CA2232859A1

CA2232859A1 - Atomising nozzle

Info

Publication number: CA2232859A1
Application number: CA002232859A
Authority: CA
Inventors: Andrew J. Yule
Original assignee: Individual
Current assignee: Glaxo Group Ltd
Priority date: 1995-09-27
Filing date: 1996-09-24
Publication date: 1997-04-03
Also published as: ATE190868T1; HUP9802742A2; BR9610699A; CN1197414A; CZ94198A3; IL123519A0; MX9802160A; NO981370D0; DE69607361D1; EP0852518B1; US5996576A; TR199800562T1; PL325971A1; AU718759B2; DE69607361T2; GB9519692D0; EA199800231A1; HUP9802742A3; NO981370L; JPH11512644A

Abstract

An atomising nozzle assembly and a method for generating a respirable spray of droplets of a size suitable for medical inhalation therapy from a liquid medicament. The nozzle assembly comprises a gas nozzle (2) for producing a jet of gas and a liquid nozzle (3) for ejecting the liquid to be atomised into the jet of gas at a position downstream of the gas nozzle (2). The gas nozzle (2) and the liquid nozzle (3) are configured such that the jet of gas impinges on the liquid at an acute angle to atomise the liquid. The nozzle assembly and method can create a respirable spray using a gas/liquid mass ratio of less than 0.5.

Description

CA 022328~9 1998-03-24 W O 97/11783 PCTrEP96/04153 ATOMISING NOZLE

This invention relates to atomising nozzles used for hand held sprayers such as 5 so-called aerosols and pump type atomisers, intended for the application of liquid pharmaceutical products.

Aerosol type sprayers are used throughout the world for dispensing a wide range of products, for example, hair lacquer, furniture polish, cleaners, paint, insect 10 killers and medicaments. Until recently, chlorofluorocarbons (CFC's) were themost common of the propellant gases used in aerosols because they are inert, miscible with a wide range of products, are easily liquefied under low pressures, give a sl ~hstantially constant product flow-rate, and can produce sprays of droplets having mean diameters in the range of 3 to over 100 micrometers. However, in 15 the 1970's it was co"li""ed that CFC's were probably responsible for depleting the Earth's protective ozone layer, and in 1987, most countries signed the Montreal Protocol to phase out the use of CFC's and have since agreed to stop use of CFC's for non-essential applications by the end of 1995. One notable exemption to this deadline for cess~tion of use is in relation to metered dose 20 inhalers (MDl's) for medicaments, which are regarded as an essential use of CFC's, but even this use of CFC's will eventually be phased out.

Gases such as air and nitrogen have the advantages of causing no environmental damage, being non-flanll"able and causing no ill effects if inhaled. Such gases 25 can be used to propel liquid from a canister, but with a simple orifice or a swirl orifice very high pressures are required to produce a fine spray suitable for anMDI.

Other types of aerosol generalo~ for delivery of liquid pharmaceutical products 30 exist for research and hospital applications, such as nebulisers. However, these generally contain baffles to remove larger droplets and use high air flowrates so - making them unsuitable for use in portable, convenient atomisers.

It is also possible to force liquid at high pressure through a very small hole (5-10 35 micrometers diameter) to produce droplets of about 5 micrometers diameter, but CA 022328~9 1998-03-24 WO 97/11783 PCT~EP96/04153 these methods are unsuitable or uneconomic for large scale manufacture, mainly because of the difficulty in making very small holes in a suitable ~l~alerial, and, to prevent blockage of the hole, the need for exceptional cleanliness in the manufacture of the parts, together with ultrafiltration of the fluid to be sprayed.

Many of the drugs used in the treatment of respiratory disorders are insoluble in vehicles such as water and are dispensed as suspensions. The drug particles are produced In a respirable size of 1-5 micrometers. Particles of this size tend toblock the very small holes (5-10 micrometers) used by known devices.
For veterinary and some human vaccination applications, high pressure (125-500 bars) spring or gas operated pumps (so-called needle-less injectors) are in cor"mo, l use to inject a jet of drug through the skin ("intra-dermal injection") without the use of needles, and attachments are available to convert the jet to a spray for administering drugs to the nasal passages of large animals such as swine. However, the smallest droplet size obtainable is in the order of 40 micrometers, and the range of applications for these injectors is limited.

Compressed air atomisers such as air brushes and commercial paint sprayers consume large quantities of air, and to obtain droplets of 5 micrometers with water for example, a gas to liquid mass ratio of over 36:1 is required which is impractical for convenient, portable sprayers.

Spray nozles in which a liquid is atomised by impingement of multiple jets of fluid on each other, e.g. air and liquid jets, are known. US Patent No. 5385304 describes an air assisted ~lonlisi"g spray nozle in which a jet of liquid is atomised within a mixing chamber by the shearing action of several jets of air directed in sl ~hstAntially perpendicular relation to the liquid jet. The nozle may be used to deliver liquid in a finely atomised state and suitable applications include use for the delivery of agricultural chemicals and pesticides, humidifying systems and scrubbing systems for coal furnaces. The nozle described is believed to provide a high air efficiency by the use of an opposing cross-flow of air and the air/liquid mass ratio of the embodiment described is from 0.13 to 0.27.
Although the spray particle size is not defined, the nozle is described as CA 022328~9 1998-03-24 W O 97/11783 PCTrEP96/04153 producing a fine liquid droplet spray, and the applications tiisc~ssed suggest that it might produce droplet sizes down to a minimum of 50 micrometers in diameter.

For MDl's used for treating certain respiratory disorders it is essential that the 5 aerodynamic particle size should be less than 15 n,ic~""eters, prt:rerably less than 10 micrometers, so that the droplets are able to penetrate and deposit in the tracheobronchial and alveolar regions of the lung. For a spray composed of droplets w;th a range of sizes, more than 5% by weight of the droplets should have an aerodynamic diameter less than 6.4 I"ic~o",eters, preferably more than 20% by10 weight of the particles have an aerodynamic diameter less than 6.4 micrometers.

Inhalers may also be designed to deliver drugs to the alveolar sacs of the lung to provide a route for adsorption into the blood stream of drugs that are poorly adsorbed from the alimentary tract. To reach the alveoli it is essential that the 15 aerodynamic diameter of the particles is less than 10 micrometers, preferably 0.5-5 micrometers Current thinking suggests that to create smaller spray droplets from impinging fluid nozles it is necessary to increase the gas/liquid mass ratio (GLR) resulting in an 20 associated increase in gas reservoir size required to deliver the necessary mass of propellant. However, for the application of such technology to portable hand held inhalation devices, it is desirable for the GLR to be small to limit the size of reservoir required. The alternative of using hand or finger driven, or primed pumps to meter and produce the liquid and gas flows also requires that the volume and 25 pressure of gas required are minimised to allow a small pump size and to minimise the effort required by the patient.

The present invention aims to provide a design of atomising nozle assembly suitable for use in a hand held inhalation device and which is capable of being 30 used to produce a spray of droplets of a size suitable for inhalation, without the use of conventional liquefied gas propellants.
-According to the present invention there is provided an atomising nozzle assemblyfor generating a respirable spray of droplets of a size suitable for medical 35 inhalation therapy from a liquid medicament, the nozle assembly comprising a CA 022328~9 1998-03-24 W O 97/11783 PCT~EP96/04153 gas nozle for producing a jet of gas and a liquid nozle for ejecting the liquid to be alonlised into the jet of gas at a position downstream of the gas nozle, wherein the gas nozle and the liquid nozle are configured such that the jet of gas impinges on the liquid at an acute angle to atomise the liquid.
The present invention further provides an atomising nozle assembly comprising at least one nozle for ejecting the liquid to be atomised and at least one nozlefor producing a jet of gas, the at least one liquid nozle and the at least one gas nozle being configured such that the liquid is impacted upon by the gas jet so as 10 to produce a respirable spray of droplets of a size suitable for medical inhalation therapy, the gas to liquid mass flowrate ratio being less than 0.5.

By use of a gas and liquid nozle configuration wherein the jet of gas impinges on the liquid at an acute angle it is possible to create a respirable spray with a GLR
15 less than 0.5.

Preferably the gas to liquid mass ratio is 0.2 or less.

Suitably, the gas nozle is at least partially obscured by the liquid nozle such that 20 the liquid is delivered from the liquid nozle directly into the jet of gas.

Pl ~r~, ~bly the liquid nozle is bevelled.

Suitably, the liquid and gas nozles have an outlet diameter between 50 25 micrometers and 200 micrometers.

The liquid and gas nozles are suitably configured to give a fluid impingement angle of between 30~ and 90~. Preferably the liquid and gas nozles are configured to give a fluid impingement angle of between 40~ and 60~.
Suitably, the liquid nozle outlet is positioned up to 10 gas nozle outlet diameters downstream of the gas nozle outlet. Preferably the liquid nozle outlet is positioned between 1 and 4 gas nozle outlet diameters downstream of the gas nozle outlet.

CA 022328~9 1998-03-24 In a further aspect of the present invention there is provided a method for generating a respirable spray of droplets of a size suitable for medical inhalation therapy from a liquid medicament by introducing the said liquid into a jet of gas, wherein the jet of gas impinges on the liquid at an acute angle to the direction of flow of the liquid.

The present invention also provides a method for creating a respirable spray of droplets of a size suitable for medical inhalation therapy from a liquid medicament by introducing the said liquid into a jet of gas such that the said liquid is impacted 10 upon by the said jet of gas, the gas to liquid mass flowrate ratio being less than 0.5.

Preferably the gas to liquid mass flowrate ratio is 0.2 or less.

1~ In a preferred embodiment the shapes and sizes of the liquid and gas supply no~les are chosen to maximise the inhalable proportion of the spray whilst minimising the amount of gaseo~ ~s propellant required. This requires that the liquid ejection nozle has a shape and position that disturbs the gas jet in such a manner that the break-up of the liquid occurs throughout the cross section of the 20 gas flow and, in particuiar, in regions of high gas velocity, and that turbulence, vortex formation and shock wave production created by interaction of the gas jetwith the liquid no~le act to improve break-up into small droplets and the dispersion of droplets across the gas jet.

2~ The invention will now be described with reference to the accompanying drawings, in which:

Figures 1a, 1b, 1c and 1d are section, end and schematic views showing a liquid and gas nozle configuration according to the invention;
Figures 2a, 2b, 2c and 2d are graphs showing the percentage by mass of drops ~ Iess than 6.4 micrometers in diameter created with varying parameters relating to the liquid and gas nozles as shown in figures 1 a, 1 b and 1 c;

CA 022328~9 1998-03-24 W O 97/11783 PCT~EP96/04153 Figures 3a, 3b and 3c are perspective and sectional views showing alternative shapes and arrangements of liquid and gas nozle configurations according to the invention;

5 Figure 4 is a graph showing average drop sizes produced by a nozle according to the invention with var,ving liquid flowrates; and Figure 5 is a graph showing mean drop velocities produced by a nozle according to the invention.
Referring to Figures 1a, 1b, 1c and 1d, a preferred form of the atomising nozle assembly 1 consists of a cylindrical gas nozle 2 having a circular orifice of 125 microns internal diameter, and a bevelled liquid nozle 3 of a similar internal diameter but presenting an eliptical outlet orifice positioned partly in front of gas 15 nozle 2. Liquid nozle 3 is arranged such that the liquid outlet orifice is positioned approximately 1 gas outlet orifice diameter downstream of the gas outlet orifice.
The lateral position of liquid nozle 3 relative to gas nozle 2 may be expressed as percentage obscuration of the gas nozle and is determined according to Figure 1 c by the equation:
L = 100 r/ D (%).

The liquid and gas nozles may be made from stainless steel hypodermic 316 or any other suitable material. Gas nozle 2 and liquid nozle 3 define an acute angle 25 of 40~ between them.

In use, air 4 is delivered at sonic velocity through gas nozle 2 and liquid ~ under pressure is introduced into the gas jet at a velocity around 1.4m/s through liquid nozle 3. For the purposes of the experimental results given below the liquid used 30 is water. However, the liquid may, for example, consist of an aqueous suspension or solution of a medicament or other bioactive molecule. Bioactive molecules suitable for this purpose include proteins, peptides, oligonucleosides and genessuch as DNA complexed with an appropriate lipid carrier, for example, DNA
encoding cystic fibrosis transmembrane conductance regulator (CFTR) 3~ protein/cationic lipid complex, useful for the treatment of cystic fibrosis.

CA 022328~9 1998-03-24 Medicaments suitable for this purpose are, for example for the treatment of respiratory disorders such as asthma, bronchitis, chronic obstructive pulmonary diseases and chest infections. Additional medicaments may be selected from any 5 other suitable drug useful in inhalation therapy and which may be presented as an aqueous suspension or solution. Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g.
cromoglycate, ketotir~" or neodocromil; antiinfectives e.g. cephalosporins, 10 penicillins, sll t:ptomycin, sulphonamides, tetracyclines and pentamidine;
antihistamines, e.g. methapyrilene anti-inflammatories, e.g. fluticasone, flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g. noscapine;
bronchodilators, e.g. salmeterol, salbutamol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metap, uterenol, phenylephrine, phenylpropanolamine, 15 pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol orciprenaline, or (-)4-amino-3,5-dichloro oc-[[[6-[2-(2-pyridinyl)ethoxy]-hexyljamino]methyl]bel ,~el ,er"ethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, al,~ ,i"e or oxitropium; hormones, e,g, cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, Iysine 20 theophyllinate or theophylline and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. Iower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament. Preferred 25 medicaments are salbutamol, salbutamol sulphate, salmeterol, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate and terbutaline sulphate. It is to be understood that the suspension or solution of medicament may consist purely of one or more active ingredients.

30 The shape and position of the liquid nozle 3 c~ses interaction with the air jet such that the liquid flows mainly to the tip 6 of the nozzle and detaches and rapidly atomises in the high velocity gas zone to form a slow moving spray. Slow moving sprays are particularly suitable for delivery to the tracheobronchial and alveolar regions of the lung as they reduce the amount of impingement of droplets at the 35 back of the throat which tends to result from faster moving sprays. Slow moving CA 022328~9 1998-03-24 sprays are also beneficial to the user by facilitating coordination of actuation of the device with the act of inhalation. The size of the droplets is controlled, inter alia, by the respective gas and liquid flowrates, and the shapes of both nozles. The positioning of liquid nozle 3 in front of gas nozle 2 creates turbulence, vortex5 shedding and shock wave formation in the jet of air which is beneficial to atomisation of the liquid 5, and as described with reference to figure 2a below, it has been found that use of a bevelled orifice rather than a square edge orifice allows increased flexibility with respect to the lateral position of the liquid nozle relative to the gas nozle, so relaxing the tolerances required during manufacture.
Figure 1d shows how liquid and gas nozles might be incorporated into a single moulded component. The nozles themselves might be manufactured by laser drilling or by injection moulding with or without hypodermic capillary inserts.

15 Figure 2a demonstrates the results of tests carried out on one atomising nozle with a bevelled liquid orifice as described above and one atomising nozle with asquare edge liquid orifice using difFerent liquid flowrates but co"~la~ It gas flowrate to deter",i"e how the lateral position of the liquid nozle relative to the gas nozle (percentage obscuration) affects the percentage of fine particle mass created; that 20 is droplets with a diameter less than 64 micrometers as measured by the deposition of spray in the second stage of a twin impinger device. It is evident from figure 2a that the optimum results at liquid flowrates of 1.0ml/min and 1.2ml/min are obtained at approximately 50% obscuration, though the deterioration of spraycharacteristics with different obscuration values is much less marked with the 25 bevelled orifice than with the square edge orifice Figure 2b shows the variation in fine particle mass creation with variation in GLR
for one atomising nozle with a bevelled liquid orifice and one atomising nozle with a square edge liquid orifice using different percentage obscurations with 30 constant liquid flowrate. This demonstrates that a significant improvement inatomisation efficiency is obtained using the bevelled liquid orifice with over 20%
fine particle mass being attained with a GLR of around 0.12.

Figure 2c shows the variation in fine particle mass created with variation in GLR at 35 selected liquid flowrates and gas nozle obscurations using a bevelled liquid CA 022328~9 1998-03-24 W O 97/11783 PCT~P96/04153 nozle. This figure demonstrates that improved performance results from increased GLR and that 20% deposition is achieveable at a GLR of around 0.12 with 50% obscuration.

Figure 2d shows the optimum gas nozzle obscuration for different gas flowrates using a constant liquid flowrate of 1.0mlJmin. For manufacturing purposes it is desirable to be able to achieve the required spray characteristics over a range of liquid orifice positions in order to allow for manufacturing inaccuracies. This also aids the achievement of consistent performance throughout the lifetime of the 10 nozle. From figure 2d it is clear that for the creation of 20% of droplets with a diameter less than 6.4 micrometers, gas flowrates of 120ml/min and above will allow for some tolerance on obscuration.

Increasing the liquid flowrate allows the gas flowrate to be increased 15 proportionately to maintain the same GLR, and similar trends to those shown in figure 2d are found, but with optimum spray characteristics occurring at higher obscurations. Using 125 micrometer diameter nozles and GLR values of 0.2, liquid flowrates of 1.2ml/min and 1.8ml/min exhibit optimum obscurations of ~iO+/-!;% and 7~+/-5% respectively.
Figure 3a shows an alternative nozle assembly design which is similar to that shown in figures 1a-1c but in which the gas nozle 6 has a rectangular profile.
Such a gas nozle profile may reduce the chance of the liquid jet 'punching' through the gas jet leading to non atomisation or partial ~Lol"is~lion. By suitable 25 design of the gas and liquid nozles it may be possible to increase atomisation efficiency through increased gas vortex shedding around the liquid nozle outlet.
Figure 3b shows another nozle assembly in which the gas nozle 7 has a profile similar to that depicted in figures 1a to 1c, and the liquid nozle 8 presents a 30 'square edge' circular orifice. A blade 9 is positioned partly in front of gas nozle 7, and this helps to generate turbulence, vortex shedding and shock waves in the~ gas jet to aid atomisation and dispersion of liquid. Blade 9 may additionally be made to vibrate to enhance its effect.

CA 022328~9 1998-03-24 W O 97/117~3 PCTAEP96/04153 Figure 3c shows a further nozle assembly in which the gas nozle incorporates side wall extensions 10 and the liquid nozzle has a cut away section 11 to enhance the spray shape and liquid-gas mixing.

5 Figure 4 shows the average drop size produced by an atomiser using two 125 micrometer diameter nozzles with a bevelled liquid outlet orifice. Two methods of defining mean drop diameter are used; Dv,0 5 is the volume median diameter and D32 is the Sauter mean diameter. Measurements were made using a Malvern ST2600 laser diffraction instrument at a position 100mm downstream from the 10 liquid nozle. The results show that for a constant atomising air flow rate the drop size increases as the liquid flow rate is increased. However, the full drop sizedistributions for liquid flow rates of 1.0ml/min and 1.2ml/min show that 21.3% by mass of droplets produced are smaller than 6.3 micrometers diameter, and this issufficient to render satisfactory operating conditions for an MDI.
Figure 5 shows the mean drop velocity at axial distances from the liquid nozle along the centre line of a spray produced by an atomiser using two 125 micrometer diameter nozles at 40~ with a gas flowrate of 1 80ml/min.
Measurements were made using a Dantec phase doppler anemometer. The drop 20 velocities exhibited are less than those delivered by conventional propellant based MDls. Such reduced drop velocity leads to lower deposition in the oropharnygeal region when sprayed into the mouth for delivery of drug to the respiratory tract.
Such characteristics may provide a distinct advantage over conventional propellant based MDI delivery by leading to a reduction in local effects and 25 systemic exposure due to oral absorption.

It will be appreciated that an atomising device may comprise a plurality of atomising nozle assemblies as described arranged in an array.

Claims

1. An atomising nozzle assembly comprising at least one nozzle for ejecting a liquid medicament to be atomised and at least one nozzle for producing a jet of gas, the at least one liquid nozzle and the at least one gas nozzle being configured such that the liquid medicament is impacted upon by the gas jet so as to produce a respirable spray of droplets of a size suitable for medical inhalation therapy, characterised in that the liquid is delivered under pressure to provide a gas to liquid mass flowrate ratio of less than 0.5.

2. An atomising nozzle assembly according to claim 1, characterised in that the gas to liquid mass ratio is 0.2 or less.

3. An atomising nozzle assembly according to any proceeding claim, characterised in that the gas nozzle and the liquid nozzle are configured such that the jet of gas impinges on the liquid at an acute angle to atomise the liquid.

4. An atomising nozzle according to any preceding claim, characterised in that the gas nozzle is at least partially obscured by the liquid nozzle such that the liquid is delivered from the liquid nozzle directly into the jet of gas.

5. An atomising nozzle assembly according to any preceding claim, characterised in that the liquid nozzle is bevelled such that the plane of the outlet orifice is approximately parallel to the plane of the outlet orifice of the gas nozzle.

6. An atomising nozzle assembly according to any preceding claim, characterised in that the liquid and gas nozzles have an outlet diameter between50 micrometers and 200 micrometers.

7. An atomising nozzle assembly according to any preceding claim, characterised in that the gas nozzle and liquid nozzle are configured such that the jet of gas impinges on the liquid at an angle of between 40° and 60°.

8. An atomising nozzle assembly according to any preceding claim, characterised in that the liquid nozzle outlet is positioned up to 10 gas nozzleoutlet diameters downstream of the gas nozzle outlet.

9. An atomising nozzle assembly according to claim 8, characterised in that the liquid nozzle outlet is positioned between 1 and 4 gas nozzle outlet diameters downstream of the gas nozzle outlet.

10. An atomising nozzle comprising a plurality of atomising nozzle assemblies according to any of claims 1 to 10 arranged in any array.

11. A method for creating a respirable spray of droplets of a size suitable for medical inhalation therapy from a liquid medicament by introducing the liquid medicament under pressure into a jet of gas such that the liquid is impacted upon by the said jet of gas, the gas to liquid mass flowrate ratio being less than 0.5.

12. A method according to claim 11, characterised in that the gas to liquid mass flowrate ratio is 0.2 or less.

13. A method according to claim 11, characterised in that the jet of gas impinges on the liquid at an acute angle to the direction of flow of the liquid.

14. A method according to any of claims 11 to 13, characterised in that the liquid is introduced into the jet of gas by means of a nozzle which is at least partially positioned within the jet of gas.

15. A method according to any of claims 11 to 14, characterised in that the liquid is introduced into the jet of gas by means of a nozzle having an outlet diameter between 50 micrometers and 200 micrometers.

16. A method according to any of claims 13 to 15, characterised in that the gas impinges on the liquid at an angle of between 40° and 60°.