaler firmly or reliably holds inhaler to open inhaler and loads or unloads tube. The housing 320 can also include flanges configured to define air passages or ducts, such as two parallel flanges configured to direct airflow into the inhaler air inlet 310 and into the cartridge air inlet of the cartridge air duct in the inhaler. The flanges 310 are also configured to prevent a user from obstructing the inlet 310 of the inhaler 302.

Figure 15 I has described the isometric view of the inhaler of Figure 15 C that opens in the structure, and it has the mouth of pipe that covers for example cap 342 and tube 170, and wherein tube 170 is configured to and allows tube to be installed in the tube support 315 for use corresponding to the tube mounting area.In one embodiment, in case tube is installed in the tube support 315, can carry out the reconstruction of the accommodating position that tube provides after manufacturing, wherein, tube support 315 is configured in the housing 320 and is adapted to inhaler, makes tube have the orientation that is fit to in inhaler, and can only insert or install with only a mode or orientation.For example, tube 170 can be configured with locking mechanism 301, its matching is configured in the locking mechanism in the inhaler housing (for example, inhaler mounting area), and perhaps support can comprise oblique edge 301, and it corresponds to the oblique edge 180 of the tube 170 that will be installed in the inhaler.In this embodiment, oblique edge formation prevents the locking mechanism that tube ejects from support 315 in the motion process of slide plate 317. In a specific embodiment illustrated among Figure 15 J and 15K, tube cover is configured with bevel edge, makes it remain in the housing securely when in use.Figure 15 J 15K also shows rack mechanism 319, it is configured with slide plate 317 so that when inhaler 302 is prepared for user quantitatively, in the closed position of inhaler or the structure, the tube container 175 of the tube 170 below the tube top is carried out slidably to align the container below the tube top lower surface, and said tube top lower surface is configured to have at distribution openings.In quantitative structure, form air inlet by the boundary of tube top and the edge of container, this is because the lower surface of tube top is projected with respect to container lower surface.In this structure, air duct is defined as by tube by air inlet, the opening in the internal volume of the tube that is exposed to ambient air and the tube top or the distribution openings in the tube top, and this air duct is communicated with the air duct 340 fluids of the mouth of pipe.

Inhaler 302 also comprises mouthpiece cap 342 that protects the oral placement portion of mouthpiece.Figure 15K describes the cross section through the middle longitudinal axis of the inhaler of Figure 15C, wherein cartridge is mounted in cartridge holder and is in open configuration, and in closed configuration.

15J illustrates the position of the cartridge 350 mounted in the bracket or mounting area 315 and shows the internal chamber components including the boss 326 with the dispensing opening 327; the gear mechanism 360, 363 and the buckle 380 that assists in retaining the device in the closed configuration.

In another embodiment, as shown in Figure 16-18, Diskus 400 has a relatively round body and comprises mouth of pipe 430; Tube support portion 415 and housing 420. Figure 16 illustrates the three-dimensional view of the optional embodiment of the Diskus in the closed position, wherein, mouth of pipe 430 comprises the top of the body of inhaler, and housing 420 comprises the bottom of the inhaler in the quantitative position. Mouth of pipe 430 also comprises the oral cavity placement part with air outlet 435.

Figure 17 illustrates the embodiment of Figure 16 in opening, the loading/unloading structure, and shows the tube 450 that is in the tube holder 415, and also shows the top 456 of tube 450.In this embodiment, the mechanism that is used to actuate tube 450 to move to open structure from the accommodating position is for example a cam.The handle or the lever 480 that comprise tube 450 move to the closed position by the rotation of lever 480.In the closed position, the tube 450 in the lever 480 moves below the oral cavity placement part 412 of the mouth of pipe 430.

Figure 18 illustrates the middle longitudinal section of the embodiment described in Figure 16 in the closed suction position, and wherein tube 450 is installed in the tube holder 415 in the open structure.As seen from Figure 18, in the quantitative structure of tube, air inlet 459 is formed or limited by the gap between tube top 456 and the container 451, and wherein container 451 is communicated with the distribution opening 427 on the boss 426.Distribution opening 427 is communicated with air duct 440 fluids, thus during the suction operation, the air-flow that enters air duct 440 from tube 450 flows out tube and combines with the air-flow in the air duct in the inlet 410, and sweeps and flows on the direction of air outlet 435.

Figure 19 to Figure 28 illustrates two optional embodiments of Diskus.In these embodiments, the structure of Diskus is configured to the unit dose inhaler for single use, and is assembled together with the tube to form a disposable unit that can not be reused.Make the inhaler among the present embodiment to comprise the unit dose pharmaceutical formulation of expectation in advance metering in the tube container that forms.In this embodiment, container can also move to quantitatively or distribute structure from the accommodating position.

Figure 19-Figure 23 illustrates the three-dimensional view of the embodiment of the Diskus for single use.Figure 19 shows the inhaler that is in the structure of holding.In this embodiment, inhaler 500 comprises top surface 563 and bottom surface or lower surface 562; Mouth of pipe 530 and mounting tube assembly or slide plate 590.Mouth of pipe 530 has elongated shape, and is configured with air inlet 510 and air outlet 535.Air duct extends to the air outlet 535 that is formed and is used for the secondary path that air-flow enters inhaler 500 in the suction process from air inlet 510.

Figure 20 illustrates the three-dimensional view of the inhaler embodiment shown in Figure 19, and wherein, inhaler is in the quantitative structure of setting up the flow path through the inside of tube and distribution openings, and wherein inhaler is prepared for use.Figure 20 has described the mouth of pipe 530 and has the cross-sectional area that widens gradually from air inlet 510 to air outlet 535 air ducts 540, and air duct 540 narrows at inlet end 510.The structure of the mouth of pipe 530 is also configured to have the side or the panel 532 that extends from the wall of the mouth of pipe pipeline 540 of supporting slide plate 590.At intervals are set between the mouth of pipe air duct wall 540 and the panel, and it allows slide plate 590 to slide on the mouth of pipe 530.Slide plate 590 has first bridge 567 that strides across the mouth of pipe 530 on the top side, and has wing or flange 656, which allows to grip slide plate 590 with hand so that device is constructed to quantitative position from the accommodating position, or on the contrary.

Figure 21 illustrates the three-dimensional view of the middle longitudinal section of the inhaler shown in Figure 19 in the accommodated position.In Figure 21, cartridge container 551 is adapted to the mouth of pipe 530 in one piece, makes it and the surface flush of the mouth of pipe 530 and seals with it.Container 551 has wing-shaped structure, it can hang on the pipe and can move on the pipe, and wherein pipe is constructed on the bottom surface of the mouth of pipe panel or side (extension) 532.The structure of the mouth of pipe panel 532 is configured to make the movement of container 551 be included in the panel 532. Figure 23 has described lower surface 562, and shows the slide plate 590 that is configured to have the second bridge 568 at the bottom side of inhaler 500, and the bottom side of inhaler 500 can be configured to contact with container 551 to translate to distribution or quantitative position from the accommodated position.When slide plate 590 moved towards inlet 510, it carried container 551 to the open position in translation, and aligned with the distribution opening 527 that is positioned at the mouth of pipe pipeline 540. 527 is provided with the aid of the air duct 526 of the invention.In quantitative structure, inlet is limited by container edge and mouth of pipe lower surface to allow inner space to be exposed to ambient air.Quantitative structure also limits the air duct between inlet, the inner space of container and the distribution opening to allow air flow through container and to carry the powder dose that is included therein.By slide plate is moved to the quantitative position from the accommodating position, can not further move in panel 532 and realize the complete alignment of container 551 and distribution opening 527. Figure 22 illustrates the three-dimensional view of the longitudinal section of the inhaler shown in Figure 20, and wherein tube is in open or quantitative position.In this structure, main air channel is set up by the container represented by the inner space of inlet 556, distribution opening 527 and container.Auxiliary flow channel is by being provided with from mouth of pipe duct 540 from air inlet 510 to outlet 535, and is configured to provide the air flow of the air flow that impacts the air flow that flows out the distribution opening in the middle of use to provide shearing force, and promotes the disintegration of powder particles along with they flow out the distribution opening.

Figure 24-28 illustrates the three-dimensional view of another embodiment of the Diskus inhaler for single use.In this embodiment, inhaler 600 has top surface 665 and bottom surface or lower surface 652, and comprises mouth of pipe 630 and container 651.Figure 24 shows the container 651 parts that are in the accommodating structure.In this embodiment, inhaler 600 comprises mouth of pipe 630 and is installed and can be installed with respect to the container 651 that moves of mouth of pipe 630. Mouth of pipe 630 has elongated shape, and structural configuration has air inlet 610 and air outlet 635.Air duct 640 extends to air outlet 635 from inlet 610, and air outlet 635 is configured to form and is used for the additional or auxiliary path that air flow enters inhaler during inhalation.Figure 28 shows the lower surface 652 of mouth of pipe 630, and it is configured with parallel side panels 612 at every side of inhaler, and is configured to have projection or wing 653 that is used to keep or grip inhaler 600 firmly. Panel 612 is constructed on its bottom end and has, for example, a flange to form a track for fitting and supporting wing 666 on a cartridge container. Figure 26 shows a lower surface 652 of the nozzle 630 configured to hold the cartridge container in a sealed or contained position, and in this region, the lower surface 652 is flush with the top of the cartridge container 651. The nozzle lower surface 615 is configured to have a concave or hollow form so that when the container 651 is moved to an inhalation or metered position, an air inlet 656 is formed by the container wall and the nozzle lower surface. An air flow path is then established between the inlet 656 and the dispensing port 627.

Figure 25 illustrates the stereoscopic view of the inhaler shown in Figure 24, and wherein, the tube parts are in the inside opening structure that allows air flow through tube.Figure 26 illustrates the stereoscopic view of the middle longitudinal section of the inhaler shown in Figure 24, and wherein, container 651 is in the accommodating position.Figure 27 illustrates the stereoscopic view of the middle longitudinal section of the inhaler shown in Figure 25, and wherein, tube is in opening or quantitative position.In quantitative structure, container inlet 656 and distribution openings 627 form air duct, and wherein distribution openings 627 is communicated with mouth of pipe air duct 640.Container 651 is supported by the lower surface of container wing 666 through parallel tracks and device.

The three-dimensional view of the optional embodiment of Diskus inhaler is illustrated in Figure 29-34. In this embodiment, inhaler is in closing-accommodating structure and in closing-quantitative structure. Accompanying drawing has described the inhaler that has tube or does not have tube, and has described the relatively circular disc-shaped body that is formed by the part of mouth of pipe 730 and housing 720 and has end surface and bottom surface. Mouth of pipe 730 has inlet 710, outlet 735 and opening 755 on its lower surface. Mouth of pipe 730 is configured as the top 731 of inhaler body, and is movably installed by hinge 760, and wherein hinge 760 allows inhaler to open with load and unload tube with angled motion from accommodated position. Mouth of pipe 730 can also rotatably move about 180 ° to the closed quantitative position of inhaler from accommodated position with respect to housing 720. Figure 30 A also illustrates the drug cartridge 780 that is used for this inhaler (it also describes in Figure 40 to Figure 44), and comprises top or lid 756 and the container 751 that is configured to be assembled in the support 715 in the housing 720.Housing 720 comprises tube support 715, and is configured to limit the bottom of inhaler body.Figure 30 A, 30B and 31 show the inhaler that is in the structure of holding, and wherein mouth of pipe 730 and housing 720 can allow the loading tube.When drug cartridge shown in Figure 30 B, 31,32 and 34 was installed in the support 715, mouth of pipe 730 had the matching mechanism (such as snap ring) with housing, and can rotate with respect to housing 720.Figure 30 A additionally shows that mouth of pipe 730 can cooperate with intermediate structure or rotor 717, and intermediate structure or rotor 717 are configured to be adapted to housing 720 by ring and groove mechanism, and are configured to keep tube. As shown in Figure 32, the mouth of pipe 730 also cooperates tube top 756, tube top 756 limits the air duct between tube top and the mouth of pipe air duct 740, wherein the mouth of pipe 730 and tube top 756 move together with respect to housing 720 so that tube boss 726 is positioned on the container 751, with distribution openings 727 and container 751 and support 715 alignment.Inlet 719 is limited to allow air to enter the tube 780 by distribution openings 727 in quantitative structure by the tube top 756 on the container 751. Figure 33 and Figure 34 illustrate and are in the inhaler that closes the quantitative structure, wherein, the rotation of inhaler on the tube container 751 also limits the inhaler inlet 710 that is positioned at the inhaler body on the hinge 760 and the air flow between the inside of the inhaler body with tube inlet 719 is communicated, and wherein tube inlet 719 is placed in the inhaler that closes the quantitative structure. In one embodiment, the inhaler is configured to have a recording structure in a predetermined position with the rotary motion process of the mouth of pipe in case it arrives and just represents quantitative position and accommodating position.For other embodiments herein, a part of the flow in use diverges, and remains in the inner space of the container to circulate with the coil (entrainment) and the lifting of the powder medicine in the container, and promotes the disintegration of powder to flow through the formation fritter powder of the distribution openings.

The tube embodiment that is used for inhaler has been described above, such as respectively at Fig. 4 B and 35; Figure 15I and 39A; Figure 40 and Figure 45 illustrated tube 150,170,780 and 800.This tube is configured to comprise dry powder medicine in the position that stores tightly sealed or comprises, and can be reconfigured to suction or quantitative structure from powder holding position in inhaler.In certain embodiments, tube comprises lid or top and the container with one or more perforations, holds structure and quantitative structure, outer surface, the inner surface that limits inner space; And hold structure restriction and be communicated with inner space, and distribute structure and form air passage by described inner space to allow air flow to enter or leave inner space in a predetermined manner.For example tube container can be configured to make the air flow that enters tube air inlet be guided by the air outlet in the inner space to meter the medicine that leaves tube, so that the discharge rate of powder is controlled; And wherein, the air flow in the tube can be roughly perpendicular to the air outlet flow direction tumbling, mixing and make the powder fluidization in the inner space before flowing out distribution opening.

Figures 35-38B further illustrate a cartridge including a top or lid 156 and a container 151 defining an interior space. Figure 36 illustrates a cartridge top 156 having opposite ends and including a recessed area 154 and a boss 126 at opposite ends of a longitudinal axis X. The cartridge top 156 also includes a set of relatively rectangular panels 152 along the sides and in the direction of the longitudinal axis X. The panels 152 are integrally constructed and attached to the top 156 at their ends. A boundary 158 of the cartridge top 156 extends downward and is continuous with the panels 152. The panels 152 extend downward from each side of the top 156 in the longitudinal axis X and are separated from the area of the boss 126 and the recessed area 154 by a longitudinal space or slot 157. Figures 35-37 further illustrate that each panel also includes a flange 153 configured to engage with a protrusion or wing 166 of the container 151, supporting the container 151 and allowing the container 151 to move from a receiving position below the recessed area 154 to a dosing position below the area of the boss 126. The structure of panel 152 is configured with stopper 132 at every end to prevent that container 151 from moving beyond its end, and that end panel is mounted to boundary 158.In this embodiment, for example, container 151 or lid 156 can be moved by the translation on the top 156 and removable, and perhaps top 156 can be removable with respect to container 151.In one embodiment, container 151 can be moved by the sliding on the flange 153 on the lid 156, when lid or top 156 are static, or lid 156 can be moved by sliding on static container 151, and this depends on the structure of inhaler.Near the boundary 158 of boss 126 has the recessed area of the part of the diameter that forms entrance 119 in the quantitative structure of tube.

Figure 37 illustrates a bottom view of tube 150, shows the structural relationship of the area below such as container 151, dispensing opening 127, panel 152, flange 153 and relatively hollow or recessed boss 126 or lower surface 168 in the containment structure. Figure 38 A illustrates a cross section through the middle longitudinal axis X of the tube 150 in the containment structure, and shows the container 151 in close contact with lid 156 and supported by flange 153 at recessed area 154. The lower surface of boss 126 is hollow and can be relatively visible at a position higher than the top boundary of container 151. Figure 38 B illustrates the tube 150 in the quantitative structure, wherein the panel 158 below the upper boundary of container 151 and the area of boss 126 forms an inlet 119 that allows air flow to enter the interior of tube 151.

In another embodiment, in Figure 39 A-39I, illustrated translation tube 170 is the optional embodiment of tube 150, and can be used for the inhaler of describing in Figure 15 C-15K for example.Figure 39 A has described the tube 170 that comprises shell, and this shell comprises top or lid 172 and the container 175 that limits inner space, and wherein tube is illustrated in and holds in the structure.In this tube structure, tube top 172 is configured to form the sealing with container 175, and container or lid can be moved relative to each other.Tube 170 can be configured to quantitative position (Figure 39 C-39G and 39I) and to can arbitrarily use position (not shown) from accommodating position (Figure 39 A and 39H), for example, in the centre of tube, has used tube to represent.Figure 39 A also illustrates the various features of tube 170, and wherein top 172 comprises side panel 171, and it is configured to the outside of local covering container. Each side panel 172 comprises flange 177 at its lower edge, and it forms the track of the wing-like structure of support container 175, and allows container 175 to move along the lower boundary of top 175.Tube top 172 also comprises outside relatively flat surface, relative rectangular boss 174 with opening or distribution openings 173 and inner configuration to be kept tightly sealed recess or the recessed area of the contents of container 175 at one end.In one embodiment, distribution openings can be configured to have various sizes, for example, and in the inside of tube, the width and the length of opening can be: whole width is from about 0.025cm to about 0.25cm, and whole length is about 0.125cm to about 0.65cm.In one embodiment, distribution openings measurement is about 0.06cm wide, 0.3cm long. In certain embodiments, tube top 172 can comprise various shapes, comprises that tube is positioned in right position to be placed on gripping surface (for example, short projection 176,179) and other structures in the support compatibly, and the fastening mechanism (for example, chamfer or bevel edge 180) that is adapted to corresponding inhaler securely.The external geometry of flange, boss and various other shapes can constitute keying surface, and it can represent, promote and/or need tube to be placed in the inhaler compatibly.Additionally, these mechanisms can be changed to another system from an inhaler-tube paired system, so that the specific medicine or dosage that are provided by tube are associated with specific inhaler.In this way, can prevent the tube that is intended to be used for the inhaler that is associated with the first medicine or dosage from being placed in the similar inhaler relevant with the second medicine or dosage or work with it.

Figure 39 B is the overall shape that explanation has the tube top 172, distribution openings 173, recessed area 178 and short projection 176 and 179 of boss 174.Figure 39 C is the upward view of tube 170, shows the container 175 that is in the accommodated position, and it is supported from the top by wing-shaped projection 182 and each flange 171.Figure 39 D has described the flange that is in the quantitative structure and also comprises the air inlet 181 that is formed by the upper boundary of the otch on the tube top 172 and container 175.In this structure, air inlet 181 is communicated with the inside of tube, and forms the air duct with distribution openings 173.In use, tube air inlet 181 is configured to guide the air flow that enters tube inside at distribution openings 173.

Figure 39 F illustrates the side view of tube 150, and shows the relation of the structure such as container 175, boss 174, side panel 172 and short projection 176 that is in the quantitative structure.Figure 39 G illustrates the tube 170 that is in the quantitative structure for use, and comprises container 175 and the top 172 with relative rectangular air inlet 181 and relative rectangular distribution openings 173, distribution openings 173 pierces the relative center boss 174 of the upper surface that is positioned at tube top 172.Boss 174 is configured to be fitted in the perforation in the wall of the mouth of pipe of inhaler.Figure 39 H and Figure 39 I illustrate respectively the cross section of the intermediate longitudinal axis X that passes through tube 170 of structure and quantitative structure, and show the container 175 that contacts and is supported by flange 177 with the lower surface of the lid 172 of recessed area 178, wherein flange forms the track that is used for container to slide to another position from one position. As shown in Figure 39 H, in holding structure, container 175 forms the sealing with the lower surface of tube top 172 in recessed area 178.Figure 39 I has described the tube 170 that is in quantitative structure, wherein, container is in the opposite end of recessed area 181, and container 175 and tube top form the air inlet 181 that allows ambient air to enter tube 170 and form the inside of air duct and container 175 with distribution openings 173.In this embodiment, the tube top lower surface that wherein reaches quantitative position is relatively flat, and the inner surface of container 175 is configured to have slightly U-shaped.Boss 174 is configured to protrude slightly above the top surface of tube top 172.

In another embodiment of a cartridge, cartridge 780 is described with reference to Figure 30A above and illustrated herein in Figures 40-44. Cartridge 780 can be adapted to the dry powder inhaler disclosed herein and is partially adapted for use in an inhaler having a rotatable mechanism for moving the inhaler from a containment configuration to a metered position, wherein the cartridge top is movable relative to the container, or the rotatable mechanism is used to move the container relative to the top to achieve alignment of the dispensing port with the container to a metered position, or to move the container or the top to a containment configuration.

As mentioned above, Figure 44-Figure 44 also illustrates the three-dimensional view of the embodiment of the tube 780 that is used for the inhaler of Figure 29 for example, and shows and is in and holds in the structure and comprises the tube top or lid 756 and the tube of container 751 that are installed in one piece with each other.Container 751 and top 756 can move to quantitative or suction position relative to each other from the accommodating position with rotational motion, and return.The tube top 756 is relatively circular form, and also comprises recessed area 754 and protrusion area or boss 726 with distribution openings 727 and extends downwards with closed container, is installed to container and limits the circular panel 752 of inner space.Top 756 also has top boundary or the top edge 759 that is configured to the projection that is adapted with inhaler, and is in the groove that cooperates with container 751 in the inner surface of panel 752.

Figure 41 illustrates the exploded view of the tube embodiment of Figure 40, and shows the container 751 that is limited to the chamber 757 that is used to hold medicine, chamber 757 is continuous with the wider top 747 of relatively circular diameter, and is configured to have the matching mechanism that cooperates and moves with respect to tube top 756.The upper boundary 758 that Figure 42 for example shows container can have the circular structure (for example, hasp ring) that is used to cooperate with the groove 761 of panel 752 to form tube 780. Figure 42 also illustrates the cross section through vertical axis of the embodiment of the tube of Figure 40 and the three-dimensional view that holds structure, and shows the recessed area 754 of sealed container 751 and the lower surface 767 of hollow boss 726.When recessed area 754 was above container chamber or inner space 757, tube was in the holding structure shown in Figure 42.

Figure 43 illustrates a perspective view of the cartridge embodiment of Figure 40 in a dosing configuration, wherein the chamber 757 of the container 751 is directly below the boss 726, and the cartridge is configured with an inlet 719 in communication with the dispensing opening 727. Figure 44 illustrates a cross-sectional and dosing configuration perspective view of this embodiment to illustrate the location of the air inlet 719 and the container and boss 726 with the dispensing opening 727. In this embodiment, the recessed area 754 of the lid 756 and the area 747 of the container form a tight abutment or seal against one another.

The air inlet of the tube that is used for this inhaler can be configured at any point of tube, makes the powder medicine in the container can remain in the accommodating position before sucking.For example, Figure 45,46A,46B,47A and 47B illustrate two optional embodiments of the tube that is used for Diskus, comprise lid or top 856, structure and be configured to container 851 as shown in above Figure 35-39.Yet in this embodiment, the air inlet 819 that enters tube inside can be combined in tube top or the lid 851 with one or more distribution openings 827.In this embodiment, tube comprises container 851 and lid or top 856.Lid or top 856 can be provided with groove on its inner surface, to cooperate as locking mechanism with the upper boundary of container 851.Tube can also be provided with seal 860 to comprise powder medicine in tube, and can be made by for example plastic film or laminated foil.Seal 860 can be made into single tube or a plurality of single dose tubes that comprise for single dose use on the strip. 46A and 46B illustrate the embodiment of the tube of convex 5, and comprise the container 851 that can be adapted to lid 856, wherein, relatively square lid has relatively circular inlet 819 and two outlets 827 and is configured to have the side panel 852 of the groove that is adapted to container 851, wherein container 851 is relatively shaped as a cup, and has protrusion for cooperating lid 856 on its upper boundary. Figure 46 B illustrates the cross section of the embodiment of the tube of Figure 45 and the three-dimensional view of quantitative structure. In this embodiment, tube top air inlet can have various structures. For example, Figure 47 A and Figure 47B illustrate the optional embodiment of tube 800, wherein tube top 856 is relatively semicircular flat shape, and has the air inlet that is shaped as a rectangle. In this embodiment, container and tube top can be made by the thermoforming material (for example, polyethylenepterephthalate) that is convenient to production by storage.

In the embodiment described herein, tube can be configured to carry the dry powder medicine of the dosage of single unit pre-metering.Structure such as tube 150,170,780 and 800 can be configured to comprise the dry powder formulation of for example from 0.1mg to about 50mg dosage.Thus, the size and shape of container can depend on the size of inhaler and the amount or the quality of the powder medicine that will be carried and change.For example, container can have two relatively flat relatively circular shapes of opposite sides, and have the approximate distance from about 0.4cm to about 2.0cm.In order to make the inhaler performance optimum, the inside of tube can depend on the powder amount that is intended to be contained in the chamber and change along the height of Y axis.For example, the powder that fills 5mg to 15mg can require the height from about 0.6cm to about 1.2cm best.

In an embodiment, a medicine container for a dry powder inhaler is provided, comprising a shell configured to keep medicine; at least one inlet allowing to flow into the shell and at least one distribution opening allowing to flow out of the shell; the at least one inlet configured to direct a portion of the flow entering the at least one inlet to the at least one distribution opening in response to pressure differential in the shell. In one embodiment, the inhaler tube is formed by a high-density polyethylene material. The tube has a container having an inner surface that limits an inner space, and comprises a bottom wall and a sidewall that are continuous with each other, and has one or more openings. The tube can have a cup-shaped structure, and has an opening with an edge, and the tube is formed by a tube top and a tube bottom, and the tube top and the tube bottom can be configured to limit one or more inlets and one or more distribution openings. The tube top and the tube top can be configured to accommodate a position and distribute or a quantitative position.

In the embodiment described herein, Diskus and tube form an intake system, and the structure of this intake system is configured to carry out adjustable or modular airflow resistance by the sectional area of any cross section of the airflow duct that changes system.In one embodiment, the Diskus system can have the airflow resistance value of approximately 0.200 (kPa)/liter from per minute approximately 0.065.In other embodiments, check valve can be adopted to prevent that air flow through inhaler falls (such as 4kPa) until having reached the pressure of expectation, and the pressure of this expectation falls place, and the resistance of expectation arrives the value in the given range here.

Figure 48-Figure 54 illustrates another embodiment of Diskus.Figure 48 has described the opening structure of inhaler 900, and its structural configuration is similar to the inhaler 300 shown in Figure 12-15B.Inhaler 900 comprises the mouth of pipe 930 and the housing subassembly 920 that are installed to each other by hinge, makes mouth of pipe 930 pivot with respect to housing subassembly 920.The mouth of pipe 930 also comprises the side panel that is integrally formed and wider than housing 920, and this side panel 932 cooperates with housing projection 905 to realize the closed structure of inhaler 900.The mouth of pipe 930 also comprises air inlet 910, air outlet 935, extends to air outlet 935 from air inlet 910 with the air flow duct 940 that contacts user's lip or mouth and on base plate or bottom surface with the perforate 955 that is communicated with the air flow duct 940 of inhaler.The exploded view of Figure 49 illustrates inhaler 900, shows the component parts of inhaler, comprises the assembly 920 of mouth of pipe 930 and housing. As shown in FIG49 , the nozzle is constructed as a single component and further includes a rod, cylinder, or tube 911 configured with teeth or gears 913 articulated with the housing 920 such that movement of the nozzle 930 relative to the housing 920 in an angular direction effects closure of the device. An air passage 912 may be provided to the housing and configured to direct air toward the nozzle air inlet 910. The air passage 912 is configured such that a user's finger placed on the passage cannot restrict or obstruct the flow of air into the air conduit 940.

Figure 48 illustrates housing subassembly 920, and it comprises that tube places or installation area 908 and otch 918, and otch 918 is configured to limit air inlet when inhaler is in the closed structure.Figure 49 illustrates housing 920 as shell, also comprises two components for easy manufacture, but can also use more or less parts, comprises dish 922 and lid 925.Dish 922 is configured with the otch 914 of its far-end structure, and otch 914 holds rod-shaped cylinder or pipe 911 to form the hinge with the mouth of pipe 930.Dish 922 also holds slide plate 917. Slide plate 917 is configured to move in dish 922, and has tube receiving area 921 and arm-like structure, described arm-like structure has the tooth that is used to cooperate the mouth of pipe 930 or the opening 915 of gear 913, make in order to use the closing device, the mouth of pipe 930 moves slide plate in the proximal direction with respect to the movement of housing 920, cause slide plate to abut against the tube container on inhaler support or the mounting area 908, and remotely with container from the accommodated position to the quantitative position.In this embodiment, the tube that is positioned at the tube support 908 has the air inlet opening in the quantitative structure towards the near-end of inhaler or user.Housing lid 925 is configured to make by having the projection 926 that for example extends from the bottom boundary and can be securely installed to dish 922 as fastening mechanism.Figure 50 illustrates in the inhaler 900 that opens in the structure, and has described the position and the orientation of the tube 150 that is in the structure that holds and is used to be installed on the inhaler.Figure 51 also illustrates in the inhaler 900 that opens in the structure, and tube 150 is positioned at the tube support that is in the structure that holds. Figure 52 illustrates the middle longitudinal section of the inhaler of Figure 51, and shows the position of gear 913 relative to slide plate 917 in the accommodating structure of the tube container 151 against slide plate 917.In this embodiment, container 151 moves relative to tube top 156.When closing inhaler 900 (Figure 53), along with the mouth of pipe 930 moves to the closed structure, slide plate 917 is pushing container 151, up to realize quantitative structure, and the mouth of pipe opening 955 slides on tube boss 126, makes distribution openings 127 be communicated with mouth of pipe pipeline 940, and sets up the air flow path that is used for quantitative by the distribution openings 127 in air inlet perforate 918, tube air inlet 919 and the air duct 940.As Figure 54 seen, the mouth of pipe 930 and thereby air duct 940 have the relatively shrinking funnel shape structure to the far-end in the approximate middle.In this embodiment, slide plate 917 is configured to make when inhaler opens after use, and slide plate can not be reconfigured to the accommodating structure with tube.In some deformations of this embodiment, can or expect to reconfigure tube.

In the disclosed embodiment herein, for example, inhaler perforate 155,255,355,955 can be provided with seal, and for example broken rib, deformable surface, pad and O-ring are leaked into system to prevent air flow, so that air flow only travels by tube.In other embodiments, in order to carry out sealing, seal can be arranged to tube.Inhaler is also provided with the disintegration in one or more zones, and it is configured to heap up or the deposition that powder is minimized.In tube (being included in container and distribution opening) and one or more positions of the air duct of the mouth of pipe for example provide disintegration zone.

In the embodiment disclosed herein, the Diskus system is configured to have predetermined flow balance distribution in use, has the first flow path by tube and by the second flow path of for example the mouth of pipe air duct.Figure 55 and Figure 56 have described the schematic representation of the air duct of the balance of the guiding flow distribution that is set up by tube and inhaler structural configuration.Figure 55 has described the distribution of Diskus or the quantitative position in tube by the total direction of flow represented by arrow.Figure 56 illustrates the flow motion of the embodiment of Diskus, and has shown the flow path of the inhaler that is in the quantitative position by arrow.

The balance of the mass flow in the inhaler is approximately 10% to 70% of the volume that flows through the tube flow path, and is approximately 30% to 90% of the beginning of the mouth of pipe pipeline.In this embodiment, the mode that the air flow distribution by tube is mixed medicine in tumbling so that the dry powder medicine fluidization or aerosolization in the tube container.The air flow that makes the powder fluidization in the container promotes powder then, and it flows out the tube container by the distribution opening gradually, enters the air flow of the mouth of pipe conduit then and mixes with the air flow that comprises the medicine from the tube container.Predetermined or metered air flow from the tube outflow mixes with the bypass air flow that enters the air duct of the mouth of pipe with further dilution and disintegrating powder medicine before leaving the mouth of pipe outlet and entering the patient.

In another embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided, comprising an inhaler including a container mounting area configured to receive a container and a mouthpiece having at least two outlet openings and at least one outlet opening; wherein one of the at least two inlet openings is in fluid communication with the container area, and one of the at least two inlet openings is in fluid communication with the at least one outlet opening via a flow path, the flow path being configured to bypass the container area to deliver the dry powder formulation to the patient; wherein the flow conduit is configured to bypass the container to deliver 30% to 90% of the total flow through the inhaler during inhalation.

In another embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided, comprising a dry powder inhaler including a container area and a container; the dry powder inhaler and container combination is configured to have a rigid flow conduit in a metered configuration and multiple structural areas that provide a mechanism for disintegration of the powder of the inhalation system during use; wherein at least one of the multiple mechanisms for disintegration is an aggregate size exclusion opening in the container area having a minimum size between 0.5 mm and 3 mm.

In an optional embodiment, an inhalation system for delivering a powder formulation to a patient is provided, comprising a dry powder inhaler (DPI) comprising a nozzle and a container; wherein the DPI and container combination is configured to have a rigid flow conduit in a quantitative configuration and a plurality of structural regions, wherein the structural region provides a mechanism for disintegrating the powder of the inhalation system during use; wherein at least one of the plurality of mechanisms for disintegrating is configured in the nozzle and guides flow at an outlet opening in communication with the container fluid. In a specific embodiment, the inhalation system comprising the container further comprises a mechanism for disintegrating viscous powders and having a cup-shaped structure, wherein the cup-shaped structure is configured to guide the airflow entering the container to rotate, circulate again in the inner space of the cup-shaped structure, and promote the powder medicament to entrain powder aggregates in the flow until the powder mass is sufficiently small before leaving the container. In this embodiment, the cup-shaped structure has one or more radii configured to prevent flow stagnation.

In the embodiment described herein, the cartridge is constructed with an inlet opening proximal to the dispensing opening on both the horizontal and vertical axes. For example, the inlet opening can be immediately adjacent to the air inlet within the width of the cartridge, though this relationship can vary depending on the flow rate and the physical and chemical properties of the powder. Because of this proximity, the flow within the cartridge from the inlet across the opening to the dispensing opening creates a flow configuration that inhibits fluidized powder, or powder entrained in the airflow, from exiting the container. In this manner, during an inhalation operation, flow entering the cartridge container can tumble the dry powder formulation within the cartridge container, while fluidized powder approaching the cartridge outlet or dispensing opening can be blocked by flow entering the cartridge inlet, thereby limiting flow from the cartridge container out of the cartridge container. Due to differences in inertia, density, velocity, charge interaction, and flow position, only some particles can traverse the path required to exit the dispensing opening. Particles that do not pass through the outlet must continue tumbling until they achieve the desired mass, charge, velocity, or position. In effect, this mechanism meters the amount of drug exiting the cartridge and can aid in the disintegration of the powder. To further aid in metering the exiting fluidized powder, the number and size of the dispensing openings can be varied. In one embodiment, two dispensing openings are used. The dispensing openings are circular in shape, each with a diameter of 0.10 cm, and are located near the inlet opening, from the centerline of the container to approximately 0.2 cm from the centerline toward the air inlet. For example, other embodiments have dispensing openings of various shapes, including rectangular, with one or more dispensing openings having a cross-sectional area ranging from 0.05 ^cm² to approximately 0.25 ^cm² . In some embodiments, the dispensing opening diameter can range in size from approximately 0.05 cm² to approximately 0.25 cm². Other shapes and cross-sectional areas can be used, as long as their cross-sectional areas are similar to the values given herein. Alternatively, for more viscous powders, dispensing openings with larger cross-sectional areas can be provided. In some embodiments, the cross-sectional area of the dispensing openings can be increased depending on the size of the aggregate relative to the minimum opening dimension of the opening or openings, while the length remains relatively large relative to the width of the openings. In one embodiment, the size of the air inlet opening is wider than the size of the dispensing opening or openings. In embodiments where the air inlet openings are rectangular, the air inlet openings have a width ranging from 0.2 cm² to approximately the maximum width of the container. In one embodiment, the height is approximately 0.15 cm and the width is approximately 0.40 cm. In an alternative embodiment, the container has a height of from about 0.05 cm to about 0.40 cm. In a particular embodiment, the container has a width of from about 0.4 cm to about 1.2 cm and a height of from about 0.6 cm to about 1.2 cm. In an embodiment, the container includes one or more dispensing openings, each having a diameter between 0.012 cm and about 0.25 cm.

In a specific inhalation system, a cartridge for a dry powder inhaler is provided, comprising a cartridge top and a container, wherein the cartridge top is configured to be relatively flat and has one or more openings and one or more flanges, wherein the flange is configured to have a track for fitting the container; the container has an inner surface defining an interior space and is movably mounted on the track on the one or more flanges on the cartridge top, and can be configured to reach a accommodating position and a dispensing or dosing position by moving along the one or more flanges.

In another embodiment, an inhalation system includes a housing having one or more outlets configured to remove agglomerates of a dry powder component having a minimum dimension greater than 0.5 mm and less than 3 mm. In one embodiment, a cartridge for a dry powder inhaler includes a housing having two or more rigid portions; the cartridge having one or more inlets and one or more dispensing ports, wherein the one or more inlets have a total cross-sectional area greater than a total cross-sectional area of the dispensing ports, wherein the total cross-sectional area of the one or more dispensing ports ranges from 0.05 ^cm2 to approximately 0.25 ^cm2 .

In one embodiment, a method for disintegrating and dispensing a dry powder formulation for inhalation includes the following steps: generating an airflow within a dry powder inhaler comprising a nozzle and a container having at least one inlet and at least one dispensing port and containing the dry powder formulation; the container forming an air conduit between the at least one inlet and the at least one dispensing port, wherein the inlet directs a portion of the airflow entering the container to the at least one dispensing port; allowing the airflow to tumble the powder within the container to lift and mix the dry powder medicament within the container to form an airflow-medicament mixture; and accelerating the airflow to exit the container through the at least one dispensing port. In this embodiment, the reduced cross-sectional area of the outlet relative to the inlet allows the powder medicament passing through the dispensing port to be instantly accelerated. This change in velocity can further disintegrate the fluidized and aerosolized powder medicament during inhalation. Optionally, due to the inertia of particles or groups of particles in the fluidized medicament, the particles exit the dispensing port at different velocities. The faster-moving airflow in the nozzle conduit imparts drag or shear forces to each particle or group of particles of the slower-moving fluidized powder exiting the outlet or dispensing port or ports, which can further disintegrate the medicament.

The powdered drug passing through the dispensing opening or openings is immediately accelerated due to the reduced cross-sectional area of the outlet or opening relative to the container, which is designed to have a smaller cross-sectional area than the container's air inlet. This change in velocity further disintegrates the fluidized powdered drug. Additionally, due to the inertia of particles or groups of particles in the fluidized drug, the velocity at which the particles exit the dispensing opening differs from the velocity at which they flow through the dispensing opening.

In the embodiments described herein, the powder exiting the dispensing port can be further accelerated by imparting a change in the direction and/or velocity of the fluidized medicament. The change in direction of the fluidized powder exiting the dispensing port and entering the nozzle conduit occurs at an angle of approximately 0° to approximately 180° (e.g., approximately 90°) relative to the axis of the dispensing port. This change in flow rate and direction can further disintegrate the fluidized powder through the air conduit. This change in direction can be accomplished by changing the geometry of the air flow conduit and/or by preventing air flow from exiting the dispensing port while assisting air flow into the nozzle inlet. Prior to exiting, the fluidized powder in the nozzle conduit expands and decelerates as it enters the oral placement portion of the nozzle due to the increased cross-sectional area of the conduit. Gas trapped within the aggregate also expands and can help to break down individual particles. This is another disintegration mechanism of the embodiments described herein. The airflow containing the medicament can enter the patient's oral cavity and, for example, be effectively delivered to the pulmonary circulation.

Each expression of disintegration mechanism described herein and a part of inhalation system makes the multistage method of maximizing powder disintegration.By making the effect of each mechanism (comprising one or more acceleration/deceleration pipelines, dragging or being caught in the interaction of expansion, powder attributes and the inhaler component material attribute of the gas in the aggregation block, wherein the attribute of the inhaler component material is the overall characteristic of this inhaler system) best obtain maximum disintegration and the conveying of powder.In the embodiment described herein, inhaler is provided with relatively rigid air duct or ducting system so that the disintegration of powder medicine maximizes, makes that the powder medicine of discharging from inhaler consistent in the reuse process.Because this inhaler is provided with rigid pipeline or keeps identical and can not change, avoided using the variation of the air duct structure that punctures film or stripping film causes in the prior art inhaler of blister.

In one embodiment, a method for disintegrating a powder formulation in a dry powder inhalation system is provided, comprising: providing the dry powder formulation to the dry powder inhaler in a container having an interior space; allowing flow to enter the container, the container being configured to direct the flow to lift, tumble, and circulate the dry powder formulation until the powder formulation comprises powder clumps small enough to pass through one or more dispensing openings and into a nozzle. In this embodiment, the method can further include the step of accelerating the tumbling powder clumps in the flow exiting the one or more dispensing openings and entering the nozzle.

In the embodiment disclosed herein, dry powder medicine is uniformly distributed from the inhaler in less than about 2 seconds. This inhaler system has a high resistance value of about 0.065 to about 0.20 (kPa)/liter per minute. Thus, in the system comprising the tube, the peak inhalation pressure drop between 2 and 20Pa applied produces a synthetic peak flow rate between about 7 and 70 liters per minute through the system. These flow rates cause 75% of the copper content distributed between 1 and 30mg of powder greater than the filling mass. In certain embodiments, these performance characteristics are produced by the end user in a single inhalation operation with a tube distribution percentage greater than 90%. In certain embodiments, inhaler and tube system are configured to provide a single dose by discharging powder as a continuous flow or as one or more pulse powders delivered to the patient from suction. In an embodiment, an inhalation system for dry powder formulations to be delivered to the patient's lungs is provided, comprising a dry powder inhaler configured to have a flow conduit, which has a total flow resistance of from 0.065 to about 0.200 (kPa)/liter per minute in a quantitatively constructed median value. In this and other embodiments, the overall resistance to flow of the inhalation system is relatively constant over a pressure differential range between approximately 0.5 kPa and 7 kPa.

The structural configuration of inhaler allows disintegration mechanism to produce greater than 50% respirable part and less than the particle of 5.8 μ m.Inhaler can discharge more than 85% of the powder medicine that is included in the container in the suction operation.Usually, the inhaler of describing here among Figure 15 I can discharge more than 90% of tube contents or container contents with up to the filling mass of 30mg less than 3 seconds under the pressure differential between 2 and 5kPa.

Although this inhaler is mainly described as respiratory power, in some embodiments, inhaler can be provided with the source that is used to produce the required pressure difference of disintegration and convey dry powder formulation.For example, inhaler can be adapted to gas power source, such as compressed gas storage energy source, such as the nitrogen tank at air inlet is set.Spacer can be provided to capture stream so that the patient can inhale with the rhythm that is fit to.

In the embodiment described herein, the inhaler can be provided as a reusable inhaler or as a single-use inhaler. In an optional embodiment, the similar principle of disintegration can be applied to a multi-dose inhaler, wherein the inhaler can include, for example, multiple tubular structures in a single disc, and can indicate a single dose as needed. In the variation of this embodiment, the multi-dose inhaler can be provided with, for example, enough doses for a drug supply for a day, a week, or a month. In the multi-dose embodiment described herein, the convenience of the end user is optimized. For example, in the breakfast of a prandial regimen, the quantitative amount of lunch and dinner is achieved for a seven-day schedule in a single device. The convenience of the additional end user is provided by an indicator mechanism indicating the day and quantitative amount (for example, the third day (D3), lunch time (L)). An exemplary embodiment is shown in Figures 57-68, wherein an inhaler 950 comprises a relatively circular shape, comprising multiple quantitative units as a part of a disc-shaped barrel system. The inhaler 950 has a nozzle 852 and a housing subassembly 960 with an air inlet 953 and an air outlet 954. The nozzle 952 is configured to have a relative hourglass shape, and the air duct 980 ( FIG. 67 ) is configured to have a corresponding shape. The nozzle 952 also includes a tube for mating with the housing subassembly 960 and the air duct 980 has an opening 985 ( FIG. 67 ) that communicates with the interior of the housing subassembly 960.

FIG58 is an exploded view of the inhaler of FIG57 showing its components, including the nozzle 952; a housing subassembly 960 comprising multiple parts; a bottom cover or disk 955; an actuator 956 having a ratchet 957; a cartridge-disc system comprising a base portion 958 and a cover portion 959; and a sealing disk or plate 961. In one embodiment, a spring can be provided with the ratchet 958 attached to the indexing disk 958. The housing disk 955 is configured to securely engage the nozzle via a snap-fit, ultrasonic welding, threads, or the like. FIG59 illustrates the base portion 958 of the cartridge-disc system and shows an outer gear mechanism 963 and an inner gear mechanism 964 positioned relative to each other about the central axis of the cartridge. The cartridge system is configured with a centrally located opening for engagement with the actuator. FIG59 also shows the location of multiple unit dose containers 962, each configured to be of the same size and shape and positioned radially toward the periphery of the cartridge-disc system. FIG60 illustrates the housing disc, and shows the actuator 956 without a return spring and the ratchet system 957, 957' in place. FIG61 depicts the base 958 of the cartridge disc system, and shows a plurality of containers radially located within the disc, and also shows a relatively circular raised area 965, which includes two raised areas 966 located in the horizontal plane of the disc and a second raised area 967 located in the central axis and pointing upward and perpendicular to the disc's raised areas. FIG62 illustrates the housing disc 955 with the cartridge disc system 958, 959, the actuator 956, and the ratchet mechanism assembled therein.

Figure 63 has described the assembly structure of the barrel disc system of inhaler 950, and shows a plurality of containers 962, and a plurality of containers can be installed to each other cooperatively so that powder is provided to hold.By barrel system cover part 959 comprises a plurality of tubular tops 970, and it aligns with the container 962 of the chassis of barrel disc system to form a plurality of unit dose barrel units in barrel disc system.The alignment of barrel system cover 959 and chassis part is realized by the cover part 959 with the perforation 969 that is positioned at the center, and perforation 969 is constructed with two otches 968, and this otch 968 and the protrusion area of chassis part 958 cooperate securely.In this embodiment, barrel disc system also is constructed to have a plurality of air inlets 971 and a plurality of distribution openings 972, and wherein each unit dose barrel comprises at least one air inlet 971 and one or more distribution openings 972. Figure 64 shows a cross section of the cartridge tray system 958 and 959 and shows an air inlet 971 establishing an air duct path in the interior chamber of a container having a dispensing port 972 so that airflow entering the unit chamber flows through the air inlet 971, tumbles within the container and flows out of the dispensing port.

Figure 65 illustrates the housing assembly 960 that is made up of its component parts, and particularly, sealing disk 961 illustrates and comprises the perforated hole 977 that locates towards the edge of dish, and perforated hole 977 aligns with the distribution opening 972 of the unit dose barrel of barrel disc system in quantitative position.Sealing disk 961 is also configured to be sealed in the unit dose barrel of barrel disc system with distribution opening 972 and air inlet 971, except the unit dose barrel aligned with perforated hole 977.In this way, the powder in the barrel system of maintenance filling is accommodated.Sealing disk 961 also has central opening 975 and a plurality of spring-like structures (for example, wave element) or the arm 973 that extends from the inside of dish relative to central axis, thereby forms a plurality of openings 976 that allow air to flow into the inside of inhaler 960 and flow into the unit dose barrel of distributing when in use.Figure 66 is the cross section of housing subassembly 960 and shows the structure of sealing disk 961, and this structure limits the air passage of the unit dose barrel of entering all barrel units, except the perforated hole 977 of sealing disk barrel disc system. 67 shows a cross section of the inhaler 950 and shows a metered configuration, wherein the nozzle shows an air conduit 980 and nozzle opening 985 aligned with the dispensing opening 972 of the unit dose cartridge and the opening 977 of the sealing disk. The other units in the cartridge are contained by the sealing disk 961.

In this embodiment, inhaler device 950 uses simply, and can use a tube to be used for quantitative in one time.After distributing all dosages, inhaler can arrange or reload new tube disc system.In this embodiment, the motion from starting position to adjacent tube is carried out by complementary ratchet system 95 by actuator 956.One is installed to the ratchet propulsion tube disc of actuator, and another tube disc is remained on the position that is suitable when actuator resets to its original position.

Figure 68 to Figure 79 illustrates the optional embodiment of multidose inhaler 990, and it comprises the mouth of pipe 952 and inhaler body 991.The mouth of pipe 952 has air inlet 953, air outlet 954, and is configured to have relative hourglass shape, and it has the perforate that is communicated with body 991 and is installed to inhaler body 991. Figure 69-Figure 73 discloses the various components of inhaler 990.In this embodiment, inhaler body 991 comprises several parts, and wherein the barrel disc system forms the bottom of body 991. Figure 74 shows the gear drive assembly that comprises first gear 992 and second gear 993, and it is used for rotating the unit dose barrel to align with the mouth of pipe perforate and distribute.The alphanumeric indicator system can be applied to the tube container to indicate the dosage unit that is distributing. Figure 75 shows the tube unit system that comprises chassis part 958 and lid or top 959, chassis part 958 comprises a plurality of radially positioned wells or unit dose container 962 and a plurality of air inlets, lid or top 959 comprises a tube cover plate, and this tube cover plate can be permanently glued or welded on the chassis that comprises the well.Figure 76 shows the back view of the tube disc system, and Figure 77 shows the elevation view of the tube disc that comprises a plurality of tube tops, and wherein a plurality of tube tops can move to quantitative position from accommodating position in tube.Figure 78 shows the upward view of the tube system of inhaler 990, and has shown with digital the sequence number 994 that is represented by at least one distribution dose.Figure 79 shows the disc seal with the perforation that aligns with the dispensing opening of the unit dose tube of the tube disc system.

In one embodiment, dry powder medicine for example can comprise diketopiperazine and pharmaceutical active ingredient.In this embodiment, pharmaceutical active ingredient or activating agent can be any type depending on the disease to be treated or symptom.In another embodiment, diketopiperazine can for example comprise symmetrical molecule and the asymmetric diketopiperazine with effectiveness to form granule, microparticle etc., and these granule, microparticle can be used as the carrier system for activating agent being transported to the target location of health.Term " activating agent " refers to therapeutic agent or will be encapsulated in, be associated, engage, compound or fall into or be sucked into the molecule such as protein or peptide or biomolecule on the diketopiperazine formula here.Any form of activating agent can be combined with diketopiperazine.Drug delivery system can be used to carry the bioactive agent with treatment, prophylaxis or diagnosis activity.

One class of drug delivery agents that has been used to produce microparticles and overcome problems in existing pharmaceutical technologies, such as drug instability and/or poor absorption, is 2,5-diketopiperazine. 2,5-Diketopiperazine is represented by the general molecular formula 1 shown below, where E=N. One or both nitrogen atoms can be replaced with oxygen to form the substitution analogs diketomorpholine and diketodioxane, respectively.

Molecular formula 1

These 2,5-diketopiperazines have been shown to be useful in drug delivery, particularly those bearing an acidic R group (see U.S. Pat. No. 5,352,461, entitled "Self-Assembling Diketopiperazine Drug Delivery System"; U.S. Pat. No. 5,503,852, entitled "Method For Making Self-Assembling Diketopiperazine Drug Delivery System"; U.S. Pat. No. 6,071,497, entitled "Microparticles For Lung Delivery Comprising Diketopiperazine"; and U.S. Pat. No. 6,331,318, entitled "Carbon-Substituted Diketopiperazine Delivery System," the contents of each of which are incorporated herein by reference in their entirety for their teachings of diketopiperazines and diketopiperazine drug delivery). Diketopiperazines can be formed into drug-absorbing microparticles. The combination of drug and diketopiperazine can improve the stability and/or absorption characteristics of the drug. These microparticles can be administered by various administration procedures. As a dry powder, these microparticles can be delivered by inhalation to specific areas of the respiratory system, including the lungs.

Fumaryl diketopiperazine (bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-disketopiperazine; FDKP) is a preferred diketopiperazine for pulmonary application.

FDKP provides a beneficial microparticle matrix because it has low solubility in acid but readily dissolves at neutral or basic pH. These properties allow FDKP to crystallize under acidic conditions, and the crystals to self-assemble to form particles. The particles readily dissolve under neutral pH conditions, resulting in lithium production. In one embodiment, the microparticles disclosed herein are FDKP microparticles loaded with an active agent, such as insulin.

FDKP is a chiral molecule with trans and cis isomers at substituted carbons on the DKP ring relative to the arrangement of the substitutions. As described in U.S. Provisional Patent Application No. _/____, entitled DIKETOPIPERAZINE MICROPARTICLES WITH DEFINED ISOMER CONTENTS, filed on the same date as this disclosure, greater aerodynamic robustness and consistency of particle morphology can be achieved by limiting the isomer content to approximately 45-65% trans. The isomer ratio can be controlled during the synthesis and recrystallization of the molecule. For example, during the removal of the protecting group from the terminal carboxylate group, exposure to the matrix promotes ring epimerization, which results in racemization. However, increasing the methanol content of the solvent during this step results in an increased trans isomer content. The trans isomer is less soluble than the cris isomer, and temperature control and solvent composition during recrystallization can be used to promote or reduce the enrichment of the trans isomer during this step.

Microparticles with diameters between about 0.5 and about 10 microns can reach the lungs, successfully negotiating most natural barriers. A diameter of less than about 10 microns is required to navigate the turns of the throat, and a diameter of about 0.5 microns or greater is required to avoid being exhaled. DKP microparticles with a specific surface area (SSA) between about 35 and about 67 m2/g have properties that are beneficial for drug delivery to the lungs, such as improved aerodynamics and enhanced lung absorption.

As described in U.S. Provisional Patent Application No. _/____, entitled DIKETOPIPERAZINE MICROPARTICLES WITH DEFINED ISOMER CONTENTS, filed on the same date as the present disclosure, the size distribution and shape of FDKP crystals are influenced by the balance between nucleation of FDKP crystals and the production of existing crystals. Both phenomena are strongly dependent on the concentration and supersaturation of the solution. The characteristic size of FDKP crystals indicates the relative rates of nucleation and production. When nucleation dominates, many crystals form, but they are relatively small because they compete for the FDKP in solution. When growth dominates, there are fewer competing crystals, and the characteristic size of the crystals is larger.

Crystallization is strongly dependent on supersaturation, which in turn is strongly dependent on the concentrations of the components in the feed stream. Higher supersaturation is associated with the formation of many small crystals; lower supersaturation produces fewer, larger crystals. With respect to supersaturation: 1) increasing the FDKP concentration increases supersaturation; 2) increasing the ammonia concentration shifts the system to a higher pH, increasing equilibrium solubility and reducing supersaturation; and 3) increasing the acetic acid concentration increases supersaturation by shifting the endpoint to a lower pH where equilibrium solubility is lower. Reducing the concentrations of these components has the opposite effect.

Temperature influences FDKP microparticle formation through its effects on FDKP solubility and the dynamics of FDKP crystal nucleation and growth. At low temperatures, small crystals form with high SSA. Suspensions of these particles exhibit high viscosity and strong interparticle attraction. Temperatures ranging from about 12°C to about 26°C produce particles with acceptable (or better) aerodynamic properties, and various inhaler systems, including those disclosed herein, have been shown to be effective.

These devices and systems are used in pulmonary delivery or powders with a wide range of properties. Embodiments of the present invention include systems having an inhaler, an integral or mountable unit dose cartridge, and a powder having defined properties that provide an improved or optimal performance range. For example, the device constitutes an effective disintegration engine, thereby effectively delivering cohesive powders. This is different from the process pursued by many others who have been working on developing dry powder inhalation systems based on free-flowing or flow-optimized particles (see, for example, U.S. Patent Nos. 5,997,848 and 7,399,528, U.S. Patent Application No. 2006/0260777; and Ferrari et al. AAPS Pharm SciTech 2004; 5(4) Article 60). Thus, embodiments of the present invention include systems of the device plus cohesive powders.

The viscosity of a powder can be assessed based on its flowability or in association with an assessment of shape and irregularities (such as wrinkle). As discussed in Section 1174 of the United States Pharmacopoeia USP 29, 2006, four techniques are commonly used in pharmaceutical technology to assess powder flowability: angle of repose; compressibility (Carr) index and Haunus ratio; flow through a hole; and the shear cell method. For the latter two, a common scale has not yet been developed due to the diversity of methods. Flow through a hole can be used to measure flow rate or, alternatively, to determine the critical diameter that allows flow. The relevant variables are the shape and diameter of the hole, and the apparatus is made of the diameter and height and material of the powder bed. The shear cell apparatus includes cylindrical, angled, and planar deformations and provides a large degree of experimental control. For either of these two methods, a description of the apparatus and method is crucial, but despite the lack of an overall scale, they are successfully used to provide qualitative and relative characterization of powder flowability.

The angle of repose is determined as the angle of the conical pile of material relative to the horizontal base on which it has been poured. The Hounslow Ratio is the volume after the tapping is divided by the volume after the tapping (i.e., no further change in volume) or alternatively by the tapped density divided by the bulk density. The compressibility index (CI) can be calculated from the Hounslow Ratio (HR) as

CI = 100 × (1-(1-(1/HR)

Despite some variations in experimental methods, generally accepted ratios of flow properties have been published for the angle of repose, compressibility index, and Hounslow's ratio (Carr, RL, Chem. Eng. 1965, 72: 163-168).

Flow characteristics Angle of repose Hounsby Compressibility index

(%) Excellent 25-30° 1.00-1.11 ≤10 good 31-35° 1.12-1.18 11-15 Can 36-40° 1.19-1.25 16-20 qualified 41-45° 1.26-1.34 21-25 Difference 46-55° 1.35-1.45 26-31 Very poor 56-65° 1.46-1.59 32-27 Very bad ≥66° ≥1.60 ≥38

The CEMA code provides a slightly different characteristic for the angle of repose.

Angle of repose Liquidity ≤9° Very free-flowing 20-29° Free flow 30-39° generally ≥40° Slow

Powders with excellent or good flow characteristics according to the above table are characterized by non- or minimal stickiness in terms of cohesiveness, and powders with lower flowability are sticky. Powders are further divided between moderate stickiness (corresponding to acceptable or acceptable flow characteristics) and high stickiness (corresponding to any degree of poor flow characteristics). Among the angles of repose assessed by the CEMA ratio, powders with an angle of repose of ≥30° can be considered sticky, and powders of ≥40° can be considered highly sticky. Powders within each of these ranges or combinations thereof constitute various aspects of different embodiments of the present invention.

Stickiness can also be related to rugosity (a measure of the irregularities on the particle surface). Rugosity is the ratio of the actual specific surface area of a particle to that of an equivalent sphere:

Methods for direct measurement of wrinkle (such as air permeability particle measurement) are well known in the prior art. A wrinkle of 2 or greater has been associated with increased viscosity. It should be remembered that particle size also affects flowability, so that larger particles (e.g., on the order of 100 microns) can have reasonable flowability despite a slightly increased wrinkle. However, for particles intended for delivery to the deep lungs (such as particles with a primary particle diameter of 1-3 microns), even a moderately increased ruggedness or 2-6 can be sticky. Highly viscous powders can have a wrinkle of ≥10 (see Example A below).

Many of the examples below involve the use of a dry powder comprising fumaryl diketopiperazine (di-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP). The constituent particles are self-assembled assemblies of crystalline plates. It is known that powders composed of particles having plate-like surfaces have generally poor flow properties, i.e., they are sticky. Truly smooth spherical particles generally have the best flow properties, and flow properties generally decrease as the particles become elliptical, have sharp angles, become roughly two-dimensional irregular shapes, have irregular interlocking shapes, or contain fibers. Although not intending to bind, applicants understand that the crystalline plates of FDKP particles can intersect and interlock, which contributes to the stickiness (the inverse of flow properties) of the powder mass comprising them and additionally makes the powder more difficult to disintegrate than less sticky powders. Furthermore, factors affecting the structure of the particles can have an effect on aerodynamic properties. It has been found that as the specific surface area of the particles increases above a threshold value, the aerodynamic properties, measured as the respirable portion, tend to decrease. Additionally, FDKP has two chiral carbon atoms on the piperazine ring, allowing the N-fumaryl-4-aminobutyl arm to be in either a cis or trans configuration relative to the plane of the ring. It has been found that as the trans-cis ratio of FDKP used in microparticles moves away from the optimal range (or at most from the preferred range) for the respirable portion of the mixture, including racemic particles, the morphology of the particles in SEM becomes visibly different. Thus, embodiments of the present invention include this device plus FDKP powder having a specific surface area within the preferred range, as well as this device plus FDKP powder having a trans-cis isomer ratio within the preferred range.

FDKP microparticles that are not modified or loaded with drugs (e.g., insulin) form highly viscous powders. FDKP microparticles have been measured to have a Hounslow ratio of 1.8, a compressibility index of 47%, and an angle of repose of 40 °. FDKP microparticles equipped with insulin (INSULIN; Ti) have been measured to have a Hounslow ratio of 1.57, a compressibility index of 36%, and an angle of repose of 50 ° ± 3 °. Additionally, in the critical aperture test, it is estimated that in order to establish flow under gravity, a pore diameter of the order of 2 to 3 inches (60-90 cm) is required (assuming that the bed height is 2.5 inches; the pressure increased increases the size of the required diameter). Under similar conditions, free-flowing powders require a pore diameter of only the order of 1-2 cm (Taylor, M.K. et al. AAPS PharmSciTech 1, art 18).

Thus, in one embodiment, a present inhalation system is provided that includes a dry powder inhaler and a container for disintegrating a cohesive powder, including a cohesive dry powder having a calorie index ranging from 16 to 50. In one embodiment, the dry powder formulation includes a diketopiperazine including FDKP and a peptide or protein including an endocrine hormone such as insulin, parathyroid hormone, oxyntomodulin, and others mentioned in this disclosure.

Microparticles having a diameter between about 0.5 and about 10 microns are able to reach the lungs, successfully passing most natural barriers. A diameter of less than about 10 microns is required to pass through the bends in the throat, and a diameter of about 0.5 microns is required to avoid being exhaled. The embodiments disclosed herein show a specific surface area (SSA) between about 35 and about 67 ^m2 /g, which exhibits properties beneficial for drug delivery to the lungs, such as improved aerodynamic performance and enhanced drug absorption.

Disclosed herein are fumaryl diketopiperazine (FDKP) microparticles having a specific trans isomer ratio of about 45 to about 65%. In this embodiment, the microparticles provide enhanced flowability.

In one embodiment, a system for delivering an inhalable dry powder is also provided, comprising: a) a cohesive powder comprising a drug, and b) an inhaler comprising a shell defining an interior space for containing the powder, the shell comprising a gas inlet and a gas outlet, wherein the inlet and the outlet are positioned to direct the flow of gas flowing into the interior space through the inlet toward the outlet. In an embodiment, the system is used to disintegrate a cohesive powder having a Karl index from 18 to 50. The system is also used to deliver the powder when the cohesive powder has an angle of repose from 30° to 55°. The cohesive powder is characterized in that the critical pore size is ≤3.2 for funnel flow, or ≤2.4 for mass flow, and the rugosity is >2. An exemplary cohesive powder comprises particles composed of FDKP crystals, wherein the ratio of FDKP isomers is in the range of 50% to 65% trans:cis.

In another embodiment, the inhalation system can include an inhaler comprising a mouthpiece and producing a stream of particles emitted from the mouthpiece when a pressure drop of ≥2 kPa is applied across the inhaler, wherein 50% of the emitted particles have a VMAD of ≤10 microns, wherein 50% of the emitted particles have a VMAD of ≤8 microns, or wherein 50% of the emitted particles have a VMAD of ≤4 microns.

In another embodiment, a system for delivering an inhalable dry powder comprises: a) a dry powder comprising particles consisting of FDKP crystals and a drug, wherein the FDKP isomer ratio is in the range of 50% to 60% trans:cis; and b) an inhaler comprising a shell containing the powder, a shell comprising a gas inlet and a gas outlet, and a housing mounting the chamber and defining two flow paths, wherein a first flow path allows gas to enter the gas inlet of the chamber and a second flow path allows gas to bypass the gas inlet of the chamber; wherein the flow of gas bypassing the shell is directed to collide with a flow exiting the shell in a direction generally perpendicular to the gas outlet.

In some embodiments, a system for delivering an inhalable dry powder is provided, comprising: a) a dry powder comprising particles comprised of FDKP crystals and a drug, wherein the particles have a specific surface area (SSA) between about 35 and about 67 ^m2 /g and exhibit properties beneficial for drug delivery to the lungs, such as improved aerodynamics and increased drug absorption per gram; and b) an inhaler comprising a housing containing the dry powder, wherein the housing comprises a gas inlet and a gas outlet; and a housing in which the chamber is mounted and defines two flow paths, a first flow path allowing gas to enter the chamber gas inlet and a second flow path allowing gas to bypass the chamber gas inlet; wherein the flow bypassing the chamber gas inlet is directed to collide with a flow exiting the housing approximately perpendicular to a flow direction of the gas outlet.

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 cartridge containing the powder, the cartridge comprising a gas inlet and a gas outlet, and a housing in which the cartridge is mounted and defines two flow paths, a first flow path allowing gas to enter the cartridge gas inlet and a second flow path allowing gas to bypass the housing gas inlet, and a nozzle from which a stream of particles is emitted upon application of a pressure drop of ≥ 2 kPa to the inhaler, wherein 50% of the emitted particles have a VMAD of ≤ 10 microns, wherein the flow bypassing the cartridge gas inlet is directed to collide with a flow exiting the housing generally perpendicular to a flow direction of the gas outlet.

Active agents useful in the compositions and methods described herein may include any pharmaceutical agent. Examples include synthetic organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, inorganic compounds, and nucleic acid sequences with therapeutic, prophylactic, or diagnostic activity. Peptides, proteins, and polypeptides are chains of amino acids linked by peptide bonds.

Examples of active agents that can be delivered to a target or location in the body using diketopiperazine formulations include hormones, anticoagulants, immunomodulators, vaccines, cytotoxic agents, antibiotics, vasoactive agents, neurostimulants, anesthetics or analgesics, steroids, decongestants, antivirals, antisense drugs, antigens, and antibodies. More specifically, these compounds include insulin, heparin (including low molecular weight heparin), calcitonin, felbamate, sumatriptan, parathyroid hormone and its active fragments, growth hormone, erythropoietin, AZT, DDI, granulocyte macrophage colony-stimulating factor (GM-CSF), lamotrigine, chorionic gonadotropin-releasing factor, luteinizing hormone, beta-galactosidase, insulinotropic peptide, vasoactive intestinal peptide, and argatroban. Antibodies and fragments thereof may include, in a non-limiting manner, anti-SSX-2 _41-49 (synovial sarcoma, x breakpoint 2), anti-NY-ESO-1 (esophageal tumor-associated antigen), anti-PRAME (preferably expressed melanoma antigen), anti-PSMA (prostate-specific membrane antigen), anti-Messylate-A (melanoma-associated antigen), and anti-Tyrosinase (melanoma-associated antigen).

In some embodiments, dry powder formulations for delivery to the pulmonary circulation include an active ingredient or agent, including a peptide, protein, hormone, analog thereof, or combination thereof, wherein the active ingredient is insulin, calcitonin, production hormone, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), chorionic gonadotropin-releasing factor, luteinizing hormone, follicle-stimulating hormone (FSH), vasoactive intestinal peptide, parathyroid hormone (including black-bearing PTH), parathyroid hormone-related protein, glucagon-like peptide-1 (GLP-1), insulin secretagogue, oxyntomodulin, peptide YY, interleukin-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1 (RE1) or an analog, active fragment, PC-DAC-modified derivative or O-glycosylated form thereof. In certain embodiments, the pharmaceutical composition or dry powder formulation comprises a fumaryl diketopiperazine and the active ingredient is selected from the group consisting of insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin, and analogs thereof.

In one embodiment, a method of self-administering a dry powder formulation into a person's lungs using a dry powder inhalation system is also provided, comprising: obtaining a dry powder inhaler in a closed position and having a mouthpiece; obtaining a cartridge comprising a pre-metered dose of the dry powder formulation in a contained configuration; opening the dry powder inhaler to install the cartridge; closing the inhaler to execute movement of the cartridge to a metered position; placing the mouthpiece in a person's mouth, and taking a deep inhalation to deliver the dry powder formulation.

In one embodiment, a method of delivering an active ingredient comprises: a) providing a dry powder inhaler having a cartridge having a dry powder formulation comprising a diketopiperazine and an active agent; and b) delivering the active ingredient or agent to a person at a time of need. The dry powder inhaler system is capable of delivering a dry powder formulation, such as insulin FDKP, having a respirable fraction greater than 50% and a particle size less than 5.8 μm.

In another embodiment, a method for treating obesity, hyperglycemia, insulin resistance, and/or diabetes is disclosed. The method comprises administering a respirable dry powder composition or formulation comprising a composition having the formula 2,5-diketo-3,6-dione (4-X-aminobutyl) piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder composition comprises a diketopiperazine salt. In another embodiment of the present invention, a dry powder composition or formulation is provided wherein the diketopiperazine is 2,5-diketo-3,6-dione (4-X-aminobutyl) piperazine with or without a pharmaceutically acceptable carrier or excipient.

An inhalation system for delivering a dry powder formulation to a patient's lungs includes a dry powder inhaler configured with a flow conduit having a total resistance to flow ranging from a value of 0.065 to about 0.200 (kPa) per liter per minute in a metered configuration.

In one embodiment, a dry powder inhalation kit is provided comprising the dry powder inhaler described above, one or more drug cartridges comprising a dry powder formulation for treating a disease or condition such as respiratory airway disease, diabetes, and obesity.

Example 1

Measure the resistance and the flow distribution of Diskus-tube system: test some Diskus and design to measure their flow resistance-the important feature of the inhaler.Inhaler with high resistance requires bigger pressure drop to produce the flow rate identical with the inhaler of lower resistance.Importantly, in order to measure the resistance of each inhaler and tube system, various flow rates are applied to the inhaler, and measure the pressure that obtains on the inhaler. These measurements can be realized by utilizing the vacuum pump that is installed to the inhaler mouth of pipe with the supply pressure drop and change the flow controller and the manometer that flows and records the pressure that obtains. According to Bernoulli's principle, when drawing the square root of the pressure drop and the relation curve of flow rate, the resistance of inhaler is the slope of the linear portion of the curve. In these experiments, the resistance of the inhaler system that comprises Diskus described herein and tube uses resistance measuring device to measure in quantitative configuration.Quantitative configuration forms the air path by inhaler air duct and by the tube in the inhaler.

Because different inhaler designs exhibit different resistance values due to slight variations in the geometry of their air paths, multiple experiments were conducted to determine the ideal interval for pressure settings for a specific design. Based on the Bernoulli principle of linearity between the square root of pressure and flow rate, a predetermined interval for assessing linearity was determined for three inhalers used after multiple experiments, so that suitable settings could be used for other batches of the same inhaler design. An exemplary graph for an inhaler can be seen in Figure 80 for the inhalation system depicted in Figure 15I. The graph depicted in Figure 80 shows that the resistance of the inhalation system depicted in Figure 15I correlates well with the Bernoulli principle over a flow rate range of approximately 10 to 25 L/min. The graph also shows that the resistance of the exemplary inhalation system was determined to be 0.093 kPa/LPM. Figure 80 illustrates that flow and pressure are related. Thus, as the slope of the square root of pressure vs. flow curve decreases—that is, the inhalation system has a lower resistance—the flow rate changes more for a given pressure change. Thus, for a given pressure change provided by a patient using a powered breathing system, an inhalation system with higher resistance will have lower flow rate variability.

The data in Table 1 show the results of a set of experiments using the inhalers described in Figure 50 (DPI1) and Figures 15C-15K (DP12). For dry powder inhaler 1 (DPI1), the tube illustrated in design 150, Figures 35-38, was used, and the tube illustrated in design 170, Figures 39A-I was used for DP12. Thus, DP1 used tube 1 and DP2 used tube 2.

Table 1

Table 1 illustrates that the resistance of the inhalation systems tested here were 0.0874 and 0.0894 kPa/LPM for DPI 1 and DPI 2, respectively. The data shows that the flow resistance of the inhalation system is determined in part by the geometry of the air duct within the cartridge.

Example 2

Use the measurement of particle size distribution of the inhaler system with insulin formulation: with the laser diffraction equipment (Helos laser diffraction system, Sympatec Inc.) with adapter (MannKind Corp.) measure particle size distribution, the formulation of each milligram (mg) amount of insulin and fumaryl diketopiperazine granules is provided in the cartridge-inhaler system (inhaler of Figure 15C-15K with cartridge 170 shown in Figure 39 A-39I) here. One end of this device is installed to the pipe that is adapted to flow meter (TSI, Inc.Model 4043) and the valve that regulates the pressure or flow from compressed air source. Once the laser system is started, and when the laser beam is ready to measure the stream, the pneumatic valve is started to allow powder to be discharged from the inhaler. The laser system automatically measures the stream that leaves the inhaler device based on predetermined measurement conditions. The laser diffraction system is operated by the software combined with this equipment and is controlled by computer program. The measurement is made up of the sampling of powder and different powder batches that comprise different amounts. The measurement conditions are as follows:

Laser measurement start trigger condition: when ≥0.6%, the laser intensity is detected on a specific detector channel;

Laser measurement end trigger condition: when ≤0.4%, the laser intensity is detected on a specific detector channel;

The distance between the vacuum source and the inhaler chamber was approximately 9.525 cm.

Use different amounts of powder or filling mass in the tube to perform multiple tests. Only use a tube once. Determine the weight of the tube before and after the powder is discharged from the inhaler to determine the weight of the powder discharged. Under various pressure drops, determine the measurement in the equipment as shown in the following table 2 with a plurality of repeated times. Once the powder flow is measured, analyze the data and plot it into a curve. Table 2 has described the data obtained from the experiment, wherein, CE represents empty tube (powder discharge), and Q3 (50%) is the geometric diameter of the 50th percentile of the cumulative powder size distribution of the sample, and q3 (5.8 μm) represents the percentage of the particle size distribution less than 5.8 μm geometric diameter.

Table 2

The data in Table 2 shows that 92.9% to 98.4% of the total powder fill mass was ejected from the inhalation system. Furthermore, the data indicates that regardless of fill mass, 50% of the particles emitted from the inhalation system had a geometric diameter less than 4.7 μm, measured at the various times and pressure drops tested. Furthermore, between 60% and 70% of the emitted particles had a geometric diameter less than 5.8 μm.

Figure 81 depicts data obtained from another experiment using a 10 mg powder fill mass. The curve shows the particle size distribution of a sample comprising a particle formulation comprising insulin and fumaryl diketopiperazine, with 78.35% of the measured particles having a particle size of ≤5.8 μm. The laser detected an optical concentration of 37.67% under the above measurement conditions during a measurement period of 0.484 seconds. The data demonstrate that the inhalation system effectively disintegrates the insulin-FDKP formulation into small sizes within a relatively small range of user inhalation capabilities (i.e., pressure drop). These small geometric dimensions for this viscous (Carr's Index = 36%) formulation are considered respirable.

Example 3

Measurement of powder discharged from the cartridge as a measure of inhalation system performance

Use described herein to have a plurality of inhaler prototypes of describing in Figure 15 C-15K to experiment, wherein the prototype of tube 170 is shown among Figure 39 A-39I.A plurality of tubes are used for each inhaler.Each tube measures weight with electronic scale before filling.Tube is filled with the powder of predetermined mass, and measures weight again, and each tube of filling is placed in the inhaler, and tests for emptying powder formulation (that is, insulin w/w) powder batch).A plurality of pressure drops are used to characterize the consistency of performance.Table 3 has described the result that uses 35 tubes of each inhaler to discharge and measure and carry out this test.In the data in table 3, the insulin-FDK powder of clinical specification of use same batch is carried out all tests.The result shows the pressure drop of relevant user, and its scope has shown the high efficiency from tube emptying powder from 2 to 5kPa.

Table 3

Example 4

Measurements to predict deposition by the Andersen Cascade impact:

Use Andersen Cascade impactor to collect platen powder deposition in the simulation dose delivery process of flow rate 28.3LPM to carry out experiment.This flow rate causes the pressure drop in the inhalation system (DPI adds tube) to be about 6kPa.Use filter and electronic scale to analyze deposition on platen in the mode of measuring weight.For the performance evaluation of inhalation system, 10mg, 6.6mg and 3.1mg sticky powder fill weight of filling mass are measured.According to the cumulative powder mass collected on platform 2-F less than 5.8μm aerodynamic particle size measurement.Determine the ratio of the powder mass collected to the tube filling content, and be set to the percentage of respirable part (RF) to filling weight.Data are presented in Table 4.

The data shows that a range of respirable fractions from 50% to 70% is achieved using multiple powder batches. This range represents the normalized performance characteristic of the inhalation system.

Utilize different tubes to repeat inhaler system performance measurement 35 times.For the inhaler tube system of each use, measure filling mass (mg) and discharge time (second).Additionally, also measure the per-cent of respirable part (that is, the particle that is suitable for pulmonary delivery) in the powder.The result is presented in the following table 4.In table, %RF/fill equals the per-cent of the particle that can advance to the size (≤5.8 μ m) of pulmonary in the powder; CE represents the powder of empty tube or delivery; RF represents respirable part.In table 4, use the insulin-FDKP powder of the clinical specification of second batch to carry out the 1st and the 10th test, but the 11th-17th test uses the powder identical with the test that carries out and presents in table 3.

Table 4

The above data show that the present inhalation system comprising a dry powder inhaler and containing a cohesive powder (i.e., insulin (FDKP particles comprising insulin)) can effectively expel nearly all of the powder content, as a consistent and significant degree of emptying can be achieved to obtain greater than 85% and in most cases greater than 95% of the total powder content of the cartridge at varying fill masses. Andersen cascade impact measurements indicate that greater than 50% of the particles are in the respirable range, where particles are smaller than 5.7 μm and range from 53.5% to 73% of the total emitted powder.

Example 5

Insulin (TI) wrinkle

The rugosity is the ratio of the actual area of the particle to the area of an equivalent sphere. The specific surface area of a sphere is:

where _deff = 1.2 μm is the surface-weighted diameter of the TI particles from Sympatec/RODOS laser diffraction measurements.

An average sphere with the same density as the TI particle matrix (1.4 g/cm ³ ) thus has an SSA of:

Thus, for TI particles with a specific surface area (SSA) of approximately 40 m ² /g,

For similarly sized particles with a specific surface area of 50 or 60 m ² /g, the rugosity is approximately 14 and 16, respectively.

Example 6

Geometric particle size analysis of the emitted formulations by volume median geometric diameter (VMGD) characterization

Laser diffraction of dry powder formulations emitted from dry powder inhalers is a common method used to characterize the level of disintegration of powders. This method represents the measurement of geometric dimensions (not aerodynamic dimensions) that occur in industry-standard impact methods. Typically, the geometric dimensions of the emitted powder include a volume distribution characterized by the median particle size (VMGD). Importantly, the geometric dimensions of the emitted particles are distinguished with improved resolution compared to the aerodynamic dimensions provided by the impact method. Smaller sizes are preferred and result in a greater likelihood that individual particles will be delivered to the airways of the lungs. Thus, it is easier to use diffraction to distinguish differences in inhaler disintegration and final performance. In these examples, the inhaler in Example 3 and a predetermined inhaler were tested with laser diffraction at pressures similar to actual patient breathing capacity to determine the efficiency of the inhalation system's disintegrating powder formulation. Specifically, the formulations included a viscous diketopiperazine powder with or containing an ingredient containing active insulin. These powder formulations possess characteristic surface areas, isomer ratios, and Carr's indices. The VMGD and the efficiency of emptying the container during the test are reported in Table 5. FDKP powder has a Calorie index of about 50, and TI powder has a Calorie index of about 40.

Table 5

These data in Table 5 show the improvement of powder disintegration of the predetermined inhaler system compared with the inhaler system described herein. Diketopiperazines ranging in surface area from 14-56 m ² /g showed emptying efficiencies exceeding 85% and VMGDs below 7 microns. Similarly, formulations with trans isomer ratios of 45-66% showed improved performance in the predetermined device. Finally, the performance of the inhaler system characterized by a Carr index of 40-50 was also improved on the predetermined device. In all cases, the reported VMGD values were below 7 microns.

The foregoing disclosures are illustrative embodiments. Those skilled in the art will appreciate that the devices, techniques, and methods disclosed herein illustrate representative embodiments that function well in the practice of the present disclosure. However, those skilled in the art will appreciate that, based on this disclosure, many variations may be made in the disclosed embodiments without departing from the spirit and scope of the present invention, and still achieve the same or similar effects.

Unless otherwise noted, all numerical values of the amount (such as molecular weight, reaction conditions) etc. of the expression composition, performance used in the specification and claims are to be understood as being modified by the term "about" in all cases. Thus, unless otherwise noted, the numerical parameters set forth in the following specification and the appended claims are approximate values that can be devoted to the desired performance obtained and changed according to the present invention. At least, without attempting to limit the scope and purpose of the present invention, each numerical parameter should at least be understood according to the important numerical values reported and by applying common rounding techniques. Although the numerical range and parameters setting forth the scope of the present invention are approximate values, the numerical value set forth in the specific embodiments is reported as accurately as possible. However, any numerical value inherently comprises some errors, and these errors are necessarily caused by the standard deviation found from their respective test measurements.

The terms "a" and "an" and "the" and similar references used in the context of describing the present invention (particularly in the context of the claims) are to be understood to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. References to ranges of values herein are intended merely to be used as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated herein, each respective value is incorporated into the specification as if it were individually referenced therein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., such as) provided herein is intended solely to better illustrate the present invention and is not intended to limit the scope of the present invention to be protected. No language in the specification should be understood to indicate a non-protected element necessary to implement the present invention.

The use of the term "or" in the claims is intended to mean "and/or" unless explicitly stated to refer to only alternatives or the alternatives are mutually exclusive, although this disclosure supports a definition referring to only alternatives.

The groups of alternatives or embodiments of the present invention disclosed herein are not to be construed as limiting. Each group of components may be referenced or claimed individually or in combination with other components of the group or other items found herein. It is understood that one or more components of a group may be included in or deleted from the group for convenience and/or patentability. In the event of any such inclusion or deletion, the specification is deemed to contain the group as modified to complete the writing of all Markush groups used in the claims.

Preferred embodiments of the present invention are described herein, including the best embodiments known to the inventors for carrying out the present invention. Of course, variations of these preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to adapt such variations as appropriate, and the inventors intend to practice the present invention rather than to describe them specifically herein. Thus, the present invention includes all modifications and equivalents of the subject matter cited in the claims as permitted by law. Furthermore, any combination of the above in all its possible variations is encompassed by the present invention, unless otherwise indicated herein or clearly contradicted by the context.

The specific embodiments disclosed herein may be limited only in the claims that utilize the language consisting of or consisting essentially of. When used in the claims, regardless of each amendment, filing, or addition, the term "consisting of" excludes any item, step, or ingredient not specified in the claim. The term "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic. The embodiments of the invention to be protected are inherently or expressly described therein.

Additionally, throughout this specification, several references have been cited to patents and printed publications. Each of the above-cited references and printed publications is hereby incorporated by reference in its entirety.

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

Claims (20)

1. An inhalation system for delivering a dry powder drug to the trachea of the lungs, comprising a dry powder inhaler configured to have at least two inlet openings, wherein a first inlet opening communicates with a first airflow path, and a second inlet opening communicates with a second airflow path, and during inhalation, the first airflow path and the second airflow path converge perpendicularly. The inhalation system, in its metering configuration, has a total flow resistance ranging from 0.065 to 1/L/min. 2. The inhalation system of claim 1 further includes a shell for containing a dry powder drug for inhalation. 3. The inhalation system according to claim 2, wherein the shell comprises a tube. 4. The inhalation system of claim 3, wherein the cartridge includes a top and a bottom, wherein the top and bottom are configured to reach a receiving position and a metering or dispensing position. 5. The inhalation system according to claim 3, wherein the dry powder inhaler includes an inlet and a movable component. 6. The inhalation system according to claim 5, further comprising a housing. 7. The inhalation system according to claim 5, wherein the movable component comprises a slide plate, a slide disc, or a cylinder. 8. The inhalation system of claim 5, wherein the port comprises a flow conduit having a first inlet in fluid communication with ambient air, a second inlet in fluid communication with the cylinder, and an outlet. 9. The inhalation system of claim 2, wherein the shell has an internal space configured to contain the dry powder drug and has at least one inlet allowing inflow into the shell and at least one dispensing port allowing outflow from the shell; the at least one inlet is configured to direct at least a portion of the flow entering the at least one inlet at the at least one dispensing port into the shell in response to a pressure differential. 10. The inhalation system according to claim 1, wherein the total flow resistance is relatively constant over a pressure difference range between 0.5 kPa and 7 kPa. 11. The inhalation system according to claim 1, wherein the dry powder drug comprises an active ingredient. 12. The inhalation system according to claim 11, wherein the active ingredient is a hormone, anticoagulant, immunomodulator, vaccine, cytotoxic agent, antibiotic, vasoactive agent, neurostimulant, anesthetic, analgesic, steroid, decongestant, antiviral agent, antitranscription agent, antigen, or antibody. 13. The inhalation system according to claim 11, wherein the active ingredient is insulin, heparin, calcitonin, nonamino ester, sumatriptan, parathyroid hormone, growth hormone, erythropoietin, AZT, DDI, granulocyte-macrophage population stimulating factor, lamotrigine, human chorionic gonadotropin-releasing factor, corpus luteum partial-release hormone, β-lactose, insulin-secreting peptide, vasoactive intestinal peptide, vesicle-stimulating hormone, vasoactive intestinal peptide, parathyroid hormone, protein-associated parathyroid hormone, glucagon-like peptide-1, insulin-secreting peptide, gastrin, peptide YY, interleukin-2-inducible tyrosine kinase, Bruton's tyrosine kinase, cellulose-requiring kinase 1, PC-DAC-modified derivatives or O-glycosylated forms of PC-DAC, parathyroid hormone 1-34, argatroban, and combinations thereof. 14. The inhalation system according to claim 13, wherein the active ingredient is insulin. 15. The inhalation system according to claim 13, wherein the active ingredient is a gastric acid regulator. 16. The inhalation system according to claim 13, wherein the active ingredient is glucagon peptide-1. 17. The inhalation system of claim 1, wherein the dry powder drug comprises diketopiperazine. 18. The inhalation system of claim 17, wherein the diketopiperazine is 19. The inhalation system of claim 11, wherein the dry powder drug comprises a drug-acceptable carrier, an excipient, and/or a drug agent. 20. The inhalation system of claim 19, wherein the pharmaceutical agent comprises synthetic organic compounds, proteins, peptides, polysaccharides and other sugars, lipids, inorganic compounds, nucleic acid sequences and combinations thereof.