RU2809679C2 - Devices for intranasal delivery - Google Patents

Abstract

FIELD: medical equipment.

SUBSTANCE: group of inventions relates to a device for intranasal delivery and methods of its use and manufacture. The device contains a nozzle having a reservoir located inside the nozzle. The device includes a globe valve inserted into the reservoir. The device has a retainer that is hollow and configured to hold the through valve. The device contains a manual air pump having a working connection with the inlet end of the nozzle and the outlet end of the clamp. The straight-through valve has a contact area with the latch and is motionless when the hand pump is activated. The reservoir contains a powder medicinal product placed in it. The retainer contains a groove configured to catch the powdered medicinal product falling from the nozzle. According to the method of use, the nozzle of the device is placed into the nostril of the subject, and a manual air pump is activated. The nozzle contains a powdered drug. The manufacturing method includes the following steps: inserting a through valve into the nozzle, inserting a retainer into the hand air pump, and attaching the hand air pump to the nozzle.

EFFECT: administration of a powdered medicinal product to a subject in need of treatment.

50 cl, 7 dwg, 4 ex

Description

Technical field of the invention

[0001] CROSS REFERENCE

This application claims priority to US Provisional Application No. 62/563,244, filed September 26, 2017, which is incorporated by reference in its entirety.

[0002] INCLUDE FEATURES BY REFERENCE

All publications and patent applications referred to in this specification are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and separately identified as being incorporated by reference.

The essence of the invention

[0003] In some embodiments, the present invention provides a device that includes: a nozzle including a reservoir located within the nozzle, a passage valve at least partially inserted into the reservoir, a retainer that is hollow and receives the passage valve, and a manual air pump , for example, having an operative connection with the inlet end of the nozzle and the outlet end of the latch, the passage valve having one or more contact areas with the latch. In certain embodiments, the one or more contact zones comprise one or more internal ribs. In some embodiments, the retainer has an internal circumferential groove extending from the input end of the retainer. In some embodiments, the collar of the retainer's circumferential groove is in contact with one or more contact areas of the globe valve. In some versions, the retainer prevents the free movement of the globe valve. In some embodiments, when the device is activated, a portion of the air from the pump flows into the retainer along the circumferential groove and moves along the surface of the retainer groove, forming a vortex flow into the reservoir. In some embodiments, one or more retainer air inlets allow outside air to enter the pump after the device is actuated. In some embodiments, the reservoir holds a powdered medicinal product. In certain embodiments, the device is configured to deliver at least about 85% of the powdered drug to the nostril of a subject after one, two, or three activations of the hand-held air pump. In certain embodiments, at least about 90% of the powdered drug is delivered to the subject's nostril after one, two, or three activations of the hand-held air pump. In certain embodiments, the powdered drug is present in an amount of from about 1 mg to about 30 mg. In some embodiments, the powdered drug is present in an amount of approximately 20 mg. In some embodiments, the nozzle additionally includes a breakable tongue located at the outlet end of the nozzle. In some embodiments, the device is a disposable device. In some embodiments, the globe valve additionally includes a conical upper section. In some embodiments, the conical top section is connected to the first shoulder, which is connected to the first cylindrical section. In some embodiments, the first cylindrical section is connected to a second shoulder, which is connected to the second cylindrical section. In some embodiments, the globe valve has one or more surface grooves. In some embodiments, the globe valve has from about 3 to about 20 surface grooves, such as about 8 surface grooves. In some embodiments, one or more surface grooves create a vortex flow in the reservoir when the device is actuated. In some embodiments, one or more surface grooves are provided on the second shoulder. In some embodiments, the globe valve has from about 2 to about 10 internal ribs. In some versions, the globe valve has approximately 3 internal ribs. In some embodiments, the globe valve is at least partially located inside the reservoir. In some embodiments, the globe valve is at least partially located within the hand air pump. In some embodiments, the globe valve contains a cavity. In some embodiments, the device is less than about 10 cm ³ in volume. In some embodiments, the device is less than about 50 cm ³ in volume. In some embodiments, the device is approximately 30 cm ³ in volume. In some embodiments, the device has a mass of less than about 20 grams. In some embodiments, the device has a mass of less than about 10 grams. In some versions, the device has a mass of approximately 6-7 grams. In some embodiments, the reservoir has an internal diameter of less than about 10 mm. In some embodiments, the reservoir has an outer diameter of from about 8 to about 9 mm. In some embodiments, the outer diameter of the reservoir is from about 8.7 to about 8.9 mm. In some embodiments, the inlet end of the reservoir has a smooth surface configured to contact the pass-through valve. In certain embodiments, the globe valve has an outer diameter of from about 7 to about 8 mm, such as from about 7.7 to about 7.9 mm. In some versions, the opening of the hand air pump is wider than the outer diameter of the globe valve. In some embodiments, the retainer includes an outer circumferential collar that is wider than the opening of the hand air pump. In some versions, the clamp has two air inlets. In some embodiments, one or more air inlets have a width of approximately 0.2-0.4 mm. In some embodiments, the retainer is at least partially inserted into the hand air pump. In certain embodiments, the port valve portion inserted into the nozzle has a length of from about 5 mm to about 6 mm, such as from 5.7 mm to about 5.9 mm, parallel to the axis from the inlet to the outlet of the flow. In some versions, the nozzle has a length parallel to the axis from the inlet to the flow outlet from 5 mm to 40 mm. In some embodiments, the nozzle of the device contains a transparent, lightly colored or light-transmitting material.

[0004] In some embodiments, the present invention provides a method of using a device disclosed herein to deliver a powdered drug to a subject in need thereof, comprising the step of placing a nozzle of the device at least partially into the subject's nostril and the step of bringing it into the action of a hand-held air pump, the nozzle containing a powdered medicinal product. In certain embodiments, the method treats a disease or illness of a subject, such as migraine. In some embodiments, the powdered medicinal product contains an active ingredient disclosed herein, for example, dihydroergotamine or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises the step of visually monitoring the amount of powdered drug remaining in the reservoir and repeating the method until a sufficient dose is delivered.

[0005] In some embodiments, the present invention provides a method of manufacturing a device comprising: the step of inserting a passage valve into a nozzle, the step of inserting a retainer into a hand air pump, and the step of connecting the hand air pump to the nozzle. In some embodiments, the method additionally comprises the step of filling the reservoir with a powdered medicinal product.

Brief description of drawings

[0006] FIG. 1 shows two views of the parts of the device. The device contains a nozzle (1), a through valve (2), a clamp (3) and a pump (4). The device may further comprise a cap to protect the nozzle.

[0007] FIG. 2 shows the contact and seal areas between the parts. The nozzle and the retainer are sealed together. The clamp and the pump are tightly coupled. The globe valve, raised by the latch, is always in contact with the nozzle and therefore there is no clearance between the nozzle and the globe valve. This reduces the potential risk of pre-loaded powder entering the pump.

[0008] FIG. 3 shows that the retainer includes a trough for catching powder falling from the nozzle. This reduces the potential risk of powder from the nozzle entering the pump.

[0009] FIG. 4 shows a main air flow for delivering powder and a side air flow for delivering captured powder through a nozzle. If necessary, the pump can be operated up to 3 times to deliver the powder. Air inlets in the retainer prevent powder remaining in the nozzle from entering the pump when the pump returns to its original shape.

[0010] FIG. 5 represents the dimensions of the parts. The pump thread diameter "a" is in the range of 10.1-10.7 mm and can be adjusted up or down by 0.4 mm to minimize the risk of insufficient sealing between the retainer and the pump and between the nozzle and the retainer.

[0011] FIG. 6 represents the assembly procedure of the device.

[0012] FIG. 7 represents delivered placebo weights in normal condition and after exposure to climatic and transport conditions when testing the device to determine delivery efficiency.

Description of Embodiments

[0013] DETAILED DESCRIPTION

This application describes devices for intranasal delivery. The intranasal delivery device can be used to administer a powdered drug to a subject in need of treatment. Delivery of the powdered drug may be performed by a medical professional and/or a subject in need of treatment (eg, a human subject). As described herein, the devices may be pre-loaded with a dry powder drug. The intranasal delivery device may be a disposable device. The device described herein may comprise at least four parts, for example, a nozzle, a retainer, a globe valve and a pump. The powdered drug may be introduced into a nozzle of the device, which may serve as a reservoir. The nozzle can be connected to a pump. The device described herein can provide complete delivery of the drug powder, with minimal powder drug remaining in the device after actuation of the device. The passage valve may be configured to regulate air flow from the pump to the nozzle when the device is actuated. The passage valve may be configured to prevent the powdered drug from moving from a reservoir in the device against flow to a pump in the device. The passage valve may include slots (channels or grooves) that may serve to create a vortex flow in the reservoir to allow efficient delivery of the powdered drug. Grooves in the passage valve may be positioned to allow laminar airflow into the reservoir. Grooves in the passage valve may be positioned to create a rotating air stream in the reservoir when the pump is driven. Also provided are methods for treating or preventing an ailment or disease using a device or preparation disclosed herein.

[0014] Unless otherwise defined, all technical and scientific terms used in this application have a meaning that is generally understood by one of ordinary skill in the art to which the present invention relates. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the compositions or dosage units provided herein, several methods and materials are described herein. Unless otherwise indicated, the methods used or implied in this application are standard methods. The materials, methods, and examples are merely illustrative and non-limiting.

[0015] Details of one or more embodiments of the invention are shown in the accompanying drawings and set forth in the claims and description of this application. A feature, purpose, or advantage of an embodiment of the invention disclosed and contemplated in this application may be combined with a feature, purpose, or advantage of any other embodiment disclosed and contemplated in this application, unless expressly excluded.

[0016] Unless otherwise indicated, non-limiting terms such as “comprise”, “comprising”, “include”, “comprising” and the like mean containing.

[0017] The singular forms used in this application must include references to the plural forms unless the context clearly indicates otherwise. Accordingly, unless otherwise indicated, the numerical parameters given in this application are approximate values that may vary depending on the desired properties that are desired to be obtained using the present invention.

[0018] Unless otherwise indicated, some examples in this application provide ranges of numerical values. When a range of numeric values is provided, unless otherwise specified, the range includes the ends. Unless otherwise noted, ranges of numeric values include all of their values and subranges as if they were written explicitly. Unless otherwise specified, any ranges of numbers and/or values in this application may be 80-125% of the ranges of numbers and/or values.

[0019] The term “approximately” means the referenced numerical reading plus or minus 15% of the referenced numerical reading.

[0020] The term “subject” as used herein refers to a mammal (eg, human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a lesser primate such as a monkey, chimpanzee, or baboon). In the specific example, the subject is a human subject.

[0021] I. Devices

General overview

In some embodiments, the present invention provides a device that includes: a nozzle including a reservoir located within the nozzle, a passage valve at least partially inserted into the reservoir, a retainer that is hollow and receives the passage valve, and a hand air pump having an operating connecting to the inlet end of the nozzle and the outlet end of the retainer, wherein the globe valve has one or more contact areas with the retainer. In certain embodiments, the one or more contact zones comprise one or more internal ribs. In some embodiments, the retainer has an internal circumferential groove extending from the input end of the retainer. In some embodiments, the collar of the retainer's circumferential groove is in contact with one or more contact areas of the globe valve. In some versions, the retainer prevents the free movement of the globe valve. In some embodiments, when the device is activated, part of the air from the pump flows into the retainer along the circumferential groove and moves along the surface of the retainer groove, forming a vortex flow into the reservoir. In some embodiments, one or more retainer air inlets allow outside air to enter the pump after the device is actuated. In some embodiments, the reservoir holds a powdered medicinal product. In certain embodiments, the device is configured to deliver at least about: 70%, 75%, 80%, 85%, 90%, or 95% of the powdered drug to the nostril of a subject after one, two, or three manual activations. air pump. In certain embodiments, the powdered drug is present in an amount of from about 1 to about 30 mg, or from about 1 to about 50 mg. In some embodiments, the powdered drug is present in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, or 45 mg. In some embodiments, the nozzle additionally includes a breakable tongue located at the outlet end of the nozzle. In some embodiments, the device further includes a cap that at least partially covers the nozzle. In some versions, the cap contains polypropylene. In some embodiments, the nozzle further includes an engagement thread for attaching the nozzle to a hand-held air pump. In some embodiments, the hand air pump further includes an engagement thread for the hand air pump to the nozzle. In some embodiments, the engagement thread has a diameter in the range of about 9-12 mm, for example, about 9.7-10.3 mm, 10.1-10.7 mm or 10.5-11.1 mm. In some embodiments, the device is a disposable device. In some embodiments, the globe valve additionally includes a conical upper section. In some embodiments, the conical top section is connected to the first shoulder, which is connected to the first cylindrical section. In some embodiments, the first cylindrical section is connected to a second shoulder, which is connected to the second cylindrical section. In some embodiments, the globe valve has one or more surface grooves. In some embodiments, the globe valve has from about 3 to about 20 surface grooves, such as about 4, 6, 8, 10, 12, 14, 16, or 18 surface grooves. In some embodiments, one or more surface grooves create a vortex flow in the reservoir when the device is actuated. In some embodiments, one or more surface grooves are provided on the second shoulder. In some embodiments, the globe valve has from about 2 to about 10 internal ribs. In some versions, the globe valve has approximately: 3 internal ribs. In some embodiments, the globe valve is at least partially located inside the reservoir. In some embodiments, the globe valve is at least partially located within the hand air pump. In some embodiments, the globe valve contains a cavity. In some embodiments, the device is less than about 10 cm ³ in volume. In some embodiments, the device is less than about 50 cm ³ in volume. In some versions, the device is approximately: 20 ^cm3 or 30 cm3 in volume. In some embodiments, the device has a mass of less than about 20 grams, such as about 11, 12, 13, 14, 15, 16, 17, 18, or 19 grams. In some embodiments, the device has a mass of less than about 10 grams, such as about 1, 2, 3, 4, 5, 6, 7, 8, or 9 grams. In some versions, the device has a mass of approximately 6-7 grams. In some embodiments, the reservoir has an internal diameter of less than about 10 mm. In some embodiments, the reservoir has an outer diameter of from about 8 to about 9 mm. In some embodiments, the outer diameter of the reservoir is from about 8.7 to about 8. mm. In some embodiments, the inlet end of the reservoir has a smooth surface configured to contact the pass-through valve. In certain embodiments, the globe valve has an outer diameter of from about 7 to about 8 mm, such as from about 7.7 to about 7.9 mm. In some versions, the opening of the hand air pump is wider than the outer diameter of the globe valve. In some embodiments, the retainer includes an outer circumferential collar that is wider than the opening of the hand air pump. In some versions, the clamp has two air inlets. In some embodiments, one or more air inlets have a width of approximately 0.2-0.4 mm. In some embodiments, the retainer is at least partially inserted into the hand air pump. In certain embodiments, the port valve portion inserted into the nozzle has a length of about 5 mm to about 6 mm, such as about 5.7 mm to about 5.9 mm, parallel to the inlet-to-outlet axis of the flow. In some embodiments, the nozzle has a length parallel to the axis from the inlet to the outlet of the flow from about 5 mm to about 40 mm. In some embodiments, the nozzle of the device contains a transparent, lightly colored or light-transmitting material.

[0022] In some embodiments, the present invention provides a method of using a device disclosed herein to deliver a powdered drug to a subject in need thereof, comprising the step of placing a nozzle of the device at least partially into the subject's nostril and the step of bringing it into the action of a hand-held air pump, the nozzle containing a powdered medicinal product. In certain embodiments, the method treats a disease or illness of a subject, such as migraine. In some embodiments, the powdered medicinal product contains an active ingredient disclosed herein, for example, dihydroergotamine or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises the step of visually monitoring the amount of powdered drug remaining in the reservoir and repeating the method until a sufficient dose is delivered.

[0023] In some embodiments, the present invention provides a method of manufacturing a device comprising: the step of inserting a passage valve into a nozzle, the step of inserting a retainer into a hand air pump, and the step of connecting the hand air pump to the nozzle. In some embodiments, the method additionally comprises the step of filling the reservoir with a powdered medicinal product.

[0024] In some embodiments, a device is provided comprising: a) a nozzle having an inlet end and an outlet end configured to accommodate a portion of said nozzle into a subject's nostril; b) a reservoir containing one dose of powdered drug, the reservoir having an inlet end and an outlet end and located inside said nozzle; c) a pass-through valve having an inlet end and an outlet end, the pass-through valve being configured to cause a spray of powdered medicament when the device is actuated; and d) a pump having an operative connection to the inlet end of the globe valve, the device being a disposable device. In some embodiments, the globe valve is configured to create a rotating air flow in the reservoir when the pump is activated. In some embodiments, the globe valve is configured to cover the entire tank wall with air flow when the pump is activated. In some embodiments, the globe valve is at least partially located in the nozzle. In some embodiments, the powdered drug is located along the inner wall of the nozzle and between the passage valve and the inner wall of the nozzle. In some embodiments, the passage valve is configured to minimize the residue of powdered drug between the passage valve and the inner wall of the nozzle when the pump is driven. In certain embodiments, the device is configured to deliver from about 80% to about 99% of a single dose of the powdered drug to the nostril of a subject. In certain embodiments, the device is configured to deliver from about 80% to about 99% of a single dose of powdered drug to the nostril of a subject after a single actuation of the pump. In some embodiments, the pump contains a hole for releasing the flow. In some embodiments, the passage valve is configured to prevent movement of the powdered drug through the flow outlet when the device is not actuated. In some embodiments, the passage valve is configured to prevent the powdered drug from moving through the flow outlet when the device is actuated. In some embodiments, the pass-through valve closes the flow outlet when the device is not actuated. In some embodiments, the globe valve does not close the flow outlet when the device is actuated. In some embodiments, the globe valve includes an upper section connected to the first cylindrical section, and the first cylindrical section is connected to the first shoulder, and the first shoulder is connected to the second cylindrical section.

[0025] In some embodiments, the upper section has a conical shape. In some embodiments, the surface of the first shoulder contains at least one groove. In some embodiments, the first shoulder contains at least one groove. In some embodiments, the first shoulder contains approximately 1-50 grooves. In some embodiments, the first shoulder contains approximately 1-20 grooves. In some embodiments, the first shoulder contains approximately 1-10 grooves. In some embodiments, at least one groove is located at an angle of 45 degrees relative to the edge of the first shoulder. In some embodiments, at least one groove is configured to allow air flow from the pump to the nozzle when the pump is turned on. In some embodiments, the nozzle includes a nozzle pipe. In some versions, the through valve is partially located inside the nozzle pipe. In some embodiments, the upper section and the first cylindrical section of the passage valve are located inside the nozzle nozzle. In some embodiments, the second cylindrical section of the passage valve is not located inside the nozzle pipe.

[0026] In some embodiments, the first shoulder contacts the nozzle nozzle when the pump is activated. In some embodiments, the pump is designed to deliver approximately 2-7 ml of air. In some embodiments, the device is configured to deliver approximately 1-50 mg of powdered drug. In some embodiments, the device is less than about 50 cm ³ in volume. In some embodiments, the device has a mass of less than about 20 grams. In some embodiments, the pump is operable by a user to force air from the pump through the flow outlet, along the surface of at least one groove in the first shoulder, into the reservoir, and out of the outlet end of the nozzle. In certain embodiments, the device is configured to provide laminar air flow within at least a portion of the reservoir when the device is in use. In certain embodiments, the device is configured to deliver a powdered drug into the nostril of a subject when a compression force of about 5 to about 30 kilopascals is applied to the pump. In some embodiments, the pump additionally contains a deformable volume configured to be actuated by the user. In some embodiments, the pump contains a manual air pump. In some embodiments, the hand-held air pump is operable by a user by squeezing the pump with the thumb, index finger, middle finger, ring finger, little finger, or any of the fingers together. In some embodiments, the reservoir has an internal diameter of less than about 10 mm. In some embodiments, the nozzle additionally has a width perpendicular to the axis from the inlet to the outlet of the flow from about 5 mm to about 20 mm. In some embodiments, the nozzle additionally has a length parallel to the axis from the inlet to the outlet of the flow from about 5 mm to about 40 mm.

[0027] In certain embodiments, the pump further comprises a flow inlet, wherein said flow inlet is less than 10% of the size of the flow outlet. In some embodiments, said flow inlet hole has a diameter of approximately 0.1-2 mm. In some embodiments, the nozzle further comprises an airtight cap located at the inlet end of the nozzle and configured to prevent contact of outside air with the powdered medicinal product. In some embodiments, the nozzle further includes a removable or breakable tab located at the outlet end of the nozzle and configured to prevent air flow through the nozzle. In some embodiments, the outlet end of the nozzle further comprises a nozzle opening.

[0028] In some embodiments, the passage valve is configured to provide laminar air flow along at least a portion of the reservoir. In some embodiments, sufficient air flow is generated by a compression force of at least 20 kilopascals applied to the pump. In some embodiments, the nozzle consists of a substantially transparent or light-transmitting material. In some embodiments, the nozzle additionally contains a thread configured to secure the nozzle to the pump.

[0029] In some embodiments, there is provided a method of using a device for delivering a powdered drug, wherein said method comprises the step of placing a nozzle of the device into the nostril of a subject and the step of operating a pump, and wherein said device is a disposable device that includes: a) a nozzle having an inlet end and an outlet end, wherein said nozzle is configured to place at least a portion of said nozzle into the nostril of a subject; b) a reservoir containing a dose of powdered medicinal product and having an inlet end and an outlet end having an operative connection with and located inside said nozzle; c) a pass-through valve having an inlet end and an outlet end, the pass-through valve being configured to cause a spray of powdered medicament when the device is actuated; d) a retainer having internal ribs mating with the passage valve; and e) a pump having an operative connection to the inlet end of the retainer. In some embodiments, the device is a disposable device. In some embodiments, the nozzle and reservoir of the device contain transparent or light-transmitting material. In some embodiments, the method further comprises the step of visually monitoring the amount of powdered drug remaining in the reservoir and the step of repeating the method until a sufficient dose is delivered. In some embodiments, the method further comprises the step of driving a pump to create laminar flow along at least a portion of the reservoir. In some embodiments, the method further comprises the step of delivering from 1 mg to 50 mg of the powdered drug into the nostril of the subject. In certain embodiments, the method further comprises the step of delivering approximately 80%-99% of a single dose of the powdered drug to the nostril of the subject. In some embodiments, the method additionally comprises the step of compressing a manual air pump with a force of approximately 5-30 kilopascals. In certain embodiments, the method further comprises the step of removing the cap from the nozzle before the nozzle is placed into the nostril of the subject.

[0030] In some embodiments, a method is provided for making a device for delivering a powdered drug to a subject, said method comprising the step of placing the powdered drug into a reservoir and then attaching a nozzle to a pump, said device comprising: a) a nozzle having an inlet end and an outlet end, wherein said nozzle is configured to place a portion of said nozzle into the nostril of a subject; b) a reservoir containing a dose of powdered medicinal product and having an inlet end and an outlet end having an operative connection with and located inside said nozzle; c) a pass-through valve having an inlet end and an outlet end, the pass-through valve being configured to cause a powder medicament to be sprayed when the device is actuated; d) a retainer having internal ribs mating with the passage valve; and e) a pump having an operative connection to the inlet end of the retainer.

[0031] In some embodiments, the device does not include a flow inlet when the removable cover mounted at the outlet end of the nozzle is not removed. In some embodiments, the drug powder reservoir is a closed system when the removable lid is not removed, which increases the stability of the drug powder in the reservoir. In some embodiments, the device includes an opening for flow inlet when a removable cover mounted at the outlet end of the nozzle is removed. In some embodiments, the outlet end of the nozzle further includes a nozzle opening, and the nozzle opening includes a flow inlet opening.

[0032] In certain embodiments, the globe valve includes an internal inlet section, and the internal inlet section is connected to the first cylindrical section, and the first cylindrical section is connected to the first shoulder, and the first shoulder is connected to the second cylindrical section. In some embodiments, the globe valve further includes an inner inlet section, and the inner inlet section is connected to the upper section. In some embodiments, the globe valve includes a globe valve cavity. In some embodiments, the globe valve cavity includes a hollow chamber within the globe valve cavity, an opening at the inlet end of the globe valve cavity, and an opening at the outlet end of the globe valve cavity. In some embodiments, the globe valve cavity extends the entire length of the globe valve. In some embodiments, the globe valve cavity and an opening at the inlet end of the globe valve cavity are connected to a reservoir, and the hole at the outlet end of the globe valve cavity is connected to a pump.

[0033] Device height

The devices disclosed herein may be of any convenient size for administering the powdered medicinal product contained herein. For example, the device may have a height in the range of approximately: 3-15 cm, 4-15 cm, 5-15 cm, 6-15 cm, 7-15 cm, 8-15 cm, 3-10 cm, 3-9 cm or 3-8 cm. The device may have a height of about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm , about 13 cm, about 14 cm or about 15 cm. The device may have a height greater than: about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, approximately 11 cm, approximately 12 cm, approximately 13 cm, approximately 14 cm, or approximately 15 cm. The device may have a height less than: approximately 3 cm, approximately 4 cm, approximately 5 cm, approximately 6 cm, approximately 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm or about 15 cm. The dimensions of the device can be selected based on the amount of powder drug to be delivered, convenience application, ease of carrying or ease of manufacture.

[0034] Device volume

As described herein, the device may be designed to be small in size so that it can be easily stored or transported. The device may have a volume in the range of about 1-100 cm ³ , about 5-90 cm ³ , about 10-80 cm ³ , about 25-80 cm ³ , about 50-100 cm ³ , about 1-50 cm ³ , about 5-75 cm ³ , about 1-25 cm ³ , about 5-50 cm ³ , about 10-50 cm ³ or about 25-50 cm ³ . The device may have a volume of at least about: 1, 2, 5, 10, 25, 30, 40, 50, 75 or 100 cm ³ . The device may have a volume of less than about: 250, 200, 175, 150, 125, 100, 75, 70, 65, 60, 55, 50, 40, 30, 25, 10, 5, 2 or 1 cm ³ .

[0035] Device width

At its widest point, the device may have a width of approximately 0.5-5 cm. The device at its widest point may have a width of approximately: 0.5, 1, 1.5, 2, 2.5, 3, 3 .5, 4, 4.5 or 5 cm. The device at its widest point may have a width greater than approximately: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 , 4.5 or 5 cm. The device at its widest point may have a width less than, approximately: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 cm.

[0036] Device weight

The device can be made with low weight. For example, the device may have a total weight of from about 1 to about 50 grams, from about 5 to about 40 grams, from about 10 to about 35 grams, from about 10 to about 30 grams, from about 10 to about 25 grams, from about 1 to about 10 grams, from about 1 to about 5 grams, or from about 10 to about 20 grams. The device may have a total weight less than approximately: 100 grams, 90 grams, 80 grams, 75 grams, 70 grams, 65 grams, 60 grams, 55 grams, 50 grams, 45 grams, 40 grams, 35 grams, 30 grams, 25 gram, 20 gram, 10 gram, 9 gram, 8 gram, 7 gram, 6 gram, 5 gram, 4 gram, 3 gram, 2 gram, 1 gram, 0.5 gram or less. The device may have a total weight greater than approximately: 0.5 grams, 1 grams, 2 grams, 3 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams, 9 grams, 10 grams, 11 grams, 12. gram, 13 gram, 14 gram, 15 gram, 16 gram, 17 gram, 18 gram, 19 gram, 20 gram, 25 gram, 30 gram, 35 gram, 40 gram, 45 gram, 50 gram, 55 gram, 60 gram, 65 grams, 70 grams, 75 grams, 80 grams, 85 grams, 90 grams, 95 grams or 100 grams. The device may have a total weight of approximately: 1 gram, 2 grams, 3 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams, 9 grams, 10 grams, 11 grams, 12 grams, 13 grams, 14 grams , 15 grams, 16 grams, 17 grams, 18 grams, 19 grams, 20 grams, 25 grams, 30 grams, 35 grams, 40 grams, 45 grams, 50 grams, 55 grams, 60 grams, 65 grams, 70 grams, 75 gram, 80 gram, 85 gram, 90 gram, 95 gram or 100 gram. The total weight may be the weight of the device without the powdered drug or the weight of the device with the powdered drug.

[0037] Device delivery efficiency

As described herein, the device may be configured to deliver a significant portion of a single dose of a powdered drug formulation (powdered formulation) into the nostril of a subject. The device may be configured to deliver a significant portion of the amount of powdered drug contained within the device to the nostril of a subject. The powdered drug, or a significant portion thereof, may be delivered after a single actuation of the device. The device can be activated, for example, by squeezing a flexible bottle that serves as a hand-held air pump. A significant portion of the powder drug may be delivered after several activations of the device, for example, 2, 3, 4, 5, 6, 7, 8, 9 or 10 activations. Multiple activations of the device may constitute a single use of the device. The significant proportion of powder drug that can be delivered by the device can be at least about: 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90.5 %, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.5%, 99 .6%, 99.7%, 99.8% 99.9%, 99.95%, or 100% of the amount of powdered drug product, such as the amount per dose or the amount contained in a device. The significant proportion of powder drug that can be delivered by the device may be approximately: 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90.5%, 91%, 91. 5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5% , 98%, 98.5%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.5%, 99.6%, 99.7 %, 99.8% 99.9%, 99.95%, or 100% of the amount of powdered drug product, such as the amount per dose or the amount contained in a device. In some variants, approximately: 60-100%, 60-99%, 60-95%, 60-90%, 60-85%, 60-80%, 60-75%, 60-70%, 70-100% , 70-99%, 70-95%, 70-90%, 70-85%, 70-80%, 75-100%, 75-99%, 75-95%, 75-90%, 75-85% , 75-80%, 80-100%, 80-99%, 80-95%, 80-90%, 80-85%, 85-100%, 85-99%, 85-95%, 85-90% 90-100%, 90-99%, 90-95%, 95-100% or 95-99% of the amount of powdered drug is expelled from the device after the first actuation. In such embodiments, the second actuation may result in the release of substantially all of the drug powder. A residue of no more than 1% of the drug powder in the device, typically in the form of powder remaining on the walls of the chamber, can be considered to have delivered substantially all of the drug powder.

[0038] A. Nozzle

The nozzles provided herein are configured to deliver a powdered drug into the nostril of a subject. In certain embodiments, the nozzle is configured to be placed partially or completely within the nostril of a subject during use. In some embodiments, the nozzle is designed to be placed outside and near the nostril, with complete or partial closure of the nostril opening.

[0039] Nozzle shape

The nozzle disclosed herein is not limited to a particular shape. The nozzle can be of the same width, for example, in the shape of a cylinder, cube, rhombohedron or parallelepiped. The nozzle may also be funnel-shaped or truncated with a wide end and a narrow end. The nozzle shape can be wider at the inlet end and narrower at the outlet end. The nozzle can be wider at the outlet end and narrower at the inlet end. In some embodiments, however, the widest and narrowest sections of the nozzle are not located at either end. For example, the widest section of the nozzle can be in any position along the axis from the inlet to the outlet of the flow. In nozzles in which the widest section is mid-length along the axis, the widest section may function as a stop that allows the nozzle to be inserted further into the nostril. In some embodiments, the nozzle is comprised of at least two shapes, for example, any of the shapes provided herein. For example, the nozzle may include a cylindrical shaped portion and a conical shaped portion. The nozzle may include a section, such as a nozzle body, for insertion into a nostril and a section, such as a nozzle base, for attachment to a pump, such as attachment to the neck of a flexible bottle.

[0040] Nozzle material

The nozzle may be composed of a variety of polymers, plastics, rubber, silicones, metal, composites, or any other materials described herein as suitable for use in the manufacture of an applicator device, or any other material suitable for use as an applicator nozzle. The nozzle can be made of one material or one type of materials. The nozzle may be composed of at least two different materials or types of materials. The entire nozzle or portion thereof may be a biocompatible material or a hypoallergenic material. In certain embodiments, the nozzle is composed of one or more of a cycloolefin copolymer (COC), silicone, styrene-butadiene block copolymer (SBC), polyacetal, polyoxymethylene, acrylates, polyethylenes, polyurethane, hydrogel, polyester (e.g., material DACRONB from E. I. Du Pont de Nemours and Company, Wilmington, Del.), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyetheretherketone (PEEK), nylon, extruded collagen, foam, rubber, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene , polycarbonate-urethane, polyimides, aluminum, stainless steel, nickel-titanium alloy (e.g., nitinol), titanium, stainless steel, or cobalt-chromium alloy (e.g., ELGILOYB alloy from Elgin Specialty Metals, Elgin, Ill.; CONICHROMEB alloy from Carpenter Metals Corp., Wyomissing, Pa.).

[0041] Nozzle opacity

The nozzle may consist, in part or entirely, of transparent or light-transmitting materials. The use of a clear or translucent nozzle may allow visual inspection of the nozzle to determine whether a significant amount of residual powdered drug(s) remains in the reservoir after use. If, during monitoring, the subject notices that there is residual powdered drug in the reservoir, the subject may operate the pump one or more times and then verify by visual inspection of the clear or light-transmitting nozzle whether the delivery has been sufficient. This process can be repeated as necessary to ensure a sufficient dose is delivered. The nozzle may be composed, partially or entirely, of opaque or substantially opaque materials. For example, if the device contains a photosensitive drug powder, then a light-proof nozzle or substantially light-blocking material may protect the photosensitive drug powder from exposure to light.

[0042] Nozzle stiffness

The nozzle material may be a soft, pliable or pliable material so that the nozzle can conform to the shape of the subject's nostril. The nozzle may be composed of rigid, substantially rigid, flexible or substantially flexible materials, or a combination thereof. The nozzle may be a rigid material, such as a polymer, plastic, silicone, metal, or composite, at one end, and a soft, plastic, or pliable material at the other end, such as the end of the nozzle that is placed in the nostril. A soft, pliable or pliable material may be advantageous in reducing the likelihood of injury during contact between the subject's nostril and the nozzle. Reducing the likelihood of injury may be beneficial if the device is used by a third party, such as a doctor, nurse, home care worker, emergency responder, paramedic, parent, guardian or other caregiver, to deliver powdered medication. drug into a subject (eg, a child or elderly subject).

[0043] Inserting the nozzle into the nose

In certain embodiments, the nozzle is sized to substantially fit inside the subject's nostril. For example, at least about: 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95% of the nozzle may be inserted inside the subject's nostril at time of device use. During use of the device, less than approximately: 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95 can be inserted inside the subject's nostril. % nozzle. During use of the device, from about 5% to about 90% of the device nozzle may be inserted into the subject's nostril. In certain embodiments, during use of the device, approximately 5% to 75%, 10% to 50%, 10% to 30%, 20% to 60%, or 30% to 90% may be inserted into the subject's nostril. % of the device nozzle. During use of the device, approximately 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95% of the nozzle may be inserted into the subject's nostril.

[0044] Inserting the nozzle pipe into the nose

The nozzle may include a nozzle tube for insertion into a nostril and a base section, for example, for attachment to a pump. In certain embodiments, the nozzle port is substantially designed to fit inside the subject's nostril. For example, at least about: 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95% of the nozzle may be inserted inside the subject's nostril while using the device. During use of the device, less than approximately: 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95 can be inserted inside the subject's nostril. % nozzle pipe. During use of the device, from about 5% to about 90% of the nozzle port of the device may be inserted into the subject's nostril. In certain embodiments, during use of the device, approximately 5% to 75%, 10% to 50%, 10% to 30%, 20% to 60%, or 30% to 90% may be inserted into the subject's nostril. % of the device nozzle pipe. During use of the device, approximately 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95% of the nozzle tube may be inserted into the subject's nostril. . In some embodiments, a nozzle base section may be inserted inside the subject's nostril. For example, at least about: 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95% of the nozzle base may be inserted inside the subject's nostril while using the device. During use of the device, less than approximately: 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95 can be inserted inside the subject's nostril. % nozzle base. During use of the device, from about 5% to about 90% of the base of the device nozzle may be inserted into the subject's nostril. In certain embodiments, during use of the device, approximately: 5% to 75%, 10% to 50%, up to 10% to 30%, 20% to 60%, or 30% to 90% may be inserted into the subject's nostril. % base of the device nozzle. During use of the device, approximately 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 95% of the base may be inserted into the subject's nostril. nozzles Alternatively, in certain embodiments, the nozzle base section is not inserted inside the subject's nostril.

[0045] Nozzle length

The length of the nozzle may be measured from the inlet end to the outlet end, where inlet and outlet refer to the direction of flow of air or other propellant during operation of the device (i.e., air or other propellant may flow from the inlet end to the outlet end). The length of the nozzle may include the length of the nozzle nozzle and the nozzle base section. The length of the nozzle can be the length of the nozzle pipe. The length of the nozzle from inlet to outlet stream may be less than about 5 cm, less than about 4.5 cm, less than about 4 cm, less than about 3.5 cm, less than about 3 cm, less than less than about 2.5 cm, less than about 2 cm, less than about 1.5 cm, less than about 1.0 cm, or less than about 0.5 cm. The nozzle length can be within the range of about from 0.5 cm to 5 cm, from about 1 cm to 5 cm, from about 1 cm to 4 cm, from about 1 cm to 3 cm, from about 2 cm to 5 cm or from about 2 cm to 4 cm. Nozzle length can be approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm. Nozzle length can exceed approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm.

[0046] Nozzle Length

The nozzle may include a nozzle tube for insertion into a nostril and a neck section for attachment to a pump. The nozzle port length may be measured from the inlet end to the outlet end, where inlet and outlet refer to the direction of flow of air or other propellant during operation of the device (i.e., air or other propellant may flow from the inlet end to the outlet end). The length of the nozzle connection from the inlet to the flow outlet may be less than about 5 cm, less than about 4.5 cm, less than about 4 cm, less than about 3.5 cm, less than about 3 cm, less less than about 2.5 cm, less than about 2 cm, less than about 1.5 cm, or less than about 1.0 cm. The length of the nozzle nozzle can range from about 0.5 cm to 5 cm, approximately 1 cm to 5 cm, approximately 1 cm to 4 cm, approximately 1 cm to 3 cm, approximately 2 cm to 5 cm or approximately 2 cm to 4 cm Length The nozzle pipe length can be approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm. Nozzle pipe length may exceed approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm.

[0047] Nozzle outer width

In some versions, the external width perpendicular to the nozzle axis from the inlet to the flow outlet, on its widest section, is approximately: from 0.1 cm to 4 cm, from 1 cm to 4 cm, from 1 cm to 3 cm, from 1 cm to 2 cm, from 2 cm to 4 cm or from 2 cm to 3 cm, from 0.1 cm to 2 cm, from 0.5 cm to 2 cm or from 1 cm to 2 cm. In individual versions, external width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, on its widest section, does not exceed approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, or 5 cm. In some versions, the external width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, at its widest section, is approximately equal to: 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1.0 cm, 1.2 cm, 1.4 cm, 1.6 cm, 1.8 cm, 2.0 cm, 2.2 cm, 2.4 cm, 2.6 cm, 2.8 cm, 3 cm, 3.2 cm, 3.4 cm, 3.6 cm, 3, 8 cm, 4 cm, 4.2 cm, 4.4 cm, 4.6 cm, 4.8 cm or 5 cm. In some versions, the outer width is perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, at its widest section, exceeds approximately: 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1 .0 cm, 1.2 cm, 1.4 cm, 1.6 cm, 1.8 cm, 2.0 cm, 2.2 cm, 2.4 cm, 2.6 cm, 2.8 cm, 3 cm, 3.2 cm, 3.4 cm, 3.6 cm, 3.8 cm, 4 cm, 4.2 cm, 4.4 cm, 4.6 cm, 4.8 cm or 5 cm.

[0048] In some embodiments, the outer width perpendicular to the axis of the nozzle from the inlet to the flow outlet, at its narrowest section, does not exceed approximately: 0.1 cm, 0.25 cm, 0.5 cm, 0.75 cm, 1 .0 cm, 1.5 cm, 2.0 cm, 2.5 cm or 3.0 cm. In some versions, the outer width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, on its narrowest section, is within the range of approximately : from 0.5 cm to 3.0 cm; from 1.0 to 2.5 cm, from 1.0 to 2.0 cm, from 0.1 cm to 2.0 cm or from 0.5 cm to 1.5 cm. In some versions, the external width is perpendicular to the axis nozzle from inlet to outlet flow, at its narrowest section, is approximately equal to: 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm , 0.8 cm, 0.9 cm, 1.0 cm, 1.2 cm, 1.4 cm, 1.6 cm, 1.8 cm, 2.0 cm, 2.2 cm, 2.4 cm , 2.6 cm, 2.8 cm, 3 cm, 3.2 cm, 3.4 cm, 3.6 cm, 3.8 cm, 4 cm, 4.2 cm, 4.4 cm, 4.6 cm, 4.8 cm or 5 cm. In some versions, the external width perpendicular to the axis of the nozzle from the inlet to the flow outlet, on its narrowest section, exceeds approximately: 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1.0 cm, 1.2 cm, 1.4 cm, 1.6 cm, 1.8 cm, 2.0 cm, 2.2 cm, 2.4 cm, 2.6 cm, 2.8 cm, 3 cm, 3.2 cm, 3.4 cm, 3.6 cm, 3, 8 cm, 4 cm, 4.2 cm, 4.4 cm, 4.6 cm, 4.8 cm or 5 cm.

[0049] The nozzle width may vary continuously, may vary in steps, may not vary, or may vary by a combination of these changing methods. The inner width or outer width of the nozzle may be changed continuously, may be changed in steps, may not be changed, or may be changed by a combination of these changing methods. The inlet and outlet ends of the nozzle may be the same width or may vary in width. In certain embodiments, the narrowest end is the end that is placed into the subject's nostril before and during insertion. In some embodiments, the widest and narrowest sections of the nozzle are located at the ends. For example, the widest section of the nozzle may be at the inlet end and the narrowest section of the nozzle may be at the outlet end, or vice versa. In some embodiments, the widest and/or narrowest sections of the nozzle are not at the end. In some embodiments, the widest section of the nozzle accommodates a reservoir for the powdered drug. In some embodiments, the widest section of the nozzle is the base of the nozzle for attachment to the hand air pump.

[0050] Inner nozzle width

In some versions, the internal width perpendicular to the nozzle axis from the inlet to the flow outlet, on its widest section, is approximately: from 0.1 cm to 4 cm, from 1 cm to 4 cm, from 1 cm to 3 cm, from 1 cm to 2 cm, from 2 cm to 4 cm or from 2 cm to 3 cm, from 0.1 cm to 2 cm, from 0.5 cm to 2 cm or from 1 cm to 2 cm. In some versions, internal width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, on its widest section, does not exceed approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm. In some versions, the internal width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, on its widest section, exceeds approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm , 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm. In some versions, the internal width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, at its widest section, is approximately equal to: 0 ,1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1.0 cm, 1 ,2 cm, 1.4 cm, 1.6 cm, 1.8 cm, 2.0 cm, 2.2 cm, 2.4 cm, 2.6 cm, 2.8 cm, 3 cm, 3.2 cm, 3.4 cm, 3.6 cm, 3.8 cm, 4 cm, 4.2 cm, 4.4 cm, 4.6 cm, 4.8 cm or 5 cm.

[0051] In some embodiments, the internal width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, at its narrowest section, does not exceed approximately: 0.1 cm, 0.25 cm, 0.5 cm, 0.75 cm, 1 .0 cm, 1.5 cm, 2.0 cm, 2.5 cm or 3.0 cm. In some versions, the internal width perpendicular to the nozzle axis from the inlet to the outlet of the flow, at its narrowest section, exceeds approximately: 0 .1 cm, 0.25 cm, 0.5 cm, 0.75 cm, 1.0 cm, 1.5 cm, 2.0 cm, 2.5 cm or 3.0 cm. In selected versions, internal width perpendicular to the axis of the nozzle from the inlet to the outlet of the flow, on its narrowest section, is within the range of approximately: from 0.5 cm to 3.0 cm; from 1.0 to 2.5 cm, from 1.0 to 2.0 cm, from 0.1 cm to 2.0 cm or from 0.5 cm to 1.5 cm. In some versions, the internal width is perpendicular to the axis nozzle from inlet to outlet flow, at its narrowest section, is approximately equal to: 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm , 0.8 cm, 0.9 cm, 1.0 cm, 1.2 cm, 1.4 cm, 1.6 cm, 1.8 cm, 2.0 cm, 2.2 cm, 2.4 cm , 2.6 cm, 2.8 cm, 3 cm, 3.2 cm, 3.4 cm, 3.6 cm, 3.8 cm, 4 cm, 4.2 cm, 4.4 cm, 4.6 cm, 4.8 cm or 5 cm.

[0052] Nozzle internal volume

The nozzle may be hollow and may contain an internal volume. The internal volume of the nozzle can be approximately: no more than 5 cm ³ , no more than 4 cm ³ , no more than 3 cm ³ , no more than 2 cm ³ , no more than 1 cm ³ , no more than 0.5 cm ³ . In some embodiments, the internal volume of the nozzle ranges from about 1 cm ³ to about 5 cm ³ , from about 1 cm ³ to about 4 cm ³ , from about 1 cm ³ to about 3 cm ³ , from , about 1 cm ³ to about 2 cm ³ , from about 0.1 cm ³ to 2 cm ³ and from about 0.1 cm ³ to about 1 cm ³ . The internal volume of the nozzle can be approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1, 2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0 cm ³ . The internal volume of the nozzle may exceed approximately: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 cm ³ . The internal volume of the nozzle may be less than about: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 cm ³ .

[0053] Nozzle as reservoir

The nozzle may include a powdered medicament reservoir configured to receive the powdered medicament for delivery to the nostril of a subject. In some embodiments, the reservoir for the powdered medicinal product is completely formed by the nozzle. In other embodiments, the reservoir is formed partly by the nozzle and partly by the device's passage valve and/or pump, or components thereof. For example, the outlet end of the reservoir may be formed by a nozzle, and the inlet end of the reservoir may be formed by a globe valve and a pump or components thereof. The reservoir may be an integral part of the nozzle in the sense that it cannot be removed or replaced separately without removing or replacing the nozzle itself. The reservoir may be a separate, replaceable, insertable or removable part. In some embodiments, the replaceable, insertable or removable reservoir is in the form of a capsule or cartridge. In some embodiments, the replacement reservoir is not a capsule. A flow valve or other means may be present to regulate the flow of air, propellant, or powdered drug from the reservoir. A pass-through valve or other means may be present to regulate the flow of air, propellant, or powdered drug into the reservoir. In some embodiments, the nozzle accommodates a separate reservoir for the powdered medicament, which is located within the nozzle and is configured to receive the powdered medicament for delivery to the nostril of a subject. By designing a medicine reservoir in the nozzle, close to the outlet, the amount of residual medicine after actuation of the device can be minimized, for example for sticky medicine or for powders that stick to plastic due to, for example, adhesion, static electricity, etc. P.

[0054] Tank nozzle volume

In some embodiments, the reservoir for the powdered medicinal product has a volume of approximately: no more than 5 cm ³ , no more than 4 cm ³ , no more than 3 cm ³ , no more than 2 cm ³ , no more than 1 cm ³ or no more than 0.5 cm ³ . In certain embodiments, the powder drug reservoir has a volume ranging from about 1 cm ³ to about 5 cm ³ , from about 1 cm ³ to about 4 cm ³ , from about 1 cm ³ to about 3 cm ³ , from about 1 cm ³ to about 2 cm ³ , from about 0.1 cm ³ to 2 cm ³ and from about 0.1 cm ³ to about 1 cm ³ . The powder drug reservoir may have a volume of approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2 ,4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3 ,7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 .0 cm ³ . The powder drug reservoir may have a volume greater than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 cm ³ . The powder drug reservoir may have a volume of less than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 cm ³ .

[0055] Amount of drug powder in the reservoir

In certain embodiments, the reservoir is suitable for storing a dose of powdered drug in the range of: about 1 mg to 200 mg, about 2 mg to 100 mg, about 5 mg to 50 mg, about 10 mg to 50 mg , about 10 mg to 40 mg or about 10 mg to 25 mg of powdered drug product. In certain embodiments, the reservoir is suitable for storing at least about: 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg , 150 mg or 200 mg powdered medicinal product. In certain embodiments, the reservoir is suitable for storing at most approximately: 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg , 80 mg, 90 mg, 100 mg, 150 mg or 200 mg powdered drug. The reservoir can store approximately: 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg or 200 mg powdered drug. In some embodiments, the reservoir is configured to hold one dose of powdered medicinal product, and, in other embodiments, the reservoir is configured to accommodate multiple (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10) doses of powdered medicinal product. medicinal product. Dose may refer to the amount of powdered drug that a subject uses at one time.

[0056] The reservoir may be filled with powdered drug during manufacture of the device. The reservoir may be filled with the powdered drug before fixing or attaching the nozzle to the pump. The reservoir can be filled after fixing or attaching the nozzle to the pump or connecting them.

[0057] Inner wall and nozzle slots

The inner wall of the nozzle may also include one or more slots (channels or grooves). The slot or groove may be formed by a curved surface, two surfaces, three surfaces, four surfaces, five surfaces, six surfaces, seven surfaces, eight surfaces, nine surfaces, or 10 surfaces. The inner wall of the nozzle may have slots or grooves having at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 different shapes. The one or more slits may serve to create a vortex flow in the device reservoir when the device is actuated (eg, when air enters the powder drug reservoir from a pump). The vortex flow may enable complete delivery of the powdered drug. One or more slots may be positioned to permit laminar air flow within the reservoir.

[0058] Number of slots or grooves

The inner wall of the nozzle may comprise at least about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 slots or grooves. The inner wall of the nozzle may contain less than about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 slots or grooves. The inner wall of the nozzle may contain, approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 slots or grooves. The inner wall of the nozzle may contain approximately: 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-40, 1-30, 1-25, 1-20 or 1- 10 slots or grooves.

[0059] Arrangement of slots or grooves

The slots or grooves may be substantially parallel to each other in the inner wall of the nozzle. In some embodiments, all of the slots or grooves are not located substantially parallel to each other in the inner wall of the nozzle. In some embodiments, all of the slots or grooves are not spaced at equal intervals in the inner wall of the nozzle. In some embodiments, all slots or grooves are located at equal intervals on the inner wall of the nozzle.

[0060] Length of slots or grooves

The slot or groove may have a length of approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 , 97, 98, 99 or 100 mm. The slot or groove may have a length less than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 , 96, 97, 98, 99 or 100 mm. The slot or groove may have a length greater than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 , 96, 97, 98, 99 or 100 mm.

[0061] Powdered drug container shape

The powder drug reservoir is not limited to any particular shape and may be located within the nozzle in the form of a sphere, an ellipsoid, a cylinder, a cube, a truncated figure, or any other suitable shape, such as any of the shapes described herein. In some embodiments, the shape of the reservoir is selected to minimize the presence of corners, sharp edges or other surface features that could disrupt airflow. In some embodiments, the shape of the reservoir is selected to exclude areas that are not exposed to uniform, laminar or strong air flow during operation of the device. This may reduce the number of places within the reservoir and nozzle where the powdered drug can clump or accumulate and thereby reduce the total amount of powdered drug delivered to the nostril of the subject. For example, the shape of a reservoir for a powdered drug may be a truncated figure or a parallelepiped in which all corners are rounded. In some embodiments, the powder drug reservoir consists of at least two forms, for example, any of the forms described in this application. For example, the powder drug reservoir may include a cylindrical shaped portion and a conical shaped portion. Alternatively, by way of example only, the powder drug reservoir may include two conical shaped portions connected at their widest ends or two conical shaped portions connected by an intermediate cylindrical shaped portion. In some embodiments, the inner surface of the powder medicinal product reservoir is smooth. Alternatively, the inner surface may be rough. In some embodiments, one or more internal surface features may be provided within the powder drug reservoir. One or more orientation ridges, grooves, projections, bumps, channels, or other surface features may be provided on the interior surface of the reservoir. Such surface features can affect airflow and delivery of the powdered drug product.

[0062] Nozzle Flow Restrictor

The nozzle may include a flow restrictor configured to restrict the flow of air through at least a portion of the device and thereby increase or decrease the speed or redirect the air flow within the device. In some embodiments, the flow restrictor is located at the outlet end of the nozzle. The flow restrictor may be located at the inlet end of the nozzle. The flow restrictor can be located at both the inlet and outlet ends of the nozzle. In some embodiments, the flow restrictor is located at the outlet end of the nozzle and smoothly tapers in width from the inlet to the outlet end. Alternatively, the flow restrictor may taper in steps, or may taper with a combination of stepped and continuous tapers from the inlet to the outlet end. This constriction may provide increased velocity of air and/or powdered drug from the nozzle into the subject's nostril during operation of the device. In some embodiments, a flow restrictor located at the outlet end of the nozzle tapers to a nozzle opening through which air and drug powder are discharged from the nozzle during operation.

[0063] Nozzle Flow Restrictor Shape

The flow restrictor may provide redirection of the flow of air or other propellant away from the interior walls of the nozzle and toward the center of the air stream. The flow restrictor may be configured to direct the flow of air from moving along the inner walls of the nozzle in the form of a laminar flow. The flow restrictor may be configured to direct air flow into the powder drug reservoir in the form of a turbulent flow. The flow restrictor may be configured to provide vortex flow in at least a portion of the powder drug reservoir during use of the device. The redirected air flow provided by the flow restrictor can break up at least a portion of the clumps or lumps of powdered drug present in the reservoir. The redirected airflow may ensure that a significant portion of the powdered drug contained in the reservoir is delivered to the subject's nostril during normal use of the device. For example, the redirected air flow provided by a flow restrictor can turbulently mix and therefore effectively aerosolize a powdered drug. The flow restrictor may have any of a variety of shapes, including, but not limited to, cone, cylinder, tapered cylinder, frustum and parallelepiped, or any other shape provided herein, including a combination of one or more shapes.

[0064] Nozzle Flow Restrictor Width

The flow restrictor can vary in width from slightly less than the width of the nozzle, down to the width of the nozzle opening. For example, the flow restrictor may vary in width from at least about: 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm , 0.8 mm, 0.9 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm , 11 mm, 12 mm, 13 mm, 14 mm or 15 mm at the widest part to less than approximately: 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, or 10mm in the narrowest section of the flow restrictor. The flow restrictor at its widest point may have a width of from about 5 mm to about 15 mm or from about 8 mm to about 12 mm. The flow restrictor at its narrowest point may have a width of from about 1 mm to about 10 mm, from about 2 mm to about 7 mm, from about 0.1 mm to about 2 mm, or from about 0. 5 mm to approximately 1.5 mm.

[0065] Nozzle Flow Restrictor Length

The flow restrictor may have a length from the inlet end to the outlet end of at least about: 20 mm, 15 mm, 10 mm, 5 mm, 4 mm, 3 mm, 2 mm or 1 mm. The flow restrictor may have a length from the inlet end to the outlet end of less than about: 20 mm, 15 mm, 10 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. The flow restrictor may have a length ranging from about 5 mm to about 20 mm, from about 5 mm to about 15 mm, from about 5 mm to about 10 mm, from about 1 mm to about 5 mm or from about 0.5 mm to about 2.5 mm. The flow restrictor may have a length of approximately: 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 5, 5mm, 6mm, 6.5mm, 7mm, 7.5mm, 8mm, 8.5mm, 9mm, 9.5mm or 10mm.

[0066] Nozzle hole

The nozzle opening may be configured to discharge the powdered medicinal product from the nozzle in the form of a single jet. In some embodiments, the nozzle includes multiple openings that can release the powdered drug in multiple jets that remain separate, or that can be combined into a single jet. In some embodiments, the nozzle opening is located at the outlet end of the nozzle. In some embodiments, the nozzle opening is also the outlet end of the flow restrictor. The nozzle opening may have any of a variety of shapes, including, but not limited to, round, oval, triangular or rectangular, or a combination thereof. In certain embodiments, the nozzle is configured to deliver a high velocity of propellant and/or powdered medicament into the nostril of the subject. For example, the nozzle may be configured to provide a maximum propellant velocity of from about 1 m/s to about 10 m/s, from about 2 m/s to about 8 m/s, or from about 3 m/s to , approximately 6 m/s.

[0067] Nozzle opening width

In certain embodiments, the nozzle opening size, when there is only one opening, when measured at its widest section, is less than 20 mm, less than about 15 mm, less than about 12 mm, less than about 10 mm , less than about 8 mm, less than about 5 mm, less than about 3 mm, less than about 2 mm, less than about 1 mm, or less than about 0.5 mm. In embodiments where there are at least two nozzle openings, the width of the individual openings is less than 10 mm, less than about 8 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm , less than about 3 mm, less than about 2 mm, less than about 1 mm, or less than about 0.5 mm. The width of the nozzle opening at its widest section can be approximately: 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0. 45mm, 0.5mm, 0.55mm, 0.6mm, 0.65mm, 0.7mm, 0.75mm, 0.8mm, 0.9mm, 1mm, 1.1mm , 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm , 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm. The nozzle opening at its widest section may exceed approximately: 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, 0.65 mm, 0.7 mm, 0.75 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, 2.0mm, 2.1mm, 2.2mm, 2.3mm, 2.4mm, 2.5mm, 2.6mm, 2.7mm, 2.8mm, 2.9mm, 3.0mm. The nozzle opening at its widest section may be smaller than approximately: 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0 .45 mm, 0.5 mm, 0.55 mm, 0.6 mm, 0.65 mm, 0.7 mm, 0.75 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm. The nozzle opening at its widest section may range from approximately 0.1 mm to 2 mm, 0.5 mm to 1.5 mm, or 0.75 mm to 1.25 mm.

[0068] Nozzle hole depth

In certain embodiments, the depth of the nozzle opening from the inlet end to the outlet end, which is the length of the channel formed from the surface of the nozzle at the opening to the tip of the reservoir or flow restrictor, is less than about 50 mm, less than about 40 mm, less than less than about 30 mm, less than about 25 mm, less than about 20 mm, less than about 15 mm, less than about 10 mm, less than about 7 mm, less than about 5 mm, less than about 3 mm or less than about 1 mm. In some embodiments, the nozzle surface at the opening is the top of the reservoir or flow restrictor at its outlet, resulting in an effective depth of 0 mm. Nozzle hole depth can exceed approximately: 0.1mm, 0.25mm, 0.5mm, 0.75mm, 1mm, 1.5mm, 2mm, 3mm, 4mm, 5mm, 6mm , 7 mm, 8 mm, 9 mm, 10 mm, 12.5 mm, 15 mm, 17.5 mm, 20 mm, 22.5 mm, 25 mm, 27.5 mm, 30 mm, 35 mm, 40 mm , 45 mm or 50 mm. The depth of the nozzle hole can be approximately 0.1mm, 0.25mm, 0.5mm, 0.75mm, 1mm, 1.5mm, 2mm, 3mm, 4mm, 5mm, 6mm , 7 mm, 8 mm, 9 mm, 10 mm, 12.5 mm, 15 mm, 17.5 mm, 20 mm, 22.5 mm, 25 mm, 27.5 mm, 30 mm, 35 mm, 40 mm , 45 mm or 50 mm.

[0069] Nozzle base

The nozzle may also include a base. The base may be configured to provide air flow from the manual air chamber to the powder drug reservoir or nozzle. In some embodiments, the base is located at the inlet end of the nozzle. Additionally or alternatively, a spout may be provided at the inlet end of the reservoir. In some embodiments, the base is part of the nozzle. The base may form part of the inlet end of the powder drug reservoir. In some embodiments, the base is partly formed by a nozzle and partly formed by a globe valve. In some embodiments, the base may accommodate all or part of the globe valve.

[0070] The base may be configured to allow air or propellant to flow out of the hand air pump, thereby allowing air or propellant to flow into the nozzle and/or powder drug reservoir. In some embodiments, the base is configured to accommodate a straight-through valve or a straight-through valve section. In some embodiments, the neck is configured to movably accommodate a passage valve or a portion of the passage valve. In some embodiments, a passage valve located inside the base keeps the powdered drug inside the nozzle from moving against the flow, for example, into a pump. The base may have any of a variety of shapes, including, but not limited to, cone, cylinder, tapering cylinder, frustum and parallelepiped, or any other shape provided herein, including a combination of one or more shapes.

[0071] In certain embodiments, the length from the inlet end to the outlet end of the base is approximately: less than 20 mm, less than 15 mm, less than 12 mm, less than 11 mm, less than 10 mm, less than 9 mm, less than 8 mm, less than 7 mm, less than 6 mm, less than 5 mm, less than 4 mm or less than 2 mm. In certain embodiments, the length from the inlet end to the outlet end of the base is in the range of about 2 mm to 20 mm, about 5 mm to 15 mm, or about 5 mm to 10 mm.

[0072] In certain embodiments, the width of the base perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, is from about 2 mm to about 10 mm, from about 2 mm to about 8 mm, or from about 2 mm mm to approximately 5 mm. In some embodiments, the width of the base perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, is at least approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm or 30 mm. The width of the base perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, can be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm , 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm or 30 mm.

[0073] The base of the neck may include one or more threads for attachment to, for example, a hand air pump and/or a flexible bottle. One or more threads can be used to screw together the nozzle and hand air pump.

[0074] Cover

The nozzle may include a cover. The cap may be located at the outlet end of the nozzle. Alternatively or in addition, the cap may be located at the outlet end of the nozzle opening. The lid may be configured to block unintentional emptying of the device. For example, the cap may be airtight to prevent any leakage of air from the outlet end of the nozzle and thereby prevent accidental activation of the pump causing the release of the powdered drug. Such accidental activation may occur due to rough handling of the device, for example during storage or transport. The lid may also be configured to provide an environment suitable for storing the powdered drug within the powdered drug reservoir. For example, the cap may retard or block entry of outside air and/or water into the nozzle and, therefore, retard or block entry of air or water into the powder drug reservoir. The cover may be a replaceable cover so that it can be removed and replaced. If you have a replacement cap, you can use removable tape to securely attach the cap to the nozzle. Alternatively, the cap may be removable or break-away so that it can be removed once by breaking off from the nozzle or can be removed and replaced (eg, put back in place) one or more times. The cap may be a removable or breakable tab, or a removable or breakable membrane, or a removable or breakable cap (eg, an airtight cap).

[0075] B. Globe Valve

The passage valve in the device disclosed herein may be configured to regulate the flow of air from the pump and into the nozzle of the device. The passage valve may further be configured to control the movement of the powdered medicinal product. The passage valve may be configured to block the flow of air or gas from the pump to the nozzle when the device is not actuated (e.g., a manual air pump is not compressed) and may allow the flow of air or gas from the pump to the nozzle when the device is actuated ( for example, a hand air pump is compressed). In some embodiments, the globe valve has one or more retainer contact areas, such as about 2 to about 10 internal ribs. In some versions, the globe valve has approximately: 3 internal ribs. In some embodiments, the length of each internal rib is approximately: 1-20 mm, 1-10 mm or 1-5 mm, for example, approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. In some embodiments, the length of each internal rib is approximately: 0.1-5 mm, for example, approximately: 0.1, 0.2, 0.5, 1, 2, 3, 4 or 5 mm. In some embodiments, the height of each internal rib is approximately: 0.1-5 mm, for example, approximately: 0.1, 0.2, 0.5, 1, 2, 3, 4 or 5 mm.

[0076] In some embodiments, the passage valve is configured to block movement of the powdered drug (eg, under the influence of gravity) in a direction against flow (eg, into a pump). The globe valve may be configured to be in one position in the device when the device is not driven (eg, a pump is not driven) and in another position in the device when the device is driven (eg, a pump is driven). into action). The passage valve may be configured to block movement of the powdered drug (e.g., by gravity) in a counterflow direction (e.g., into a flexible vial and/or hand air pump) when the device is not actuated (e.g., the hand air pump is not compresses) and when the device is actuated (for example, a hand air pump is compressed). The passage valve may include slots (or channels or grooves) located diagonally relative to the main axis of the device, which can create a vortex flow along the walls of the tank.

[0077] Globe Valve Composition

The passage valve may be composed of a variety of polymers, plastics, rubber, silicones, metal, composites, any other materials described herein as suitable for use in the manufacture of an intranasal delivery device, or any other material suitable for use in an intranasal delivery device. delivery. The globe valve can be made of one material or one type of material. Alternatively, the globe valve may be composed of at least two different materials or types of materials. The entire orifice of the passage valve may be a biocompatible material or a hypoallergenic material. The globe valve may be composed of rigid, substantially rigid, flexible or substantially flexible materials, or a combination thereof. In some embodiments, the globe valve may be composed of one or more of: cycloolefin copolymer (COC), paper, silicone, styrene-butadiene block copolymer (SBC), polyacetal, polyoxymethylene, acrylates, polyethylenes, polyurethane, hydrogel, complex polyester (e.g. DACRONB from E. I. Du Pont de Nemours and Company, Wilmington, Del.), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether ether ketone (PEEK), nylon, extruded collagen, polystyrene foam, rubber, silicone rubber , polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate urethane, polyimides, aluminum, stainless steel, nickel-titanium alloy (e.g., nitinol), titanium, stainless steel, or cobalt-chromium alloy (e.g., ELGILOYB alloy from Elgin Specialty Metals, Elgin, Ill. ; alloy CONICHROMEB from Carpenter Metals Corp., Wyomissing, Pa.).

[0078] Globe Valve Dimensions

The globe valve may have any of a variety of shapes, including, but not limited to, disc, ring, torus, cone, pyramid, cylinder, tapered cylinder, frustum, cube and parallelepiped, or any other shape provided herein, including a combination of one or more forms. A globe valve can have a narrow end and a wide end. In some embodiments, the widest portion of the globe valve may be at the inlet or outlet end. In some embodiments, the narrowest portion of the globe valve may be at the inlet or outlet end. The globe valve may be hollow. A globe valve may have a hole at one end. In some embodiments, the globe valve does not have a hole at one end.

[0079] The length from the inlet end to the outlet end of the globe valve may be less than about: 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15 , 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 mm. The length of the bore valve may range from about 5 mm to about 30 mm, from about 5 mm to about 20 mm, from about 5 mm to about 15 mm, or from about 5 mm to about 10 mm . The length of the globe valve can exceed approximately: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mm. The length of the globe valve can be approximately: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mm.

[0080] The width perpendicular to the axis of the globe valve from inlet to outlet flow, at its widest section, can range from about 1 mm to about 30 mm, from about 1 mm to about 25 mm, from about 1 mm to about 20 mm, from about 1 mm to about 15 mm, from about 1 mm to about 10 mm, or from about 1 mm to about 5 mm. The width perpendicular to the axis of the globe valve from inlet to outlet flow, at its widest section, may exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm or 10 mm. The width perpendicular to the axis of the globe valve from inlet to outlet flow, at its widest section, may be less than approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm or 10 mm.

[0081] The width perpendicular to the axis of the globe valve from the inlet to the flow outlet, at its narrowest section, can range from about 1 mm to about 30 mm, from about 1 mm to about 25 mm, from about 1 mm to about 20 mm, from about 1 mm to about 15 mm, from about 1 mm to about 10 mm, or from about 1 mm to about 5 mm. In some embodiments, the globe valve has a width at its narrowest section that does not exceed approximately: 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. In some embodiments, the globe valve has a width at its narrowest section that exceeds approximately: 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm , 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The width perpendicular to the axis of the globe valve from inlet to outlet flow, at its widest section or narrowest section, can be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm or 20mm.

[0082] Globe valve dimensions relative to nozzle

The globe valve may be configured to slide fit within part or all of the nozzle. The width of the passage valve portion may be smaller than the internal width of the nozzle port. For example, the width at the base of the top section and the width of the first cylindrical section may be less than the width of the widest portion of the nozzle nozzle. The difference between the width of the first cylindrical section of the globe valve and the internal width of the widest part of the nozzle pipe can be approximately: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0. 08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0, 33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 047, 0.48, 0.49 or 0.5 mm. The difference between the width of the first cylindrical section of the globe valve and the internal width of the widest part of the nozzle nozzle may be less than approximately: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07 , 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0 ,2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32 , 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0 .45, 0.46, 047, 0.48, 0.49 or 0.5 mm. The difference between the width of the first cylindrical section of the globe valve and the internal width of the widest part of the nozzle nozzle may exceed approximately: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0 .08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2 , 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0 .33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45 , 0.46, 047, 0.48, 0.49 or 0.5 mm. The difference between the width of the first cylindrical section of the passage valve and the inner width of the widest portion of the nozzle port may allow air from the hand air pump to flow into the nozzle when the hand air pump is actuated.

[0083] Upper section

The globe valve may have several sections. The globe valve may have an upper section in the shape of, for example, a cone, pyramid or trapezoid. The upper section may have a convex surface. The upper section may allow powdered drug to accumulate along the wall of the nozzle port to flow and assist in obtaining proper airflow when the intranasal delivery device is actuated. In some embodiments, the upper section may further comprise an additional section. The additional section may be connected to an upper portion of the upper section and may be shaped, for example, like a cone, a pyramid, or a trapezoid.

[0084] Top section height

The height of the top section of the globe valve can be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the top section of the globe valve can exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the top section of the globe valve can be less than approximately: 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm , 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the top section of the globe valve may be approximately: 1-20 mm, approximately: 1-10 mm, approximately: 1-5 mm or approximately: 1-2.5 mm.

[0085] Top section width

The diameter of the bottom of the upper section can be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the bottom of the upper section can exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the bottom of the upper section may be smaller than approximately: 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm , 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the bottom of the upper section can be approximately: 1-20 mm, 1-10 mm, 1-7.5 mm, 1-5 mm, 2.5-20 mm, 2.5-10 mm or 2.5- 7.5 mm.

[0086] Angle of the upper section

The angle formed by the surface of the top section of the globe valve and a plane parallel to the base of the top section may be an obtuse angle. The obtuse angle formed by the surface of the top section of the globe valve and a plane parallel to the base of the top section may range from about 179 degrees to about 91 degrees, about 170 to 100 degrees, from about 160 to about 110 degrees, from about 150 to about 120 degrees or from about 140 to about 130 degrees. The obtuse angle formed by the surface of the upper section of the globe valve and a plane parallel to the base of the upper section may be approximately: 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141 , 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116 , 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92 or 91 degrees . The obtuse angle formed by the surface of the top section of the globe valve and a plane parallel to the base of the top section may be less than approximately: 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142 , 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117 , 116,115,114,113,112,111,110,109,108,107,106,105,104,103,102,101,100,99,98,97,96,95,94,93,92 or 91 degrees. The obtuse angle formed by the surface of the upper section of the globe valve and the plane parallel to the base of the upper section may exceed approximately: 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141 , 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116 , 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92 or 91 degrees .

[0087] First shoulder of the globe valve

The first shoulder may connect the upper section and the first cylindrical section. The shortest length of the first shoulder surface from the base of the top section to the top of the first cylindrical section may be approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 , 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2 ,1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3 , 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4 .6, 4.7, 4.8, 4.9 or 5 mm. The shortest length of the first shoulder surface from the base of the top section to the top of the first cylindrical section may exceed approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 , 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2 ,1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3 , 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4 .6, 4.7, 4.8, 4.9 or 5 mm. The shortest length of the first shoulder surface from the base of the top section to the top of the first cylindrical section may be less than about: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0 ,8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 , 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3 ,3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5 , 4.6, 4.7, 4.8, 4.9 or 5 mm. The shortest length of the first shoulder surface from the base of the top section to the top of the first cylindrical section may be approximately: 0.1-5 mm, 0.1-4 mm, 0.1-3 mm, 0.1-2 mm, 0.1 -1.75 mm, 0.1-1.5 mm, 0.1-1.25 mm or 0.1-1 mm.

[0088] The angle formed between the side of the first cylindrical section and the surface of the first shoulder may be approximately: 91-179 degrees, 100-170 degrees, 110-160 degrees, 120-150 degrees, or 130-140 degrees. The angle formed between the side of the first cylindrical section and the surface of the first shoulder may be approximately: 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164 , 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 1 39 , 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 115, 1 14 , 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92 or 91 degrees. The angle formed between the side of the first cylindrical section and the surface of the first shoulder may exceed approximately: 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164 , 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 1 39 , 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 115, 1 14 , 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92 or 91 degrees. The angle formed between the side of the first cylindrical section and the surface of the first shoulder may be less than about: 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165 , 164, 163, 162, 161, 160, 159, 158, 157, 156, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 1 40 , 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 1 15 , 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92 or 91 degrees. The angle formed between the side of the first cylindrical section and the surface of the first shoulder may be an obtuse angle.

[0089] Dimensions of the first shoulder relative to the nozzle nozzle

The first shoulder can be made with a diameter that is wider than the internal diameter of the nozzle pipe. The first shoulder may be configured to contact the base of the nozzle when the device is actuated. The first shoulder may be configured to block entry of the entire passage valve into the nozzle port when the device is actuated. The first shoulder may be configured to prevent the powdered drug from moving upstream into a hand-held air pump (eg, a flexible vial) when the device is actuated.

[0090] First cylindrical section of globe valve

The first shoulder may be connected at its base to the first cylindrical section. The width of the first cylindrical section may be the same as the width of the base of the first shoulder.

[0091] Height of the first cylindrical section

The height of the first cylindrical section of the globe valve may be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the first cylindrical section of the globe valve may exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the first cylindrical section of the globe valve may be less than about: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the first cylindrical section of the globe valve may be approximately: 1-20 mm, approximately: 1-10 mm, approximately: 1-7.5 mm, approximately: 1-5 mm, approximately: 2.5-20 mm, approximately: 2.5-10 mm, approximately: 2.5-7.5 mm or approximately: 2.5-5 mm.

[0092] Width of the first cylindrical section

The diameter of the first cylindrical section may be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the first cylindrical section may exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm , 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the first cylindrical section may be less than about: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the first cylindrical section may be approximately: 1-20 mm, 1-10 mm, 1-7.5 mm, 1-5 mm, 2.5-20 mm, 2.5-10 mm or 2.5-7 .5 mm.

[0093] Second ledge

The globe valve may have a second shoulder that extends inward and downward from the base of the first cylindrical section. The second shoulder may be configured to close the flow release hole on the hand air pump when the hand air pump is not compressed to prevent the powdered drug from moving upstream into the hand air pump.

[0094] Second shoulder length

The shortest length of the second shoulder surface from the bottom of the first cylindrical section to the top of the second cylindrical section can be approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0, 8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3, 3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 mm. The shortest length of the second shoulder surface from the bottom of the first cylindrical section to the top of the second cylindrical section may exceed approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0, 8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3, 3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 mm. The shortest length of the second shoulder surface from the bottom of the first cylindrical section to the top of the second cylindrical section may be less than about: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4, 5, 4.6, 4.7, 4.8, 4.9 or 5 mm. The shortest length of the second shoulder surface from the bottom of the first cylindrical section to the top of the second cylindrical section can be approximately: 0.1-5 mm, 0.1-4 mm, 0.1-3 mm, 0.1-2 mm, 0. 1-1.75 mm, 0.1-1.5 mm, 0.1-1.25 mm or 0.1-1 mm.

[0095] Second shoulder angle

The angle formed between the side of the second cylindrical section and the surface of the second shoulder may be approximately: 0-90 degrees, 10-80 degrees, 20-70 degrees, 30-60 degrees, or 40-50 degrees. The angle formed between the side of the second cylindrical section and the surface of the second shoulder may be approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 degrees. The angle formed between the side of the second cylindrical section and the surface of the second shoulder may exceed approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 degrees. The angle formed between the side of the second cylindrical section and the surface of the second shoulder may be less than about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 or 90 degrees. The angle formed between the side of the second cylindrical section and the surface of the second shoulder may be an acute angle or a right angle.

[0096] Slots or grooves

The second shoulder may have one or more slots or grooves on the surface of the shoulder. The grooves may allow air flow from the hand air pump into the nozzle when the device is actuated (eg by compression). The one or more grooves may serve to create a vortex flow in the device reservoir when the device is actuated (eg, when air enters the powder drug reservoir from a pump). The resulting vortex flow is capable of creating the possibility of complete delivery of the powdered drug. The slots or grooves may be positioned to allow laminar air flow within the reservoir.

[0097] Length of slots or grooves

The slot or groove may extend from the base of the first cylindrical section to the top of the second cylindrical section on a surface of the second shoulder of the globe valve. The slot or groove may extend for a distance of approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder. The slot or groove may extend a distance greater than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder. The slot or groove may extend a distance less than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder. The slot or groove may extend a distance of approximately: 1-100%, 10-100%, 20-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100% or 90-100% of the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder.

[0098] Angle of slot or groove

The slot or groove may be located at an angle of 90 degrees or not 90 degrees with respect to a line representing the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder. With respect to a line representing the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder, the slot or groove may be located at an angle of approximately: 0-90 degrees, 5-90 degrees, 10-80 degrees, 15-75 degrees , 20-70 degrees, 25-65 degrees, 30-60 degrees, 35-55 degrees or 40-50 degrees. With respect to a line representing the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder, the slot or groove may be located at an angle of approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 , 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 , 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 , 86, 87, 88, 89 or 90 degrees. With respect to a line representing the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder, the slot or groove may be located at an angle greater than about: 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 , 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 , 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 , 85, 86, 87, 88 or 89 degrees. With respect to a line representing the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder, the slot or groove may be located at an angle less than about: 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 , 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 , 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 , 85, 86, 87, 88, 89 or 90 degrees. When one or more grooves are positioned at a 0 degree angle (parallel to a line representing the shortest length from the bottom of the first cylindrical section to the top of the second cylindrical section on the surface of the second shoulder), air can flow directly along the walls of the reservoir. When the grooves are angled greater than 0 degrees and less than 90 degrees, a vortex flow can be created along the walls of the reservoir, allowing complete delivery of drug from the reservoir.

[0099] Depth of slots or grooves

The maximum slot or groove depth may be approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the length of the slot or groove. The maximum slot or groove depth may exceed approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the length of the slot or groove. The maximum slot or groove depth may be less than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the length of the slot or groove. The maximum slot or groove depth may be approximately: 1-50%, 1-40%, 1-30%, 1-25%, 1-20%, 1-15%, 1-10%, 1-5% or 1-2.5% of the length of the slot or groove.

[0100] Shape of slot or groove

The slot or groove may be formed by a curved surface, two surfaces, three surfaces, four surfaces, five surfaces, six surfaces, seven surfaces, eight surfaces, nine surfaces, or 10 surfaces. The second shoulder may have slots or grooves with at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 different shapes.

[0101] Number of slots or grooves

The globe valve may comprise at least: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 , 97, 98, 99 or 100 slots or grooves. A globe valve may contain less than: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 slots or grooves. The globe valve may comprise approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 , 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 , 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 , 98, 99 or 100 slots or grooves. Globe valve contains approximately: 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-40, 1-30, 1-25, 1-20 or 1-10 slots or grooves.

[0102] Placement of slots or grooves

When the second shoulder includes at least two slots or grooves, the slots or grooves may be substantially parallel to each other. In certain embodiments, all of the slots or grooves are not substantially parallel to each other. In some embodiments, all of the slots or grooves are not spaced at equal intervals on the second shoulder. In some embodiments, all slots or grooves are located at equal intervals on the second shoulder.

[0103] Second cylindrical section

The globe valve may have a second cylindrical section below the second shoulder.

[0104] Height of the second cylindrical section

The height of the second cylindrical section of the globe valve may be greater than the height of the first cylindrical section. The height of the second cylindrical section of the globe valve may be less than the height of the first cylindrical section. The height of the second cylindrical section of the globe valve may be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the first cylindrical section of the globe valve may exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the first cylindrical section of the globe valve may be less than about: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The height of the first cylindrical section of the globe valve may be about 1-20 mm, about 1-10 mm, about 1-7.5 mm, about 1-5 mm, about 1-4 mm, about 1-3 mm, or about 1-3 mm. 2 mm.

[0105] Width of the second cylindrical section

The second cylindrical section of the globe valve may be wider than the first cylindrical section of the globe valve. The second cylindrical section may be wider than the inner diameter of the nozzle nozzle. The second cylindrical section may be narrower than the inner diameter of the nozzle nozzle. The diameter of the second cylindrical section may be approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm , 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the second cylindrical section may exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm , 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the second cylindrical section may be less than approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The diameter of the second cylindrical section can be approximately: 1-20 mm, 1-10 mm, 1-7.5 mm, 1-5 mm, 2.5-20 mm, 2.5-10 mm or 2.5-7 .5 mm. In some embodiments, the second cylindrical section of the passage valve includes an orienting ridge. When the device is not actuated, the orienting ridge may rest against a convexity in the nozzle nozzle. This arrangement may block the movement of the globe valve against flow into the hand air pump. This arrangement may also prevent the powdered drug from moving upstream into the hand air pump. In combination, the guide ridge and the second cylindrical section may be wider than the width of the second cylindrical section. The orientation ridge may be located at any location along the length of the second cylindrical section. The orientation ridge may form a ring around all or a portion of the second cylindrical section. The orientation ridge can be any of a variety of shapes or sizes.

[0106] Globe Valve Base

The globe valve may be configured with a base that is wider than the second cylindrical section. In some embodiments, the base does not contact the nozzle port when the device is actuated or when the device is not actuated.

[0107] Configurations

In some embodiments, the globe valve has a top section, a first shoulder, a first cylindrical section, a second shoulder, and a second cylindrical section or base. In some embodiments, the globe valve does not necessarily have to contain all of the sections mentioned. For example, the passage valve may be formed as a single cylinder or other shape that rests on the neck of the bottle in its disengaged position and is positioned below the rim of the nozzle. The passage valve may have one or more grooves or passage that is blocked by the neck of the vial when the passage valve rests on the neck of the bottle. When the hand pump is compressed, the passage valve may be pushed upward toward the nozzle lip in its actuated position, and air may flow through one or more grooves or passage that is not blocked by the nozzle lip into the nozzle.

[0108] The passage valve may be of any shape with one or more sections that may allow the passage valve to rest on the neck of the vial and not fall into the vial. In some embodiments, the passage valve is not limited when it moves upward by the side of the nozzle or other profiled element of the nozzle. The globe valve may have one or more fluid flow passages (eg, slots, channels, grooves, tunnels, tubes) that are not in fluid communication with a source of air or gas when the globe valve is in the disengaged position. In some embodiments, the passage for fluid flow is blocked directly by the nozzle lip, or fluid communication is blocked by a portion of the passage valve resting on the lip of the bottle. The fluid flow passage may provide fluid communication between a source of air or gas and the internal volume of the nozzle when the passage valve is in an actuated position. The fluid flow passage may be positioned so as not to be blocked by the nozzle flange when the port valve is in the actuated or disengaged position.

[0109] Lock

The device described herein may include a latch, such as that shown in FIG. 1. The retainer may hold the passage valve of the device by one or more contact areas, for example, one or more internal ribs (for example, 3 ribs), for example, as shown in FIG. 2. In the device, the nozzle and the retainer can be sealed together; and/or the retainer and pump may be sealed together. In some versions, the retainer is hollow. In some embodiments, the retainer includes a trough for catching powder falling from the nozzle to prevent it from falling into the pump, for example, as shown in FIG. 3. The groove may be an inner circumferential groove extending from the upstream end of the retainer. In some embodiments, the collar of the retainer's circumferential groove is in contact with one or more contact areas of the globe valve. In some embodiments, the inner circumferential groove has a height of 1-20 mm, for example, approximately: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 mm. In some embodiments, the latch prevents the free movement of the through-flow valve in the device. All captured powder may be delivered by side air flow through the nozzle when the device is actuated, for example as shown on the left in FIG. 4. When the device is driven, some of the air from the pump can flow into the retainer through the circumferential groove and moves along the surface grooves of the retainer to form a vortex flow in the reservoir. The retainer may have air inlet(s) to prevent residual powder in the nozzle from entering the pump when the pump returns to its original shape, for example, as shown on the right in FIG. 4. In some versions, the clamp has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 air inlets. In some embodiments, one or more air inlet openings have a width of approximately: 0.1-1, 0.1-0.5 or 0.2-0.4 mm, for example 0.3 mm. In some embodiments, one or more retainer air inlets allow outside air to enter the pump after the device is actuated. In some embodiments, the retainer includes an outer circumferential collar that is wider than the pump bore. In some embodiments, the retainer is at least partially inserted into the hand air pump.

[0110] The retainer may have any of a variety of shapes, including, but not limited to, disk, ring, torus, cone, pyramid, cylinder, tapered cylinder, frustum, cube and parallelepiped shape, or any other shape described herein, including a combination of one or more forms. The retainer may have a narrow end and a wide end. In some embodiments, the widest portion of the retainer may be at the inlet or outlet end. In some embodiments, the narrowest portion of the retainer may be at the inlet or outlet end. The retainer may have a hole at one end. In some versions, the latch does not have a hole at one end.

[0111] The length from the inlet end to the outlet end of the latch may be less than about: 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 mm. The length of the retainer may range from about 5 mm to about 30 mm, from about 5 mm to about 20 mm, from about 5 mm to about 15 mm, or from about 5 mm to about 10 mm. The length of the clamp can exceed approximately: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 , 27, 28, 29 or 30 mm. The length of the clamp can be approximately: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mm.

[0112] The width of the retainer perpendicular to the axis from the inlet to the outlet flow of the retainer, at its widest section, can range from about 1 mm to about 30 mm, about 1 mm to about 25 mm, about 1 mm to about 20 mm, approximately 1 mm to approximately 15 mm, approximately 1 mm to approximately 10 mm, or approximately 1 mm to approximately 5 mm. The width of the retainer perpendicular to the axis from the inlet to the outlet of the retainer flow, at its widest section, may exceed approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm. The width of the clamp perpendicular to the axis from the inlet to the outlet of the clamp flow, at its widest section, may be less than approximately: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 m.

[0113] The width of the retainer perpendicular to the axis from the inlet to the outlet flow of the retainer, at its narrowest section, may range from about 1 mm to about 30 mm, from about 1 mm to about 25 mm, from about 1 mm to about 20 mm, from about 1 mm to about 15 mm, from about 1 mm to about 10 mm, or from about 1 mm to about 5 mm. In some embodiments, the retainer has a width, at its narrowest section, that does not exceed approximately: 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. In some embodiments, the retainer has a width, at its narrowest section, that exceeds approximately: 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm , 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm. The width of the clamp perpendicular to the axis from the inlet to the outlet of the clamp flow, at its widest section or narrowest section, can be approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm.

[0114] The retainer may be composed of a variety of polymers, plastics, rubber, silicones, metal, composites, any other materials described herein as suitable for use in the manufacture of an applicator device, or any other material suitable for use in a medical device - applicator. The retainer may be made from a single material or type of materials. Alternatively, the retainer may be composed of at least two different materials or types of materials. In some embodiments, the retainer as a whole or a portion thereof may be a biocompatible material or a hypoallergenic material. The retainer may be composed of rigid, substantially rigid, flexible or substantially flexible materials, or a combination thereof. In some embodiments, the fixative consists of one or more of: COC (cycloolefin copolymer), silicone, acrylates, polyethylenes, polyurethane, polyurethane, hydrogel, polyester (for example, DACRONB material from E. I. Du Pont de Nemours and Company, Wilmington , Del.), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyetheretherketone (PEEK), nylon, extruded collagen, polyfoam, rubber, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimides, aluminum, stainless steel, nickel-titanium alloy (e.g., nitinol), titanium, stainless steel, or cobalt-chromium alloy (e.g., ELGILOYB alloy from Elgin Specialty Metals, Elgin, Ill.; CONICHROMEB alloy from Carpenter Metals Corp., Wyomissing, Pa.) .

[0115] Pump

The device described in this application may include a pump. The pump may be configured to provide a flow of air or other propellant, or a combination thereof, through the powder drug reservoir, out of the nozzle, and into the nostril or nasal cavity of the subject. The pump may be configured to provide air flow through a passage valve that controls air flow into the nozzle or reservoir. In some embodiments, the pump has a smooth internal surface or a smooth external surface.

[0116] The pump may be composed of a variety of polymers, plastics, rubber, silicones, metal, composites, any other materials described herein that are suitable for use in the manufacture of an applicator device, or any other material suitable for use in an applicator pump. The pump can be made from one material or type of materials. Alternatively, the pump may be composed of at least two different materials or types of materials. In some embodiments, the pump as a whole or a section thereof may be a biocompatible material or a hypoallergenic material. The pump may be composed of rigid, substantially rigid, flexible or substantially flexible materials, or a combination thereof. In some embodiments, the pump is composed of one or more of silicone, acrylates, polyethylenes, polyurethane, polyurethane, hydrogel, polyester (for example, DACRONB material from E. I. Du Pont de Nemours and Company, Wilmington, Del.), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyetheretherketone (PEEK), nylon, extruded collagen, polyfoam, rubber, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimides, aluminum, stainless steel, nickel-titanium alloy (eg, nitinol), titanium, stainless steel, or cobalt-chromium alloy (eg, ELGILOYB alloy from Elgin Specialty Metals, Elgin, Ill.; CONICHROMEB alloy from Carpenter Metals Corp., Wyomissing, Pa.).

[0117] The pump may be one of a variety of pumps suitable for use in a nasal applicator, such as those described in US Patent Application Nos. US20090025720, US20090064997, US20080819617, US20080161771, US20080289629, US20080142018, US20070129665, US20060219240, US20060024185, US20060254585, US20040187868 , US20040149289, US20040112378, US20020174865; US Patent Nos. US3856185, US4017007, US4200099, US5046493, US5683361, US5702362, US6488648, US6824080, US6866039, US6938798, US6186141, US6345737, US6585172, US6 543448, US6089228, US6427680, US6644305, US6494204, US6290667, US7481218, international patent applications No. WO2002 /00282, WO2005/000477, WO2008/026730, WO2007/102089, WO1990/07351 and WO/2003/000310, European Patent Nos. EP1673123 and EP1390091, and Japanese Patents and Applications Nos. JP2006122189 , JP2001095918, JP3678955, JP11226127, JP3488624, JP11221280, JP11197245, JP3547605, JP10028735, JP9248342, JP09028805, JP08322934, JP08280808, JP8206208, JP8103499 and JP8071152, which, each in its entirety, incorporated herein by reference.

[0118] The pump may be a high pressure container. In certain embodiments, the pressure container contains air or another propellant, such as one or more of low molecular weight hydrocarbons, such as butane or propane, dimethyl ether, methyl ethyl ether, nitric oxide, carbon monoxide, nitrogen, hydrofluorocarbon, compressed air, chlorofluorocarbon, or hydrofluoroalkane, for example 1,1,2,-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pressure container may contain from about 0.1 g of propellant to about 5 g of propellant, including at least about: 4 g, 3 g, 2 g, 1.5 g, 1 g, 0.75 g, 0.5 g, 0.25 g, 0.2 g, or 0.1 g propellant. The high pressure container may be configured to contain the propellant at a maximum pressure of at least about: 1.5 atm, 2 atm, 2.5 atm, 3 atm, 3.5 atm, 4 atm, 4.5 atm, 5 atm, 5.5 atm, 6 atm, 7 atm, 8 atm, 9 atm, 10 atm, 11 atm or 12 atm. In some embodiments, the high pressure container may be configured to contain propellant at a maximum pressure of about 2 atm to about 10 atm, about 3 atm to about 9 atm, about 4 atm to about 8 atm, from about 4 atm to about 7 atm or from about 4 atm to about 6 atm.

[0119] The pressure container can be operated to release the propellant in any manner known in the art. For example, a pressure valve may engage a pump to release propellant upon application of a compression force, or a lever may engage a pump to release propellant upon movement of the lever. In another example, the pressure container may be actuated to release propellant by a digital or analog signal. For example, a user may press a button that controls the release of propellant, such as by controlling a servomotor or a microprocessor-controlled valve. In some embodiments, the container may be actuated by a mechanism that detects nasal inhalation. For example, a lever or other sensing means, such as a pressure sensor, may be actuated by placing a device described herein into a subject's nostril and inhaling from the subject. The pressure container may be configured to release a controlled or metered amount of propellant each time the container is actuated. In some embodiments, the pressure container may continue to release propellant until the user stops delivering the actuation input.

[0120] The pump may be an electric pump or a hand pump. The pump may include an inner container movably positioned within the outer container. Moving one or more of the inner and outer containers, manually or otherwise, can provide air flow out of the pump and into the flow passage. The inner and outer pump containers may be configured to return to their original state in the absence of an external compression force, for example, through the action of a spring or other return mechanism. In another example, the pump includes a displaceable piston. The piston can be driven manually or electrically. Moving the piston manually or otherwise can cause air to flow out of the pump and into the flow passage. The piston may be configured to return to its original state in the absence of external force, for example, through the action of a spring or other return mechanism.

[0121] The pump may contain a deformable volume. For example, the pump may contain plastic, rubber, or other deformable material. The pump may also include an articulated volume so that the accordion-like folds allow compression of the pump to supply air. The deformable volume can be squeezed, for example, by one or more fingers (eg, between the thumb and index finger, middle finger, ring finger, little finger) or a combination thereof, or at least one hand. Alternatively, the deformable volume may be compressed by electronic or hydraulic means. In some embodiments, the deformable volume is compressed, for example, by applying a compressive or other compressive force, and may return to its uncompressed form when the compressive force is removed. In some cases, return to an uncompressed shape can be ensured by the own elastomeric force of the profile and materials of the deformed volume. Return may be assisted by a spring or other energy return mechanism.

[0122] The pump may have any shape suitable for use in the apparatus described herein, including, but not limited to, a sphere, ellipsoid, cylinder, cube, truncated figure, or any other suitable shape, such as any of the shapes described in this application, or a combination thereof. The length from the inlet end to the outlet end of the pump may be less than approximately: 10 cm, 9 cm, 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, or 2 cm. In some embodiments, the length of the pump can range from about 2 cm to about 10 cm, from about 2 cm to about 8 cm, from about 2 cm to about 5 mm, from about 4 cm to about 10 cm or from about 4 cm to about 6 cm. The length from the inlet end to the outlet end of the pump can be at least about: 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm or 10 cm. The length from the inlet end to the outlet end of the pump can be approximately: 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm or 10 cm.

[0123] In certain embodiments, the width of the pump perpendicular to the axis from inlet to outlet flow, at its widest section, is less than about: 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3 .5 cm, 4 cm, 4.5 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 12 cm, 15 cm or 20 cm. Pump width perpendicular to the axis from inlet to outlet flow, on its widest section, may be at least approximately: 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 12 cm, 15 cm or 20 cm. The width of the pump perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, can be approximately: 1 cm, 1.5 cm, 2 cm, 2.5 cm , 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 12 cm, 15 cm or 20 cm.

[0124] In certain embodiments, the pump has a volume that is less than about: 10 cc ^. 9 ^cc . 8 ^cc . 7 ^cc . 6 cc ^. 5 cc ^. 4 ^cc . ³ cc. 2. cm ³ or 1 cm ³ . In some embodiments, the pump contains a volume of from about 1 cm ³ to about 10 cm ³ , from about 2 cm ³ to about 10 cm ³ , from about 2 cm ³ to about 7 cm ^{3 ,} or from about 4 cm 3 cm ³ to approximately 8 cm ³ . The pump may have a volume greater than approximately: 10 cm ³ , 9 cm ³ , 8 cm ³ , 7 cm ³ , 6 cm ³ , 5 cm ³ , 4 cm ³ , 3 cm ³ , 2 cm ³ or 1 cm ³ . The pump can have a volume of approximately: 10 cm ³ , 9 cm ³ , 8 cm ³ , 7 cm ³ , 6 cm ³ , 5 cm ³ , 4 cm 3, ^{3 cm 3 ,} 2 cm ³ or 1 cm ³ .

[0125] The pump may be configured to deliver from about 1 ml to about 10 ml of air or other propellant into the nostril of a subject during a single actuation. The pump may be configured to deliver from about 1 ml to about 10 ml of air or other propellant to the powdered drug reservoir of the device during a single actuation. In certain embodiments, the pump is configured to deliver at least about: 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml or 10 ml of air or other propellant in the subject's nostril or into the device's reservoir. In some embodiments, the pump is designed to deliver approximately: from 1 ml to 10 ml, from 1 ml to 8 ml, from 1 ml to 5 ml, from 2 ml to 10 ml, from 2 ml to 8 ml, from 2 ml up to 7 ml, 2 ml to 6 ml, 2 ml to 5 ml, 3 ml to 10 ml, or 3 ml to 8 ml of air or other propellant into the subject's nostril or device reservoir. The pump may be configured to deliver less than: 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, or 10 ml of air or other propellant into the subject's nostril or reservoir devices. The pump may be configured to deliver approximately: 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, or 10 ml of air or other propellant into the subject's nostril or reservoir of the device. The pump may be configured to be driven by a force of from about 5 kPa to about 100 kPa. The pump may be configured to be driven by a force less than about: 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 10 kPa, 11 kPa, 12 kPa, 13 kPa, 14 kPa, 15 kPa, 16 kPa , 17 kPa, 18 kPa, 19 kPa, 20 kPa, 21 kPa, 22 kPa, 23 kPa, 24 kPa, 25 kPa, 26 kPa, 28 kPa, 30 kPa, 32 kPa, 33 kPa, 35 kPa, 38 kPa, 40 kPa, 42 kPa, 45 kPa, 48 kPa or 50 kPa pressure. The pump may be configured to provide a pressure of air or other propellant at the flow outlet from about 1 kilopascal to about 100 kilopascals, from about 2 kilopascals to about 50 kilopascals, from about 4 kilopascals to about 40 kilopascals, from about 5 kilopascals to about 35 kilopascals or from about 10 kilopascals to about 30 kilopascals.

[0126] Flow inlet

The pump may include a flow inlet for filling the pump with air or other propellant. In some embodiments, the flow inlet is in fluid communication with the pump and the environment. The flow inlet opening may further comprise a passage valve or means for adjusting the flow of air through the flow inlet opening. In some embodiments, the flow inlet may be configured to provide unidirectional air flow from outside the pump into the interior of the pump. In some embodiments, the flow inlet is configured to allow movement from a compressed pump shape created by applying a compression force and into an uncompressed pump shape created by removing the compression force. For example, applying a compression force by manually squeezing a pump can move air from the pump through the flow outlet and ultimately out of the nozzle, and releasing the compression force forces air into the pump through the flow inlet, allowing some or all of the pump to return into an uncompressed state.

[0127] The flow inlet hole may be any of a variety of shapes, including, but not limited to, cone, cylinder, tapered cylinder, frustum and parallelepiped, or any other shape provided herein, including a combination of one or more of the shapes given in this application. In some embodiments, the width or diameter of the flow inlet opening depends on the width or diameter of the flow outlet opening. For example, the flow inlet hole may be configured with a width or diameter less than about: 1%, 2%, 2%, 4%, 5%, 6%, 8%, 8%, 9%, 10%, 11% , 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40 %, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 90% of the width or diameter of the flow outlet. In either case, the size of the flow inlet hole is consistent with the size of the flow outlet hole. For example, the flow inlet hole may be configured to be larger than approximately: 1%, 2%, 2%, 4%, 5%, 6%, 8%, 8%, 9%, 10%, 11%, 12 %, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 90% of the flow outlet size.

[0128] The flow inlet diameter may range from about 0.05 to about 2 mm, from about 0.05 mm to about 1 mm, from about 0.05 to about 0.5 mm , from about 0.05 to about 0.1 mm. The flow inlet diameter can be approximately: 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2 mm. The flow inlet diameter may exceed approximately: 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2 mm. The flow inlet diameter may be smaller than about: 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0. 3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2 mm.

[0129] The flow inlet may be located on the pump. The flow inlet may be located in the neck of the pump. In some embodiments, the opening may also be a nozzle opening for the flow inlet.

[0130] Flow outlet

The flow outlet may be configured to provide a pressure of from about 1 kilopascal to about 100 kilopascals, from about 2 kilopascals to about 50 kilopascals, from about 4 kilopascals to about 40 kilopascals, or from about 5 kilopascals to , approximately 35 kilopascals. The flow outlet can be any of a variety of shapes, including, but not limited to, cone, cylinder, tapered cylinder, frustum and parallelepiped, or any other shape provided herein, including a combination of one or more shapes. In certain embodiments, the length from the inlet end to the outlet end of the flow outlet is less than about 20 mm, less than about 15 mm, less than about 10 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm, or less than about 3 mm. In certain embodiments, the length of the flow outlet hole ranges from about 3 mm to about 20 mm, from about 3 mm to about 15 mm, from about 3 mm to about 10 mm, or from about 5 mm up to approximately 10 mm. The flow outlet hole may have a length of approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mm. In certain embodiments, the width of the flow outlet opening perpendicular to the inlet to outlet axis of the flow at its widest section ranges from about 5 mm to about 20 mm or from about 5 mm to about 15 mm. In certain embodiments, the width of the flow outlet perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, is at least about: 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11mm, 12mm, 13mm, 14mm, 15mm or 20mm. In some embodiments, the width of the flow outlet hole, perpendicular to the axis from the inlet to the flow outlet, at its narrowest point, has a value less than approximately: 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm or 20 mm. The width of the flow outlet perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, can be approximately: 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm , 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm or 30 mm.

[0131] Globe valve for airtight device

In some embodiments, the passage valve may be configured to minimize or prevent exposure of the powder formulation to air and moisture, which may result in increased stability of the powder formulation prefilled in the device or reservoir when the device does not include an air inlet passage, or when the device is closed system. The globe valve can be manufactured using simpler technology for the production of device parts and, as a result, can be more economical.

[0132] The globe valve may be a globe valve for a powder formulation and a two-way valve for air. The passage valve may be configured to discharge powdered drug from the nozzle, and to discharge air from the pump through the nozzle, and to admit air from the outside environment through the nozzle, allowing air to enter the pump. This may allow for repeated actuation of the device, without the need for a flow inlet in the pump of the device.

[0133] In some embodiments, the device may be an airtight container or closed system, for example, the device, such as a pump, may lack inlet ports or openings when the removable or break-off cap is in place or has not been removed. In some embodiments, the pump does not contain an air inlet channel. The device comprising an air inlet passage in the pump (described above) may have access to outside air. When a pump is driven in such a device, air may flow out from within the device through an air inlet passage in the pump. Such leakage of air through the air inlet passage in the pump during pump activation may result in the use of a volume of air less than the maximum volume within the pump to expel the drug from the device. In a device without an air inlet duct in the pump, there is no leakage of air from inside the pump into the external environment through the inlet air duct. This prevention of air leakage in the pump during pump actuation may result in the use of a maximum volume of air within the pump to force the drug out of the device. In certain embodiments, all of the air that is forced out of the pump, when the pump is driven in a device without an air inlet passage in the pump, may act to expel the drug. The above design of the device (without an air inlet channel in the pump) allows for a reduction in pump volume and a reduction in the size of the device, compared to a device with an air inlet channel in the pump. The reduced pump volume and smaller size of the device can reduce the manufacturing cost and make the device without an air inlet port in the pump easier to carry, compared to a device with an air inlet port in the pump.

[0134] In some embodiments, when the removable or break-off cover is in place or has not been removed, there is no communication with the pump or with the external environment. In some embodiments, when the removable or break-off cap is removed, the device may include a flow inlet. In some embodiments, the flow inlet opening may include a nozzle opening when the removable or break-off cap is removed. The nozzle opening (flow inlet opening) may be configured to discharge the powdered drug from the nozzle in a single jet. In some embodiments, the nozzle includes multiple openings (flow inlets) that can discharge the powdered drug in multiple jets that remain separate, or that can combine into a single jet when the device is actuated. In some embodiments, the nozzle opening is located at the outlet end of the nozzle. In some embodiments, the nozzle opening is also the outlet end of the flow restrictor. The nozzle opening may be any of a variety of shapes, including, but not limited to, round, oval, triangular or rectangular, or a combination thereof.

[0135] In some embodiments, the passage valve is configured to block movement of the powdered drug (eg, by gravity) in a direction against flow (eg, into a pump). The globe valve may be configured to be in one position in the device when the device is not driven (eg, a pump is not driven) and in another position in the device when the device is driven (eg, a pump is driven). into action). The passage valve may be configured to block movement of the powdered drug (eg, by gravity) in a counterflow direction (eg, into a flexible vial and/or hand air pump) when the device is not actuated (eg, the hand air pump is not is compressed) and when the device is actuated (for example, a hand air pump is compressed).

[0136] The passage valve may be configured to regulate the flow of air from the pump and into the nozzle of the device. The passage valve may further be configured to control the movement of the powdered medicinal product. The passage valve may be configured to block the flow of air or gas from the pump to the nozzle when the device is not actuated (e.g., a manual air pump is not compressed) and may allow the flow of air or gas from the pump to the nozzle when the device is actuated (for example, a hand air pump is compressed).

[0137] In some embodiments, the passage valve may be configured to allow air from the external environment to flow in a counterflow direction (e.g., into a flexible vial and/or hand air pump) when activation of the device is stopped (e.g., decompression of the hand air pump), and in the downstream direction when the device is actuated (for example, a hand air pump is compressed). When the pump decompresses, air can be drawn from the external environment through the nozzle opening (eg, flow inlet) and into the nozzle reservoir, through the globe valve cavity and into the pump.

[0138] In some embodiments, the nozzle opening (flow inlet opening) may be configured to provide bi-directional air flow from outside the pump to the inside of the pump and from inside the pump to the outside of the pump. In some embodiments, the nozzle orifice or flow inlet is configured to allow movement from a compressed pump shape created by applying a compression force to an uncompressed pump shape created by releasing the compression force. For example, applying a compressive force by manually squeezing the pump can force air from the pump through the flow outlet and ultimately out of the nozzle. The release of the compression force may allow air to move into the pump through the flow inlet (nozzle port), through the port valve cavity, and the flow outlet, which partially or completely returns the pump to an uncompressed state. For example, when the compression force is released, air from the external environment moves into the pump through the nozzle orifice (flow inlet), into the nozzle reservoir, through the cavity extending inward through the globe valve, and into the pump.

[0139] The passage valve may include slots (or channels or grooves) located diagonally with respect to the major axis of the device, which can create a vortex flow along the walls of the reservoir when the device is actuated.

[0140] Length of inner inlet section

The length of the internal inlet section may be measured from the inlet end to the outlet end, where inlet and outlet refer to the direction of flow of air or other propellant during operation of the device (i.e., air or other propellant may flow from the inlet end to the outlet end). The length of the inner inlet section may be the length of the powder drug reservoir. The length of the inner inlet section may be the length of the nozzle pipe. The length of the inner inlet section may be, at most, the approximate length from the top (inlet end) of the upper section of the passage valve to the bottom (outlet end) of the nozzle opening. The length of the inner inlet section may be at least approximately the length from the top (inlet end) of the upper section of the passage valve to a length above the height (inlet end) of the powdered drug when the powdered drug is present in the powdered drug reservoir. The length of the inner inlet section may be at least approximately the length from the top (inlet end) of the upper section of the passage valve to such a length that the powder drug in the reservoir cannot enter or be drawn into the pump when the pump is no longer driven, or when Negative pressure appears in the device.

[0141] The length from the inlet end to the outlet end of the inner inlet section may be less than about 5 cm, less than about 4.5 cm, less than about 4 cm, less than about 3.5 cm, less than about 3 cm, less than about 2.5 cm, less than about 2 cm, less than about 1.5 cm, less than about 1.0 cm, or less than about 0.5 cm. Inner inlet length sections may range from about 0.5 cm to about 5 cm, from about 1 cm to about 5 cm, from about 1 cm to about 4 cm, from about 1 cm to about 3 cm , from about 2 cm to about 5 cm or from about 2 cm to about 4 cm. The length of the inner inlet section can be approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2, 5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm. The length of the inner inlet section can exceed approximately: 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm or 5 cm.

[0142] Outer width of inner inlet section

In some embodiments, the outer width of the inner inlet section, perpendicular to the inlet-to-outlet axis of the flow, at its widest portion, is approximately: 0.01 cm to 0.2 cm, 0.01 cm to approximately 0.15 cm , from 0.01 cm to approximately 0.1 cm, from 0.01 cm to approximately 0.05 cm, from 0.02 cm to 0.2 cm, from 0.02 cm to approximately 0.15 cm , from 0.02 cm to approximately 0.1 cm, from 0.02 cm to approximately 0.05 cm, from 0.03 cm to 0.2 cm, from 0.03 cm to approximately 0.15 cm , from 0.03 cm to approximately 0.1 cm, from 0.03 cm to approximately 0.05 cm, from 0.04 cm to 0.2 cm, from 0.04 cm to approximately 0.15 cm , from 0.04 cm to about 0.1 cm or from 0.04 cm to about 0.05 cm. In some embodiments, the outer width of the inner inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, is not exceeds approximately: 0.01 cm, 0.02 cm, 0.03 cm, 0.04 cm, 0.05 cm, 0.06 cm, 0.07 cm, 0.08 cm, 0.09 cm, 0 ,1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm, 0 .2 cm, 0.3 cm or 0.4 cm. In some versions, the external width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, is approximately: 0.01 cm, 0.02 cm, 0.03 cm, 0.04 cm, 0.05 cm, 0.06 cm, 0.07 cm, 0.08 cm, 0.09 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm, 0.2 cm, 0.3 cm or 0.4 cm. In some embodiments, the external width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, exceeds approximately: 0.01 cm, 0.02 cm, 0.03 cm, 0.04 cm, 0.05 cm, 0.06 cm, 0.07 cm, 0.08 cm, 0.09 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm, 0.2 cm, 0.3 cm or 0.4 cm.

[0143] In certain embodiments, the outer width of the inner inlet section, perpendicular to the inlet-to-outlet flow axis, at its narrowest portion, does not exceed approximately: 0.01 cm, 0.02 cm, 0.03 cm, 0.04 cm, 0.05 cm, 0.06 cm, 0.07 cm, 0.08 cm, 0.09 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm, 0.2 cm, 0.3 cm or 0.4 cm. In selected options, the outer width of the inner inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its narrowest section, is in the range of approximately: from 0.01 cm to 0.2 cm, from 0.01 cm to approximately 0.15 cm, from 0.01 cm to approximately 0.1 cm, from 0.01 cm to approximately 0.05 cm, from 0.02 cm to 0.2 cm, from 0.02 cm to approximately 0.15 cm, from 0.02 cm to approximately 0.1 cm, from 0.02 cm to approximately 0.05 cm, from 0.03 cm to 0.2 cm, from 0.03 cm to approximately 0.15 cm, from 0.03 cm to approximately 0.1 cm, from 0.03 cm to approximately 0.05 cm, from 0.04 cm to 0.2 cm, from 0.04 cm to approximately 0.15 cm, from 0.04 cm to approximately 0.1 cm or from 0.04 cm to approximately 0.05 cm. In some embodiments, the outer width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its narrowest section is approximately: 0.01 cm, 0.02 cm, 0.03 cm, 0.04 cm, 0.05 cm, 0.06 cm, 0.07 cm, 0.08 cm, 0.09 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm, 0.2 cm, 0.3 cm or 0.4 cm. In some versions, the external width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its narrowest section exceeds approximately: 0.01 cm, 0.02 cm, 0.03 cm, 0 .04 cm, 0.05 cm, 0.06 cm, 0.07 cm, 0.08 cm, 0.09 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0 .14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm, 0.2 cm, 0.3 cm or 0.4 cm.

[0144] The width of the inner inlet section may be changed continuously, may be changed in steps, not changed, or changed by a combination of these changing methods. The inner width or the outer width of the inner inlet section may be changed continuously, may be changed in steps, may not be changed, or may be changed by a combination of these changing methods. The inlet and outlet ends of the inner inlet section may be the same width or may vary in width. In some embodiments, the widest and narrowest portions of the inner inlet section are at the ends (ie, the top (inlet end) of the upper section of the globe valve and the inlet of the globe valve cavity). For example, the widest portion of the inner inlet section may be at the inlet end and the narrowest portion of the inner inlet section may be at the outlet end, or vice versa. In some embodiments, the widest and/or narrowest portions of the inner inlet section are not at the end. In some embodiments, the widest portion of the inner inlet section is the base of the inner inlet section for attachment to the upper section of the globe valve.

[0145] Inner width of inner inlet section

In certain embodiments, the internal width of the internal inlet section, perpendicular to the inlet-to-exhaust flow axis, at its widest portion, is about: about 0.001 cm to about 0.2 cm, about 0.001 cm to about 0.15 cm, from 0.001 cm to approximately 0.1 cm, from 0.001 cm to approximately 0.06 cm, from 0.001 cm to approximately 0.05 cm, from 0.005 cm to approximately 0.2 cm, from 0.005 cm to approximately 0, 15 cm, from 0.005 cm to approximately 0.1 cm, from 0.005 cm to approximately 0.06 cm, from 0.005 cm to approximately 0.05 cm, from 0.01 cm to 0.2 cm, from 0. 01 cm to approximately 0.15 cm, from 0.01 cm to approximately 0.1 cm, from 0.01 cm to approximately 0.06 cm, from 0.01 cm to approximately 0.05 cm, from 0.015 cm to 0.2 cm, 0.015 cm to approximately 0.15 cm, 0.015 cm to approximately 0.1 cm, 0.015 cm to approximately 0.06 cm, 0.015 cm to approximately 0.05 cm, from 0.02 cm to 0.2 cm, from 0.02 cm to approximately 0.15 cm, from 0.02 cm to approximately 0.1 cm, from 0.02 cm to approximately 0.06 cm or from 0.02 cm to approximately 0.05 cm. In some embodiments, the internal width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its widest section, does not exceed approximately: 0.001 cm, 0.002 cm, 0.003 cm, 0.004 cm, 0.005 cm, 0.006 cm, 0.007 cm, 0.008 cm, 0.009 cm, 0.01 cm, 0.015 cm, 0.02 cm, 0.025 cm, 0.03 cm, 0.035 cm, 0.04 cm, 0.045 cm, 0.05 cm, 0.055 cm, 0.06 cm, 0.065 cm, 0.07 cm, 0.075 cm, 0.08 cm, 0.085 cm, 0.09 cm, 0.095 cm, 0.1 cm, 0, 11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm or 0.2 cm. In individual options, the internal width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its widest section exceeds approximately: 0.001 cm, 0.002 cm, 0.003 cm, 0.004 cm, 0.005 cm, 0.006 cm, 0.007 cm, 0.008 cm, 0.009 cm, 0.01 cm, 0.015 cm, 0.02 cm, 0.025 cm, 0.03 cm, 0.035 cm, 0.04 cm, 0.045 cm, 0.05 cm, 0.055 cm, 0.06 cm, 0.065 cm, 0.07 cm, 0.075 cm, 0.08 cm, 0.085 cm, 0.09 cm, 0.095 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0 .15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm or 0.2 cm. In some versions, the internal width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its most wide area, is approximately: 0.001 cm, 0.002 cm, 0.003 cm, 0.004 cm, 0.005 cm, 0.006 cm, 0.007 cm, 0.008 cm, 0.009 cm, 0.01 cm, 0.015 cm, 0.02 cm, 0.025 cm, 0.03 cm, 0.035 cm, 0.04 cm, 0.045 cm, 0.05 cm, 0.055 cm, 0.06 cm, 0.065 cm, 0.07 cm, 0.075 cm, 0.08 cm, 0.085 cm, 0, 09 cm, 0.095 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm , 0.19 cm or 0.2 cm.

[0146] In certain embodiments, the internal width of the internal inlet section, perpendicular to the axis from the inlet to the outlet flow, at its narrowest portion, does not exceed approximately: 0.001 cm, 0.002 cm, 0.003 cm, 0.004 cm, 0.005 cm, 0.006 cm, 0.007 cm, 0.008 cm, 0.009 cm, 0.01 cm, 0.015 cm, 0.02 cm, 0.025 cm, 0.03 cm, 0.035 cm, 0.04 cm, 0.045 cm, 0.05 cm, 0.055 cm, 0 .06 cm, 0.065 cm, 0.07 cm, 0.075 cm, 0.08 cm, 0.085 cm, 0.09 cm, 0.095 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm , 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0.18 cm, 0.19 cm or 0.2 cm. In selected versions, the internal width of the internal inlet section, perpendicular to the axis from the inlet before the flow exits, at its narrowest section, exceeds approximately: 0.001 cm, 0.002 cm, 0.003 cm, 0.004 cm, 0.005 cm, 0.006 cm, 0.007 cm, 0.008 cm, 0.009 cm, 0.01 cm, 0.015 cm, 0 .02 cm, 0.025 cm, 0.03 cm, 0.035 cm, 0.04 cm, 0.045 cm, 0.05 cm, 0.055 cm, 0.06 cm, 0.065 cm, 0.07 cm, 0.075 cm, 0.08 cm, 0.085 cm, 0.09 cm, 0.095 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0, 17 cm, 0.18 cm, 0.19 cm or 0.2 cm. In some versions, the internal width of the internal inlet section, perpendicular to the axis from the inlet to the outlet of the flow, at its narrowest section, ranges from approximately: 0.001 cm to 0.2 cm, from 0.001 cm to about 0.15 cm, from 0.001 cm to about 0.1 cm, from 0.001 cm to about 0.06 cm, from 0.001 cm to about 0.05 cm , from 0.005 cm to 0.2 cm, from 0.005 cm to approximately 0.15 cm, from 0.005 cm to approximately 0.1 cm, from 0.005 cm to approximately 0.06 cm, from 0.005 cm to approximately 0.05 cm, from 0.01 cm to 0.2 cm, from 0.01 cm to approximately 0.15 cm, from 0.01 cm to approximately 0.1 cm, from 0.01 cm to approximately 0.06 cm, from 0.01 cm to approximately 0.05 cm, from 0.015 cm to 0.2 cm, from 0.015 cm to approximately 0.15 cm, from 0.015 cm to approximately 0.1 cm, from 0.015 cm to , approximately 0.06 cm, from 0.015 cm to approximately 0.05 cm, from 0.02 cm to approximately 0.2 cm, from 0.02 cm to approximately 0.15 cm, from 0.02 cm to approximately 0.1 cm, from 0.02 cm to approximately 0.06 cm or from 0.02 cm to approximately 0.05 cm. In some embodiments, the internal width of the internal inlet section, perpendicular to the axis from the inlet to the outlet flow, on its narrowest section is approximately: 0.001 cm, 0.002 cm, 0.003 cm, 0.004 cm, 0.005 cm, 0.006 cm, 0.007 cm, 0.008 cm, 0.009 cm, 0.01 cm, 0.015 cm, 0.02 cm, 0.025 cm, 0.03 cm, 0.035 cm, 0.04 cm, 0.045 cm, 0.05 cm, 0.055 cm, 0.06 cm, 0.065 cm, 0.07 cm, 0.075 cm, 0.08 cm, 0.085 cm, 0.09 cm, 0.095 cm, 0.1 cm, 0.11 cm, 0.12 cm, 0.13 cm, 0.14 cm, 0.15 cm, 0.16 cm, 0.17 cm, 0, 18 cm, 0.19 cm or 0.2 cm.

[0147] Internal volume of the inner inlet section

The inner inlet section may be hollow and may contain an internal volume. The internal volume of the internal inlet section may be approximately: not less than 0.0001 cm ³ , not less than 0.0005 cm ³ , not less than 0.001 cm ³ , not less than 0.005 cm ³ , not less than 0.01 cm ³ , not less than 0. 02 cm ³ or not less than 0.03 cm ³ . In certain embodiments, the internal volume of the inner inlet section is within the range of: from about 0.0001 cm ³ to about 0.03 cm ³ from about 0.0001 cm ³ to about 0.02 cm ³ from about 0.0001 cm ³ to about 0.01 cm ³ , from about 0.0001 cm ³ to about 0.005 cm ³ , from about 0.0001 cm ³ to about 0.001 cm ³ , from about 0.0001 cm ³ to about 0.0005 cm ³ , from about 0.0005 cm ³ to about 0.03 cm ³ , from about 0.0005 cm ³ to about 0.02 cm ³ , from about 0. 0005 cm ³ to about 0.01 cm ³ , from about 0.0005 cm ³ to about 0.005 cm ³ , from about 0.0005 cm ³ to about 0.001 cm ³ , from about 0.001 cm ³ to, about 0.03 cm ³ , from about 0.001 cm ³ to about 0.02 cm ³ , from about 0.001 cm ³ to about 0.01 cm ³ , from about 0.001 cm ³ to about 0.005 cm ³ , from about 0.005 cm ³ to about 0.03 cm ³ , from about 0.005 cm ³ to about 0.02 cm ³ , from about 0.005 cm ³ to about 0.01 cm ³ , from about 0. 01 cm ³ to about 0.03 cm ³ or from about 0.01 cm ³ to about 0.02 cm ³ . The internal volume of the inner inlet section may be approximately: 0.0001 cm ³ , 0.0002 cm ³ , 0.0003 cm ³ , 0.0004 cm ³ , 0.0005 cm ³ , 0.0006 cm ³ , 0.0007 cm ³ , 0.0008 cm ³ , 0.0009 cm ³ , 0.001 cm 3, 0.002 cm ³ , 0.003 cm ³ , 0.004 ^{cm 3} , 0.005 cm ³ , 0.006 cm ³ , 0.007 cm ³ , 0.008 cm ³ , 0.009 cm ³ , 0.011 cm ³ , 0.012 cm ³ , 0.013 cm ³ , 0.014 cm ³ , 0.015 cm ³ , 0.016 cm ³ , 0.017 cm ³ , 0.018 cm ³ , 0.019 cm ³ , 0.02 cm ³ , 0.021 cm ³ , 0.0 22 cm ³ , 0.023 cm ³ , 0.024 cm ³ , 0.025 cm 3 , 0.026 cm ³ , 0.027 cm ³ , 0.028 cm ³ , 0.029 ^{cm 3 ,} 0.03 cm ³ , 0.04 cm ³ , 0.05 cm ³ , 0.06 cm ³ , 0.07 cm ³ , 0.08 cm ³ , 0.09 cm ³ or 1.0 cm ³ . The internal volume of the inner inlet section may exceed approximately: 0.0001 cm ³ , 0.0005 cm ³ , 0.001 cm 3 , 0.005 cm ³ , 0.01 ^{cm 3} , 0.02 cm ³ or 0.03 cm ³ . The internal volume of the inner inlet section may be less than about 0.0001 cm ³ , 0.0005 cm ³ , 0.001 cm 3 , 0.005 cm ³ , 0.01 ^{cm 3} , 0.02 cm ³ or 0.03 cm ³ .

[0148] Neck ring

The pump flow outlet may be located in the neck of the pump (eg, a hand air pump and/or bottle). The hand air pump or bottle may include a neck ring in the neck of the hand air pump or bottle. The neck ring can be fused to the neck of a hand air pump or bottle. The neck ring can be inserted into the neck of a hand air pump or bottle. The neck ring may be configured to limit the width of the neck of the hand air pump or bottle. The hole in the neck ring may have a width narrower than the widest width of the passage valve.

[0149] The width of the hole formed by the neck ring may be approximately: 1-20 mm, 1-10 mm, 1-7.5 mm, or 1-5 mm. The width of the hole formed by the neck ring may be approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. The width of the opening formed by the neck ring may exceed approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. The width of the hole formed by the neck ring can be less than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm.

[0150] The neck ring diameter may be approximately: 1-20 mm, 1-17.5 mm, 1-15 mm, 1-12.5 mm, 1-10 mm, 1-7.5 mm, or 1-5 mm. The diameter of the neck ring can be approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. The diameter of the neck ring can exceed approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. The diameter of the neck ring can be smaller than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm .

[0151] The neck ring height may be approximately: 1-20 mm, 1-17.5 mm, 1-15 mm, 1-12.5 mm, 1-10 mm, 1-7.5 mm, or 1-5 mm. The height of the neck ring can be approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. The height of the neck ring can exceed approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mm. The neck ring height may be less than approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mm. The height of the neck ring may be the same as or different than the neck height of a hand air pump or bottle.

[0152] The thickness of the neck ring (the distance from the inner to the outer edge of the neck ring) can be approximately: 0.1-20 mm, 0.1-15 mm, 0.1-10 mm, 0.1-7.5 mm , 0.1-5 mm or 0.1-2.5 mm. The thickness of the neck ring (the distance from the inner to the outer edge of the neck ring) can be approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2, 2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3, 5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4, 8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6 ,2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 , 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8 ,7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10 mm. The thickness of the neck ring (the distance from the inner to the outer edge of the neck ring) can exceed approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2, 2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3, 5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4, 8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6 ,2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 , 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8 ,7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10 mm. The thickness of the neck ring (the distance from the inner to the outer edge of the neck ring) can be less than approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0, 8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5 5.6, 5.7, 5.8, 5.9, 6, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7 ,4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6 , 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10 mm.

[0153] The neck ring may be composed of a variety of polymers, plastics, rubber, silicones, metal, composites, any other materials described herein as suitable for use in the manufacture of an intranasal delivery device, or any other material suitable for use in device for intranasal delivery. The neck ring can be made from one material or type of materials. Alternatively, the neck ring may be composed of at least two different materials or types of materials. The entire neck ring or a portion thereof may be a biocompatible material or a hypoallergenic material. The neck ring may be composed of rigid, substantially rigid, flexible or substantially flexible materials, or a combination thereof. In some embodiments, the neck ring may be composed of one or more of paper, silicone, acrylates, polyethylenes, polyurethane, polyurethane, hydrogel, polyester (for example, DACRONB material from E. I. Du Pont de Nemours and Company, Wilmington, Del. ), polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether ether ketone (PEEK), nylon, extruded collagen, polyurethane foam, rubber, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimides, aluminum, stainless steel, nickel-titanium alloy (eg, nitinol), titanium, stainless steel, or cobalt-chromium alloy (eg, ELGILOYB alloy from Elgin Specialty Metals, Elgin, Ill.; CONICHROMEB alloy from Carpenter Metals Corp., Wyomissing, Pa.).

[0154] The devices disclosed herein can be used to deliver any drug that can be delivered intranasally. For example, the devices can be used to deliver dry powder preparations of pharmaceutical, nutritional or other suitable compounds.

[0155] Methods of application

This application provides methods for delivering a powdered drug to a subject using the intranasal delivery device described herein. Medicine can be filled into the nozzle, and the medicine nozzle can be attached to the pump. If the intranasal delivery device includes a lid, such as a removable or break-off lid or cap, then the lid can be removed from the intranasal delivery device. Removal can be done by breaking off, lifting, twisting, pressing or turning the cover. When the device is not actuated, the passage valve may rest on the surface of the vial neck, preventing the powdered drug from moving upstream into the pump (eg, flexible vial). The nozzle may be inserted or partially inserted into the subject's nostril. The device may be inserted into the subject's nostril by the user or another subject (eg, a healthcare professional). The device can be actuated (eg, by squeezing a pump, which is a flexible bottle, by actuating a pressure pump). Air may leak from the pump flow outlet and force the globe valve to rise in the device nozzle. When the passage valve is raised in the nozzle, it may no longer rest on the neck of the bottle. The non-slotted portions of the port valve may contact the nozzle port, preventing the powdered drug from moving upstream into the pump. Air can flow around parts of the globe valve and flow through the grooves in the globe valve. Air can then flow into the reservoir and push the powdered drug up the nozzle port, out of the nozzle opening, and into the subject's nostril.

[0156] Assembly

Powdered medicine can be inserted into the nozzle. The nozzle may have a cap, a removable or break-off lid, etc. The nozzle can then be attached to the pump. The nozzle can be attached to the pump by, for example, screwing the nozzle to the pump, crimping the nozzle to the pump, snapping the nozzle onto the pump, or the like.

[0157] II. Drugs

The device described herein is suitable for the delivery of active ingredients, including, but not limited to, free base and salt forms of drugs. The active substance can be in crystalline or amorphous forms. The powdered drug product may consist of the drug alone "without a carrier" or may additionally contain a suitable carrier, excipient, diluent, excipient, penetration enhancers, solubilizers and adjuvants, or other material.

[0158] The device described herein can protect the powdered drug from moisture and air until the device is prepared for use. The device can be prepared for use by removing or breaking off the protective cover. The reservoir may be filled with anhydrous drugs, and the device may be further packaged using materials known to resist exposure to moisture or water so that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, sealed foil, plastic or similar materials, unit dose containers, blister packs and tape packs.

[0159] Active ingredients

In some embodiments, the active substance disclosed herein is a non-peptide/non-protein drug. In certain embodiments, the active substance is selected from the group consisting of an ergot alkaloid, a serotonin receptor subtype (5-HT) -1B, -1D or -1F agonist, a 5-hydroxytryptamine (5-HT1) receptor agonist, a CGRP receptor antagonist, an antagonist NK-1 receptor, antihistamine, antiemetic, decongestant, opioid agonist, antibiotic, antifungal, sulfonamide, antituberculosis drug, antimicrobial, antiviral, hypnotic sedative, antiepileptic, narcotic analgesic, non-narcotic analgesic, sedative, psychotherapeutic drug, muscle relaxant, antiallergic drug, antirheumatic drug, cardiotonic drug, antiarrhythmic drug, antihypertensive drug, diuretic drug, vasodilator for coronary arteries, anti-dementia drug, drug to increase brain activity, drug to improve cerebral circulation, antiparkinsonian drug, antihyperlipidemic drug , anti-ulcer drug, anti-obesity drug, diabetes drug, hemostatic drug, antithrombotic drug, migraine drug, antitussive drug, expectorant, respiratory stimulant, anti-asthma drug, antidiarrheal drug, non-steroidal anti-inflammatory drug, anti-gout drug, urinary tract drug , sexual enhancement drug, uterine drug, steroid, prostaglandin, vitamin, anidote, heavy metal poisoning drug, smoking cessation drug, anti-anaphylactic drug, anti-tumor drug, immunostimulant, immunosuppressive drug and any combination thereof. In some embodiments, the active substance is selected from the group consisting of didanosine, zidovudine, lamivudine, atazanavir, nelfenavir, stavudine, emtricitabine, polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir, peramivir, laninamivir, favipiravir, amantadine, amphotericin B, mycon ash, fluconazole, itraconazole, ketoconazole, ketamine, sodium pentobarbital, thiopetal, amopentobarbital, hexobarbital, lidocaine, triazolam, zopiclone, zolpidem, eszopiclone, etizolam, clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, trazepam, flunitrazepam, diazepam, chlordiazepoxide hydrochloride, alprazolam, lorazepam, ethyl loflazepate, bromazepate, rilmafazone, chloral hydrate, carbamazepine, clonazepam, zonisamide, sodium valproate, diphenine, phenobarbital, primidone, gabapentin, opium, morphine, ethylmorphine, oxycodone, hydrocodone, codeine, dihydrocodeine, fentanyl, remifentanil, droperidol, levorphanol, methadone, meperidine, pethidine, buprenorphine, butorphanol, tramadol, tapentadol, nalfurafine, pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine, levallorphan, sulpirin, aspirin, acetaminophen, ergotamine, dihydroergotamine, sumatriptan, eletriptan, zolmitrip tan, rizatriptan, naratriptan, almotriptan, flovatriptan , avitriptan, lasmiditan, olsegepant, telcagepant, donepezil, suxamethonium, pancuronium, sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine, homatropine methyl bromide, chlorpromazine, digitoxin, levomepromazine, thioridazine, acepromazine, digoxin, methyldi goxine, isosorbide, nitroglycerin, quinidine, disopyramide, dopamine, dobutamine, epinerphine, ethylephrine, norepinephrine, phenylephrine, dimorpholamine, doxapram, naloxone, flumazenil, tipepidine, dextromethorphan, ambroxol, brogexine, salbutamol, terbutaline, procaterol, theophylline, ephedrine, sodium cromoglycate, ketotifen, oxatomide, tranilast, granisetron , azasetron, ramosetron, tropisetron, indysetron, palonosetron, cisapride, domperidone, metoclopramide, trimebutine, lorperamide, mefenamic acid, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiapro phenoic acid, thiaramide, carbazochrome, sulfonic acid, tranexamic acid, pralidoxime methyl iodide, progesterone, testosterone, dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine, leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone, risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir, famciclovir, penciclovir, lopinavir, rinavir , saquinavir, vidarabine, idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin, carmustine, betaprost sodium and any combination thereof.

[0160] In certain embodiments, the active ingredient is a small molecule drug, for example, having a molecular weight of less than about 1000 grams/mol (g/mol), about 750 g/mol, or about 500 g/mol. In some cases, the active substance is a remedy for migraines. In some cases, the active substance is an ergot alkaloid. In some embodiments, the active substance is dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof, for example, DHE mesylate. In some embodiments, the active substance is indomethacin, midacholam or phenobarbital. In some embodiments, the active substance is indomethacin or a pharmaceutically acceptable salt thereof. In some embodiments, the active substance is testosterone or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the active substance disclosed herein is a peptide or peptide compound, wherein the peptide or peptide compound has a molecular weight of no more than about 20,000 (Da), no more than about 30,000 (Da), no more than about 40,000 (Yes) or no more than about 50,000 Daltons. In certain embodiments, the active substance is selected from the group consisting of insulin, human growth hormone, calcitonin, glucagon, parathyroid hormone, parathyroid hormone (1-34), glucagon-like peptide-1, interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-releasing hormone, hypertensin, prolactin, luteinizing hormone, gastric inhibitory polypeptide (GIP), C-peptide, cyclosporine, FK-506, octreotide, carperitide, pramlintide, lanreotide, eptifibatide, albiglutide, pasireotide, teriparatide, exenatide, liraglutide, emfuvirtide, ziconotide, ecalantide, mifamurtide, neristide, peginesatide, afamelanotide, linaclotide, lixisenatide, teduglut ida, bentiromide, diethylamine ceruletide, degarelix , ghrelin, atrial natriuretic hormone, their peptide analogues and any combination thereof.

[0162] The methods and preparations presented in this application may use the active substance in free base, salt, hydrate, polymorphic, isomeric, diastereoisomeric, predrug, metabolite, ion-pair complex or chelate form. The active substance may be formed using a pharmaceutically acceptable non-toxic acid or base, including an inorganic acid or base or an organic acid or base. In certain embodiments, the active substance that can be used in connection with the methods and preparations presented herein is a pharmaceutically acceptable salt derived from acids, including, but not limited to, the following: acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic , citric, ethenesulfonic, formic, fumaric, furancarboxylic, galacturonic, gluconic, glucuronic, glutamic, glycol, hydrobromic, hydrochloric, isethic, lactic, maleic, hydroxysuccinic, mandelic, methanesulfonic, mucinic, nitric, pamic, pantothenic, phenylacetic, phosphoric, propion new , salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid or p-toluenesulfonic acid. In some embodiments, the active substance is a salt of methanesulfonic acid. An alternative name for the methanesulfonic acid salt of DHE is DHE mesylate. Additional description of pharmaceutically acceptable salts that can be used in the methods described in this application is given, for example, in the publication S.M. Barge et al., "Pharmaceutical Salts", 1977, J. Pharm. Sci. 66:1-19, which is incorporated herein by reference in its entirety.

[0163] In some embodiments, the average particle size of the active ingredient or drug disclosed herein may be less than about 100 micrometers (μm), for example, about: 95 μm, 90 μm, 85 μm, 80 μm, 75 μm , 70 µm, 65 µm, 60 µm, 55 µm, 50 µm, 45 µm, 40 µm, 35 µm, 30 µm, 25 µm, 20 µm, 15 µm, 10 µm, 5 µm or less. In some embodiments, the average particle size of the active substance or drug disclosed in this application may exceed 10 microns, for example, exceed approximately: 250 microns, 200 microns, 190 microns, 180 microns, 170 microns, 160 microns, 150 microns, 140 µm, 130 µm, 120 µm, 110 µm, 100 µm, 95 µm, 90 µm, 85 µm, 80 µm, 75 µm, 70 µm, 65 µm, 60 µm, 55 µm, 50 µm, 45 µm, 40 µm, 35 µm, 30 µm, 25 µm, 20 µm or 15 µm. The particle size of the active substance or powder preparation can be approximately: 20-100 micrometers, 25-150 micrometers, 25-175 micrometers, 25-200 micrometers, 25-250 micrometers, 25-300 micrometers, 50-150 micrometers, 50-175 micrometers, 50-200 micrometers, 50-250 micrometers, 50-300 micrometers, 10-100 microns, for example, approximately: 15-90 microns, 15-80 microns, 15-70 microns, 15-60 microns, 15-50 microns , 15-40 µm, 15-30 µm, 15-20 µm, 15-20 µm, 10-90 µm, 10-80 µm, 10-70 µm, 10-60 µm, 10-50 µm, 10-40 µm , 10-30 µm, 10-20 µm, 20-90 µm, 20-80 µm, 20-70 µm, 20-60 µm, 20-50 µm, 20-40 µm, 20-30 µm, 30-90 µm , 30-80 µm, 30-70 µm, 30-60 µm, 30-50 µm, 30-40 µm, 40-90 µm, 40-80 µm, 40-70 µm, 40-60 µm, 40-50 µm , 50-90 µm, 50-80 µm, 50-70 µm, 50-60 µm, 60-90 µm, 60-80 µm, 60-70 µm, 70-90 µm, 70-80 µm or 80-90 µm . The average particle size of the active substance or drug can be approximately: 5.0 µm, 5.5 µm, 6.0 µm, 6.5 µm, 7.0 µm, 7.5 µm, 8.0 µm, 8.5 µm, 9.0 µm, 9.5 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, 20 µm, 25 µm, 30 µm , 35 µm, 40 µm, 45 µm, 50 µm, 55 µm, 60 µm, 65 µm, 70 µm, 75 µm, 80 µm, 85 µm, 90 µm, 95 µm or 100 µm. In certain embodiments, no less than 90% of the powder formulations provided herein have a particle diameter less than 150 microns, and no more than 5% of the particles have a diameter less than 5 microns. In certain embodiments, the overall average particle size of the powder formulations provided herein is from about 15 μm to about 30 μm, from about 18 μm to about 25 μm, from about 18 μm to about 20 μm, or approximately 20 microns.

[0164] In some embodiments, the total weight of the powder formulation contains from about 0.4% to about 46%, or from about 0.4% to about 23%, or from about 0.4% to about 9 %, or from about 2% to about 9%, or from about 4% to about 9% of the active substance. In certain embodiments, the total weight of the powder formulation comprises from about 0.3% to about 37%, or from about 0.3% to about 18%, or from about 0.3% to about 7%, or from about 2% to about 7%, or from about 3% to about 9% of the active substance or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the formulation disclosed herein further comprises an additional active ingredient, such as an adenosine receptor antagonist, a phosphodiesterase inhibitor, an acetylcholinesterase inhibitor, a vasodilator, xanthine, caffeine, paraxanthine, theobromine, and theophylline. For example, the methods and preparations additionally contain caffeine. The additional active ingredient (e.g., caffeine) may constitute at least about 1% of the total weight of the powder formulation, for example, about: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8 %, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or more of the total weight of the powder preparation. Additional active ingredient (e.g. caffeine) may constitute approximately 1%-60% of the total weight of the powder formulation, for example approximately: 1%-60%, 1%-50%, 1%-40%, 1%-30% , 1%-20%, 1%-10%, 1%-5%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20 %-60%, 20%-50%, 20%-40%, 20%-30%, 30%-60%, 30%-50%, 30%-40%, 40%-60%, 40%- 50% or 50%-60% of the total weight of the powder preparation. In some embodiments, the powder preparation contains approximately 5%-10% of additional active ingredient (for example, caffeine). In certain embodiments, the caffeine is caffeine anhydrous. In some embodiments, the powder preparation contains approximately 10%-15% of additional active ingredient (for example, caffeine).

[0166] In some embodiments, the present invention provides a device containing a powder drug formulation containing particles that contain the active ingredient and at least one element selected from the group consisting of a thickener, a carrier, an acidity regulator, a sugar alcohol, and any combinations thereof, wherein: at least about 10%, about 20%, about 30%, about 40%, or about 50% by weight of the active substance in the particles is amorphous as determined by X-ray diffraction; when the active substance is in crystalline form, the solubility of the active substance in crystalline form in a liquid product in aqueous solution ranges from about 0.1 μg/ml to about 1 milligram/milliliter (mg/ml) in water at a temperature of 37 ± 0 .5°C; the particles have an average particle size of from about 10 micrometers to about 300 micrometers, as measured by laser diffraction; and, when the powder drug is administered, the pharmacokinetic parameter of the active substance is increased by at least about 15% compared to the corresponding drug that contains the active substance in crystalline form upon administration. In some embodiments, the powdered medicinal product further contains particles that contain the active ingredient and do not contain a thickener, carrier, acidity regulator, sugar alcohol, or a combination thereof. In some embodiments, the active substance is a non-peptide/non-protein drug. In certain embodiments, the particles have an average particle size of from about 15 to about 100 microns, as measured by laser diffraction. In certain embodiments, the particles have an average particle size of from about 20 to about 50 microns, as measured by laser diffraction. In some embodiments, the particles are spray dried. In some embodiments, the active ingredient is spray-dried on a carrier, thickener, acidity regulator, sugar alcohol, or combination thereof to form particles. In some embodiments, solubility is measured at pH levels of approximately 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 , 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.8, 7.9, 8.0, for example, ranging from about 6.8 to about 7.4. In certain embodiments, the particles contain a carrier that is at least partially insoluble in water at 37±0.5°C. In certain embodiments, water insolubility is measured at a pH level ranging from about 6.8 to about 7.4. In some embodiments, the particles additionally contain a thickener, and the carrier has a water solubility lower than the water solubility of the thickener. In certain embodiments, the particles contain a carrier that is at least partially adhesive to the mucosa. In certain embodiments, the particles contain a carrier that contains an oligosaccharide, a polysaccharide, or any combination thereof. In certain embodiments, the carrier contains microcrystalline cellulose, ethylcellulose, cellulose acetate, cellulose acetobutyrate, cellulose acetopropionate, cellulose acetophthalate, hydroxypropylmethylcellulose phthalate, starch, chitosan, β-cyclodextrin, or any combination thereof. In certain embodiments, the particles contain a carrier that has an average particle size of from about 10 to about 100 microns, as measured by laser diffraction. In some embodiments, the carrier has an average particle size of approximately 20 microns, as measured by laser diffraction. In certain embodiments, the particles contain a thickener that is at least partially water soluble at 37±0.5°C. In certain embodiments, water solubility is measured at a pH level ranging from about 6.8 to about 7.4. In some embodiments, the particles additionally contain a carrier, and the thickener has a higher water solubility than the carrier. In some embodiments, the particles contain a thickener that binds to the active ingredient. In some embodiments, the particles additionally contain a carrier, and the thickener is associated with the active substance and the carrier. In some embodiments, the particles contain a thickener that contains a polysaccharide. In some embodiments, the thickener contains hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, methylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium alginate, xanthan gum, acacia gum, guar gum, locust bean gum, tragacanthum, starch, carbomers, methylcellulose, polyvinylpyrrolidone or any combination thereof. In certain embodiments, the particles contain a thickener and have an average particle size of from about 10 to about 50 microns, or about 15-200 micrometers, as measured by laser diffraction. In certain embodiments, the particles have an average particle size of about 15 microns, or about 50-150 micrometers, as measured by laser diffraction. In certain embodiments, the particles contain a thickener and a carrier and have an average particle size of from about 10 to about 50 microns, as measured by laser diffraction. In certain embodiments, the particles have an average particle size of about 20 or about 23 microns, as measured by laser diffraction. In some embodiments, the powdered medicinal product additionally contains a liquefying agent. In some embodiments, the liquefying agent contains tribasic calcium phosphate. In some embodiments, administration of a powder medicinal product increases the pharmacokinetic parameter of the active substance by at least about: 20%, 25%, 30%, 40%, 45%, 50%, 60%, 70%, 80%, 90% , 100%, 150%, 200%, 250%, 300%, 400% or 500%, when compared with the administration of a corresponding drug that contains the active substance in crystalline form. In some embodiments, an increase in the pharmacokinetic parameter contains a higher relative bioavailability from 0 min to 15 min (rBA _0-15min ), a higher relative bioavailability from 0 min to 30 min (rBA _0-30min ), a higher relative bioavailability from 0 min from 60 min (rBA _0-60min ) or any combination thereof. In certain embodiments, the increase in the pharmacokinetic parameter comprises an average rBA value _{of 0-15 min} and the increase is at least about 100%, such as at least about 115% or 150%. In certain embodiments, the average rBA _{0-15 min} is approximately 150%-1500% in the subject's serum. In certain embodiments, the increase in the pharmacokinetic parameter comprises an average rBA value _{of 0-30 min} and the increase is at least about 80%, such as at least about 115%. In some cases, the increase is approximately 400%. In certain embodiments, the increase in the pharmacokinetic parameter comprises an average rBA value _{of 0-60 min} and the increase is at least 100%, such as at least about 115%. In some cases, the increase is approximately 200%. In some embodiments, an increase in the pharmacokinetic parameter includes a higher maximum blood concentration ( _Cmax ). In some embodiments, increasing the pharmacokinetic parameter includes reducing the time to reach the maximum concentration in the blood ( _Tmax ). In some embodiments, an increase in a pharmacokinetic parameter comprises an increase in the area under the curve (AUC) of the blood concentration-time profile. In some embodiments, the powder medicinal product additionally contains an additional active ingredient. In certain embodiments, the additional active ingredient comprises caffeine that is amorphous, crystalline, at least 20% by weight caffeine amorphous, or any combination thereof. In certain embodiments, at least about: 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95 % or 98% by weight of the active substance is amorphous. In certain embodiments, the powdered drug product retains at least about: 80%, 85%, 90%, or 95% by weight of the active ingredient in the closed container after a period of at least about: 30, 60, 120, 180, 360, 720 or 1080 days. In some embodiments, the container is stored at about 15°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, or about 70°C, for example, from about 20 °C to approximately 40°C, at standard atmospheric pressure and relative humidity of approximately 50% to approximately 75%. For example, the relative humidity may be about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85%. In some embodiments, the container is stored at about 25°C, standard atmospheric pressure and about 50% relative humidity. In some embodiments, the crystalline form contains polymorphic modifications.

[0167] In some embodiments, the active ingredient disclosed herein has an average particle size (eg, diameter) of about 5 microns or greater than 5 microns.

[0168] In some embodiments, the active ingredient is present in an amount of about: 2-4%, 1-5%, 1-10%, 1-15%, 1-20%, 1-25%, 1-30%, 1-40%, 10-50%, 10-40%, 10-30% or 15-25% by weight of the particle or powder drug product, for example, about: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% , 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45% or 50%.

[0169] In some embodiments, the particle size for each active ingredient, excipient and powder formulation is determined in a dispersed dry powder state by a laser diffraction system (Mastersizer 2000, Malvern Instruments Ltd.).

[0170] Excipients

In some embodiments, the drug disclosed herein contains one or more excipients, for example, different substances or the same substance but different sizes. In some embodiments, the excipient contains a carrier, for example, a water-soluble polysaccharide or oligosaccharide. In certain embodiments, the carrier is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose acetopropionate, cellulose acetophthalate, chitosan, β-cyclodextrin, ethylcellulose, hydroxypropyl methylcellulose phthalate (HPMCP), microcrystalline cellulose, starch, and any combination thereof. In some embodiments, the excipient contains a thickener, for example, a water-soluble polysaccharide. In certain embodiments, the thickener is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), gum acacia, alginic acid, colloidal silicone dioxide, calcium carboxymethylcellulose, gelatin, hydroxypropylcellulose, hydroxylpropylcellulose (hypromellose), methylcellulose, sucrose, sodium alginate, sodium carboxymethylcellulose and any combination thereof. In certain embodiments, the excipient comprises a first excipient (any excipient disclosed herein) and a second excipient (any excipient disclosed herein). In some embodiments, the excipient contains a carrier (eg, microcrystalline cellulose) and a thickener (eg, HPMC).

[0171] In certain embodiments, the particles contain a thickener that is present in an amount of about: 0.1-0.5%, 0.05-1%, 0.05-2%, 0.05-3%, 0. 05-4%, 0.05-5%, 4-6%, 3-7%, 2-8%, 1-10% or 1-20% by weight of the particle or powder drug product, for example, approximately: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 percent. In certain embodiments, the particles contain microcrystalline cellulose, which is present in an amount of about: 10-95%, 10-75%, 15-55%, 20-75%, 35-75%, or 40-75% by weight of the particles or powdered drug, for example, about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95%. In certain embodiments, the particles contain a sugar alcohol that is present in an amount of about: 10-95%, 10-75%, 15-55%, 20-75%, 35-75%, or 40-75% by weight of the particles or powdered drug, for example, about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95%. In certain embodiments, the particles contain an acidity regulator that is present in an amount of about: 10-20%, 20-30%, 5-25%, 15-35%, or 5-40% by weight of the particle or drug powder of the drug, for example, approximately: 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35% or 40%.

[0172] In certain embodiments, the particle or preparation disclosed herein contains an acidity regulator. In certain embodiments, the acidity regulator is selected from the group consisting of ascorbic acid, sodium ascorbate, tartaric acid, sodium tartrate, potassium tartrate, calcium tartrate, lithium tartrate, citric acid, sodium citrate, potassium citrate, calcium citrate, lithium citrate, phosphoric acid , sodium dihydrogen phosphate, sodium monohydrogen phosphate, lithium phosphate, potassium phosphate, calcium phosphate, sodium carbonate, sodium hydrogen carbonate, lactic acid, sodium lactate, potassium lactate, calcium lactate, acetic acid, sodium acetate, potassium acetate, calcium acetate, propionic acid, sulfuric acid, sodium sulfate, potassium sulfate, boric acid, sodium borate, maleic acid, lithium maleate, sodium maleate, potassium maleate, calcium maleate, succinic acid, lithium succinate, sodium succinate, potassium succinate, calcium succinate, fumaric acid, glutamic acid, formic acid, hydrosuccinic acid, hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, ammonia solution, monoethanolamine, diethanolamine, triethanolamine-meglumine, sodium citrate, sodium bicarbonate, potassium bicarbonate and any combination thereof. In certain embodiments, the acidity regulator disclosed herein is acetic acid; adipic acid; double salt of ammonium sulfate and aluminum sulfate; ammonium bicarbonate; ammonium carbonate; dibasic ammonium citrate; monobasic ammonium citrate; ammonium hydroxide; dibasic ammonium phosphate; monobasic ammonium phosphate; calcium acetate; calcium acid pyrophosphate; calcium carbonate; calcium chloride; calcium citrate; calcium fumarate; calcium glucanate; calcium hydroxide; calcium lactate; calcium oxide; dibasic calcium phosphate; monobasic calcium phosphate; tribasic calcium phosphate; calcium sulfate; carbon dioxide; acetic acid; sour potassium tartrate; fumaric acid; gluconic acid; gluconodeltalactone; hydrochloric acid; lactic acid; magnesium carbonate; magnesium citrate; magnesium fumarate; magnesium hydroxide; magnesium oxide; magnesium phosphate; magnesium sulfate; hydroxysuccinic acid; manganese sulfate; metatartaric acid; phosphoric acid; sour potassium tartrate; aluminum potassium sulfate; potassium bicarbonate; potassium carbonate; potassium chloride; potassium citrate; potassium fumarate; potassium hydroxide; potassium lactate; dibasic potassium phosphate; tribasic potassium phosphate; potassium sulfate; potassium tartrate; potassium tripolyphosphate; sodium acetate; sodium acid pyrophosphate; sodium tartrate; sodium aluminum phosphate; sodium aluminum sulfate; sodium bicarbonate; sodium bisulfate; sodium carbonate; sodium citrate; sodium fumarate; sodium glucanate; sodium hexametaphosphate; sodium hydroxide; sodium lactate; dibasic sodium phosphate; monobasic sodium phosphate; tribasic sodium phosphate; sodium potassium hexametaphosphate; potassium-sodium tartrate; sodium potassium tripolyphosphate; tetrabasic sodium pyrophosphate; sodium tripolyphosphate; sulfuric acid; sulfurous acid; tartaric acid; or any combination thereof.

[0173] In certain embodiments, the particle or preparation disclosed herein contains a sugar alcohol. In certain embodiments, the sugar alcohol is selected from the group consisting of mannitol, glycerol, galactitol, fucite, inositol, volemite, maltotriitol, maltotetraitol, polyglycite, erythritol, threitol, ribitol, arabitol, xylitol, allitol, dulcitol, glucite, sorbitol, altritol, iditol, maltitol, lactitol, isomalt and any combination thereof. In some embodiments, the sugar alcohol contains 3, 4, 5, 6, 7, 12, 18, or 24 carbon atoms.

[0174] In some embodiments, the formulations may additionally contain a liquefying agent. For example, the liquefying agent is a metal salt (eg a calcium salt) or a phosphoric acid salt. In some embodiments, the liquefying agent is a calcium salt of phosphoric acid, for example, tribasic calcium phosphate. Tribasic calcium phosphate may comprise from about 0.1% to about 5.0% of the total weight of the powder formulation, for example, about: 0.1%-5%, 0.1%-4%, 0.1%- 3%, 0.1%-2%, 0.1%-1%, 0.1%-0.5%, 0.5%-5%, 0.5%-4%, 0.5%- 3%, 0.5%-2%, 0.5%-1%, 1%-5%, 1%-4%, 1%-3%, 1%-2%, 2%-5%, 2 %-4%, 2%-3%, 3%-5%, 3%-4% or 4%-5% of the total weight of the powder preparation. In certain embodiments, the tribasic calcium phosphate comprises from about 0.5% to about 1.0% of the total weight of the powder formulation. In certain embodiments, the tribasic calcium phosphate comprises from about 0.5% to about 1.5% of the total weight of the powder formulation. In some embodiments, tribasic calcium phosphate constitutes approximately 0.8% of the total weight of the powder preparation.

[0175] In some embodiments, the excipient has an average particle size of no more than about 100 µm, for example, no more than about 95 µm, 90 µm, 85 µm, 80 µm, 75 µm, 70 µm, 65 µm , 60 µm, 55 µm, 50 µm, 45 µm, 40 µm, 35 µm, 30 µm, 25 µm, 20 µm, 15 µm, 10 µm, 5 µm. In certain embodiments, the formulation herein may contain a first excipient with an average particle diameter of no more than about 30 microns, and a second excipient with an average particle diameter of from about 30 to about 100 microns. The first excipient may have an average particle diameter of no more than about 30 μm, for example, about: 30-25 μm, 30-20 μm, 30-15 μm, 30-10 μm, 30-5 μm, 25-20 μm, 25-15 µm, 25-10 µm, 25-5 µm, 20-15 µm, 20-10 µm, 20-5 µm, 15-10 µm, 15-5 µm or 10-5 µm. In certain embodiments, the first excipient has an average particle diameter of approximately 15-30 microns. In some embodiments, the first excipient has an average particle diameter of approximately 18-20 microns. In certain embodiments, the first excipient has an average particle diameter of approximately 20 microns. The second excipient may have an average particle diameter of from about 30 to about 100 microns, for example, about: 30-90 microns, 30-80 microns, 30-70 microns, 30-60 microns, 30-50 microns, 30- 40 µm, 40-90 µm, 40-80 µm, 40-70 µm, 40-60 µm, 40-50 µm, 50-90 µm, 50-80 µm, 50-70 µm, 50-60 µm, 60- 90 microns, 60-80 microns, 60-70 microns, 70-90 microns, 70-80 microns or 80-90 microns. In certain embodiments, the second excipient has an average particle diameter of approximately 45-65 microns. In certain embodiments, the second excipient has an average particle diameter of approximately 45-55 microns. In some embodiments, the second excipient has an average particle diameter of approximately 50-55 microns. In certain embodiments, the second excipient has an average particle diameter of approximately 50 microns. In certain embodiments, the first excipient has an average particle diameter of from about 15 microns to about 30 microns, and the second excipient has an average particle diameter of from about 45 to about 65 microns. In certain embodiments, the first excipient has an average particle diameter of about 20 microns, and the second excipient has an average particle diameter of from about 50 microns to about 55 microns. In certain embodiments, the first excipient has an average particle diameter of about 20 microns, and the second excipient has an average particle diameter of about 50 microns. In some embodiments, the excipient is substantially free of particles with an average particle diameter of from about 31 microns to about 44 microns. In certain embodiments, the excipient is substantially free of particles with an average particle diameter of from about 31 to about 49 microns. In some embodiments, substantially no particles with a certain average particle diameter means that less than 15%, 10%, 5%, or 2% of all particles fall within that range.

[0176] In some embodiments, one or more excipients (e.g., microcrystalline cellulose, HPMC, mannitol, TCP (tribasic calcium phosphate)) may comprise at least about 5% of the total weight of the powder formulation, e.g., at least at least approximately: 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% of the total weight of the powder preparation. Excipients may comprise from about 15% to about 99% of the total weight of the powder formulation, for example, about: 15%-99%, 20%-99%, 30%-99%, 40-99%, 50-99 %, 60-99%, 70-99%, 80-99%, 90-99%, 15%-90%, 20%-90%, 30%-90%, 40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 15%-80%, 20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70- 80%, 15%-70%, 20%-70%, 30%-70%, 40-70%, 50-70%, 60-70%, 15%-60%, 20%-60%, 30% -60%, 40-60%, 50-60%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 15%-40%, 20%-40%, 30 %-40%, 15%-30%, 20%-30% or 15-20% of the total weight of the powder drug. In some embodiments, the first excipient contains from about 10 to about 90% of the total weight of the powder formulation, for example, about: 10%-90%, 15%-90%, 20%-90%, 30%-90% , 40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 10%-80%, 15%-80%, 20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70-80%, 10%-70%, 15%-70%, 20%-70%, 30%-70%, 40-70%, 50 -70%, 60-70%, 10%-60%, 15%-60%, 20%-60%, 30%-60%, 40-60%, 50-60%, 10%-50%, 15 %-50%, 20%-50%, 30%-50%, 40-50%, 10%-40%, 15%-40%, 20%-40%, 30%-40%, 10%-30 %, 15%-30%, 20%-30%, 10%-20%, 15-20%, or 10%-15% of the total weight of the powder drug. In certain embodiments, the first excipient comprises from about 70% to about 90% of the total weight of the powder formulation. In certain embodiments, the first excipient comprises from about 70% to about 90% of the total weight of the powder formulation. In certain embodiments, the second excipient comprises from about 5% to about 15% of the total weight of the powder formulation, such as about 5%-15%, 5%-10%, or 10%-15% of the total weight of the powder formulation. In some embodiments, the second excipient contains approximately 10% of the total weight of the powder formulation. For example, the first excipient contains from about 8% to about 90% of the total weight of the drug, and the second excipient contains about 10% of the total weight of the drug. In certain embodiments, the first excipient constitutes from about 5% to about 90% of the total weight of the powder formulation, and the second excipient constitutes about 10% of the total weight of the powder formulation.

[0177] With respect to the microcrystalline cellulose component of the powder formulations provided herein, in general, suitable microcrystalline cellulose may include microcrystalline cellulose obtained by decomposition of cellulosic materials, such as cellulose pulp, through hydrolysis in either an acidic or alkaline environment or in both media, followed by purification of the hydrolyzate and its grinding and grinding before, during or after drying. Microcrystalline cellulose with a selected average particle diameter can be obtained, for example, by appropriate processing, for example, by fine grinding using a high-speed rotary impact mill or an air attrition mill, if necessary, and size fractionation. In certain embodiments, the microcrystalline cellulose components used in the microcellulose powder formulations provided herein may include products sold under the trade names Ceolus® PH-F20JP (e.g., with an average particle size of approximately 20-23 micrometers, volume density of approximately 0.23 g/cm ³ , angle of repose not less than 60 degrees), Ceolus® PH-301 (for example, with an average particle size of approximately 50 micrometers, bulk density of approximately 0.41 g/cm ³ , angle of repose, approximately 41 degrees), Ceolus® PH-101 (e.g., average particle size, approximately 50 micrometers, bulk density, approximately 0.29 g/cm ³ , angle of repose, approximately 45 degrees), Ceolus® PH-102 (e.g., with an average particle size of about 90 micrometers, bulk density of about 0.3 g/cm ³ , angle of repose of about 42 degrees) and Ceolus® PH-302 (from Asahi Kasei Corporation, e.g. with an average particle size of approximately 90 micrometers, bulk density of approximately 0.43 g/cm3, angle of repose of approximately 38 degrees), and Avicel® PH-105 (e.g., with an average particle size of approximately 20 micrometers, bulk density of approximately 0 .20-0.30 g/cm ³ ), Avicel® PH-101 (for example, with an average particle size of approximately 50 micrometers, bulk density of approximately 0.26-0.31 g/cm ³ ), Avicel® PH- 102 (e.g., average particle size of approximately 100 micrometers, bulk density of approximately 0.28-0.33 g/cm ³ ), Avicel® PH-301 (e.g., average particle size of approximately 50 micrometers, bulk density, about 0.34-0.45 g/cm ³ ) and Avicel® PH-302 (from FMC BioPolymer Corporation, for example, with an average particle size of about 100 micrometers, bulk density of about 0.35-0.46 g/cm cm ³ ). In certain embodiments, powder formulations that can be used in connection with the methods and formulations provided herein may contain Ceolus® PH-F20JP and Ceolus® PH-301.

[0178] Average particle diameters, for example, average particle diameters of the microcrystalline fractions of the powder formulations described herein, can be determined using standard methods, for example, by means of a laser diffraction particle size distribution analyzer or using fractionation methods. Average particle diameter means the diameter that divides particles into two groups of equal numbers: a group with larger diameters and a group with smaller diameters. The average diameter found using a laser diffraction particle size distribution analyzer corresponds to 50% of the volume in the found integral particle size distribution curve. The average particle diameter can, for example, be determined by a fractionation method that corresponds to 50% (by weight) of an integral particle size distribution curve, which can be obtained by fractionating an appropriate number of particles to be evaluated for an appropriate time, for example ten minutes, on an electromagnetic apparatus for sieve analysis, using standard sieves and weighing the samples remaining on each sieve.

[0179] In certain embodiments, the microcrystalline cellulose component of the formulation comprises a first fraction of microcrystalline cellulose with an average particle diameter of no more than about 30 microns, and a second fraction of microcrystalline cellulose with an average particle diameter of about 30-100 microns. In some embodiments, the first fraction of microcrystalline cellulose has an average particle diameter of approximately 15-30 microns. In some embodiments, the first fraction of microcrystalline cellulose has an average particle diameter of approximately 18-20 microns. In certain embodiments, the first fraction of microcrystalline cellulose has an average particle diameter of approximately 20 microns. In some embodiments, the second fraction of microcrystalline cellulose has an average particle diameter of approximately 45-65 microns. In some embodiments, the second fraction of microcrystalline cellulose has an average particle diameter of approximately 45-55 microns. In some embodiments, the second fraction of microcrystalline cellulose has an average particle diameter of approximately 50-55 microns. In some embodiments, the second fraction of microcrystalline cellulose has an average particle diameter of approximately 50 microns. In certain embodiments, the first microcrystalline cellulose fraction has an average particle diameter of about 20 microns, and the second microcrystalline cellulose fraction has an average particle diameter of about 50 microns. In certain embodiments, the first microcrystalline cellulose fraction has an average particle diameter of no more than about 30 microns, such as about 15-30 microns, about 18-20 microns, or about 20 microns, and the second microcrystalline cellulose fraction has an average particle diameter of about 45-45 microns. 65 µm, about 45-55 µm, about 50-55 µm or about 50 µm.

[0180] In certain embodiments, the microcrystalline cellulose component of the powder formulation comprises from about 10 to about 99%, such as from about 15 to about 99%, of the total weight of the formulation. In certain embodiments, the microcrystalline cellulose component of the powder formulation contains from about 53 to about 99%, from about 76 to about 99%, from about 76 to about 97%, from about 90 to about 97%, or from approximately 90 to approximately 95% of the total weight of the drug. In certain embodiments, the microcrystalline cellulose component of the powder formulation contains from about 10 to about 98%, from about 18 to about 98%, from about 18 to about 91%, from about 67 to about 91%, or from about 67 to about 83%. In certain embodiments, the microcrystalline cellulose component of the powder formulation comprises about 53%, about 76%, about 90%, about 95%, about 97%, or about 99% of the total weight of the formulation. In certain embodiments, the microcrystalline cellulose component of the powder formulation comprises about 10%, about 18%, about 66%, about 83%, about 91%, or about 98% of the total weight of the formulation. In certain embodiments, the first microcrystalline cellulose fraction contains from about 3.0 to about 90%, for example, from about 8.0 to about 90%, by weight of the total formulation, and the second microcrystalline cellulose fraction contains about 10% of the total weight of the drug. In certain embodiments, the first microcrystalline cellulose fraction contains from about 43 to about 89%, from about 66 to about 89%, from about 66 to about 87%, from about 80 to about 87%, or from , about 80 to about 85% of the total weight of the drug, and the second fraction of microcrystalline cellulose contains about 10% of the total weight of the drug. In certain embodiments, the microcrystalline cellulose component of the powder formulation contains from about 1 to about 88%, from about 8 to about 88%, from about 8 to about 81%, from about 57 to about 81%, or from about 57 to about 83%, and the second fraction of microcrystalline cellulose contains about 10% of the total weight of the preparation. In certain embodiments, the microcrystalline cellulose component of the powder formulation comprises about 43%, about 66%, about 80%, about 85%, about 87%, or about 89% of the total weight of the formulation, and the second microcrystalline cellulose fraction contains about 10% of total weight of the drug. In certain embodiments, the microcrystalline cellulose component of the powder formulation contains about 1%, about 8%, about 57%, about 73%, about 81%, or about 88% of the total weight of the formulation, and the second microcrystalline cellulose fraction contains about 10% of total weight of the drug.

[0181] With respect to tribasic calcium phosphate (also known as hydroxyapatite), any pharmaceutically acceptable tribasic calcium phosphate may be used in connection with the methods and formulations provided herein. In certain embodiments, the tribasic calcium phosphate used has an average particle diameter of about 10-100 microns, such as about 10-75 microns, about 10-50 microns, about 10-30 microns, or about 10 microns. In certain embodiments, no less than 90% of the tribasic calcium phosphate particles in the powder preparations provided herein have a diameter of less than 150 microns, and no more than 5% of the particles in the powder preparation have a diameter of less than 10 microns. In certain embodiments, the overall average particle size for tribasic calcium phosphate particles in the powder formulations provided herein is from about 15 to about 30 microns, from about 18 to about 25 microns, from about 18 to about 20 microns or approximately 20 microns.

[0182] In certain embodiments, at least about 90% of the tribasic calcium phosphate particles have a diameter of less than 150 microns. In certain embodiments, the overall average particle size for the tribasic calcium phosphate particles is from about 15 to about 30 microns, from about 18 to about 25 microns, from about 18 to about 20 microns, or about 20 microns. In some embodiments, at most about 5% of the tribasic calcium phosphate particles have a diameter of less than 10 microns. In certain embodiments, for tribasic calcium phosphate particles, at most about 90% of the particles have a diameter of less than 150 microns; and the overall average particle size is from about 15 to about 30 μm, from about 18 to about 25 μm, from about 18 to about 20 μm, or about 20 μm; and at most, about 5% of the particles have a diameter less than 10 μm.

[0183] In certain embodiments, tribasic calcium phosphate contains at least: about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6 %, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, 2.0%, for example, 0.5-1.0% of the total weight of the drug. In particular embodiments of methods for treating headaches, including migraine, tribasic calcium phosphate comprises approximately 0.8% by weight of the total formulation.

[0184] Doses

In some embodiments, the total dose of the powder formulation administered may be at least about 0.1 mg, such as at least about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg or 50 mg. The total dose of the powder formulation administered may be from about 0.1 to about 50 mg, for example, about 0.1-50 mg, about 0.1-25 mg, about 0.1-20 mg, about 0.1- 15 mg, about 0.1-10 mg, about 0.1-5 mg, about 0.1-2 mg, about 0.1-1 mg, about 0.1-0.5 mg, about 0.2- 50 mg, about 0.2-25 mg, about 0.2-20 mg, about 0.2-15 mg, about 0.2-10 mg, about 0.2-5 mg, about 0.2-2 mg , about 0.2-1 mg, about 0.2-0.5 mg, about 0.5-55 mg, 0.5-25 mg, about 0.5-20 mg, about 0.5-15 mg, about 0.5-10 mg, about 0.5-5 mg, about 0.5-2 mg, about 0.5-1 mg, about 1-25 mg, about 1-50 mg, about 1-20 mg, about 1-15 mg, about 1-10 mg, about 1-5 mg, about 1-2 mg, about 2-50 mg, about 2-25 mg, about 2-20 mg, about 2-15 mg, about 2 -10 mg, about 2-5 mg, about 5-25 mg, about 5-20 mg, about 5-15 mg, about 5-10 mg, about 10-50 mg, about 0.5-25 mg, about 10 -20 mg, about 10-15 mg, about 15-25 mg, or about 15-20 mg. For example, the total dose of the administered powder drug is approximately 25 mg.

[0185] In some embodiments, the powder formulation contains a total dose of active ingredient administered of at least about 0.1 mg, such as at least about: 0.1 mg, 0.2 mg, 0.3 mg, 0 ,4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3, 5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg. The powder preparation may contain a total dose of active substance administered from about 0.1 to about 10.0 mg, for example, about 0.1-10.0 mg, about 0.1-9.0 mg, about 0.1-8.0 mg , about 0.1-7.0 mg, about 0.1-6.0 mg, about 0.1-5.0 mg, about 0.1-4.0 mg, about 0.1-3.0 mg , about 0.1-2.0 mg, about 0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-10.0 mg, about 0.2-9.0 mg , about 0.2-8.0 mg, about 0.2-7.0 mg, about 0.2-6.0 mg, about 0.2-5.0 mg, about 0.2-4.0 mg , about 0.2-3.0 mg, about 0.2-2.0 mg, about 0.2-1.0 mg, about 0.2-0.5 mg, about 0.5-10.0 mg , about 0.5-9.0 mg, about 0.5-8.0 mg, about 0.5-7.0 mg, about 0.5-6.0 mg, about 0.5-5.0 mg , about 0.5-4.0 mg, about 0.5-3.0 mg, about 0.5-2.0 mg, about 0.5-1.0 mg, about 1.0-10.0 mg , about 1.0-5.0 mg, about 1.0-4.0 mg, about 1.0-3.0 mg, about 1.0-2.0 mg, about 2.0-10.0 mg , about 2.0-9.0 mg, about 2.0-8.0 mg, about 2.0-7.0 mg, about 2.0-6.0 mg, about 2.0-5.0 mg , about 2.0-4.0 mg, about 2.0-3.0 mg, about 5.0-10.0 mg, about 5.0-9.0 mg, about 5.0-8.0 mg , about 5.0-7.0 mg, about 5.0-6.0 mg, about 6.0-10.0 mg, about 6.0-9.0 mg, about 6.0-8.0 mg , approximately 6.0-7.0 mg, approximately 7.0-10.0 mg, approximately 7.0-9.0 mg, approximately 7.0-8.0 mg, approximately 8.0-10.0 mg , about 8.0-9.0 mg, or about 9.0-10.0 mg. For example, the total dose administered is approximately 0.5 mg. In some embodiments, the total dose administered is approximately 0.1-5 mg. In some embodiments, the total amount administered is approximately 0.5-5 mg. In some embodiments, the total amount administered is approximately 0.5-3 mg. In some embodiments, the total amount administered is approximately 1-2 mg.

[0186] Pharmaceutical kits

For the use of the drugs described in this application, a pharmaceutical kit is proposed. In some embodiments, a kit is provided containing a unit dose of a dry powder preparation suitable for intranasal administration and an intranasal delivery device or dispenser. In some embodiments, the drug is present in a therapeutic amount. In some embodiments, the kits include a carrier, package, or container that is divided into compartments to receive one or more blister packs, vials, ampoules, capsules, and the like. In some embodiments, the pharmaceutical preparation is present in a package or dispensing device that contains one or more unit dosage forms containing a compound provided herein. In some embodiments, the packaging contains metal foil or plastic film, for example, blister packaging. In some embodiments, the packaging contains capsules, cartridges, bottles or ampoules. In some embodiments, instructions for administration are included with the package or dosing device. In some embodiments, the dispenser is consumable or disposable, while in some embodiments, the dispenser is reusable. In some embodiments, the pharmaceutical is pre-loaded into the device. In certain embodiments, the nasal applicator has a volume of no more than about 3 mL, 5 mL, 10 mL, 15 mL, 20 mL, 30 mL, 40 mL, or 50 mL.

[0187] In some embodiments, a notice is also attached to the package or dispenser as required by the government agency that regulates the manufacture, use or sale of medicinal products. This notification certifies that the medicine has been approved by the designated authority for human or veterinary use. Such a notice, for example, is a US Food and Drug Administration-approved label for a prescription drug or approved product. Formulations containing a compound provided herein formulated in a compatible pharmaceutical carrier are also formulated, placed in a suitable container, and labeled for the treatment of the indicated ailment.

[0188] The products proposed herein may also include a device for intranasal administration or dosing. The device may rely on the patient's inhalation to transport the drug, or pumps may be provided or incorporated into the devices to support aerosolization and transport of the drug. Alternatively, a propellant can be used and this can be stored inside the devices.

[0189] These kits optionally contain an identifying description or label for the containers. In some embodiments, the label is on the container with letters, numbers or other symbols forming the label and affixed, stamped or etched onto the container itself; The label refers to a container when it is present inside a container or carrier that also contains the container, for example, in the form of instructions for use of a drug. In some embodiments, the label serves to indicate that the contents are intended for use for a specific medicinal purpose. In some other embodiments, the label also contains instructions for use of the contents, for example, within the framework of the methods described in this application. It is also possible to include a set of instructions, usually in the form of instructions for use of the drug. The information material may contain instructions on the method of dosing of the pharmaceutical product, including a description of the type of patients that can be treated, the regimen (eg, dose and frequency), and the like.

[0190] III. Treatment

In certain embodiments, the powdered drug product or method disclosed herein is used in the treatment or prevention of a disease or illness of a subject in need thereof. In certain embodiments, the disease or illness is pain, hormonal disorder, headache, amyotrophic lateral sclerosis, Parkinson's disease, stress, nervousness, nausea, vomiting, aggression, pain, neuropathic pain, insomnia, asomnia, restless leg syndrome, depression, or any their combination. In some embodiments, the disease or illness is a headache. In certain embodiments, the headache is a migraine headache, a histamine headache, a continuous migraine headache, a chronic headache, a tension headache, a chronic tension headache, or any combination thereof. In certain embodiments, the headache is a migraine headache. In some embodiments, the headache is a migraine headache with a precursor condition to an epileptic seizure. In some embodiments, the headache is a migraine headache with a precursor condition to an epileptic seizure. In some cases, the headache ranges from moderate to severe. In some cases, the headache is acute. In some embodiments, the powdered drug is administered over at least one day, two days, three days, four days, five days, six days, one week, one month, or one year. In some embodiments, the administration of the powder medicinal product is performed 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold or 8-fold every day. In some embodiments, the powdered drug is present in one unit dose. In certain embodiments, the powder drug product is a unit dose of about 5 mg to about 50 mg, such as about 10, 15, 20, 25, 30, 35, 40, or 45 mg. In some embodiments, the unit dose of the powdered medicinal product contains from about 0.1 mg to about 25 mg of active ingredient, for example, about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20 mg. In some variants, the subject is a primate. In some cases, the subject is a person. In some embodiments, the subject is a monkey.

[0191] In certain embodiments, this application provides a method of treating a disease or illness, including pain, headache, or hormonal disorder, comprising intranasally (eg, through the nasal cavity) administration of a powder formulation containing an active ingredient. Other possible routes of mucosal administration include conjunctival administration, buccal administration and sublingual administration. Buccal and sublingual administration have the advantage of being convenient and non-invasive for the user and can be self-administered. Another alternative route to oral administration is transdermal delivery of active substances through the patient's skin. The last form of administration is intradermal injection (injection into the dermis) and subcutaneous injection (injection into the fatty layer under the skin). In some embodiments, the powder preparation contains the active substance, microcrystalline cellulose with an average particle diameter of no more than about 100 microns, and tribasic calcium phosphate. In some embodiments, the powder preparation contains the active substance, a fraction of microcrystalline cellulose with an average particle diameter of about 50-55 microns, for example, about 50 microns, containing, about 10% of the total weight of the powder preparation, a fraction of microcrystalline cellulose with an average particle size of about 20 microns, containing from about 3 to about 90%, for example from about 8 to about 90%, of the total weight of the powder preparation, and, if necessary, a liquefying agent. In certain embodiments, the powder formulations used in the methods further contain an active ingredient disclosed herein, for example caffeine, for example caffeine anhydrous.

[0192] In certain embodiments, the headache treated by the methods provided herein is histamine headache, chronic daily headache, or migraine, including adult migraine or childhood migraine. Migraine can be migraine with an epileptic seizure precursor condition or migraine without an epileptic seizure precursor condition. In certain embodiments, the methods provided herein are methods for the acute treatment of a person suffering from migraine with or without a seizure precursor condition. In some embodiments, the methods presented herein are methods for the long-term treatment of migraine with or without a seizure precursor condition.

[0193] "Treatment" in the context of the methods disclosed herein means the alleviation, amelioration, or elimination of at least one symptom of the disease being treated. In certain embodiments, methods of treating headache or pain mitigate, reduce, or eliminate at least one or more symptoms. Headache symptoms, such as histamine headaches, chronic daily headaches, or migraines, may include pain. Symptoms may also include, for example, nausea, vomiting, photophobia, phonophobia, pathological fear of certain odors (aversion or hypersensitivity to odors), vertigo and/or allodynia. A symptom or symptoms can, for example, be rated on a four-point severity scale as follows: 0=no symptom, 1=mild symptom, not interfering with normal daily activities, 2=moderate symptom, somewhat limiting normal activities, 3=severe symptom, leading to inability to perform normal daily activities. Alternatively or additionally, a symptom or symptoms that include the four above can be assessed on a four-point functional disability scale, which assesses the degree of impairment the symptom makes to the patient's ability to perform normal daily activities, as follows: 0=not at all impaired, 1 =slightly worsening, 2=moderately worsening 3=severely or completely worsening. See Cephalalgia 1991; 11:1-12. In some embodiments, the headache or pain is of a severity greater than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a scale of 0 to 10. In some embodiments, the intensity headache or pain, such as pain associated with migraine, can be measured on a 4-point severity scale (0=no pain, 1=mild, 2=moderate, 3=severe). In certain embodiments, methods of treating headaches, such as migraines, provided herein reduce the severity of headaches, such as pain associated with migraines, by at least one point on a given 4-point severity scale.

[0194] In certain embodiments, methods of treating a disease or illness may alleviate, reduce, or eliminate at least one symptom within 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 1 hour, 1, 5 hours, 2 hours, 2.5 hours, 3 hours or 4 hours after intranasal administration of the powder preparation presented in this application. In certain embodiments, the attenuation, attenuation, or elimination of at least one symptom is sustained for about 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 36 hours, or 48 hours.

[0195] In certain embodiments presented herein, a method is provided comprising: intranasally administering to a subject a powder formulation containing: a) an active ingredient, wherein the total dose of active ingredient administered is approximately 0.1-10.0 mg; b) a microcrystalline cellulose component with an average particle diameter of not more than about 100 microns; and c) tribasic calcium phosphate. As used herein, unless otherwise indicated, "total dose of DHE (dihydroergotamine) administered" and similar expressions mean the total amount of parent DHE in the form of DHE, for example, the amount of free base DHE administered in a pharmaceutically acceptable DHE salt. In certain embodiments, the powder formulation contains DHE mesylate, and the total amount of free base DHE mesylate DHE administered is about 0.1-10.0 mg. In some embodiments, the powder formulation is administered into one nostril of the subject. In some embodiments, a portion of the powder formulation is administered into each nostril of the subject. For example, in certain embodiments of the method, about half of the powder formulation is administered into one nostril, and about half of the powder formulation is administered into the other nostril of the subject.

[0196] In certain embodiments, to treat a disease or ailment, the total amount of powder formulation administered is about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg in one or both nostrils. In some embodiments, the total amount of the powder drug is administered into one nostril. In some embodiments, part of the total amount of the powder drug is injected into each nostril. In some embodiments, approximately half of the total amount of powder formulation is administered into one nostril, and the remaining half is administered into the other nostril.

[0197] In some embodiments, the total dose of active ingredient administered is approximately 0.1-6.0 mg. In some embodiments, the total dose of the administered active substance is approximately 0.5-6.0 mg. In some embodiments, the total dose of the administered active substance is approximately 1.0-6.0 mg. In some embodiments, the total dose of the administered active substance is approximately 2.0-4.0 mg. In some embodiments, the total dose of active substance administered is about 0.1 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4. 0 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg. In some embodiments, the total dose is administered into one nostril. In some embodiments, part of the total dose is administered into each nostril. In certain embodiments, approximately half of the total dose is administered into one nostril and the remaining half is administered into the other nostril.

[0198] In certain embodiments presented in this application, a method is proposed, comprising: intranasal administration to a person in need of it, a powder preparation containing: a) an active substance; b) an excipient component comprising a first excipient fraction with an average particle diameter of no more than about 30 μm, for example, about 15-30 μm, about 18-20 μm, or about 20 μm, and a second excipient fraction with an average particle diameter , about 45-65 μm, for example about 45-55 μm or about 50-55 μm, for example about 50 μm, wherein the first fraction of the excipient contains from about 80 to about 90%, for example from about 85 up to approximately 90% of the total weight of the drug, and the second fraction of the excipient contains approximately 10% of the total weight of the drug; and c) a liquefying agent (eg tribasic calcium phosphate) containing about 0.5-1.0%, eg about 0.8%, of the total weight of the preparation. In some embodiments, the powder formulation further contains caffeine, for example, about 1-2% of the active ingredient disclosed herein, for example, caffeine, for example, caffeine anhydrous.

[0199] In certain embodiments presented herein, a method of treating headaches, including migraines, is provided, comprising: intranasal administration to a person in need thereof of a powder formulation containing: a) an active ingredient (e.g., DHE or a salt thereof, DHE mesylate ), while the total dose of the administered active substance is approximately 2.0 mg; b) a microcrystalline cellulose component comprising a first fraction of microcrystalline cellulose with an average particle size of no more than about 30 microns, for example, about 15-30 microns, about 18-20 microns or about 20 microns, and a second fraction of microcrystalline cellulose with an average particle size , about 45-65 µm, for example about 45-55 µm or about 50-55 µm, for example about 50 µm, wherein the first fraction of microcrystalline cellulose contains from about 75 to about 90%, for example from about 80 up to about 90% of the total weight of the drug, and the second microcrystalline fraction contains about 10% of the total weight of the drug; and c) tribasic calcium phosphate containing about 0.5-1.0%, for example about 0.8%, of the total weight of the preparation. In some embodiments, the powder formulation further contains a thickening agent, for example, HPMC, which may be present in an amount of about 0.1-5% by weight. In some embodiments, the powder preparation additionally contains an acidity regulator, for example, ascorbic acid, which may be present in an amount of approximately 0.5-5% by weight. In some embodiments, the powder formulation further contains a sugar alcohol, such as mannitol, which may be present in an amount of about 10-95.0% by weight. In some embodiments, the powder preparation additionally contains an active ingredient, for example, about 5-10% caffeine, for example, caffeine anhydrous.

[0200] In certain embodiments of such methods of treating headaches, including migraines, the powder formulation further contains a liquefying agent. Liquefaction agents include, but are not limited to, tribasic calcium phosphate, silicon hydroxide, non-concentrated anhydrous silicic acid, crystalline cellulose, synthetic aluminosilicate, calcium silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, talc, corn starch, metasilicate magnesium aluminate, anhydrous calcium hydrogen phosphate, synthetic hydrotalcite and magnesium metasilicate aluminate. In some embodiments, the liquefying agent is tribasic calcium phosphate. In some embodiments, tribasic calcium phosphate contains approximately 0.5-1.0% of the total weight of the drug. In specific embodiments of methods for treating migraine, tribasic calcium phosphate contains approximately 0.8% of the total weight of the drug.

[0201] In certain embodiments, powder formulations used in such methods of treating headaches, including migraines, further contain an active ingredient disclosed herein, such as caffeine, such as caffeine anhydrous. In some embodiments, powder preparations used in methods of treating migraine contain approximately 1-60% of the active substances.

[0202] Some embodiments provided herein provide a powder formulation containing one or more active ingredients (eg, DHE, indomethacin, testosterone); microcrystalline cellulose component (for example, CEOLUS PH-F20JP with a particle size of approximately 20-23 micrometers or a mixture of CEOLUS PH-F20JP and CEOLUS PH-301); thickener (eg HPMC); d) sugar alcohol (eg mannitol with a part size of about 53-300 micrometers); an acidity regulator (for example, ascorbic acid), a liquefying agent (for example, tribasic calcium phosphate); and, if necessary, an additional active ingredient disclosed herein, for example caffeine, for example caffeine anhydrous.

[0203] In some embodiments, the powder formulation is prepared by granulating all of its components in a fluidized bed. In some embodiments, the powdered medicinal product contains an active ingredient, a thickener, a carrier and a sugar alcohol. In some embodiments, the active substance is amorphous, for example, at least 20% amorphous. In some embodiments, the active substance is spray dried, for example with a thickener. In some embodiments, the thickener is a low viscosity binder, such as HPMC. In certain embodiments, the sugar alcohol is mannitol. In certain embodiments, the sugar alcohol has a particle diameter of from about 53 to about 300 micrometers. In certain embodiments, all components are aggregated into a unit sufficient to withstand delivery from the device and allow deposition in one location. In some embodiments, the aggregation is weak enough to immediately disintegrate into individual components after deposition on mucous membranes. In certain embodiments, the particle diameter of the powder formulation is from about 50 micrometers to about 150 micrometers, such as about 150 micrometers. In some embodiments, the powder formulation has an angle of repose less than 55°, such as less than: 50°, 45°, 40°, 35°, 30°, or 25°. In some embodiments, the powder preparation does not contain a liquefying agent.

Examples

[0204] Example 1: Device Design

The device contains a nozzle (1), a flow valve (2), a clamp (3) and a pump (4), as shown in Fig. 1. The device may additionally contain a cap to protect the nozzle. The nozzle and the retainer are tightly coupled; both the clamp and the pump are also tightly coupled, as shown in Fig. 2. The passage valve, raised by the clamp, is always in contact with the nozzle, so there is no clearance between the nozzle and the passage valve. This reduces the potential risk of pre-loaded powder entering the pump. The retainer includes a trough for catching powder falling from the nozzle, as shown in FIG. 3. This reduces the potential risk of powder entering the pump from the nozzle. Fig. 4 shows a main air flow for delivering powder and a side air flow for delivering captured powder through a nozzle. If necessary, the pump can be operated up to 3 times to deliver the powder. Air inlets in the retainer prevent powder remaining in the nozzle from entering the pump when the pump returns to its original shape. Fig. 5 represents the dimensions of the parts. The diameter of the pump thread "a" is 10.1-10.7 mm and can be adjusted up or down by 0.4 mm to minimize the risk of insufficient sealing between the retainer and the pump and between the nozzle and the retainer.

[0205] Design features of parts

The nozzle has no undercut design and can be conveniently manufactured using a multi-cavity mold. The pump does not contain an air inlet, which eliminates the piercing process from making the pump. To hold the through valve, a clamp is added to the nozzle, which performs the air inlet function. These features very effectively ensure high manufacturability, facilitating mass production. Additionally, the pass-through valve is secured with a retainer and nozzle to further improve the delivery efficiency of the device. In addition, the size of the nozzle outlet is adapted to suit powder preparations with large particles.

[0206] Material and color of parts

Nozzle: Cycloolefin copolymer, blue color,

Globe valve: Cycloolefin copolymer, transparent

Fixative: Cycloolefin copolymer, transparent,

Pump: Low density polyethylene, white,

Cap: Polypropylene, transparent,

[0207] Example 2: Device Test to Determine Delivery Efficiency

According to the assembly procedure shown in FIG. 6, 60 assembled devices filled with 15 mg (±0.8 mg) placebo (containing tribasic calcium phosphate and two types of microcrystalline cellulose) were prepared and packaged in aluminum bags (1 device/aluminum bag). Thirty bagged devices were tested for delivery in normal condition (no weathering or transportation). The remaining 30 devices were bagged and packed in 5 cartons (6 devices/carton) per case. The top of the device nozzle was oriented towards the top of the box. The box was weathered and transported before being tested for delivery.

[0208] Exposure to climatic exposure and transportation was carried out as follows. To withstand the test samples under extreme environmental conditions, in accordance with the ASTM Standard Practice for the Preparation of Containers, Containers, or Container Components for Testing (ASTM D4332-01), the test samples were stored at -30°C for 24 hours (extreme cold conditions) , at 40°C/90%RH (relative humidity) for 24 hours (tropical conditions) and at 60°C/15%RH for 24 hours (desert conditions), in the order listed. After exposure to climatic conditions to expose the test samples to extreme shipping/sales conditions, the test samples were subjected to impacts in accordance with the ASTM Standard Practice for Performance Testing of Shipping Containers and Systems (ASTM D4169-14) and related ASTM standards. in the sequence and order listed, initial shock during manual handling (ASTM D5276-98), vibration shock on a loose load (ASTM D999-08), vibration shock in a vehicle, both road and air transport (D4728-06), and final impact during manual handling (ASTM D5276-98). The sequence is described in ASTM D4169-14 Sales Cycle 2. In addition, all safety levels for these impacts are set to safety level II, which is most often used for medical devices.

[0209] For the delivery test, after removing the aluminum bag and cap, the device was weighed and then actuated 3 times by an automatic actuator (Vereo DSx, Proveris Scientific Corp.), using parameters based on actual human actuation patterns. The weight of the device after actuation was measured, and the delivered weight was calculated from the following equation:

[0210] Weight delivery results in normal condition and after exposure to climatic exposure and transportation are shown in FIG. 7. Results show no noticeable difference between the delivered scales in normal condition (mean ± standard deviation (SD): 98.0 ± 0.9%, minimum: 96.5%, maximum: 99.4%) and the delivered scales soaked under climatic influence and transportation conditions (mean ± SD: 98.2 ± 1.6%, minimum: 93.8%, maximum: 100.1%).

[0211] Example 3: Device Application

After removing the device from the packaging, the subject manipulates the device by removing the protective cap, tearing off the end tab of the nozzle, placing the nozzle at least partially inside the subject's nostril, and manually operating the pump 1, 2, or 3 times to eject the powdered drug product, which is pre-filled in the nozzle.

[0212] Example 4 Treatment

The device disclosed herein is used for delivering a powdered drug formulation that contains an effective amount of an active ingredient for the treatment or prevention of a disease to a subject in need thereof. The disease or condition may be pain, hormonal disorder, headache, amyotrophic lateral sclerosis, Parkinson's disease, stress, nervousness, nausea, vomiting, aggression, pain, neuropathic pain, insomnia, asomnia, restless leg syndrome, depression, or any combination thereof. The powdered drug can be administered 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times or 8 times a day. The powdered medicinal product may be in the form of one unit dose. The powdered medicament may be in a unit dose of about 5 mg to about 50 mg, such as about 15, 20, 25, or 30 mg. A unit dose of the powder medicinal product may contain from about 0.1 mg to about 25 mg of active ingredient, for example, about 2, 4, 6, or 8 mg.

[0213] Certain cases and variations have been presented and described above in this application, however, it will be apparent to those skilled in the art that such disclosure is provided by way of example only. Numerous modifications, changes and substitutions will be developed by those skilled in the art without deviating from the devices, methods and formulations described herein. It should be understood that, in the practice of the devices, methods and formulations described herein, various alternatives to the embodiments described herein can be used. It is intended that the following claims define the scope of protection of methods, preparations and devices, and that methods, preparations and devices within the scope of the present claims and their equivalents will be covered thereby.

Claims (61)

1. A device for intranasal delivery, containing: a nozzle having a reservoir located inside the nozzle, a passage valve at least partially inserted into the reservoir, a retainer that is hollow and configured to hold the passage valve, and a manual air pump having an operating connection with the inlet end of the nozzle and the outlet end of the clamp, wherein the through valve has at least one contact area with the latch, the straight-through valve is stationary when the hand pump is activated, the reservoir contains a powdered medicinal product disposed therein, and said retainer includes a groove configured to catch powdered medicinal product falling from the nozzle. 2. The device according to claim 1, in which each of the at least one contact zones is an internal rib. 3. The device according to claim 1 or 2, in which the latch has an internal circumferential groove extending from the input end of the latch. 4. The device of claim 3, wherein the collar of the circumferential groove of the retainer is in contact with at least one contact area of the globe valve. 5. The device according to any of the previous paragraphs, in which the latch is configured to fix the globe valve. 6. The apparatus of any one of the preceding claims, wherein when the apparatus is actuated, a portion of the air from the pump flows into the retainer along the circumferential groove and moves along the surface of the groove of the globe valve to form a vortex flow into the reservoir. 7. The apparatus of any one of the preceding claims, wherein after the apparatus is actuated, at least one air inlet of the retainer allows outside air to enter the pump. 8. The device of any one of the preceding claims, configured to deliver at least 85% of the powdered drug into the nostril of a subject after at least one actuation of the hand-held air pump. 9. The device of any one of the preceding claims, configured to deliver at least 90% of the powdered drug into the nostril of a subject after at least one actuation of the hand-held air pump. 10. The device as claimed in any one of the preceding claims, wherein the powdered drug is present in an amount of 5 mg to 50 mg. 11. The device according to any of the preceding claims, wherein the powdered drug is present in an amount of 20 mg. 12. The device as claimed in any one of the preceding claims, wherein the nozzle further comprises a breakable tab located at the outlet end of the nozzle. 13. The device according to any of the preceding paragraphs, which is a disposable device. 14. The device as claimed in any one of the preceding claims, wherein the globe valve further comprises a conical top section. 15. The device of claim 14, wherein the conical top section is connected to the first shoulder, which is connected to the first cylindrical section. 16. The device of claim 15, wherein the first cylindrical section is connected to a second shoulder, which is connected to the second cylindrical section. 17. The device according to any of the preceding claims, wherein the globe valve has at least one surface groove. 18. The device according to claim 17, in which the globe valve has 3 surface grooves. 19. The device according to claim 17, in which the globe valve has 8 surface grooves. 20. The device according to any one of paragraphs. 17-19, in which at least one surface groove is configured to create a vortex flow in the reservoir when the device is activated. 21. The device according to any one of paragraphs. 17-20, in which at least one surface groove is provided on the second shoulder. 22. The device according to any of the previous paragraphs, in which the globe valve has 3 internal ribs. 23. An apparatus as claimed in any one of the preceding claims, wherein the globe valve is at least partially located within the container. 24. The apparatus of any one of the preceding claims, wherein the globe valve is at least partially located within the hand air pump. 25. The device according to any of the preceding claims, in which the passage valve contains a cavity. 26. A device according to any of the preceding paragraphs, having a volume of less than 100 cm ³ . 27. The device according to claim 26, having a volume of less than 50 cm ³ . 28. The device according to claim 26, having a volume of 30 cm ³ . 29. A device according to any of the preceding paragraphs, having a mass of less than 20 grams. 30. The device according to claim 29, having a mass of less than 10 grams. 31. The device according to any of the preceding claims, wherein the reservoir has an internal diameter of less than 10 mm. 32. The device according to any of the preceding claims, wherein the reservoir has an outer diameter of from 8.67 mm to 8.87 mm. 33. The device according to any of the preceding claims, wherein the inlet end of the reservoir has a smooth surface configured to contact the passage valve. 34. The device according to any of the preceding claims, wherein the globe valve has an outer diameter of from 7.73 mm to 7.93 mm. 35. A device as claimed in any one of the preceding claims, wherein the opening of the hand air pump is wider than the outer diameter of the globe valve. 36. The device of any one of the preceding claims, wherein the retainer includes an outer circumferential collar that is wider than the opening of the hand air pump. 37. The device according to any of the preceding paragraphs, in which the latch has two air inlets. 38. The device according to any one of the preceding claims, in which at least one air inlet hole has a width of from 0.2 mm to 0.4 mm. 39. The device as claimed in any one of the preceding claims, wherein the retainer is at least partially inserted into the hand air pump. 40. A device as claimed in any one of the preceding claims, wherein the nozzle of the device comprises a transparent material, a colored material, or a light-transmitting material. 41. Method of using the device according to any one of paragraphs. 1-40 for delivering a powdered medicament to a subject in need thereof, the method comprising placing a nozzle of the device at least partially into the subject's nostril and actuating a hand-held air pump, the nozzle containing the powdered medicament. 42. The method of claim 41, wherein a disease or illness of a subject is treated. 43. The method of claim 41, wherein a disease of the subject is treated. 44. The method according to claim 43, according to which the disease is migraine. 45. Method according to any one of paragraphs. 41-44, in which the powder medicinal product contains the active substance. 46. The method according to claim 45, in which the active substance is dihydroergotamine. 47. The method according to claim 45, in which the active substance is a pharmaceutically acceptable salt of dihydroergotamine. 48. Method according to any one of paragraphs. 41-47, according to which they additionally visually monitor the amount of powdered drug remaining in the reservoir and repeat the method according to claim 41 until a sufficient dose is delivered. 49. A method for manufacturing a device according to any one of paragraphs. 1-40, including the steps in which: insert the through valve into the nozzle, insert the clamp into the hand air pump, and attach a hand air pump to the nozzle. 50. The method of claim 49, further comprising the step of filling the reservoir with the powdered medicinal product.

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