GB2320900A

GB2320900A - Inhalers

Info

Publication number: GB2320900A
Application number: GB9700176A
Authority: GB
Inventors: Timothy William Higenbottam; Benjamin Wolf Heller; Keith Muir Mccormack
Original assignee: University of Sheffield
Current assignee: University of Sheffield
Priority date: 1997-01-07
Filing date: 1997-01-07
Publication date: 1998-07-08
Anticipated expiration: 2017-01-07
Also published as: GB9700176D0; GB2320900B

Abstract

The invention proposes treatment apparatus, and in particular small (pocket-sized) hand-held apparatus. It suggests apparatus for the delivery of a medicament into the Patient's lungs in the form of a bolus, pulse, or spike of the medicament entrained in and driven by the normal respiration air, which apparatus comprises a conventional nebuliser 11 (in the reservoir of which is stored the medicament to be administered) driven by some suitable pressurised gas from a valved cylinder 18 thereof to deliver an aerosol cloud of medicament into a tube 105 through which the Patient is breathing (by mouth) normal air, the gas cylinder valve being controlled by a suitably programmed computing device 101 that is fed data describing the pressure within the breathing tube and so is able to open and close the valve at and for a time such as to drive the nebuliser to deliver a required pulse of medicament at any selected point within the Patient's respiratory cycle.

Description

Inhalers This invention relates to inhalers, and concerns in particular medical inhaler apparatus for use in the treatment of certain lung diseases or conditions.

In the Specification of British Patent Application No: 2,283,179 (which corresponds to published PCT International Application WO 95/10,315) there is described and claimed a novel method, and associated apparatus, for the use of nitric oxide in the treatment of various lung conditions and diseases. The present invention relates to improved apparatus which can be used not only for this purpose but also in the treatment of other lung problems.

There are many lung diseases and conditions suffered both by humans and by other animals - for which the preferred form of treatment involves delivering a medicament of the appropriate sort down the Patient's airways into the lungs themselves, where the medicament can act upon, and perhaps be absorbed into, the tissues of the lungs. One such condition is asthma (an increasingly prevalent and worrying problem), in which the peripheral parts of the lung, namely those tiny airways and air spaces known respectively as bronchioles and alveoli, constrict to restrict the flow of air therethrough. In other lung conditions the lung's small peripheral arteries - the pulmonary arteries - also constrict, typically those deep in the lungs where the oxygen tension falls as in an asthmatic attack, pneumonia, or chronic lung diseases like bronchitis and emphysema (and it should also be noted that such constriction often occurs without the causative mechanism being fully explained; this is the so-called primary pulmonary hypertension).

The most effective treatments for asthma and like conditions involve the inhalation as an aerosol of some suitable chemical agent in normally inhaled air. At present, to deal with the problem of constricted small pulmonary arteries only a few relieving substances are known, and one of the most powerful - that known as prostacyclin, an extremely potent vasodilator - has to be administered on a continuous basis by infusion into a vein and so to the pulmonary arteries.

The aforementioned British and International Specifications relate to the use of nitric oxide (NO), another well-known and effective dilating agent for treating both lung problems of the blood-vesselconstriction type and of the asthma airway type. More specifically, these Specifications concern the manner in which nitric oxide is administered, and the apparatus used for this administration; they propose that the nitric oxide be administered to the Patient not continuously (either in admixture with, or separately but side by side with a supply of, air, oxygen or oxygen-enriched air) but intermittently and in short pulses of known, pre-determined volume at one or more suitable time during each inhalation. In the treatment of the constriction of the small pulmonary arteries the very short pulse of nitric oxide is provided at the start of the inhalation, such that the resultant bolus of nitric oxide mixture inhaled by the Patient has a nitric oxide concentration high enough to have the desired therapeutic effect, even if admixed with some additional air, but is of such short duration (both in time and, as a result, in physical length) that, pushed by the following much larger volume of plain, and therefore nitric oxide-free, air/oxygen, it reaches deeper into the lungs, where it both acts on the small pulmonary arteries and is taken up into the capillaries to react with haemoglobin (so preventing the formation of nitrogen dioxide). By contrast, in the treatment of asthma-like airway diseases or conditions the very short pulse of nitric oxide is timed to fall just before the end of the inhalation. This leaves the nitric oxide in contact with the airway smooth muscle in sufficient concentration to cause relaxation, but because at the end of the inhalation the airway is flushed of all the nitric oxide by the air coming from alveoli and lung periphery, so there is avoided prolonged exposure with the consequent risk of the formation of toxic nitrogen dioxide.

This previous invention concerns the administration of nitric oxide. The present invention stems from the appreciation that the same controlled breathing-related "pulsatile" delivery to the Patient's lungs can be usefully employed with many other medicaments; the invention is thus treatment apparatus - and in particular small (pocket-sized) hand-held apparatus that utilises the "spike" principle. More specifically, the invention proposes apparatus for the delivery of a medicament into the Patient's lungs in the form of a bolus, pulse, or spike of the medicament entrained in and driven by the normal respiration air, which apparatus comprises in essence a conventional nebuliser (in the reservoir of which is stored the medicament to be administered) driven by some suitable pressurised gas from a valved cylinder thereof to deliver an aerosol cloud of medicament into a tube through which the Patient is breathing (by mouth) normal air, the gas cylinder valve being controlled by a suitably programmed computing device that is fed data describing the pressure within the breathing tube and so is able to open and close the valve at and for a time such as to drive the nebuliser to deliver (to the tube and thence to the Patient's lungs) a required pulse of medicament at any selected point within the Patient's respiratory cycle.

In one aspect, therefore, the invention provides apparatus for the delivery of a medicament into the Patient's lungs in the form of a bolus, pulse, or spike of the medicament entrained in and driven by the normal respiration air, which apparatus comprises: a tube through which the Patient is able to breath (by mouth) normal air; a nebuliser (in the reservoir of which is storable the medicament to be administered) the output of which is deliverable into the tube for inhalation by the Patient; a valved cylinder for a suitable pressurised gas, which cylinder is connectable to the nebuliser so as in use to drive the nebuliser to deliver an aerosol cloud of medicament into the tube; pressure sensing means located within or operably connected to the tube, and able to provide data about the air pressure therewithin, and thus about the Patient's respiratory cycle; and programmed computing means operatively connectable to the gas cylinder valve so as to be able to open and shut that valve, and able to receive pressure data from the pressure sensing means; such that the computing means can utilise the pressure data to enable the gas cylinder to drive the nebuliser to deliver (to the tube and thence to the Patient's lungs) a required pulse of medicament at any selected point within the Patient's respiratory cycle.

Although notionally the apparatus of this invention could be large and heavy enough for it not to be portable - for it to be a bed-side device, for instance - it is the primary purpose of the invention to provide the apparatus in light, pocket-sized form small enough to be held in the hand, and to be used while being so held. Accordingly, while hereinafter the apparatus is described in terms most appropriate for such a small hand-held piece of kit, that does not exclude it being much larger if circumstances demand it.

The invention provides apparatus for the delivery of a medicament into the Patient's lungs. The medicament can be any such material that might need to be administered to the lungs. For example, to treat asthma the medicament could be a bronchodilator such as SALBUTAMOL or TERBUTALINE or a steroid such as BECLOMETHASONE or FLIXOTIDE, while to treat an actual lung infection the medicament might be an antibiotic such as TICARCILLIN or COLISTIN.

The medicament may be formulated in any way that is both appropriate to the active ingredient of the medicament and to the need to have it turn into an aerosol spray in use. It may be presented as a solution or suspension in some liquid - water, perhaps - or it may even be supplied as a fine powder, possibly with or absorbed onto a powder carrier. By way of example, the asthma-treating medicament FLIXOTIDE is conveniently used in the form of dry powder, while the sputum lytic agent rhDNAse is advantageously delivered in the form of an aerosol (droplets of liquid suspended in gas).

The invention's apparatus delivers its medicament into the lungs in the form of a bolus, pulse, or spike of the medicament entrained in and driven by the normal respiration air. The idea of this is simply to ensure that a high proportion of the medicament reaches and affects the target area and the target area only, rather than having the whole of the lungs subjected to it. The smaller the bolus - the shorter the pulse - the better this specificity is achieved. In some cases the pulse will be very short indeed, and while it is difficult to define precisely what is meant by "very" short, the following comments may be of assistance. The term "very short" means primarily that the provision of sufficient medicament for each bolus thereof is achieved by supplying the driving gas for a time period - of the order of a few tens of milliseconds - that is very short compared with the length of an average inhalation (which is about 1.5 second). However, there is more to the shortness of the pulse than just its temporal duration, for, the purpose of the pulse being to provide a bolus of medicament both of relatively high concentration and of relatively short physical length, both the actual flow rate of the medicament (perhaps in its carrier mixture form) as it is fed to the Patient and also the actual concentration of the medicament in that fed gas are important factors. What has been determined by experiment is that very satisfactory results are obtained using pulse durations of a few tens of milliseconds, and typically 20 to 30 msec. Thus, while it will clearly be understood that what is a "very short" pulse depends upon the flow rate and concentration of the administered medicament, nevertheless it can now be said that the term "very short" means "of the order of a few units or tens of milliseconds". Or, to put it another way, the term means roughly one thousandth of the length of an average inhalation.

In the apparatus of the invention the medicament is driven into the Patient's lungs through a tube through which the Patient is breathing (by mouth) normal air.

This tube is essentially nothing more than a short openended hollow cylinder - say, 5in (13cm) long and lin (2.5cm) external diameter - possibly with a flattened mouthpiece to make it more convenient for the Patient to use, and nothing more need be said about it here.

The apparatus of the invention incorporates a nebuliser in the reservoir of which is storable the medicament to be administered. It is the output of the nebuliser which is deliverable into the tube for inhalation by the Patient. Nebulisers - "cloud-formers" - are in general well-known items of equipment, commonly encountered in scent sprays, aerosol sprays, and carburettors, and little need be said about them here.

Even so, it is convenient to note that a nebuliser is a basically a reservoir that has a fine orifice through which its contents may exit and across which is blown a stream of gas along a pipeway. As the gas flows past the orifice it causes an external pressure drop (relative to the reservoir's internal pressure: this pressure drop can be enhanced by shaping the pipeway as a Venturi constriction at the appropriate position), and so some of the reservoir's contents is "sucked" out into the gas stream and breaks up into an aerosol-like cloud of drops or particles that is then swept along the pipeway by the driving gas. It is convenient to include within the pipeway downstream of the orifice an obstacle, or baffle, that is positioned within the path of the emerging drop/particle stream so as to impede all but the smallest drops/particles, which smallest ones are of a size most appropriate to being transported to the farthest reaches of the lung. For a small hand-held device the nebuliser is conveniently around 2.5in (6cm) long and an inch (2.5cm) or so across, the reservoir holding perhaps 1.5cu.in (25cc) of medicament formulation.

The nebuliser employed in the invention's apparatus is driven by a suitable gas from a valved cylinder thereof, so as to produce the desired aerosol cloud of medicament and drive it into the tube. This gas can be simply a carrier - thus, an effectively inert (to the Patient) gas such as carbon dioxide or nitrogen - but it may be advantageous if the gas itself have some suitable medicinal action. For example, the gas might well be nitrous oxide (NzO). There is little else to say about this, save that gas in the cylinder is likely to be at a high pressure, and so should be regulated to provide a lower, and constant, pressure appropriate to the operation of the nebuliser, and save also that the gas cylinder (and any regulating means) should clearly be of a size and strength suitable to its intended purpose and for a hand-held device an appropriate size is, much like the nebuliser, around 3in (7.5cm) long and an inch (2.5cm) or so across, and holding perhaps 2cu.in (35cc) of liquified gas under a pressure of 50bar (3MPa, or 7001bs/sq.in).

The cylinder is, of course, a valved cylinder, and the operation of the valve is controlled by the computing means (via some suitable actuating means) in response to the computing means' programming and input from the pressure sensor. The valve mechanism may take any appropriate form - it is typically be an electromagnetically-actuated device such as one of those miniature solenoid valves available from Parker Hannifin Corp., Pneutronics Div., Hollis, New Hampshire, USA, and is conveniently powered from the computing means' power source.

The invention's apparatus includes pressure sensing means located within or connectable to the tube, and in use providing the computing means with data about the air pressure therewithin, and thus about the Patient's respiratory cycle. The sensor may be any suitable pressure-detecting transducer with an electrical output, and one preferred sensor is that available under the designation 24/26PC from Honeywell Inc., Freeport, Illinois, USA.

Controlling the whole operation of the medicament administering apparatus of the invention is the programmed computing means. This is operatively connectable to the gas cylinder valve (via its actuating means) so as to be able to open and shut that valve, it receives pressure data from the pressure sensing means so that it "knows" at all times the progress of the Patient's respiratory cycle, and it is programmed to make use of that information so as to enable the gas cylinder to drive the nebuliser to deliver (to the tube and thence to the Patient's lungs) a required pulse of medicament at any selected point within that cycle.

Notionally, the computing means could be a general purpose microcomputer appropriately programmed and able to deal with the relevant inputs and outputs from and to the real world. In practice, though, the computing means is most advantageously a simple single chip computer "hard wired", or programmed in ROM, to take the relevant actions. Such a computer can be no more than 2in (5cm) or so long and wide, and .5in (1.25cm) deep, and can run off a small battery. It is ideally suited for use in a hand-held medicament-delivery system.

The programmed computing means takes the pressure data and in accordance with its program makes use of that information so as to enable the gas cylinder to drive the nebuliser to deliver (to the tube and thence to the Patient's lungs) a required pulse of medicament at any selected point within that cycle. Which point that is, and for how long the pulse will last, is dependent upon the Patient's illness and the medicament being taken (this has been touched upon hereinbefore).

The treatment of some conditions might require very short pulses to be delivered right at the beginning of the inspiration phase of the respiratory cycle - as the Patient draws in the next breath - while in contrast the treatment of others might require rather longer pulses to be delivered at the end of the inspiration phase of the respiratory cycle - as the Patient finishes inhaling the present breath and just before the exhale starts.

An embodiment of the invention is now described, though by way of illustration only, with reference both to the Tests described hereinafter and to the accompanying Drawings in which: Figure 1 shows in cut-away perspective form apparatus of the invention for administering a medicament in controlled pulses to the Patient's lungs; Figure 2 shows a bolus of medicament/air mixture travelling down deep into the Patient's lungs; Figure 3 shows graphically the Patient's respiration, and the timing of the medicament pulses at the start of an inhalation; and Figure 4 is a black box schematic of the overall nebuliser/microcomputer system of the invention; The apparatus shown in Figure 1 is in principle very simple. It comprises a nebuliser (generally 11) having a reservoir (12) of medicament formulation (13) having an output tube (14) open as a "jet" (15) at the top (as viewed) to the "outside". The jet orifice is within a Venturi portion (16) of a deliver pipe (17) along which is fed pressurised gas from a storage cylinder (18) via a control valve (19). The valve is operated by actuating means (100) itself driven by control signals from a single chip microcomputer (101: shown as a flat board).

The released gas and the "sucked out" medicament pass, via a baffle (102), into the apparatus' main breathing tube (103) by way of a second jet orifice (104), and there it mixes with the air that the Patient (not shown) draws in through a mouthpiece (105) at the tube's open end to provide lung-filling breaths.

A pressure-sensing transducer (106) is connected by a short pipe (107) opening into the tube 103 roughly intermediate the two ends. The transducer's output is fed to the microcomputer 101. The microcomputer uses this information to enable the gas cylinder valve 19 at predetermined times and for a predetermined duration in accordance with its programming (which is tailored to fit the Patient's disease or condition).

Figure 2 shows the progress of a bolus (21) of medicament/air mixture down the Patient's windpipe (22) and on deep into his lungs (23). Though at first sight it looks as though there are several bolus preceding one after the other, in fact there is only one, shown at different times on its journey, and the object of the Figure is to show how the bolus remains as an entity, and does not disperse as it progresses (and so reaches the deepest part of the lungs as a concentrated burst of medicament with the full therapeutic effect required).

The timing of the bolus delivery is shown graphically in Figure 3. Airflow in and out of the lungs takes place at regular intervals, as the Patient breathes, and just as the flow starts a pulse of medicament is delivered, and "washed down" with the remaining inhaled air.

The black box schematic of Figure 4 indicates the manner in which the microcomputer 101 operates in connection with the other parts. It needs no further comment at this time.

Claims

1. Apparatus for the delivery of a medicament into the Patient's lungs in the form of a bolus, pulse, or spike of the medicament entrained in and driven by the normal respiration air, which apparatus comprises: a tube through which the Patient is able to breath (by mouth) normal air; a nebuliser (in the reservoir of which is storable the medicament to be administered) the output of which is deliverable into the tube for inhalation by the Patient; a valved cylinder for a suitable pressurised gas, which cylinder is connectable to the nebuliser so as in use to drive the nebuliser to deliver an aerosol cloud of medicament into the tube; pressure sensing means located within or operably connected to the tube, and able to provide data about the air pressure therewithin, and thus about the Patient's respiratory cycle; and programmed computing means operatively connectable to the gas cylinder valve so as to be able to open and shut that valve, and able to receive pressure data from the pressure sensing means; such that the computing means can utilise the pressure data to enable the gas cylinder to drive the nebuliser to deliver (to the tube and thence to the Patient's lungs) a required pulse of medicament at any selected point within the Patient's respiratory cycle.

2. Apparatus as claimed in Claim 1, wherein the tube through which the Patient is to breath is a short openended hollow cylinder with a flattened mouthpiece.

3. Apparatus as claimed in either of the preceding Claims, wherein the nebuliser is a reservoir that has a fine orifice through which its contents may exit and across which is blown a stream of gas along a pipeway, and included within the pipeway downstream of the orifice is an obstacle, or baffle, that is positioned within the path of the emerging drop/particle stream so as to impede all but the smallest drops/particles.

4. Apparatus as claimed in any of the preceding Claims, wherein the nebuliser employed in the invention's apparatus is driven by a suitable gas under pressure from a valved cylinder thereof, and there is a regulator to provide a lower, and constant, pressure appropriate to the operation of the nebuliser.

5. Apparatus as claimed in any of the preceding Claims, wherein the valve of the gas cylinder, which valve is controlled by the computing means, is an electromagnetically-actuated miniature solenoid valve.

6. Apparatus as claimed in any of the preceding Claims, wherein the pressure sensing means is spaced from but connectable to the tube.

7. Apparatus as claimed in any of the preceding Claims, wherein the pressure sensing means is, or includes, a pressure-detecting transducer with an electrical output.

8. Apparatus as claimed in any of the preceding Claims, wherein the programmed computing means is a simple single chip computer "hard wired", or programmed in ROM, to take the relevant actions.

9. Apparatus as claimed in any of the preceding Claims and substantially as described hereinbefore.

AMENDMENTS TO THE CLAIMS HAVE BEEN FILED AS FOLLOWS 1. Apparatus for the delivery of a medicament into the Patient's lungs in the form of a bolus, pulse, or spike of the medicament entrained in and driven by the normal respiration air, which apparatus is sized to fit within a pocket, and to be held during operation in the hand of the Patient, and comprises: a tube through which the Patient is able to breath (by mouth) normal air; a nebuliser (in the reservoir of which is storable the medicament to be administered) the output of which is deliverable into the tube for inhalation by the Patient; a valved cylinder for a suitable pressurised gas, which cylinder is connectable to the nebuliser so as in use to drive the nebuliser to deliver an aerosol cloud of medicament into the tube; pressure sensing means located within or operably connected to the tube, and able to provide data about the air pressure therewithin, and thus about the Patient's respiratory cycle; and programmed computing means operatively connectable to the gas cylinder valve so as to be able to open and shut that valve, and able to receive pressure data from the pressure sensing means; such that the computing means can utilise the pressure data to enable the gas cylinder to drive the nebuliser to deliver (to the tube and thence to the Patient's lungs) a required pulse of medicament at any selected point within the Patient's respiratory cycle.