Delivery of gases to the nasal airway

Abstract

A delivery device for and a method of delivering gases to the nasal airway, in particular therapeutic gases and gases in combination with active substances, either as powders or liquids, for enhanced uptake of the active substances.

Claims

1. A pharmaceutical delivery device for delivering a substance and a gas to a nasal airway of a subject, comprising: a nosepiece configured to fit to one nostril of the subject in use; a mouthpiece fluidly connected to the nosepiece and configured to fit to an oral cavity of the subject in use, through which the subject in use exhales creating a flow of exhalation breath; a substance supply unit fluidly connected to the nosepiece and configured to provide the substance into the flow of exhalation breath for delivery to the nasal airway of the subject; and a gas generation unit fluidly connected to the nosepiece and configured to provide the gas into the flow of exhalation breath for delivery to the nasal airway of the subject, wherein the gas generation unit includes an air-permeable container, containing a powder.

2. The delivery device of claim 1, wherein the powder, when exposed to the flow of exhalation breath, reacts to generate the gas.

3. The delivery device of claim 2, wherein the powder is configured to react to moisture in the flow of exhalation breath.

4. The delivery device of claim 2, wherein the powder includes a mixture of a carbonate or a bicarbonate salt and an acid.

5. The delivery device of claim 4, wherein the powder includes a mixture of sodium bicarbonate and an acid.

6. The delivery device of claim 4, wherein the acid is citric acid.

7. The delivery device of claim 4, wherein the powder includes a mixture of sodium bicarbonate and citric acid.

8. The delivery device of claim 2, wherein the gas is carbon dioxide.

9. The delivery device of claim 1, wherein the gas is carbon dioxide.

10. The delivery device of claim 1, wherein the container is replaceable.

11. The delivery device of claim 1, wherein the container is a sachet.

12. The delivery device of claim 1, wherein exhalation by the subject causes closure of an oropharyngeal velum of the subject.

13. The delivery device of claim 12, wherein closure of the oropharyngeal velum prevents inhalation of the gas by the subject.

14. The delivery device of claim 1, wherein the substance supply unit is configured to deliver an aerosol spray.

15. The delivery device of claim 1, wherein the substance is a powder.

16. The delivery device of claim 1, wherein the substance is a liquid.

17. A pharmaceutical delivery device for delivering a substance to a nasal airway of a subject, comprising: a nosepiece configured to fit to one nostril of the subject in use; a mouthpiece fluidly connected to the nosepiece and configured to fit to an oral cavity of the subject in use, through which the subject in use exhales creating a flow of exhalation breath; a substance supply unit fluidly connected to the nosepiece and configured to provide the substance into the flow of exhalation breath for delivery to the nasal airway of the subject; and a gas generation unit fluidly connected to the nosepiece and configured to generate carbon dioxide gas and provide the carbon dioxide gas into the flow of exhalation breath for delivery to the nasal airway of the subject, the gas generation unit including an air-permeable container, which contains a powder configured to react with, to the flow of exhalation breath to generate the carbon dioxide gas.

18. The delivery device of claim 17, wherein the substance is a powder.

19. The delivery device of claim 17, wherein the substance is a liquid.

20. The delivery device of claim 17, wherein the powder is configured to react to moisture in the flow of exhalation breath.

21. The delivery device of claim 17, wherein the powder includes a mixture of sodium bicarbonate and citric acid.

22. A pharmaceutical delivery device for delivering a substance and a gas to a nasal airway of a subject, comprising: a nosepiece configured to fit to one nostril of the subject in use; a mouthpiece fluidly connected to the nosepiece and configured to fit to an oral cavity of the subject in use, through which the subject in use exhales creating a flow of exhalation breath; a substance supply unit fluidly connected to the nosepiece and configured to provide the substance into the flow of exhalation breath for delivery to the nasal airway of the subject; and a gas generation unit fluidly connected to the nosepiece and configured to provide the gas into the flow of exhalation breath for delivery to the nasal airway of the subject, wherein the gas generation unit includes an air-permeable container.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Preferred embodiments of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which:

(2) FIG. 1 illustrates a delivery device in accordance with a first embodiment of the present invention;

(3) FIG. 2 illustrates a delivery device in accordance with a second embodiment of the present invention;

(4) FIG. 3 illustrates a delivery device in accordance with a third embodiment of the present invention;

(5) FIG. 4 illustrates a delivery device in accordance with a fourth embodiment of the present invention;

(6) FIG. 5 illustrates a delivery device in accordance with a fifth embodiment of the present invention;

(7) FIG. 6 illustrates a delivery device in accordance with a sixth embodiment of the present invention;

(8) FIG. 7 illustrates a delivery device in accordance with a seventh embodiment of the present invention;

(9) FIG. 8 illustrates a delivery device in accordance with an eighth embodiment of the present invention; and

(10) FIG. 9 illustrates a delivery device in accordance with a ninth embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(11) FIG. 1 illustrates a delivery device in accordance with a first embodiment of the present invention.

(12) The delivery device comprises a nosepiece 21 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 23 through which the subject exhales, and a flow channel 25 fluidly connecting the nosepiece 21 and the mouthpiece 23.

(13) The delivery device further comprises a scrubber 27 which is disposed in the flow channel 25 such as to remove one or more gases, in this embodiment one or both of oxygen and nitrogen, from the exhaled air and provide a gas flow which has an increased concentration of at least one gas, in this embodiment a concentration of carbon dioxide, which is increased to a concentration which provides a therapeutic effect.

(14) Alveolar air typically has a composition of N2—74.9 vol %, O2—13.6 vol % and CO2—5.3 vol %, which has a significantly increased concentration of carbon dioxide as compared to atmospheric air, which typically has the composition of N2—78.62 vol % O2—20.84 vol % and CO2—0.04 vol %. Through use of the scrubber 27 to remove nitrogen and oxygen from the exhaled air, the concentration of carbon dioxide in the delivered gas flow can be increased significantly.

(15) In one embodiment the scrubber 27 provides for a gas flow which has a concentration of therapeutic gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(16) In one embodiment the scrubber 27 could be configured to provide a visual indication, such as by way of changing colour, to indicate when the efficiency of the scrubber 27 has reduced below a predetermined threshold.

(17) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, thereby providing for the delivery of at least one therapeutic gas to the nasal airway and preventing inhalation of the at least one therapeutic gas.

(18) FIG. 2 illustrates a delivery device in accordance with a second embodiment of the present invention.

(19) The delivery device comprises a nosepiece 121 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 123 through which the subject exhales, and a flow channel 125 fluidly connecting the nosepiece 121 and the mouthpiece 123.

(20) The delivery device further comprises a scrubber 127 which is disposed in the flow channel 125 such as to remove one or more gases, in this embodiment one or both of oxygen and nitrogen, from the exhaled air and provide a gas flow which has an increased concentration of at least one gas, in this embodiment a concentration of carbon dioxide, which provides for enhanced uptake of a substance as delivered to the nasal airway, as will be described in more detail hereinbelow.

(21) Alveolar air typically has a composition of N2—74.9 vol %, O2—13.6 vol % and CO2—5.3 vol %, which has a significantly increased concentration of carbon dioxide as compared to atmospheric air, which typically has the composition of N2—78.62 vol % O2—20.84 vol % and CO2—0.04 vol %. Through use of the scrubber 127 to remove nitrogen and oxygen from the exhaled air, the concentration of carbon dioxide in the delivered gas flow can be increased significantly.

(22) In one embodiment the scrubber 127 provides for a gas flow which has a concentration of the uptake enhancing gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(23) The delivery device further comprises a substance supply unit 129 for supplying metered doses of an active substance for delivery to the nasal airway of the subject.

(24) In one embodiment the substance supply unit 129 is configured to deliver an aerosol spray, either as a liquid or a powder aerosol spray, but in an alternative embodiment could be configured to deliver a jet, that is, as a column of the substance, either as a liquid or powder jet.

(25) In this embodiment the substance supply unit 129 comprises a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of substance, on actuation thereof.

(26) In another alternative embodiment the substance supply unit 129 could comprise a dry powder delivery unit which delivers metered doses of substance, as a dry powder, on actuation thereof. In one embodiment the substance supply unit 129 could provide for delivery of substance from a container, such as a capsule or blister.

(27) In yet another alternative embodiment the substance supply unit 129 could comprise an aerosol canister which delivers metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing substance, either as a suspension or solution.

(28) In this embodiment the substance supply unit 129 is a multi-dose unit for delivering a plurality of metered doses of the active substance. In another embodiment the substance supply unit 129 could be a single-dose unit for delivering a single metered dose of the active substance.

(29) The substance supply unit 129 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism which, when triggered, releases the resilient element and actuates the substance supply unit 129 to deliver a metered dose of the active substance.

(30) In this embodiment the trigger mechanism is configured to cause actuation of the substance supply unit 129 on generation of a predetermined flow rate through the flow channel 125.

(31) In an alternative embodiment the trigger mechanism could be configured to cause actuation of the substance supply unit 129 on generation of a predetermined pressure in the flow channel 125.

(32) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and a metered dose of an active substance is delivered into the nasal airway on generation of a predetermined flow rate through the nasal airway, or in an alternative embodiment a predetermined pressure in the nasal airway.

(33) The gas flow as delivered through the nasal airway includes at least one uptake enhancing gas, in this embodiment carbon dioxide, which provides for enhanced uptake of the active substance, and inhalation of this gas is prevented by closure of the velum.

(34) FIG. 3 illustrates a delivery device in accordance with a third embodiment of the present invention.

(35) The delivery device comprises a nosepiece 221 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 223 through which the subject exhales, and a flow channel 225 fluidly connecting the nosepiece 221 and the mouthpiece 223.

(36) The delivery device further comprises a gas generation unit 227 which is disposed in the flow channel 225 and provides for the generation of a therapeutic gas, in this embodiment carbon dioxide, which is entrained by the gas flow, as developed by the exhalation breath, into the nasal airway, and thereby provides a therapeutic effect on delivery into the nasal airway.

(37) In this embodiment the gas generation unit 227 contains a powdered agent, here a mixture of a carbonate or bicarbonate salt, such as sodium bicarbonate, and an acid, such as citric acid, which, when exposed to moisture as contained in the exhaled breath, reacts to generate the therapeutic gas, here carbon dioxide. In addition to generating a therapeutic gas, the gas generation unit 227 has the particular benefit of acting as a moisture trap.

(38) In this embodiment the powdered agent is contained in an air permeable member, typically a sachet, which can be replaced after one or more uses of the delivery device.

(39) In this embodiment the gas generation unit 227 is disposed at an upstream end of the flow channel 225, such that substantially no condensation of moisture from the exhalation breath occurs prior to the exhalation breath being exposed to the gas generation unit 227.

(40) In one embodiment the gas generation unit 227 provides a gas flow which has a concentration of the therapeutic gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(41) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, thereby providing for the delivery of at least one therapeutic gas to the nasal airway and preventing inhalation of the at least one therapeutic gas.

(42) FIG. 4 illustrates a delivery device in accordance with a fourth embodiment of the present invention.

(43) The delivery device comprises a nosepiece 321 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 323 through which the subject exhales, and a flow channel 325 fluidly connecting the nosepiece 321 and the mouthpiece 323.

(44) The delivery device further comprises a gas generation unit 327 which is disposed in the flow channel 325 and provides for the generation of an uptake enhancing gas, in this embodiment carbon dioxide, which is entrained by the gas flow, as developed by the exhalation breath, into the nasal airway, and acts to enhance the uptake of an active substance as delivered to the nasal airway, as will be described in more detail hereinbelow.

(45) In this embodiment the gas generation unit 327 contains a powdered agent, here a mixture of a carbonate or bicarbonate salt, such as sodium bicarbonate, and an acid, such as citric acid, which, when exposed to moisture as contained in the exhaled breath, reacts to generate the uptake enhancing gas, here carbon dioxide. In addition to generating an uptake enhancing gas, the gas generation unit 327 has the particular benefit of acting as a moisture trap, which reduces undesirable condensation within the remainder of the delivery device. Such condensation is particularly problematic in the delivery of powdered substances.

(46) In this embodiment the powdered agent is contained in an air permeable member, typically a sachet, which can be replaced after one or more uses of the delivery device.

(47) In this embodiment the gas generation unit 327 is disposed at an upstream end of the flow channel 325, such that substantially no condensation of moisture from the exhalation breath occurs prior to the exhalation breath being exposed to the gas generation unit 327.

(48) In one embodiment the gas generation unit 327 provides a gas flow which has a concentration of the uptake enhancing gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(49) The delivery device further comprises a substance supply unit 329 for supplying metered doses of an active substance for delivery to the nasal airway of the subject.

(50) In one embodiment the substance supply unit 329 is configured to deliver an aerosol, either as a liquid or a powder aerosol, but in an alternative embodiment could be configured to deliver a jet, that is, as a column of the substance, either as a liquid or powder jet.

(51) In this embodiment the substance supply unit 329 comprises a dry powder delivery unit which delivers metered doses of substance, as a dry powder, on actuation thereof. In one embodiment the substance supply unit 329 could provide for delivery of substance from a container, such as a capsule or blister.

(52) In one alternative embodiment the substance supply unit 329 could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of substance, on actuation thereof.

(53) In yet another alternative embodiment the substance supply unit 329 could comprise an aerosol canister which delivers metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing substance, either as a suspension or solution.

(54) In this embodiment the substance supply unit 329 is a multi-dose unit for delivering a plurality of metered doses of the active substance. In another embodiment the substance supply unit 329 could be a single-dose unit for delivering a single metered dose of the active substance.

(55) The substance supply unit 329 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism which, when triggered, releases the resilient element and actuates the substance supply unit 329 to deliver a metered dose of the active substance.

(56) In this embodiment the trigger mechanism is configured to cause actuation of the substance supply unit 329 on generation of a predetermined flow rate through the flow channel 325.

(57) In an alternative embodiment the trigger mechanism could be configured to cause actuation of the substance supply unit 329 on generation of a predetermined pressure in the flow channel 325.

(58) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and a metered dose of an active substance is delivered into the nasal airway on generation of a predetermined flow rate through the nasal airway, or in an alternative embodiment a predetermined pressure in the nasal airway. The gas flow as delivered through the nasal airway includes at least one uptake enhancing gas, in this carbon dioxide, which provides for enhanced uptake of the active substance, and inhalation of this gas is prevented by closure of the velum.

(59) FIG. 5 illustrates a delivery device in accordance with a fifth embodiment of the present invention.

(60) The delivery device comprises a nosepiece 421 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 423 through which the subject exhales, and a flow channel 425 fluidly connecting the nosepiece 421 and the mouthpiece 423.

(61) The delivery device further comprises a delivery unit 429 for delivering metered doses of an active substance and an uptake enhancing agent for delivery to the nasal airway of the subject.

(62) In this embodiment the uptake enhancing agent comprises a powdered substance, here a mixture of a carbonate or bicarbonate salt, such as sodium bicarbonate, and an acid, such as citric acid, which, when exposed to moisture at surfaces of the nasal mucosa, reacts to generate an uptake enhancing gas, here carbon dioxide, which provides for enhanced uptake of the active substance.

(63) In one alternative embodiment the uptake enhancing agent could comprise an uptake enhancing gas, for example, carbon dioxide, which, when exposed to the nasal mucosa, provides for enhanced uptake of the active substance.

(64) In another alternative embodiment the uptake enhancing agent could comprise an uptake enhancing gas, for example, carbon dioxide, which is generated from a powdered substance, for example, a mixture of a carbonate or bicarbonate salt, such as sodium bicarbonate, and an acid, such as citric acid, which, when exposed to moisture in the exhaled breath of the subject, reacts to generate the uptake enhancing gas, which provides for enhanced uptake of the active substance.

(65) In this embodiment the delivery unit 429 is configured to deliver a powder aerosol, but in an alternative embodiment could be configured to deliver a powder jet, that is, as a powder column.

(66) In this embodiment the substance supply unit 429 comprises a dry powder delivery unit which delivers a metered dose of an active substance and an uptake enhancing agent on actuation thereof.

(67) In this embodiment the active substance and the uptake enhancing agent are dry powders, and the uptake enhancing agent reacts with moisture on the nasal mucosa to generate an uptake enhancing gas.

(68) In the one alternative embodiment the active substance is a dry powder and the uptake enhancing agent is an accompanying gas.

(69) In the other alternative embodiment the active substance is a dry powder and the uptake enhancing agent is a gas which is generated from the reaction of a powdered substance and moisture in the exhaled breath of the subject.

(70) In this embodiment the substance supply unit 429 provides for delivery of the active substance and the uptake enhancing agent, both as dry powders, from a container 431, such as a capsule or blister, where a gas flow as developed from the exhalation breath of the subject acts to entrain the powder from the container 431 following opening, typically rupturing, of the same.

(71) In the one alternative embodiment the substance supply unit 429 provides for delivery of the active substance, as a dry powder, and the uptake enhancing agent, as a gas, from a container 431, such as a capsule or blister, where the uptake enhancing agent is a gas which is released on opening, typically rupturing, the container 431, and a gas flow as developed from the exhalation breath of the subject acts to entrain the powdered active substance from the container 431 following opening of the same.

(72) In the other alternative embodiment the substance supply unit 429 provides for delivery of the active substance, as a dry powder, and the uptake enhancing agent, as a gas, from a container 431, such as a capsule or blister, where the uptake enhancing gas is generated from a powdered substance contained within the container 431 on exposure to moisture in the exhaled breath of the subject following opening, typically rupturing, of the container 431, and a gas flow as developed from the exhalation breath of the subject acts to entrain the active substance from the container 431 following opening of the same.

(73) In the described embodiments the delivery unit 429 could be a multi-dose unit for delivering a plurality of metered doses of the active substance and uptake enhancing agent, or a single-dose unit for delivering a single metered dose of the active substance and uptake enhancing agent.

(74) In the configuration of this embodiment, a gas flow as developed from the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and a metered dose of an active substance and an uptake enhancing agent in combination is delivered into the nasal airway. In this embodiment the uptake enhancing agent reacts with moisture on contact with surfaces in the nasal cavity such as to generate an uptake enhancing gas thereat, here carbon dioxide, which provides for enhanced uptake of the active substance, and inhalation of this gas is prevented by closure of the velum.

(75) In the configuration of the one alternative embodiment, a gas flow as developed from the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and a metered dose of an active substance and an uptake enhancing agent, as a gas, is delivered into the nasal airway. In this embodiment the uptake enhancing gas, here carbon dioxide, provides for enhanced uptake of the active substance, and inhalation of this gas is prevented by closure of the velum.

(76) In the configuration of the other alternative embodiment, a gas flow as developed from the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and a metered dose of an active substance and an uptake enhancing agent, as a gas, for example, carbon dioxide, is delivered into the nasal airway. In this embodiment the uptake enhancing gas is generated by the reaction of a powdered substance, as contained within the container 431, with moisture from the exhalation breath of the subject, which provides for enhanced uptake of the active substance, and inhalation of this gas is prevented by closure of the velum.

(77) FIG. 6 illustrates a delivery device in accordance with a sixth embodiment of the present invention.

(78) The delivery device comprises a nosepiece 521 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 523 through which the subject exhales, and a flow channel 525 fluidly connecting the nosepiece 521 and the mouthpiece 523.

(79) The delivery device further comprises a gas supply unit 527 which is disposed in the flow channel 525 such as to deliver at least one therapeutic gas, in this embodiment carbon dioxide, to the gas flow as developed by the exhalation breath at such a concentration as to provide for a therapeutic effect.

(80) In one embodiment the gas supply unit 527 provides for a gas flow which has a concentration of therapeutic gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(81) In this embodiment the gas supply unit 527 includes a gas supply 535 and a breath-actuated release mechanism 537 which, when triggered, actuates the gas supply 535 to supply a therapeutic gas to the gas flow as developed through the flow channel 525. In one embodiment the gas supply 535 comprises a pressurized container which is vented to the flow channel 525 on triggering of the breath-actuated release mechanism 537.

(82) In this embodiment the release mechanism 537 is configured to cause actuation of the gas supply unit 527 on generation of a predetermined flow rate through the flow channel 525.

(83) In an alternative embodiment the release mechanism 537 could be configured to cause actuation of the gas supply unit 527 on generation of a predetermined pressure in the flow channel 525.

(84) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and at least one therapeutic gas is delivered to the gas flow. The at least one therapeutic gas is thus entrained into the nasal airway and inhalation of the at least one therapeutic gas is prevented by closure of the velum.

(85) FIG. 7 illustrates a delivery device in accordance with a seventh embodiment of the present invention.

(86) The delivery device comprises a nosepiece 621 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 623 through which the subject exhales, and a flow channel 625 fluidly connecting the nosepiece 621 and the mouthpiece 623.

(87) The delivery device further comprises a gas supply unit 627 which is disposed in the flow channel 625 such as to deliver at least one uptake enhancing gas, in this embodiment carbon dioxide, to the gas flow as developed by the exhalation breath of the subject at such a concentration as to provide for enhanced uptake of an active substance as delivered to the nasal airway, as will be described in more detail hereinbelow.

(88) In one embodiment the gas supply unit 627 provides for a gas flow which has a concentration of an uptake enhancing gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(89) In this embodiment the gas supply unit 627 includes a gas supply 635 and a breath-actuated release mechanism 637 which, when triggered, actuates the gas supply 635 to supply an uptake enhancing gas to the gas flow as developed through the flow channel 625. In one embodiment the gas supply 635 comprises a pressurized container which is vented to the flow channel 625 on triggering of the breath-actuated release mechanism 637.

(90) In this embodiment the release mechanism 637 is configured to cause actuation of the gas supply unit 627 on generation of a predetermined flow rate through the flow channel 625.

(91) In an alternative embodiment the release mechanism 637 could be configured to cause actuation of the gas supply unit 627 on generation of a predetermined pressure in the flow channel 625.

(92) The delivery device further comprises a substance supply unit 639 for supplying metered doses of an active substance for delivery to the nasal airway of the subject.

(93) In one embodiment the substance supply unit 639 is configured to deliver an aerosol, either as a liquid or a powder aerosol, but in an alternative embodiment could be configured to deliver a jet, that is, as a column of the substance, either as a liquid or powder jet.

(94) In this embodiment the substance supply unit 639 comprises a dry powder delivery unit which delivers metered doses of substance, as a dry powder, on actuation thereof. In one embodiment the substance supply unit 639 could provide for delivery of substance from a container, such as a capsule or blister.

(95) In one alternative embodiment the substance supply unit 639 could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of substance, on actuation thereof.

(96) In yet another alternative embodiment the substance supply unit 639 could comprise an aerosol canister which delivers metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing substance, either as a suspension or solution.

(97) In this embodiment the substance supply unit 639 is a multi-dose unit for delivering a plurality of metered doses of the active substance. In another embodiment the substance supply unit 639 could be a single-dose unit for delivering a single metered dose of the active substance.

(98) The substance supply unit 639 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism which, when triggered, releases the resilient element and actuates the substance supply unit 639 to deliver a metered dose of the active substance.

(99) In this embodiment the trigger mechanism is configured to cause actuation of the substance supply unit 639 on generation of a predetermined flow rate through the flow channel 625.

(100) In an alternative embodiment the trigger mechanism could be configured to cause actuation of the substance supply unit 639 on generation of a predetermined pressure in the flow channel 625.

(101) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation, and, on generation of a predetermined flow rate through the nasal airway, or in an alternative embodiment a predetermined pressure in the nasal airway, at least one uptake enhancing gas is delivered to the gas flow and a metered dose of an active substance is delivered into the nasal airway. The at least one uptake enhancing gas, in this embodiment carbon dioxide, provides for enhanced uptake of the active substance, and inhalation of this gas is prevented by closure of the velum.

(102) FIG. 8 illustrates a delivery device in accordance with an eighth embodiment of the present invention.

(103) The delivery device comprises a nosepiece 721 for fitting in one nostril of a subject, in this embodiment to provide a fluid-tight seal therewith, and a mouthpiece 723 through which the subject exhales.

(104) The delivery device further comprises a gas supply unit 727 which is fluidly connected to the nosepiece 721 such as to deliver at least one therapeutic gas, in this embodiment carbon dioxide, to the nasal airway at such a concentration as to provide for a therapeutic effect, as will be described in more detail hereinbelow.

(105) In one embodiment the gas supply unit 727 provides for a gas flow which has a concentration of a therapeutic gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(106) In this embodiment the gas supply unit 727 includes a gas supply 735 and a release mechanism 737 which, when triggered, actuates the gas supply 735 to deliver a therapeutic gas to the nosepiece 721 and into the nasal airway of the subject. In one embodiment the gas supply 735 comprises a pressurized container which is vented to the nosepiece 721 on triggering of the release mechanism 737.

(107) The delivery device further comprises an exhalation sensor 741 which is fluidly connected to the mouthpiece 723 such as to detect exhalation through the mouthpiece 723 by the subject and operatively connected to the release mechanism 737 of the gas supply unit 727, such as to provide for triggering of the gas supply unit 727 in response to exhalation by the subject.

(108) In this embodiment the exhalation sensor 741 is a flow sensor which is configured to cause actuation of the gas supply unit 727 on generation of a predetermined flow rate through the mouthpiece 723.

(109) In an alternative embodiment the exhalation sensor 741 could be a pressure sensor which is configured to cause actuation of the gas supply unit 727 on generation of a predetermined pressure at the mouthpiece 723.

(110) With this configuration, a gas flow containing at least one therapeutic gas is delivered through the nasal airway of the subject in response to exhalation by the subject whilst the oropharyngeal velum of the subject is closed, with the velum being closed by the positive pressure as created in the oral cavity on exhalation. In this way, at least one therapeutic gas is delivered to the nasal airway, and inhalation of the at least one therapeutic gas is prevented by closure of the velum.

(111) FIG. 9 illustrates a delivery device in accordance with a ninth embodiment of the present invention.

(112) The delivery device comprises first and second nosepieces 821, 822 for fitting in the respective nostrils of a subject, in this embodiment to provide a fluid-tight seal therewith, a mouthpiece 823 through which the subject exhales, and a flow channel 825 which fluidly connects one nosepiece 821 and the mouthpiece 823.

(113) The delivery device further comprises a scrubber 827 which is disposed in the flow channel 825 such as to remove one or more gases, in this embodiment one or both of oxygen and nitrogen, from the exhaled air and provide a gas flow which has an increased concentration of at least one gas, in this embodiment a concentration of carbon dioxide, which is increased to a concentration which provides a therapeutic effect.

(114) Alveolar air typically has a composition of N2—74.9 vol %, O2—13.6 vol % and CO2—5.3 vol %, which has a significantly increased concentration of carbon dioxide as compared to atmospheric air, which typically has the composition of N2—78.62 vol % O2—20.84 vol % and CO2—0.04 vol %. Through use of the scrubber 827 to remove nitrogen and oxygen from the exhaled air, the concentration of carbon dioxide in the delivered gas flow can be increased significantly.

(115) In one embodiment the scrubber 827 provides for a gas flow which has a concentration of therapeutic gas of at least 10 vol %, preferably at least 15 vol %, more preferably at least 20 vol %, still more preferably at least 30 vol %, yet more preferably at least 40 vol %, and yet still more preferably at least 50 vol %.

(116) In one embodiment the scrubber 827 could be configured to provide a visual indication, such as by way of changing colour, to indicate when the efficiency of the scrubber 827 has reduced below a predetermined threshold.

(117) The delivery device further comprises a pressure regulator 845 which is fluidly connected to the other nosepiece 822 such as provide for a predetermined pressure regime in the nasal airway. In one embodiment providing an increased pressure in the nasal airway acts to open ostia in the treatment of nasal conditions, such as sinus ostia in the treatment of sinusitis.

(118) In this embodiment the pressure regulator 845 comprises a progressive flow resistor which provides a progressively increasing resistance to the exhaled air from the exhalation breath of a subject. In one embodiment the progressive flow resistor comprises an inflatable balloon which is manipulatable by the user to allow for control the pressure within the nasal cavity.

(119) In another embodiment the pressure regulator 845 could be configured to provide a predetermined flow resistance to the exhaled air flow.

(120) In a further embodiment the pressure regulator 845 could be configured to maintain a predetermined pressure regime in the nasal airway.

(121) In one embodiment the pressure regulator 845 could be configured to maintain a fixed pressure in the nasal airway, where as one of either of a negative or positive pressure, in one embodiment through the use of an auxiliary pump.

(122) In an alternative embodiment the pressure regulator 845 could be configured to generate an alternating pressure within the nasal airway of a subject. By cycling the pressure within the nasal airway, improved delivery of therapeutic gas to the paranasal sinuses, the tuba auditiva and the middle ears can be achieved.

(123) In a further embodiment the delivery device could include a vibration generator for generating vibrations in structures of the nasal airway of the subject, such as by the provision of sound waves of a predeterminable frequency, which act to improve communication through the ostia, in particular in ventilating the sinuses.

(124) With this configuration, a gas flow as developed by the exhalation breath of a subject is delivered through the nasal airway of the subject whilst the oropharyngeal velum of the subject is closed, thereby providing for the delivery of at least one therapeutic gas to the nasal airway and preventing inhalation of the at least one therapeutic gas.

(125) Finally, it will be understood that the present invention has been described in its preferred embodiments and can be modified in many different ways without departing from the scope of the invention as defined by the appended claims.

(126) For example, in one modification, the first to eighth embodiments could be modified in the manner of the ninth embodiment to include a second, outlet nosepiece and an associated pressure regulator.

(127) Also, embodiments have been described specifically in relation to the generation of carbon dioxide as either a therapeutic or uptake enhancing gas. In other embodiments, which utilize nitric oxide as either the therapeutic or uptake enhancing gas, the nitric oxide can be generated from a mixture of sodium nitroprusside and an acid, such as citric acid, which, when exposed to moisture, as, for example, contained in the exhaled breath, reacts to generate the therapeutic gas. Also, in such reactions, GRAS excipients can be utilized to control the rate of gas generation.

(128) Further, in one alternative embodiment, in order to alter the relative concentrations of carbon dioxide, nitrogen and oxygen in the exhaled breath of a subject, the exhaled breath could be passed through a liquid which is saturated with carbon dioxide, has substantially the same partial pressure of oxygen as the exhaled breath and a reduced partial pressure or absence of nitrogen, which results in the carbon dioxide equilibrating into the gas phase, the nitrogen equilibrating into the liquid and the oxygen concentration remaining substantially unchanged.