WO2024100652A1

WO2024100652A1 - High performance dry powder inhaler

Info

Publication number: WO2024100652A1
Application number: PCT/IL2023/051139
Authority: WO
Inventors: Amnon KRITZMAN-KADRON; Guy ARFIE; Arie HOLTZ
Original assignee: Kritzman Kadron Amnon; Arfie Guy; Holtz Arie
Priority date: 2022-11-07
Filing date: 2023-11-06
Publication date: 2024-05-16

Abstract

This invention is directed to dry-powder inhaler devices, kits comprising same, methods of use of same, including propellant elements for use with same. The dry powder inhaler devices comprise a casing further comprising an air inlet slit of a width slightly narrower than the width of said casing and is positined within a top vertical half whereas a powder delivery port comprising a semi-oval insert structure is located at a second terminus of the casing, distal to the air inlet, said powder delivery port and wherein the casing further contains an elongated assembly located within the interior of the casing, comprising a compartment containing a dry-powder and a porous structure encasing the dry-powder located proximally to the terminus of the elongated assembly located proximally to the powder delivery port, wherein the elongated assembly partially rotates within said casing about a single axis; and wherein air flow through the device causes rocking back and forth of the elongated assembly so that dry-powder located thereon is thereby released and becomes entrained in the air flow and air circulation through the air inlet slit and semi-oval insert structure results in enhanced vibration of the elongated assembly promoting enhanced dry-powder release from the compartment.

Description

HIGH PERFORMANCE DRY POWDER INHALER

BACKGROUND OF THE INVENTION

[0001] Dry powder inhalers (DPIs) are well-established in the treatment of various lung diseases and are also useful for systemic drug delivery. Other uses of DPIs include applications in other therapeutic treatments such as insulin delivery, allergy treatment, and cannabinoid and other cannabis plant components, such as, for example, cannabidiol (CBD).

[0002] Another advantage to the use of DPIs is their ability to be adapted for requirements of a single-dose device, which provides several advantages such as application in acute therapy, economic integration into treatment regimen in hospitals and once-only use and especially for delivering CBD for various medical treatment applications.

[0003] With the increase in life expectancy with a recognized increase in unhealthy lifestyles in many countries globally, there has been a siginficant increase in the prevalence of new industrial diseases such as asthma and COPD, where delivery of therapeutics directly via the airway would seem to have obvious benefits, including potentially reduced dosages needed for known therapeutics, as well as reduced side effects, in part due to the bypass of first pass metabolism of these agents.

[0004] In addition to the benefit of local delivery to the lungs of therapeutic agents targeting the airways, (for example bronchodilatators), DPIs may be used for systemic delivery of therapeutics, including, for example, peptides such as insulin or others, which may also provide greater bioavailability than when delivered through oral administration.

[0005] Some emerging important features of a disposable DPI device would be the presence of low resistance, the ability to deliver a dry powder under very low inhaling flow conditions of below 50 liter per minute, while also not delivering a dry powder under very high exhaling flow, so that the DPIs can be a suitable device for use by infants, elderly people, very ill pepopie, or patients with physically or mentally restricted air flow.

[0006] Widespread use of DPIs has been severly limited, since to date, the DPI dvices are difficult to use, involving complex instructions for use, which cannot be easily addressed in major populations in need, such as in young children, elderly adults, patients with any cognitive impairment and even the infirmed. As such, currently, these populations cannot make use of DPIs, despite the obvious advantages per se to local lung delivery of a therapeutic.

[0007] While DPI devices have been developed, to date, an ideal device that provides these advantages and important features and overcomes the noted difficulties in use is as yet lacking. SUMMARY OF THE INVENTION

[0008] This invention provides an inhaler device, kits and methods of use of same, with great advantages over other dry powder inhaler devices and methods.

[0009] In some aspects, the unique inhaler device, kits and methods of this invention are particularly suitable for delivery of a dry cannabinoid- or cannabidiol- containing powder.

[00010] In some aspects, the unique inhaler device, kits and methods of this invention are suitable for delivery of the dry-powder in limiting air-flow conditions, even in flow conditions far below that currently possible with existing DPIs. According to this aspect, and in some embodiments, the limiting air-flow conditions may range from 20 -50 liters per minute. In some embodiments, the limiting air-flow conditions are particularly suitable for administration to infant, elderly or mentally disabled subjects.

[00011] In some aspects, the unique inhaler device, kits and methods of this invention provide for effective dry-powder delivery wherein the particles of said dry-powder do not suffer significant agglomeration and/or provide even distribution of the released dry-powder particles.

[00012] In some aspects, the unique inhaler device, kits and methods of this invention address some of the current limitations in existing devices, in that they overcome known critical inhaler errors, which significantly reduce, or prevent entirely, deposition of medicine in the lungs. In some aspects, the inhaler devices, kits and/or methods of this invention uniquely are useful for subjects of any age, and even under conditions of low air flow resistance, while still providing a high percentage of deagglomeration and high efficiency of API deliver, thereby.

[00013] In some aspects, the invention provides unique inhaler device, kits and methods of this invention, including a booster support element, to specifically address delivery to populations, such as patients that are quite ill, elderly or young children or infants, where the inhalation air flow in these populations may be limited to less than 20 liters per minute.

[00014] In some ambodiments the devices of this invention are easy-to-use, across all populations, so that even children, the elderly and the cognitively imparted can readily and correctly use the device.

[00015] In some ambodiments, while previous DPIs had a not insignificant failure rate in use, the devices of this invention have essentially no failure rate in use.

[00016] In some ambodiments the fine praticles fraction efficiency is at least 85%, in that the percent of delivery of fine particles to the lung is at least 85% of the total loaded powder in the devices/kits of this invention, as compared to the state of the art dry powder inhalers that typically deliver from 20-50% of the loaded powder to the subject . [00017] In some ambodiments the devices of this invention can be adapted to deliver a dosage comprising different particles sizes of from 4-5 microns, or even delivery of particles sizes of from 1-2 microns.

[00018] In some aspects, the particle size may in turn be adjusted to suit a particular therapeutic use, for example, with 4-5 micron particles for delivery of therapeutics such as, for example, COPD, asthma and antibiotics for local lung delivery. In some aspects, smaller particle sizes, such as on the order of 1-2 microns may be desired for systemic delivery of a therapeutic, such as, for example, insulin, antibiotics, heart disease or cancers, where access of the terminal ramifications of the respiratory tree facilitates rapid access to the circulation.

[00019] In some ambodiments, the devices accomodate single dose administration and in some embodiments, the devices of this invention may deliver mutliple dosages.

[00020] According to this aspect, despite the fact that the devices of this invention can accomodate multi-dosage delivery, the devices do not suffer the known limitations with same in terms of drug agglomeration, due to the unique structure and organization of the device.

[00021] This invention provides, in some embodiments, a dry-powder inhaler device comprising:

• a casing comprising: o an air inlet slit located at a first terminus of said casing, wherein said slit is of a width slightly narrower than the width of said casing and wherein said slit is positined within a upper vertical half of said casing the dimensions and location of which ensures regulated air flow through the device only upon inhalation; o a powder delivery port located at a second terminus of said casing and positioned distal to said air inlet; said powder delivery port further comprising an semi-oval insert structure; and

• an elongated assembly located within an interior of said casing, comprising: o a first terminus located proximally to said air inlet; o a second terminus located proximally to said powder delivery port; o a compartment containing a dry-powder and a porous structure encasing said drypowder located proximally to said second terminus of said elongated assembly; wherein said elongated assembly is fitted within said casing such that said elongated assembly partially rotates within said casing about a single axis; and wherein inhaled air flow through said device causes said elongated assembly to rock back and forth within said casing about the single axis and to beat against said casing, and air circulation through said air inlet slit and said semi-oval insert structure results in enhanced vibration of said elongated assembly such that dry-powder is thereby released from said compartment and becomes entrained in said air flow, and wherein exhaled air flow through said device results in restricted mobility of said elongated assembly such that all rotation and vibration of said elongated assembly in said casing ceases such that dry-powder is thereby prevented from being released from said compartment during exhalation. In some embodiments, same is evident even with an exhaled air flow of over 100 L/minute.

[00022] In some aspects, the elongated assembly is comprised of stainless stell, or a Nickel- Silver alloy. In some aspects, the elongated assembly will be characterized by an elasticity of 193 Gpa. In some aspects, the elongated assembly will ahve a thickness of 0.1 mm. In other aspects, the elongated assembly will insert within a specialized housing in said casing promoting rotation about the axis as described. For example, and in some embodiments, lateral protrusions of said elongated assembly insert within specialized slots located at the appropriate connection point within the casing.

[00023] In some embodiments, the rotation of the elongated assembly within the casing about the described axis results in a beating motion of the assembly against the casing surface, which in turn facilitates release of the dry-powder from the mesh.

[00024] In some embodiments, the invention provides for a method of dispensing dry powder from an inhaler, comprising facilitating air flow through a dry-powder inhaler device including any single or combined embodiments described herein, to cause the assembly to partially rotate within the casing about a single axis and thereby release dry -powder from the compartment to become entrained in the air flow, thereby dispensing dry powder from the inhaler.

[00025] In some aspects, this invention provides a method of dispensing dry powder from an inhaler to a subject, the method comprising the steps of providing to a subject a dry-powder inhaler device of this invention, wherein :

• upon a first inhalation through said device, said elongated assembly partially rotates within said casing about a single axis to thereby release said dry-powder from said compartment to become entrained in said air flow;

• upon a first exhalation, rotation of said elongated assembly is disrupted, maintaining said dry-powder entrained in suspended air in said device; and

• upon subsequent repeat inhalations of said air suspended in said device in which said dry powder is entrained, said dry powder is delivered to a respiratory system of said subject thereby being a method of dispensing dry powder from an inhaler to a subject.

[00026] In some aspects as regarding this and other methods as described herein, the device can deliver the dry-powder in limiting air-flow conditions, as noted hereinabove, which limiting air-flow conditions are from 20-50 liters per minute, which in some aspects, provide air-flow conditions particularly suitable for administration to infant, elderly, infirmed or mentally disabled subjects.

[00027] In other embodiments, this invention provides a method of dispensing evenly- distributed dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of this invention, wherein :

• upon a first inhalation through said device, said elongated assembly partially rotates within said casing about a single axis to thereby release said dry -powder from said compartment to become entrained in said air flow;

• turbulent air flow is created within said device through the contribution of said semi-oval insert structure and said inlet slit structure, which further promotes even distribution of released dry-powder; and

• upon subsequent repeat inhalations of said air suspended in said device in which said dry powder is entrained, said dry powder is delivered to a respiratory system of said subject thereby being a method of dispensing evenly-distributed dry powder from an inhaler to a subject.

[00028] In still further aspects of thie invention method of dispensing small particle sized dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of this invention, wherein :

• turbulent air flow is created within said device through the contribution of said semi-oval insert structure and said inlet slit structure, which further promotes enhanced small particles dry-powder release and decreased agglomeration of said dry-powder particles; and

• upon a first exhalation, rotation of said elongated assembly is disrupted, maintaining said dry-powder entrained in suspended air in said device; and • upon subsequent repeat inhalations of said air suspended in said device in which said dry powder is entrained, said dry powder is delivered to a respiratory system of said subject, whereby smaller particle sizes of said dry-powder effectively access terminal ramifications of the respiratory tree in a subject; thereby being a method of dispensing small particle sized dry powder from an inhaler to a subject. [00029] According to this aspect, and in some embodiments, the invention further provides for low inhalation air flow populations, an air unique inhaler device, kits and methods of this invention, which further comprise an added propellant element, to specifically address delivery to populations, such as patients that are infirmed or ill, elderly or young children or infants, or patients with signficant respiratory problems, where the inhalation air flow in these populations may be limited to less than 20 liters per minute.

[00030] According to this aspect, and in some embodiments, the added propellant element may be referred to as a “booster kit” which can be readily fitted with other inhaler devices known in the art, for example, retrofitting existing capsule deliver inhaler devices, which are to be considered as part of this invention. In some embodiments, the propellant element may be specifically tailored for “retrofitting” commercially available inhaler devices, such as, in some embodiments, capsule inhaler devices (described further hereinunder) and this invention also contemplates kits to supply the propellant element as a “booster kit” for use with for example, specific commercially available inhalers as an add-on element.

[00031 ] This invention is also to be understood to include kits of this invention, to further manually regulate the flow through the inlet even under low air flow conditions, facilitating delivery while maintaining low pressure in the device, further regulating and preventing operation when delivery is no longer desired.

[00032] According to this aspect, and in some embodiments, the propellant element comprises:

-a container of pressurized air or gas;

-a housing through which a fluid path from an aperture of the container to the drug containing compartment is created; and

-a controller regulating release of the gas through the fluid path to a drug containing compartment. [00033] In some embodiments, the propellant element is specifically for use with the dry powder inhaler devices as herein described.

[00034] In some embodiments, the propellant element is adapted for use with any capsule delivery inhaler device.

[00035] In some embodiments, according to this aspect, the housing is operationally connected to an inhaler device casing as herein described, proximally to said air inlet slit and said pressurized air or gas upon release to said fluid path promotes dry powder release from said drug compartment and conveys said dry powder to said powder delivery port.

[00036] In some embodiments the operation of the propellant element is powered by a battery. In some embodiments, the controller of the propellant element is a solenoid. In still other embodiments, the propellant element housing further comprises a regulator flap which regulates passage of said pressurized air or gas in said fluid path from accessing said drug-containing compartment, operationally connected to said controller. In still further embodiments, the housing further comprises a relief valve for shunting excess pressurized air or gas out of said device.

[00037] In other embodiments, the propellant element furthe comprises a drug compartment in which a capsule comprising a drug is contained therein, which capsule is further modified to permit release of drug contents contained therein, whereby passage of said pressurized air or gas in said fluid path to said drug compartment promotes substantial release of the drug contents of said capsule. According to this aspect, and in some embodiments, the propellant element further comprises a conveying channel operationally connected to said capsule, wherein passage of said pressurized air or gas in said fluid path to said drug compartment promotes substantial release of the drug contents of said capsule into said conveying channel.

[00038] This invention also provides a kit comprising a dry powder inhaler device as herein described, propellant element as herein described or a combination thereof, including any embodiment described herein regarding the dry powder inhaler devices or propellant elements.

[00039] This inveniton also provides a key comprising a capsule delivery inhaler device and a propellant element as herein described.

[00040] This invention also provides a .method of dispensing drug product from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device as herein described further adapted to comprise a propellant element of this invention, wherein :

• upon release of said pressurized air or gas to said fluid path, said elongated assembly at least partially rotates or vibrates within said casing about a single axis to thereby release said dry-powder from said compartment to become entrained in said air flow; and

• inhalation of said air in which said dry powder is entrained, promotes rapid and efficient dry powder delivery to a respiratory system of said subject thereby being a method of dispensing dry powder from an inhaler to a subject.

[00041] This invention still further provides a method of dispensing drug product from an inhaler to a subject, said method comprising the steps of providing to a subject a capsule inhaler device further adapted to comprise a propellant element as herein described, wherein : • upon release of said pressurized air or gas to said fluid path, a capsule containing drug compartment in said capsule inhaler device is adapted to release drug product contents from said compartment to become entrained in air flow through said device promoted by release of said pressurized air or gas; and

• inhalation of said air in which said drug product is entrained, promotes rapid and efficient drug product delivery to a respiratory system of said subject thereby being a method of dispensing drug product from an inhaler to a subject.

[00042] According to these method aspects and in some embodiments, the device can deliver said dry-powder in limiting air-flow conditions. In some embodiments the limiting airflow conditions are from 20 -50 liters per minute and in some embodiments, the limiting air-flow conditions are from 5 -15 liters per minute. In some embodiments, the limiting air-flow conditions are particularly suitable for administration to infant, elderly or mentally disabled subjects, or subjects with respiratory diseases or disorders.

[00043] The devices, kits and/or methods of this invention provide some improvements to known dry powder inhaler devices.

[00044] Uniquely, the structural aspects of the devices of this invention provide for drypowder delivery, even in circumstances of low inhaled air flow in use of the device.

[00045] Also uniquely, and representing embodied attributes of the devices, kits and methods of this invention, whereby only inhalation facilitates the rotation of the elongated assembly comprising the dry-powder containing compartment and rotation is prevented during exhalation, even under circumstances of very high exhaled air flow through the device. According to this aspect, the dry-powder is then prevented from being released from sthe drug compartment. [00046] Still further uniquely, and representing embodied attributes of the devices, kits and methods of this invention, the semi-oval insert structure comprising part of the powder delivery port incorporation in conjunction with the narrow slit opening of the air inlet reduces the agglomeration of the delivered dry powder, in part by significantly enhancing the vibration of the rotatable elongated member (also referred to herein as the rocker), which in turn also promotes greater more consistent release of the dry powder from the compartment and which further promotes even distribution of the released dry-powder.

[00047] It will be appreciated that the semi-oval component comprising part of the powder delivery port may be prepared as an integral component of the device casing, in some aspects, and in some aspects, a separately constructed semi-oval component may be affixed within the indicated region of the casing, both of which construction methods represent embodied aspects of the invention. To encompass the fact that the semi-oval component can be an integral or attachable component to the casing, same is referred to herein as a semi-oval insert structure,

[00048] In other aspects, the device uniquely prevents rotation/vibration of the elongated assembly thereby preventing powder release during exhalation, which in turn promotes ease of use such that no special instructions are required for use to ensure proper inhalation of the full dosage being administered.

[00049] These features, in turn, in some embodiments, provide for improved treatment for the subject and potentially for reduced dosage and/or frequency as a result thereto.

[00050] In still further aspects, the invention provides a multi-use device, whereby multiple dosages or mutliple drugs can be administered to a subject, including being provided as a kit, as described further hereinunder.

BRIEF DESCRIPTION OF THE DRAWINGS

[00051] Figure 1A - IB show a dry powder inhaler device and the orientation of components therein, as representing the state of the art. Paired air inlets (1-10) are shown as is the rectengular powder delivery port (1-20) in this device. In some aspects, the casing (1-30) can comprise two components (1-30-1 and 1-30-2) that seamlessly join to assembly the full casing, for example along a plane perpendicular to a long axis of the casing.

[00052] Figure 2 schematically depicts the different powder delivery ports (2-20) constituting part of this invention, shown herein as inserts A, B and C, which were compared to the standard and their accomodation within the casing 2-30.

[00053] Figure 3A - 3D schematically depict an embodied inhaler device of the invention and the orientation of components therein. In contrast to the standard inhaler, as described further herein, unique pairing of the single slit opening of the air inlet (3-10) with a semi-oval powder delivery port (3-20) contribute to the ideal drug deliver with even distribution of de-agglomerated particles during inhalation only. Referring to Figure 3A, the midline connection point (3-90) is seen, whereby the casing components can connect. A grip on the casing (3-80) may facilitate opening of the casing and/or gripping same in use, as an optional feature. Referring to Figure 3B, the elongated assembly 3-15 may comprise lateral protrusions (3-60) on each side that are accomodated within a modified insertion part of the casing (3-70) to promote at least partial rotation of the rocker (3-40) about an axis, so that the drug containment compartment 3-50 containing the dry powder (3-55) can provide for release of the dry powder. A specilized release element, such as a mesh may further promote de-agglomeration. A removable cover 3-110 may serve to prevent contamination/promote preservation of the drug prior to use. Figure 3E depicts a top view of the elongated assembly 3-40 with lateral protrusions 3-60 and their accomodation within a specialized region 3-70 of the housing. The drug compartment 3-50 drawn to highlight a potential mesh or other specialized release modification is evident as well. An immobilizer cap 3- 100 as depicted in Figure 3F may be used to immobilize the elongated assembly during shipping and storage, for example, through its insertion in the drug delivery port 3-20. Figure 3G depicts the inclusion of a covering 3-110 placed over the elongated assembly 3-15, which may in some aspects prevent powder/drug from being dispersed prior to intended use and in some aspects, may serve to prevent contamination of the product or retention of humidity.

[00054] Figure 4 plots the results of a de-agglomeration assay of dry powder distribution when the newly embodied devices containing the indicated insert were compared to the standard device in conditions of. In the final product according to the new invention the result, the selected oval insert solution is implemented in the final structure of the device case. Bar 2.1 is the standard DPI comparison, 2.2 refers to use of hte small turbulence insert (A); 2.3 refers to the big turbulence insert (B) and 2.4 refers to the semi-oval turbulence insert (C).

[00055] Figure 5 plots the results of a 3 repeated tests of the precentage dry powder release when the newly embodied devices containing the indicated oval insert at different air flows conditions from 40 L/min up to 100 L/min with 45 micron sieve covering the dry powder.

[00056] Figure 6A plots the sustainable consistent results of evenly distributed dry powder release of different products at a flow rate of 1001/minute, when using an embodied inhaler device of this invention.

[00057] Figure 6B plots the sustainable consistent results of DPI insipiratory resistance different products at a flow rate of 20 1/minute, when using an embodied inhaler device of this invention.

[00058] Figure 7A-7B schematically depicts an embodied inhaler device of this invention, illustrating an alternate means by which the casing may be opened (as compared to figure IB) to provide access to replace the embodied elongated assembly 7-40, for example, by separating along an axis parallel to the long axis of the casing. The basic components as described in Figures 3A- 3F are also depicted in this figure, with Figure 7B providing an exploded view of how the upper and lower halves of the casings can be joined with a fitted mechanism to promote seamless joining. Figure 7C depicts the elongated assembly 7-40 with a removable cover 7-110 with arrows indicating the direction of removal when assembled with Figure 7D shows depicting the exposed upper release element of the drug powder compartment 7-55 once the cover is removed. Figure 7E provides an embodied kit tray 7-120 containing multiple embodied elongated assemblies 7-40. [00059] Figures 8A-8B schematically depict an embodied inhaler device, further adapted to incorporate a mask element 8-150, which can cover the mouth and nose of a user, such as a small child, and a connector 8-160 may be included to attach same to the inhaler devices 8-05. [00060] Figures 9A-9B schematically depict embodied inhaler devices, further adapted for insertion in a single nostril when direct delivery to the nasopharynx for example is desired. Figures 9C-9D schematically depict embodied inhaler devices, further adapted for insertion in both nostrils when direct delivery to the nasopharynx for example is desired.

[00061] Figures 10A-10B schematically depict embodied inhaler devices, further adapted to incorporate a pacifier element for delivery of the drug product.

[00062] Figure 11A-11B schematically depict a non-limiting embodied inhaler device which incorporates a propellant element to promote greater release of the dry powder contents, for example for use with subjects who are infirmed or otherwise unable to promote good air flow through the device, in assembled (11A) and exploded (1 IB) view.

[00063] Figure 12A-12B schematically depict a non-limiting embodied capsule inhaler device, comprising a propellant element to promote greater release of the capsular contents, in assembled (12A) and exploded (12B) view.

[00064] Figure 13 schematically depicts another non-limiting embodied capsule inhaler device, comprising a propellant element to promote greater release of the capsular contents, in assembled (inset) and exploded view.

[00065] Figure 14 schematically depicts another non-limiting embodied capsule inhaler device, comprising a propellant element to promote greater release of the capsular contents, in assembled (inset) and exploded view.

DETAILED DESCRIPTION OF THE INVENTION

[00066] This invention provides, in some embodiments, a dry-powder inhaler device comprising:

• a casing comprising: o an air inlet slit located at a first terminus of said casing, wherein said slit is of a width slightly narrower than the width of said casing and wherein said slit is positined within an upper vertical half of said casing; o a powder delivery port located at a second terminus of said casing and positioned distal to said air inlet, said powder delivery port further comprising a semi- oval insert structure; and

• an elongated assembly located within an interior of said casing, comprising: o a first terminus located proximally to said air inlet; o a second terminus located proximally to said powder delivery port; o a compartment containing a dry -powder and a porous structure encasing said dry-powder located proximally to said second terminus of said elongated assembly; wherein said elongated assembly is fitted within said casing such that said elongated assembly partially rotates within said casing about a single axis; and wherein air flow directed through said device from the air inlet to the powder delivery port causes said elongated assembly to rock back and forth within said casing about the single axis and to beat against said casing, whereby dry-powder is thereby released from said compartment and becomes entrained in said air flow; and wherein air circulation through said air inlet slit and said oval insert structure results in enhanced vibration of said elongated assembly promoting enhanced dry-powder release from said compartment.

[00067] In some aspects, the dry-powder is release from the compartment is via release from a porous structure, which promotes de- agglomeration of the powder particles while the released powder becomes entrained in the air flow.

[00068] In other aspects, the air circulation through the air inlet slit and semi-oval powder delivery port structure results in enhanced vibration and beating of the structure against the interior part of the casing, promoting enhanced dry-powder release from the compartment, in a unidirectional manner, i.e. only when the air flow direction is from the inlet slit to the powder delivery port. According to this aspect, the elongated assembly is prevented form vibration/rotation when the air flow direction is from the delivery port to the inlet, during exhaling.

[00069] The inhalers of this invention are dry-powder inhaler devices, comprising a casing, such as, for example, a rectangular or tubular shaped box or enclosure. In certain embodiments, the casing includes an elongated longitudinal assembly, and includes a first terminus and a second terminus opposite the first terminus. The casing further includes an air inlet located at the first terminus of the casing and a powder delivery port located at the second terminus of the casing, said powder delivery port being located distal to the air inlet.

[00070] The term “casing” refers to, inter alia, the container comprising the various elements of the device as described herein.

[00071] The casing may be of any appropriate material, including, in some embodiments, any plastic or other appropriate synthetic material, which may be prepared to conform to the desired structure and will contain or comprise the elements described herein. In some embodiments, the casing may comprise a polypropylene, which may optionally further comprise additives that prevent static, or in some aspects, the casing may be constucted of other suitable materials, such as, but not limited to polycarbonate, or HPE.

[00072] In some embodiments, the casing is substantially rectangular. In some embodiments, the casing is substantially cuboidal, or in some embodiments, the casing is substantially columnar, or in some embodiments, the casing is substantially oval, in shape.

[00073] In some embodiments, the casing length may vary from about 35 - 55 mm in length and from about 10-25 mm in in height and from 10 - 25 mm in width.

[00074] In some embodiments, the casing length may be about 40 or in some embodiments, about 43, or in some embodiments, about 45, or in some embodiments, about 46, or in some embodiments, about 47, or in some embodiments, about 48, or in some embodiments, about 49 mm in length.

[00075] In some embodiments, the casing height may be about 10 or in some embodiments, about 11, or in some embodiments, about 12, or in some embodiments, about 13, or in some embodiments, about 14, or in some embodiments, about 15, or in some embodiments, about 16, or in some embodiments, about 17, or in some embodiments, about 18, or in some embodiments, about 19, mm in height.

[00076] In some embodiments, the casing height may be about 10 or in some embodiments, about 11, or in some embodiments, about 12, or in some embodiments, about 13, or in some embodiments, about 14, or in some embodiments, about 15, or in some embodiments, about 16, or in some embodiments, about 17, or in some embodiments, about 18, or in some embodiments, about 19, mm in width.

[00077] In some embodiments, the air inlet slit will be about 10 or in some embodiments, about 11, or in some embodiments, about 12, or in some embodiments, about 13, or in some embodiments, about 14, or in some embodiments, about 15, or in some embodiments, about 16, or in some embodiments, about 17, or in some embodiments, about 18, or in some embodiments, about 19, mm in width and in some embodiments, the air inlet slit is positioned at about 1-5 mm from the top of the casing.

[00078] The casing will include two openings placed at opposite ends of the casing. One such opening is the air inlet, which inlet is sufficient in size to facilitate air entry and exit therefrom. Another opening in the casing is a powder delivery port, which powder delivery port is positioned at an opposite end of the casing from that of the air inlet and is of sufficient size and shape to promote greater turbulence as described herein

[00079] As described herein, the air inlet conains a horizontal slit, which is of a width, which in some embodiments, is slightly narrower, or in some embodiments, from 1-5% narrower, or in some embodiments, from 1-10% narrower in dimension than the width of said casing.

[00080] In some embodiments, the air inlet slit is positioned within an upper half of said casing, relative to a vertical which in some embodiments, is from 0.5 - 7 mm from the upper surface of the casing

[00081] The powder delivery port is an opening, and is, generally, larger in size, in terms of overall area, than the size of the air inlet.

[00082] The casings of this invention may be prepared by any means and may include, for example, designs which include two halves of the casing, which may be hermetically and permanently sealed, or in some aspects, the casing may comprise joint regions to allow access to the drug-containing component of the device located therein. In some embodiments, the casing is connected substantially at a midline along a vertical axis and in some embodiments, the casing is connected substantially at a midline along a horizontal axis to allow the interior of same to be sealably accessible.

[00083] In some aspects, the casing is connected at a desired location along a vertical axis and in some embodiments, the casing is connected at a desired location along a horizontal axis to allow the interior of same to be sealably accessible.

[00084] It will be appreciated that the casing may be prepared by molding or other conventional means.

[00085] In some embodiments, the casings may be constructed so as to constitute substantially separately slidable halves which are substantially displaceable in an orientation parallel to a long axis of the casing. According to this aspect, and referring for example to Figures 7A-7D, such separation reveals the elongated assembly located therein, and facilitates exchange of same, for example, as would be helpful in a multi-dose or kit version of the devices of this invention.

[00086] For example, and as depicted herein, an upper separatable section of the casing (7- 30-1) can be slidably separated from a lower section of the casing (7-30-2), which when joined, seamlessly connect ensuring rotation of the elongated assembly (7-40) such that striking of the assembly on an inner surface of the casing can promote release of the drug (7-55) from the dry powder compartment (7-50) through the specialized containment means, such as a mesh. The elongated assembly (7-40) is rotatably affixed to the casing interior at a specialized insertion region (7-70) which promotes rotation about an axis.

[00087] Figure 7B schematically depicts the separation of the upper and lower casing sections showing insertion regions accomodating the seamless fit promoted between the two halves.

[00088] As described herein this invention envisions kits containing replaceable elongated assemblies containing multiples of the same dosage of a desired drug, different drugs, or different dosages of a desired drug, etc., according to any prescribed, desired regimen. According to this aspect, and in some embodiments, a sealed tray such as depicted in Figure 7E or other appropriate packaging is envisioned, whereby multiple elongated assemblies (7-40) are contained therein. Figure 7D depicts one such elongated assembly 7-40, where the specialized containment means (7-55) for the drug powder compartment is highlighted. This containment means can be a mesh or a covered depot or any suitable release aspect, promoting delivery of the powder contained in the compartment, and in some aspects, may further promote de-agglomeration of the powder, for example, via sieving action. In a kit setting, for example, containment of the drug within the compartment for long term storage may be further facilitated by a removable cover (7-110), whcih can be pulled in the direction of the arrows as evident in Figure 7C, such that when the new elongated assembly is placed in the device, as depicted in Figure A after assembly, the drug compartment is now exposed and ready for use.

[00089] In other embodiments, the casings may be constructed so as to constitute substantially separating halves displaceable in an orientation perpendicular to a long axis of the casing, whereby the elongated assembly located therein is also fully accessible, and the releasable sealing of the separated parts of the casing facilitates exchange of same, as described.

[00090] According to this aspect, and in some embodiments, the powder delivery port is further adapted to comprise an oval insert structure. In some embodied aspects, the oval insert structure comprises an oval hollowed region, which is located at or near a central axis of the device. [00091] In some embodiments, the oval hollowed region occupies most of the volume of the oval insert structure.

[00092] In other embodiments, the oval hollowed region is located substantially centrally in said oval insert structure.

[00093] In some embodiments, the oval hollowed region may further comprise apertures assuming a slit-like structure, flanking said oval hollowed region, wherein said apertures are located approximately midway between an upper and lower boundary of said oval insert structure. [00094] The inhaler devices of the present invention further include an elongated assembly located within an interior cavity of the casing. The elongated assembly includes a first terminus and a second terminus opposite the first terminus. In some embodiments, the first terminus is located proximally to the air inlet, and the second terminus is located proximally to the powder delivery port. In certain embodiments, the elongated assembly is fitted, affixed or otherwise rotatably arranged, within the casing such that the elongated assembly partially rotates, angles or pivots, within the casing about a single axis. [00095] In some embodiments, the elongated assembly comprises a compartment containing a dry -powder and a porous structure encasing the dry-powder located proximally to the second terminus of the elongated assembly.

[00096] In some embodiments, the elongated assembly will comprise metal, which in some embodiments, may be steel or other suitable material.

[00097] In some embodiments, the elongated assembly will comprise a different material than that of the compartment. In some embodiments, the compartment is contiguous in structure with that of elongated assembly, for example it has an indent for containing the medicament. In some embodiments, the compartment is bonded, welded or otherwise attached to the elongated assembly.

[00098] In some embodiments, according to this aspect, dry-powder exit from the inhaler device of this invention is facilitated by the beating action, or abutment of the elongated assembly against an interior surface of the casing, which results in powder egress from the porous structure encasing the dry-powder and further facilitated by vibration and turbulent flow created as a result of the structural elements, of the slit aperture inlet and the semi-oval insert structure as described herein.

[00099] In other embodiments of this aspect, the air inlet slit structure enables roation of the elongated assembly about the axis during inhalation, and in some embodiments, the air inlet slit structure prevents rotation of the elongated assembly during exhalation.

[000100] In other embodiments, according to this aspect, the air inlet slit structure is substantially rectangular in shape

[000101] In still further embodiments of this aspect of the invention, the porous structure is a woven stainless steel material and in some embodiments, the porous structure is comprised of a stainless steel foil.

[000102] In still further embodiments of this aspect of the invention, the porous structure is comprised of a material such as a non-woven mesh material or perforated stainles steel or perforated appropriate material which in some embodiments, may be comprised of a stainless steel foil.

[000103] In still further embodiments of this aspect of the invention, the porous structure comprises a pore size range of about 25-200 microns, which in some embodiments is a pore size range of about 45 or 150 microns.

[000104] In still further embodiments of this aspect of the invention, the porous structure can be welded, glued or crimped to the elongated assembly.

[000105] In still further embodiments of this aspect of the invention, the porous structure can be welded, glued, or crimped to a non- integral part of the elongated assembly, which following dry powder filling can be appropriately affixed to the elongated assembly. [000106] In still further embodiments of this aspect of the invention, the porous structure can be an integral part of the elongated assembly wherein the compartment is assembeled under the perforated part of the elongated assembly.

[000107] In still further embodiments of this aspect of the invention, the dimensions of the porous structure encasing the dry-powdermay be scaled to accomodate smaller and larger quantities of dry powder for inclusion in said device. According to this aspect, and in some embodiments, a quantity of said powder may range from about 1-250 mg. It will be appreciated however, that the quantity of powder may be any appropriate amount that can be accomodated within the devices of this invention and this range is by way of example, but should not be construed to be limiting to same.

[000108] In some embodiments, the inhaler furhter comprises an immobilizer cap, which immobilizer cap attaches to said powder delivery port and which immobilizer cap prevents substantial rotation of said elongated assembly about said single axis.

[000109] In some aspects, the unique inhaler device, kits and methods of this invention provide for hygienic handling for inexperienced patients and in some aspects, which in some embodiments may be provided when the inhaler device is a single-use disposable inhaler.

[000110] In other aspects, the inhaler device may be resealable, such that certain elements of the device may be provided separately, for example, for administration of multiple dosages provided over time. According to this aspect, in some embodiments, the resealable device provides for the elongated assembly being replaced in the device.

[000111] In some aspects, this invention also provides a kit comprising at least one drypowder inhaler device of this inventionand one or more mouthpieces, which mouthpieces may attach to the powder delivery port of the device.

[000112] According to this aspect and in some embodiments, the kit contains a plurality of elongated assembly components, comprising multiple dosages of dry powder to deliver a desired dosage regimen.

[000113] . In some embodiments, the mulitple dosages represent identical daily administration dosages. In some embodiments, the multiple dosages represent different administration dosages, different therapeutics or a combination thereof.

[000114] In another embodiment, the elongated assembly components may be fitted with replacable cartridges containing the porous structure encasing the dry-powder, and the cartridges are readily replaced.

[000115] It will be appreciated that any number of means to render the inhaler device as reusable are envisioned and known to the skilled artisan and any such disposable or reusable inhaler with the structural and functional attributes described herein as part of the envisioned devices are to be considered as part of this invention.

[000116] In some aspects, the unique inhaler device, kits and methods of this invention deliver a dry powder, which is a plant-based therapeutic, which in some aspects is cannabidiol or a cannabinoid.

[000117] In some embodiments, the dry powder may comprise any therapeutic agent, for example, and in some embodiments, a drug, anibiotic or vaccine.

[000118] In some embodiments, any drug or drugs which may be administered by inhalation and which are either a solid or may be incorporated in a solid carrier are envisioned for incorporation within the inhalers, kits and/or methods of this invention.

[000119] In some embodiments, the drug will be a drug for the treatment of a respiratory disease or condition .

[000120] In some embodiments, one of the respiratory diseases/conditions envisioned as being helped through use of the devices/methods/kits of this invention is COPD.

[000121] In some embodiments, such drugs may comprise bronchodilators, corticosteroids and drugs for the prophylaxis of asthma.

[000122] Other drugs such as anorectics, anti-depressants, anti-hypertensive agents, anti- neoplastic agents, anti-cholinergic agents, dopaminergic agents, narcotic analgesics, beta- adrenergic blocking agents, prostaglandins, sympathomimetics, tranquilizers, steroids, vitamins and/or hormones may be employed.

[000123] Exemplary drugs may include: Salbutamol, Terbutaline, Rimiterol, Fentanyl, Fenoterol, Pirbuterol, Reproterol, Adrenaline, Isoprenaline, Ociprenaline, Ipratropium, Beclomethasone, Betamethasone, Budesonide, Disodium Cromoglycate, Nedocromil Sodium, Ergotamine, Salmeterol, Fluticasone, Formoterol, Insulin, Atropine, Prednisolone, Benzphetamine, Chlorphentermine, Amitriptyline, Imipramine, Cloridine, Actinomycin C, Bromocriptine, Buprenorphine, Propranolol, Eacicortone, Hydrocortisone, Fluocinolone, Triamcinclone, Dinoprost, Xylometazoline, Diazepam, Lorazepam, Folic acid, Nicotinamide, Clenbuterol, Bitolterol, Ethinyloestradiol and Levenorgestrel. Drugs may be formulated as a free base, one or more pharmaceutically acceptable salts or a mixture thereof.

[000124] The devices, kits and/or methods of the present invention may be particularly suitable to dispense dry powder substances in vivo to subjects, including animals and, typically, human subjects. The dry powder substance may include one or more active pharmaceutical constituents as well as biocompatible additives that form the desired formulation or blend.

[000125] As used herein, the term “dry powder” is used interchangeably with “dry powder formulation” and means the dry powder can comprise one or a plurality of constituents or ingredients with one or a plurality of (average) particulate size ranges. [000126] In some embodiments, individual dispensable quantities of dry powder formulations can be a single ingredient or a plurality of ingredients, whether active or inactive. The inactive ingredients can include additives added to enhance flowability or to facilitate aerosolization delivery to the desired systemic target. The dry powder drug formulations can include active particulate sizes that vary.

[000127] The dry powder formulation can also include desired excipients. Examples of excipients include lactose and trehalose. Other types of excipients can also be employed, such as, but not limited to, sugars which are approved by the United States Food and Drug Administration (“FDA”) as cryoprotectants (e.g., mannitol) or as solubility enhancers (e.g., cyclodextrine) or other generally recognized as safe (“GRAS”) excipients.

[000128] Examples of diseases, conditions or disorders that may be treated or prevented with the inhalers, kits and/or methods of the invention include, but are not limited to, asthma, COPD (chronic obstructive pulmonary disease), viral or bacterial infections, influenza, allergies, and other respiratory ailments as well as diabetes and other related insulin resistance disorders. The dry powder inhalant administration may be used to deliver locally acting agents such as antimicrobials, protease inhibitors, and nucleic acids/oligionucleotides as well as systemic agents such as peptides like leuprolide and proteins such as insulin or anti-cancers agents.

[000129] For example, inhaler-based delivery of antimicrobial agents such as antitubercular compounds, proteins such as insulin for diabetes therapy or other insulin-resistance related disorders, peptides such as leuprolide acetate for treatment of prostate cancer and/or endometriosis and nucleic acids or ogligonucleotides for cystic fibrosis gene therapy may be performed. See e.g. Wolff et al., Generation of Aerosolized Drugs, J. Aerosol. Med. pp. 89-106 (1994). See also U.S. Patent Application Publication No. 20010053761, entitled Method for Administering ASPB28- Human Insulin and U.S. Patent Application Publication No. 20010007853, entitled Method for Administering Monomeric Insulin Analogs, the contents of which are hereby incorporated by reference as if recited in full herein.

[000130] Typical dose amounts of the unitized dry powder mixture dispersed in the inhaler will vary depending on the patient size, the systemic target, and the particular drug. Typical doses that can be delivered by the inhaler range from about 5-250 mg.

[000131] In some embodied aspects of the invention, the inhalers of this invention uniquely provide for even distribution and reduced agglomeration of dry powders, even with dry powder quantities that exceed 10 mg having ah fine particles fraction (FPF) of over 85%.

[000132] Some additional exemplary dry powder drugs include, but are not limited to, albuterol, fluticasone, beclamethasone, cromolyn, terbutaline, fenoterol, P-agonists (including long-acting P-agonists), salmeterol, formoterol, cortico-steroids and glucocorticoids. [000133] In certain embodiments, the administered bolus or dose can be formulated with an increase in concentration (an increased percentage of active constituents) over conventional blends or even pure API (active pharmaceutical ingredient). Further, the dry powder formulations may be configured as a smaller administrable dose compared to the conventional doses. For example, each administrable dry powder dose may be on the order of less than about 60-70% of that of conventional doses.

[000134] In certain particular embodiments, using the active dispersal systems provided by certain embodiments of the DPI configurations of the instant invention, the adult dose may be reduced to under about 15 mg, such as between about lmg-5 mg but not limited to any administration quantity.

[000135] The active constituent(s) concentration may be between about 5-10%. In other embodiments, active constituent concentrations can be in the range of between about 10-20%, 20- 25%, or even larger, up to the case where only pure drug is delivered.

[000136] In certain particular embodiments, during dose dispensing, the dry powder in a particular dose receptacle may be formulated as an active pharmaceutical constituent(s) (API) substantially without additives (such as excipients). As used herein, “substantially without additives” means that the dry powder is in a substantially pure active formulation with only minimal amounts of other non-biopharmacological active ingredients. The term “minimal amounts” means that the non-active ingredients may be present, but are present in greatly reduced amounts, relative to the active ingredient(s), such that they comprise less than about 10%, and preferably less than about 5%, of the dispensed dry powder formulation, and, in certain embodiments, the non-active ingredients are present in only trace amounts.

[000137] In some embodiments, the therapeutic agent can be a biologic, which includes but is not limited to proteins, polypeptides, carbohydrates, polynucleotides, and nucleic acids. In some embodiments, the protein can be an antibody, which can be polyclonal or monoclonal. In some embodiments, the therapeutic can be a low molecular weight molecule. In addition, the therapeutic agents can be selected from a variety of known pharmaceuticals such as, but are not limited to: analgesics, anesthetics, analeptics, adrenergic agents, adrenergic blocking agents, adrenolytics, adrenocorticoids, adrenomimetics, anticholinergic agents, anticholinesterases, anticonvulsants, alkylating agents, alkaloids, allosteric inhibitors, anabolic steroids, antacids, antidiarrheals, antidotes, antifolics, antipyretics, antirheumatic agents, psychotherapeutic agents, neural blocking agents, anti-inflammatory agents, antihelmintics, anti- arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antifungals, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antimalarials, antiseptics, antineoplastic agents, antiprotozoal agents, immunosuppressants, immunostimulants, antithyroid agents, antiviral agents, anxiolytic sedatives, bone and skeleton agents, astringents, beta-adrenoceptor blocking agents, cardiovascular agents, chemotherapy agents, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, enzymes and enzyme cofactors, gastrointestinal agents, growth factors, hematopoietic or thrombopoietic factors, hemostatics, hematological agents, hemoglobin modifiers, hormones, hypnotics, immunological agents, antihyperlipidemic and other lipid regulating agents, muscarinics, muscle relaxants, parasympathomimetics, parathyroid hormone, calcitonin, prostaglandins, radio pharmaceuticals, sedatives, sex hormones, anti-allergic agents, stimulants, steroids, sympathomimetics, thyroid agents, therapeutic factors acting on bone and skeleton, vasodilators, vaccines, vitamins, and xanthines. Antineoplastic, or anticancer agents, include but are not limited to paclitaxel and derivative compounds, and other antineoplastics selected from the group consisting of alkaloids, antimetabolites, enzyme inhibitors, alkylating agents and antibiotics. [000138] Exemplary proteins, include therapeutic proteins or peptides, or carrier proteins or peptides, including GCSF; GMCSF; EHRH; VEGF; hGH; lysozyme; alpha-lactoglobulin; basic fibroblast growth factor basic fibroblast growth factor; (bFGF); asparaginase; tPA; urokin- VEGF; chymotrypsin; trypsin; streptokinase; interferon; carbonic anhydrase; ovalbumin; glucagon; ACTH; oxytocin; phosphorylase b; secretin; vasopressin; levothyroxin; phatase; betagalactosidase; parathyroid hormone, calcitonin; fibrinogen; polyaminoacids (e.g., DNAse, alphal antitrypsin; polylysine, poly arginine); angiogenesis inhibitors or pro-immunoglobulins (e.g., antibodies); somatostatin and analogs thereof; casein; collagen; soy protein; and cytokines (e.g., interferon, interleukin and others); immunoglobulins.

[000139] Exemplary hormones and hormone modulators include proinsulin, C -peptide of insulin, a mixture of insulin and C-peptide of insulin, hybrid insulin cocrystals, growth hormone, parathyroid hormone, luteinizing hormone-releasing hormone (LH-RH), adrenocorticotropic hormone (ACTH), amylin, oxytocin, luteinizing hormone, (D-Tryp6)-LHRH, nafarelin acetate, leuprolide acetate, follicle stimulating hormone, glucagon, prostaglandins, steroids, estradiols, dexamethazone, testosterone, and other factors acting on the genital organs and their derivatives, analogs and congeners.

[000140] Exemplary hematopoietic or thrombopoietic factors include, among others, erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF), leukocyte proliferation factor preparation, thrombopoietin, platelet proliferation stimulating factor, megakaryocyte proliferation (stimulating) factor, and factor VIII.

[000141] Exemplary therapeutic factors acting on bone and skeleton and agents for treating osteoporosis include calcium, alendronate, bone GLa peptide, parathyroid hormone and its active fragments, histone H4-related bone formation and proliferation peptide and their muteins, derivatives and analogs thereof.

[000142] Exemplary enzymes and enzyme cofactors include: pancrease, L-asparaginase, hyaluronidase, chymotrypsin, trypsin, tPA, streptokinase, urokinase, pancreatin, collagenase, trypsinogen, chymotrypsinogen, plasminogen, streptokinase, adenyl cyclase, and superoxide dismutase (SOD).

[000143] Exemplary vaccines include Hepatitis B, Influenza, MMR (measles, mumps, and rubella), and Polio vaccines and others.

[000144] Exemplary growth factors include nerve growth factors (NGF, NGF-2/NT-3), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transforming growth factor (TGF), platelet-derived cell growth factor (PDGF), hepatocyte growth factor (HGF) and so on.

[000145] Exemplary agents acting on the cardiovascular system include factors which control blood pressure, arteriosclerosis, etc., such as endothelins, endothelin inhibitors, endothelin antagonists, endothelin producing enzyme inhibitors vasopressin, renin, angiotensin I, angiotensin II, angiotensin III, angiotensin I inhibitor, angiotensin II receptor antagonist, atrial naturiuretic peptide (ANP), antiarrythmic peptide and so on.

[000146] Exemplary factors acting on the central and peripheral nervous systems include opioid peptides (e.g. enkephalins, endorphins), neurotropic factor (NTF), calcitonin gene-related peptide (CGRP), thyroid hormone releasing hormone (TRH), salts and derivatives of TRH, neurotensin and so on.

[000147] Exemplary chemotherapeutic agents, such as paclitaxel, mytomycin C, BCNU, and doxorubicin.

[000148] Exemplary agents acting on the respiratory system include factors associated with asthmatic responses, e.g., albuterol, fluticazone, ipratropium bromide, beclamethasone, and other beta- agonists and steroids.

[000149] Exemplary steroids include but are not limited to beclomethasone (including beclomethasone dipropionate), fluticasone (including fluticasone propionate), budesonide, estradiol, fludrocortisone, flucinonide, triamcinolone (including triamcinolone acetonide), and flunisolide. Exemplary beta-agonists include but are not limited to salmeterol xinafoate, formoterol fumarate, levo-albuterol, bambuterol, and tulobuterol.

[000150] Exemplary anti-fungal agents include but are not limited to itraconazole, fluconazole, and amphotericin B .

[000151] Numerous combinations of active agents may be desired including, for example, a combination of a steroid and a beta-agonist, e.g., fluticasone propionate and salmeterol, budesonide and formoterol, etc.

[000152] In some aspects of this invention, the compartment containing a dry-powder and a porous structure encasing said dry-powder may also be referred to herein as the dry-powder assembly, which may comprise, in some embodiments, one or more compartments, with each compartment comprising a dry-powder. In some embodiments, when the dry-powder assemblies comprise more than one compartment, each compartment may comprise the same or different drypowders.

[000153] In some embodiments, the dry-powder assembly comprises two or three compartments containing a dry-powder. According to this aspect, and in some embodiments, the two or three compartments comprise two or three different dry-powders.

[000154] In some embodiments, the dry-powder assembly comprises a compartment containing at least one or two partitions, which partitions create separate chambers in the compartment. According to this aspect, and in some embodiments, the separate chambers may contain different dry -powders.

[000155] The inhalers, kits and/or methods of the present invention, inter alia is well suited to deliver two or more inhaled dry-powder drugs simultaneously while storing them separately. In some embodiments, according to this aspect, a technical challenge in the inhaler industry involving the storage of two or more drugs, which is potentially problematic for both chemical and regulatory reasons, is obviated by certain embodiments of this invention.

[000156] From a chemical perspective, the co-storage of two or more drugs within the same physical compartment can be problematic as the two drugs may interact, especially if they have different pHs. From a regulatory standpoint, it may be necessary to prove that there is no such interaction over a long time period, and this can add significant expense to the regulatory approvals process.

[000157] In some embodiments, the rotation of the elongated assembly within the casing about the described axis results in a beating motion of the assembly against the casing surface, which in turn facilitates release of the dry-powder from the mesh.

[000158] In some embodiments, the invention provides for a method of dispensing dry powder from an inhaler, comprising facilitating air flow through a dry-powder inhaler device including any single or combined embodiments described herein, to cause the assembly to at least partially rotate within the casing about a single axis and thereby release dry-powder from the compartment to become entrained in the air flow, thereby dispensing dry powder from the inhaler. [000159] In some aspects, this invention provides a method of dispensing dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device as herein described, wherein : • upon a first inhalation through said device, said elongated assembly at least partially rotates within said casing about a single axis to thereby release said dry-powder from said compartment to become entrained in said air flow;

[000160] In some aspects as regarding this and other methods as described herein, the device can deliver the dry-powder in limiting air-flow conditions, as noted hereinabove, which limiting air-flow conditions are from 35 -50 liters per minute, which in some aspects, provide air-flow conditions particularly suitable for administration to infant, elderly or mentally disabled subjects. [000161] According to this aspect and in some embodiments, the methods and devices as described herein can deliver the dry powder even in circumstances, wherein the air flow resistance is 0.011 kPa min/L, the lowest as compared to other DPIs, as presented in Figure 4B is the invention.

[000162] In other embodiments, this invention provides a method of dispensing evenly- distributed dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of this invention, wherein :

• turbulent air flow is created within said device through the contribution of said semi-oval insert structure and said inlet slit structure, which further promotes even distribution and exceeding from about 85% precent of the released dry powder to the patient; and

• upon subsequent repeat inhalations of said air suspended in said device in which said dry powder is entrained, said dry powder is delivered to a respiratory system of said subject thereby being a method of dispensing evenly-distributed dry powder from an inhaler to a subject. [000163] In still further aspects of thie invention method of dispensing small particle sized dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of this invention, wherein :

• upon a first inhalation through said device, said elongated assembly at least partially rotates within said casing about a single axis to thereby release said dry -powder from said compartment to become entrained in said air flow;

• upon subsequent repeat inhalations of said air suspended in said device in which said dry powder is entrained, said dry powder is delivered to a respiratory system of said subject, whereby smaller particle sizes of said dry-powder effectively access terminal ramifications of the respiratory tree in a subject; thereby being a method of dispensing small particle sized dry powder from an inhaler to a subject. [000164] The devices, kits and/or methods of this invention provide major improvements to known dry powder inhaler devices.

[000165] Uniquely, the structural aspects of the devices of this invention provide for drypowder delivery, even in circumstances of low inhaled air flow in use of the device, for example, within the range of 20-50 L/min.

[000166] Also uniquely, and representing embodied attributes of the devices, kits and methods of this invention, whereby only inhalation facilitates the rotation of the elongated assembly comprising the dry-powder containing compartment and rotation is prevented during exhalation, even under circumstances of very high exhaled air flow through the device, for example, at a range of over 200 L/min. According to this aspect, the dry-powder is then prevented from being released from sthe drug compartment.

[000167] Still further uniquely, and representing embodied attributes of the devices, kits and methods of this invention, the semi-oval insert structure incorporation in conjunction with the narrow slit opening of the air inlet reduces the agglomeration of the delivered dry powder, in part by significantly enhancing the vibration of the rotatable elongated member (also referred to herein as the rocker), which in turn also promotes greater more consistent release of the dry powder from the compartment, which for example, can be further sieved when the mesh-like compartment as well may participate in the de- agglomeration and which further promotes even distribution of the released dry-powder. These features, in turn, in some embodiments, provide for improved treatment for the subject and potentially for reduced dosage and/or frequency as a result thereto.

[000168] In some aspects, the inhaler devices of this invention are distinguished over known DPI devices, for example as depicted in Figures 1A-B versus Figures 3A-3F, herein. While the known inhaler housings have two off center air inlet slits (Figure IB-, element 1-10), in contrast, the instant inhalers incorporate a single rear top slit aperture (Figures 3A-3C, part 3-10) and wherein in other known DPI device the powder delivery port is rectengular (Figures 1A-B 1-20) while in the instant device the powder delivery port has semi-oval stucture (Figures 3A, 3D part 3-20).

[000169] As described further herein, incorporation of such a single slit aperture (1-10) and semi-oval powder delivery port stucture (1-20) result in very low air flow resistance. For example, measurment of the air flow resistance through the inlet apertures of the known inhaler device (as depicted in Figure 6B) provided an air flow resistance is 0.011 kPa min/L the lowest known, wherein in higher air flow resistance would lead to very poor uptake of the drug, when low intake flow occurs, which for example, would make the device more difficult for use with young children, the elderly or severly ill and/or the cognitively impaired.

[000170] Regarding figure 6B, please note that the X-axis plots the various devices assessed against the inspiratory resistance measured (left Y -axis, staggered bars) and patient inhalation flow (presented on the right Y -axis, diamonds). The abbeviations used are Peak Inspiratory Flow (PIF); Easyhaler M = easyhaler monotherapy; Easyhaler C = easyhaler combination therapy; and Optimal PIF refers to the lower limit of desired inspiratory flow. Devices assessed are the (left to right in the X-axis of the figure) Breezhaler; Aeorlizer, Ellipta, Novolizer; Accuhaler/Diskus, Genosair, Turbohaler Symbicort, NEXThaler, Easyhaler C, Turbohaler Pulmincort, Easyhaler M, Handihaler and CanDapi inhaler of the instant invention.

[000171] This unexpected improvement in the air pressure influences due to the modification of the structural component of the inhaler devices of this invention results in a wider potential use or ease of use of the inhaler device.

[000172] Another unexpected improvement due to the different structural components of the inhaler devices of this invention is the reduced agglomeration of the dry powder particles released in the air flow through the device, as related to in Figures 2-3.

[000173] As described herein, three different powder delivery port structures (2-20) were assessed (Figure 2, inserts A, B, C) in comparison to a standard, measuring de-agglomeration efficiency of the device was markedly improved, with the large semi-oval insert providing the best results in terms of preventing particle agglomeration, when a flow-rate of 100 L/min was assesed. [000174] Another unexpected improvement due to the different structural components of the inhaler devices of this invention is the dispensing of evenly-distributed, reproducible release highest rates of dry powder from the inhaler, as described for example, with respect to Figures 4 - 6.

[000175] Still another unexpected improvement due to the different structural components of the inhaler devices of this invention is the ability to use the inhaler devices of this invention for inhalation delivery by mouth, or nasal delivery or both, and given the improved ability to deliver the high efficiency de-agglomerated product even under low flow rates. In some aspects, the devices/kits/methods of this invention uniquely provide a means to deliver a drug dosage specifically during inhalation only, whereby during exhalation, the drug is not liberated, yet the patient may breathe with ease nonetheless, with the device. According to this aspect, this unique feature of delivering drug only with exhalation is an extremely easy to use feature, particularly helpful in treating young children, the elderly, the severely ill/weak and the cognitively imparted. In some aspects, the ability to implement this device through use of adaptors fitted for the nose and mouth of a user, as depicted in Figures 8 -10 promote such ease of use (elements 8-150 and 9- 150). For example, and as depicted schematically in Figures 9A-9D nasal delivery may be accomplished with the devices of this invention by incorporating an adaptor such as parts 9-150- 2 and 9-150-3, which facilitate insertion of the device within one or both patient nostrils for direct nasal delivery of the powder (Figures 9A-9D). In another aspect, it is possible to administer through the mouth and nose of a subject concurrently, wherein an adaptor containing a mask (8- 150) covering both the mouth and nose as depicted schematically in Figures 8A-8B may be used. In some aspects a connector 8-160 may be used to facilitate connection of the mask element 8-150 to the inhaler device 8-05. In still other aspets, the devices of the invention 10-05 may be equipped with an adaptor similar to a pacifier 10-150-4 (Figures 10A-10B) for ease of delivery in particular in young children.

[000176] In some embodiments, such choice between nasal or mouth delivery will reflect a consideration of the target area for delivery in the nasopharynx and other regions of the respiratory tree, or the particle size for delivery, or the age of the subject to which the inhaled powder is being administered, or a combination thereof.

[000177] It will be apparent to the skilled artisand that any number of additional adaptor elements can be applied to the powder delivery port of the devices of this invention to promote easier delivery of the powder to populations which will be better served by these added features and the invention is not to be limited in any way by the adjustment or providing of these or other adaptor elements to make use of the core devices as described herein.

[000178] In other embodiments, the devices as depicted schematically in Figure 7A-7B illustrate embodied inhaler devices of this invention, illustrating an alternate means by which the casing may be opened (as compared to figure IB, 3D) to provide access to replace the embodied elongated assembly 3-40, 7-40. The basic components as described in Figures 3A-3D are also depicted in this figure, with Figure 7B providing an exploded view of how the upper and lower halves of the casings can be joined with a fitted mechanism to promote seamless joining.

[000179] In some embodiments (as for example seen in Figure 7C) the elongated assembly7- 40 is equipped with a removable cover 7-110 with arrows indicating the direction of removal when assembled, whereas in Figure 7D the exposed upper release element of the drug powder compartment once the cover is removed, is shown. Such aspect, may also refer to Figure 3G, which depicts a cover 3-110, as well, which may be removed prior to use, that prevents loss/dispersion of the product while also providing, in some aspects, prevention of contamination or humidity retention. In some aspects, this cover may be a sticker, which in other aspects, is disposable and may be removed by the user before using of the product. Figure 7E provides an embodied kit tray containing multiple embodied elongated assemblies.

[000180] In some embodiments, subjects wishing to make use of the devices of this invention may suffer from a lack of ability to achieve sufficient inhalation flow to release the dry powder contents.

[000181] According to this aspect, and in some embodiments, to address this, the inhaler devices of this invention may be equipped with a propellant element, which is operationally connected to the inhaler devices of the invention, to provide regulated release of a gas into the drug/powder containment compartment, to deliver the contents to a user in need of same.

[000182] According to this aspect, and in some embodiments, the propellant element comprises:

-a container of pressurized air or gas;

-a controller regulating release of the gas through the fluid path to a drug containing compartment. [000183] Referring to Figure 11A-11B, depicting a non-limiting embodied propellant element 11-200 in assembled and exploded view, respectively.

[000184] According to this aspect, the propellant element will comprise e.g. a small cannister of compressed air 11-170-1, which for example, may be disposable, or refillable, for example, by incorporating a valve 11-170-2 to facilitate application of additional gas to the cannister.

[000185] Any appropriate pressurized container of air or gas may be used for this purpose, as long as the delivered pressurized product can be transited through the fluid path created, in a regulated manner, as herein described.

[000186] The cannister is seated in a housing 11-172, which further comprises elements to promote regulated discharge of the pressurized gas from the cannister.

[000187] The housing and other components of the propellant element may be constructed of any suitable materials, and constructed by known means. For example, the pressurized container may be a small metal container or thick plastic container that can safely store the contents under pressure.

[000188] The housing parts may easily be mold constructed, or printed from any appropriate material, such as plastics and the like.

[000189] In some embodiments, the propellant element may be battery-powered (e.g. with a slim profile battery as depicted in 11-190), in wide use in many personal delivery devices, including existing inhaler device products.

[000190] Upon activation, for example, by depressing a button 11-175, the circuit may be completed (11-230) to power opening of the gas cannister content and promoting the gas propulsion through the fluid path. The controller (11-180) may in some aspecs comprise a solenoid valve, which operationally is connected to a flipping switch mechanism 11-220 in housing 11-210, which opens the fluid path to enable the pressurized gas to enter the drug compartment 11-5 of the device, for example, so that the elongated assemblies described hereinabove liberate their powdercontaining components.

[000191] In some aspects the propellant element may comprise a safety release valve 11-205, to ensure pressure does not inappropriately build up within the device/propellant element.

[000192] It will be appreciated by the skilled artisan, that the devices of this invention may be equipped with the propellant element, or provided as a kit of parts, whereby the propellant element may be assembled onto the inhaler devices of this invention, as needed. In still other embodiments, the propellant element may be separately provided, for use with other existing inhaler devices, as further explained herein.

[000193] For example, and representing embodied aspects of the invention, the propellant elements of this invention can be readily adapted for use with existing capsule inhaler devices. Devices such as those described in Lavorini, F., et.al. Recent advances in capsule -based dry powder inhaler technology. Multidiscip Respir Med 12, 11 (2017). https://doi.Org/10.H86/s40248-017-0092-5; United States Patent 10456535, United States Patent 11517686, United States Patent Application 20110259328, United States Patent 10773034, Roman Gross et.al. Pharmaceutics 2022, 14(6), 1185; https://d0i.0rg/l 0.3390/pharmaceutics 14061185 (all of which are incorporated herein in their entirety), may be readily modified to accomodate incorporation of the propellant element, to increase dispersion and delivery of the capsular components located therein.

[000194] One non-limiting schematic depiction of such retrofitting of existing capsule-based dry powder inhalers can be envisioned as depicted in Figures 12A-12B. As is evident, the compartment containing the capsule of dry powder ready for release is positioned in the drug delivery element 12-5, within a chamber, so that the gas cannister 12-170-1, seated in its housing 12-172, can be activated to undergo regulated discharge of the pressurized gas from the cannister. For example, and representing certain embodiments, the propellant element may be battery- powered (e.g. with a slim profile battery as depicted in 12-190). Upon activation, for example, by depressing a button 12-175, the circuit may be completed (12-230) to power opening of the gas cannister content and promoting the gas propulsion through a regulating valve (12-180), and optionally flipping a switch 12-220 in housing 12-210, which opens the fluid path to enable the pressurized gas to enter the drug compartment 12-5 of the device, so that the capuslar contents described hereinabove are liberated. Here, as well, in some aspects the propellant element may comprise a safety valve 12-205, to ensure pressure does not inappropriately build up in the device. [000195] A wide array of existing capsular inhalers may be used, for example as depicted in Figure 13, where the layout of the drug delivery chamber 13-5 may vary, as will the principle of operation of release of the drug product contained therein. Importantly, by the addition of the propellant elements, 12-200 or 13-200, in Figures 12A-12B and Figure 13, respectively, it is possible to improve drug delivery from existing capsular inhalers by this retrofit to ensure that same can be more readily and reliably used, even in the severely infirmed, small children, and subjects with significant respiratory issues, as well.

[000196] Turning now to Figure 13, similar elements are shown for the propellant element (13-200) depicted. While the drug-containing capsule (13-300), per se, can have a different positioning in the chamber (13-5), and additional elements of the device, including for example, a capsule piercing element (13-360) a nose-piece insertion element 13-320, or incorporation of a screen element in the chamber (13-5) to improve drug dispersion passing therethrough, it is the propellant element that will increase the delivery of the contents, in terms of quantity and timing, in a very simply deployed, easily applicable manner.

[000197] Turning to Figure 14, a still further non-limiting embodied schematic representation of a capsule drug delivery device is shown. It is noted that the propellant elements are similar to those recited for Figures 12A-B, and Figure 13, and certain adaptations may be included in the drug chamber (14-5). For example, and in one embodiment, a conveying channel (14-350) may be operationally connected to the capsule (14-300), such that upon engagement of the inhaler device, and engagement of the propellant element, the capsule is pierced (14-360) such that pressurized air/gas is directly applied to the contents of the capsule, which are rapidly conveyed via the conveying channel (14-350) through the delivery port, for example, as shown in (14-320). [000198] Such an inhaler device can readily be applied for liquid- and solid-containing capsules, as the pressure applied can liberate the capsule contents and reliably deliver same to the subject.

[000199] As described herein, this invention provides for kits, whereby the interior of the casing is accessible and a new elongated assembly containing a second dosage of a desired drug, a different dosage, or a different drug, for example, or any combination thereof, may be inserted so that the devices of this invention are understood to encompass multi-use devices.

[000200] It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof.

[000201] The embodiments presented herein are, therefore, to be considered in all respects as illustrative and not restrictive of the scope of the invention, and the skilled artisan will appreciate the appropriate equivalents thereto, which are to be considered as part of this invention..

EXAMPLES:

EXAMPLE 1:

PERFORMANCE OF INHALERS CONTAINING MODIFIED AIR INLET SLIT AND SEMIOVAL DELIVERY PORT STRUCTURES AS COMPARED TO STANDARD DEVICES

[000202] Devices containing the semi-oval structures referred to as insert A, B or C were prepared and compared to the standard DPI described in U.S. Patent Number 9,056,173, which has a powder delivery port having a structure and opening as depicted in the panel marked "standard” in Figure 2. The device resistance to air flow was determined using a TPK trigger box, a vacuum pump, and a flow meter.

[000203] Approximately 0.5, 1, 1.75 or 3 mg of powder were accurately weighed into the rocker’s re-closable mesh cavity. The closed rocker was then placed within the device, which was subsequently sealed/closed. After dispersion, the rocker was weighed again to determine the residual fraction gravimetrically. A HELOS laser diffraction system (Sympatec, Clausthal- Zellerfeld, Germany) equipped with the DPI module ensuring controlled aerodynamic conditions was used for assessing powder dispersion. No preseparator and induction port was used. Before sample measurement, the flow rate was adjusted to 60, 80 or 100 L/min and a reference measurement was performed over 10 s using an unloaded device. The loaded device was connected to the mouthpiece adapter of the DPI module and a time-resolved measurement (time base: 50ms) was executed over 1.5 s.

[000204] Evaluation of laser diffraction data was performed using the Windox software (version 5.4.2.0, Sympatec, Clausthal-Zellerfeld, Germany) based on the Fraunhofer theory. The software calculated the mean from all measurements taken during actuation. If agglomerates larger than the actual mesh size were observed, the respective single measurements were removed before averaging. The fractions of particles < 5.25 pm and > 10.5 pm were directly read from the mean curve. xlO, x50, and x90 were calculated from the mean curve by the software.

[000205] As a reference, powders were dispersed using the HELOS with a RODOS dry dispersion module at an air pressure of 3 bar. Particles are assumed to be 100% de -agglomerated (further on referred to as “primary particle size”).

[000206] An R2 lens was used for both RODOS and INHALER measurements to maintain comparability.

Aerodynamic particle size distribution was determined by cascade impaction. Approximately 0.5 mg of powder was accurately weighed into the rocker’ s re- closable mesh cavity. The closed rocker was then placed within the opened device, which was subsequently closed. An NGI (MSP Corporation, Shoreview, Minnesota, US) equipped with a TPK trigger box (Copley Scientific, Nottingham, UK), and a vacuum pump HCP 5 (Copley Scientific, Nottingham, UK) was used. The air flow was set to 80 L/min resulting in a pressure drop of 4 kPa across the device and was applied over 3.0 s ensuring 4 L of air to be withdrawn from the mouthpiece of the inhaler.

Deagglomeration

[000207] The powder mixtures were dispersed with a HELOS laser diffraction system (Sympatec, Clausthal-Zellerfeld, Germany) equipped with an INHALER module. The deagglomeration behavior was investigated at 100 l/min because the required pressure drops of 4 kPa is reached at a flow rate higher than 100 l/min. To be able to calculate the percentage of deagglomeration, total deagglomeration was conducted by using the RODOS module at an air pressure of 3 bar.

Release

[000208] To determine the release, approximately 1 mg of powder were accurately weighed into the cavity of the rocker. After dispersion the rocker was weighed again.

Statistical analysis

[000209] For INHALER experiments using budesonide, a 3² full factorial design including replicates was set up to evaluate the influence of air flow rate (factor A) and powder loading (factor B) on inhaler performance attributes at a significance level of a = 0.05. Design Expert® software (version: 7.1.6, Stat Ease Inc., Minneapolis, MN, US) was utilized to perform statistical analysis of the results.

[000210] For the powder formulation a mixture containing salbutamol sulphate and lactose as a performance modifier was used and the primary particle size distribution (PSD; Q3 distribution) of the mixture was determined via laser diffraction (HELOS RODOS dry dispersion module, R2 lens, Sympatec GmbH, Clausthal-Zellerfeld, Germany) at an air pressure of 3 bars. A reference measurement was performed for 10 seconds following a time-resolved measurement with a time base of 200 milisecond. Each measurement was stopped after 5 second. For the investigation of the device, the empty rocker was weighed and about 1 mg of powder was filled into the cavity, which was then finally closed by crimping the mesh. The HELOS INHALER module (R2 lens) was used in order to ensure controlled aerodynamic conditions according to former laser diffraction measurements. Before each testing (RODOS and INHALER) a reference measurement was performed over 10 seconds with an empty device (for INHALER). After connecting the inhaler to the mouthpiece adapter, the actual time-resolved measurement was conducted over a period of 1.5 seconds. Depending on the experiment, different air flow- rates were set. All measurements were done in triplicate.

[000211] The fraction < 5.25 pm (calculated based on Fraunhofer theory) determined with Helos RODOS and INHALER was obtained from the corresponding software (Windox 5.4.2.0, Sympatec GmbH, Clausthal-Zellerfeld, Germany).

[000212] The de- agglomeration efficiency of the device was calculated in percentage based on the obtained RODOS primary particle size distribution, which was assumed to be 100% deagglomerated.

RESULTS

[000213] As part of the experimental set up, flow rates were varied, and an increase in deagglomeration with increasing flow-rate was found, which was related to the energy input of the air stream being primarily responsible for de- agglomeration.

[000214] It therefore was of interest to determine if using lower flow rates, whether structural modification of the device could produce reliable de-agglomeration of the powdered drug product. [000215] Toward this end a variety of embodied powder delivery ports were prepared and compared to the standard to determine the effect on powder agglomeration. Figure 4 depicts the results of these studies, whoing that Insert C provided the least agglomeration or greatest deagglomeration capability.

[000216] Figure 5 demonstrates the reproducibility of the release profile results in assessing release over varied flow rates, with the use of insert C. The results obtained were highly reproducible and demonstrated good release of the product.

[000217] To further extend these results, Figure 6A plots the results of another test assessing different sized partieles in terms of their release profiles, in the device evaluated in Figure 5. As can be readily observed from the Figure, the release profile was highly consistent, despite the variability in particle size, when a flow rate of 100 1/min was used.

[000218] To further assess the comparative efficacy of the embodied device as compared to other standard powder delivery devices currently available, the inspiratory resistance was plotted as a function of device type and patient inhalation flow, with the optimal flow (diamond) value shown for good inhalation. Only the embodied device provided good inhalation even when air flow resistance is 0.011 kPa min/L, as depicted in Figure 6B.

[000219] T aken together, the embodied inhaler devices of this invention are shown to provide consistent, well distributed particle delivery even operating in very low inhaling air flow rates.

[000220] Furthermore, in evaluation of the embodied inhaler devices of this invention, vibration of the rocker ceased as did powder release from the containment chamber, even under high air flow in exhalation.

Claims

[000221] CLAIMS [000222] What is claimed is:

1. A dry -powder inhaler device comprising:

• a casing comprising: o an air inlet slit located at a first terminus of said casing, wherein said slit is of a width slightly narrower than the width of said casing and wherein said slit is positined within a top vertical half of said casing and o a powder delivery port located at a second terminus of said casing and positioned distal to said air inlet, said powder delivery port further comprising a semi-oval insert structure; and

• an elongated assembly located within an interior of said casing, comprising: o a first terminus located proximally to said air inlet; o a second terminus located proximally to said powder delivery port; o a compartment containing a dry -powder and a porous structure encasing said drypowder located proximally to said second terminus of said elongated assembly; wherein said elongated assembly is fitted within said casing such that said elongated assembly partially rotates within said casing about a single axis; and wherein air flow through said device causes said elongated assembly to rock back and forth within said casing about the single axis and to beat against said casing, whereby dry -powder is thereby released from said compartment and becomes entrained in said air flow; and wherein air circulation through said air inlet slit and said semi-oval insert structure results in enhanced vibration of said elongated assembly promoting enhanced dry-powder release from said compartment.

2. The dry-powder inhaler device of claim 1, wherein said device can deliver said drypowder in limiting air-flow conditions.

3. The dry-powder inhaler device of claim 2, wherein said limiting air-flow conditions are from 20 -50 liters per minute.

4. The dry-powder inhaler device of claim 1, wherein said semi-oval insert structure comprises a semi-oval hollowed region.

5. The dry-powder inhaler device of claim 4, wherein said oval hollowed region occupies most of the volume of said oval insert structure.

6. The dry-powder inhaler device of claim 4, wherein said oval hollowed region is located substantially centrally in said oval insert structure and further comprises apertures assuming a slit-like structure, flanking said oval hollowed region, wherein said apertures are located approximately midway between an upper and lower boundary of said oval insert structure.

7. The dry-powder inhaler device of claim 1, wherein said air inlet slit structure and the semi-oval delivery port structure enable roation of said elongated assembly about said axis during inhalation.

8. The dry-powder inhaler device of claim 1, wherein said air inlet slit and the semi-oval insert structure prevents rotation of said elongated assembly during exhalation.

9. The dry-powder inhaler device of claim 1, wherein said air inlet slit structure is substantially rectangular in shape.

10. The dry-powder inhaler device of claim 1, wherein said elongated assembly is comprised of stainless metal.

11. The dry-powder inhaler device of claim 10, wherein said elongated assembly is characterized by an elasticity of 193 Gpa.

12. The dry-powder inhaler device of claimlO, wherein said elongated assembly is comprised of a stainless stell of a 302, 304 or 306 type.

13. The dry-powder inhaler device of claim 1, wherein said elongated is comprised of a Nikel-Silver alloy.

14. The dry-powder inhaler device of claim 1, wherein said porous structure is a woven stainless steel material.

15. The dry-powder inhaler device of claim 1, wherein said porous structure is comprised of a stainless steel foil.

16. The dry-powder inhaler device of claim 1, wherein said porous structure is comprised of a stainless steel perforated material.

17. The The dry-powder inhaler device of claim 1, wherein said porous structure is characterized by being a perforated component of the elongated assembly, assembled to form the compartment.

18. The dry-powder inhaler device of claim 1, wherein said porous structure comprises a pore size range of about 25-200 microns.

19. The dry-powder inhaler device of claim 1, wherein dimensions of said inhaler may be scaled to accomodate smaller and larger quantities of dry powder for inclusion in said device.

20. The dry-powder inhaler device of claim 19, wherein a quantity of said powder may range from about 1-250 mg.

21. The dry-powder inhaler device of claim 1, wherein said dry powder is a plant-based therapeutic.

22. The dry-powder inhaler device of claim 1, wherein said dry powder is cannabidiol or a cannabinoid.

23. The dry-powder inhaler device of claim 1, wherein said device is resealable such that said elongated assembly may be replaced in said device.

24. The dry-powder inhaler device of claim 1, further comprising an immobilizer cap, which immobilizer cap attaches to said powder delivery port and which immobilizer cap prevents substantial rotation of said elongated assembly about said single axis.

25. A kit comprising at least one dry-powder inhaler device of claim 1 and one or more mouthpieces, which mouthpieces may attach to said powder delivery port of said device.

26. The kit of claim 25, wherein said kit contains a plurality of elongated assembly components, comprising multiple dosages of said dry powder to deliver a desired dosage regimen.

27. The kit of claim 26, wherein said mulitple dosages represent identical daily administration dosages.

28. The kit of claim 26, wherein said multiple dosages represent different administration dosages, different therapeutics or a combination thereof.

29. A method of dispensing dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of claim 1, wherein :

30. The method of claim 29, wherein said device can deliver said dry-powder in limiting airflow conditions.

31. The method of claim 30, wherein said limiting air-flow conditions are from 20 -50 liters per minute.

32. .The method of claim 30, wherein said limiting air-flow conditions are particularly suitable for administration to infant, elderly or mentally disabled subjects.

33. A method of dispensing evenly-distributed dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of claim 1, wherein : • upon a first inhalation through said device, said elongated assembly partially rotates within said casing about a single axis to thereby release said dry-powder from said compartment to become entrained in said air flow;

34. A method of dispensing small particle sized dry powder from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of claim 1, wherein :

• upon a first inhalation through said device, said elongated assembly at least partiallyrotates within said casing about a single axis to thereby release said dry-powder from said compartment to become entrained in said air flow;

• upon subsequent repeat inhalations of said air suspended in said device in which said dry powder is entrained, said dry powder is delivered to a respiratory system of said subject, whereby smaller particle sizes of said dry-powder effectively access terminal ramifications of the respiratory tree in a subject; thereby being a method of dispensing small particle sized dry powder from an inhaler to a subject.

35. A propellant element comprising: -a container of pressurized air or gas; -a housing through which a fluid path from an aperture of the container to the drug containing compartment is created; and

-a controller regulating release of the gas through the fluid path to a drug containing compartment.

36. The propellant element of claim 35, wherein said propellant element is adapted for use with the dry-powder inhaler device of claim 1.

37. The propellant element of claim 36, wherein said housing is operationally connected to said casing proximal to said air inlet slit and said pressurized air or gas upon release to said fluid path promotes dry powder release from said drug compartment and conveys said dry powder to said powder delivery port.

38. The propellant element of claim 35, wherein said element is powered by a battery.

39. The propellant element of claim 35, wherein said controller is a solenoid.

40. The propellant element of claim 35, wherein said housing further comprises a regulator flap which regulates passage of said pressurized air or gas in said fluid path from accessing said drug-containing compartment, operationally connected to said controller.

41. The propellant element of claim 35, wherein said housing further comprises a relief valve for shunting excess pressurized air or gas out of said device.

42. A kit comprising said dry powder inhaler device of claim 1 and said propellant element of claim 35.

43. The propellant element of claim 35, further comprising a drug compartment in which a capsule comprising a drug is contained therein, which capsule is further modified to permit release of drug contents contained therein, whereby passage of said pressurized air or gas in said fluid path to said drug compartment promotes substantial release of the drug contents of said capsule.

44. The propellant element of claim 43, further comprising a conveying channel operationally connected to said capsule, wherein passage of said pressurized air or gas in said fluid path to said drug compartment promotes substantial release of the drug contents of said capsule into said conveying channel.

45. A method of dispensing drug product from an inhaler to a subject, said method comprising the steps of providing to a subject a dry-powder inhaler device of claim 1 further adapted to comprise a propellant element of claim 35, wherein :

• upon release of said pressurized air or gas to said fluid path, said elongated assembly at least partially rotates or vibrates within said casing about a single axis to thereby release said dry-powder from said compartment to become entrained in said air flow; and • inhalation of said air in which said dry powder is entrained, promotes rapid and efficient dry powder delivery to a respiratory system of said subject thereby being a method of dispensing dry powder from an inhaler to a subject.

46. The method of claim 45, wherein said device can deliver said dry-powder in limiting airflow conditions.

47. The method of claim 45, wherein said limiting air-flow conditions are from 20 -50 liters per minute.

48. The method of claim 45, wherein said limiting air-flow conditions are from 5 -15 liters per minute.

49. .The method of claim 45, wherein said limiting air-flow conditions are particularly suitable for administration to infant, elderly or mentally disabled subjects, or subjects with respiratory diseases or disorders.

50. A method of dispensing drug product from an inhaler to a subject, said method comprising the steps of providing to a subject a capsule inhaler device further adapted to comprise a propellant element of claim 35, wherein :

• upon release of said pressurized air or gas to said fluid path, a capsule containing drug compartment in said capsule inhaler device is adapted to release drug product contents from said compartment to become entrained in air flow through said device promoted by release of said pressurized air or gas; and

51. The method of claim 45, wherein said device can deliver said dry-powder in limiting airflow conditions.

52. The method of claim 45, wherein said limiting air-flow conditions are from 20 -50 liters per minute.

53. The method of claim 45, wherein said limiting air-flow conditions are from 5 -15 liters per minute.

54. .The method of claim 45, wherein said limiting air-flow conditions are particularly suitable for administration to infant, elderly or mentally disabled subjects, or subjects with respiratory diseases or disorders.