INHALATION DEVICE FOR GENERATING AEROSOL AND METHOD FOR GENERATING AEROSOL

Abstract

Method of generating an aerosol by means of an inhalation device for inhalation by a human or animal body, the method comprising providing liquid in the inhalation device, chemically generating gas bubbles in the liquid, bursting of the gas bubbles at the surface of the liquid, thereby generating an aerosol.

Claims

1. Method of generating aerosol in an inhalation device for inhalation by a human or animal body, the method comprising: providing liquid in the inhalation device, chemically generating gas bubbles in the liquid, bursting of said gas bubbles at the surface of the liquid, thereby generating an aerosol.

2. Method of claim 1, wherein the liquid comprises a first liquid having a first density and a second liquid having a second density which is lower than the first density, wherein the first and second liquids are (substantially) immiscible.

3. Method of claim 1, wherein the liquid and/or the bubble generating means comprises an active agent, which preferably comprises or consists of a salt or a salt solution.

4. Method of claim 3, wherein the bubble generating means further comprises a salt of carbonic acid and an organic acid.

5. Method of claim 4, wherein (i) the salt of carbonic acid is an alkali (hydrogen) carbonate and/or mixtures thereof such as sodium carbonate and potassium carbonate; sodium carbonate and/or potassium hydrogen carbonate; sodium hydrogen carbonate and/or potassium carbonate; sodium carbonate and/or sodium hydrogen carbonate; potassium carbonate and/or potassium hydrogen carbonate; and (ii) the organic acid is selected from citric acid, tartaric acid or malic acid and wherein the organic acid is preferably citric acid.

6. Method of claim 1, comprising heating of said liquid and/or said gas before generating the gas bubbles.

7. Method of claim 1, comprising chemical generating of gas bubbles by bringing the bubble generating means, preferably in the form of a powder, a pill, and/or compressed powder, in contact with liquid.

8. Method of claim 1, wherein the bubble generating means includes an effervescent tablet which optionally comprises an active agent.

9. Method of claim 1, wherein the active agent is an active agent for the local or systemic treatment of a respiratory disease.

10. Inhalation device, preferably a disposable or single-use inhalation device, for generating aerosol and for guiding aerosol to a human or animal body for inhalation, the inhalation device comprising: an inlet opening for intake of carrier gas, in particular ambient air, a housing configured to receive liquid and a bubble generating means for generating bubbles in the liquid, the bubble generating means being configured to chemically generate gas bubbles in the liquid, such that gas bubbles burst at the surface of the liquid, thereby generating an aerosol, and an outlet for guiding the aerosol to the human or animal body for inhalation.

11. The inhalation device of claim 10, the inhalation device comprising the bubble generating means, the housing accommodating the bubble generating means, and/or the inhalation device comprising the liquid.

12. The inhalation device of claim 10, wherein the bubble generating means includes a powder, a pill and/or a compressed powder, preferably an effervescent tablet, which optionally comprises an active agent.

13. The inhalation device of claim 12, wherein the bubble generating means further comprises a salt of carbonic acid and an organic acid.

14. The inhalation device of claim 13, wherein (i) the salt of carbonic acid is an alkali (hydrogen) carbonate and/or mixtures thereof such as sodium carbonate and potassium carbonate; sodium carbonate and/or potassium hydrogen carbonate; sodium hydrogen carbonate and/or potassium carbonate; sodium carbonate and/or sodium hydrogen carbonate; potassium carbonate and/or potassium hydrogen carbonate; and (ii) the organic acid is selected from citric acid, tartaric acid or malic acid and wherein the organic acid is preferably citric acid.

15. The inhalation device of claim 10, further comprising heating means to heat said liquid and/or said gas.

16. The inhalation device of claim 10, further comprising a guide for guiding carrier gas at least partially along the surface of the liquid.

17. The inhalation device of claim 16, the guide comprising a cap, the cap extending at least partially close to the surface of the liquid.

18. The inhalation device of claim 10, further comprising a terminal for connection with a gas source for introducing gas into the liquid.

19. The inhalation device of claim 10, further comprising an insulating member at least partially surrounding the housing.

20. The inhalation device of claim 10 for use in a method of treating a disease, which is preferably a respiratory disease.

21. The inhalation device for use of claim 20, wherein the respiratory disease is selected from the group consisting of (i) upper respiratory diseases such as nasopharyngitis (common cold), sinusitis, pharyngitis, pharyngitis, tonsillitis, laryngitis and tracheitis, laryngitis, tracheitis, laryngotracheitis, obstructive laryngitis and epiglottitis, obstructive laryngitism, epiglottitis, bronchitis, chronic tracheitis, chronic tracheobronchitis, emphysema, asthma, status asthmaticus, bronchiectasis, allergic rhinitis, hay fever, pollinosis, chronic rhinitis, nasopharyngitis, chronic pharyngitis, chronic sinusitis, nasal polyp; (ii) influenza; (iii) pneumonia; (iv) lower respiratory infections selected from bronchitis, bronchiolitis, tracheitis, tracheobronchitis, emphysema; and (iv) other chronic obstructive pulmonary disease such as asthma, status asthmaticus, bronchiectasis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0059] FIG. 1 shows a preferred embodiment of the present invention;

[0060] FIG. 2 shows another preferred embodiment of the present invention;

[0061] FIG. 3 schematically shows the physical background underlying the present invention.

[0062] FIG. 4 shows an aerosol spectrum.

[0063] FIG. 5 shows the release kinetics of aerosols formed in accordance with certain embodiments of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

[0064] In each of FIGS. 1 and 2, Figure (a) shows a view of separated parts of the inhalation device 1, Figure (b) shows the complete and assembled inhalation device 1, and Figure (c) shows a cross-section of the inhalation device 1 including arrows indicating the air flow upon breathing and sucking in.

[0065] FIG. 1 depicts the inhalation device 1 comprising an outlet 10 for guiding the air to the patient's mouth. The liquid 2, for example, may comprise medication. The housing 9 accomodates the liquid 2 and a bubble generating means 6. In this embodiment, the bubbles 3 are generated by means of a chemical reaction. Either the pellet 6 as bubble generating means is brought into the housing 9 comprising the liquid 2 or the liquid 2 is poured into the housing 9 in which the pellet 6 is provided.

[0066] Hence, the bubble generating means 6 of the first embodiment is configured to chemically generate the gas bubbles 3. The bubble generating means may, for example, be a pill or pellet 6. The pill or pellet 6 may, for example, comprise a salt of carbonic acid (such as sodium (hydrogen)carbonate, and/or potassium (hydrogen)carbonate), an acid and optionally an active agent. When coming into contact with the liquid 2, which may be preferably water or an aqueous solution, carbon dioxide is formed as inert gas which may be able to generate gas bubbles in the liquid 2.

[0067] Liquid 2 has been filled into the inhalation device 1, in particular in the housing 9, which forms a chamber or reservoir. By means of a chemical reaction between the bubble generating means 6 and the surrounding liquid 2, gas bubbles 3 are formed. The gas bubbles 3 (automatically) rise to the surface 4 of the liquid and are believed to form domes that partially project from the surface 4 of the liquid. This will be explained in detail in connection with FIG. 3.

[0068] The gas bubbles burst at the surface 4 of the liquid 2 and generate droplets 5, and, thereby, aerosol. An inlet opening 8, as indicated in FIG. 1(c), is provided, so that carrier gas (ambient air) can enter the inhalation device 1. When the patient sucks air upon breathing, ambient air is taken in through the inlet opening 8.

[0069] A cap 11 is formed as a guide for guiding the ambient air along the surface 4 of the liquid 2. To avoid that, due to gravity, a number of the droplets 5 fall back in the liquid 2, the stream of carrier gas (air stream) is used to collect the droplets 5 at the surface 4 of the liquid 2. The cap 11 extends at least partially close to the surface 4 of the liquid and, thus, guides the ambient air at least partially along the surface 4 of the liquid. In this embodiment, the cap 11 and the housing 9 partially overlap and form, in the overlap, the inlet opening 8. In this embodiment, the inlet opening 8 is formed in a circle, so that ambient air is guided from all angles onto the surface of the liquid 4 inside the housing 9.

[0070] As indicated in FIG. 1(c), ambient air enters the inhalation device 1 through the inlet opening 8 and enriches with droplets 5 generated by bursting of the bubbles 3 on the surface. Preferably, heating means (not shown) are provided.

[0071] In FIGS. 1(a) and 1(b), the insulating member 13 which partially surrounds the housing is shown. Such member 13 can in particular be used if the liquid 2 is heated or heat is generated during the chemical reaction.

[0072] In the embodiment of FIG. 2, the bubbles are generated on a mechanical basis. More specifically, the bubble generating means 7 comprises porous material, which is positioned below the liquid 2. The housing 9 accommodates the bubble generating means 7 and further comprises a terminal 12 for connection with a gas source for introducing gas into the bubble generating means 7. When gas advances through the porous material 7, which forms the bubble generating means, bubbles are generated in the liquid 2 and rise to the surface 4 of the liquid 2. At the surface 4, the bubbles 3 burst, whereby they generate aerosol including droplets 5 of the liquid 2.

[0073] Also in the embodiment of FIG. 2, an outlet 10 for guiding the aerosol to the patient's mouth is provided. An insulating member 13 may also be provided.

[0074] In FIG. 2 (c), the flow of ambient air into the inhalation device 1 is indicated by the arrows. Ambient air enters through the inlet opening 8 onto the surface 4 of the liquid, where it enriches with droplets 5.

[0075] In the embodiment of FIG. 2, a deflection plate 14 for filtering large droplets 5 out of the aerosol that is inhaled is provided.

[0076] FIG. 3 schematically shows the liquid 2 in which three different stages or stadia of bubbles 3 are shown. The lower bubble 3 on the left side rises in the liquid. The upper, left bubble 3 has reached the upper surface 4 and forms a dome-shaped bubble. It has a thin lamella or film 13 of the liquid. The dome-shaped lamella 13 projects from the liquid surface 4. The right bubble 3 is in the progress of bursting, as indicated by the droplets 5 discharged into the air. The liquid lamella 13 of the film surrounding the bubble 3 collapses and is released in the form of the small droplets 5.

[0077] When a bubble 3 bursts, film droplets and jet droplets can be formed. Without wishing to be bound to any theory, depending on the density of the liquid, film and jet droplets can be formed.

[0078] It was observed that jet droplet are in particular formed of a first liquid having a relatively high density (such as higher that the second density of a second liquid) and/or being provided below the second liquid. For jet droplets to be formed, liquid flows to the middle of the bubble and forms droplets. It was also observed that film droplets are in particular formed of a second liquid having a relatively low density (such as lower that the first density of a first liquid) and/or being provided above the first liquid. Film droplets are formed when the film ruptures. It is conceivable to filter off the larger jet droplets from the aerosol (by means known from the prior art), for example, if only smaller film droplets are desired for inhalation.

[0079] The diameter of the bubbles 3 is larger than 1 mm. Typically, the diameter of a droplet 5 (or the average diameter of the droplets) is between 1 m and 100 m, preferably in the range between 1 and 10 m, preferably between 1 and 5 m. According to experiments, the height h, as indicated in FIG. 3, up to which the droplets 5 are released or shoot out, is in the range of 1 or a few cm.

[0080] The diameter of the bubbles may be below 0.1 mm, wherein the diameter of the jet droplets would be about 10 to 15% of the diameter of the bubble. The height h would, in this case, be about 100 times the diameter of the bubble.

[0081] Usually, jet droplets are larger than film droplets. For example, a jet droplet can have a diameter of about 50 to 100 m, wherein a film droplet can have a diameter of about 1 to 50 m.

[0082] In general, it is advantageous that the diameter of a bubble 3 is larger than 0.5 mm, to support that a sufficient amount of droplets is generated.

[0083] The liquid may comprise the first liquid having the first density and the second liquid having the second density which is lower than the first density, wherein the first and second liquids are (substantially) immiscible (including hardly miscible liquids). Preferably, the second liquid is provided above the first liquid and/or provided at the surface of the liquid comprising the first and second liquids in the inhalation device, at least prior to generating the aerosol. Preferably, the first liquid comprises water, and the second liquid comprises an active agent. It is also conceivable that the first and second liquids comprise different active agents.

[0084] The amount of the second liquid is preferably such that the bubbles/each bubble at least partially extend(s) into the first and second liquids upon burst of the bubble. Hence, the droplets are at least partially surrounded by the first and second liquids.

[0085] If the bubble generating means is provided within the first liquid having the first density, and the second liquid is provided at least partially above the second liquid, a bubble can be embedded in or can be surrounded by the first and second liquids. Without wishing to be bound to theory, first droplets are formed on the basis of the first liquid and second droplets are formed on the basis of the second liquid. If the first liquid has a higher density that the second liquid, the first droplets are (on average) larger than the second droplets (on average). Put differently, the first liquid provides for larger (first) droplets than the second liquid leading to smaller (second) droplets.

[0086] A number of applications are conceivable: For example, the droplet size has an effect on the application distance, i.e. on how far a droplet passes through the human body: Larger droplets will only reach the upper respiratory tract (nose), wherein smaller droplets reach the lower respiratory tract (lung). Hence, depending on which part of the respiratory tract shall primarily be treated with medicament, the first and second liquids can be selected accordingly to provide for appropriate first and second droplets. If only the second (smaller) droplets are desired for inhalation, the first droplets can be removed from the aerosol prior to inhalation, by means of a filter or a buffle, for example.

[0087] A preferred application could also be for damageable medicaments and/or active agents, in particular in the second liquid. If a damageable or sensitive medicament, which might be damaged by application of high shear force, for example, is used as second liquid above the first liquid, it is protected by the first liquid to some extent. This would also be advantageous in case a sensitive (second) liquid is heated by the below first liquid. In this case, the second liquid is not directly heated, but by means of heat conducted by the first liquid.

[0088] It may depend on the surface tension and the density of the liquid how and how many droplets are formed. In general, the surface tension and the density of the liquid influence the percentage and the quality of the droplets (film droplets and jet droplets). In particular, according to the present invention, tenside might be disadvantageous and should not be comprised in the liquid. For example, the invention has been put into practice by means of a fizzy tablet as shown in the embodiment of FIG. 1 above. The skilled person is able to provide appropriate liquid 2 and bubble generating means 6, 7 so as to obtain bubbles 3 that burst at the surface 4 of the liquid.

[0089] Foam may be generated on the surface of the liquid 4. However, foam is not desired, let alone needed for the invention. Preferably, the liquid is basically free from foam generating agents. Hence, generation of aerosol does preferably not involve generation of foam, i.e. is without generation of foam.

[0090] FIG. 4 shows measurement results for an aerosol spectrum. The measurements show that the average diameter of the droplets was about 6 to 7 m.

[0091] FIG. 5 shows the release kinetics of aerosols formed from several effervescent tablets in accordance with the present invention in an impactor experiment (see also explanations above).

[0092] The following aspects also relate to the present invention:

[0093] 1. Use of an inhalation device (1), preferably a disposable or single-use inhalation device, for generating aerosol and for guiding aerosol to a human or animal body for inhalation, the inhalation device comprising:

[0094] a housing (9) configured to receive liquid (2) and a bubble generating means (6, 7) for generating bubbles (3) in the liquid,

[0095] the use comprising:

[0096] Providing liquid (2) in the inhalation device (1),

[0097] Mechanically and/or chemically generating gas bubbles (3) in the liquid (2),

[0098] Bursting of said gas bubbles (3) at the surface (4) of the liquid, thereby generating aerosol.

[0099] 2. The use of item 1, the inhalation device comprising the bubble generating means, the housing (9) accommodating the bubble generating means (6, 7).

[0100] 3. The use of item 1 or 2, wherein the bubble generating means (6) includes a powder, a pill and/or a compressed powder.

[0101] 4. The use of any of the preceding items 1 to 3, wherein the bubble generating means (7) comprises porous material and/or fabric and/or filament configured for gas to be flowed through.

[0102] 5. The use of any of the preceding items, the inhalation device further comprising heating means to heat liquid.

[0103] 6. The use of any of the preceding items, the inhalation device further comprising a guide (11) for guiding carrier gas, in particular ambient air, at least partially along the surface (4) of the liquid.

[0104] 7. The use of item 6, the guide comprising a cap (11), the cap extending close to the surface of the liquid.

[0105] 8. The use of any of the preceding items, further comprising a terminal (12) for connection with a gas source for introducing gas into the liquid.

[0106] 9. The use of any of the preceding items, further comprising an insulating member (13) at least partially surrounding the housing (9).

[0107] 10. The use of any of the preceding items, further comprising rising of the gas bubbles to the surface (4) of the liquid.

[0108] 11. The use of any of the preceding items, wherein the a bubble generating means (6, 7) is brought in contact with the liquid (2), or liquid in contact with the bubble generating means (6, 7).

[0109] 12. The use of any of the preceding items, wherein the liquid and/or the bubble generating means (6, 7) comprises an active agent, which preferably comprises or consists of a salt or a salt solution

[0110] 13. The use of any of the preceding items, comprising heating of liquid and/or of gas before generating the gas bubbles.

[0111] 14. The use of any of the preceding items, comprising generating of gas bubbles by flowing gas through porous material, fabric and/or filament (7).

[0112] 15. The use of any of the preceding items, comprising chemical generating of gas bubbles by bringing the bubble generating means (6), preferably in the form of a powder, a pill, and/or compressed powder, in contact with liquid (2).

[0113] 16. The use of item 15, wherein the active agent is an active agent for the local or systemic treatment of a respiratory disease.

[0114] Additionally, the following aspects relate to the present invention:

[0115] 1. Method of inhaling aerosol by means of an inhalation device (1) by a human or animal body, the method comprising:

[0116] Providing liquid (2) in the inhalation device (1),

[0117] Mechanically and/or chemically generating gas bubbles (3) in the liquid (2),

[0118] Bursting of gas bubbles (3) at the surface (4) of the liquid, thereby generating aerosol including droplets (5) of the liquid, and

[0119] Inhaling the aerosol by the human or animal body.

[0120] 2. Method of item 1, further comprising the step of rising of the gas bubbles to the surface (4) of the liquid.

[0121] 3. Method of item 1 or 2, further comprising the step of bringing a bubble generating means (6, 7) in contact with the liquid (2), or liquid in contact with the bubble generating means (6, 7).

[0122] 4. Method of any of the preceding items, wherein the liquid and/or the bubble generating means (6, 7) comprises an active agent, which preferably comprises or consists of a salt or a salt solution.

[0123] 5. Method of any of the preceding items, comprising heating of liquid and/or of gas before generating the gas bubbles.

[0124] 6. Method of any of the preceding items, comprising mechanical generating of gas bubbles by flowing gas through porous material, fabric and/or filament (7).

[0125] 7. Method of any of the preceding items, comprising chemical generating of gas bubbles by bringing the bubble generating means (6), preferably in the form of a powder, a pill, and/or compressed powder, in contact with liquid (2).

[0126] 8. Method of item 7, wherein the active agent is an active agent for the local or systemic treatment of a respiratory disease.

[0127] Additionally, the following aspects (also in connection with the dependent items 2 to 8) relates to the present invention:

[0128] Method of generating aerosol in an inhalation device (1) for inhalation by a human or animal body, the method comprising:

[0129] Providing liquid (2) in the inhalation device (1),

[0130] Mechanically and/or chemically generating gas bubbles (3) in the liquid (2),

[0131] Bursting of gas bubbles (3) at the surface (4) of the liquid, thereby generating aerosol droplets (5) of the liquid.

[0132] Additionally, the following aspect (also in connection with the dependent items 10 to 17) relates to the present invention:

[0133] Inhalation system comprising inhalation device (1), preferably a disposable or single-use inhalation device, and a bubble generating means, for generating aerosol and for guiding aerosol to a human or animal body for inhalation, the inhalation device comprising

[0134] an inlet opening (8) for intake of carrier gas, in particular ambient air,

[0135] a housing (9) configured to receive liquid (2) and the bubble generating means (6, 7) for generating bubbles (3) in the liquid,

[0136] the bubble generating means (6, 7) being configured to mechanically and/or chemically generate gas bubbles (3) in the liquid (2), such that gas bubbles (3) partially project from the surface (4) of the liquid and burst at the surface of the liquid, and to thereby generate aerosol droplets (5) of the liquid entrained by the carrier gas, and

[0137] an outlet (10) for guiding the carrier gas including the aerosol to the human or animal body for inhalation.

[0138] The Following Numbered Items Also Belong to the Invention:

[0139] 1. Method of generating aerosol in an inhalation device (1), the method comprising:

[0140] Providing liquid (2) in the inhalation device (1),

[0141] Mechanically and/or chemically generating gas bubbles (3) in the liquid (2),

[0142] Bursting of said gas bubbles (3) at the surface (4) of the liquid, thereby generating an aerosol.

[0143] 2. Method of 1, further comprising the step of rising of the gas bubbles to the surface (4) of the liquid.

[0144] 3. Method of 1 or 2, further comprising the step of bringing a bubble generating means (6, 7) in contact with the liquid (2), or liquid in contact with the bubble generating means (6, 7).

[0145] 4. Method of any of the preceding items, wherein the liquid and/or the bubble generating means (6, 7) comprises an active agent, which preferably comprises or consists of a salt or a salt solution.

[0146] 5. Method of any of the preceding items, comprising mechanical generating of gas bubbles by flowing gas through a porous material, fabric and/or filament (7).

[0147] 6. Method of any of the preceding items, comprising heating of said liquid and/or said gas before generating the gas bubbles.

[0148] 7. Method of any of the preceding items, comprising chemical generating of gas bubbles by bringing the bubble generating means (6), preferably in the form of a powder, a pill, and/or compressed powder, in contact with liquid (2).

[0149] 8. Method of any of the preceding items, wherein the bubble generating means (6) includes an effervescent tablet which optionally comprises an active agent.

[0150] 9. Method of any of the preceding items, wherein the active agent is an active agent for the local or systemic treatment of a respiratory disease.

[0151] 10. Inhalation device (1), preferably a disposable or single-use inhalation device, for generating aerosol and for guiding aerosol to a human or animal body for inhalation, the inhalation device comprising

[0152] an inlet opening (8) for intake of carrier gas, in particular ambient air,

[0153] a housing (9) configured to receive liquid (2) and a bubble generating means (6, 7) for generating bubbles (3) in the liquid,

[0154] the bubble generating means (6, 7) being configured to mechanically and/or chemically generate gas bubbles (3) in the liquid (2), such that gas bubbles (3) burst at the surface of the liquid, thereby generating an aerosol, and

[0155] an outlet (10) for guiding the aerosol to the human or animal body for inhalation.

[0156] 11. The inhalation device of 10, the inhalation device comprising the bubble generating means, the housing (9) accommodating the bubble generating means (6, 7), and/or the inhalation device comprising the liquid (2).

[0157] 12. The inhalation device of 10 or 11, wherein the bubble generating means (6) includes a powder, a pill and/or a compressed powder, preferably an effervescent tablet, which optionally comprises an active agent.

[0158] 13. The inhalation device of any of the preceding items 10 to 12, wherein the bubble generating means (7) comprises a porous material and/or fabric and/or filament configured for gas to flow therethrough.

[0159] 14. The inhalation device of any of the preceding items 10 to 13, further comprising heating means to heat said liquid and/or said gas.

[0160] 15. The inhalation device of any of the preceding items 10 to 14, further comprising a guide (11) for guiding carrier gas at least partially along the surface (4) of the liquid.

[0161] 16. The inhalation device of 15, the guide comprising a cap (11), the cap extending at least partially close to the surface of the liquid.

[0162] 17. The inhalation device of any of the preceding items 10 to 16, further comprising a terminal (12) for connection with a gas source for introducing gas into the liquid.

[0163] 18. The inhalation device of any of the preceding items 10 to 17, further comprising an insulating member (13) at least partially surrounding the housing (9).

[0164] 19. The aerosol generated by the method of any of the preceding items 1 to 9 or the inhalation device of any of the preceding claims 10 to 18 for use in a method of treating a disease, which is preferably a respiratory disease.

[0165] 20. The aerosol or the inhalation device for use of items 19, wherein the respiratory disease is selected from the group consisting of (i) upper respiratory diseases such as nasopharyngitis (common cold), sinusitis, pharyngitis, pharyngitis, tonsillitis, laryngitis and tracheitis, laryngitis, tracheitis, laryngotracheitis, obstructive laryngitis and epiglottitis, obstructive laryngitism, epiglottitis, bronchitis, chronic tracheitis, chronic tracheobronchitis, emphysema, asthma, status asthmaticus, bronchiectasis, allergic rhinitis, hay fever, pollinosis, chronic rhinitis, nasopharyngitis, chronic pharyngitis, chronic sinusitis, nasal polyp; (ii) influenza; (iii) pneumonia; (iv) lower respiratory infections selected from bronchitis, bronchiolitis, tracheitis, tracheobronchitis, emphysema; and (iv) other chronic obstructive pulmonary disease such as asthma, status asthmaticus, bronchiectasis.